MALE LOWER URINARY

TRACT DYSFUNCTION
Evaluation and Management
EDITORS
J. MCCONNELL, P. ABRAMS, L. DENIS,
S. KHOURY, C. ROEHRBORN

6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases
June 24-27, 2005

Co-sponsored by
International Union Against Cancer

I.C.U.D (International Consultation on Urological Diseases)

S.I.U (International Society of Urology)
EORTC-GU (European Organisation for Research and Treatment of Cancer)

Edition 2006
 Acknowledgement
We would like to thank :

• The Urology Department at La Pitié Hospital in Paris and its chairman

Professor F. Richard

for kindly providing logistic assistance for the editing of this book.

We would also like to thank all the contributors for their enthusiastic support and help.

Distributor : EDITIONS 21
76, rue de la Pompe - 75016 Paris - FRANCE
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ISBN 0-9546956-6-6

LAY-OUT: Stephanie TAIEB

2
 FOREWORD

The great tragedy of science :

The slaying of a beautiful hypothesis by an ugly fact
Thomas Huxley (1825-1895)

These proceedings represent the consensual text and recommendation of the 16 committees that met in
Paris at the occasion of the 6th International Consultation on New developments in Prostatic diseases and
Prostate Diseases June 24-27, 2005. On behalf of the International Consultation on Urological Diseases
(ICUD) and its Steering Committee composed of the representatives of the major urological associations
of the world (SIU, AUA, EAU, UAA, CAU, ICS) we would like to thank the chairmen and their commit-
tee members for again meeting the highest expectations.
The formula adopted in 1996 and 1999 shows no sign of fatigue with the innovations introduced each mee-
ting. Basically, of course, we stay with our time tested multiprofessional approach under the auspices of
the International Agency on Cancer Research, and the International Union against Cancer and advice from
the European Organisation on Research and Treatment of Cancer, the American Cancer Society and the
International Prostate Health Council that provides access and collaboration with some of the world’s best
experts on the disease. The Steering Committee, with support of the International Society of Urology,
assures the collaboration of the world’s urological experts on the subject in a truely global endeavour.
The 6th meeting brought us not only an updated present knowledge for the community, but focused on
evidence based facts and widely accepted recommendations with a model to define standards for clinical
research in the future. In short, a product that can serve as a reference and guide in the different aspects of
Prostatic diseases treatment prepared by a 150 member multidisciplinary and international team.
In meeting this milestone, we should not forget that this result was only possible by the advice and gui-
dance of the leading organizations, but also by the enthousiastic support of urologists from more than 20
national organizations.
We want to thank them all personally.

The Editors,

3
Some of the members of the international committees
Paris - June 24-27, 2005

4
5
 EDITORS
J. McConnell (USA),
P. Abrams (U.K)
L. Denis (Belgium),
S. Khoury (France),
C. Roehrborn (USA)

MEMBERS OF THE COMMITTEES

(Alphabetical order - Chairmen in bold print)

ALGABA F. Spain 1 COCHLIN D. UK 4

ABBAS F. Pakistan 12 CONORT P. France 12
ABBOU Cl. France 12 CRUZ F. Portugal 9
ABRAHAMSSON P.A. Sweden 2 CUSSENOT O. France 3
ABRAMS P. UK 5 D'ANCONA C. Brazil 5
AKAZA H. Japan 11 DE LA ROSETTE J. The Netherlands 7
AKIN O. USA 4 DEARNALEY D. UK 12
ALBERTSEN P. USA 10 DEBRUYNE F. The Netherlands 13
ANDERSON R. USA 15 DESCOTES J.L. France 4
ANDERSSON K. E. Sweden 9 DJAVAN B. Austria 2
ARAI A. Japan 12 DONOVAN J. UK 3
ARTIBANI W. Italy 6 EISENBERGER M. USA 13
BABA S. Japan 7 ELHILALI M. Canada 7
BADLANI G. USA 7 EMBERTON M. UK 8
BARRY M. USA 3A ETZIONI R. USA 3
BARTSCH G. Austria 12 FAULDS WOOD L. UK 16
BERGES R. Germany 6 FOO K. T. R of Singapore 5
BOCCON GIBOD L. France 10 FOURCADE R. France 13
BOLLA M. France 12 FRENKEL E. USA 13
BOSCH R. The Netherlands 3A GANN P. USA 11
BOSTWICK D.G. USA 1 GELET A. France 12
BRAECKMAN J. Belgium 4 GETZENBERG R.H. USA 2
BRAWLEY O. USA 10 GIULIANO F. France 8
CANTO E.I. USA 2 GOSPODAROWICZ M. Canada 12
CARTER H.B. USA 10 GRAVAS S. Greece 7
CATALONA W. USA 12 GRIFFITHS D. USA 5
CHAPPLE C. UK 6 HABIB F. UK 11
CHENG Ch. Singapore 3B HIRAO Y. Japan 8
CHINNAIYAN A. USA 2 HORIE A. Japan 14
CIATTO S. Italy 10 HUDSON T. Ireland 16
COAKLEY F. USA 4 HUGOSSON J. Sweden 10

6
IGAWA M. Japan 4 PAIS J. Belgium 16
ISAACS J.T. USA 1 PERRIN P. France 6
JACOBSEN S. USA 3 PIECHAUD T France 12
JARDIN A. France 8 PREZIOSO D. Italy 6
JEVTICH HM USA 7 REDMOND K. Italy 16
KANTOFF Ph. USA 13 RESNICK M. USA 4
KAPLAN S. USA 6 ROEHRBORN C. USA 8
KAUFMAN J.M. Belgium 14 ROSEN R. USA 8
KEUPPENS F. Belgium 8 SAAD F. Canada 13
KHAULI R. Lebanon 3B SAHABUDDIN R.M. Malaysia 3B
KIRBY R. UK 11 SASIDHARAN K. India 3B
KLOCKER H. Austria 9 SCHAEFFER A. USA 15
KORFAGE I The Netherlands 10 SCHALKEN J. The Netherlands 1
KRIEGER J. USA 15 SCHRÖDER F. The Netherlands 10
KUMON H. Japan 13 SCHULMAN C. Belgium 14
LAXMAN B. USA 2 SCHULTHEISS D. Germany
LEE W.R. USA 12 SHIRAISHI T. Japan 1
LEE E. Korea 3B SLAWIN K. USA 2
LOBEL B. France 15 STANFORD J. USA 3
MACHTENS S. Germany 10 TAKEDA M. Japan 6
MAHLER C. Belgium 14 TAMMELA T.L. Finland 6
MENDOZA-VALDES A. Mexico 11 TAVIO H. Finland 16
MENON M. USA 12 TEILLAC P. France 6
MICHEL M.C. The Netherlands 6 TERRIS M. USA 4
MORALES A. Canada 14 THOMPSON I. USA 11
MORGENTALER A. USA 14 TOMLINS S.A. USA 2
MUNTZ R. France 16 TOSTAIN J. France 14
MURAI M. Japan 3B TRACHTENBERG J. Canada 12
MUSCHTER R. Germany 7 TSUKAMOTO T. Japan 3B
NABER K.G. Germany 15 TUBARO A. Italy 5
NAITO S. Japan 7 UMBAS U. Indonesia 1
NAKAGAWA M. Japan 15 VALLANCIEN G. France 12
NASU Y. Japan 13 VAN KERREBROECK P. The Netherlands 5
NELSON W. USA 13 VAN POPPEL H. Belgium 11
NETTO N.R. Brazil 7 WALDBAUM R.S. USA
NICKEL C.J. Canada 15 WATSON B. Ireland 1
NISHIZAWA O. Japan 5 WEIDNER W. Germany 15
NITTI V. USA 5 WEIN A. USA 5
NYBERG L. USA 15 WIRTH M. Germany 13
O’LEARY M. USA 8 WYLLIE M. UK 9
OGAWA O. Japan 2 YAMAGUCHI O. Japan 9
OUDARD S. France 13 YU J. USA 2
PAGE J. USA 16 ZHOU L. China 3B

7
 MEMBERS OF THE COMMITTEES (by Committee)
History of Prostatic Diseases 5 LUTS: Etiology and Patient Assessment
SCHULTHEISS D. Germany ABRAMS P. U.K.
WALDBAUM R.S. USA D'ANCONA C. Brazil
FOO K. T. R of Singapore
1 New Developments in the Pathobiology
GRIFFITHS D. USA
of Prostate Disease
NISHIZAWA O. Japan
ALGABA F. Spain
NITTI V. USA
BOSTWICK D.G. USA
TUBARO A. Italy
ISAACS J.T. USA
VAN KERREBROECK P. The Netherlands
SCHALKEN J. The Netherlands
WEIN A. USA
SHIRAISHI T. Japan
UMBAS U. Indonesia 6 New Medical Developments in the management
WATSON B. Ireland of LUTS in Adult Men
ARTIBANI W. Italy
2 Advances in Biomarkers for Prostate Disease
BERGES R. Germany
ABRAHAMSSON P.A. Sweden
CHAPPLE C. UK
CANTO E.I. USA
KAPLAN S. USA
CHINNAIYAN A. USA
MICHEL M.C. The Netherlands
DJAVAN B. Austria
PERRIN P. France
GETZENBERG R.H. USA
PREZIOSO D. Italy
LAXMAN B. USA
TAKEDA M. Japan
OGAWA O. Japan
TAMMELA T.L. Finland
SLAWIN K. USA
TEILLAC P. France
TOMLINS S.A. USA
YU J. USA 7 New Minimally-Invasive and Surgical
Developments in the management of BPO
3A Epidemiology and Natural History of
BABA S. Japan
Prostate Disease
BADLANI G. USA
BARRY M. USA
DE LA ROSETTE J. The Netherlands
BOSCH R. The Netherlands
ELHILALI M. Canada
CUSSENOT O. France
GRAVAS S. Greece
DONOVAN J. UK
JEVTICH HM USA
ETZIONI R. USA
MUSCHTER R. Germany
JACOBSEN S. USA
NAITO S. Japan
STANFORD J. USA
NETTO N.R. Brazil
3B Epidemiology and Natural History of
8 Prevention of BPH Outcomes and
Prostate Disease
Clinical Progression
CHENG Ch. Singapore
EMBERTON M. U. K.
KHAULI R. Lebanon
GIULIANO F. France
LEE E. Korea
HIRAO Y. Japan
TSUKAMOTO T. Japan
JARDIN A. France
SAHABUDDIN R.M. Malaysia
KEUPPENS F. Belgium
SASIDHARAN K. India
O’LEARY M. USA
MURAI M. Japan
ROEHRBORN C. USA
ZHOU L. China
ROSEN R. USA
4 New Development in the Anatomical and
9 New Therapeutic Targets in BPH and LUTS
Metabolic Imagery of the Prostate and
(Research Priorities)
Metastatic Sites.
ANDERSSON K. E. Sweden
AKIN O. USA
CRUZ F. Portugal
BRAECKMAN J. Belgium
KLOCKER H. Austria
COAKLEY F. USA
WYLLIE M. U.K.
COCHLIN D. UK
YAMAGUCHI O. Japan
DESCOTES J.L. France
IGAWA M. Japan
RESNICK M. USA
TERRIS M. USA

8
10 New Developments in Screening and Early 13 New Therapeutic Targets and Treatments
Detection for Prostate Cancer for Metastatic Prostate Cancer
ALBERTSEN P. USA DEBRUYNE F. The Netherlands
BOCCON GIBOD L. France EISENBERGER M. USA
BRAWLEY O. USA FOURCADE R. France
CARTER H.B. USA FRENKEL E. USA
CIATTO S. Italy KANTOFF Ph. USA
HUGOSSON J. Sweden KUMON H. Japan
KORFAGE I The Netherlands NASU Y. Japan
MACHTENS S. Germany NELSON W. USA
SCHRÖDER F. The Netherlands OUDARD S. France
SAAD F. Canada
11 Prostate Cancer Chemoprevention
WIRTH M. Germany
AKAZA H. Japan
GANN P. USA 14 Androgen Replacement Therapy in Men at
HABIB F. UK Risk for Prostate Disease
KIRBY R. UK HORIE A. Japan
MENDOZA-VALDES A. Mexico KAUFMAN J.M. Belgium
THOMPSON I. USA MAHLER C. Belgium
VAN POPPEL H. Belgium MORALES A. Canada
MORGENTALER A. USA
12 New Developments in the Treatment of SCHULMAN C. Belgium
Localized Prostate Cancer
TOSTAIN J. France
ABBAS F. Pakistan
ABBOU Cl. France 15 Prostatitis and Chronic Pelvic Pain
ARAI A. Japan ANDERSON R. USA
BARTSCH G. Austria KRIEGER J. USA
BOLLA M. France LOBEL B. France
CATALONA W. USA NABER K.G. Germany
CONORT P. France NAKAGAWA M. Japan
DEARNALEY D. UK NICKEL C.J. Canada
GELET A. France NYBERG L. USA
GOSPODAROWICZ M. Canada SCHAEFFER A. USA
LEE W.R. USA WEIDNER W. Germany
MENON M USA
PIECHAUD T France 16 Patient’s Perspectives in Prostate Diseases
TRACHTENBERG J. Canada FAULDS WOOD L. UK
VALLANCIEN G. France HUDSON T. Ireland
MUNTZ R. France
PAGE J. USA
PAIS J. Belgium
REDMOND K. Italy
TAVIO H. Finland

9
 Professor Louis Denis, Hon. President,
4th International Consultation on Prostate Cancer

It was with particular pleasure, that the delegates to the Fourth International Consultation on Prostate Can-
cer, held in Paris during the last days of June 2005, welcomed Professor Louis Denis as their Honorary
President. As one of the founding fathers of the ICUD, the internationally recognised and universally
popular Louis Denis, played a principal role in the establishment of the innovative annual consensus mee-
ting, as the most successful discussion forum available to the Urological Community, worldwide. From
its inception in the 1980s and its subsequent recognition by the WHO and UICC, Louis Denis actively
promoted the value of the consultation to international urology. The ICUD Board was delighted and
honoured, that he accepted the Presidency for 2005.
Louis Denis graduated in 1957 from the University of Ghent, where he completed his medical studies. As
a trained sportsman, he won medals in the swimming pool and a bronze medal with the Belgium basket-
ball team in the 1952 University Olympic Games. After residencies at the Antwerp City Hospitals, he
moved to the Medical College of Virginia, USA where, under the guidance of his mentor, Professor Geor-
ge Prout, he honed his surgical skills, enjoyed his research activity that gained AUA and EAU prizes and
realised an inherent real ability to teach. Most importantly, with Bill Scott’s support, he acquired experti-
se as a clinical trialist.
In late 1964, however, Louis Denis returned to Belgium, because he was a military man: he retired in 1991
as Lt-Colonel. He was required to help in Operation Red Dragon and joined an American and Belgian
assault into Stanleyville, the capital of the North East Belgium Congo, in order to rescue 700 European
and American citizens taken hostage by rebels.
With the hostages rescued and military honours awarded, this ‘simple urologist from a little country cal-
led Belgium’, a comment he often uses, consolidated his position in the forefront of Belgian urology, with
successive appointments as Chief of Urology in the Antwerp Military Hospital and AZ Middleheim Hos-
piital, Antwerp, Professor of Urology, University of Brussels and President of the Medical Board of the
Middleheim Hospital. Belgian civil honours, a Knighthood of the Order of the Crown and Commander of
the Order of Leopold II, were awards that nationally recognised his clinical and academic prowess.
Contemporaneously, a worldwide recognition of his ability was seen by invitations to present prestigious
lectures, the award of honorary degrees and Medical Society Medals, as well as the membership of
influential committees and advisory boards. His clinical research was always to the forefront and he
contributed substantially to the medical literature with more than 350 peer-reviewed papers, 205 chapters
of medical textbooks and the editorship of 50 books. As the European leader, not only in the value and
promotion of scientifically sound, randomised, controlled clinical trials, but in the development of trans-
urethral ultrasonography, Louis Denis introduced the international Urological Community to the use of
such diagnostic procedures in order to test their potential in the Pan-European screening initiatives for the
identification of early cancer of the prostate.

10
Professor Louis Denis is a renowned
figure in international urological
affairs, recognised as a founder
member of the European School of
Oncology in Milan, a former Secre-
tary General and long-time treasurer
of the UICC and former President of
the EORTC, for which he was able
to negotiate a two million euro
award from Belgium. Louis Denis,
together with the formidable Saad
Khoury, Yoshio Aso and the late
Gerry Murphy, established the Inter-
national Consultations in Urological
Diseases, global consultations invol-
ving multi-professional expertise,
which aimed to achieve by consensus, international strategies for the diagnosis and treatment of urologi-
cal diseases, a concept that has been immensely successful. Through the past decade, he has chaired the
International Prostate Health Council, the IPHC, a sort of ‘think tank’, that in the early 1990s, was asked
to help to increase the worldwide awareness of prostate disease. With the backing of Council members
such as Adolphe Steg, Fritz Schroeder, Peter Boyle, Roger Kirby and Tag Hald, Louis’ IPHC has impres-
sively initiated a range of teaching programmes, organised the Pan-European Screening initiative and pro-
moted the now rapidly growing belief that the growth of prostate cancer can be restrained, possibly even
prevented.
‘Europe’s Foremost Free Thinker’ is now retired. ‘So much achieved, but so much more to be done’. As
well as appreciating the love and company of his many grandkids, the Emeritus Professor has now assu-
med another responsibility, that of Director of the Oncology Centre in Antwerp and he continues to travel
widely, in the promotion of the Euro-
pa Uomo programme, directed to a
better relationship between patients
and their doctors, attempting to
ensure that patients with prostate
cancer, worldwide, have ready
access to responsible information
that will offer some reassurance and
a better understanding of their disea-
se and its treatment.
‘Europe’s Foremost Free Thinker’ is
now retired. ‘So much achieved, but
so much more to be done’. As well as
appreciating the love and company
of his many grandkids, the Emeritus
Professor has now assumed another responsibility, that of Director of the Oncology Centre in Antwerp and
he continues to travel widely, in the promotion of the Europa Uomo programme, directed to a better rela-
tionship between patients and their doctors, attempting to ensure that patients with prostate cancer, world-
wide, have ready access to responsible information that will offer some reassurance and a better unders-
tanding of their disease and its treatment.
The Consultation was indeed honoured that the 2005 Presidency was accepted by Louis Denis, a urologist
of great skill, an accomplished clinical researcher, sportsman, soldier and exemplary medical diplomat, but
most importantly, a wonderful friend and teacher to so many.
Keith Griffiths, ICUD Board Member.

11
 CONTENTS

FOREWORD 3

Prof. Louis Denis Honorary President of the 4th Consultation on Prostate Cancer 10

Chapter 1 A Brief History of Prostatic Diseases 17

D. SCHULTHEISS (GERMANY), R.S. WALDBAUM (USA)

Chapter 2 Committee 3A Epidemiology and Natural History of

Benign Prostatic Hyperplasia 35
M. BARRY, M. MURAI, R. BOSCH, C. CHENG, O. CUSSENOT, J. DONOVAN ,
R. ETZIONI, S. JACOBSEN , R. KHAULI, E. LEE, R. SAHABUDIN,
K. SASIDHARAN, J. STANFORD, T. TSUKAMOTO, L. ZHOU

Chapter 3 Committee 3B Epidemiology of Benign prostatic Hyperplasia in Asia 55

M. MURAI, CH. CHENG, R. KHAULI, E. LEE, R.M. SAHABUDDIN,
K. SASIDHARAN, T. TSUKAMOTO, L. ZHOU

Chapter 4 Committee 5 Lower Urinary Tract Symptom: Etiology, Patient

Assessment and Predicting Outcome from Therapy 69
P. ABRAMS, C. D’ANCONA, D. GRIFFITHS , P. VAN KERREBROECK,
O. NISHIZAWA, V. NITTI, F. KEONG TATT, A. TUBARO, A. WEIN , M. BELAL

Chapter 5 Committee 6 New Medical Developments in the Management

of LUTS in Adult Men 143
C. CHAPPLE, W. ARTIBANI, R. BERGES, S. KAPLAN, M. C.MICHEL,
P. PERRIN, D. PREZIOSO, M. TAKEDA, T.L. TAMMELA, P. TEILLAC

Chapter 6 Committee 7 New Minimally Invasive and Surgical

Developments in the management of BPO 195
J. DE LA ROSETTE, S. BABA, G. BADLANI, M. ELHILALI, S. GRAVAS,
R. MUSCHTER, S. NAITO, N. R. NETTO

Chapter 7 Committee 8 Prevention of Progression and Adverse

Outcomes in BPH/BPE/BPO 235
C. ROEHRBORN, J. EMBERTON, F. GIULIANO, Y. HIRAO, A. JARDIN,
M. O’LEARY, F. KEUPPENS , R. ROSEN

12
Chapter 8 Committee 9 New therapeutic targets in BPH
and LUTS (Research priorities) 299
K-E ANDERSSON, F CRUZ, H KLOCKER, M WYLLIE, O YAMAGUCHI

Chapter 9 Committee 14 Androgen Therapy in Men at Risk for

Prostate Disease 325
C. SCHULMAN, S. HORIE, J.M KAUFMAN, C. MAHLER,
A. MORALES, A. MORGENTALER, J. TOSTAIN

Chapter 10A Committee 15 The Assessment and Management of

Male Pelvic Pain Syndrome, Including Prostatitis 341
A. J. SCHAEFFER,R. U. ANDERSON, J. N. KRIEGER, B. LOBEL,
K. NABER, M. NAKAGAWA , J. C. NICKEL, L. NYBERG, W. WEIDNER

Chapter 10B Committee 15 Diagnostic Workup and Algorithms 377

A. J. SCHAEFFER, R. U. ANDERSON, J. N. KRIEGER, B. LOBEL,
K. NABER, M. NAKAGAWA , J. C. NICKEL, L. NYBERG, W. WEIDNER

Summary of the Recommendations of the International

Scientific Committee 387

13
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14
MALE LOWER URINARY
TRACT DYSFUNCTION
Evaluation and Management
EDITORS
J. MCCONNELL, P. ABRAMS, L. DENIS,
S. KHOURY, C. ROEHRBORN

15
16
 CHAPTER 1

History of Prostatic Diseases

Chairman
D. SCHULTHEISS (GERMANY)
R. S. WALDBAUM (USA)

17
18
History of Prostatic Diseases
Chairman
D. SCHULTHEISS , R. S. WALDBAUM

Leonardo da Vinci (1452-1519)

was the first master of anatomical
and medical illustration, although
his outstanding work on the anato-
my and physiology of the human
body was almost unknown to his
contemporaries. The incident that
he never gave a description of the
prostate gland can be explained by
the fact, that most of his knowled-
ge was drawn from anatomical dis-
sections of castrated oxen only
having a small and atrophic
prostate.

The ”Tabulae Anatomicae“ of the

anatomist Andreas Vesalius (1514-
1564) from 1538 gave the first
illustration of the prostate gland
but omitted the seminal vesicles. A
more detailed illustration can be
found in “De Humani corporis
fabrica Libri septem“ from 1543.

19
 In his “Dix Livres de la Chirur-
gie” from 1564 the master of
French Renaissance surgery
Ambroise Paré (1510-1590) dedi-
cated one chapter to “des chaudes
pisses, des pierres et des réten-
tions d´urine“. He described obs-
tructive urinary symptoms and
related them to “carnosities“ or
“caruncles“ deriving from the
prostate.

Ambroise Paré even suggested

catheters or sounds with sharp
ridges on their surfaces designed
to remove these “carnosities“ or
“caruncles“ by repeatedly pas-
sing these instruments through the
urethra.

In his “Tractus de virorum orga-

nis generationi inservientibus, de
clysteribus et de usu siphonis in
anatomia“ (1668) the Dutch phy-
sician Regnier de Graaf (1641-
1673) gave a very detailed and
exact anatomical description and
illustration of the prostate, the
seminal vesicles and the ejacula-
tory ducts.

20
 The famous surgeon and anato-
mist John Hunter (1728-1793)
from London is well-known for
his contributions on venereal
diseases, the prostate and urethral
strictures. In his book “A Treatise
on the Venereal Disease” from
1786 he illustrated an enlarged
middle lobe of the prostate. In his
later works he precisely described
obstructive symptoms caused by
enlargement of the prostate and
the resulting effects on the blad-
der muscularis and of dilation of
the upper urinary tract. Hunter
also realized that these changes
did not occur in castrates.

Jean Civiale (1796-1867) from

Paris devised the “kiotome“
around 1830 for incision of the
obstructing bladder neck. In 1836,
his contemporary Louis-Auguste
Mercier (1811-1882) introduced
several instruments to incise the
median bar or even to remove
small tissue particles similar to a
punch.

In 1874 Enrico Bottini (1835-

1903) from Pavia in Italy was the
first to apply electric surgery to
the prostate. His “Cauterio termo-
galvanico“ facilitated destruction
and incision of a prostate lobe and
median bar without producing
hemorrhages.

21
 Based on the “Cauterio termo-
galvanico“ of Bottini several
modified galvano-cautery and
–incision instruments were sug-
gested by Freudenberg (A),
Chetwood (B) and Wishard (C).

Sir Henry Thompson (1820-1904)

from London won the prestigous
Jacksonian Prize in 1860 with his
monography “The enlarged Pros-
tate, its Pathology and Treat-
ment“. He gained reputation as
the world´s greatest specialist sur-
geon after he successfully remo-
ved the bladder stone of King
Leopold I, King of Belgium, in
1863.

Theodor Billroth (1829-1894)

was one of the greatest surgeons
of his time and before coming to
Vienna he most likeley performed
the first planned removal of carci-
nomatous prostatic tissue as par-
tial perineal excision of the pros-
tate in 1867 while still working in
Zurich.

22
 George Goodfellow (1855-1910),
from Tombstone and Tuscon per-
formed the first perineal enuclea-
tion of the enlarged prostate in
1891. In 1904 (July and Novem-
ber issue of JAMA) he first repor-
ted on 72 cases which he had ope-
rated with only 2 fatalities. Many
surgeons followed him and contri-
buted various technical aspects to
perineal prostatectomy. His defi-
nition of a good surgeon was: “A
surgeon should have the eye of an
eagle, the heart of a lion, and the
touch of a woman.“

Eugene Fuller (1858-1930) from

New York published suprapubic
transvesical enucleation of the
prostate in 1895 as performed by
him the previous year. He accom-
plished for the first time not only
removal of the intravesical but
also of the intraurethral enlarge-
ment of the prostate by digital
enucleation.

Peter Freyer (1852-1921) from St.

Peter´s Hospital in London must
have learned about Fuller´s tech-
nique of transvesical prostatecto-
my through a visit of Fuller´s
assistant Ramon Guitéras in 1900.
One year later Freyer then clai-
med priority for the technique and
by this gave ground to some dis-
pute. Freyer however became the
major prostatectomist of the time
and deserves credit for populari-
zing the operation and making it a
standard procedure.

23
 During the 1890s men with seve-
re symptoms of prostatic hyper-
trophy were occasionally castra-
ted. Mansell Moullin from Lon-
don described the effect of castra-
tion in 1894: “Removal of the
testes is followed in a large pro-
portion of cases by complete and
rapid absorption of the enlarged
prostate. The gland entirely disap-
pears; nothing is left but a little
fibrous mass.“ The symptomatic
improvement in over a half of
patients with an enlarged prostate
treated with castration was repor-
ted by William White from Phila-
delphia in 1895 and 1904.

Searching for alternatives to cas-

tration for the treatment of enlar-
ged prostate, vasectomy was first-
ly suggested by James Ewing
Mears in 1890, although Felix
Guyon of Paris was also cited as
the first to achieve this doubtful
distinction. This treatment was en
vogue for a short period of time as
it was claimed to be a method with
minimal morbidity and great
effectiveness. Further applications
of this technique soon resulted in
less enthusiastic reports (e.g. by
Harrison and Wood both in 1900),
showing an only 15% improve-
ment in micturition. Shortly later
the method fell into disrepute.

Hugh H. Young (1870-1945) from

Baltimore performed the first
radical perineal prostatectomy for
prostate cancer on the 7th April
1904. The respective illustrations
are taken from a later publication
of Young from 1919. In the early
1940`s he reported on 184
patients he had operated with this
technique of whom 34 had lived
cancer-free and died from unrela-
ted disease 5 to 27 years later.

24
 Robert Proust (1873-1935), bro-
ther of the famous French author
Marcel Proust, was the most
important early promoter of per-
ineal prostatectomy in France or
even Europe at the beginning of
the 20th century. At that time the
operation was called “Proustatec-
tomie“ in France. The starting
point was his doctoral thesis in
1900, which was written under
the guidance of Felix Guyon and
Joaquin Albarran at the Hôpital
Necker in Paris. Later Proust
designed a special operating table
to put the patient in perfect posi-
tion for perineal surgery.

As in the US by Young perineal

prostatectomy was not only per-
formed in benign disease but even
for localized prostatic cancer in
France by Joaquin Albarran
(1860-1912). Notice wide exci-
sion at the bladder neck and ana-
stomosis. These illustrations are
taken from the textbook “Médici-
ne opératoire des voies urinaires“
published by Albarran in 1909.

Edmond Papin, like Proust wor-

king at the Hôpital Necker in
Paris, wrote an extensive book of
over 200 pages on “Sexual Func-
tion after Prostatectomy“ in 1908.
On the basis of anatomical exami-
nations he analyzed sexual dys-
function after prostatectomy,
including 55 documented case
reports.

25
 “Prostatectomia suprapubica
extravesicalis“ had already been
performed by W. J. van Stockum
(1860-1913) from Rotterdam,
The Netherlands, in 1908 and
published one year later in the
German journal “Zentralblatt der
Chirurgie“. However, the wide
clinical establishment of retropu-
bic approach to the prostate after
1945 must be credited to the Irish
surgeon Terence J. Millin (1903-
1980), who was working in Lon-
don.

In 1909 Hugh H. Young (1870-

1945) performed the first “cold
punch“ resection of the median
bar of the prostate under direct
vision control. In 1913 he already
reported on 100 patients treated
with this new technique.

James Buchanan „Diamond Jim“

Brady (1856-1917) made money
with selling railroad equipment
and loved diamonds. Besides
from being obese, hypertensive
and diabetic he suffered from
prostatic obstruction. Hugh H.
Young (1870-1945) performed
the cold punch on him in April
1912 and his patient later donated
the Brady Urological Institute at
The Johns Hopkins Hospital.

26
 In 1914 Georges Luys from Paris
– depicted here as the great explo-
rer in a sketch of the magazine
Chanteclair - reported endosco-
pic electrocoagulation of the pros-
tate, which he called “forage de la
prostate (drilling of the prostate)“.

In January 1926 Maximillian

Stern (1873-1946) from New York
presented his “resectoscope“
before the Genito-Urinary Section
of the New York Academy of
Medicine on the basis of 46 trea-
ted patients. The instrument had
two lens systems, one indirect
vision for examination and a
direct vision lens for bipolar
resection.

Joseph McCarthy (1874-1965)

from New York incorporated a
bakelite non-conducting sheath
and his foroblique lens system to
improve the Stern resectoscope in
1931. It was the first instrument to
move the loop from the bladder
towards the instrument as in
today´s instruments.

27
 Some alternatives were looked
for during that era, e.g. in 1928
the endothermal prostatic excisor
of Frederic Foley (1891-1966)
from Minneapolis. A conical sec-
tion of the prostate was burned
out with a thin steel music wire
under electric current by rotating
the instrument.

Finally, the improvements of

Stern and McCarthy were united
in the classical Stern-McCarthy
resectoscope which was then in
use for many decades.

Other countries had different and

individual developments of
TURP. Maximillian Stern came to
Berlin in 1927 to present his new
resectoscope before the Berlin
Urological Society and operated
on two patients. As both of them
died after surgery the new tech-
nique of TUR was not well adop-
ted in Germany initially. Alexan-
der von Lichtenberg (1880-1949,
Berlin) realized the importance of
TURP and developed his own
resectoscope, the “Prostata-
Cutor“ in 1932, which was later
improved as the “Lichtenberg-
Heywalt-Elektrotom“.

28
 After World War II several Euro-
pean urologists were trained in
the US and transferred the tech-
nique of TURP to Europe. One of
them was Wolfgang Mauermayer
(1919-1994) from Munich, Ger-
many, who designed a famous
resectoscope with two light
sources and for one-handed use in
1952.

Edward L. Keyes and Russell S.

Ferguson from New York City had
performed radioorchiectomy in
several patients since 1932. In the
6th edition of their textbook “Uro-
logy“ from 1936 they pronounced
the “Extension of the life of the
patient in comfort, even in the
face of widespread metastatic
disease”. In some of their patients
roentgen castration combined
with local irradiation was success-
ful in arresting the primary tumor
and the metastatic lesions.

The experimental studies which

finally established the knowledge
about androgen control of mali-
gnant prostatic growth were initia-
ted in 1939 by Charles Brenton
Huggins (1901- 1997) at that time
working in Chicago. He demonstra-
ted that castration in man decreases
the height of prostatic epithelial
cells in normal prostatic tissue, that
testosterone stimulates secretory
activity of dogs’ prostatic cells and
diethylstilbestrol inhibits this activi-
ty. He further proved that acid phos-
phatase was elevated in metastatic
prostate cancer and that castration
produced a relief of pain and a sta-
bilization or regression of local and
metastatic osseous lesions.

29
 In the beginning Huggins won a
gold medal of the American
Medical Association for his work
in benign prostatic hyperplasia in
1940 and only a merit for his
study on prostate cancer the year
after. Finally, these fundamental
investigations on the influence of
the endocrine system onto the
development of a human mali-
gnancy were honored with the
Noble Prize for Medicine and
Physiology in 1966.

R. Paschkis from Vienna devised

the first cystoscopic radium
applicator in 1911. The radium
capsule was situated at the very
tip of the instrument and no exter-
nal fxation of the cystoscope hol-
ding it in the correct position was
used. In 1913 O. Pasteau and
Degrais from Paris reported seve-
ral cases of prostate cancer which
had been successfully treated by
the use of radium introduced
through a simple coudé gum
catheter.

Benjamin Barringer (1877-1953)

Chief at Memorial Hospital New
York was the first to perfom trans-
perineal implantation of radium
into the prostate in hundreds of
cases between 1915 and 1930;
first published in JAMA in 1917.
Initially, Barringer used radon-tip-
ped needles introduced through
the perineum and left for several
hours.
Later gold-encapsulated Radon
seeds were applied by the same
route as permanent implants.

30
 In the 1930‘s Barringer also expe-
rimented with the open approach
for radon seed application already
using a template for controlled
placement of the seeds as in
today´s technique. He even com-
bined the perineal and suprabupic
approach for brachytherapy of the
prostate.

Immediately after Barringer´s

reports Hugh H. Young adopted
and investigated various tech-
niques of prostate brachytherapy
at his institute in Baltimore.

Young placed needles with

Radium tips alternatively intraure-
thrally and transrectally for short
periods of time over several
weeks. For this he designed his
own radium applicator.

31
 Rubin Flocks (1906-1975) from
Iowa State University treated
more than 400 prostate carcinoma
patients in the 1950´s by injection
of a colloidal suspension of radio-
active gold into the prostate.
Injection was either performed by
the closed perineal or the open
transvesical route.

Since 1970 Willet F. Whitmore

from the Memorial Sloan-Kette-
ring Cancer Center in New York
combined open retropubic
implantation of permanent Iodine
125 seeds with bilateral pelvic
lymph node dissection allowing a
more refined treatment.

Hiroki Watanabe from Sendai,

Japan, obtained the first clinically
useful tomogram of intrapelvic
organs via the rectum in 1967.
This equipment was used in 400
patients with one examination
being accomplished in 15
minutes.

32

REFERENCES
Ballenger EG, Frontz WA, Hamer HG, Lewis B
(1933) History of Urology. Williams and Wilkins,
Baltimore
Musitelli S (2001) Who was Who in European Uro-
logy. European Association of Urology, Arnhem
Reuter MA, Reuter JH, Engel RM (1999) History of
Endoscopy. Vol. 1-4. Krämer, Stuttgart
Reuter JH, Reuter MA, Engel RM (2003) History of
Endoscopy. Vol. 5-7. Krämer, Stuttgart
33
Holm and Gammelgaard from the
University of Copenhagen perfor-
med the first ultrasound-guided
perineal prostatic biopsies in 1982
and first Iodine 125 seed implan-
tation was reported from the same
institution in 1983.
CORRESPONDENCE
Dirk Schultheiss, M.D.
Chairman, History Office of the European
Association of Urology
Department of Urology, Protestant Hospital Giessen
Paul-Zipp-Str. 171
35398 Giessen, Germany
Robert S. Waldbaum, M.D., F.A.C.S.
Historian of the American Urological Association
Clinical Professor of Urology, Cornell University
Medical School
Chaiman, Department of Urology, North Shore
University Hospital
535 Plandome Road
Manhasset, New York 11030, USA
34
 CHAPTER 10 A

Committee 15

The Assessment and Management

of Male Pelvic Pain Syndrome,
Including Prostatitis
PART I

Chairman
A. J. SCHAEFFER (USA)

Members
R. U. ANDERSON (USA),
J. N. KRIEGER (USA),
B. LOBEL (FRANCE),
K. NABER (GERMANY),
M. NAKAGAWA (JAPAN),
J. C. NICKEL (CANADA),
L. NYBERG (USA),
W. WEIDNER (GERMANY)

341
 CONTENTS

A. INTRODUCTION D. TREATMENT

I. ACUTE BACTERIAL
I. DEFINITIONS
PROSTATITIS (NIH CATEGORY I)

B. EPIDEMIOLOGY AND II. CHRONIC BACTERIAL

PATHOGENESIS PROSTATITIS (NIH CATEGORY II)

I. EPIDEMIOLOGY III. CHRONIC

PROSTATITIS/CHRONIC PELVIC
PAIN SYNDROME
II. PATHOGENESIS (NIH CATEGORY III)

IV. ASYMPTOMATIC PROSTATITIS

(NIH CATEGORY IV)
C. EVALUATION
E. EVIDENCE AND
RECOMMENDATIONS
I. ACUTE BACTERIAL PROSTATITIS
(NIH CATEGORY I)
I. LEVELS OF EVIDENCE AND
GRADING OF RECOMMENDATIONS
II. CHRONIC BACTERIAL
PROSTATITIS (NIH CATEGORY II)
II. EVALUATION

III. CHRONIC
PROSTATITIS/CHRONIC PELVIC III. TREATMENT
PAIN SYNDROME
(NIH CATEGORY IIIA, IIIB)

IV. ASYMPTOMATIC PROSTATITIS F. REFERENCES

(NIH CATEGORY IV)

342
The Assessment and Management of Male
Pelvic Pain Syndrome, Including Prostatitis
A. J. SCHAEFFER,
R. U. ANDERSON, J. N. KRIEGER, B. LOBEL, K. NABER, M. NAKAGAWA , J. C. NICKEL,
L. NYBERG, W. WEIDNER
A. INTRODUCTION
The male pelvic pain syndrome, including prostati-
tis, affects approximately 10% of men and causes
significant morbidity and cost. Less than 10% of the
patients suffer from acute or chronic bacterial pro-
statitis, conditions which are well defined by clinical
and microbiologic parameters and usually amenable
to antimicrobial therapy. Acute prostatitis is charac-
terized by a severe systemic infection and irritative
voiding symptoms, responds promptly to antimicro-
bial therapy, and is usually self-limiting. Chronic
bacterial prostatitis may or may not be associated
with mild pelvic pain symptoms and intermittent
episodes of acute cystitis. Long-term antimicrobial
therapy cures approximately 80% of the patients.
The majority of men with “chronic prostatitis” have
chronic pelvic pain syndrome (CPPS), which is char-
acterized by pelvic pain, urinary symptoms and sex-
ual dysfunction. The National Institutes of Health-
Chronic Prostatitis Symptom Index (NIH-CPSI) is a
reliable means of capturing the symptoms and
impact of CPPS. Because the etiology of this syn-
drome is not known, the evaluation and treatment is
varied and, unfortunately, frequently unsuccessful.
Because of the substantial emotional and economic
impact of this condition, significant research is being
conducted which hopefully will lead to a better
understanding and management of this condition.
I. DEFINITIONS
Male pelvic pain syndromes describe a combination
of infectious diseases (acute and chronic bacterial
prostatitis); chronic pelvic pain syndrome; or asymp-
tomatic prostatitis. The National Institutes of Health
classification of prostatitis syndromes [1] includes:
343
1. Category I: Acute Bacterial Prostatitis (ABP)
which is associated with severe prostatitis symp-
toms, systemic infection and acute bacterial urinary
tract infection (UTI).
2. Category II: Chronic Bacterial Prostatitis
(CBP) which is caused by chronic bacterial infection
of the prostate with or without prostatitis symptoms
and usually with recurrent UTIs caused by the same
bacterial strain.
3. Category III: Chronic Prostatitis/Chronic
Pelvic Pain Syndrome (CP/CPPS), characterized
by chronic pelvic pain symptoms and possibly void-
ing symptoms in the absence of UTI. Category III is
subdivided into category IIIA (inflammatory) and
IIIB (noninflammatory) prostatitis. Pain is the pri-
mary symptom distinguishing CP/CPPS from OAB
and other LUTS.
Category IV: Asymptomatic Inflammatory Pro-
statitis, in which evidence of prostate inflammation
exists in the absence of genitourinary tract symp-
toms. It is an incidental finding during evaluation for
other conditions such as infertility or elevated PSA.
B. EPIDEMIOLOGY AND
PATHOGENESIS
I. EPIDEMIOLOGY
1. METHODS
The International Consultation on Urological Dis-
eases (ICUD) recommendations were designed pri-
marily to evaluate treatment studies, but do not work
well for epidemiological studies. To stay true to con-
cepts underlying evidence-based medicine, we began
by reviewing the literature following the ICUD rec-
ommendations, using defined criteria for epidemio-
logical studies. Suitable studies were then synthe-
sized to determine the current level of available data
and to identify opportunities for further research.
a) Identification of Studies for Systemic Analysis
Following the ICUD recommendations, papers pub-
lished or accepted for publication in the peer
reviewed issues of journals were included in this sys-
temic review. Papers published in non-peer reviewed
supplements were not included. An exhaustive list
was obtained through the major databases covering
the last 10 years (e.g. Medline, Embase, Cochrane
Library, Biosis, Science Citation Index). Search
terms employed included: prostatitis, pelvic pain,
epidemiology and survey. We also reviewed the
tables of contents of the major journals of urology
and other relevant journals for the previous 3 months
to take into account possible delay in indexing of
papers in the databases. These approaches identified
3,908 references. After reviewing the titles and
abstracts, 73 articles were identified for detailed
review.
b) Criteria for Including Epidemiological Studies
(Table 1)
Included studies possessed at least four of the five
criteria that have been outlined for epidemiological
studies of prostatitis [2].
1. Studies should be population-based. Therefore,
case series of referral patients from tertiary care
institutions were excluded.
2. A clear case and standardized definition was
required. The optimal case definition should bear
a reasonable relationship to patients seen in rou-
tine clinical practice. In practice, this is often
accomplished by choosing a restrictive case defi-
nition, such that most experienced clinicians
Table 1. Criteria for Inclusion of Epidemiological Studies
Characteristic Desirable
1. Study subjects Population-based
2. Case-definition Clear and standardized
3. Survey instrument NIH-CPSI*, with evaluation for exclusion criteria
4. Survey-strategy Standardized and representative
Clinical verification to exclude inappropriate cases No clinical evaluation
5. Population size Sufficient to provide statistical power
* Use of the NIH-CPSI was considered a desirable study characteristic, but this was not required for inclusion in this systemat-
ic review.
344
would agree that cases included in the study truly
suffer from the condition.
3. It is desirable to incorporate a recognized and val-
idated survey instrument such as the NIH-CPSI
[3]. To facilitate evaluation of varied populations
the NIH-CPSI has been translated and validated
for use in English [3], Spanish [4], Japanese [5],
Chinese [6], Malay [6], German [7], Finnish [8]
and Korean [9]. However, a recent population-
based study found low agreement between physi-
cian diagnosed prostatitis and the NIH-CPSI pain
measures, suggesting that the index, by itself, may
have limited ability to determine the presence or
absence of prostatitis [10]. Therefore, use of the
NIH-CPSI was considered desirable, but was not
required for inclusion in this systematic review.
4. A standard strategy for surveying the population
should be used to assure that the participants are
likely to represent the overall population. The
ideal survey strategy should incorporate a mecha-
nism to verify that cases identified in the survey
actually met the case definition.
5. The population studied should be large enough to
provide reasonable statistical power for the
desired comparisons. It is also important to limit
confounding issues such as treatment bias, selec-
tion bias and referral bias that pose special prob-
lems for studies of tertiary care patients from
referral centers.
2. RESULT
a) Acute and Chronic Bacterial Prostatitis (NIH
Categories I and II)
1. PREVALENCE
We identified no studies on the prevalence of either
acute or chronic bacterial prostatitis that met the
Undesirable
Tertiary-care
Patient recall or standard of care
None
Retrospective record review
Small, providing low statistical power
inclusion criteria. Traditionally, the prevalence of
these conditions has been believed to be low based
on clinical experience from tertiary care urology
practices [11-13]. Recent, population-based studies
suggest that the prevalence of bacterial prostatitis
might be higher than previously appreciated [14].
2. INCIDENCE
The incidence of bacterial prostatitis may also be
higher than previously reported [15]. A recent study
evaluated new physician-diagnosed prostatitis cases
in a managed care population over a 2-year interval
[15]. The incidence of acute or chronic bacterial pro-
statitis was 1.26 cases per 1,000 men per year, repre-
senting an incidence of 102,000 cases per year if
these data could be extrapolated to the entire US
population.
b) Chronic Prostatitis/Chronic Pelvic Pain Syn-
drome (NIH Category III)
1. PREVALENCE
We identified 11 studies that met the criteria for
inclusion (Table 2). Of these studies seven were
from North America [14; 16-21], three were from
Table 2. Epidemiological Studies of Prostatitis
Author, Year, Country Population
[Reference]
Asia [6; 22-23], and one was from Europe [24].
The prevalence of prostatitis symptoms (e.g. pelvic
pain, urinary symptoms and/or sexual dysfunction)
could be compared in eight studies that surveyed var-
ied ambulatory populations including a total of
12,369 men [6; 14; 16; 18; 20-22; 24]. Overall, 816
participants met criteria for symptoms of prostatitis,
representing an overall rate of 6.6%. In these studies
the prevalence of prostatitis symptoms ranged from
2.2% [20] to 9.7% [18], with a median rate of 6.3%.
Three additional studies met the inclusion criteria but
were not directly comparable to those summarized
above because these studies employed different
denominators or different outcome measures [17; 19;
24].
2. INCIDENCE
One study evaluated the incidence of CP/CPPS in a
managed care population [15]. The incidence was
3.30 cases per 1,000 men per year, representing an
incidence of 267,000 cases per year if these data
could be extrapolated to the overall US population.
c) Asymptomatic Inflammatory Prostatitis (NIH
Number, Prevalence of Prostatitis-Like
Age-Range (Years) Symptoms

Roberts, 1998, USA [16] Minnesota 2,115 men 9%

40-79
Collins, 1998, USA [17] National Ambulatory
Medical Care Survey 58,955 visits 5% overall
>18 Urology: 8%
Primary care: 1%
Mehik, 2000, Finland [24] Randomly selected 1,832 men Lifetime prevalence (incidence)
20-59 14.2%
Nickel, 2001, Canada [18] Patients of family 868 men 9.7%
practitioners 20-74
Tan, 2002, Singapore [22] Cross-sectional study 1,087 men 2.7%
21-70
Kunishima, 2002, Japan [23] Random sample 502 men 5%
20-79
Collins, 2002, USA [19] Health care professionals 31,681 men Self-reported history: 16%
without prostate cancer
Roberts, 2002, USA [20] Random community- 1,541 men 16% GU pain
dwelling men, Minnesota 40-79 2.2% prostatitis
Cheah, 2003, Malaysia [6] Random sample 3,147 men 8.7%
20-50
Calhoun, 2005, USA [14] Managed care population, 1,550 men 6.0% or 7.6%, depending on
Oregon definition
Daniels, 2005, USA [21] Community health survey, 1,559 men 3.9%
Massachusetts 30-79

345
Category IV)
Asymptomatic inflammation is commonly diagnosed
during evaluation of prostate secretions and tissue
removed for diagnosis and treatment of prostate disor-
ders and also in patients undergoing evaluation for
infertility [25-27]. In one recent report from a man-
aged care population, the incidence of physician-diag-
nosed asymptomatic inflammatory prostatitis was
0.33 cases per 1,000 men per year [15].
3. COMMENTARY AND CONCLUSIONS ON
EPIDEMIOLOGY
Although only a limited number of studies met the
evidence-based criteria, these studies support the
conclusion that prostatitis is an important worldwide
problem that merits additional investigation. The
prevalence of prostatitis-like symptoms (defined var-
iously) ranged from 2% to 16%, with a median
prevalence rate approximating 7% for chronic pro-
statitis/chronic pelvic pain syndrome, the most com-
mon category.
Prostatitis results in a substantial number of physi-
cian visits. Among participants with prostatitis-like
symptoms, 60% sought medical help [18]. The odds
of a prostatitis diagnosis were thirteen-fold greater at
visits to urologists compared with visits to primary
care physicians. Patients with prostatitis received
antimicrobials 45% of the time compared to 27% of
the time for those without genitourinary symptoms
[17]. Prostatitis was a diagnosis in 2,000,000 visits
annually in the US, including 8% of all visits to urol-
ogists and 1% of all primary care physician visits
[17]. Patients with symptoms of prostatitis appear to
be at increased risk for persistent symptoms and for
recurrent episodes. Participants with a previous diag-
nosis of prostatitis had a much higher cumulative
probability of subsequent episodes of prostatitis [16;
28]. Symptom surveys alone may have limited abili-
ty to distinguish patients with prostatitis [10]. Clini-
cal evaluation appears necessary to verify that pro-
statitis is indeed responsible for patients’ symptoms
[6].
These studies provide an important foundation for a
research agenda. Future studies should be popula-
tion-based. The case definition should be clear and
should have some relationship to clinical practice.
Clinical evaluation is necessary to verify that chron-
ic prostatitis is responsible for subjects’ symptoms. It
is also important to limit confounding issues, includ-
ing treatment bias, selection bias and referral bias,
that can pose special problems for studies limited to
346
tertiary care patients from referral centers. We need
to define the natural history and consequences of
prostatitis.
II. PATHOGENESIS
1. METHODS
The ICUD evidenced-based recommendations
proved unsuitable for evaluating the pathogenesis of
prostatitis. Therefore, we considered prominent stud-
ies supporting the major etiologic theories.
2. RESULTS
There is little debate that infection is responsible for
acute and chronic bacterial prostatitis. However,
there is no consensus on the cause(s) of the other
prostatitis syndromes.
a) Risk Factors
Although there are limited epidemiological data,
clinical experience suggests that prostatitis may be
related to genitourinary tract procedures and manip-
ulation, such as catheterization. An increased rate of
ABP related to increased use of TRUS-guided
prostate biopsy for evaluation of possible prostate
cancer has been found.
A history of UTI appears to be associated with
chronic prostatitis (unspecified as to type). For
example, the Boston Area Community Health Sur-
vey found that 79 (3.9%) of 1559 men aged 30-79
years experienced symptoms of prostatitis [21]. The
prevalence of symptoms of prostatitis did not differ
significantly by race/ethnicity. However, symptoms
of prostatitis increased significantly with age
(p=0.0091). The rate was 1.2% among 30-39 year
old men, 2.2% among 40-49 year old men, 8.1%
among 50-59 year old men, and 7.7% among 60-79
year old men. A history of UTI increased the risk for
prostatitis symptoms (p=0.0270). While 12.6% of
participants with a history of UTI had prostatitis,
only 3.0% of participants without a history of UTI
had prostatitis. Multiple logistic regression analyses
showed that men with a history of UTI had an odds
ratio of 3.80 (95% confidence interval of 1.83, 7.86)
of having symptoms of prostatitis compared to men
without history of UTI.
b) Acute and Chronic Bacterial Prostatitis (NIH
Categories I and II)
Although clinicians accept that bacterial UTI is the
cause of category I and category II prostatitis, there
are limited data on the bacterial species associated
with these syndromes. Cho and associates completed
a retrospective review of 255 inpatients with ABP
from 10 hospitals [29]. The most common bacterial
species identified were Escherichia coli (67%),
Pseudomonas aeruginosa (13%), Klebsiella sp.
(6%), and various Gram-positive species (5%). In
this respect, the species associated with ABP are very
similar to the species associated with acute bacterial
UTI in healthy men without urological abnormalities
[30].
The bacteriology of CBP has been described in care-
fully investigated patients from tertiary care institu-
tions [11-13]. Similar to the experience with acute
prostatitis, these series report that facultative Gram-
negative bacilli (especially E. coli) were responsible
for the great majority of cases. Recently, reports
from clinical series of patients used to support
approval of antibiotics for treatment of chronic bac-
terial prostatitis have reported a preponderance of
Gram-positive cocci [31-32]. In these latter series,
the median duration of patients’ symptoms was 3.5
weeks [32]. One recent report suggests that cultures
suggesting localization of Gram-positive bacteria are
not consistent in >90% patients [33]. Thus, the dis-
tribution of bacteria causing chronic bacterial pro-
statitis is currently the subject of active debate.
c) Chronic Prostatitis/Chronic Pelvic Pain Syn-
drome (NIH Category III)
The major pathogenic theories may be considered in
five general categories: infection, voiding or neuro-
muscular dysfunction, interstitial cystitis, neuropath-
ic pain, and immune dysfunction. Prominent evi-
dence supporting each major theory is summarized
in Table 3.
d) Asymptomatic Inflammatory Prostatitis (NIH
Category IV)
The causes of asymptomatic inflammation in the
prostate and/or seminal fluid are unknown. The
mechanisms outlined in Table 3 represent the major
theories.

Table 3. Proposed Pathogenetic Mechanisms in Prostatitis

Mechanism Prostatitis Author, Year, Evidence

Categories Country [Reference]

Infection I, II Meares (1987), USA [34] Culture of bacteria in VB3, EPS or

Krieger (1989), USA [11]
Weidner et al (1991), Germany [12]
Bundrick et al (2003), USA [31]
Cho et al (2005), Korea [29]
III Krieger et al (1996, 2000, 2002),
USA [35-37]
Nickel et al (1994), Canada [38]
Hochreiter et al (2000), USA [39]
Voiding or III Hruz et al (2003), Switzerland [40]
neuromuscular Kaplan et al (1996), USA [41-42]
dysfunction
semen from patients with
category I and II prostatitis
PCR detection of bacterial DNA in prostatic
biopsy specimens from CP/CPPS patients,
but not from normal men
Bladder outlet obstruction (BOO) associated
with abnormal urodynamic findings

Neuropathic pain III Miller et al (2002), USA [43] Nerve growth factor correlates with pain
severity

Interstitial cystitis III Peeker et al (2002), Sweden [44] Proposed hypotheses include mast
Parsons et al (1987, 2000, 2002), cell activation, defects in the urothelium,
USA [45-47] autoimmunity, toxic agents, and
neuroendocrine-autoimmune interactions

Immune dysfunction III, IV
Alexander et al (1997), USA [48]
Orhan et al (2001), Turkey [49]
Ruggieri et al (2000), USA [50]
Hochreiter et al (2000), USA [51]
Proposed hypotheses include autoimmune
reaction, increased levels of
pro-inflammatory cytokines, decreased
levels of anti-inflammatory cytokines, and T
cell proliferation in response to seminal
antigens

347
3. COMMENTARY AND CONCLUSIONS ON
PATHOGENESIS
In contrast to ABP and CBP, CP/CPPS is defined
based on clinical symptoms in the absence of obvi-
ous urological causes. Asymptomatic inflammatory
prostatitis is diagnosed during evaluation of other
conditions. There is no consensus on the cause of
either CP/CPPS or asymptomatic inflammatory pro-
statitis. Proposed pathogenetic mechanisms include:
infection, voiding or neuromuscular dysfunction,
neuropathic pain, interstitial cystitis, and immune
dysfunction. Better understanding of the causes and
pathophysiology would facilitate development of
better diagnostic strategies and development of spe-
cific markers that might facilitate prevention, better
diagnosis and management strategies.
C. EVALUATION
I. ACUTE BACTERIAL PROSTATITIS
(NIH CATEGORY I)
1. URINE ANALYSIS AND CULTURE
What is the role of urine analysis and culture in the
diagnosis/evaluation of ABP?
• In patients presenting with ABP, urine culture is
considered the only laboratory evaluation of the
lower urinary tract that is required. A midstream
urine specimen will show significant leukocyto-
sis and bacteriuria microscopically, and culturing
usually shows typical uropathogens.
• A comparative, controlled study evaluated the
utility of urinary alpha 1-microglobulin, alpha 2-
macroglobulin and albumin in the diagnosis of
acute prostatitis in 133 men, and a reference pop-
ulation of 36 without urinary tract infection [52].
The combination of hematuria and absence of
urinary alpha 2-macroglobulin is diagnostic for
acute prostatitis.
Evidence summary: urinalysis and culture are
essential for the diagnosis of ABP. There is evi-
dence that urinary alpha 2-macroglobulin is diag-
nostic for acute prostatitis. Other urine markers
may be of benefit but this is currently unknown.
348
2. IMAGING
What is the role of radiolabel scintigraphy in the
diagnosis/evaluation of ABP?
• In a small prospective study, 10 male patients
with prostatitis were compared with 6 males with
UTI but without prostatitis to determine whether
111indium labelled leukocytes (ILLs) accumulat-
ed in the infected tissue and if uptake responded
to treatment [53]. Urinary and blood cultures
were also carried out. Scintigraphs prior to antibi-
otic treatment showed uptake in prostates of all
patients with ABP; after treatment, no uptake was
noted in 9 out of 10 and 1 out of 10 had marked-
ly decreased uptake. No uptake occurred in
prostates of patients with UTI. ILLs could be use-
ful in detecting ABP, especially in clinically
ambiguous patients with urological infections.
What is the role of transrectal ultrasound (TRUS) in
the diagnosis/evaluation of ABP?
• In a prospective study of 45 patients with a clini-
cal diagnosis of ABP, TRUS was performed upon
admission and one month after antibiotic therapy
and findings correlated with clinical presentation
and evolution of disease [54]. The authors con-
clude that TRUS does not need to be performed
on every patient with suspected ABP (as only
47% had sonographically demonstrable lesions
on admission and 61% had lesions improved or
disappeared post treatment) but TRUS would be
indicated in ABP to exclude the presence of pro-
static abscess.
3. SERUM PSA
What is the role serum PSA in the differential diag-
nosis/evaluation of ABP?
• In a prospective study of 39 men with pyrexia
(>38.3 degrees C), serum PSA levels were used
to categorize patients according to an initial diag-
nosis of ABP, pyelonephritis, urogenital infection
or fever of unknown origin [55]. All of the 20
cases with pyrexia and elevated PSA were diag-
nosed and treated as ABP; treatment with antibi-
otics resulted in significantly reduced serum
PSA, fever and normalization of C-reactive pro-
tein. The authors recommend PSA as a concise,
accurate, rapid and cost-effective tool for identi-
fying ABP.
Evidence summary: no RCTs or systematic
reviews found. Application of methods such as
scintigraphy, TRUS and serum PSA may further
assist in the diagnosis of ABP in addition to the

physical examination and urine culture for patients
with ambiguous pyrexia. Based on the small num-
bers of subjects in the abovementioned studies
there is insufficient evidence to recommend their
use as a single method for final diagnosis.
II. CHRONIC BACTERIAL
PROSTATITIS (NIH CATEGORY II)
1. 4-GLASS TEST AND 2-GLASS PRE- AND
POST-MASSAGE TEST (PPMT)
What is the role of the 4-glass and 2-glass test and
cultures in the diagnosis/evaluation of CBP?
• In an analysis using the 4-glass test in 50 men
with symptomatic prostatitis, anaerobic bacteria
were cultivated in high numbers in 18 patients
[56]. The authors postulate an association
between symptoms and the evidence of these
bacteria after antiaerobic therapy.
• In a prospective evaluation of 164 patients with
prostatic symptoms, men were categorized by the
NIH classification system using segmented urine
analysis and culture. The evaluation revealed
38% (64 patients) with category II prostatitis, 7%
(12) with category IIIA and 55% (92) with cate-
gory IIIB [57]. Leukocytes in EPS were detected
in only 36% (24) of patients with positive bacte-
rial and chlamydial cultures. The authors con-
clude that differential diagnosis and therapy
based on the results of the 4-glass test and cul-
tures seems to be difficult.
• Using standard techniques including the 4-glass
test, the Giessen cohort study demonstrated the
evidence of proven CBP in 4.2% of 168 men
[58]. This figure is lower than the 7% of 656
patients in the first study 10 years. E. coli was the
predominant strain.
• Nickel et al conducted a study to evaluate a sim-
pler screening test to assess inflammation, the 2-
glass pre- and post-massage test (PPMT), and
compare it with the 4-glass test for the initial
evaluation of men with a clinical diagnosis of
CP/CPPS [59]. A total of 353 men enrolled in the
NIH Chronic Prostatitis Cohort (CPC) study with
complete values for baseline leukocytes counts
and two-day bacterial cultures on the 4-glass
specimens were evaluated. A receiver operating
349
characteristics (ROC) curve was constructed to
determine the optimal cut point of WBCs in VB3
predicting WBCs in EPS. The PPMT has a strong
concordance with the 4-glass test and is a reason-
able alternative when EPS is not obtained.
Evidence summary: the 4-glass test is the criteri-
on standard for the diagnosis of CBP. The PPMT is
a simple and reasonably accurate screen for bacte-
ria.
2. SEMEN CULTURES
What is the role of semen cultures in the diagno-
sis/evaluation of CBP?
• A comprehensive survey describes the study
results in 40 men with CBP (NIH category II) due
to E. coli infection and who were treated with a
fluoroquinolone [13]. In these patients, semen
cultures demonstrated significant bacteriosper-
mia (>103/ml) in 21 of 40 men prior to treatment.
Evidence summary: no RCTs or systematic
reviews were found. Based on limited evidence,
semen cultures were shown to identify significant
bacteriospermia in only about 50% of semen spec-
imens from men with CBP.
3. TRANSRECTAL PROSTATIC
ULTRASONOGRAPHY
What is the role of transrectal prostate ultrasonogra-
phy (TRUS) in the diagnosis/evaluation of CBP?
• In a prospective study, 164 patients with pro-
statitic symptoms were evaluated with a variety
of diagnostic methods including TRUS, segment-
ed urinalysis and urine cultures, EPS evaluation,
and urodynamics [57]. Patients were classified as
having category II (CBP) or category IIIA or IIIB
prostatitis. TRUS and urodynamic findings were
similar in the three groups indicating that differ-
ential diagnosis and therapy would be difficult
relying on TRUS.
• Imaging may be beneficial in highly selected
treatment refractory patients.
Evidence summary: no RCTs or systematic
reviews were found. Based on limited evidence,
TRUS and urodynamics cannot be relied upon for
differential diagnosis of categories of prostatitis.
 III. CHRONIC
PROSTATITIS/CHRONIC PELVIC
PAIN SYNDROME
(NIH CATEGORY IIIA, IIIB)
1. SYMPTOM SCORING, QUESTIONNAIRES AND
PSYCHOLOGICAL FACTORS
a) Symptom Scoring and Questionnaires
What is the role of the NIH-CPSI in the diagnosis/
characterization of CP/CPPS or evaluation after
treatment?
• One systematic review discusses prostate-related
pain in patients with CP/CPPS; it includes a dis-
cussion of psychological and psychosomatic fac-
tors [60]. The consensus is that for evaluation of
pain, the validated versions of the NIH-CPSI are
recommended for clinical use world-wide.
• A large series of studies were reviewed including
double-blind RCTs [61-64], RCTs without verifi-
cation of double-blind [65-69], and an open-label
study [70] using a variety of therapeutic agents to
treat CP/CPPS. The NIH-CPSI was the evalua-
tion measure to indicate or negate clinical effica-
cy. With the exception of two studies, most were
small trials involving a total of 30 to 100
patients/controls. Studies are representative of
the use of the index for drug trials; only studies
reported in English were reviewed.
• A group of studies involved validation of the
NIH-CPSI including validation of psychometric
properties and translation and linguistic valida-
tion [3-4; 7-9; 71-72].
• Three studies focused on a questionable symp-
tomatic difference between type IIIA and IIIB pro-
statitis patients. Krieger et al [73] demonstrated an
increased severity and frequency of symptoms in
men with inflammatory CP/CPPS and in two stud-
ies Schneider et al [71; 7] demonstrated that NIH
category IIIB patients are significantly more
symptomatic than category IIIA patients.
• The interaction between CP/CPPS symptoms and
urgency/frequency questionnaires (PUF) has
been investigated prospectively in 50 patients and
correlated with potassium-sensitivity testing [74].
A high rate of PUF scores indicates a question-
able overlap of CP/CPPS and interstitial cystitis
(aka painful bladder syndrome) symptoms in
men.
350
• A study evaluating the agreement between self-
reported physician-diagnosed prostatitis and pain
questions from the NIH-CPSI using a randomly
selected cohort of men and review of medical
records [10] concludes that “while the CPSI is an
important evaluative tool for chronic prostatitis, it
may not perform well as a diagnostic tool for
chronic prostatitis/CPPS. As an evaluative tool,
the CPSI provides insight into the severity of
symptoms relevant to chronic prostatitis. Howev-
er, its role as a diagnostic tool is debatable
because not all of the questions/scores in the
CPSI adequately distinguish between chronic
prostatitis and other urological conditions.”
• One study involving 174 patients assessed the
responsiveness of the NIH-CPSI to changes over
time and attempted to define thresholds for
changes perceptible to patients [75]. A six-point
decline in NIH-CPSI total score identified an
optimal threshold to predict response. Index total
and subscale scores were shown to be responsive
over time and should be used as a primary end-
point in clinical trials for CP/CPPS.
• A prospective study of symptom follow-up for
two years in men with CP/CPPS enrolled in the
CPC [76] was completed. The NIH-CPSI total
scores of 293 men with complete data showed
substantial variations in symptoms. The study
provides useful clinical information on the longi-
tudinal course of disease, but also incidentally
indicates the merits of the NIH-CPSI in the eval-
uation process.
1. SEXUAL AND EJACULATORY DISORDERS: SYMPTOM
SCORING WITH THE NIH-CPSI OR OTHER INDEX
• Recent data demonstrate a strong association
between LUTS and pain/discomfort on ejacula-
tion [77]. The symptom seems to be related to
LUTS severity and age.
• Evaluations were conducted in 486 men from the
NIH CPC Study to assess the impact of post-ejac-
ulatory pain in men with CP/CPPS [78]. There
was some evidence that patients with CP/CPPS
who have persistent ejaculatory pain have more
severe symptoms.
Evidence summary1: the NIH-CPSI has become
the established international standard for symptom
evaluation (not for diagnosis) of prostatitis. The
index has been shown to be reliable with validated
versions in English [3], Spanish [4], Korean [9],
German [7], Finnish [8], Japanese [5], Chinese [6]
1 Other symptom scoring questionnaires (i.e., University of Wash-
ington Symptom Score, GPPS, IPPS, ICPPS, PSSI, Stanford
Pelvic Pain Symptom Score, and AUA Symptom Scale) that have
preceded the NIH-CPSI have not been included in this evaluation.

and Malay [6]. Results from numerous represen-
tative studies indicate that the NIH-CPSI total
score, but not the subscales, show high internal
consistency and can evaluate the severity of cur-
rent symptoms and be used as an outcome measure
to evaluate the longitudinal course of symptoms
with time or treatment.
b) Psychological Assessments
What is the role of psychological factors/psychoso-
matic aspects in the evaluation of CP/CPPS?
• Two reviews of the psychological/psychosomatic
factors associated with CPPS have been pub-
lished.
• The first review (published in German) [79]
states that psychosomatic factors are often
neglected in evaluation of CP/CPPS in urologic
practice. Diagnostic and therapeutic strategies
should address the involvement of somatic and
psychogenic factors in the pathogenesis of the
syndrome. Personality variables such as somati-
zation, depression, anxiety, hypochondriasis and
weak masculine identity play an important role in
questionnaire-based studies.
• The second article [60] reviews the hypotheses
and data on the psychosomatic causes of pelvic
pain in patients with CP/CPPS. The authors
underline the current opinion that intraprostatic
reflux is the major trigger mechanism for pelvic
pain. Psychosomatic factors, psychological
stress, hysteric neuroses, hypochondriac reac-
tions and depressive reactions were also judged
to be significant causes. In the experience of the
authors, the data must be evaluated predominant-
ly by semi-structured interviews, questionnaires
and scales, which while considered to be helpful
are not indicative and useful in this field. Con-
cerning sexual dysfunction, premature ejacula-
tion, decrease of libido and erectile dysfunction
(ED) are considered to be relevant in CP/CPPS
patients. The Giessen data provide some evidence
that in CP/CPPS patients 42% complain of ED
and 26% of premature ejaculation. Furthermore,
such conditions lead to reduced frequency of sex-
ual contact. For evaluation, the International
Index of Erectile Function (IIEF) is accepted to
be the gold standard. Unfortunately, standardized
questionnaires for libido disturbances and also
for premature ejaculation are not available. For
evaluation of pain, consensus is that the validated
versions of the NIH-CPSI are recommended for
clinical use worldwide.
351
• The association of impaired quality of life (QOL)
with CP/CPPS was evaluated in two separate
uncontrolled studies using men from the NIH-
CPC study.
In 278 men with CP/CPPS, the health-related
QOL (HRQOL) instruments revealed lower Men-
tal Component Summary scores than among
patients with severe congestive heart failure and
diabetes and lower Physical Component Summa-
ry scores than the general US male population
[80].
In the second report of 463 men with CP/CPPS,
depressive symptoms and pain intensity signifi-
cantly predicted poor QOL [81]. Therefore the
authors concluded that CP/CPPS is associated
with negative psychological factors and reduced
QOL; administration of HRQOL instruments
may assist in understanding the impact of disease
on patients’ lives. Pain intensity was the most
robust predictor of poorer QOL.
• The finding of psychological stress being com-
mon in men with prostatitis and symptoms
increasing the likelihood of impaired QOL is sup-
ported by a Korean study on 1,057 men [82] and
in a population-based cross-sectional survey of
Finnish men [83].
• In a controlled study, 51 men with CP and a con-
trol group of 34 men without any chronic pain
condition were evaluated for psychological fac-
tors [84]. The scores of CP patients were consis-
tently more elevated than those of controls on
hypochondria, depression and hysteria (MMPI)
and on somatization and depression (BSI) scales.
Evidence summary: two systematic reviews were
found. Evidence from a series of studies in CP
patients, some with control comparisons, indicate
that depression and psychosocial distress are com-
mon among CP patients, calling for careful evalu-
ation and attention to psychological symptoms in
fully understanding and caring for these patients.
2. PHYSICAL EXAMINATIONS (DRE, MYOFAS-
CIAL TRIGGER POINTS, ABDOMINAL EXAM)
a) Myofascial Trigger Points and Musculoskeletal
Dysfunction
What is the role/value of evaluating myofascial trig-
ger points or possible musculoskeletal dysfunction in
patients with CP/CPPS?
• A retrospective uncontrolled study of at least 12
months’ duration of 103 men with pelvic pain
involved urodynamics [85]. Pathological tender-
ness of the striated pelvic muscle was observed in
91 men (88.3%). This myofascial tenderness was
virtually always associated with the inability to
relax the pelvic floor efficiently with a single or
repetitive effort. In 84 men (81.6%), urodynamic
evaluation revealed principal findings of hyper-
sensitivity during the attempted voiding period.
DRE revealed tenderness in the external urethral
sphincter region, a hypertonic sphincter and
detrusor-sphincter dyssynergia.
• A controlled study of 62 men with CPPS IIIA and
IIIB and 89 healthy controls showed that patients
with CPPS had significantly greater pain and ten-
sion with palpation by DRE of the psoas muscle
and groin [86]. The abnormal pelvic musculature
in men with CPPS may contribute to the pain syn-
drome.
• In an uncontrolled study, 19 men with CPPS who
were refractory to other treatments were enrolled
in a 12-week biofeedback pelvic floor re-educa-
tion and bladder training program [87]. A signifi-
cant improvement was found in all outcome mea-
sures.
• In an uncontrolled study 138 men with refractory
CPPS were treated with myofascial trigger point
release in conjunction with cognitive behavior
therapy [88]. More than half of the patients had
improvements in pain and urinary scores.
Evidence summary: no systematic reviews or
RCTs were found. Primarily, the studies reviewed
were uncontrolled, retrospective or treatment out-
comes which may implicate a role for tension
myalgia in pelvic pain. Currently the benefits of
identifying or treating myofascial trigger points or
musculoskeletal dysfunction are not known.
b) Digital Rectal Examination and Abdominal
Examination
Evidence summary: no systematic reviews, RCTs
or clinical trials were found to contribute to the
evaluation of these procedures.
3. URINE AND EXPRESSED PROSTATIC SECRE-
TION (EPS) FOR EVALUATIONS
What is the role/value of urine and EPS in the eval-
uation of men with CP/CPPS?
352
• An uncontrolled, retrospective reevaluation of a
case series of 53 patients and literature review of
59 patients with prostatitis sought to determine
the value of the PPMT for diagnosis of prostatitis
[89]. The calculated sensitivity and specificity for
the PPMT were both 91.1% (102/112 patients);
results were similar to those of the 4-glass test,
indicating that the PPMT alone would have led to
the same bacteriological diagnosis. This test was
considered a simple diagnostic tool superior to
doing no workup at all.
• A prospective study of 328 patients without ure-
thritis involved microscopic analysis of urine
after prostatic massage (VB3) with EPS to assess
the significance of leukocyte analysis in VB3 and
to give a first hint of the diagnosis of inflamma-
tory CPPS when EPS cannot be obtained [90].
The presence of elevated leukocytes in VB3 pre-
dicted the presence of increased leukocytes in
EPS with a high certainty: 91.9% sensitivity,
98.9% specificity.
• An uncontrolled, comparative study of 164
patients with chronic male pelvic pain syndrome
(including 64 with CBP, 12 with inflammatory
CPPS, and 92 with non-inflammatory CPPS)
evaluated segmented urinalysis and culture, and
TRUS uroflowmetry and residual urine [57].
Leukocytes in EPS were detected in 24 (36%)
patients with positive bacterial cultures; TRUS
and urodynamics and complaints were similar in
all groups. Thus differential diagnosis based on
the 4-glass test, cultures and TRUS remains diffi-
cult.
• One prospective study compared diagnostic out-
comes based on fluid samples to evaluate inflam-
mation in symptomatic patients (without urethri-
tis, acute or chronic bacterial prostatitis) using
EPS, VB3 and seminal fluid analysis (SFA) [91].
With EPS alone, 39 of 140 (28%) patients had
inflammatory CP/CPPS; however, with NIH con-
sensus criteria (EPS, VB3, SFA) almost twice as
many, 52%, had inflammatory disease. In a later
study [73] involving 130 men with CP/CPPS
(perhaps the same cohort reported above), those
with inflammatory diseases had significantly
greater severity and frequency of symptoms
when evaluated using the NIH consensus criteria.
• A prospective examination of leukocytes and
bacteria in EPS, VB3 or semen and correlation
with symptom severity in men with CP/CPPS
participating in the NIH-CPCRN study [92] eval-
uated samples from 397 patients. Leukocytes and
 bacterial counts as we define them do not corre-
late with severity of symptoms.
• A comparison of methods of evaluating WBCs in
EPS involved 92 CPPS patient samples [93] and
quantitatively determined WBC concentration by
hemacytometer and staining. This proved superi-
or to the standardized wet mount procedure or
gram stain smear, an important consideration for
research studies. This result is also supported by
an earlier study [94].
Note: The traditional cover slip count of WBCs is
easier and more accessible to clinicians in practice
and has been used to set historical standards for the
definition of traditional prostatitis. However, the
counting chamber technique is more accurate but
time-consuming.
• One review compared the traditional classifica-
tion of prostatitis based on evaluation of EPS
alone with the new NIH consensus classification
that also considers VB3 and SFA findings [95].
For the NIH classification, inflammatory
CP/CPPS was diagnosed for subjects with
inflammation in their EPS, VB3, or SFA. Sub-
jects without inflammation in any of these three
samples were classified in the non-inflammatory
group. Thus an optimal diagnostic strategy
requires evaluation of VB3 and SFA in addition
to the traditional EPS examination. Such preci-
sion is necessary for research studies, but whether
such precision is important clinically remains
unproved.
• A prospective evaluation of 143 patients with
prostatitis was conducted to analyze whether the
simple PPMT urine culture compares with the
results of the 4-glass test [96]. Results were sim-
ilar, confirming Nickel’s 1997 report [89], and
the authors recommend replacing the 4-glass test
with the PPMT.
• A case controlled study compared LUTS evalua-
tion in 463 men enrolled in the NIH CPC study
with that of 121 age-matched men without uri-
nary symptoms. Leukocyte counts were per-
formed and five-day bacterial cultures on speci-
mens obtained from a standard 4-glass test (VB1,
VB2, EPS, VB3) and semen [97]. Men with
CP/CPPS had statistically higher leukocyte
counts in all segmented urine samples and EPS,
but not in semen compared to asymptomatic con-
trol men. However, the control population also
had a high prevalence of leukocytes. The high
353
prevalence of WBCs and positive bacterial cul-
tures in the asymptomatic control population rais-
es questions about the clinical usefulness of the
standard 4-glass test as a diagnostic tool for
CP/CPPS.
• One study evaluated a simple screening test to
assess inflammation, the 2-glass PPMT, and com-
pared it with the Meares-Stamey 4-glass for the
initial evaluation of men with a clinical diagnosis
of CP/CPPS [59]. A total of 353 men enrolled in
the NIH CPC study had the 4-glass test for base-
line leukocytes counts and two-day bacterial cul-
tures. A ROC curve was constructed to determine
the optimal cut point of WBCs in VB3 predicting
WBCs in EPS. The PPMT has a strong concor-
dance with the 4-glass test and is a reasonable
alternative when EPS is not obtained.
• A controlled study evaluated the inflammatory
marker prostaglandin E2 (PGE2) and beta-endor-
phin (natural opioid produced by immune cells at
site of injury, which may modulate pain) in the
EPS of 70 patients with CP and 8 asymptomatic
controls [98]. In symptomatic patients the levels
of both substances were similar in categories IIIA
and IIIB, and higher than in controls. After treat-
ment with antibiotics or antioxidant phytotherapy
the levels of beta-endorphin increased while
PGE2 decreased; thus pain in prostatitis may be
due to increased prostaglandin production, which
may then inhibit local beta-endorphin production.
• A prospective study evaluated peroxidase-posi-
tive leukocytes (PPL) and PMN-elastase in EPS
and VB3 of 112 consecutive CP/CPPS symp-
tomatic patients to contribute to differential diag-
nosis between inflammatory category IIIA and
non-inflammatory category IIIB [99]. Leuko-
cytes increased in 64 men and did not in 48. PPL
and elastase were significantly elevated in the
EPS of men with category IIIA CP and cut points
were suggested to indicate diagnosis of inflam-
matory disease.
• A controlled, comparative study evaluated urine
markers (antiproliferative factor APF, HB-EGF,
EGF) in 41 symptomatic CP/CPPS men, 36
asymptomatic men without bladder disease, and
24 men with IC [100]. APF activity and
decreased HB-EGF levels were found in the urine
specimens of men with IC vs. CP or controls, but
none of the three markers differed between con-
trols and CP/CPPS. Perhaps these markers could
be used to distinguish IC from CP/CPPS.
a) Role of C. trachomatis and ureaplasma
• There is one systematic review analyzing the role
of C. trachomatis findings in EPS and VB3 in
men with CP/CPPS [101]. The major problem,
i.e. that diagnostic material passing through the
urethra may reflect only urethral contamination,
is not resolved.
• A total of 137 symptomatic men with CP/CPPS
were evaluated by the 4-glass test, including EPS
and VB3 analysis [58]. 31.5% of patients were
categorized as having NIH category IIIA and
50% as having NIH category IIIB CP/CPPS. CBP
(NIH category II) was excluded in all cases.
Occurrence of bacteria in EPS/VB3 did not
reflect the typical pattern of CBP. In 24 men U.
urealyticum and in one man C. trachomatis was
detected in different specimens of the 4-glass test
using PCR techniques.
• In 165 symptomatic men with CP/CPPS the 4-
glass test was extended for a search for
C. trachomatis and U. urealyticum using PCR-
testing of semen. Chlamydial infections were
established in 12 cases and ureaplasmal infec-
tions in 13 cases. There was no correlation
between these findings and the NIH prostatitis
category of the patient [102].
Evidence summary: no RCTs were found.
• The case studies, including one age-matched con-
trolled study, suggest that the 4-glass test, i.e.
microscopic evaluation and culture of EPS and/or
VB3 (post-massage urine specimen), can be
accurate and an indirect indicator for diagnosis of
prostate specific inflammation and infection. The
PPMT (2-glass) test is a simple and reasonably
accurate screen.
• The detection of U. urealyticum and/or C. tra-
chomatis in 4-glass test specimens does not
reflect the identification of causative microorgan-
isms.
b) Autoimmune Markers in Genital Fluids
What is the role of autoimmune markers in evalua-
tion of CP/CPPS?
• A small controlled study evaluated CD4 T-cell
proliferative response to seminal plasma in 10
men with CPPS compared to 15 normal controls
[48]. T-cell reactivity occurred in 3 out of the 10
CPPS patients but none of the controls, suggest-
ing an autoimmune component to the disease.
354
• A controlled study of 14 patients with CPPS and
12 normal volunteers examined recall prolifera-
tive response of T-cells using purified seminal
plasma antigens and autologous dendritic cells to
determine if these secretory proteins could be
candidate antigens for autoimmune prostatitis
[103]. A proliferative response observed in 5 out
of 14 patients with CPPS suggests that PSA is a
candidate antigen.
• A study of 20 patients with CPPS and 20 age-
matched controls evaluated T-cell proliferation
response to autologous seminal plasma (SP) and
seminal plasma from other individuals [104].
CPPS patients had a statistically greater response
to autologous and allogenous SP, thus supporting
an autoimmune hypothesis for the disease.
• A prospective controlled study examined
immunophenotypic patterns in fractionated urine,
EPS and ejaculate of 88 patients with category
IIIB CPPS and 100 normal controls [105]. Inter-
leukin, complement and immunoglobulin deter-
minations in serum and ejaculate revealed an
inflammatory process in the apparently non-
inflammatory (category IIIB) CPPS. Findings of
intra-acinar T-rich infiltrates and associated
inflammatory reaction may be an advance in
defining the disease as caused by an autoimmune
component.
• A prospective controlled study of immunopheno-
typic patterns (IgG, IgA, IgM, IL-1-alpha,
sIL02R, IL-6) in ejaculate of 35 patients with cat-
egory IIIB CPPS and 96 normal controls, and of
immunohistochemical detection of T and B lym-
phocytes in prostate biopsies of 71 patients and
25 controls [106], found intra-acinar T-rich infil-
trates and associated inflammatory reaction
which may indicate a possible autoimmune com-
ponent to the disease.
• An uncontrolled, prospective study of 110 men
with CP/CPPS category IIIA demonstrated an
increase of macrophages (7.6-fold), T-lympho-
cytes (7.6-fold) and B-lymphocytes (four-fold) in
VB3 after prostatic massage compared to VB2
[107].
Evidence summary: no systematic reviews or
RCTs were found. Three small but controlled stud-
ies provide support for an autoimmune hypothesis
of CP/CPPS but at present, the role of this type of
characterization is unknown in the evaluation of the
disease.
c) Cytokines as Biochemical Markers of Inflamma-
tion in CP/CPPS
What is the role of pro-inflammatory and anti-
inflammatory cytokines in evaluation of CP/CPPS?
• A controlled study evaluated the levels of nerve
growth factor (NGF) and IL-6 compared to IL-8,
IFN-gamma, IL-2 and IL-10 in the seminal plas-
ma, as well as correlating results with QOL, in 31
patients with CPPS and 14 controls [43]. NGF
correlated directly with pain severity (p <0.01)
and IL-10 levels (p <0.04), and IL-6 correlated
inversely with pain severity (p <0.03). These
results suggest that NGF and cytokines that regu-
late inflammation (IL-6 and IL-10) may play a
role in the pain symptoms experienced by
patients with CPPS.
• A controlled study evaluated the levels of IL-8,
IFN-gamma, and IL-2 vs. IL-10 in the seminal
plasma, as well as correlating results with QOL,
in 31 patients with CPPS and 14 controls [108].
IFN-gamma, IL-2 and IL-10 levels were signifi-
cantly greater in patients with CPPS; IL-10 levels
correlated directly with measures of life interfer-
ence and pain severity.
• A controlled study quantified IL-10 and IL-8 lev-
els in VB3 in 29 randomly selected patients with
different types of CP and 11 controls [109]. Lev-
els of IL-10 were significantly higher in 8
patients with clinical symptoms than in the 11
controls or 21 patients with asymptomatic pro-
statitis; IL-8 was higher in 8 symptomatic and 13
asymptomatic patients than in 7 controls. IL-10
and IL-8 can be detected in VB3 and routine
semen and EPS and are important in the etiology
of CP.
• An early small controlled study from Japan
detected significantly higher levels of TNF-alpha
and IL-6 in 6 out of 10 cases of nonbacterial pro-
statitis (NBP) vs. 11 normal controls; IL-1 beta
was detected in only 2 out of 10 cases [110]. The
authors conclude that cytokines are useful indica-
tors of NBP.
• In two controlled studies of CP/CPPS, levels of
TNF-alpha and TNF-alpha in conjunction IL-
1beta were elevated in seminal plasma (18 CPPS
patients vs. 8 controls [111]; 20 CPPS patients vs.
10 controls [49]). Other pro-inflammatory
cytokines, IL-6 and -8, were also significantly
elevated vs. controls [49].
• A controlled study of a total 78 men including
355
CPPS patients (category IIIA, IIIB, IV, and BPH
vs. controls) evaluated proinflammatory
cytokines TNF-alpha and IL-1 beta in EPS [112].
Increased concentrations of both cytokines were
reported in category IIIA as opposed to category
IIIB cases vs. controls. EPS of those with catego-
ry IV, or asymptomatic inflammation, also had
increased concentrations.
• In a controlled study from China, TNF-alpha and
IL-1 beta levels in EPS were significantly higher
in patients with CP with WBC ≥10/HPF and
asymptomatic prostatitis (34 patients) vs. those
with CP <WBC 10/HPF, 12 with BPH or 8
healthy controls [113]. Therefore, these markers
could be used to identify men with CP with high
WBC and asymptomatic inflammatory prostati-
tis.
• In a controlled study from China, TNF-alpha and
IL-8 levels in EPS were higher in men with CBP
or CPPS category IIIA but lower in CPPS cate-
gory IIIB and controls [114]. The cut-points of
cytokine levels to discriminate CBP or CPPS IIIA
from IIIB or controls need further investigation.
In controlled studies the following were reported:
• IL-2 (secreted by T-lymphocytes stimulated by
antigen activated antigen presenting cells, result-
ing in T-cell clonal proliferation) was not
detectable in seminal plasma of patients with
CP/CPPS [49], whereas
• IL-6 (involved in T-cell activation, growth and
differentiation) is significantly increased in semi-
nal plasma of category IIIA and IIIB cases com-
pared to controls [49].
• According to some studies, IL-8 (recruits and
activates lymphocytes) had significantly higher
concentrations in seminal plasma [49] and EPS
[51] of CP/CPPS patients compared to controls,
whereas no differences were found in another
study [108].
• A controlled clinical study of 207 men with CP
vs. 62 controls reported significantly higher lev-
els of IL-6 and IL-8 in seminal plasma of 177 out
of 207 (85.5%) CP cases vs. controls [115].
Leukocyte counts had positive results in only 85
out of 177 (48%) of cases. Two cytokines may
prove to be markers to identify CP.
Cytokine polymorphisms, differences in DNA
sequences, are reported in the literature. However,
this is an area of research and exploration that has
unknown clinical utility.
d) Association of cytokine concentration with
cp/cpps symptoms and/or changes with clinical
response to treatment
• In a clinical trial of men with CPPS category
IIIB, serum and ejaculate IL-6 levels significant-
ly increased and then dropped again correlating
with clinical symptoms [105]. IL-6 levels corre-
lated inversely with pain severity [43] and IL-10
levels correlated directly with measures of life
interference and pain severity [43].
• In a controlled comparable study IL-8 and ENA-
78 were elevated in the EPS of men with bacteri-
al prostatitis, CPPS category IIIB and category
IV; however, there were no appreciable differ-
ences to differentiate the categories from one
another [39].
• In an uncontrolled study from Russia, TNF-alpha
and IL-1-beta levels were elevated in blood
serum, urine, ejaculate and EPS of 30 patients
with CP before and after 3 to 6 months of treat-
ment with Prostamol-uno [116]. IPSS scores and
QOL were assessed. The elevated cytokines
returned to “normal value” at 6 months, and this
was associated with a 36% decrease in IPSS score
and 42% improved QOL.
Evidence summary: one systematic review [117]
summarized the status of cytokines as well as other
mechanisms in CP/CPPS. No RCTs were found.
Based on the several controlled clinical studies
available for review it appears that cytokines are
currently the subject of extensive research to deter-
mine the occurrence and levels associated with cat-
egories of CP/CPPS but are not useful for diagnosis
or evaluation. The various cytokines are associated
with inflammation although they cannot be used to
distinguish between symptomatic and asymptomat-
ic cases; levels in genital fluids may vary with
patient symptoms although there is some question
whether they are associated with pelvic pain.
Although cytokines and other inflammatory media-
tors are frequently elevated in men with inflamma-
tory CP/CPPS, they are also elevated in men with
asymptomatic prostatitis. Cytokines are likely to be
of benefit in evaluation but the specific role of each,
or the balance between pro-inflammatory and anti-
inflammatory cytokines, is currently unknown.
4. EJACULATE AND SEMINAL PLASMA
What is the value of examining the ejaculate and
seminal plasma in evaluation of CP/CPPS?
356
• There is one review on the relevance of male
accessory gland infection for male infertility and
prostatitis [118].
a) Ejaculate Findings
• We found predominantly systematic investiga-
tions of the Giessen group that compared the
inflammatory and infectious status of 168 men
with prostatitis syndrome with the results from
their previous cohort study in 1992. Ejaculate
analysis followed the WHO criteria [58]. Com-
pared with the study 10 years earlier, the propor-
tion of different subtypes of the syndrome
remained stable. Using WHO cut-points for
leukocytospermia, the inclusion of seminal
leukocytes in the diagnostic process did not influ-
ence the distribution of NIH category IIIA and
IIIB CPPS.
b) Ejaculate Quality
• Secretory parameters of the prostate, seminal
vesicles and epididymis in the ejaculate have
been analyzed prospectively in 112 men with
CP/CPPS [119]. Significant differences, usable
for clinical diagnosis, in the levels of the marker
enzymes have not been detected in inflammatory
or non-inflammatory CP/CPPS patients.
• A prospective investigation of 112 men with
CP/CPPS did not demonstrate a negative impact
on total sperm count, sperm density, motility,
morphology or sperm vitality. Leukocytospermia
was not associated with reduced standard semen
parameters in either EPS or semen [120].
• In one comparative study of 30 patients with
CP/CPPS category IIIB and age-matched con-
trols, ejaculate volume, sperm density, motility
and morphology and fructose content were eval-
uated. Patients with CP/CPPS category IIIB
demonstrated a significant reduction of motility
and fructose content in seminal plasma [121].
c) Ejaculate Volume
• One systematic review evaluated obstructions of
the male reproductive tract caused by accessory
gland infections including prostatitis [122]. In 10
of 78 men with infertility, accessory gland infec-
tion was revealed by medical history (12.8%). In
only two men did transurethral resection of the
ductus ejaculatorii (TURED) become necessary
following TRUS and cystoscopy, demonstrating
the male accessory gland infection as a cause of
obstruction of the seminal pathways in prostatitis.
d) Sperm Morphology
• In a controlled study, semen analysis for strict cri-
teria on sperm morphology was performed on 34
males with inflammatory CP/CPPS, 18 males
with non-inflammatory CP/CPPS and 17 con-
trols. A significantly lower percentage of mor-
phologically normal spermatozoa were found in
the NIH category IIIA group as compared to NIH
category IIIB and controls [123].
Evidence summary: accessory glands, especially
the prostate, contribute 70% to the volume of sem-
inal fluid, while less than 5% derives from the tes-
ticles. The available data suggest that inflammation
associated with CPPS does not significantly alter
parameters of sperm quality relevant for male fer-
tility as compared to non-inflammatory CP/CPPS
patients and fertile controls.
e) Ejaculate and Leukocytes
What is the role of evaluating leukocytes in semen
compared to evaluations in EPS in CP/CPPS
patients?
• We found no systematic reviews.
• In a study of 140 subjects, 73 men (52%) were
classified having inflammatory and 67 (48%)
non-inflammatory CP/CPPS following the con-
ventional classification techniques (EPS, VB3,
ejaculate). Adding the analysis of any leukocytes
in seminal fluid, the combination of EPS and
seminal fluid analysis detected 69 of 73 cases
(95%) [124].
• In one study, 112 men with CP/CPPS were cate-
gorized into inflammatory and non-inflammatory
CP/CPPS according to leukocyte analysis in EPS
and urine after prostatic massage [99]. Analyzing
ejaculate for PPL and PMN-elastase in men with
CP/CPPS category IIIA found that PPL and elas-
tase in the seminal fluid were significantly
increased. Cut points for both parameters have
been suggested using ROC curves.
Evidence summary: analysis of leukocytes in
seminal fluid improves the classification of
CP/CPPS patients in categories IIIA and IIIB.
Semen analysis increases the proportion of
patients with category IIIA prostatitis. The count-
ing chamber is more accurate than the cover-slip
technique for enumeration of WBCs in EPS and
semen.
357
5. CYSTOSCOPY
What is the role of cystoscopy in the diagnosis/eval-
uation of CP/CPPS?
• In a prospective study in 48 men with CPPS cat-
egory IIIB, cystoscopy revealed bladder neck
hypertrophy in 29 men (60%) [40]. This finding
was associated with an increased detrusor pres-
sure (pdet) at maximum urinary flow rate
(Qmax), decreased Qmax and increased residual
urine when compared to 19 men with an appar-
ently normal bladder neck. The authors suggest
routine cystoscopy in men with non-inflammato-
ry CPPS and decreased flow rates and residual
urine volume who fail to respond to drug treat-
ment.
Evidence summary: no systematic reviews or
RCTs were found. In the European literature
[125], bladder neck obstruction historically has
been associated with prostatitis symptoms, but it is
not known why bladder neck hypertrophy should
cause these symptoms. Endoscopy cannot be sug-
gested as a routine procedure in CP/CPPS.
6. IMAGING METHODS OF EVALUATION
a) Transrectal Ultrasound (TRUS)
What is the role of transrectal ultrasound of the
prostate in the diagnosis/characterization of
CP/CPPS or evaluation after treatment?
• We found no systematic reviews or RCTs specif-
ic to CP/CPPS. Relevant to this evaluation are
two reviews [126-127] dealing with TRUS in
diagnosis of prostate cancer, in which it was con-
cluded that
1. no TRUS modalities can replace systemic biopsies
in the early detection of prostate cancer; and
2. sensitivity and specificity values are disappointing
in the differential diagnosis, but application of
new ultrasound agents for clinical detection and
staging are promising.
• One prospective series of case studies [128]
showed that sonographic abnormalities are
indicative of but not definitive for the presence of
CP. Included in the study were 88 men with CP
and 53 with prostadynia. Statistically significant
prostatic calcifications and unilateral seminal
gland abnormalities were present in those with
chronic inflammation, but both findings (22%
and 11%, respectively) were also present in
patients with prostadynia.
• One study used automated analysis of ultrasono-
graphic prostate images (AUDEX) to predict the
presence of inflamed prostate tissue in patients
with prostatitis [129]. Comparison was made
with histological results from those with unam-
biguously inflamed or noninflamed conditions. A
sensitivity of 90.6% and specificity of 64.2% was
reached. The prospective positive and negative
predictive values for prostatitis were 50% and
94.6%.
• One study used color Doppler and endorectal
ultrasonography to evaluate 25 patients with
acute prostatic syndrome (APS, 13 acute and 12
chronic recurrent), 7 with asymptomatic chronic
prostatitis, 13 with prostate cancer, and 6 healthy
controls [130]. Marked color increase indicative
of acute inflammation was observed in the 25
men with APS; color was greater than in the nor-
mal controls and 8 out of the 9 with cancer. Color
intensity matched severity of APS symptoms.
• One study evaluated the presence of abnormal
blood flow in patients with CP/CPPS using color
Doppler ultrasonography: 53 with inflammation,
80 without inflammation, and 22 healthy controls
[131]. Images were scored by two reviewers. Sig-
nificant blood flow increases in the prostatic cap-
sule (102/133 or 77% patients vs. 4/22 or 18%
controls) and diffuse flow throughout the prostat-
ic parenchyma (64% patients vs. 36% controls)
were observed. Patients with and without objec-
tive evidence of inflammation demonstrated sim-
ilar abnormalities. CP/CPPS may be associated
with abnormal prostate blood flow as demon-
strated by this technique.
Evidence summary: no RCTs or systematic
reviews were found. Application to differential
diagnosis remains debatable and ultrasound fea-
tures alone cannot be used for final diagnosis.
Color Doppler ultrasound may be of some assis-
tance.
b) Nuclear Isotope Scanning
What is the role of nuclear isotope scanning in the
diagnosis/characterization or evaluation after treat-
ment of CP/CPPS?
• We found no systematic reviews or RCTs. One
prospective study evaluated the value of Tc-99m
ciprofloxacin and single photon emission com-
puted tomography (SPECT) in the differential
diagnosis of CBP in patients with prostatitis syn-
358
drome [132]. The study included 4 normal sub-
jects as negative controls, 2 with acute prostatitis
or cystourethritis as positive controls, and 59
patients diagnosed with CBP [21] or CPPS [42]
by traditional laboratory tests. Images were read
by two radiologists blinded to the microbiologi-
cal findings. Images showed negative uptake in
normal subjects, strong hot uptake in the positive
controls and in 13 out of 19 (68%) and 28 out of
40 (70%) of those with CBP and CPPS, respec-
tively. No uptake occurred in 32% of those with
positive cultures; therefore the results were false-
negatives. Sensitivity and specificity were 85.5%
and 82.3%, respectively. Tc-99 imaging might be
useful to discern CBP not diagnosed with stan-
dard lab tests; its major limitation is the lack of
evidence of its diagnostic accuracy (sensitivity
and specificity) in larger prospective studies.
Evidence summary: the effectiveness of nuclear
isotope scanning in the diagnosis/characterization
or evaluation of CP/CPPS is currently unknown.
c) Magnetic Resonance Imaging (MRI)
In men with chronic prostatitis/CPPS, what is the
value of prostate MRI in the diagnosis/characteriza-
tion of CP/CPPS or evaluation after treatment?
• No systematic reviews or RCTs were found.
• In one study, prostatic MRI was performed in 72
patients including 20 patients with prostate can-
cer, 20 with BPH, 4 with ABP, 5 with CPB, 19
with chronic nonbacterial prostatitis and 6 symp-
tom-free controls [133]. Two radiologists ran-
domly reviewed images. Accuracy in diagnosis of
prostate cancer was 74% (sensitivity 53% and
specificity 83%); positive and negative predictive
values were 53% and 82%, respectively. Accura-
cy of diagnosis of cancer was high, but differen-
tiation of bacterial prostatitis from cancer was
difficult because the former showed some fea-
tures similar to those of the latter. Without the
integration of clinical data, MRI was insensitive
in the differentiation of cancer from other pro-
static disorders.
• In one retrospective study of 9 out of 12 patients
with histologic chronic prostatitis, the findings at
histopathologic examination correlated with
metabolic abnormality suggestive of prostate
cancer at MR spectroscopic imaging [134].
Metabolic abnormalities from the regions of
chronic prostatitis appeared similar to those for
 low-, intermediate-, and high-grade cancer. At
MRI, chronic prostatitis most commonly demon-
strated focal low SI that was not specific for can-
cer. In one patient, however, the diagnosis of can-
cer could not be excluded. The study was small
and had no comparators or controls.
Evidence summary: no systematic reviews or
RCTs were found. Based on the limited informa-
tion in small numbers of patients, and the inability
definitively to distinguish CP from prostate cancer,
the effectiveness of MRI in the diagnosis/charac-
terization or evaluation of CP/CPPS is currently
unknown.
7. PHYSIOLOGICAL METHODS OF EVALUATION
a) Urodynamic Parameters
What is the role of urodynamic parameters in the
evaluation of CP/CPPS?
• A comparison study of 201 men with LUTS
referred for urodynamics and 123 prostatitis
patients was conducted. Only 1.6% of CP patients
had BOO [135].
• A prospective controlled study evaluated
flowmetry, bladder capacity and post voiding
residual volume (PVR) in 42 patients with CBP
(category II) compared with 42 age-matched con-
trol men and 279 men with prostadynia/non-
inflammatory CPPS (category IIIB) [136]. The
CBP patients had significantly lower flowmetry
parameters than the controls, but CBP and CPPS
parameters were similar.
• A urodynamic study of 48 patients with CPPS
(category IIIB) revealed 29 (60%) with signifi-
cant bladder abnormalities [40]. It can be con-
cluded that CPPS patients who do not respond to
antibiotics and/or anti-inflammatory drugs may
have morphological alterations of the bladder.
Evidence summary: no systematic reviews or
RCTs were found. In men with CPPS and obstruc-
tive voiding symptoms, it is reasonable to consid-
er urodynamic evaluation (e.g. flow rates, PVR,
pressure flow studies).
b) Neurophysiological Testing
What is the role of neurophysiological testing in the
evaluation of CP/CPPS?
• A pilot controlled CT used electrodiagnostic
studies (thermal sensory analysis) to examine
359
heat sensation and visceral pain in 31 patients
with CPPS and 14 controls [137]. Men with
CPPS reported both significantly (p=0.03) higher
pain intensity at lower temperatures and higher
peak computer-generated analog visual pain
scores than controls. The study suggests that neu-
ral mechanisms involving sensitization (similar
to those found in other chronic pain syndromes)
are involved in the pathophysiology of CPPS.
• A controlled CT used heat thermal sensory tests
to evaluate 36 men with CPPS and 66 healthy
men with CPPS [138], based on the premise that
chronic pelvic pain likely results in hyper-
excitability of dorsal horn neurons and thus ther-
mal algometry may be useful in assessment of
CPPS. Thermal sensation was measured on a
computerized visual analog scale (COVAS). Men
with CPPS had altered (higher mean peak
COVAS values) heat sensation/pain sensitization
in the perineum compared to controls. This study
is the first clinical attempt to define CPPS by
quantitatively assessing thermal sensory func-
tion.
Evidence summary: no systematic reviews or
RCTs were found. These two controlled CTs
involved a total of 67 men with CPPS and 80 con-
trols. The results indicate potential for further
investigation of thermal sensory tests in the evalu-
ation of CPPS.
c) Prostate Tissue Pressure Testing
What is the role of prostate tissue pressure testing in
the evaluation of CP/CPPS?
• A pilot controlled study reviewed intraprostatic
tissue measurements under spinal anesthesia in
42 patients with chronic nonbacterial prostatitis
and 12 men without urological complaints [139].
Tissue pressure at three points (at 10, 60, 120
minutes) after saline injection was elevated in
prostatitis patients compared to controls, and
according to the authors probably reflected
increased tissue resistance and poor tissue micro-
circulation status.
• A prospective controlled CT reviewed intrapro-
static tissue measurements in 48 patients with
CP/CPPS (18 with inflammatory category IIIA
and 30 with IIIB) and 12 symptomatic controls
[140]. All patients with CP/CPPS had significant-
ly higher pressure at all time points (10, 60, 120
minute) compared with controls (p <0.01); mean
 pressure was significantly higher in category
IIIA, with >10 leukocytes per HPF, compared
with category IIIB, with <10 leukocytes. The
study validates initial observations and provides a
rationale for differentiating inflammatory and
non-inflammatory categories of CP.
Evidence summary: no systematic reviews or
RCTs were found. Both controlled studies indi-
cate that prostate tissue measurements may be
valuable for gaining insights into the pathogenesis
of CP/CPPS.
d) Intravesical Potassium Chloride Sensitivity Test
What is the role of intravesical potassium chloride
sensitivity testing in the evaluation of CP/CPPS?
• An uncontrolled study of intravesical potassium
chloride (KCl) sensitivity was conducted in 44
patients diagnosed with prostatitis [45]. The KCl
instillation is known to cause pain in most
patients with IC or CP/CPPS, reflecting urinary
epithelial dysfunction. Positive KCl tests
occurred in 37 out of 44 men (84%), which is
almost identical to rate reported for IC (79%).
• A controlled study of intravesical potassium chlo-
ride (KCl) sensitivity involved 40 men with
CP/CPPS and 6 healthy controls [141]. Although
there was a significant increase in pain and urgen-
cy scores after KCl instillation, the scores and
rates of positive sensitivity (50%) and specificity
(63.5%) were not statistically different from the
controls.
Evidence summary: no systematic reviews or
RCTs were found. Based on the observations
from the one controlled study, the potassium sen-
sitivity test is not warranted for evaluation of
CP/CPPS.
8. SERUM STUDIES
a) Serum PSA Levels
What is the role/value of serum PSA levels in the
evaluation (diagnosis and follow-up after therapy) of
prostatitis?
• We found no systematic reviews or RCTs.
Pathophysiology of elevated PSA levels in prostatitis
is not clearly understood.
• In 72 patients (<50 y.o.) with prostatitis, elevated
PSA levels (>4 ng/ml) were found in 5 out of 7
(71%) with acute prostatitis, 2 out of 13 (15%)
360
and 2 out of 32 (6%) with chronic bacterial and
nonbacterial prostatitis, and none in those with
chronic pelvic pain (prostadynia). After antibiot-
ic treatment, most patients with bacterial prostati-
tis had PSA levels decrease to normal [142].
• In 42 patients who had TURs for BPH but no
clinical evidence of prostatitis, PSA values sig-
nificantly correlated with extent of histologically-
proven acute or chronic active prostatitis (with
inflammatory infiltrate); no correlation with inac-
tive prostatitis was found [143].
• In 700 men who had prostate needle biopsy for
elevated PSA or abnormal DRE, 27% had histo-
logical evidence of prostatitis: 94% of these had
chronic inflammation, 6% acute inflammation,
and 0.2% granulomatous changes [144].
• Normalization of serum PSA levels was demon-
strated after a full course of antibiotics in patients
with clinical acute prostatitis. Failure of PSA lev-
els to normalize in 20% of cases was associated
with biopsy-proven prostate cancer [145-146]
suggests that significant lowering of PSA after
antibiotics occurs in patients who are cancer-neg-
ative vs. cancer-positive.
• In 6 cases of clinically diagnosed acute bacterial
prostatitis (serum PSA levels 4-13.6 ng/ml), all 6
patients had PSA levels significantly reduced fol-
lowing antimicrobial treatment. PSA levels were
also elevated in 6 out of 9 patients with
pyelonephritis and 8 out of 18 with fever of
unknown origin. These patients had PSA levels
decrease after therapy. The authors recommend
PSA as a diagnostic tool for ABP [55].
• A prospective control and comparative study of
seminal plasma parameters (including PSA) was
carried out to evaluate the value of diagnosis and
localization of inflammation or infection [147].
The study included 13 patients with chronic pro-
statitis, 31 with leukocytospermia, and 58 with
non-inflammatory diseases as controls. No statis-
tically relevant difference was found in PSA lev-
els; PMN elastase and complement C3 were sig-
nificantly different in CP patients vs. controls.
• A study including 187 asymptomatic men with
elevated PSA who were screened for laboratory
signs of prostatitis revealed: 122 were evaluated
with 51 (42%) with NIH category IV prostatitis.
It can be concluded that screening for category IV
prostatitis should be performed in men with ele-
vated PSA to reduce the number of biopsies for
cancer [148].
• One prospective study included 300 men from a
prostate cancer screening program who were
evaluated for NIH category IV prostatitis [149].
32% of the men were in category IV, and PSA
levels were significantly higher (2.3) than in men
without prostatitis (1.4).
• A retrospective study reviewed, scored and asso-
ciated the extent and aggressiveness of inflam-
mation in prostate specimens (post-TURP or
prostatectomy with a pathological diagnosis of
BPH and prostatitis) with serum PSA-PSA densi-
ty [150]. The aggressiveness grade of inflamma-
tion in subclinical prostatitis was described as the
most important morphological factor responsible
for PSA elevation.
• A controlled study evaluated 421 patients with
CP/CPPS and 122 age-matched asymptomatic
control patients to determine if PSA, free PSA, or
PSA isoforms could be diagnostic markers for
CP/CPPS (NIH categories IIIA and IIIB). Total
and free PSA were elevated significantly in
CP/CPPS cases and percent free PSA was not sig-
nificantly different between cases and controls.
These minor elevations of total and free PSA are
not considered clinically relevant. ROC analysis
indicated that these serum biomarkers are not
useful markers for CP/CPPS.
Comparison of serum PSA and PSA in EPS
• A study of 31 consecutive patients with prostatic
disease tested PSA in both serum and prostatic
fluid [151]. PSA in EPS was no more specific
than serum PSA in evaluating prostatic carcino-
ma, and there were no statistical differences
between prostate cancer, prostatitis and BPH
patients.
• A controlled study of 62 patients with prostatitis
(9 bacterial, 53 nonbacterial) and 22 controls
explored the content of lecithin mass and WBCs
in EPS and serum PSA [152]. Elevated serum
PSA does correlate with the content of WBC in
EPS but not with content of lecithin mass or the
type of prostatitis.
Evidence summary: no systematic reviews or
RCTs were found to support determination of
serum PSA levels in patients with CPPS.
b) LH, FSH, Testosterone, Beta-estradiol
What are the roles of various hormones (LH, FSH,
testosterone, beta-estradiol) in the diagnosis and/or
evaluation of CP/CPPS after treatment?
361
• We found no systematic reviews or RCTs. We
found one placebo-controlled RCT examining the
role of mepartricin (40 mg daily for 60 days) for
the treatment of CP/CPPS and the relation to hor-
monal levels (decreasing estrogen plasmatic lev-
els) and clinical improvement [68]. The study
was based on the hypothesis that CPPS might be
a result of an increased estrogen/androgen ratio,
which in turn leads to a reduction of dihy-
drotestosterone in the prostate epithelium and an
increase in estradiol and estrone in the stroma. 26
subjects were randomized into two groups of 13
each. Drug treatment produced a significant
symptomatic improvement compared to placebo
as evaluated by the total NIH-CPSI scores and
pain and QOL domains. Levels of LH, FSH, and
testosterone were similar in both groups before
and after treatment. 17-beta-estradiol levels were
significantly lower in the active drug group after
treatment.
Evidence summary: based on this single, small
sample study there is inconclusive evidence to
support the role of LH, FSH, and testosterone in
the diagnosis/characterization of CPPS or evalua-
tion after treatment.
c) Immunoglobulins and Antibodies
What is the role of immunoglobulins in the diagno-
sis and/or evaluation of CP/CPPS after treatment?
• We found no RCTs on the identification of
immunoglobulins specific to CP/CPPS. One con-
trolled study identified proteins expressed in a
prostate cDNA expression library recognized by
IgG from sera of patients with CP [153]. The
study was originated to identify antigens of the
prostate for the development of antigen-specific
vaccines for treatment of prostate cancer. Candi-
date proteins were evaluated in sera from 62 sub-
jects with symptomatic prostatitis and 71 control
male blood donors. Two proteins were recog-
nized: MAD-Pro-34, a nucleolar autoantigen, in 6
out of 62 CP patients and 0 out of 71 controls
(p =0.008), and NY-CO-7 protein in 9 out of 62
CP patients vs. 3 out of 71 controls (p=0.06). The
proteins used could be further investigated but
the study demonstrated that only some patients
with CP/CPPS have auto antibodies to specific
proteins; however, these cannot be used as diag-
nostic tools.
Evidence summary: currently, the effectiveness
of immunoglobulins in the diagnosis and/or eval-
uation of CP/CPPS is unknown.
9. TISSUE SAMPLING
What is the role of prostate histopathology in the
evaluation of CP/CPPS?
• A prospective study examined prostate
histopathology in 368 biopsies from 97 patients
with symptoms of CP/CPPS in order to systemat-
ically characterize inflammation [154]. The
degree of prostatic inflammation was minimal to
absent in 95% of patients; 4% had moderate and
1% severe inflammation. There was no correla-
tion between leukocytes in EPS and the prostate
in this population.
• A systematic literature review of articles from
1979-1999, prospective evaluation in two pro-
statitis research centers, and consensus of experts
from the CPCRN were used to develop a
histopathological classification for CP inflamma-
tion [155]. It was concluded that prostatic inflam-
mation is a common histopathological observa-
tion albeit its association with CP/CPPS has not
yet been completely defined. The establishment
of a standard classification will permit compari-
son of future studies evaluating, describing or
associating the prostatic inflammation with lower
GU conditions.
a) Prostate Biopsy Cultures
• In a controlled comparative study of 120 patients
with CPPS categories IIIA and IIIB and 60
asymptomatic controls, bacteria cultured from
prostatic biopsies did not differ [156]. Therefore
use of prostate tissue biopsies for this purpose is
not useful for evaluation.
b) Prostate Molecular Biopsy Studies
• One systematic review concerns the role of
molecular studies in prostatic biopsies of
CP/CPPS patients [157]. The authors indicate
that new data recently acquired with molecular
techniques may redefine the role of the bacteria
identified in the prostatic tissue and involvement
in the pathogenesis of the syndrome in a conven-
tional manner. 135 men with CP/CPPS were eval-
uated with a molecular approach; potential
pathogenic bacteria were identified in ~7 % of
patients.
• Prostate biopsy study using modern molecular
362
techniques (real time PCR) was conducted in 31
men with CP/CPPS proven by standard diagnos-
tic procedures. Bacterial DNA was detected in 8
out of 31 specimens and 3 samples were positive
for E. coli infection, demonstrating approximate-
ly 103 cfu/ml prostatic tissue [158].
Evidence summary: based on the systematic liter-
ature review and consensus report and one biopsy
study, prostate biopsies in patients with CPPS may
have research benefits.
IV. ASYMPTOMATIC PROSTATITIS
(NIH CATEGORY IV)
1. SEMEN ANALYSIS AND CULTURE
What is the role of semen analysis in men with
asymptomatic prostatitis presenting with infertility?
• The WHO has suggested requiring two of the fol-
lowing criteria to diagnose male accessory gland
infection in men with oligo-, astheno- or terato-
zoospermia:
1. history or physical signs of UTI, epididymitis, or
abnormal rectal examination;
2. abnormal urine after prostatic massage (describ-
ing the 4-glass test); or
3. elevated numbers of peroxidase positive WBCs,
high numbers of bacteria in semen, C. trachoma-
tis findings, and/or abnormal biochemistry or ele-
vated inflammatory markers in the seminal fluid.
Analysis of prostatic fluid is not recommended
Evidence summary: the suggested classification
does not differentiate between prostatitis, epi-
didymitis, and inflammatory alterations of the ure-
thral compartment (chronic urethritis). Elevated
WBCs may exert an unfavorable effect on the via-
bility, mobility, and fertilizing capacity of sperm.
• One review [118] analyzes questionable deleteri-
ous effects of “chronic prostatitis” on sperm qual-
ity in infertile patients based on the literature. The
authors suggest that even recent investigations
for sperm parameters are contradictory and do
not really confirm a negative role of chronic pro-
statitis for sperm density, motility, and morpholo-
gy.
• Evaluating the gold standard of leukocyte analy-
sis [159] in semen for leukocytospermia (≥ 106
 peroxiden positive leukocytes/ml) by immunocy-
tological analysis demonstrated a failure of the
peroxidare staining in about the half of the
patients.
• Evaluating a total of 112 men with symptomatic
prostatitis [120] demonstrated increased numbers
of peroxidare positive leukocytes in patients with
prostatitis (category IIIA) provided the ejaculate
analysis was performed on the same day after
lower urinary tract localization studies.
• In a comparison of first urine, midstream urine,
and semen samples [160], 51% of the ejaculates
demonstrated bacteriospermia. There was no cor-
relation between seminal microbes, raised leuko-
cytes, and pregnancy, however.
• Standard semen analysis has been performed and
morphological defects analyzed in 56 infertile
men, and the results compared to those of healthy
sperm donors [161]. Sperm motility was signifi-
cantly negatively correlated with leukocyte con-
centrations in semen.
Evidence summary: no RCTs or systematic
reviews concerning semen analysis, the use of the
4-glass test, and/or PPMT in category IV prostati-
tis were found in men diagnosed for infertility.
Deleterious effects of proven prostatitis on sper-
matozoa remain debatable. There are hints at a
correlation between a high number of leukocytes
and decreased sperm motility. Microorganisms are
commonly found in the semen of asymptomatic
men without biological relevance.
2. ELEVATED PSA, 4-GLASS TEST, PPMT
What is the role of the 4-glass test and/or PPMT in
men with asymptomatic prostatitis presenting with
elevated PSA in serum?
• In men without symptoms and elevated PSA
[162], the presence of acute and/or chronic pro-
statitis in biopsy specimens may be a contributing
factor to PSA elevation. Antimicrobial therapy
may normalize PSA; TRUSP biopsy should be
performed in cases that do not normalize.
• EPS analysis for increased numbers of white
blood cells (>10/HPF) identified 95 men with
serum PSA greater than 4.0 µg/ml [163]. After a
four-week course of antimicrobials and a nons-
teroidal anti-inflammatory agent, PSA in serum
was normalized in almost half of the patients.
• 122 asymptomatic men with elevated PSA levels
363
were evaluated for leukocytes in EPS and/or
VB3. Men with signs of prostatitis received a
four-week course of antimicrobials and were
reevaluated after 6 to 8 weeks [148]. In the 51
men with signs of prostatitis, PSA was normal-
ized in 22 patients. Biopsy revealed prostate can-
cer in 9 of the 29 patients who did not respond to
this therapy.
Evidence summary: no RCTs or systematic
reviews concerning the standardized use of the 4-
glass test/PPMT were found. The value of these
tests in asymptomatic men with elevated PSA
requires further research.
D. TREATMENT
I. ACUTE BACTERIAL
PROSTATITIS (NIH CATEGORY I)
ABP can be a serious infection with fever, intense
local pain and general symptoms. Septicemia and
urosepsis are always a potential risk.
The following factors must be taken in account when
treating ABP: potential urosepsis, choice of antimi-
crobial agent, urinary drainage, risk factors justify-
ing hospitalization and auxiliary measures intended
to enhance treatment outcomes [164].
1. ANTIMICROBIAL THERAPY
The choice and duration of antimicrobial therapy for
ABP are based on experience and expert opinion and
are supported by many uncontrolled clinical studies
[165-166]. For initial treatment of severely ill
patients, intravenous administration of high doses of
bactericidal antimicrobials such as aminoglycosides
in combination with ampicillin, a broad spectrum
penicillin in combination with a beta-lactamase
inhibitor, a third generation cephalosporin or a fluo-
roquinolone is required until defeverescence and
normalization of associated urosepsis (this recom-
mendation is based on treatment of complicated
UTIs and urosepsis). Patients who are not severely ill
or vomiting may be treated with an oral fluoro-
quinolone [165-166]. Trimethoprim-sulfamethoxa-
zole (TMP/SMX) is no longer recommended as first
line empirical therapy in the guidelines from the
Infectious Diseases Society of America (IDSA)
[167] and the European Association of Urology
(EAU) [168] in areas where TMP/SMX resistance
for E. coli, the most frequent pathogen, is greater
than 10% to 20% [169-171]. Low success rates in
CBP (see next section) would indicate that it should
be reserved for second line oral therapy for ABP as
well. Treatment should continue for 2 to 4 weeks
[165-166].
2. URINARY DRAINAGE
Three choices are available for the management of
acute urinary retention in acute prostatitis: suprapu-
bic, intermittent or indwelling catheterization.
Suprapubic tube placement has traditionally been
advocated for theoretical and practical reasons: it
was believed to reduce the risk of prostatic abscess
and urethral stricture. This has never been substanti-
ated and many urologists adopt either a single
catheterization with trial of voiding or short term
small caliber urethral catheterization. A small retro-
spective series [172] suggested that urethral stenting
may provide the same benefits of suprapubic
catheterization.
3. HOSPITALIZATION
ABP can present as a severe infection with a risk of
sepsis. Hospitalization is imperative in cases of high
fever, vomiting, dehydration, tachycardia, tachyp-
nea, hypotension and other symptoms related to
urosepsis. High risk patients (diabetes, immunosup-
pressed patients, old age or prostatic abscess) and
those with severe voiding disorders should be con-
sidered for hospitalization [164].
4. AUXILIARY MEASURES
Analgesics and antipyretics are usually indicated.
Nonsteroidal anti-inflammatory agents have been
suggested for reducing symptoms including fever
[164-166]. Alpha-blockers may be considered, par-
ticularly in men with moderately severe voiding
symptoms, to reduce the risk of urinary retention and
facilitate micturition [164-166].
II. CHRONIC BACTERIAL
PROSTATITIS (NIH CATEGORY II)
Because of their unique and favorable pharmacoki-
netic properties and their broad antibacterial spectra,
the fluoroquinolones are the agents of choice for the
antimicrobial treatment of CBP [165-166; 168-169].
The duration of antimicrobial treatment is based on
experience and expert opinion and is supported by
364
many clinical studies [165-166; 168-169]. Relatively
high doses of antimicrobials are needed and oral
therapy is preferred. In CBP, an oral fluoroquinolone
should be given for at least 4-6 weeks after the initial
diagnosis. After treatment the patient should be
reassessed periodically to determine appropriate
treatment. Treatment with intraprostatic injection of
antimicrobials is not recommended as it is supported
only by anecdotal reports [173-174]. In general, ther-
apeutic results (defined as bacterial eradication) are
good in CBP due to E. coli and other members of the
family Enterobacteriaceae. CBP due to P. aeruginosa
and Enterococci shows poorer response to antimicro-
bial therapy [169].
Numerous studies have been performed in the past in
patients with CPB, the majority of which are uncon-
trolled and with a short follow-up period of 4-6
weeks. Since relapse is commonly observed in these
patients, only the results of studies with follow-up of
at least 6 months should be taken into consideration.
In this respect, the most experience has been gath-
ered with ciprofloxacin, although newer fluoro-
quinolones like levofloxacin, which has improved
activity against so-called atypical pathogens, appear
to be equally efficacious. Table 4 shows data from
CBP fluoroquinolone treatment trials with a follow-
up of at least 6 months [31; 175-181]. The combina-
tion of antimicrobials and alpha-blockers has been
suggested to reduce the high recurrence rate [182]
and this combination of two therapeutic regimens
could be considered for evaluation in properly
designed prospective studies [183].
CBP associated with a confirmed uropathogen that is
resistant to the fluoroquinolones can be considered
for treatment with trimethoprim-sulfamethoxazole
(or other antimicrobials), but the treatment duration
should be 8-12 weeks [169]. For treatment refracto-
ry patients the following are acceptable treatment
strategies:
1. intermittent antimicrobial treatment of acute
symptomatic episodes (cystitis);
2. low-dose antimicrobial suppression; or
3. radical TURP or open prostatectomy if all other
options have failed.
III. CHRONIC
PROSTATITIS/CHRONIC PELVIC
PAIN SYNDROME
(NIH CATEGORY III)
Many medical and invasive interventions have been
proposed to treat CP/CPPS and numerous small,
Table 4. Fluoroquinolones in the Treatment of Chronic Bacterial Prostatitis with a Follow-up of at Least 6 Months
uncontrolled studies with poorly defined patients and
invalidated outcome analyses have suggested effica-
cy for these interventions [184]. The introduction of
an internationally accepted classification system [1]
and a validated outcome index, the NIH-CPSI [5],
has stimulated the design and implementation of
comparable randomized placebo-controlled trials
[185-186] that have allowed researchers and clini-
cians to objectively evaluate evidence based efficacy
data as well as compare the various therapies advo-
cated for CP/CPPS.
The following criteria were developed to determine
whether a clinical intervention trial in CP/CPPS met
strict criteria for an evidence-based treatment recom-
mendation:
1. clearly defined population of CP/CPPS men;
2. randomized placebo-controlled design;
3. validated outcome analyses (NIH-CPSI); and
4. peer reviewed (published in a peer reviewed jour-
nal).
1. EVIDENCE-BASED THERAPIES
At the time of the Paris 2005 consensus conference,
eleven clinical trials [61-70] met these criteria
(Table 5). Since these 11 randomized placebo-con-
trolled trials differ in the number of patients random-
ized and duration of follow-up but have similar
365
inclusion/exclusion criteria and outcome analyses,
we can compare these studies and make some early
evidence-based recommendations.
• Antimicrobials cannot be recommended for men
with longstanding, previously treated CP/CPPS
[64-65]. However, uncontrolled clinical studies
suggest that some clinical benefit can be obtained
with antimicrobial therapy in antimicrobial naïve
early onset prostatitis patients [165; 187].
• Alpha-blockers can be recommended as a first
line medical therapy, particularly in alpha-block-
er naïve men with moderately severe symptoms
who have relatively recent onset of symptoms
[62-63; 67]. Alpha-blockers must be continued
for over 6 weeks (likely over 12 weeks) [62; 68].
Alpha-blockers cannot be recommended in men
with long standing CP/CPPS who have tried and
failed alpha-blockers in the past [64].
• Anti-inflammatory therapy is not recommended
as a primary treatment [66]; however, it may be
useful in an adjunctive role in a multi-modal ther-
apeutic regime [188].
A number of uncontrolled clinical studies have
strongly suggested that multi-modal therapy is more
effective than monotherapy in patients with long
term symptoms [188-189]. Future trials will have to
assess such multi-modal therapy. At this time, hor-
monal therapy cannot be recommended as a
Table 5. The 11 randomized placebo-controlled trials that met the strict criteria defined above evaluated various medical ther-
apies for the treatment of CP/CPPS. The treatment affect is defined as the mean change from baseline in the active treatment
group minus the mean change from baseline in the placebo group. A clinically effective treatment should produce a treatment
affect of at least 3-4 points (adapted from Nickel et al [189]).

366
monotherapy [68-69], but should be evaluated in
selected patients such as older men with concurrent
BPH [68-69]. The early data on herbal therapies, par-
ticularly quercetin [61], are intriguing, but a larger
multi-center randomized placebo-controlled trial is
required before a high level of evidence recommen-
dation can be made on its use.
2. POTENTIAL THERAPIES
Many other medical therapies have been suggested
and tested in pilot studies; however, the studies were
usually small and uncontrolled. Muscle relaxants
[190], Cernilton or bee pollen extract [191-192], saw
palmetto [193-194], corticosteroids [195] and allop-
urinol [196-197] have all been suggested and used
but recommendations will have to wait for results
from properly designed randomized placebo-con-
trolled trials. Promising approaches employing neu-
romodulatory, neuroendocrine and immune modula-
tory agents will require evaluation and randomized
controlled trials before their efficacy can be deter-
mined.
A number of physical therapies have been recom-
mended, but they also suffer from a lack of prospec-
tive controlled data obtained from properly designed
controlled studies. Prostatic massage has been the
primary therapy for prostatitis since the turn of the
century and there has been a re-emergence of inter-
est in its potential [198-199]. Refinement of the pro-
static massage therapy (perineal or pelvic floor mas-
sage and myofascial trigger point release) has also
been suggested as a beneficial treatment modality for
patients [88]. Biofeedback [200] and acupuncture
[201] also show promise, but like all the other phys-
ical therapeutic modalities, require sham-controlled
trials before recommendations can be made. Electro-
magnetic therapy is intriguing and shows interesting
results in a small randomized sham-controlled trial
[202] and further efforts should be made to test this
modality of therapy. Psychological support and ther-
apy has been advocated based on new psycho-social
modeling of this syndrome [81].
A number of minimally invasive therapies such as
balloon dilation [203-205], neodymium:Yag laser
[206], transurethral needle ablation [207-208] and
microwave hyperthermia [209-210] and thermother-
apy [211] have been suggested. Two trials assessing
transrectal microwave hyperthermia [209-210] and
one trial assessing transurethral thermotherapy [211]
have indicated that these may be better than sham
therapy while a trial comparing TUNA to sham [208]
found that the efficacy of TUNA in CPPS was com-
parable to sham treatment. Further assessment of
367
heat therapy employing sham controls, standardized
inclusion exclusion criteria and validated symptom
outcome measures are recommended. Pudendal
nerve blocks or neurolysis surgery [212-213] have
been suggested for chronic pelvic pain that can be
shown to be secondary to pudendal nerve entrap-
ment. Other surgery such as radical transurethral
resection of the prostate and total prostatectomy
should not be encouraged or recommended at this
time for CP/CPPS since no definitive clinical series
or long term follow up has ever been presented.
IV. ASYMPTOMATIC PROSTATITIS
(NIH CATEGORY IV)
Therapy is not indicated since these patients by def-
inition are asymptomatic. However, antimicrobial
therapy for selected patients with category IV pro-
statitis associated with elevated PSA (for a complete
review of this topic see Kawakami et al [214]) and
infertility (for a complete review of this topic see
Branigan et al [215]; Yanushpolsky et al [216]) may
warrant consideration.
E. EVIDENCE AND
RECOMMENDATIONS
I. LEVELS OF EVIDENCE AND
GRADING OF RECOMMENDATIONS
A recommended test should be done on every patient
during the initial evaluation.
An optional test is a test of proven value in the eval-
uation of selected patients during a specialized eval-
uation usually performed by a urologist.
1. EPIDEMIOLOGY
a) Levels of Evidence
1. Approximately 5% to 15% of men have symp-
toms consistent with CP/CPPS (level 2/3).
2. Asymptomatic inflammatory prostatitis occurs
frequently in men evaluated for prostate disorders
and less frequently in patients presenting with
infertility (level 3).
3. ABP and CBP appear to be less common than
CP/CPPS, but we have very limited population-
based data on the incidence and prevalence of
these conditions (level 3/4).
b) Recommendation
Further studies are needed to define the epidemiolo-
gy of all categories of prostatitis (grade A).
2. PATHOGENESIS
a) Levels of Evidence
1. Prostatitis syndromes cause substantial morbidity
and a large number of physician visits (level 1/2).
2. Although limited data support a number of theo-
ries, the pathogenesis of both CP/CPPS and
asymptomatic inflammatory prostatitis remain
undefined (level 2/3).
3. Risk factors for development of prostatitis appear
to include genitourinary tract instrumentation,
including prostate biopsies (level 3), and a history
of UTI (level 2/3). Other risk factors for develop-
ment of prostatitis remain undefined (level 3).
4. ABP and CBP are caused by Gram-negative rods
(level 1/2) and by Gram-positive cocci (level 3).
b) Recommendation
1. Further studies are needed to define the pathogen-
esis of all categories of prostatitis (grade A).
II. EVALUATION
1. ACUTE BACTERIAL PROSTATITIS
(NIH CATEGORY I)
1. Men with symptoms of ABP should undergo uri-
nalysis and culture/sensitivity. (2:A)
2. Initial imaging of the prostate is not recommend-
ed. Ultrasound is indicated if suspicion for pro-
static abscess is entertained. (3:B)
2. CHRONIC BACTERIAL PROSTATITIS
(NIH CATEGORY II)
1. Traditional 4-glass or 2-glass test for white blood
cell count and culture. (3:A)
2. Culture of semen has a low sensitivity but is rec-
ommended for evaluation in selected men (e.g.
infertility). (3:D)
3. Imaging of the prostate is indicated only in highly
selected patients (e.g. treatment refractory). (4:D)
3. CHRONIC PROSTATITIS/CHRONIC PELVIC
PAIN SYNDROME (NIH CATEGORY III)
a) Recommended Investigations
1. 4-glass or 2-glass test for WBC count and culture.
(3:A)
368
2. The NIH-CPSI instrument should be utilized for
symptomatic evaluation and assessment of treat-
ment but not as a diagnostic tool. (3:A)
3. Physical examination of the prostate and other
pelvic structures (e.g. myofascial trigger points).
(3:B)
4. Psychological evaluation in selected patients may
be warranted. (3:B)
b) Optional Investigations
1. Flow rate, post-void residual and other urodynam-
ic studies. (3:C)
2. Semen analysis and culture. (3:D)
c) Investigations Which are Not Recommended
1. Serum PSA. (3:B)
2. Potassium chloride sensitivity test. (3:D)
3. Routine imaging of the prostate. (3:D)
4. Test for C. trachomatis and Ureaplasma. (3:D)
5. Cystoscopy. (4:D)
d) Investigational Tests Requiring Further Evalu-
ation
1. Histopathological and molecular microbiological
evaluation of the prostate. (3:D)
2. Immune cells and mediators. (3:D)
4. ASYMPTOMATIC PROSTATITIS (NIH CATE-
GORY IV)
1. No evaluation unless considering antimicrobial
therapy for elevated PSA or infertility. (3:C)
III. TREATMENT
I. ACUTE BACTERIAL PROSTATITIS
(NIH CATEGORY I)
1. Patients with severe symptomatic febrile acute
bacterial prostatitis:
• aminoglycosides in combination with ampicillin,
a broad spectrum penicillin in combination with a
beta-lactamase inhibitor, a thrid generation
cephalosporin or a fluoroquinolone is required
until defeverescence and normalization of associ-
ated urosepsis (2:A based on treatment of com-
plicated UTIs and urosepsis),
• observation/hospitalization, initial parenteral
wide-spectrum antimicrobials, and if indicated,
bladder drainage. (3:B)
2. Prostatic abscess in treatment refractory patients 4. Biofeedback. (3:B)
requires drainage. (4:A)
5. Physical therapy. (3:B)
3. Following resolution of severe infection and for
6. Acupuncture. (3:C)
less severely ill patients, outpatient oral fluoro-
quinolones for 2-4 weeks are appropriate. (4:B) 7. Electromagnetic stimulation. (3:C)
8. Immunomodulating agents. (3:C)
2. CHRONIC BACTERIAL PROSTATITIS
(NIH CATEGORY II) 9. Muscle relaxants. (3:C)

1. Oral fluoroquinolone therapy for susceptible bac-
teria for 4-6 weeks. (2:A)
2. Trimethoprim-sulfamethoxazole (or other antimi-
crobials) for fluoroquinolone resistant bacteria.
(3:B)
10. Neuromodulating agents. (3:C)
11. Pudendal nerve modulation. (3:C)
4. ASYMPTOMATIC INFLAMMATORY PRO-
STATITIS (NIH CATEGORY IV)

3. Treatment refractory patients: Antimicrobial therapy for selected patients with ele-
vated PSA or infertility warrants consideration. (3:B)
• intermittent antimicrobial treatment of acute
symptomatic cystitis; (3:A)
• low-dose antimicrobial suppression; (3:A)
• radical TURP or simple prostatectomy (as a last
resort if all other options have failed). (4:C)
3. CHRONIC PROSTATITIS/CHRONIC PELVIC
PAIN SYNDROME (NIH CATEGORY III)
a) Recommended Therapies
1. Alpha-blocker therapy for newly diagnosed,
alpha-blocker naïve patients. (1:A)
2. Antimicrobial therapy for newly diagnosed,
antimicrobial naïve patients. (4:D)
3. Multi-modal therapy. (4:D)
b) Therapies Which are Not Recommended
1. Alpha-blocker therapy in chronic heavily pretreat-
ed patients. (1:A)
2. Anti-inflammatory monotherapy. (1:A)
3. Antimicrobial therapy in chronic heavily pretreat-
ed patients. (1:A)
4. Five alpha-reductase inhibitor monotherapy. (1:A)
5. Minimally invasive therapies such as TUNA, laser
therapies, etc. (2:A)
6. Invasive surgical therapies such as TURP and rad-
ical prostatectomy. (4:D)
c) Therapies Requiring Further Evaluation
1. Heat therapy in the form of microwave. (2:B)
2. Mepartricin. (2:B)
3. Quercetin and other phytotherapies. (2:B)

369

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 CHAPTER 10 B

Committee 15

Summary of
The Assessment and Management of
Male Pelvic Pain Syndrome,
Including Prostatitis
PART II
DIAGNOSTIC WORKUP AND ALGORITHMS

Chair
A. J. SCHAEFFER (USA)

Members
R. U. ANDERSON (USA),
J. N. KRIEGER (USA),
B. LOBEL (FRANCE),
K. NABER (GERMANY),
M. NAKAGAWA (JAPAN),
J. C. NICKEL (CANADA),
L. NYBERG (USA),
W. WEIDNER (GERMANY)

377
 CONTENTS

A. DIAGNOSTIC WORKUP OF MALE B. ALGORITHMS

PELVIC PAIN SYNDROME,
INCLUDING PROSTATITIS
I. ACUTE PROSTATITIS
I. INITIAL EVALUATION:
RECOMMENDATIONS II. APPARENT RECURRENT
“PROSTATITIS”
II. OPTIONAL EVALUATIONS:
UROLOGIC (SPECIALIZED) III. CHRONIC PELVIC PAIN
EVALUATION SYNDROME

III. EVALUATIONS WHICH ARE

NOT RECOMMENDED

378
 Part II - Diagnostic Workup and
Algorithms
A. J. SCHAEFFER,
R. U. ANDERSON, J. N. KRIEGER, B. LOBEL, K. NABER, M. NAKAGAWA , J. C. NICKEL,
L. NYBERG, W. WEIDNER
A. DIAGNOSTIC WORKUP OF MALE
PELVIC PAIN SYNDROME,
INCLUDING PROSTATITIS
A recommended test should be done on every patient
during the initial evaluation.
An optional test is a test of proven value in the eval-
uation of selected patients during a specialized eval-
uation usually performed by a urologist.
I. INITIAL EVALUATION:
RECOMMENDATIONS
The initial evaluation should be done on every
patient presenting to a physician with symptoms of
male pelvic pain syndrome (including prostatitis).
1. HISTORY
An adequate medical history should be obtained
focusing on the:
• nature and duration of reported genitourinary
tract symptoms,
• previous surgical procedures (in particular, as
they affect the genitourinary tract),
• general health issues, including sexual function
history,
• medication currently taken by the patient, and
• the patient’s fitness for possible surgical proce-
dures or other treatments.
2. QUANTIFICATION OF SYMPTOMS: NATION-
AL INSTITUTES OF HEALTH CHRONIC PRO-
STATITIS SYMPTOM INDEX (NIH-CPSI)
Severity of symptoms in men with CP/CPPS should
be assessed by using the NIH-CPSI. This instrument
is a validated questionnaire, completed by the
patient, consisting of four questions about pain, three
379
about voiding symptoms, and two about quality of
life (QOL). The scores in these three individual
domains (pain, voiding and QOL) are combined
without weighting to yield the NIH-CPSI total score.
3. PHYSICAL EXAMINATION AND DIGITAL
RECTAL EXAM
A focused physical examination should be per-
formed to assess the suprapubic area to rule out blad-
der distention.
A digital rectal examination (DRE) should be per-
formed to evaluate the anal sphincter tone and
prostate gland with regard to approximate size, con-
sistency, shape and abnormalities suggestive of
prostate cancer.
In men who may have acute bacterial prostatitis,
prostate massage is contraindicated.
In men with CP/CPPS, evaluation of myofascial trig-
ger points may be useful.
4. URINALYSIS AND URINE CULTURE
The urine should be analyzed using a dipstick test,
with or without examination of the urinary sediment
after centrifugation, to determine if the patient has
hematuria, proteinuria, pyuria, or other pathological
findings (e.g. nitrite-producing bacteria or glucose).
A conventional 4-glass test or PPMT (pre- and post-
prostatic massage urine test) for WBC and bacterial
culture is indicted in men with possible CBP, CPPS
or selected men with elevated PSA (Figure 1).
Figure 1. The classic Meares-Stamey 4-glass urine test.
VB1 (voided bladder 1) is the initial 10 cc of the urinary
stream and represents the urethral specimen. VB2(voided
bladder 2) is a midstream from the bladder itself. EPS
(expressed prostatic secretion) VB3(voided bladder 3, the
first 10 cc of urine after prostatic massage) are representa-
tive of the prostatic microbiologic environment.
NATIONAL INSTITUTES OF HEALTH CHRONIC PROSTATITIS SYMPTOM INDEX (NIH-CPSI)
PAIN OR DISCOMFORT
1. In the last week, have you experienced any pain or discomfort in the following areas?
Yes No
a. Area between rectum and testicles (perineum) _1 _0
b. Testicles _1 _0
c. Tip of the penis (not related to urination) _1 _0
d. Below your waist, in your pubic or bladder area _1 _0
2. In the last week, have you experienced: Yes No
a.Pain or burning during urination? _1 _0
b. Pain or discomfort during or after sexual climax (ejaculation)? _1 _0
3. How often have you had pain or discomfort in any of these areas over the last week?
_0 Never
_1 Rarely
_2 Sometimes
_3 Often
_4 Usually
_5 Always
4. Which number best describes your AVERAGE pain or discomfort on the days that you had it, over the last week?
- - - - - - - - - - -
0 1 2 3 4 5 6 7 8 9 10
NO PAIN PAIN AS BAD AS
YOU CAN IMAGINE
URINATION
5. How often have you had a sensation of not emptying your bladder completely after you have finished urinating,
over the last week?
_0 Not at all
_1 Less than 1 time in 5
_2 Less than half the time
_3 About half the time
_4 More than half the time
_5 Almost always
6. How often have you had to urinate again less than two hours after you had finished urinating, over the last week?
_0 Not at all
_1 Less than 1 time in 5
_2 Less than half the time
_3 About half the time
_4 More than half the time
_5 Almost always
IMPACT OF SYMPTOMS
7. How much have your symptoms kept you from doing the kinds of things you would usually do, over the last week?
_0 None
_1 Only a little
_2 Some
_3 A lot
8. How much did you think about your symptoms, over the last week?
_0 None
_1 Only a little
_2 Some
_3 A lot
9. If you were to spend the rest of your life with your symptoms just the way they have been during the last week,
how would you feel about that?
_0 Delighted
_1 Pleased
_2 Mostly satisfied
_3 Mixed (about equally satisfied and dissatisfied)
_4 Mostly dissatisfied
_5 Unhappy
_6 Terrible

Scoring the NIH-Chronic Prostatitis Symptom Index Domains

Pain: Total of items 1a, 1b, 1c, 1d, 2a, 2b, 3 and 4 =
Urinary Symptoms: Total of items 5 and 6 =
Quality of Life Impact: Total of items 7, 8 and 9 =
380

II. OPTIONAL EVALUATIONS:
UROLOGIC (SPECIALIZED)
EVALUATION
1. FLOW RATE RECORDING
Urinary flow rate measurement is useful in the initial
diagnostic assessment and during or after treatment to
determine response. Because of the non-invasive
nature of the test and its clinical value, it should be
performed prior to embarking on any active therapy.
Maximum urinary flow rate (Qmax) is the best single
measure, but a low Qmax does not distinguish
between obstruction and decreased bladder contractil-
ity.
Because of the great intra-individual variability and
the volume dependency of the Qmax, at least two flow
rates, both with a volume ideally of >150 ml voided
urine, should be obtained. If such a voiding volume
cannot be obtained by the patient despite repeated
recordings, the Qmax results at available voiding vol-
umes should be considered.
2. RESIDUAL URINE
The determination of post-void residual urine is use-
ful in the initial diagnostic assessment of the patient
and during subsequent monitoring as a safety parame-
ter.
The determination is best performed by non-invasive
transabdominal ultrasonography.
Because of the marked intra-individual variability of
residual urine volume, the test should be repeated to
improve precision if the first residual urine volume is
significant and suggests a change in the treatment
plan.
3. PRESSURE-FLOW STUDIES
This optional test is of proven value in the evaluation
of patients prior to invasive therapies or when a pre-
cise diagnosis of bladder outlet obstruction (BOO)
is important. Pressure-flow urodynamic studies are
the only method with the potential to separate men
with a low urinary flow rate due to a detrusor under-
activity from those with obstruction. This is done by
relating the detrusor pressure (pdet) at the time of the
Qmax to the maximum flow rate achieved (see com-
mittee on Urodynamics).
If patients are found not to have BOO, yet suffer
from severe Lower Urinary Tract Symptoms
(LUTS), they are less likely to benefit from tradi-
tional treatments such as surgery, designed to relieve
outlet obstruction. Consequently, it is recommended
that these patients have their symptoms treated in an
appropriate fashion. Such treatment can consist of
therapy aimed at other underlying disease processes,
including anticholinergics, bladder behavioral train-
ing, biofeedback, etc.
381
The most important parameter of the pressure-flow
study is the pdet at the time of the Qmax.
4. SEMEN ANALYSIS AND CULTURE
There is no conclusive proof of prostatitis exerting a
negative effect on spermatozoa, although some stud-
ies suggest prostatitis is linked with decreased sperm
motility. In general, semen analysis of asymptomat-
ic patients is not indicated.
5. ELEVATED PSA
Evaluation of patients with elevated PSA should fol-
low guidelines for those conditions.
6. IMAGING OF THE PROSTATE BY TRANSREC-
TAL ULTRASOUND (TRUS) OR COMPUTED
TOMOGRAPHY (CT)
Imaging of the prostate is indicated in selected
patients who are treatment refractory (e.g. to rule out
related disorders such as prostatic abscess or ejacula-
tory duct obstruction).
III. EVALUATIONS WHICH ARE
NOT RECOMMENDED
These tests are not recommended in an otherwise
healthy patient with an initial evaluation consistent
with prostatitis.
Endoscopy of the lower urinary tract
Serum PSA
Potassium chloride sensitivity test
Test for C. trachomatis and Ureaplasma
DIAGNOSTIC TEST
I. INITIAL EVALUATION:
RECOMMENDATIONS
1. HISTORY
2. QUANTIFICATION OF SYMPTOMS: NATIONAL
INSTITUTES OF HEALTH CHRONIC PROSTATITIS
SYMPTOM INDEX (NIH-CPSI)
3. PHYSICAL EXAMINATION AND DIGITAL RECTAL EXAM
4. URINALYSIS AND URINE CULTURE
II.OPTIONAL EVALUATIONS: UROLOGIC
(SPECIALIZED) EVALUATION
1. FLOW RATE RECORDING
2. RESIDUAL URINE
3. PRESSURE-FLOW STUDIES
4. SEMEN ANALYSIS AND CULTURE
5. ELEVATED PSA
6. IMAGING OF THE PROSTATE BY TRANSRECTAL ULTRA-
SOUND (TRUS) OR COMPUTED TOMOGRAPHY (CT)
III. EVALUATIONS WHICH ARE NOT
RECOMMENDED
1. ENDOSCOPY OF THE LOWER URINARY TRACT
2. SERUM PSA
3. POTASSIUM CHLORIDE SENSITIVITY TEST
4. TEST FOR C. TRACHOMATIS AND UREAPLASMA
 B. ALGORITHMS

I. ACUTE PROSTATITIS

DEFINED BY
• Febrile illness
• Tender prostate
• Pyuria ± bacteriuria

Note: avoid prostatic

INITIAL EVALUATION
massage
• Urine culture

TREAT AS ACUTE Consider hospitalization

depending on severity of
BACTERIAL PROSTATITIS1 illness and personal cir-
cumstances

VOIDING EFFECTIVELY?

YES NO

CATHETERIZE2

RESPONDS TO TREATMENT?

YES NO

OTHER INVESTIGATION
• Imaging (CT, sonography or MRI) to
evaluate for prostate abscess3
1. Treatment: Acute Bacterial Prostatitis (NIH Category I)
• Recommendation 1: Patients with severe symptomatic febrile acute bacterial prostatitis.
a. Aminoglycosides in combination with ampicillin, a broad spectrum penicillin in combination with a beta-lactamase
inhibitor, a third generation cephalosporin or a fluoroquinolone is required until defeverescence and normalization of
associated urosepsis (2:A based on treatment of complicated UTIs and urosepsis).
b. Observation/hospitalization, parenteral wide-spectrum antimicrobials. (3:B)
• Recommendation 2: Following resolution of severe infection and for less severely ill patients, outpatient parenteral
fluoroquinolones for 2-4 weeks are appropriate. (4:B)
2. Attempt gentle passage of small Foley catheter; if unsuccessful, insert a suprapubic drainage tube.
3. Prostate abscess is a rare complication that may require drainage.

382
 II. APPARENT RECURRENT “PROSTATITIS”

DEFINED BY
• RECURRENT SYMPTOMS OF PELVIC PAIN AND “CYSTITIS”
• EPISODIC IN NATURE
• WITH OR WITHOUT PROSTATE TENDERNESS

PROVEN URINARY TRACT INFECTION?1

YES NO

URINE CULTURE WHEN

LOCALIZATION STUDIES2
SYMPTOMS OF “CYSTITIS”

TREAT WITH NON-PROSTATE

PENETRATING ANTIMICROBIALS
POSITIVE NEGATIVE

ENTRY FROM ALGORITHM III ALGORITHM III

NEGATIVE FOR POSITIVE FOR

PROSTATIC PROSTATIC
DIAGNOSIS CHRONIC TREATMENT - APPRO-
INFECTION INFECTION
BACTERIAL PROSTATITIS PRIATE ANTIMICROBIALS
FOR ADEQUATE TIME3

1. It is important to establish whether the

WORKUP FOR
“cystitis” episodes are associated with
YES INFECTION NO
UTIs. If not, urine culture should be RECURRENT URINARY
RESOLVED?
obtained during subsequent symptomat- TRACT INFECTIONS
ic episodes. If urine cultures are nega-
tive, consider CPPS. If cultures are positive, treat with non-
prostate penetrating antimicrobials such as nitrofurantoin or a
beta-lactam to treat the acute cystitis and preserve the oppor- FURTHER TREATMENT4
tunity to identify the pathogen via the 4-glass test.
SYMPTOMS
2. Evaluation for Chronic Bacterial Prostatitis (NIH Category II) RESOLVED?
a. Recommendation 1: Traditional 4-glass or 2-glass test for
WBC count and culture. (3:A)
b. Recommendation 2: Culture of semen has a low sensitivi-
ty but is reasonable in selected men (e.g. infertility). (3:D) SATISFACTORY
c. Repeat localization culture 3-6 months after completing NO YES YES RESPONSE?
therapy.
3. Treatment for Chronic Bacterial Prostatitis (NIH Category II)
a. Recommendation 1: Oral fluoroquinolone therapy for sus-
ceptible bacteria for 4-6 weeks. (2:A)
b. Recommendation 2: TMP-SMX (or other antimicrobials)
CPPS (III) CURED NO
for fluoroquinolone resistant bacteria. (3:B)
4. Failure to eradicate CBP requires long-term antimicrobial man-
agement with suppressive or intermittent treatment of acute
cystitis or resection of the infected tissue. Radical TURP is REMOVAL OF INFECTIVE TISSUE BY
effective in only one-third of patients [1] and can cause uri-
nary incontinence; therefore, surgical removal of infected tis-
TURP OR OPEN SURGERY IF ALL
sue should only be considered as a last resort if all other mea- OTHER OPTIONS FAIL
sures fail.
383
III. CHRONIC PELVIC PAIN SYNDROME

DEFINED AS
• NO PREVIOUS INFECTIONS
• PERSISTENT CHRONIC PELVIC PAIN SYMPTOMS
• WITH OR WITHOUT LUTS
• WITH OR WITHOUT PROSTATE TENDERNESS

ENTRY FROM
EVALUATION1
ALGORITHM II

EVIDENCE OF PROSTATE INFLAMMATION?

• POSITIVE PROSTATIC FLUID - WBC OR BACTERIA

NO YES 2 BACTERIA ±
ALGORITHM II
WBCS

UROFLOW WBCS ONLY

CONSIDER 4-6 WEEKS OF

ANTIMICROBIAL TREATMENT

ABNORMAL NORMAL
RESPONDS?

URODYNAMICS
NO YES

POSITIVE OPTIONAL EVALUATION

• SEMEN ANALYSIS AND CULTURE NEGATIVE
• PROSTATE IMAGING
NEGATIVE

TREATMENT
FOR LUTS
POSITIVE TREATMENT 2
EMPIRIC
TREATMENT3
SPECIALIZED UROLOGIC
TREATMENTS

384
1. Evaluation for Chronic Prostatitis/Chronic Pelvic Pain Syndrome (NIH Category III)
a. 4- or 2-glass test for WBC count and culture. (3:A)
b. The NIH-CPSI (see page 40) should be used for symptomatic evaluation and assessment of treatment
but not as a diagnostic tool. (3:A)
c. Physical examination of the prostate and other pelvic structures (e.g. myofascial trigger points). (3:B)
d. Psychological evaluation in selected patients may be warranted. (3:B)
2. If prostatic fluid tests positive for WBCs but not for bacteria, proceed to antimicrobial treatment as per the
algorithm above. If prostatic fluid tests positive for bacteria (regardless of the presence or absence of
WBCs), the patient is positive for prostatic infection as detailed on Algorithm II: Apparent Recurrent “Pro-
statitis,” and we recommend following the course specified there. It is possible the patient has a positive
prostatic infection (which can be treated via Algorithm II) as well as non-infective Chronic Pelvic Pain syn-
drome, in which case both algorithms must be utilized.
3. Treatment
a. Lifestyle intervention
i. Diet
b. Behavioral treatment
i. Pelvic floor relaxation
c. Drug Therapies
i. Alpha adrenergic
ii. Nonsteroidals
iii. Analgesic
iv. Neuromodulating agents
v. Muscle relaxants
vi. Immunomodulating agents
vii. Quercetin and other phytotherapies
viii. Mepartricin
d. Additional Therapies
i. Acupuncture
ii. Pudendal nerve modulation
iii. Electromagnetic stimulation

385
 CHAPTER 2

Committee 3A

Epidemiology and Natural History of

Benign Prostatic Hyperplasia

Chairmen
M. BARRY (USA),
M. MURAI (JAPAN)

Members
R. BOSCH (THE NETHERLANDS),
C. CHENG (SINGAPORE),
O. CUSSENOT (FRANCE),
J. DONOVAN (UK),
R. ETZIONI (USA),
S. JACOBSEN (USA),
R. KHAULI (LEBANON),
E. LEE (KOREA),
R. SAHABUDIN (MALAYSIA),
K. SASIDHARAN (INDIA),
J. STANFORD (USA),
T. TSUKAMOTO (JAPAN),
L. ZHOU (CHINA)

35
 CONTENTS

I. INTRODUCTION V. GENETIC MARKERS OF RISK

AND PROGRESSION FOR BPH
II. DESCRIPTIVE EPIDEMIOLOGY
1. INTRODUCTION

2. BENIGN PROSTATIC HYPERPLASIA (BPH)

III. RISK FACTORS SUSCEPTIBILITY GENES

1. SEX STEROIDS AND HORMONES REFERENCES

2. GROWTH FACTORS

3. ERECTILE DYSFUNCTION

4. CARDIOVASCULAR DISEASE

5. LIFESTYLE: DIET AND EXERCISE

6. OVERALL SUMMARY

IV. NATURAL HISTORY

1. CLINICAL MANIFESTATIONS OF BPH

a) Lower Urinary Tract Symptoms
b) Acute Urinary Retention (AUR)

2. PHYSIOLOGIC MEASURES
a) Urinary flow rate (usually expressed as the max-
imal urinary flow rate or Qmax)
b) Post-void Residual Urine
c) Pressure-flow Study Parameters

3. ANATOMIC MEASURES (TOTAL PROSTATE

VOLUME, CENTRAL HYPOECHOIC VOLUME)

4. BIOCHEMICAL MEASURES

5. OVERALL SUMMARY

36
 Epidemiology and Natural History of
Benign Prostatic Hyperplasia
M. BARRY, M. MURAI
R. BOSCH, C. CHENG, O. CUSSENOT, J. DONOVAN , R. ETZIONI, S. JACOBSEN , R. KHAULI,
E. LEE, R. SAHABUDIN, K. SASIDHARAN, J. STANFORD, T. TSUKAMOTO, L. ZHOU
I. INTRODUCTION
Benign prostatic hyperplasia (BPH) is a histologic
condition that is common among older men. BPH
ultimately produces its morbidity through lower uri-
nary tract symptoms (LUTS) and outcome events
such as acute urinary retention, urinary tract infec-
tions, and rarely, obstructive kidney disease. The his-
tologic condition is linked to LUTS and outcome
events through incompletely defined mechanisms
that involve but are probably not limited to prostate
enlargement and bladder outlet obstruction with sec-
ondary bladder changes in response to obstruction.
Other disease processes that affect the lower urinary
tract can produce LUTS, which are not specific for
BPH. Similarly, not all men with histologic BPH will
have clinical manifestations.
Strictly speaking, then, studies of the epidemiology
of BPH should focus on the distribution and deter-
minants of the histologic condition. However, the
epidemiology of the clinical manifestations of BPH
is of much greater relevance to the health of older
men. Moreover, documentation of the presence of
histologic BPH, or even urodynamic evidence of
bladder outlet obstruction, require invasive testing
that is usually not practical, particularly in large,
population-based epidemiologic studies. Therefore,
most epidemiologic studies focus on prostatic
enlargement and clinical manifestations suggesting
BPH, with the caveat that not all counted “cases”
will necessarily have histologic BPH, and that even
if they do, the clinical picture may actually be
attributable to another cause.
37
While much has been learned from such epidemio-
logic studies, there is still much that is not under-
stood. Indeed, despite advances in treatment, the
pace of advances in knowledge about causes and risk
factors for BPH and its clinical manifestations is not
as great as might be hoped. This relative lack of
progress might be due to the lingering effects of the
historical perspective that BPH is a natural conse-
quence of aging and that its consequences are solely
related to quality of life. Alternatively, some of the
slow progress may be due to vexing design and mea-
surement issues.
In regards to design, one of the most important issues
for future studies is to ensure the alignment of the
study population with the epidemiologic question
being addressed. For example, it may not be appro-
priate to rely on subjects recruited from urology
practices to generate population inferences. It might
be reasonable to use such a sample to characterize
patients normally seen by a urologist but even so,
one must be concerned about referral patterns that
can vary from practice to practice and the particular
characteristics that might affect the mix of study sub-
jects. A particularly problematic misalignment is the
attempt to draw population inferences from the expe-
rience of subjects enrolled in the placebo arms of
clinical trials. Selection factors and placebo and
Hawthorne effects can all lead to outcomes that
would be different than in the general population.
The discrepancies between outcomes in the commu-
nity and those in trial cohorts have been empirically
demonstrated [1, 2].
In the search for risk factors for BPH with clinical
manifestations, another design issue is the ability to
sort out temporal relationships. Comparisons across
settings and countries may lead to insights about eti-
ology but may always be suspect because of the eco-
logic fallacy [3]. Equally of concern is the practice of
drawing conclusions about the risk of developing
signs of BPH based upon cross-sectional data. That is,
a man with moderate-severe lower urinary tract symp-
toms today may have developed them over the past
several months or over the past several decades. Clin-
ically, these represent different entities and it is prob-
ably of greater interest to identify risk factors for
“aggressive” disease as opposed to more indolent
forms. This is difficult to do in cross-sectional studies.
In addition to these basic design issues, there are sev-
eral measurement issues that should be considered.
As yet, there is no widely accepted working epi-
demiologic definition for “clinically important
BPH.” That lack of consensus in part reflects the
uncertain mechanisms that link the histologic condi-
tion with its clinical manifestations. Several studies
have highlighted that even the basic prevalence of
clinically important BPH is very sensitive to the
working epidemiologic decision applied (Figure 1)
[4, 5]. Each of the clinical manifestations of BPH is
a syndrome, much like heart failure. Each clinical
presentation has multiple possible etiologies. How-
ever, this situation presents an opportunity in that
comparisons of the patterns of these signs and symp-
Figure 1. Prevalence of clinical BPH in men aged 55-74 years based on various different case definitions [39].
38
toms can give some insight into the underlying
pathology. Thus, future studies should not focus
solely on LUTS but also assess the constellation of
other signs and symptoms related to BPH. And even
if not their primary focus, future studies must
account for other conditions that might result in
LUTS [6]. Finally, studies should consider the spec-
trum of severity of the signs and symptoms, and not
just dichotomize them. By examining them as quan-
titative traits, there will be increased power to detect
associations by avoiding the use of arbitrary cut-
points and consequent misclassification.
This report reviews new data on the epidemiology
and natural history of BPH and its clinical manifes-
tations, focusing on new developments since the last
International Consultation report on this disease in
2000.
II. DESCRIPTIVE EPIDEMIOLOGY
Since the previous report of this Consultation, addi-
tional studies have assessed the occurrence of LUTS
in the community setting. In a study conducted in
Surahammar, Sweden, [7] all men ages 40-80 years
were asked about stress incontinence, post-void drib-
bling or urgency. If they answered yes to any, they
were asked to complete the DAN-PSS. The two-
stage design and use of DAN-PSS make it difficult to
compare the results to other studies. Andersson, et al
[8] surveyed men in two Swedish counties. Among
the nearly 40,000 participants, the prevalence of
moderate-severe LUTS based on the IPSS increased
from 12% in men ages 45-49 years to 38% in men
ages 70-79 years. The correlation between IPSS
score and age (rs=0.25, p < 0.001) was similar to cor-
relations from other population-based studies.
Logie, et al., [9] used the General Practice Research
Database from the UK to evaluate the prevalence of
LUTS. The investigators used a broad definition of
LUTS by identifying any mention of diagnoses,
signs and symptoms of LUTS, or BPH; but excluded
LUTS mentioned in conjunction with a diagnosis of
Parkinson’s disease, diabetes or concurrent urinary
tract infection. As with virtually every study, they
found a dramatic increase in prevalence with age,
from 3.5% for men in their forties to more than 30%
for men age 85 years and older. The estimated inci-
dence of these diagnoses increased from about 5 per
1000 person-years among men ages 45-49 years to
more than 50 per 1000 person-years among men in
their eighties (Figure 2).
These authors’ attention to other diseases that may
cause LUTS is somewhat unique in the field despite
an emphasis on the importance of this step in diag-
nostic and treatment guidelines [10, 11]. Data from
the baseline recruitment of the Olmsted County
Study [6] demonstrate that over ten percent of men in
their seventies have a condition other than BPH that
could cause LUTS and in 1990, 20% of men in their
seventies had a prior surgical procedure on their
prostate, which might cause an underestimation of
the impact of BPH if judged by measurement of cur-
rent symptoms alone.
Two large international studies recently reported on
the prevalence of LUTS in different populations.
Boyle, et al. published prevalence rates from the four
39
centers in the UrEpik study [12]. While there were
slight differences across the four centers, there was a
remarkable concordance in the age-related increases
in prevalence. Similar results were obtained in the
Multinational Survey of the Aging Male, [13] with
the prevalence of moderate-severe LUTS increasing
from 22% among men ages 50-59 years to 45%
among men ages 70-80 years.
Several unique populations also have been surveyed
in recent years. Tuncay Aki, et al [14] surveyed 257
men from a rural village of Turkey. The prevalence
of moderate-severe LUTS, as assessed by the IPSS,
increased from 10% among men in their forties to
40% among men age 70 years and older. Campbell
conducted a study of Ariaal men in Northern Kenya
[15] and found that among the men ages 22 to 96
years, the overall prevalence of moderate-severe
LUTS was 49% and that it was higher in the settled
men as compared to the nomadic (40% vs. 60%,
p=0.05). Age was positively correlated with IPSS in
both subpopulations. In a study conducted in New
Zealand, Gray, et al [16] found a similar strong rela-
tionship of the prevalence of LUTS measured with
age in men of European descent but not among men
of Maori or Pacific Island descent. The authors sug-
gested that this finding may be due to a “premature
aging process” but this notable exception to the near-
ly universal finding of a direct correlation of LUTS
with age deserves further follow-up.
In summary, there have been a number of studies in
recent years that have replicated the fairly consistent
finding of age related increases in the prevalence of
LUTS. There remains some variation in absolute
age-specific prevalences across settings and it is dif-
ficult to determine whether this variation represents
true differences or differences in interpretation of the
questions on the IPSS, despite rigorous efforts at
Figure 2. Mean incidence (red solid
line) and prevalence (green dotted line)
of lower urinary tract symptoms,
(LUTS) on the GPRD, 1992-2999 inclu-
sive. Incidence is new cases per 1,000
observed years, prevalence is existing
cases per 1,000 patients. [9]
translation. The expansion of studies beyond the use
of survey instruments may help disentangle these
potential explanations. It is encouraging that several
studies have attempted to be more comprehensive in
their assessment of LUTS. These studies have high-
lighted the need to take treatment and secondary
causes into account. Moreover, more studies have
begun to change their focus to risk (incidence) rather
than prevalence. The latter is a good measure for
population burden and the number of men who are
potentially treatable, but prevalence does not help
much with understanding etiology or potential tar-
gets for prevention or treatment.
III. RISK FACTORS
The purpose of this section is to review the recent
findings on risk factors for clinical manifestations of
BPH. In the following paragraphs, new data are sum-
marized on hormonal factors, growth factors, comor-
bid conditions and lifestyle that have been published
since the last Consultation. There have been a num-
ber of comprehensive reviews of risk factors for clin-
ical manifestations of BPH including the exception-
al review in 1992 by Guess, [17] the most recent
summary from the International Consultation, [18]
and a recent article by Newhouser et al [19]. For
studies published since 2000, we describe the study
sample, findings and summarize the state of knowl-
edge for each of these classes of potential risk fac-
tors.
1. SEX STEROIDS AND HORMONES
It is well accepted that BPH is androgen-dependent,
as castrate men do not develop BPH. Moreover, hor-
monal therapies are effective in reducing the mor-
bidity associated with this condition. Despite these
observations, there has been relatively little data
demonstrating a relationship between circulating sex
steroid levels, either androgens or estrogens, and
clinical manifestations of BPH at the population
level. To this end, three studies have been published
in recent years that have attempted to assess this
association.
The first was based on the Massachusetts Male
Aging Study [20]. In this study, 1,709 men were
recruited from randomly selected cites and towns
near Boston, Massachusetts, in the United States.
Baseline blood samples were measured for testos-
terone, free testosterone, dihydrotestosterone,
estrone and estradiol. The cohort was followed up by
40
questionnaire for up to nine years. Men who report-
ed frequent urination or difficulty urinating and were
told by a health professional that they had an
enlarged prostate or were surgically or medically
treated for BPH were considered to have a clinical
picture attributable to BPH. There was no associa-
tion with any of the baseline hormone levels or ratios
of hormone levels with this outcome.
Joseph et al. examined data from the Flint Men’s
Health Study [21]. They studied a random sample of
African-American men, ages 40-79 years, from
Flint, Michigan, in the United States. The investiga-
tors found that androstanediol glucuronide, estrone
sulfate and the ratio of estradiol to total testosterone
were all directly associated with prostate volume
after adjusting for age; while sex hormone-binding
globulin was inversely associated with prostate vol-
ume. After further adjustment for body mass index,
only sex hormone-binding globulin remained signif-
icantly associated with prostate volume. The authors
recognized the limits of their cross-sectional design.
It may be more appropriate to focus on the age-
adjusted associations reported in this study, as
adjustment for body mass index may be an example
of “over-adjustment.”
Roberts et al [22] examined data from the Olmsted
County Study. The study population is a random
sample of Caucasian men ages 40-79 years from
Olmsted County, Minnesota, in the United States.
These men were recruited in 1990 and have been fol-
lowed biennially thereafter. In the seventh biennial
examination, serum levels of testosterone, bioavail-
able testosterone, and estradiol were measured and
compared cross-sectionally with the IPSS, peak uri-
nary flow rate, prostate volume and serum PSA level.
There was no clear relationship between any one of
the urologic measures and any hormone level alone.
There was, however, a strong interaction between
bioavailable testosterone and estradiol levels, in that
among men with low levels of bioavailable testos-
terone, there was a monotonic increase in prostate
volume across tertiles of estradiol; whereas no asso-
ciation was observed between estradiol and prostate
volume among men with higher levels of bioavail-
able testosterone.
Thus, despite the evidence that histologic BPH is an
androgen-dependent condition, there is still little evi-
dence of an effect of hormone levels on clinical man-
ifestations of BPH that is measurable at the popula-
tion level. The crude observations related to castrat-
ed men represent extreme conditions. In less extreme
conditions, modest associations may be missed due
to the complicated and redundant pathways and
homeostatic mechanisms in sex steroid metabolism.
That is, as androgen levels decline, there may be a
resulting up- or down-regulation that compensates
for these shifts. There is some indirect evidence for
this hypothesis in the association in ratio measures in
the Olmsted County Study. Moreover, circulating
levels of hormones may not be a good indication of
intracellular levels where the biologic activity
occurs. There may be some hope in sorting out this
complex relationship through better-designed longi-
tudinal studies with multiple outcome measures and
in looking at the interaction between genes involved
in the androgen and estrogen pathways and their
interplay with circulating hormone levels.
2. GROWTH FACTORS
As with sex steroids, growth factors are thought to be
important in the etiology of histologic BPH. In par-
ticular, insulin-like growth factor 1 (IGF-1) is
thought to work through a proliferative mechanism
and/or anti-apoptotic mechanism [23]. Thus, a num-
ber of investigators have attempted to examine the
association between circulating growth factor levels
and clinical manifestations of BPH at the population
level.
Stattin and colleagues [24] performed a nested case-
control study within the Northern Swedish part of the
MONICA Trial. The investigators identified 60 men
who had been treated for a clinical picture attributed
to BPH and a set of controls, matched on age, sex
and city. The investigators thawed plasma samples
that had been frozen at -20ºC for 31/2 years and mea-
sured IGF-1 and its primary binding protein IGFBP-
3. These investigators found a modest but statistical-
ly insignificant trend in the association between IGF-
1 levels and a clinical picture suggesting BPH, after
adjustment for IGFBP-3. While longitudinally
designed, the very small number of men with BPH as
they defined it limited their ability to identify trends.
Chokkalingam and colleagues [25] provided further
insight by examining data collected as part of a case-
control study of prostate cancer in Shanghai, China.
For the substudy, cases were comprised of patients
admitted to Shanghai hospitals with a diagnosis com-
patible with BPH. Control subjects were randomly
selected from household registration records and
found not to have prostate cancer by digital rectal
examination and transrectal ultrasonography. These
investigators found that plasma IGF-1 levels were
higher in cases compared to controls (137.1 ng/ml
vs. 122.6 ng/ml, p<0.01), but there were no differ-
41
ences in IGFBP-3 levels. There were, however,
strong trends across the tertiles of plasma IGF-1 lev-
els (direct) and for IGFBP-3 levels (inverse after
adjustment for age and each other).
Sarma and colleagues [26] examined this association
in the Flint Men’s Health Study. They found that
prostate volume was not associated with IGF-1 lev-
els but IGFBP-3 levels were directly associated with
prostate volume. They found similar results in multi-
variable models accounting for other factors.
Roberts et al. examined data from the Olmsted
County Study [27]. They found that IGFBP-3 levels
were inversely associated with age, LUTS, prostate
volume and serum PSA level and directly associated
with peak flow rate. These associations all disap-
peared with adjustment for age, however. There was
an inverse association between serum IGFBP-3 lev-
els and prostate volume after adjustment for age and
IGF-1 levels. This association was not present for
symptoms or peak urinary flow rates.
More recently, Oliver and colleagues, [28] in a sub-
study of control subjects from a case-control study of
prostate cancer in the UK found that IGF-1 levels
increased with serum PSA level (r=0.14, p<0.001).
Moreover, the relationship was stronger in older ver-
sus younger men (p=0.05).
Taken together, these results suggest that there is
some association between growth factors and clini-
cal manifestations of BPH that is detectable at the
population level. It is not clear, however, whether it
is the growth factor or its binding protein that is most
important, but the data suggest that there may be
some dependency between these two. Of interest are
the discrepant findings from the Flint Men’s Health
Study. As a group, these studies represent method-
ologic advances for epidemiologic studies of BPH in
that they are all population-based rather than clinic
or practice based. However, most of the studies to
date, with the exception of the Swedish study, have
not had a longitudinal component. This makes it dif-
ficult to sort out the temporal sequence and therefore
cause and effect.
3. ERECTILE DYSFUNCTION
In recent years, several authors have tried to provide
further insight into the potential association between
clinical manifestations of BPH and erectile dysfunc-
tion (ED). Green and colleagues [29] reported on a
study of men ages 55-70 years who were identified
from patient lists of general practices in the United
Kingdom. Of the 4,060 men invited, 2,064 partici-
pated. These men were asked about their ability to
attain an erection sufficient for satisfactory sexual
activity. Men with ED were compared to those with-
out on the basis of prostate volume and peak urinary
flow rate. While age was associated with both ED
and prostate volume, these investigators found no
association between ED and prostate volume or peak
urinary flow rate.
Braun and colleagues [30] identified men between
the ages of 30 and 80 years from a population reg-
istry of the Cologne region in Germany. Of the 8,000
men contacted, 4,489 participated. Men responded to
a survey that assessed sexual function and the IPSS.
In contrast to the findings by Green et al., these
investigators found an association between sexual
function and LUTS severity, for the entire population
and within every age stratum.
Boyle and colleagues reported on data from the UrE-
pik study [12]. The sample was comprised of men
between the ages of 40 and 79 years selected in four
countries. Participants completed the O’Leary Brief
Male Sexual Function Inventory [31] and the IPSS.
These investigators found that in all four countries,
there was an association between LUTS severity and
erectile dysfunction and loss of libido after adjust-
ment for age. These findings were replicated by
Chung and colleagues using data from the Olmsted
County Study [32]. In this study, all five domains of
the Brief Male Sexual Function Inventory were asso-
ciated with LUTS severity. These relationships per-
sisted with adjustment for age, albeit they were
somewhat attenuated.
Table 1. Epidemiologic studies relating lower urinary tract symptoms with sexual dysfunction.
42
With the exception of the study by Green et al., most
studies have shown an association between ED and
clinical manifestations of BPH, even after taking into
account potential confounding by age (Table 1). To
date, there is no clear explanation of this association,
whether through a common pathway or some as yet
unmeasured confounding. While these studies were
community-based, all were cross-sectional. Longitu-
dinal studies could, perhaps, clarify this relationship.
4. CARDIOVASCULAR DISEASE
Other investigators have attempted to provide
insights into the relationship between cardiovascular
disease and clinical manifestations of BPH. Michel
et al [33] studied nearly 10,000 men who had sought
treatment for clinical presentations attributed to BPH
and were enrolled in a post-marketing study of tam-
sulosin. These men were sorted as to whether or not
they had hypertension on the basis of measured
blood pressure, diagnosed, or treated disease.
Regardless of how hypertension was determined,
there was an association between hypertension and
both LUTS severity and peak urinary flow rate that
persisted after adjustment for age. The interpretation
of these findings in the population context, however,
is difficult given the select sample. Weisman and col-
leagues examined the relationship between a clinical
diagnosis of BPH and history of coronary heart dis-
ease [34]. They performed a chart review of 702 men
seen in a urology practice. Serum PSA level was
used as a surrogate for prostate volume after exclud-
ing men on medication or with a condition that
would alter serum PSA level (n=562). Of the remain-
ing 140 men, 3 of 32 in the low PSA group and 31 of
108 of the high PSA group had coronary heart dis-
ease. There was no adjustment for age in these anal-
yses. Moreover, the measurements were of prevalent
disease and prostate volume, making the temporal
relationships difficult to sort out. Moreover, by
recruiting subjects from a referral population, the
potential for Berkson’s bias to influence the associa-
tion was increased.
Meigs and colleagues [20] reported on data from the
Massachusetts Male Aging Study. After adjustment
for age, these investigators found an inverse associa-
tion with measured systolic blood pressure and clin-
ical manifestation of BPH.
In summary, based on these studies, there is only
weak evidence of an association between clinical
manifestations of BPH and cardiovascular disease.
5. LIFESTYLE: DIET AND EXERCISE
In recent years several investigators have attempted
to look at lifestyle factors and their association with
BPH. Lagiou and colleages [35] conducted a hospi-
tal-based case-control study in Athens, Greece. Case
subjects had surgery for clinical problems attributed
to BPH and control subjects were selected from the
same hospital, matched to the age frequency of
prostate cancer cases collected in a parallel study. All
men completed a semi-quantitative food frequency
questionnaire adapted for the Greek diet. The inves-
tigators examined many food items for possible asso-
ciations. Of these, only added lipids (margarine and
butter) and potentially zinc demonstrated an associa-
tion. Overwhelmingly, the results were negative.
Gass and colleagues [36] conducted a population-
based cross-sectional study in Switzerland. Subjects
completed a questionnaire that included the IPSS and
reported whether or not they had had surgery for
BPH. Alcohol intake, coffee intake and smoking
habits were also assessed. Their results indicated that
alcohol was inversely associated with surgery for
BPH, coffee consumption was directly associated
and smoking was inversely associated with clinical
manifestations of BPH. The lowest prevalence of
BPH surgery was noted among men with the heavi-
est alcohol consumption but no coffee consumption.
Meigs and colleagues looked at a variety of factors in
the Massachusetts Male Aging Study cohort [20].
There was a trend towards greater physical activity
(more than 860 k/cal/day) being protective against
clinical manifestations of BPH. They also replicated
43
the finding of an inverse association with smoking
but found no association whatsoever with fat intake
or alcohol consumption.
Lacey and colleagues [37] conducted a case-control
study in Shanghai, China. They measured physical
activity by questionnaire and converted the respons-
es to metabolic equivalents. They found no associa-
tion with a diagnosis of BPH and physical activity.
Overall, these several studies of lifestyle factors
found no clear associations with clinical manifesta-
tions of BPH. Some of these negative studies may
have been due to the cross-sectional and case-control
study designs and the potential ambiguity about tem-
poral relationships inherent in these designs. This
limitation can be particularly problematic as activi-
ties can be affected by LUTS (need for proximity to
rest rooms). Moreover, diet, and in particular fluid
intake, may be changed in response to symptoms.
Thus, it is still not clear whether the lack of strong
associations is because they don’t exist or if there are
methodologic issues and/or unmeasured confounders
that explain the findings.
6. OVERALL SUMMARY
Over the last four years, there has not been a lot of
new information about risk factors for BPH. Much of
the work prior to this time used surgical therapy as
an outcome. This definition can be problematic as
factors related to access to and utilization of care
may confound relationships. Moreover, factors that
may make surgery a higher risk option could con-
found relationships as well. Even with the newer
studies, many employ designs and methodologies
that make it difficult to identify clear-cut associa-
tions. Even more so, the complex pathways and
potentially mixed phenotypes make it very difficult
to identify associations that may reflect risk factors
or cause and effect relationships. While somewhat
discouraging, this state of affairs actually presents an
opportunity for new breakthroughs. Longitudinal
studies of subjects with multiple occurrence mea-
sures relating to BPH may lead to important new
insights about factors that might be related to its
pathogenesis.
IV. NATURAL HISTORY
Prostatic enlargement due to histopathologic benign
prostatic hyperplasia (BPH) is common in older
men. In a significant proportion of these men, BPH
will lead to bladder outflow obstruction (BOO) or
other urodynamically characterized abnormalities of
the lower urinary tract such as detrusor overactivity,
incomplete bladder emptying or even acute urinary
retention (AUR). Although BPH rarely presents as a
life threatening condition nowadays, it is recognised
that it is a slowly progressive condition [38]. Never-
theless, the natural history of BPH is still incom-
pletely described and understood, although our
knowledge of the problem has significantly
increased since the previous Consultation in 2000.
The identification of factors that predict the occur-
rence of complications or clinical progression has
become an important goal of analytic epidemiology
because treatment strategies that could help to pre-
vent progression are emerging.
Since there is no generally accepted epidemiological
definition of clinically important BPH [39], the nat-
ural history is described separately for its various
clinical manifestations (symptoms, bother, quality of
life, acute urinary retention), pathophysiologic mea-
sures (urinary flow rate, post-void residual urine vol-
ume, pressure-flow study parameters), anatomic
measures (total prostate volume, transition zone vol-
ume) and biochemical measures (serum PSA and its
derivatives). Additionally, much attention has been
given to the analysis of predictive factors for pro-
gression, particularly in terms of acute urinary reten-
tion (AUR) and the need for surgery or invasive ther-
apy. Rates of surgery or invasive therapy for a diag-
nosis related to BPH are heavily influenced by
capacity of the health care system and therefore
problematic for comparing the natural history of
BPH across countries.
The available information on the natural history of
LUTS and/or BPH is derived from three types of
sources:
1. Longitudinal population-based studies.
2. Control groups of men in randomised comparative
studies of various treatment modalities.
3. Watchful waiting cohorts.
None of these designs is completely free of bias; the
very fact that measurements are taken or question-
naires are administered may modify the disease’s
natural history through the Hawthorne effect.
1. CLINICAL MANIFESTATIONS OF BPH
a) Lower Urinary Tract Symptoms
The prevalence of moderate and/or severe symptoms
44
as measured by the IPSS has been described in cross-
sectional surveys in various populations from many
countries around the world [40]. The most important
common theme that can be derived from these stud-
ies is an age-related increase in the prevalence of
moderate to severe LUTS across different cultures.
In recent years, a number of papers have been pub-
lished that have contributed to knowledge of longitu-
dinal changes and outcomes related to BPH. In 1996,
Jacobsen and colleagues [41] reported on longitudi-
nal changes in lower urinary tract symptom severity
in the Olmsted County cohort. In follow-up, there
was a great deal of movement across categories of
symptom severity. For example, of the men with
mild symptoms at baseline, 86% and 73% still
reported to have mild symptoms at the 18- and 42-
month follow-up respectively. At the 18- and 42-
month follow-up, 14% and 22%, respectively, of the
men who reported mild symptoms at baseline had
progressed to moderate to severe symptoms. In the
Olmsted county study, an age-related increase of
about 0.1 points per age year was noted in initial
cross-sectional analyses [42]. Longitudinally, how-
ever, an average increase in IPSS (AUASI) of
approximately 0.18 (95% confidence interval = 0.13,
0.24) points per year of follow-up was noted [42].
The average annual symptom score slope and vari-
ability in slope increased with age at baseline, with
considerable within-subject variability (Figure 3).
A 5-year follow-up study has been reported from
Austria in men (mean age 52 ± 12 years at baseline)
originally participating in a free-of-charge voluntary
health examination [43]. Of the eligible men, 53%
responded at follow-up. In these men, IPSS had
worsened in 50%, improved in 31% and remained
unchanged (i.e. exactly the same number of points)
in 19%. Moreover, the average IPSS had increased
from 4.6 ± 0.05 to 5.5 ± 0.24, or about 0.18 points
per year.
In another population-based study, the Krimpen
study from the Netherlands, a 4.2 years follow-up
has been reported [44]. Of the men, 10% improved
(IPSS decreased ≥ 4 points), 20% worsened (IPSS
increased ≥ 4 points) and 70% remained the same
symptomatically. The average increase was 0.9
points in 4.2 years or 0.21 points per year. Men who
were older had a greater increase from baseline dur-
ing the follow-up period.
The Medical Therapy of Prostatic Symptoms
(MTOPS) study was designed to determine whether
therapy with the alpha-blocker doxazosin or the 5-

alpha-reductase inhibitor finasteride, alone or in
combination, would delay or prevent clinical pro-
gression due to benign prostatic hyperplasia [45]. In
the placebo arm of the MTOPS study, the incidence
of a ≥ 4 points increase in IPSS (AUASI) was 36 per
1000 person-years [46]. At 4 years 14% of the men
in the placebo-arm had a ≥ 4 points increase in IPSS.
In contrast to the population-based studies, there was
a mean reduction of 4.9 points (median 4.0 points) in
the MTOPS placebo-group at 4 years. The median
baseline IPSS in the MTOPS placebo-group was
17.0. In the Olmsted County study and the Krimpen
study a median baseline IPSS of 5 (for men aged 40-
79 years) [42] and 4 points (for men aged 50-78
years) [47], respectively, was noted. The mean
reduction in IPSS in the MTOPS placebo group
probably reflects a regression to the mean among
MTOPS subjects, who were selected because of
higher symptom levels. On the other hand, it can be
expected that the rate of progression in terms of a ≥
4 points increase in symptom score is lower in the
MTOPS placebo group than in a population based
sample of men with a lower base line mean or medi-
an IPSS.
An average increase of about 0.2 points per year of
follow-up has thus been found in several population-
based studies with different designs. Furthermore,
50-80% of the individual men either improve or
remain the same symptomatically after a follow-up
of 1 to 5 years. Progression in terms of an increase in
symptom severity is seen in 20-50% of the men
depending on the definition of progression and the
type of population that is studied.
45
Figure 3. Six-year longitudinal changes in
International Prostate Symptom Score in the
Olmsted County Study. Each line connects the
score for an individual for up to four biennial
assessments. (Adapted from Sarma AV, et al.
[88]).
The difference between cross-sectional and longitu-
dinal data indicates that further studies of possible
baseline selection bias as an explanation of these dif-
ferences are necessary. It is already evident that
changes as noted in population based studies cannot
be extrapolated to placebo cohorts of clinical studies,
and vice versa.
b) Acute Urinary Retention (AUR)
The epidemiology of acute urinary retention (AUR)
is better understood in recent years and it has even
been demonstrated from randomized trials that,
probably, a portion of AURs can be prevented [47].
An AUR can occur spontaneously (that is without
any external triggering event) or can be provoked by
triggers like general or regional anesthesia, non-
prostate related surgery, transurethral instrumenta-
tion, certain medications that have an effect on lower
urinary tract function, excessive fluid (particularly
alcohol) intake and sexual activity.
In older studies of the occurrence of AUR the range
of the incidence rates has varied widely between 4
and 130 per 1000 person-years [48]. In more recent
studies, rates range from about 2 to 18 per 1000 per-
son-years (Figure 4).
Follow-up of the Olmsted County cohort has also
provided new information on the occurrence of
adverse events in community-dwelling men. Men
enrolled in the cohort were passively followed
through their medical record for the occurrence of
outcomes such as acute urinary retention [48]. For
the entire cohort, there were 8,344 person-years of
follow-up during which 57 men developed acute uri-
Figure 4. Incidence rate of acute urinary retention, per 1,000 person years, in community-based epidemiologic studies, the
placebo arms of randomized trials, and a longitudinal study of men with documented bladder outlet obstruction (BOO) [46,
48-54].

nary retention for a rate of 6.8 per 1000 person-years.
While the determination of factors precipitating an
episode of acute urinary retention can be difficult
through a review of medical records, there are sever-
al trends worth noting. Nearly half of all episodes of
acute urinary retention in this cohort were associated
with surgical procedures; nearly 90% of these were
performed under general anesthesia.
The relative risk of AUR appeared to be increased
for older men (3.5 to 11.6 times depending on symp-
tom severity), those with moderate to severe symp-
toms (3.2 times), those with a urinary flow rate less
than 12 ml/sec (3.9 times) and those with a prostate
volume of more than 30 cm3 as measured by tran-
srectal ultrasonometry (3.0 times). In a multivariate
analysis, age at baseline, symptom severity and
Qmax were independently predictive of AUR. The
number of events among men in whom prostate vol-
ume measurements were available was too small to
allow assessment of prostate volume in the multi-
variate analysis.
In the Health Professionals Follow-up Study 6100
men aged 45 to 83 years were followed for 3 years
[49]. The data generated in this study could be sub-
ject to recall bias. Furthermore there was no infor-
mation regarding the circumstances surrounding the
episodes of AUR. An incidence rate of 4.5 per 1000
person-years was reported. As in the Olmsted Coun-
ty study, the incidence increased with age and symp-
tom severity.
In the Proscar Long Term Efficacy and Safety Study
(PLESS), 1367 men with enlarged prostates and
moderate symptoms were followed for 4 years on
placebo treatment [50]. In this group of men the inci-
dence rate of AUR was 18 per 1000 person years.
The occurrence of acute urinary retention was inves-
tigated by Andersen et al. in a pooled analysis of
three placebo-controlled, randomized clinical trials
of two years of finasteride therapy (5 mg daily) in
men with benign prostatic hyperplasia [51]. These
studies involved a total of 4222 men with moderate-
ly symptomatic BPH: a total of 2113 men received
finasteride and 2109 placebo: an incidence rate of 14
per 1000 person years was found.
In the placebo-arm of the MTOPS study an AUR rate
of 6 per 1000 person years was noted, lower than the
rate of 18 per 1000 person years reported in the pre-
viously-published Proscar Long Term Efficacy and
Safety Study [47, 50].
Thomas and colleagues reported the follow-up of a
cohort of men aged more than 45 years with urody-
namically proved bladder outflow obstruction
(BOO) who opted not to be treated surgically [52].
Of 1068 men with BOO, 581 were alive at the time
of follow-up. Of these men 358 (62%) could be
studied. 170 men were followed with watchful wait-
ing for an average of 13.9 years. Of 29 men who
failed during follow-up, 7 did so because of an AUR.
The incidence rate of AUR therefore was 3.0 per
1000 person-years. Furthermore, in this follow-up
study, there was no significant increase in urody-
namic bladder outflow obstruction with time; how-

46
ever, a small but significant reduction in detrusor
contractility was seen. The authors identified older
age at presentation and greater prostate size (as indi-
cated by prostate length on urethral pressure profile)
at baseline as the only significant factors that pre-
dicted future failure (either AUR or significant
symptomatic deterioration leading to surgery).
Verhamme et al reported on a retrospective cohort
study in the Integrated Primary Care Information
(IPCI) database, a general practice research data-
base in the Netherlands, during the period 1995-2000
[53]. The study population comprised all males aged
45 years or older without a history of AUR. Amongst
56,958 males with a mean follow-up of 2.8 years,
344 AUR cases occurred (incidence rate 2.2 per 1000
person-years). Of these cases 77 (22.3%) were pro-
voked by surgical procedures. AUR was the first
symptom of LUTS/BPH in 49% of the AUR cases
occurring in men newly diagnosed with LUTS/BPH.
Since 49% of AUR cases amongst the LUTS/BPH
patients presented with AUR as the first symptom,
i.e. without previous contacts with a health care
provider, it is clear that earlier patient identification
is needed if we aim to reduce the incidence of AUR
by means of pharmacological treatment [54].
Presently this type of risk assessment is only possi-
ble in men who have seen a health care provider for
an assessment.
2. PHYSIOLOGIC MEASURES
a) Urinary flow rate (usually expressed as the max-
imal urinary flow rate or Qmax)
In an analysis of cross-sectional data from the Olm-
sted County study the peak urinary flow rate (Qmax)
decreased with age [55]. In a longitudinal analysis
from the same study, younger men showed a lower
percentage decrease per year than older men; men in
their 40’s at baseline had a 1.3% per year decrease,
whereas men in their 70’s had a 6.5 % per year
decrease [56]. The age related difference in rate of
decrease in the longitudinal analysis is in contrast to
the 2% decrease per year that was found to be con-
sistent across all age groups in the cross sectional
analysis. In sharp contrast to the decrease seen in the
population-based studies, there was a median
increase of 1.4 ml/sec in the MTOPS study placebo-
group at 4 years [47].
b) Post-void Residual Urine
Post-void residual urine measurements are highly
variable and single measurements with long periods
in between measurements are not very helpful in the
47
characterization of lower urinary tract function. The
occurrence of acute urinary retention as an adverse
outcome of BPH can be seen a special pathophysio-
logic variant of this phenomenon.
c) Pressure-flow Study Parameters
Thomas and colleagues also reported on serial uro-
dynamic parameters in the natural history study dis-
cussed above under AUR [52]. Among their 170 men
followed with watchful waiting for an average of
13.9 years, pressure-flow studies showed no signifi-
cant increase in bladder outflow obstruction with
time; however, a small but significant reduction in
detrusor contractility was seen. The prevalence of
detrusor overactivity had increased with follow-up.
In analogy to the other parameters described above it
should be clear that results from an analysis of
selected clinical cohorts (placebo groups or watchful
waiting cohorts) should be interpreted with caution.
Extrapolating these results to the general population
is inappropriate.
3. ANATOMIC MEASURES (TOTAL PROSTATE
VOLUME, CENTRAL HYPOECHOIC VOLUME)
Prostate volume is an important factor in the clinical
manifestations of BPH. In general, prostates of men
with the LUTS suggesting BPH tend to be larger.
Most often total prostate volume is assessed, but
with transrectal ultrasound it is also possible to selec-
tively measure the volume of the central part of the
prostate [57]. The central part, surrounding the ure-
thra, approximately corresponds to the transition
zone of the prostate. It is this part of the prostate that
is known to be most prone to histologic BPH [58].
Prostate volume is associated with age. The cross-
sectional analysis of the population-based Olmsted
County study has shown that among men aged 40-79
years, total prostatic volume increases approximate-
ly 0.6% per year of age, while central hypoechoic
part of the prostate increased 2.3% per year [59].
In the longitudinal analysis of the same study an
increase of 1.6% per year of follow-up was seen on
average. Furthermore, men with larger prostates at
baseline had a greater growth rate than men with
smaller prostates [60].
In a population based cross-sectional study of men
aged 55-75 years in Rotterdam, the Netherlands,
Bosch et al have shown that total prostate volume
increased 2% per year of age, whereas the central
hypoechoic part of the prostate increased 3.5% per
year of age [57].
In the MTOPS study’s placebo group, prostate vol-
ume increased by a median of 18% after 4 years, or
4.5% per year [46]. The mean baseline volume in the
MTOPS placebo group was 35 cc, compared to 29 cc
among Olmsted county men. This difference may
explain the faster growth rate in the former study.
In spite of the interesting information from these
studies, it remains unclear what proportion of men
actually exhibit a growing prostate. In an analysis of
prostate volumes measured longitudinally in the
population-based Krimpen study among men aged
50-78 years, intra- and inter-observer variability of
the transrectal ultrasound measurement was taken
into account in order to define a “true” change in
prostate volume [61]. In this study a true change in
volume was considered to exist if there was a mini-
mal absolute change of 10 cc or a minimal relative
change of 26%. Based on these two different
approaches and using the planimetric method of vol-
ume measurement, a real increase in prostate volume
after a follow-up of 4.2 years is found in 22.6% or
16.3% of the men using the 26% cut-off or the 10cc
cut-off, respectively. The 26% cut-off can detect a
true increase with greater sensitivity than the 10 cc-
cut-off. Irrespective of the cut-off, only a small per-
centage of men have a real decrease in prostate vol-
ume (<1.5%).
4. BIOCHEMICAL MEASURES
A number of cross-sectional studies have examined
the correlation between serum prostate-specific anti-
gen (PSA) and age, and between serum PSA and
prostate volume. In one study, 16 men without BPH
showed a PSA doubling time (PSAdt) ranging from
54 ± 13 years at age 40 to 84 ± 13 years at age 70,
whereas doubling times ranged from 2± 13 years at
age 40 to 17± 5 years at age 85, for 20 men with BPH
[62]. In the same study, 18 men with prostate cancer
were studied; those with local/regional disease had
doubling times of 2.4 ± 0.6 years.
Cross-sectional data from the Olmsted County study
have suggested that PSA increases 4% per cc of
prostate volume and that serum PSA concentration is
directly correlated with patient age and prostate vol-
ume, which are in turn correlated with each other
[63].
In an analysis of longitudinally determined PSA val-
ues in men without prostate cancer from the Krimpen
48
study, an increase of 5% in serum PSA per year of
increasing age was found [64]. PSA has been identi-
fied as a proxy for prostate volume in men in whom
prostate cancer has been excluded or is at least
unlikely [65, 66]. This impression has been based on
the analysis of data from clinical cohorts of men.
These studies seem to indicate that an enlarged
prostate (i.e. volume more than 30 cc) is very likely
if serum PSA is 1.5 ng/ml or higher. PSA performs
better in the estimation of prostate volume than dig-
ital rectal examination (DRE). The validity of this
approach has been confirmed for men in the commu-
nity [67]. Unfortunately, it is not possible to accu-
rately estimate prostate volume based on the serum
PSA level and patient age in individual men [66].
5. OVERALL SUMMARY
An average increase in IPSS of about 0.2 points per
year of follow-up has been found in several popula-
tion-based studies with different populations and
designs. Furthermore, 50-80% of the individual men
either improve or remain the same symptomatically
after a follow-up of 1 to 5 years. Progression in terms
of an increase in symptom severity is seen in 20-50%
of the men depending on the definition of progres-
sion and the population being studied.
In the longitudinal analysis of the Olmsted County
cohort, an increase of 1.6% in prostate volume per
year of follow-up was seen on average. Furthermore,
men with larger prostates at baseline had a greater
growth rate than men with smaller prostates. In sev-
eral studies, the central hypoechoic part of the
prostate increased faster than the total prostate vol-
ume. PSA has been identified as a proxy for prostate
volume; but, unfortunately, it is not possible to accu-
rately estimate the prostate volume based on the
serum PSA level and patient age in individual men.
An analysis of data from clinical cohorts and popu-
lation-based data has shown that age at baseline,
symptom severity, Qmax and prostate volume are
predictive of the risk of AUR. Since about 50% of all
new AUR cases among men with LUTS attributed to
BPH present without previous contacts with a health
care provider, it is clear that earlier patient identifi-
cation is needed to reduce the incidence of AUR by
means of pharmacological treatment. Presently this
type of risk assessment is only possible in men who
have seen a health care provider for an evaluation.

V. GENETIC MARKERS OF RISK
AND PROGRESSION FOR BPH
1. INTRODUCTION
Benign prostatic hyperplasia (BPH) is common
among aging men. A better understanding of its
pathogenesis is evolving, particularly from the
development of molecular epidemiological studies
of similar complex diseases. BPH is multifactorial
and heterogeneous in its potential causes, which may
include environmental, endocrine and genetic fac-
tors. The study of the interactions between genes and
multifactorial diseases has expanded in recent years.
DNA polymorphisms in genes involved in hormone
synthesis, signaling and metabolism may, therefore,
be involved in these changes. Furthermore, identifi-
cation of the genetic determinants of age-related
changes in the prostate could provide insights for
risk assessment, prevention and new therapeutic tar-
gets.
2. BENIGN PROSTATIC HYPERPLASIA (BPH)
SUSCEPTIBILITY GENES
Age-related changes in the size of prostate gland and
associated lower urinary tract symptoms are vari-
able. A large proportion of older men have prostate
enlargement while only a few show prostate involu-
tion. The age-related prostate enlargement is due to
benign prostatic hyperplasia marked by the develop-
ment of fibro-muscular (mesenchymal) nodules that
occur in the periurethral gland with associated glan-
dular (epithelial) hyperplasia. The process takes
years, with the first microscopic changes of BPH
beginning at about age 35. The incidence of histo-
logic BPH is fairly consistent across national and
ethnic groups, with the prevalence of BPH increas-
ing with age in all male populations. The
etiopathogeny of BPH remains unclear. A disruption
in the endocrine/autocrine-paracrine prostatic home-
ostasis, involving growth factors and steroid hor-
mones, is likely a key factor. These molecular alter-
ations may contribute to the pathogenesis of BPH
and could be enhanced by specific biologic suscepti-
bility or genetic predisposition in association with
exposure to environmental factors.
Several specific etiologic hypotheses have been put
forward based on histologic, hormonal [68, 69] and
age-related changes resulting in an increase in the
stem cell population and a decrease in cell death.
There are two factors necessary for BPH to occur:
49
the presence of dihydrotestosterone (DHT) and
aging. The importance of DHT in prostate growth
after puberty has been shown in patients with con-
genital deficiency of 5-a reductase, the enzyme
responsible for conversion of testosterone to DHT
[70]. Affected males have ambiguous genitalia at
birth, but at puberty the availability of normal levels
of testosterone causes [71] normal virilisation, func-
tional erections, and ejaculation. The low levels of
serum DHT, however, result in a vestigial prostate
that never develops BPH.
The effects of aging on the prostate are manifold.
Serum testosterone levels decrease due to decreased
stimulation of Leydig cells and increased conversion
of testosterone to estrogen in the peripheral tissues
and the prostate [72, 73]. The relative roles of andro-
gens and estrogens in inducing BPH are complex and
not completely understood. It is known that patients
with genetic disorders of androgen function have
poor prostatic growth and that castration prior to
puberty prevents BPH. Castration in patients who
already have clinical manifestations of BPH has lit-
tle therapeutic effect. A probable explanation is that
androgens are required for the initiation and proba-
bly for progression of BPH, but not for its mainte-
nance. The role of estrogen may be to initiate stromal
hyperplasia, which, in turn, induces epithelial hyper-
plasia through androgen-induced mediators, such as
growth factors. Prostate Growth Factor (PrGF) was
the first growth factor isolated from prostate; it
induces proliferation of fibroblasts and was subse-
quently identified as basic Fibroblast Growth Factor
and renamed fibroblast growth factor-2 (bFGF
/FGF2) [74]. Ultimately, endocrine pathways may
only be permissive in BPH pathogenesis, influencing
the prostatic microenvironment to modulate the
direct mediators, peptide growth factors. The fibrob-
last growth factor family contains at least 14 mem-
bers, including acidic (FGF1) and basic fibroblast
growth factor (FGF2), keratinocyte growth factor
(FGF7) [75] and FGF8, which are possibly involved
in both normal and abnormal prostatic growth.
Although distinct receptors have been identified and
described with high affinity for FGF1, FGF2 and
FGF7, all members of the fibroblast growth factor
family can signal through common tyrosine kinase
receptors. Four independent genes (FGFR1, FGFR2,
FGFR3 and FGFR4) encode for four FGF receptors
with several isoforms, which share 50%-75% homol-
ogy. However, fibroblast growth factors are not the
only growth factors involved in BPH pathogenesis,
as studies of gene expression in BPH have shown the
involvement of genes related to prostatic embryolo-
gy, angiogenesis, and inflammatory cytokines as
well [76, 77].
The possible role of familial factors in the develop-
ment of BPH has been established, and a heritable
form of BPH has been suggested with a dominant
Mendelian transmission for a gene found in 7% of
men with BPH (89% lifetime penetrance), providing
the most likely explanation for familial aggregation
of clinical manifestations of BPH with an early age
of onset [78]. Recently, Pearson and colleagues have
shown that a family history of clinical manifestations
of BPH significantly enhances the risk of LUTS and
surgery for BPH among family members [79].
Few allelic variations have been studied in men with
BPH. Some genetic polymorphisms affecting andro-
gen receptor or metabolism genes or growth factor
pathways or alpha 1-adrenoceptor gene variants have
been studied for associations with BPH. The fre-
quencies of the different alleles of the alpha 1a-
adrenoceptor polymorphism were not different
between patients with BPH and normal subjects and
did not provide any evidence to support the hypoth-
esis that the alpha 1a-adrenoceptor gene is associat-
ed with BPH [80]. In another study, a variant NQO1
allele was slightly more frequent in benign prostatic
hyperplasia patients but did not correlate with a sig-
nificant risk for BPH [81]. It has been suggested that
variability in an AR gene CAG repeat influences the
development of symptomatic BPH, particularly in
predicting obstructive urinary symptoms [82].
Cussenot and colleagues have also correlated AR
gene CAG repeat length with age related prostate
weight. The results showed a correlation between an
increasing AR gene CAG repeat length and a lower
risk for prostate overgrowth. These data support the
hypothesis that AR gene CAG repeat length predicts
BPH risk. Moreover, it has also been demonstrated
that polymorphisms in CYP17 enzyme gene,
involved in testosterone synthesis, are also correlat-
ed with the risk of BPH [83]. Conversion of testos-
terone to its major intraprostatic metabolite, dihy-
drotestosterone (DHT), is catalysed by the enzyme
5alpha-reductase type 2. The fact that different alle-
les of the 5alpha-reductase type 2 gene may be asso-
ciated with different levels of 5-alpha-reductase
activity and thereby perhaps BPH and prostate can-
cer risk has motivated studies of ethnic variation in
the allelic distribution of this gene. Two main poly-
morphisms in the 5-alpha reductase gene have been
studied. On the one hand, the VL89 mutation, which
replaces valine at codon 89 with leucine, reduces
50
5alpha-reductase activity. On the other hand, the
AT49 mis-sense substitution results in an alanine
residue at codon 49 being replaced with threonine.
Increased conversion of testosterone to dihy-
drotestosterone catalysed by the AT49 variant has
been considered as a significant contributor to the
incidence of prostate cancer in about 8% of African-
American and Hispanic men in the US. Regarding
BPH, no clear correlation with 5-alpha reductase
polymorphisms have been establish with BPH
risk[83, 84], but these polymorphisms change the
power of inhibition of the enzyme by the 5-alpha
reductase inhibitors finateride or dutasteride [85].
Recently , investigators have shown that a specific
polymorphism in the fibroblast growth factor for
FGF8: FGFR4, as well as a transforming growth fac-
tor-beta 1 gene polymorphism could be both associ-
ate with the likelihood of prostate enlargement [86,
87].
Based on these findings, it would appear that genet-
ic mechanisms can explain at least some component
of BPH initiation and progression, justifying future
studies that may lead to new therapeutic approaches
based on pharmacogenomics.
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L, Cancel-Tassin G, Fournier G, Mangin P, De The H, Cussenot
O: Age related changes in human prostate are associated with
the FGFR4 ARG388 allele. J Urol 2004; 171(4 supp): 348-349.
87. Li Z, Habuchi T, Tsuchiya N, Mitsumori K, Wang L, Ohyama C,
Sato K, Kamoto T, Ogawa O, Kato T: Increased risk of prostate
cancer and benign prostatic hyperplasia associated with trans-
forming growth factor-beta 1 gene polymorphism at codon10.
Carcinogenesis 2004; 25(2): 237-240.
88. Sarma A, Jacobsen S, Girman C, Jacobson D, Roberts R,
Rhodes T, Lieber M: Concomitant longitudinal changes in fre-
quency of and bother from lower urinary tract symptoms in
community dwelling men. J Urol 2002; 168: 1446-1452.

53
54
 CHAPTER 3

Committee 3B

Epidemiology of Benign Prostatic

Hyperplasia in Asia

Chairman
M. MURAI (JAPAN)

Members
CH. CHENG (SINGAPORE),
R. KHAULI (LEBANON),
E. LEE (KOREA),
R.M. SAHABUDDIN (MALAYSIA),
K. SASIDHARAN (INDIA),
T. TSUKAMOTO (JAPAN),
L. ZHOU (CHINA)

55
 CONTENTS

I. INTRODUCTION II. GENE POLYMORPHISM

1. PREVALENCE OF BPH III. COMPLICATIONS OF BPH

a) Histologic or Autopsy Prevalence
b) Clinical Prevalence
IV. CURRENT SURGICAL
c) Racial Differences TREATMENT OF BPH
d) Medical Care
e) Symptom Severity
V. CONCLUSION
f) Nocturia
g) Bother, Interference, and Health-related quality
of Life
REFERENCES
h) Urethral Function
i) Clinical Bph and PSA
ANNEX 1
Tuberculous Prostatitis

56
 Epidemiology of Benign Prostatic
Hyperplasia in Asia
M. MURAI
CH. CHENG, R. KHAULI, E. LEE, R.M. SAHABUDDIN , K. SASIDHARAN, T. TSUKAMOTO,
L. ZHOU
I. INTRODUCTION
Traditionally in East Asian countries, socio-cultural
atmosphere of accepting lower urinary tract symp-
toms (LUTS) as a natural part of aging process has
been dominant. However, countries like Japan or
Korea are quickly becoming an “aging society” and
the ever-growing public interest in their health and
well-being, public awareness towards BPH has been
increasing rapidly along with the number of patients
who visit hospitals seeking medical care for voiding
symptoms. Thus, it can be expected that BPH will
soon become a major issue with regard to public
health and welfare in these countries, as is already
the situation for many western countries.
1. PREVALENCE OF BPH
a) Histologic or Autopsy Prevalence
There have been no Asian studies about the presence
of histologic BPH on a surgical specimen or, in the
case of autopsy series, in whole prostates removed
after death from men not dying of prostate conditions
since 2000. In BPH patients, racial differences in cel-
lular composition in Caucasian-American (CA),
African-American (AA), and Japanese (JP) men
were studied by Aoki et al. The stained cores were
quantitatively analyzed for the percentage of the area
with different cellular composition (stroma (S),
epithelium (E), epithelial lumen (L), and glandular
component (E + L = G)), using computer-assisted
color imaging. The mean percent area density of S,
E, and L in the prostate of CA men was 84.2, 12.1,
and 3.8%, respectively; for AA, 84.4, 12.4, and
3.2%; for JP, 77.4, 15.2, and 7.5%. The S/E ratio is
57
significantly lower in JP than in CA men. The S/G
ratio is significantly lower in JP than in CA and AA
men (Table 1). Overall, JP contained more glandular
lumen and less stromal component than that of CA
and AA. CA and AA showed no significant differ-
ence in cellular composition [1].
b) Clinical Prevalence
There is no globally accepted clinical definition of
BPH, and, thus, clinical prevalence and incidence
rates must be viewed in the context of the definitions
chosen by the investigator. In 1996, Masumori et al.
compared prostate volume and peak urinary flow
rate in Japanese and American men 40 to 79 years
old. Prostate volume and peak urinary flow rate were
measured in eligible Japanese men and results were
compared to those of a randomly selected American
cohort. According to their data, mean prostate vol-
ume averaged 20.3 ± 10.6 ml. in Japanese and 29.6 ±
13.4 ml. in American men, while predicted cross-
sectional increases with age decade were 1.5 and 5.5
ml, respectively. Peak urinary flow rate was higher
but the decrease with increasing age was greater in
Japanese men. Therefore, prostate volume is larger
and the increase with age is more pronounced in
American than in Japanese men (Figure 1). Howev-
er, Japanese men may have a higher peak urinary
flow rate and greater cross-sectional decrease with
age[2]. Looking at the data from Korean men in a
community-based study in 1998, the prevalence of
LUTS among Korean men may actually be similar to
that of westerners. According to the results of a com-
munity-based study, 23.2% of Korean men 50 or
older complained of moderate to severe degree of
LUTS (IPSS ≥ 8) likely to be associated with BPH
based on evaluation with IPSS questionnaire.
Table 1. Cellular Component of the Prostates among Three Races
P value
CA AA JP (ANOVA)
WHOLE PROSTATE
Stroma (%) 84.2 (1.9) 84.4 (1.5) 77.4 (1.2) 0.0042*
Epithelium (%) 12.1 (1.4) 12.4 (1.3) 15.2 (0.8) 0.1529
Epithelial lumen (%) 3.8 (0.6) 3.2 (0.3) 7.5 (0.5) <0.0001*
S/E ratio 9.3 (1.5) 8.4 (1.4) 5.4 (0.4) 0.0730**
S/G ratio 7.2 (1.2) 6.6 (1.1) 3.6 (0.3) 0.0281***
TRANSITION ZONE
Stroma (%) 79.9 (2.9) 83.6 (2.2) 75.5 (1.3) 0.0481¶
Epithelium (%) 15.3 (2.3) 13.1 (1.8) 16.6 (1.0) 0.3903
Epithelial lumen (%) 4.9 (0.8) 3.2 (0.5) 7.9 (0.5) <0.0001§
S/E ratio 8.3 (1.6) 10.3 (2.6) 5.4 (1.4) 0.0956¶
S/G ratio 6.2 (1.2) 7.6 (1.6) 3.2 (0.2) 0.0329+
PERIPHERAL ZONE
Stroma (%) 88.5 (1.6) 85.0 (2.5) 78.9 (2.0) 0.0070***
Epithelium (%) 8.9 (1.2) 11.9 (2.1) 14.0 (1.3) 0.0741**
Epithelial lumen (%) 2.6 (0.6) 3.2 (0.5) 7.0 (0.8) <0.0001*
S/E ratio 15.7 (3.4) 10.8 (1.7) 7.5 (1.7) 0.0637**
S/G ratio 12.5 (2.7) 8.3 (1.3) 5.4 (1.5) 0.0383**

S/E ratio, storoma-to-epithelial ratio; S/G ratio, storoma-to-glandular ratio; grandular component, stroma + epithelium.
Data presented as the mean with standard error in parentheses.
*JP p<0.01 vs. CA/AA, **JP p<0.05 vs. CA, ***JP p<0.05 vs. CA/AA, ¶JP p<0.01 vs. AA, §JP p<0.05 vs. CA, JP p<0.01 vs.
AA, +JP p<0.05 vs. AA
(Data published in Aoki, Y., et al.: Racial differences in cellular composition of benign prostatic hyperplasia. Prostate, 49: 243-
250, 2001)

Figure 1. Destination of prostate volume and maximum flow rate for participants in community-based study in Shimamaki-
mura, Japan and Olmsted County, USA. (Data published in Masumori, N., et al: Japanese men have smaller prostate vol-
umes but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol,
155: 1324-1327, 1996)

58
Assessing by the age group, the prevalence of LUTS
were 17.7 %, 23. 3%, and 35.3 %, respectively, in
those who were 50-59 years, 60-69 years, and 70 or
older [3]. The comparison of prevalence of moderate
to severe LUTS among various countries is shown
Table 2A and 2B, based on the published data until
1999.
c) Racial Differences
To identity differences in prevalence of symptomatic
BPH between different ethnic groups residing within
metropolitan Kuala Lumpur, IPSS, Qmax and
prostate size were measured from 575 volunteers
aged 50 and above. The prevalence of moderate to
severe lower urinary tract symptoms (LUTS) in
Malays, Chinese and Indians were 70 %, 59 % and
50 %, respectively (p=0.004). The mean prostate size
was 25.1cc. There is no significant difference in term
of maximal flow rate and prostate size among
Malays, Chinese and Indians in Malaysia [4].
d) Medical Care
Because Japan is a rapidly aging society and men
aged 55 or older are expected to increase from 15
million in 1995 to 21 million in 2010, the number of
patients receiving treatment for BPH is increasing.
Terai et al. analyzed several nationwide health statis-
tics by the Ministry of Health and Welfare of Japan.
The cross-sectional surveys revealed that the esti-
mated total number of patients receiving treatment
increased from 202,000 in 1987, to 335,000 and
590,000, respectively, in 1995 and 1998. Approxi-
mately 73-80% of patients were men aged 65 years
or over and 94-98% were 55 years or older. The inci-
dence of prostatectomies remained relatively stable
at 50,000/year (3.0-3.8 prostatectomies /1,000 men
aged 55 or over). The total cost of BPH therapy near-
ly doubled between 1988 and 1998. The total value
of the market for medical therapy increased from 30-
40 billion yen in 1989 to more than 80 billion yen in
1998. The application of alpha-blockers increased
from 243,000 men (70% of all patients) in 1995 to
452,000 (77%) in 1998, whereas the number of
patients taking antiandrogens, plant extracts and
antispasmodic agents/ Ca antagonists (for pollak-
isuria), respectively, remained relatively stable at
60,000-70,000, 180,000 and 300,000 [5].

Table 2A. Prevalence of moderate to severe lower urinary tract symptoms among various countries.

Country Mode of evaluation Age No. of subjects Prevalence (%)

USA AUA-7 40-80 2,119 28
Canada AUA-7 50-70 508 23
The Netherlands IPSS 55-74 502 30
Japan AUA-7 55-87 961 27.6
Korea IPSS 50-70 514 23.2

Table 2B. Prevalence of moderate to severe lower urinary tract symptoms according to age group in various countries.

Countries Prevalence (%)

50-59 years 60-69 years 70-79 years
USA 31 36 44
Canada 15 27 31
France 8 14 27
The Netherlands 26 30 36*
Japan 29 31 56
Korea 18 23 35†

† * Examined for subjects 70-74 years old † Examined for subjects 70 years or older
(Data published in Jeong MK. Epidemiology of BPH. Lee HM, editor; Textbook of benign prostatic hyperplasia.
The Korean Prostate Society. 2004, pp 95-104)

59
e) Symptom Severity
International Prostate Symptom Score (IPSS) has
been widely accepted to use in the research of LUTS
and BPH. To evaluate linguistic validity of the
Japanese version of International Prostate Symptom
Score (IPSS) and BPH Impact Index (BII), the trans-
lation was performed by Homma et al. The develop-
ers generally approved the translation, but had 2
major concerns in the Japanese version; 1) “how
often” in every sentence of English version was not
translated into Japanese, and 2) the Japanese expres-
sion in the response choices of QOL index should be
more emotional. The former concern was compro-
mised by placing a sentence at the beginning of the
questionnaire explaining that the response should be
considered in frequency [6]. They also evaluate psy-
chometric properties of the Japanese version of Inter-
national Prostate Symptom Score (IPSS) and BPH
Impact Index (BII). It was not significantly affected
by age, symptom severity, institution type, or
whether the patients were asked symptoms during
the last week or during the last month. Japanese
translations of IPSS and BII were shown to be reli-
able, valid and one-dimensional instruments in the
Japanese patients. They would be equivalent to the
original English questionnaires [7].
Masumori et al. evaluated the IPSS and QOL score
of 235 outpatients having lower urinary tract symp-
toms and 242 participants in a community-based
study of Japanese men aged 50 to 79 years old.
Although the proportion of outpatients in the severe
IPSS category (IPSS 20 to 35) was greater than that
in the participants of the community-based study in
each age decade, the proportion in the moderate
IPSS category (IPSS 8 to 19) in both groups over-
lapped each other. On the other hand, the distribution
of QOL scores was considerably different, with only
a small portion of overlap in each age decade (Fig-
ure 2). Although scores for both voiding symptoms
(incomplete emptying, intermittency, weak stream,
and hesitancy) and storage symptoms (increased fre-
quency, urgency, and nocturia) were significantly
greater in outpatients than in study participants in
each age decade, the difference was more obvious
for voiding symptoms than for storage symptoms
[8].
The approximate 50% of sixth and seventh decade
males, classified to the middle level of symptom in
Japan [9]. Their study focused on elucidating
60
changes of the lower urinary tract symptoms (LUTS)
and changing of voiding condition with aging in the
subjects, who offered the health checks. They evalu-
ated urinary function in 225 Japanese males (age 20-
79), estimated IPSS, QOL score, uroflowmetry,
residual urine. QOL scores, IPSS, prostate volume
and residual urine were significantly increasing relat-
ed to age, and advanced age was associated with a
decline of voiding volume and Qmax.
Comparison of QOL scores and IPSS criteria demon-
strated a significantly positive correlation with
incomplete emptying and a weak stream. A signifi-
cant negative correlation was found between the
QOL score and Qmax. The distribution of middle
level of symptom, divided by clinical guideline for
BPH, significantly increased with age.
In 1999, data from community-based studies were
published from Korea. It was reported that 27.8% of
Korean men between the age of 40 to 89 have BPH
when applying diagnostic criteria of enlarged
prostate with size of 20 g or larger and IPSS of 8 or
higher [10]. In another study, the prevalence of BPH
in Korea was assessed to be 21.8% by implementing
diagnostic criteria of enlarged prostate on digital rec-
tal exam, maximum flow rate of 15mL/sec or lower,
and IPSS of 8 or higher [11].
When assessed by the age group, the prevalence of
BPH in Korea were 3.6%, 12.6%, and 24.1%,
respectively, in those who were in their sixth, sev-
enth, and eighth decade.
In Malaysia, 18.9 % and 39.6 % of the men volun-
tary participated the study were severely and moder-
ately symptomatic, respectively. The mean peak flow
rate of the subjects was 15.4 ml/s. 20.9 % and 55.2
% of the subjects had peak flow less than 10 ml/sec
and 15 ml/sec, respectively. The prevalence of symp-
tomatic benign prostate enlargement (BPE) was 39.3
%. The prevalence increased 8 % per decade from
41.7 % for men aged 50 to 59 to 65.4 % for men aged
70 or more [4].
f) Nocturia
Nocturia is one of main symptoms of patients with
BPH, although it is not specific. Homma et al. stud-
ied the relationship of nocturia with the IPSS in men
with lower urinary tract symptoms due to BPH in
219 consecutive Japanese men. The results indicate
that the nocturia score is least specific to symptoms
associated with BPH or least sensitive to the thera-
 a) 50-59

(Data published in Masumori, N., et al.: Lower urinary tract symptoms of men seeking medical care--comparison of symptoms
found in the clinical setting and in a community study. Urology, 62: 266-272, 2003)

Figure 2. Destination of QOL scores for participants in community-based study and outpatients having LUTS in each group
in Shimamaki-mura, Japan

61
peutic effect on symptoms. This finding may be
related to the high nocturia score in the age matched
control population [12]. Similar results were
obtained the data from the study of 505 newly diag-
nosed patients with symptomatic BPH [13]. Patient
age, score of urgency, and functional bladder capac-
ity were each significantly associated with nocturia.
Tamsulosin therapy and TURP significantly reduced
the number of episodes of nocturia in 17.9% and
32.2% of patients, respectively. These rates of
improvement were lowest for nocturia among the
seven individual symptom scores. They also exam-
ined the prevalence of and risk factors for nocturia in
Kurashiki city and the surrounding area, a rural area
in Japan [14]. They collected data on 4568 men as
well as 1949 women who participated in a multipha-
sic health screening. Overall, 1856 individuals
(28.5%) answered that they arose to urinate at least
twice during the night. This rate increased with age
from 16.5% in individuals younger than 50 to 60.0%
in those older than 69. Surprisingly, gender was not
associated with nocturia. In male individuals, BPH
was an independent positive risk factor (OR 1.35).
Hypertension (odds ratio [OR] 1.64) and DM (OR
1.70) were other independent positive risk factors for
nocturia. On the other hand, current smokers who
smoked 20 or more cigarettes per day were less like-
ly to have nocturia than non-smokers (OR 0.72).
g) Bother, Interference, and Health-related quality
of Life
Bother and interference with activities of daily living
caused by each factor of LUTS are not equal. To
investigate which factors are most bothersome to
preoperative patients with BPH a total of 423 newly
diagnosed patients and 388 preoperative patients
with symptomatic BPH were evaluated. Japanese
patients with BPH generally suffer from weak
stream, feeling of incomplete emptying and nocturia
in all disease phases. Frequency is problematic for
newly diagnosed patients and urgency is problemat-
ic for preoperative patients as well. Symptom-specif-
ic QOL of BPH patients cannot be estimated by
physically measurable variables [15].
In Malaysian men with clinical BPH, the commonest
bothersome symptoms were nocturia (56 %), fre-
quency (50.4 %) and sense of incomplete voiding
(43.5 %). A good correlation was found between the
total symptom score and the single disease-specific
quality of life question (r=0.69, p<0.001). The corre-
62
lation between IPSS and peak flow rate (r=-0.22,
p<0.001) and prostate volume (r=0.11, p=0.009) was
weak. There was no correlation between IPSS and
age (r=0.06, p=0.17) [4].
h) Urethral Function
Nakai et al. examined the potential correlation
between urethral function and LUTS in Japanese
men with BPH. There was a positive correlation
between hesitancy and detrusor bladder neck
dyssynergia (P = 0.0011) and between incomplete
emptying and low bladder neck pressure at maxi-
mum cystometric capacity (P = 0.0425). The hesitan-
cy proved to have no correlation with bladder neck
opening time.
Urodynamic evaluation of urethral function was ben-
eficial for attributing LUTS to clinical BPH. Among
various parameters, detrusor bladder neck dyssyner-
gia (P = 0.0011) was the most specific to clinical
BPH, suggesting it to be a situation where a steep
rise in bladder neck pressure or prostatic urethral
pressure remains greater than the increasing intra-
vesical pressure, resulting in sustained difficulty in
opening the bladder neck and subsequently the sub-
jective sensation of hesitancy [16].
i) Clinical BPH and PSA
Mean serum PSA increased with age, and the corre-
lation of PSA and prostate volume was determined to
be statistically significant in each cohort of age. A
correlation coefficient ranged from 0.315 to 0.439
from the data of 218 Japanese patients confirmed to
have BPH by histological examination [7]. Gupta et
al. compared the relationship between serum
prostate specific antigen (PSA) and indexes of
prostate volume in Japanese men with the one in
white men. PSA, total prostate volume and transition
zone volume increased almost linearly with age.
On univariate regression with age with each succes-
sive decade total prostate volume increased by
10.65% (95% CI 5.4 to 16.2), transition zone volume
increased by 20.84% (95% CI 11.84 to 30.56) and
the transition zone index increased by 3.1% (95% CI
1.66 to 4.57). On multivariate analysis the PSA-total
prostate volume relationship was statistically inde-
pendent of age. The study suggested that Japanese
men might produce or release more PSA per unit
prostate volume than white men (Figure 3) [18].
 Prostate volume (cm3)
(Data published in Gupta, A., et al: Relationship between
prostate specific antigen and indexes of prostate volume in
Japanese men. J Urol, 173: 503-506, 2005)
Figure 3. PSA - Total Prostate Volume Relation-
ship in Japanese and White Men
II. GENE POLYMORPHISM
There have been reports analytical studies address
the polymorphism of several genes relating BPH
from Japan since 2000. The CYP17 gene (CYP17)
codes for the cytochrome P450c17alpha enzyme,
which mediates two key steps in the sex steroid syn-
thesis. There is a polymorphism (a T-to-C substitu-
tion) in the 5’-untranslated region, which may influ-
ence the transcription level of CYP17 mRNA.
Habuchi explored the association between CYP17
polymorphism and a risk of BPH in a Japanese pop-
ulation. There was a significant difference (P < 0.05)
in the genotypes between BPH patients and male
controls. Men with the A1/A1 CYP17 genotype had
an increased risk of BPH (odds ratio (OR), 2.44;
95% CI = 1.26-4.72) compared with those with the
A2/A2 genotype [19]. They also focused on the asso-
ciation of polymorphisms in the 3’-untranslated
region (3’UTR) of the vitamin D receptor (VDR)
gene with BPH risk in Japanese men. In the BsmI
polymorphism, heterozygosity or homozygosity for
the absence of the BsmI restriction site was associat-
ed with one-half the risk of BPH (P < 0.005; odds
ratio, 2.07; 95% confidence interval, 1.33-3.22)
compared with the male controls (Table 3) [20].
63
CCND1 mRNA is alternatively spliced to produce 2
transcripts, and the splicing pattern may be modulat-
ed by a frequent A870G single-nucleotide polymor-
phism within the conserved splice donor site of exon
4. The A allele of the CCND1 A870G polymorphism
was recessively associated with susceptibility to
BPH in a Japanese population, giving a 2-fold
increased risk of BPH in men with the AA genotype
compared to those with the GG genotype [21].
Transforming growth factor-beta 1 (TGF-beta1)
plays a significant role in regulating the proliferation
and apoptosis of prostate epithelial and stromal cells.
Li explored the association between the T (Leu) to C
(Pro) polymorphism at codon10 of the TGF-beta1
gene (TGFB1) and the risk of BPH in 221 patients
and 303 male controls in Japan.
There were significant differences in the CC versus
TC + TT genotype distribution between BPH
patients and male controls (P=0.041). Males with the
TC or TT genotype had a 1.51-fold increased risk of
BPH (95% CI=1.02-2.24, P=0.041) compared with
those with the CC genotype, therefore suggesting the
dominant effect of the TGFB1 T allele on develop-
ment of BPH [22].
By a search for novel human imprinted genes in the
vicinity of the imprinted gene MEST, at chromo-
some 7q32, Kayashima et al. identified the car-
boxypeptidase A4 gene (CPA4) in a gene cluster of
the carboxypeptidase family, 200 kb centromeric to
MEST. RT-PCR using four intragenic polymor-
phisms as markers showed that CPA4 was preferen-
tially expressed in the BPH. These findings support
that CPA4 is imprinted and may become a strong
candidate gene for prostate cancer-aggressiveness
[23].
Insulin-like growth factor-I (IGF-I) also plays an
important role in prostate growth, hyperplasia, and
carcinogenesis. Circulating IGF-I levels may be
modulated by a genetic cytosine-adenine (CA)
repeat polymorphism in the promoter region of IGF-
I. The 19-CA-repeat allele (19-allele) was more fre-
quently observed in BPH patients compared with the
controls (BPH versus control: P=0.001). Compared
with non-carriers of the 19-allele, men homozygous
for the 19-allele had a significantly increased risk of
BPH (age-adjusted odds ratio (aOR) = 3.53, 95% CI
= 1.32-9.46, P=0.012), and those heterozygous for
the 19-allele also had an intermediate increased risk
of BPH (aOR = 1.66, 95% CI = 1.14-2.43, P=0.009).
The 19-allele of IGF-I appears to increase the risk of
BPH with a gene dosage effect in the Japanese pop-
ulation [24].
Table 3. Odds ratio by Bsml genotype in Vitamin D receptor in Japanese

Allele frequency (%) Non-age-adjusted Age-adjusted

bb Bb + BB OR (95% CI) P OR (95% CI) P
Prostate cancer 172 (77.5) 50 (22.5) Prostate cancer
n = 222 vs. Male 3.44 (2.15–5.49) <0.0001 3.31 (2.05–5.32) <0.0001
BPHn = 209 145 (69.4) 64 (30.6) Prostate cancer 1.52 (0.99–2.34) 0.0567 1.67 (1.07–2.61) <0.05
vs. BPH
Male control 64 (50.0) 64 (50.0) BPH vs. Male 2.27 (1.44–3.57) <0.0005 2.07 (1.33–3.22) <0.005
n = 128
Female control 153 (77.3) 45 (22.7)
n = 198
(Data published in Habuchi, et al.: Association of vitamin D receptor gene polymorphism with prostate cancer and benign pro-
static hyperplasia in a Japanese population. Cancer Res, 60: 305-308, 2000.)

both cost effectiveness and overall usefulness, while

III. COMPLICATIONS OF BPH
Levi et al. have considered trends in mortality from
benign prostatic hyperplasia (BPH) over the last
decades in Europe and, for comparative purposes,
the USA and Japan. Between the early 1950s and the
late 1990s, overall mortality from BPH in the Euro-
pean Union (EU) fell from 5.9 to 3.5 per million, and
the decline since the late 1950s was over 96%. Com-
parable falls were observed in the USA and Japan,
and BPH mortality rates in the late 1990s were lower
than in the EU (1.8/106 in the USA, 1.4 in Japan)
[25].
IV. CURRENT SURGICAL
TREATMENT OF BPH
In Japan, Seki et al. conducted a questionnaire sur-
vey concerning the prevalence and preference with
regard to various types of surgical treatment for
benign prostatic hypertrophy (BPH), in order to
gather preliminary data that may be helpful for stan-
dardizing the surgical treatment of BPH in Japan.
The questions dealt with the type and volume of sur-
gical treatment experienced previously, and the treat-
ments which had been performed in each institute
during 2000. Of the 155 institutes to which the ques-
tionnaire was sent, 70 responded (45% response
rate). TUVP (transurethral vaporization of the
prostate by thick-loop) was second to TURP
(transurethral resection of the prostate) both regard-
ing the volume of the surgical treatment that had
been experienced previously, and the volume that
had been performed during 2000. TURP was recog-
nized as the most preferred treatment with regard to
TURF (transurethral radiofrequency thermotherapy)
was preferred both for safety and reduced invasive-
ness, and open surgery for efficacy. Minimal inva-
sive surgical treatment, such as TUVP, followed by
ILCP (interstitial laser coagulation of the prostate)
and TUMT (transurethral microwave thermotherapy)
was recognized as the most preferable treatment for
dealing with the prevalence from now on at general
hospitals [26].
V. CONCLUSION
Because some Asian countries are rapidly becoming
aging society and men aged 55 or older are continu-
ously increasing. In Japan, the total value of the mar-
ket for medical therapy increased almost twice from
in 1989 to in 1998. In the community-base series,
Asian men have much smaller average prostate vol-
ume than Caucasian-American or African-American
people. On the other hand, Japanese contains more
glandular tissue and less stromal component than
Caucasian- American or African-American does. In
Japanese men, total prostate volume and transition
zone volume increased almost linearly with age.
Japanese men might produce or release more PSA
per unit prostate volume than white men.
The clinical prevalence of LUTS among Asian men
seems to be similar to that of westerners. In
Malaysia, the prevalence increased 8 % per decade
from 41.7 % for men aged 50 to 59 to 65.4 % for men
aged 70 or more. However, there is no significant
difference in term of maximal flow rate and prostate
size among Malays, Chinese and Indians in
Malaysia.

64
In Japan, the studies focused on nocturia have been
published. The results indicate that the nocturia score
is least specific to symptoms associated with BPH or
least sensitive to the therapeutic effect on symptoms.
Patient age, score of urgency, and functional bladder
capacity were each significantly associated with noc-
turia.
There were some analytical studies to address the
polymorphism relating BPH. The polymorphism in
several genes is associated with an increased risk of
BPH. However, there were not enough data indicat-
ing the difference the incidence of specific gene
polymorphism between in Asian men and other
races. Additionally, no polymorphism is specific for
BPH so far. Further studies are necessary to deter-
mine which polymorphism is definitive the symp-
tomatic BPH.
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1. Aoki, Y., Arai, Y., Maeda, H., Okubo, K., and Shinohara, K.
Racial differences in cellular composition of benign prostatic
hyperplasia. Prostate, 49: 243-250, 2001.
2. Masumori, N., Tsukamoto, T., Kumamoto, Y., Miyake, H.,
Rhodes, T., Girman, C. J., Guess, H. A., Jacobsen, S. J., and
Lieber, M. M. Japanese men have smaller prostate volumes but
comparable urinary flow rates relative to American men: results
of community based studies in 2 countries. J Urol, 155: 1324-
1327, 1996.
3. Lee, E., Yoo, K. Y., Kim, Y., Shin, Y., and Lee, C. Prevalence of
lower urinary tract symptoms in Korean men in a community-
based study. Eur Urol, 33: 17-21, 1998.
4. Teh, G. C., Sahabudin, R. M., Lim, T. C., Chong, W. L., Woo, S.,
Mohan, M., Khairullah, A., and Abrams, P. Prevalence of symp-
toatic BPE among Malaysian men aged 50 and above attending
screening during prostate health awareness campaign. Med J
Malaysia, 56: 186-195, 2001.
5. Terai, A., Kakehi, Y., Terachi, T., and Ogawa, O. [National trend
of management of benign prostatic hyperplasia in Japan during
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537-544, 2000.
6. Homma, Y., Tsukamoto, T., Yasuda, K., Ozono, S., Yoshida, M.,
and Shinji, M. [Linguistic validation of Japanese version of Inter-
national Prostate Symptom Score and BPH impact index]. Nip-
pon Hinyokika Gakkai Zasshi, 93: 669-680, 2002.
7. Homma, Y., Tsukamoto, T., Yasuda, K., Ozono, S., Yoshida, M.,
and Yamaguchi, T. [Evaluation of psychometric properties of
Japanese version of international prostate symptom score and
BPH impact index]. Nippon Hinyokika Gakkai Zasshi, 94: 560-
569, 2003.
8. Masumori, N., Tanaka, Y., Takahashi, A., Itoh, N., Ogura, H.,
Furuya, S., and Tsukamoto, T. Lower urinary tract symptoms of
men seeking medical care—comparison of symptoms found in
the clinical setting and in a community study. Urology, 62: 266-
272, 2003.
9. Soga, N. and Sugimura, Y. [Analysis of changes in lower urinary
tract symptoms with aging]. Nippon Hinyokika Gakkai Zasshi,
95: 766-772, 2004.
10. Lee, H.-L., Seo, J. W., and Kim, W.-J. The prevalence of benign
prostatic hyperplasia: Community-based study in Chungbuk
Province. Korean J Urol, 40: 1500-1511, 1999.
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11. Chung, T. G., Chung, J., and Lee, M.-S. Prevalence of benigpro-
static hyperplasia in Jeong-Eup area. Korean J Urol, 40: 52-58,
1999.
12. Homma, Y., Yamaguchi, T., Kondo, Y., Horie, S., Takahashi, S.,
and Kitamura, T. Significance of nocturia in the International
Prostate Symptom Score for benign prostatic hyperplasia. J Urol,
167: 172-176, 2002.
13. Yoshimura, K., Ohara, H., Ichioka, K., Terada, N., Matsui, Y.,
Terai, A., and Arai, Y. Nocturia and benign prostatic hyperplasia.
Urology, 61: 786-790, 2003.
14. Yoshimura, K., Terada, N., Matsui, Y., Terai, A., Kinukawa, N.,
and Arai, Y. Prevalence of and risk factors for nocturia: Analysis
of a health screening program. Int J Urol, 11: 282-287, 2004.
15. Yoshimura, K., Arai, Y., Ichioka, K., Terada, N., Matsuta, Y., and
Okubo, K. Symptom-specific quality of life in patients with
benign prostatic hyperplasia. Int J Urol, 9: 485-490, 2002.
16. Nakai, H., Yamanishi, T., Yasuda, K., Kitahara, S., and Suzuki, T.
Correlation between lower urinary tract symptoms and urethral
function in benign prostatic hyperplasia. Neurourol Urodyn, 23:
618-622, 2004.
17. Furuya, Y., Ohta, S., Sato, N., Kotake, T., and Masai, M.
Prostate-specific antigen, prostate volume and transition zone
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prostatic hyperplasia. Int Urol Nephrol, 33: 645-648, 2001.
18. Gupta, A., Aragaki, C., Gotoh, M., Masumori, N., Ohshima, S.,
Tsukamoto, T., and Roehrborn, C. G. Relationship between
prostate specific antigen and indexes of prostate volume in
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19. Habuchi, T., Liqing, Z., Suzuki, T., Sasaki, R., Tsuchiya, N.,
Tachiki, H., Shimoda, N., Satoh, S., Sato, K., Kakehi, Y., Kamo-
to, T., Ogawa, O., and Kato, T. Increased risk of prostate cancer
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20. Habuchi, T., Suzuki, T., Sasaki, R., Wang, L., Sato, K., Satoh, S.,
Akao, T., Tsuchiya, N., Shimoda, N., Wada, Y., Koizumi, A., Chi-
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tor gene polymorphism with prostate cancer and benign prostat-
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308, 2000.
21. Wang, L., Habuchi, T., Mitsumori, K., Li, Z., Kamoto, T.,
Kinoshita, H., Tsuchiya, N., Sato, K., Ohyama, C., Nakamura,
A., Ogawa, O., and Kato, T. Increased risk of prostate cancer
associated with AA genotype of cyclin D1 gene A870G poly-
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22. Li, Z., Habuchi, T., Tsuchiya, N., Mitsumori, K., Wang, L.,
Ohyama, C., Sato, K., Kamoto, T., Ogawa, O., and Kato, T.
Increased risk of prostate cancer and benign prostatic hyperpla-
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morphism at codon10. Carcinogenesis, 25: 237-240, 2004.
23. Kayashima, T., Yamasaki, K., Yamada, T., Sakai, H., Miwa, N.,
Ohta, T., Yoshiura, K., Matsumoto, N., Nakane, Y., Kanetake, H.,
Ishino, F., Niikawa, N., and Kishino, T. The novel imprinted car-
boxypeptidase A4 gene ( CPA4) in the 7q32 imprinting domain.
Hum Genet, 112: 220-226, 2003.
24. Tsuchiya, N., Wang, L., Horikawa, Y., Inoue, T., Kakinuma, H.,
Matsuura, S., Sato, K., Ogawa, O., Kato, T., and Habuchi, T. CA
repeat polymorphism in the insulin-like growth factor-I gene is
associated with increased risk of prostate cancer and benign pro-
static hyperplasia. Int J Oncol, 26: 225-231, 2005.
25. Levi, F., Lucchini, F., Negri, E., Boyle, P., and La Vecchia, C.
Recent trends in mortality from benign prostatic hyperplasia.
Prostate, 56: 207-211, 2003.
26. Seki, N., Naito, S., Oshima, S., Hirao, Y., and Higashihara, E.
[Prevalence and preference with regard to various surgical treat-
ments for benign prostatic hypertrophy: a survey for the Japanese
endourology and ESWL society member]. Nippon Hinyokika
Gakkai Zasshi, 94: 495-502, 2003.
 ANNEX 1
Tuberculous Prostatitis
Tuberculous Prostatitis has been depicted as a rare
disease in most of the case reports published [1, 2].
However, these reports do not reflect the true inci-
dence since evidently many cases remain without
reporting or diagnosed in many endemic pockets and
susceptible groups especially in developing coun-
tries. The survey of currently accessible literature
discloses a global distribution of its occurrence.
Cases of tuberculous prostatitis have been reported
from a number of countries such as India, Pakistan,
Bangladesh, Cuba, Spain, Russia and Japan [3-8].
There are discernible indications that increase in
infection with the human immunodeficiency virus
(HIV) will escalate the incidence of tuberculous pro-
statitis [9,10]. HIV effectively blunts the cell-medi-
ated immunity, the principal host defence against
infection with mycobacterium tuberculosis and thus
aiding and abetting the resurgence of the disease in
many parts of the globe [11]. Recently a higher inci-
dence of granulomatous prostatitis was found in
patients who had been treated with intravesicle
Bacillie Calmette-Guerin [12-14].
The issue of modes of tuberculous involvement of
the prostate has generated divergent views. Two pro-
posed routes of dissemination are haematogenous
and direct intracanalicular extension or combination
of both. There is overwhelming clinical, experimen-
tal and autopsy evidence indicating haematogenous
route as the principal mode of tuberculous involve-
ment of the prostate [15].
In developing countries where the disease has
endemic pockets and patients seek medical redress
with pronounced urogenital disease, an intracanalic-
ular route of prostatic involvement should be reck-
oned as a distinct possibility. Analysis of such cases
clearly discloses renal, ureteral and vesical disease
stigmata, whereas there is no such consistent associ-
ation when the prostate acquires tuberculosis exclu-
sively through haematogenous routes. Documenta-
tion of tuberculous prostatitis does not differ drasti-
cally from tuberculous lesions elsewhere in the body.
The traditional methods such as direct microscopy,
66
and culture of the materials harvested from the
lesions are validated investigations and assumes
importance when histological picture is equivocal.
Clinical recognition of tuberculous prostatitis
remains elusive in a fair number of cases and the dis-
ease is disclosed histologically only after
transurethral resection or prostatic enucleation for
prostatic hyperplasia and accidently in biopsies of
the prostate [16, 17]. Symptoms of cases belonging
to this subset are rather non-specific and merge with
those produced by benign prostatic hyperplasia.
Many patients in this group do not volunteer any pre-
vious history of tuberculosis nor bear any categorical
stigmata of the disease. On going tuberculosis activ-
ity in the prostate produce a variety of symptoms
such as urinary frequency, urgency, dysuria, bloody
ejaculate and haematuria. These symptoms are more
pronounced when prostatic urethra is involved
through descending infection from concurrently
infected bladder and upper tracts.
In Indian sub-continent where tuberculosis is endem-
ic in many areas, tuberculosis is reckoned as one of
the possible causes haematospermia and as well as
refractory prostatitis. However, in one retrospective
study in Japan of 107 patients with haematospermia
by Jinzas, Noguchi and Hoska there was only one
case of documented genital tuberculosis [18].
Previous history of pulmonary tuberculosis or tuber-
culous epididymo-orchitis can be extracted in some
cases of tuberculous prostatitis and provide strong
circumstantial clue for a clinical diagnosis. Tubercu-
lous epididymo-orchitis may precede tuberculous
prostatitis by several years or simultaneously coex-
ist. This concomitance is more evident in the regions
of significant disease prevalence such as India Eval-
uation of the male factor in infertile men infrequent-
ly discloses genital tuberculosis. A very recent study
by Dhole revealed a history of urogenital inflamma-
tion in 5 – 12 % of men attending infertility clinics
[19]. Spontaneous prostato-rectal fistulization due to
entrenched tuberculosis of the prostate is an uncom-
mon manifestation of the disease [20-21]. The rarity
of its reportage in literature is, perhaps, no true
reflection of its occurrence. There is unpublished
data emanating from few Indian centers indicating its
incidence more frequent than literature would indi-
cate [22]. Some of the tuberculosis afflicted prostates
by virtue of their nodularity and induration may sim-
ulate adenocarcinoma of prostate on digital rectal
examination [23]. However, the coexistence of car-
cinoma and tuberculosis of the prostate is extremely
rare [24].
In recent literature there has been increasing stress
on the value of CT and sonography in the documen-
tation of intra and periprostatic events such as non
specific and specific abscesses [25, 26]. Their utility
in the diagnosis of advanced urinary tract tuberculo-
sis has also been emphasized [27] (Figures 1, 2). Figure 1. Intraprostatic calcific foci - Tuberculous pro-
Sonographic features of prostatic abscesses run gen- statitis
erally parallel to CT findings. The echographic
images of a prostatic abscess consist of hypoechoic
cystic lesions inside an enlarged prostate [28].
The advent of cross-section imaging has dented to
some extent the reliance on cystourethrography as
the principal imaging modality in the diagnosis of
tuberculosis of the prostate. There has also been
some criticism in recent years of the non specific
character of cystourethrography. Conventional cys-
tourethrography, however, in selected cases contin-
ues to extract exquisite details of many intraprostat-
ic events which tuberculosis engender. These include
the depiction of intra prostatic cavitations, peripro-
static tracks and overt prostato-rectal fistulization
(Figure 3). Few recent reports have described MR
appearance of tuberculosis of the prostate [29]. Dif- Figure 2. Tuberculosis prostatic abscess extending on to
fuse radiating streaky low signal intensity lesion in anterior abdominal wall (HIV-positive 52 year old gentle-
the prostate ( watermelon skin sign ) on T2 weighted man)
images are presumably specific for tuberculosis of
the prostate and not seen in carcinoma of the prostate
[29].
Tuberculosis of the prostate shows adequate
response to 6 months triple drug regimen of
rifampin, ethambutol and isoniazid [30]. In earlier
literature there was stress on relatively protracted
course of chemotherapy stretching over 9 months for
tuberculosis [31]. However, subsequent literature is
replete with reports recommending shorter courses
[32 – 33].
Prostatic tuberculous abscesses will require decom-
pression. In selected cases some of them can be
sonologically targeted and transcutaneously aspirat-
ed. However, transurethral deroofing is the most
appropriate form of therapy in most of the abscesses. Figure 3. Large prostate-rectal fistula

67
The tenacious content and multi loculated character
of some abscesses make the transcutaneous route
rather ineffective. Prostato-rectal fistulas, a rare
complication of tuberculosis of the prostate, sponta-
neously close in most of the instances after the insti-
tution of chemotherapy. Few larger and refractory
ones, however, will require surgical closure and rein-
forcement with omental interposition [34].
Tuberculous prostatitis generally has no permicious
portents and is managed adequately by medical ther-
apy and appropriate surgical intervention when indi-
cated. The disease contour, however is adversely
impacted when it occurs in conjunction with infec-
tion with immuno deficiency virus (HIV) and long
term survival is exceptional in such cases [22].
REFERENCE
1. Tazi K, Nouri M, Elkhadir K, el Ghorfi A, Ibnattya A, Hachimi
M, Lakrissa A. Prostatic tuberculosis – Report of 2 cases. Ann
Urol( Paris) 1999; 33: 274-6
2. Fujikawa K, Matsui Y, Fukuzawa S, Soeda A, Takeuchi H.
Scand J Urol Nephrol 1999; 33: 268-9
3. Lanjewar DN, Maheshwari MB. Prostatic tuberculosis and
AIDS. Natl Med J India 1994 ; 7 : 166-7
4. Rafique M, Rafique T, Rauf A, Bhutta RA. Tuberculosis of
prostate. J Pak Med Assoc. 2001; 51: 408-10
5. Gafur MA, Talukder MS, Siddiqua SS. Tuberculous prostatitis –
a case report. Mymensingh Med J. 2002 ; 11: 39-41
6. Ochoa Urdangarain O, Chavez Olivera R, Sanchez Baez A,
Cabrera Gomez YJ. Prostatic tuberculosis. Report of a case. Arch
Esp Urol 1996 ; 49 : 523-4
7. Duarte Ojeda JM, Garcia Luzon A, Carrero VM, Vazquez S,
Calahorna L, Passas J, Levia O. Tuberculous prostatic abscess
in a patient with AIDS. Actas Urol Esp 1995; 19: 655-6
8. Kamyshan IS, Biazrov ST, Pogrebinskii VM. Diagnosis of
tuberculosis of the prostate. Probl Tuberk 1985 ; 9: 53-5
9. Helene Lupatkin, Norbert Brau, Phyllis Flomenberg, and
Michael S.Simberkoff. Tuberculous abscesses in patients with
AIDS. Clinical Infections Diseases 1992; 14: 1040-4
10. Gebo KA. Prostatic tuberculosis in an HIV infected male. Sex
Transm Infect. 2002; 78: 147-8
11. Collin’s FM. The immunology of Tuberculosis. Am Rev Respir
Dis 1982:125:42-9
12. Lamm DL, Stogdill VD, Stogdill BJ, and Crispen RG. Compli-
cations of bacillus Calmette- Guerin immunotherapy in 1,278
patients with bladder cancer. J Urol 1986; 135:272-4.
13. Gorse G J, Belshe RB. Male genital tuberculosis: a review of the
literature with instructive case reports. Rev Infect Dis
1985;7:511-24.
14. Mukamel E, Konichezky M, Engelstein D, Cytron S, Abranovici
A Servadio C. Clinical and pathological findings in prosates fol-
lowing intravesical bacillus Calmette- Guerin instillations. J Urol
1990 ; 144:1399-400
15. Sporer A, and Greenberger ME. Experimental studies on the
pathogenesis of renal tuberculosis. An. Rev. Tuberc1950;61:508
16. Kostakopoulos A, Economou G, Picaramenos D, Tuberculosis of
the prostate. Int Urol Nephrol 1998 ; 30: 153-7
17. Lenk S, Guddat HM, Rothkopf M, Brien G. Tuberculous pro-
statitis within the scope of urogenital tuberculosis – pathogenet-
ic and diagnostic aspects. Z Urol Nephrol. 1987; 80: 9 – 15
18. Jinza S, Noguchi K, Hosaka M. Retrospective study of 107
patients with hematospermia. Hinyokika kiyo 1997 ; 43: 103-7
19. Dohle GR. Inflammation- associated obstructions of the male
reproductive tract. Andrologia 2003; 35: 321-4
20. Okaneya T, Ogawa A, Wajiki M. Tuberculous rectourethral fistu-
la. Urology 1988; 31: 424-6
21. Rabii R, Fekak H, el Manni A, Joual A, Benjelloun S, el Mrini
M. Tuberculous prostato-rectal fistula. Prog Urol 2002; 12: 684-
6
22. Personal data and unpublished communication
23. Saw KC, Hartfall WG and Rowe RCG. Tuberculous Prostatitis:
Nodularity may simulate malignancy. Br J Urol 1993 ; 72: 24.
24. Stay E J. Tuberculosis and adenocarcinoma of prostate gland.
Urology 1980 ; 16: 422-24.
25. Washecka R, Rumancik WM. Prostatic abscess evaluated by seri-
al computed tomography. Urol Radiol 1985 ; 7: 54-56.
26. hornhill BA, Morehouse HJ, Coleman P, Hoffman-Tretin Jc. Pro-
static Abscess: CT and sonography findings AJR 1987; 899-900
27. Wang JH, Chang T. Tuberculosis of the prostate: CT appearance.
J Comput Assist Tomagr 1991; 15: 269-70
28. Nakao M, Toyoda K. A case prostatic tuberculosis: Usefulness of
transrectal ultrasound in diagnosis. Hinyokika Kiyo 1998; 44:
117-20
29. Wang JH, Sheu MH, Lee RC. Tuberculosis of the prostate: MR
appearance. J comput Assist Tomogr 1997 ; 21: 639-40
30. Lee Y, Huang W, Huang J, Wong J, Yu C, Jiwan B, Huang J. Effi-
cacy of chemotherapy for prostatic tuberculosis – a clinical and
histologic follow up study. Urology. 2001; 57:872-7
31. Bailey WC, Albert RK, Davidson PT. Treatment of tuberculosis
and other mycobacterial diseases: an Official Joint Statement of
the American Thoracic Society and the centers for Disease Con-
trol. Am Rev Respir Dis 1983; 127: 790-796.
32. Fox W: Whither short course chemotherapy ? Br J Dis Chest
1981; 73: 331- 357
33. 49. Gow JG, and Barbosa S: Genitourinary tuberculosis: a study
of 1117 cases over a period of 34 years. Br J Urol 1984 ; 56:
449-455
34. Okaneya T, Ogawa A, Waji K, M. Tuberculous rectourethral fis-
tula. Urology 1988; 31: 424-6.

68
 CHAPTER 4

Committee 5

Lower Urinary Tract Symptom: Etiology,

Patient Assessment and Predicting
Outcome from Therapy

Chairman
P. ABRAMS (UK)

Members
C. D’ANCONA (BRAZIL),
D. GRIFFITHS (USA),
P. VAN KERREBROECK (THE NETHERLANDS),
O. NISHIZAWA (JAPAN),
V. NITTI (USA),
F. KEONG TATT (SINGAPORE),
A. TUBARO (ITALY),
A. WEIN (USA)

Consultant
M. BELAL (UK)

69
 CONTENTS
A. INTRODUCTION
B. LOWER URINARY TRACT
SYMPTOMS
I. DEFINITION OF SYMPTOMS
II. LUTS IN THE COMMUNITY,
IN RELATION TO AGE
III. STORAGE SYMPTOMS
IV. NOCTURIA
V. VOIDING SYMPTOMS
C. PATIENT ASSESSMENT
I. HISTORY & PHYSICAL
EXAMINATION
II. FREQUENCY-VOLUME CHARTS
III. SYMPTOM SCORES
IV. PHYSICAL EXAMINATION
V. URINALYSIS
VI. BIOCHEMICAL TESTING
VII. POST-VOID RESIDUAL URINE
VIII. IMAGING
IX. ENDOSCOPY OF THE LOWER
URINARY TRACT
D. URODYNAMICS
I. INTRODUCTION
II. DIAGNOSING BLADDER OUTLET
OBSTRUCTION: PRESSURE-
FLOW STUDIES
70
III. PRESSURE FLOW STUDIES :
RELATIONSHIP WITH OTHER
MEASUREMENTS
IV. CLINICAL UTILITY OF NON-
INVASIVE MEASUREMENTS
V. PATHOPHYSIOLOGY OF
DETRUSOR OVERACTIVITY AND
BLADDER OUTLET OBSTRUCTION
VI. WHEN IS OBSTRUCTION
SIGNIFICANT CLINICALLY?
VII. URODYNAMICS IN
PROSTATE CANCER
VIII. RECOMMENDATIONS:
WHAT URODYNAMICS SHOULD BE
DONE, AND WHEN?
E. PREDICTING OUTCOME
AFTER THERAPY
I. WATCHFUL WAITING
II. MEDICAL TREATMENT
III. ACUTE URINARY RETENTION
IV. SURGICAL TREATMENT
V. DETRUSOR OVERACTIVITY AND
BLADDER OUTLET OBSTRUCTION
VI. ACUTE URINARY RETENTION
AND SURGERY
VII. PREDICTIVE/PROGNOSTIC
VALUE OF URODYNAMICS
F. RESEARCH QUESTIONS
REFERENCES
 Lower Urinary Tract Symptom:
Etiology, Patient Assessment and
Predicting Outcome from Therapy

P. ABRAMS
C. D’ANCONA, D. GRIFFITHS , P. VAN KERREBROECK, O. NISHIZAWA,, V. NITTI,
F. KEONG TATT, A. TUBARO, A. WEIN , M. BELAL

during filling/storage. Additionally, the term “irrita-

A. INTRODUCTION
Historically, the term “prostatism” was applied to
almost all symptoms which referred to micturition in
the older man. The term unfortunately implied that
the cause of the problem was the prostate which, in
later years, was found clearly not to be the case in
many instances. The term Lower Urinary Tract
Symptoms (LUTS: Abrams, 1994) has been adopted
as the proper terminology to apply to any patient,
regardless of age or sex, with urinary symptoms but
without implying the underlying problem. “Pro-
statism” was initially divided into “irritative” and
“obstructive” symptoms, but it became obvious that
there was a poor correlation between so-called
“obstructive” symptoms and urodynamic diagnosis
of bladder outlet obstruction and also between so-
called “irritative” symptoms and a urodynamic diag-
nosis that related to definable abnormalities seen
Table 1. LUTS
tive” implied, to some people, an infectious or
inflammatory process. Thus, the division of LUTS
into “filling/storage symptoms and emptying/void-
ing symptoms” was suggested (Abrams, 1994),
(Table 1).
LUTS replaced the term “prostatism” in the mid
1990s yet the urological community has continued to
misuse the term “BPH”.
The terminology with respect to prostate characteris-
tics has also changed. Abrams (1994) was the first to
suggest a reconsideration of the use of the term
“BPH” and a redefinition of terminology. He pointed
out that BPH was a histological diagnosis that had
been shown to occur in 88% of men older than 80
years. He added that, in some patients, the prostate
gland enlarged, and this condition should be distin-
guished from BPH and referred to as benign prostat-
ic enlargement (BPE). In approximately half of
patients with BPE, he stated that true bladder outlet
obstruction resulted, a condition which should be
termed benign prostatic obstruction (BPO). “BPH”

FILLING / STORAGE EMPTYING / VOIDING POST VOIDING SYMPTOMS

Frequency Hesitancy Post-micturition Dribbling
Urgency Straining to Void Feeling of Incomplete Emptying
Nocturia Poor Stream
Urgency Incontinence Intermittency
Stress Incontinence Dysuria
Nocturnal Incontinence Terminal Dribbling
Bladder / Urethral {Pain
Absent or Impaired Sensation

71
was previously an all encompassing term that includ-
ed prostate size, benign prostate histology and all
filling/storage or voiding/emptying symptoms
thought related to the prostate pathophysiologically
in the adult male. The current terminology recog-
nizes the imprecise and misleading implications of
the previous usage of this phrase. The terminology
related to the prostate is currently expressed as fol-
lows:
• BPH - Benign Prostatic Hyperplasia. This term is
used and reserved for the typical histopathological
pattern which defines the condition.
• BPE – Benign Prostatic Enlargement. This refers
to prostatic enlargement due to a benign cause,
generally histological BPH. If there is no prostat-
ic histologic examination available, then the term
is presumptive of a benign cause for enlargement,
usually assessed by digital rectal examination.
• BPO – Benign Prostatic Obstruction. This is a
form of bladder outlet obstruction (BOO, see
below). This term may be applied when the cause
of the outlet obstruction is BPE, due to a benign
cause, generally histological BPH.
• BOO is a term for any cause of bladder outlet
obstruction, and defined by urodynamics. It
should be noted that there are other causes of
“BOO” than prostatic enlargement (Table 2).
• “LUTS suggestive of BPO”, recommended by the
WHO-sponsored consultation on “BPH, is the
generic phrase to describe elderly men with fill-
ing/storage or voiding/emptying problems likely
to be caused by an obstructing prostate.
The relationship between BPE, LUTS, and BPO can
be pictured simply (Figure 1) or in a more compli-
cated fashion (Figure 2).
The 5th International Consultation on “BPH”
(Abrams et al 2001) and the International Continence
Society’s 2002 Terminology Report has emphasized
the importance of using the terms BPH/BPE and
BPO/BOO correctly (Abrams et al 2002).
By putting male LUTS into proper context, with
respect to the range of lower urinary tract dysfunc-
tions (LUTD), the clinician has a better chance of
understanding the causes of a man’s symptoms and
focusing management accordingly.
We have tried to use these terms consequently and
trust that it will make it easier to communicate the
patient’s lower urinary tract and prostate status,
thereby facilitating management.
72
B. LOWER URINARY TRACT
SYMPTOMS
I. DEFINITION OF SYMPTOMS
LUTS are equally bothersome to men and women.
Lower urinary tract symptoms (LUTS) greatly affect
the quality of life (QOL). These symptoms are not
specific to prostatic obstruction in men and are
almost as common in women [Boyle et al 2003].
The term “Lower urinary tract symptoms” is used to
describe patients’ urinary complaints without imply-
ing a cause (Abrams 1994). Lower urinary tract
symptoms were defined by the standardisation sub-
committee of the International Continence Society
(ICS) in its latest report in February 2002 (Abrams et
al. 2002).
LUTS are the subjective indicators of a disease or
change in conditions as perceived by the patients,
carer or partners and may lead him/her to seek
help from health care professionals. Symptoms
may either be volunteered or described during the
patient interview. They are usually qualitative.
In general, lower urinary tract symptoms cannot be
used to make a definitive diagnosis. However LUTS
can also indicate pathologies other than lower uri-
nary tract dysfunction, such as urinary infection. The
clinician will make his/her best efforts to exclude
other causes of LUTS.
Lower urinary tract symptoms are categorized as
storage, voiding, and post micturition symptoms
(Table 1).
1. STORAGE SYMPTOMS are experienced during the
storage phase of the bladder, and include daytime
frequency and nocturia.
Increased daytime frequency is the complaint by the
patient who considers that he/she voids too often by
day. This term is equivalent to “pollakisuria” used in
many countries.
Nocturia is the complaint that the individual has to
wake at night one or more times to void.
Urgency is the complaint of a sudden compelling
desire to pass urine, which is difficult to defer.
Urinary incontinence is the complaint of any invol-
untary leakage of urine.
Table 2. Causes of BOO
Intraluminal Mural Extramural
Urethral stones Bladder neck
stenosis BPE
Urethral neoplasms Urethral strictures Prostatic
carcinoma
Foreign bodies Meatal strictures Penile clamps
Prolapsed ureterocele Urethral neoplasms

From Frymann and Abrams (2000)

Figure 1. The diagram shows the three basic features of

LUTS/BPO: Symptoms, enlargement and obstruction.
These overlap but are independent variables determining
the nature of the clinical situation. From Hald T.

Figure 2

73
In each specific circumstance, urinary incontinence
should be further described by specifying relevant
factors such as type, frequency, severity, precipitat-
ing factors, social impact, effect on hygiene and
quality of life, measures used to contain the leakage,
and whether or not the individual seeks or desires
help because of urinary incontinence.
Stress urinary incontinence is the complaint of invol-
untary leakage on effort or exertion, or on sneezing
or coughing.
Urgency urinary incontinence the complaint of
involuntary leakage accompanied by or immediately
preceded by urgency. Although the ICS 2002 term is
urge urinary incontinence it was recognized in a
2004 ICS standardization workshop that this had
been an inadvertent mistake and urgency urinary
incontinence is a better term.
Mixed urinary incontinence is the complaint of
involuntary leakage associated with urgency and also
with exertion, effort, sneezing or coughing. This
form of UI is only likely to occur after prostatecto-
my.
Enuresis means any involuntary loss of urine. If it is
used to denote incontinence during sleep, it should
always be qualified with the adjective “nocturnal”.
Nocturnal enuresis is the complaint of loss of urine
occurring during sleep. This is an important,
although rare symptom in older men, as it may indi-
cate high pressure chronic retention (Abrams et al
1978)
Continuous urinary incontinence is the complaint of
continuous leakage, and only found after prostatec-
tomy.
2. BLADDER SENSATION can be defined, during histo-
ry taking, into four categories.
Normal: the individual is aware of bladder filling and
increasing sensation up to a strong desire to void.
Increased: the individual feels an early first sensa-
tion of filling and then a persistent desire to void.
Reduced: the individual is aware of bladder filling
but does not feel a definite desire to void.
Absent: the individual reports no sensation of bladder
filling or desire to void.
3. VOIDING SYMPTOMS are experienced during the
voiding phase.
Slow stream is reported by the individual as his per-
ception of reduced urine flow, usually compared to
74
previous performance or in comparison to others.
Splitting or spraying of the urine stream may be
reported.
Intermittent stream (Intermittency) is the term used
when the individual describes urine flow which stops
and starts, on one or more occasions, during micturi-
tion.
Hesitancy is the term used when an individual
describes difficulty in initiating micturition resulting
in a delay in the onset of voiding after the individual
is ready to pass urine.
Straining to void describes the muscular effort used
to initiate, maintain or improve the urinary stream.
Terminal dribble is the term used when an individu-
al describes a prolonged final part of micturition,
when the flow has slowed to a trickle or dribble.
4. POST MICTURITION SYMPTOMS are experienced
immediately after micturition.
Feeling of incomplete emptying is a self-explanatory
term for a feeling experienced by the individual after
passing urine.
Post micturition dribble is the term used when an
individual describes the involuntary loss of urine
immediately after he has finished passing urine, usu-
ally after leaving the toilet (onto his clothes).
II. LUTS IN THE COMMUNITY,
IN RELATION TO AGE
Lower urinary tract symptoms (LUTS) are fairly
common in young men. In a prospective study, 85
men with LUTS (18 to 45 years old) were investi-
gated to determine the cause of LUTS in young men
and whether noninvasive testing and symptoms
scores are useful in deciding which patients to eval-
uate with videourodynamics (Nitti et al. 2002). Mean
AUA scores were total 19.3, voiding 10.8 and stor-
age 8.5. Videourodynamic diagnoses were primary
bladder neck obstruction in 40 (47%) cases, dys-
functional voiding in 12 (14%), impaired contractili-
ty in 8 (9%), “sensory urgency” in 7 (8%), detrusor
overactivity alone in 5 (6%), detrusor overactivity
during filling and detrusor underactivity during void-
ing in 1 (1%), external detrusor-striated sphincter
dyssynergia in 1 (1%) and normal in 5 (6%). Of these
patients, 9 could not void during urodynamics and in
6 (7%) no urodynamic diagnosis was made. Thus
LUTS in young men have a variety of underlying
causes. Videourodynamics was not considered help-
ful in patients with a normal or nondiagnostic study
or “sensory urgency” only but was an extremely
helpful diagnostic test in men with abnormal uroflow
and high voiding scores.
The prevalence of LUTS increases with age such that
a large proportion of men, aged >70 years, may have
them. In the Netherlands, France, UK, Korea, the
prevalence of lower urinary tract symptoms in men
and women was studied by a population-based,
cross-sectional survey (Boyle et al. 2003). The per-
centages of men and women with an IPSS of 8–35,
indicating moderate to severe symptoms, were,
respectively, 20.7 and 18.0 (the Netherlands); 19.2
and 12.6 (France); 25.1 and 23.7 (UK); and 16.2 and
19.9 (Korea). The percentages of men and women
with moderate to severe symptoms were by age
group, respectively, 10.6, 15.5 (40–49); 19.0, 18.2
(50–59); 30.5, 23.8 (60–69); and 40.4, 28.7 (70–79).
Among those aged 40–49 the main differences
between men and women were in the questions about
frequency of urination during the day and being able
to hold back urine. Among the older groups, men
reported more symptoms on all questions apart from
urination at night and difficulty in holding back
urine, both of which were equally prevalent among
men and women. The overall prevalence of LUTS
was high and showed no marked cultural variation.
Prevalence increased with age, with severe LUTS
being more common in older men. Women reported
similar levels of the symptoms traditionally associat-
ed with LUTS in men. In each age group there were
no major cultural differences in the frequency of
LUTS. There were differences with age between
men and women; younger men had a lower preva-
lence of LUTS than younger women but older men a
much higher prevalence than older women.
In Japan an epidemiologic population-based investi-
gation on LUTS has been performed (Homma et al.
2005). Self-administered questionnaires pertaining
to micturition were mailed to 10,096 men and
women aged 40 years or older who were family
members of randomly selected households. 4,570
responses were available for the analysis (men
46.0%). The average age was 60.6 years for both
genders (range 40-100). Urinary frequency (≥8 mic-
turitions per daytime/ ≥11 micturitions per daytime)
was reported by 50.1%/11.3%, and nocturia (≥1 mic-
turition per night/≥3 micturitions per night) was
reported by 69.2%/13.5%. The proportion of cases
experiencing symptoms (≥once per week/ ≥once a
day) was 27.0%/19.8% for decreased urine stream,
75
17.8%/12.0% for “feeling of residual urine”,
2.2%/1.0% for bladder pain, 14.0%/8.0% for urinary
urgency, 8.9%/5.3% for urgency incontinence and
8.0%/3.9% for stress incontinence. The prevalence
increased with age and was generally greater in men
except for stress incontinence. Daily activities were
negatively influenced by urinary symptoms in
14.7%. More specifically, the influence was felt on
mental heath (10.2%), vitality (10.1%), physical
activities (7.1%), work/house chores (5.9%), and
social activities (4.0%). The number of problematic
symptoms was 2.0 on average. The most problemat-
ic and prevalent symptoms were nocturia (38.2%),
daytime frequency (19.3%), stress incontinence
(14.5%), urgency (10.4%), urgency incontinence
(9.8%), and reduced urinary flow (6.6%). Despite a
negative impact by LUTS only 18.0% of individuals
had visited physicians. Prevalence of LUTS was
generally higher in men and the aged population.
Appropriate management and treatment should be
encouraged by increasing publicity of urinary prob-
lems.
In Sweden, the prevalence of LUTS was estimated in
different age groups of men 45–79 years old by a
large population-based study (Andersson et al 2004).
18.5% and 4.8% of the men were moderately or
severely symptomatic; the prevalence of at least one
symptom was 83%. LUTS were strongly age-depen-
dent, with 1.8% of severe symptoms among men
aged 45–49 years and increasing to 9.7% among
those 75–79 years old. Frequent urination was the
most common symptom among men aged<70 years
and nocturia among those aged>70 years. Symptoms
like hesitancy, poor flow and intermittency were
highly correlated with each other (Spearman coeffi-
cients 0.56–0.60). There was a high correlation
between the IPSS and a poor score for quality of life
resulting from the bothersomeness of LUTS
(r=0.70).
Among symptomatic subjects, 36% reported a poor
quality of life (fairly bad, very bad or terrible). Only
29% of symptomatic subjects (IPSS>7) reported that
they had been diagnosed previously for their urinary
problems, and only 11% received medication for
that. In Sweden, irrespective of the reasons, it is
apparent that few men seek help for their urinary
symptoms. Only a third of symptomatic men report-
ed that they had been diagnosed for urinary problems
previously. This issue emphasizes the important need
for better public education and awareness of the rel-
atively high prevalence of LUTS in society.

CONCLUSIONS
• Precise internationally agreed definitions exist
for LUTS and indeed for LUTD and for
BPH/BPE/BPO. Their widespread adoption
will increase the ease of communication and
the transparency of the published literature.
• There is good quality (Level 1) evidence that
LUTS are relatively common in the communi-
ty, with an increasing prevalence with age. It is
important to note that the prevalence is little
affected by gender, suggesting the possibility
that many men’s and women’s LUTS have sim-
ilar aetiologies. There is also evidence that that
many men with LUTS do not seek help despite
having bothersome symptoms (level 2).
III. STORAGE SYMPTOMS
From the ICS-“BPH” study (Donovan, et al.,1996;
Peters, et al. 1997; Abrams, et al. 1997), it was
shown that the more prevalent symptoms were void-
ing symptoms, but the more bothersome symptoms
were the storage symptoms, with the exception of
post micturition dribbling (Table 3). Terminal drib-
bling was seen in 94%, reduced stream in 93%, inter-
mittency 88%, hesitancy 83%, and incomplete emp-
tying 81%. The five most bothersome symptoms,
however, defined by the portion of men who report-
ed the bother was at least “a bit of a problem” were
post-micturition dribbling 84%, urgency inconti-
nence 84%, nocturnal incontinence 81%, miscella-
neous incontinence 81%, and urgency 80%.
Jepson and Bruskewitz (2000) have compiled tables
from various articles (Donovan, et al. 1996; Schute,
et al. 1993; Simonsen, et al. 1988; Peters, et al. 1997)
representing the prevalence and bother of symptoms
in different age groups among community samples
and LUTS patients evaluated at a urology clinic
(Tables 4 and 5).
Although voiding symptoms are most prevalent,
storage symptoms are clearly the most bothersome to
the patient and interfere to the greatest extent with
daily life activities, having a considerable negative
effect on quality of life. Urgency, frequency and
urgency incontinence may cause social embarrass-
ment or isolation and nocturia may disturb sleep and
induce fatigue or irritability during the daytime
(Peters, et al. 1997; Sagnier, et al. 1995; Debeau, et
al. 1995; Calais, et al. 1997).

Table 3. A Summary of the prevalence and troublesomeness of LUTS, listed in decreasing rank order, from Fryman and
Abrams, 2000

Rank Prevalence Troublesomeness

Storage Symptom Voiding Symptom Storage Symptom Voiding Symptom

1 Terminal dribbling Post micturition dribbling

2 Reduced stream Urge incontinence
3 Intermittency Nocturnal enuresis
4 Hesitancy Misc. incontinence
5 Incomplete emptying Urgency
6 Urgency Terminal dribbling
7 Nocturia Frequency
8 Repeat urination Incomplete emptying
9 Frequency Nocturia
10 Strain to continue Reduced stream
11 Post micturition dribbling Strain to start
12 Strain to start Pain in bladder
13 Urge incontinence Repeated urination
14 Frequency Dysuria
15 Dysuria Strain to continue
16 Pain in bladder Hesitancy
17 Misc. incontinence Intermittency
18 Stress incontinence Frequency
19 Nocturnal incontinence Stress incontinence

From Frymann and Abrams, 2000.

76
Table 4. Lower urinary tract symptoms (LUTS) in community samples and in patients wih LUTS admitted to a urologic
clinic. From Jepsen and Bruskewitz, 2000

COMMUNITY SAMPLE (%) LUTS PATIENT (%)

Donovan et al (1996) Chute et al (1993) Donovan et al Simonsen et al (1988)
N= 423 N=2119 N=1256 N=199
<60/60-69/>70yr 40-49/50-59/60-69/>70ys <60/60-69/>70yr <65/65-74/>74yr
VOIDING SYMPTOMS
Weak stream* 30/37/52† 35/34/39/44† 94/94/93 83/81/66†
Strain start* 18/17/12 74/61/57
Strain continue 23/22/25 12/15/13/15 77/71/63 40/35/33
Hesitancy* 53/47/49 14/18/20/19 90/85/79 35/35/18
Intermittency* 44/53/53 18/25/29/32† 90/90/84 35/30/22
Incomplete emptying* 32/35/34 16/17/23/23† 82/83/77 24/28/35
Terminal dribble* 79/78/73 96/94/91
Postmicturition dribble 44/40/42 37/43/44/36 69/69/65
STORAGE SYMPTOMS
Frequency 29/43/34† 34/34/36/35≠ 51/48/43≠ 48/36/35≠
Repeated voiding 24/28/27 12/11/18/11 73/76/64 -
Nocturia* 7/15/43† 16/29/42/55† 66/74/79† 81/86/87
Urgency 44/51/64† 28/32/42/46† 67/76/77 30/36/47
Urge incontinence 13/26/41† 36/46/56† 10/10/29†
Stress incontinence 8/14/14 23/25/24/22$ 12/14/18 -
Miscellaneous incontinence 4/9/12 16/20/22
Bladder pain 15/14/19 48/43/35
Dysuria 22/15/13 5/6/7 45/44/38

* Question in the International Prostate Symptom Score (American Urological Association) Questionnaire
† Significant correlation with age
≠ Within 2 hours
$ Wet clothing

77
Table 5. Prevalence of bother from lower urinary tract symptoms in community samples, from Jepsen and Bruskewitz, 2000

Peters et al (1997) Chute et al (1993)

Any degree of problem (%) More than quite More than a little bother (%)
N = 423 a problem (%) N = 2119
<60/60-69/>70 yr all 40-49/50-59-60-69/>70 yr

Voiding symptoms
Weak stream 79/73/71 28 10/17/23/24
Strain start* 79/71/71 23 6/7/9/11
Hesitancy* 76/71/67 24 9/11/14/17
Intermittency* 72/68/63 23 8/12/18/21
Incomplete emptying 80/77/72 28 9/11/14/17
Terminal dribble 81/75/77 31
Postmicturitional dribble 84/85/82 34 23/26/28/28
Storage symptoms
Frequency* 62/65/64 26 12/15/16/16
Repeated voiding 76/72/70 24 8/7/12/9
Nocturia* 75/73/72 35 13/17/25/35
Urgency* 77/80/81 36 15/21/27/31
Urge incontinence 77/85/84 34
Stress incontinence 67/56/73 12 20/21/20/16°
Miscellaneous incontinence 75/81/84 22
Bladder pain 68/74/73 24
Dysuria 73/68/79 21 4/4/3/4

*Question in the American Urological Association Symptom Problem Questionnaire.

°Wet clothing
From Jepsen and Bruskewitz, 2000.

1. STORAGE LUTS AND THEIR ETIOLOGIES
A brief summary of the etiology of these symptoms
follows, recognizing that the major symptoms are
mostly a manifestation of the overactive bladder syn-
drome [Abrams et al 2002]. Theories regarding the
pathophysiology of this, and its possible relationship
to bladder outlet obstruction, are considered subse-
quently.
a) Frequency
found that subjects voided a median of 7 times per 24
hours (Latini et al 2004). They also reported that
even in asymptomatic men the number of daily voids
correlated with the IPSS. Furthermore they cau-
tioned against using a cutoff of 8 daily voids to
define abnormal urinary frequency since diary vari-
ables depend on patient characteristics including age
and race and also on climatic and social factors. The
mechanisms of increased urinary frequency are char-
acterized as follows:

There is surprisingly little objective data on frequen-
cy in the normal population. Abrams (1997) cites
two papers and personal experience in considering
normal diurnal frequency to be between 3-7 voids
per day. Jepsen and Bruskewitz (2000) consider the
normal 24-hour urinary frequency as 8, that more
than 3-hours between successful voids is normal and
that less than 2-hours is abnormal.
Diary data in men and women vary. One study of
asymptomatic men and women showed that females
tend to void more often (median 8 vs. 7 voids per 24
hours) and at lower mean volumes (Mueller et al
2005). Latini, et al used a 24 hour diary to study
voiding habits in 284 asymptomatic men. They
• Normal voided volumes. This is approximately
300-600 ml. in the adult. If an individual has nor-
mal voided volumes then increased frequency
must be due to an increased intake resulting in
increased output. This may be due to the follow-
ing:
- Polydipsia, osmotic diuresis, or an abnormal-
ity of antidiuretic hormone production (dia-
betes insipidus)
• Reduced voided volumes. This implies that the
bladder capacity under general or regional anes-
thesia would be normal but the voided volumes
are consistently small, <300 ml. The causes of
which include the following:

78
 - detrusor overactivity
- significant residual urine volume (emptying
failure)
- non-inflammatory causes of increased bladder
sensation including tumor ingrowth
- inflammatory bladder conditions
- fear of urinary retention (i.e., in the older male
patient who experiences hesitancy increasing-
ly as the bladder fills and who compensates by
voiding frequently)
- fear of incontinence (i.e., patients with stress
incontinence after prostatectomy and/or detru-
sor overactivity who note their problem
increases with increasing bladder volume)
- psychogenic, other than fear of urinary reten-
tion or incontinence
• Reduced structural bladder capacity. In this case
the bladder capacity is smaller than normal under
regional or deep general anesthesia and results in
consistently small voided volumes. The reduction
in capacity may be due to:
- fibrosis, non-infectious cystitis/inflammation,
post-pelvic irradiation fibrosis, previous
bladder surgery
b) Urgency, urgency incontinence and the overac-
tive bladder
Urgency is defined as a sudden compelling desire to
pass urine which is difficult to defer (Abrams, et al.
2002). It is the primary driver of frequency, nocturia
unrelated to polyuria, and, when it is correlated with
detrusor overactivity that cannot be suppressed, uri-
nary urgency incontinence. (Figure 3) (Chapple, et
al. 2005; Chapple and Wein, 2005). An earlier defi-
nition included the fact that the desire was com-
pelling, to avoid either leakage or pain (Abrams, et
al. 1998); many feel that fear of leakage should be
reinserted in the definition. Urgency is the prime
symptom of the overactive bladder symptom syn-
drome (urgency, with or without urgency inconti-
nence, usually with frequency or nocturia in the
absence of infection or other obvious pathology
(Abrams, et al. 2002). One shortcoming of this defi-
nition is that it leaves out patients with grossly
impaired or no sensation but with urinary inconti-
nence due to an involuntary detrusor contraction.
The prevalence of the symptoms of overactive blad-
der has been established in large population-based
surveys in the U.S.A. (Stewart, et al. 2003) and in
79
Europe/Scandinavia (Milsom, et al. 2001). Data
from both studies indicate that approximately 17% of
the adult population have symptoms suggestive of
overactive bladder, and that approximately one-third
of these patients have urinary urgency incontinence,
while the other two-thirds do not. The prevalence of
overactive bladder rises with age in both sexes,
another piece of evidence that symptoms which char-
acterize this symptom syndrome cannot be due sole-
ly to the presence of an enlarged and/or obstructing
prostate (Figure 4). On a relative basis, urinary
urgency incontinence is more common in women
than in men (Figures 5 and 6).
Urinary urgency is not the same as “urge”, which can
be defined in the urinary sense as “the desire to void”
or “the need to void.” There is some debate as to
whether urinary urgency is merely an extreme form
of the strong desire to void. Current thinking is that
urgency is a separate and pathological symptom;
however, patients with OAB can have both normal
storage sensations and urgency, and not every one of
their micturition cycles is associated with urgency.
By its definition, urgency is episodic and there is lit-
tle or no degradation in the sensation. Thus, “scales”
that attempt to define the intensity of urgency may be
at odds with the definition if urgency is a sensation
that is either there or not. The physiological sensa-
tions of the first sensation of filling, normal desire to
void and strong desire to void can, however, vary in
intensity, also some measurement of the intensity of
urgency may be useful in assessing symptom severi-
ty and the outcome of therapy of OAB. Chapple’s
diagrams (Figures 7 and 8) provide an understand-
able visual interpretation of how urgency drives the
symptoms of frequency and nocturia, in the absence
of nocturnal polyuria and, in the absence of the abil-
ity to abort an involuntary contraction, urgency relat-
ed incontinence. The ability to defer micturition is
one of the keys to the definition of urgency. This
might vary depending on the circumstances of the
individual, i.e., the availability of bathroom facili-
ties, whether at home or at work and the level of dis-
traction. Urgency episodes are pathological and they
result in either small volume voids and reduced and
variable inter-void intervals or urgency incontinence.
The time from the onset of the urgency episode to the
void or the incontinence episode is generally short
and may be referred to as the “deferment time” or
“warning time”. The period between episodes of
urgency can also be measured and termed the refrac-
tory or urgency free interval. The factors which
influence whether incontinence occurs or not can be
Urgency Drives the Other Symptoms of OAB

Figure 3.
1. Proven direct effect
2. Effect correlated with urgency but inconsistent due to
multifactorial etiology of the symptom

Chapple C. ICI poster, 2004

Figure 4

Figure 5

80
 Figure 7. Schematic of the relationship between bladder
volume and desire to void during the normal micturition
cycle. During the normal cycle, desire to void s intermittent
and increases with bladder volume. The cycle terminates
with a void that may or not be associated with strong sen-
Figure 6 sation

Figure 8A. A schematic of the effect of urgency on the micturition cycle. During an urgency episode, the desire to void increas-
es abruptly, resulting in a void and shortering the intervoid interval, and reducing the volume voided. Therapy can eliminate
urgency episodes and thus normalize the inter-void interval.
B. A diagram of two micturition cycles terminated by voids associated with urgency episodes. A refractory period, defined as
the interval between voiding and the next urgency episode, can be measured and may be affected by therapy. A warning or
deferral time can also be measured as the time from the onset of urgency to voiding.

81
summarized as follows:
• pelvic floor and urethral sphincter tone
• mobility
• toilet access
• timing of sensation (i.e., if sensation delayed or
impaired because of neurologic disease/injury,
then incontinence is more apt to occur)
Urgency affects nocturia as well, but successful
treatment of urgency is not well correlated with noc-
turia reduction. The reason is that nocturia (see sep-
arate section on nocturia) is related not only to noc-
turnal overactive bladder but also may be related to
other factors discussed in more detail later, for exam-
ple: nocturnal polyuria, non-urological sleep disor-
ders and congestive heart failure.
Urgency is, therefore, the pivotal clinical symptom
in overactive bladder as it is the driver for frequency,
non-polyuria related nocturia, and urgency inconti-
nence. It is also a surrogate end-point for patients
having better “control.” There is no evidence to sup-
port the hypothesis that there is a continuum between
the normal desire to void and urgency. A strong case
can be made, however, for the suggestion that the
definition of urgency be further qualified by adding
phrase “for fear of leakage” which was previously in
the definitions but abandoned at the time of the last
revision of terminology. The ICS Standardization
Committee, unfortunately, has compounded the
problem by suggesting that synonymous terms for
overactive bladder include urgency/frequency syn-
drome and urge syndrome (Abrams, et al. 2002). One
circumstance that warrants discussion is that the dif-
ference between the terms urgency and urge may not
translate into other languages.
c) Nocturia
Nocturia can be caused by any of the problems list-
ed above as causing diurnal frequency. However, in
addition, nocturnal polyuria can be a significant
causative factor. This is often due to the re-absorp-
tion of edema fluid in patients with congestive car-
diac failure, when they recline. Nocturia may also be
due to loss or reduction of antidiuretic hormone pro-
duction at night : the reversal of the diurnal pituitary
rhythm. Below there is more detailed discussion on
the aetiological factors responsible for nocturia.
d) Pain
This may be due to inflammation, infection, malig-
nant or pre-malignant bladder conditions, painful
82
bladder syndrome including interstitial cystitis, or
pelvic pain syndrome including prostatitis. None of
these have any particular relationship to BPH, BPE,
BPO. Prostate cancer can invade the posterior blad-
der base and cause nerve entrapment/irritation in the
pelvis.
e) Impaired or absent sensation
This may be due to a variety of neurological diseases
or injury or to the effects of chronic bladder overdis-
tention.
2. PATHOPHYSIOLOGY OF URGENCY, DETRU-
SOR OVERACTIVITY AND OVERACTIVE BLAD-
DER: THEORIES AND OBSERVATIONS RELE-
VANT TO BPH, BPE, BPO
In the past, the sensation of urgency, the occurrence
of urgency incontinence and the occurrence of incon-
tinence without sensation in a patient with neurolog-
ic disease or injury were all assumed to be due to
what we now call detrusor overactivity (DO). This is
undoubtedly the case with the latter two phenomena,
but urgency without incontinence is able to exist
without demonstrable DO on a urodynamic study,
although the two are often associated. Whether
urgency with or without DO represents a purely sen-
sory phenomenon or an aborted, but not recorded,
inappropriate micturition reflex remains to be seen.
In any case, the following list includes the relevant
theories regarding the pathophysiology of OAB, DO
and urgency. Source references, exclusive of the
individual ones cited, can be found in Nordling, et al.
(2001), Morrison, et al. (2005) and Mostwin, et al.
(2005). Only some of these bear potential relevance
to BPH, BPE, or/and BPO. They are indicated with
an asterisk.
a) Neurogenic
Loss of inhibition or increased afferent input at any
level of the nervous system can result in OAB (de
Groat, 1997; Chancellor and Yoshimura, 2002) (Fig-
ures 9 and 10). Evidence supporting this includes:
• Reduced suprapontine inhibition
• Damaged axonal paths in spinal cord
• Increased LUT afferent input
• Loss of peripheral inhibition
• Enhancement of excitatory neurotransmission
in the micturition reflex pathway
Figure 9. Neurogenic Etiology of Overactive Bladder. After
De Groat W.C Urology, 1997; 50 (Suppl. 6A) :36-52
Figure 10. iagram of the central reflex pathways that regulate micturition in the cat. In an animal with an intact neuraxis,
micturition is initiated by a supraspinal reflex pathway passing through the pontine micturition center (PMC) in the brain-
stem. The pathway is triggered by myelinated afferents (Aδ) connected to tension receptors in the bladder wall (detrusor).
Spinal tract neurons carry information to the brain. During micturition, pathways from the PMC activate the parasympathet-
ic outflow to the bladder and inhibit the somatic outflow to the urethral sphincter. Transmission in the PMC is modulated by
cortical-diencephalic mechanisms. Interruption of the latter mechanisms leads detrusor overactivity In spinal cord transected
animals, connections between the brainstem and the sacral spinal cord are interrupted and micturition is initially blocked. In
chronic spinal animals, a spinal micturition reflex emerges which is triggered by unmyelinated (C-fiber) bladder afferents. The
C-fiber reflex pathway is usually weak or undetectable in animals with an intact nervous system. Stimulation of the C-fiber
bladder afferents by instillation of ice water into the bladder activates voiding reflexes in patients with spinal cord injury. Cap-
saicin (20-30 mg/kg, s.c.) blocks the C-fiber reflexes in chronic spinal cats, but does not block micturition reflexes in intact
cats. Intravesical capsaicin also suppresses neurogenic detrusor overactivity and cold-evoked reflexes in patients with neuro-
genic bladder dysfunction. Glutamic acid is the principal excitatory transmitter in the ascending and descending limbs of the
micturition reflex pathway as well as in the reflex pathway controlling sphincter function. Glutamate acts on both NMDA and
AMPA glutamatergic receptors. Other neurotransmitters that regulate transmission in the micturition reflex pathway include:
gamma-aminobutyric acid (GABA), enkephalins (Enk), acetylcholine (ACh) and dopamine (DA). ACH has both excitatory and
inhibitory effects on the pathway. (+) excitatory and (-) inhibitory synapse. Dopamine acts through D1 receptors on GABAer-
gic cells and is inhibitory.

The DO seen in various supraspinal and spinal
pathologies (Wein, 2002).
• Local anesthetic injected into the prostate in
patients with DO inhibits the DO (Chalfin and
Bradley, 1982). Trans-urethral microwave therapy
and alpha blockers have been hypothesized to act
upon prostatic or prostatic urethral sensory recep-
tors
• Capsaicin, a neurotoxin for unmyelinated C-fiber
afferents, inhibits DO when given intravesically
(Andersson, et al. 2005)
• BPO is associated with a positive ice-water test (a
spinal reflex) in the majority of patients. This is
abolished by capsacin (Chai, et al. 1998)
• Neuroplasticity following obstruction has been
hypothesized to occur by a variety of mechanisms,
resulting in spinal reflexes which may persist after
the initial stimulus has been removed (Steers, et
al. 1990, Steers, et al. 1991, Steers and de Groat
1998, Spitzbergen, et al. 1998, Steers, et al. 1999).
In some models, nerve growth factor (NGF) has
been shown to be elevated in bladder tissue and to
revert to base levels when the obstruction is

83
 relieved, and NGF blockade prevented the neural
and micturition alterations.
• It is interesting to compare the results of various
types of therapy on symptoms recorded in the ICS
male questionnaire (Figure 11) (Donovan, et al.
1999). It is clear that at least in this study, the ther-
apies that would be expected to ablate periurethral
or prostate tissue produced the greatest reduction
in storage symptoms, which would suggest to
some, since the urodynamic results of surgery are
greater than those produced by the minimally
invasive non-drug therapies, but both ablate tis-
sue, that a neurologic mechanism is involved.
• During filling/storage, Andersson (2004) suggests
(see article for supporting references) that acetyl-
choline and other neurotransmitters may be
released from the urothelium and increase afferent
nerve activity by exciting receptors in the urothe-
lium or suburothelium. Presumably either the
release or the increased sensitivity would be
hypothesized to be heightened in patients with
OAB/DO.
• Andersson (2004) also suggests that a neuronal
“leak” of acetylcholine may occur during fill-
ing/storage, causing enhanced myogenic activity
(“micromotions”) similar to those hypothesized
by Turner and Brading (1997) and previously
described by Coolsaet (1993) (see 1st bullet
“myogenic” below).
• Gillespie (2004) has proposed that the inappropri-
ate augmentation of autonomous myogenic activ-
ity or the failure of inhibitory inputs are possible
causes for DO/OAB. He proposes that
autonomous activity, non-micturition contractions
and phasic sensory discharge are features of the
normal bladder during filling and that these basic
mechanisms, generating and modulating
autonomous activity are different from those
involved with micturition. The possible aetiologi-
cal factor, could be regarded as “myogenic” and
links the two principle aetiological theories.
b) Myogenic
There is some evidence to suggest a myogenic cause
for OAB / DO :
• Partial obstruction in an animal model causes
patchy detrusor denervation, increased sponta-
neous action potentials and activity, and increased
cell to cell conduction, allowing small foci of
activity to spread into localized or synchronous
contractions of portions of the bladder wall,
84
increasing intravesical pressure and/or stimulating
sensory receptors (Turner and Brading, 1997; Sib-
ley, 1997; German, et al. 1995; Speakman, et al.
1987; Andersson, 1990) (Figure 12).
• In approximately 25 percent of patients with BPO,
the response of muscle strips from the bladder
dome to norepinephrine is changed from inhibito-
ry (beta effect) to excitatory (alpha effect) (Perl-
berg and Caine, 1982).
c) Structural
DO has been reported to be associated with a distinct
ultrastructural (EM) pattern known as complete
dysjunctional (EL-Badawi, et al. 1993). This has
been hypothesized to occur with aging in some indi-
viduals and be responsible for DO in the absence of
obstruction (El-Badawi, et al. 1997).
d) OAB Symptoms, BPH, BPE, BOO, BPO: Other
Observations
It has often been assumed that the pathophysiology
of LUTS in the older man is the result of BPO asso-
ciated with BPE, presumably because all of these
phenomenon increase with age. Girman, et al. (1995)
and Barry, et al. (1993) looked at the correlation of
maximum flow rate, prostate volume and symptom
score. There were no statistically significant correla-
tions. Nitti, et al. (1994) also failed to find either
clinical or statistical correlations between the severi-
ty of bladder outlet obstruction based upon pressure
flow urodynamic studies and LUTS. In the male,
LUTS may be associated with BOO, but neither stor-
age nor voiding symptoms are diagnostic of urody-
namic obstruction (Figure 13). The situation seems
complex and in those with BOO, both neurologic
and myogenic mechanisms (Figure 12) have been
suggested (see above) and many are summarized in
Figure 14 (adapted from Steers).
3. THE PREVALENCE OF STORAGE SYMPTOMS
The AUA symptom index (IPSS) was originally
introduced in 1992, a symptom index specifically
designed for what was called “BPH” at that time. In
the years that followed, the questionnaires were
administered to samples of men and women, howev-
er, it became obvious that there is indeed a lack of
specificity for lower urinary tract symptoms attribut-
ed to BPO/BPE. Now the IPSS is suggested to be
neither gender specific nor disease specific, as symp-
tomatology found in men and women are similar
(Lepor and Machi, 1993; Chancellor and Rivas,
1993; Chai, et al., 1993). Lepor and Machi (1993)
Figure 11. Responsiveness of the items in the ICSmale questionnaire to interventions (watchful waiting, minimally invasive
therapies, and TURP) (Donovan et al 1999)

Partial denervation alters smooth muscle

Excitability

Ability for activity to spread between

cells

Coordinated myogenic contractions and

increased bladder pressure

Figure 12. Myogenic Theory. Turner WH, Brading AF.

Pharmacol Ther. 1997; 75:77-110

85
 Men with LUTS

No BOO BOO

Can this occur secondary to OAB Sx: Voiding Sx:

deformation or other types of frequency, urgency, hesitancy, weak
stimulation of afferent nerves urgency, and/or urge stream, straining,
in the prostatic urethra ? incontinence dribbling

BOO= bladder outlet obstruction; Sx= symptom

Figure 13. Symptoms related to male lower urinary tract dysfunction

administered the IPSS to 101 men and 99 women
between 55-79 years of age attending a general
health symposium with no emphasis on genitouri-
nary disease. The mean symptoms scores were 6.9
for men and 7.7 for women. When divided into
“obstructive” and “irritative” scores, their respective
“obstructive” scores were 2.7 and 2.9, and the “irri-
tative” scores 4.2 and 4.8, not significantly different.
This argues for an age related rather than obstruction
related etiology for LUTS in at least a substantial
portion of patients. It is certainly conceivable that
BPE/BPO could contribute or exacerbate this age
related process and of course it is highly likely that it
is related as an etiologic factor to LUTS, but certain-
ly not in all, and maybe not even the majority, of
cases. Homma, et al. (1994) studied 168 men and
101 women who had no spontaneous complaints.
Ages ranged from 34-84. Symptom distribution is
showed in Tables 6 and 7, and in Figures 15 and 16.
Nearly all symptoms increased with age, but it is
interesting that there is a substantial incidence of
storage symptoms in men with very small prostates
(less likely to have obstruction) and in women with
no prostates at all!
Chute, et al. (1993) reported on the evidence of
LUTS thought secondary to BPO in the Olmstead
County population. This included men 40-79 years
old who were randomly selected and excluded only
because of prostate cancer or prior surgery, bladder
cancer or prior surgery, other bladder or urethral dis-
order, urological conditions that could affect void-
ing, severe cognitive disorders, inability to void in a
standing position, and need for dialysis. The storage
symptoms evaluated were nocturia, urgency, and fre-
quent urination within 2-hours. Only the first two
showed increasing prevalence with age. The preva-
lence and the percentage of men reporting these
symptoms to be more than a bit bothersome, strati-
fied by the various age groups, were as follows: age
40-49; nocturia 16% and 13%; urgency 28% and
15%; for ages 50-59, nocturia 29% and 17%; urgen-
cy 32% and 21%; for ages 60-69, nocturia 42% and
29%; urgency 42% and 27%; for ages 70 and over,
nocturia 55% and 35%; urgency 46% and 31%. Fre-
quency did not show an age relation, and the corre-
sponding percentage of men with frequency, occur-
ring more than rarely, and those reporting frequency
to be more than a little bothersome, stratified by var-
ious age groups, is as follows: ages 40-49, 34% and
12%; ages 50-59, 34% and 15%; ages 60-69, 36%
and 16%; ages 70 and over 35% and 16%.
The prevalence of detrusor overactivity and its cor-
relative symptom, urgency, increases with age, but
the addition of prostatic obstruction does seem to
further increase its occurrence. Detrusor overactivity
is found to be present in about 50-65% of patients
with BPE/BPO. The notion that obstruction is at least
partially responsible was supported by the fact that a
62% and 69% incidence of DO in patients with BPO
was reduced to 35% and 31% respectively, after
relief of outflow obstruction by transurethral prosta-
tectomy (Abrams, et al., 1979; Andersen, et al.,
1980). Urodynamic testing in 211 men with LUTS
showed that approximately 30% did not have urody-

86
 Figure 14. Potential Etiology of Overactive Bladder in Men with Bladder Outlet Obstruction (BOO)

Partial Supersensitivity to ACh

denervation
Reduced response to intramural
nerve stimulation

Ischemia

Increased electrical coupling

between cells
OUTLET
Detrusor
OBSTRUCTION Hypertrophy/hyperplasia
muscle OVERACTIVE
Instability of membrane potential BLADDER
Alterred intracellular Ca2+

87
regulation

Expression Hypertrophy of Reorganization of spinal mic-

of nerve afferent and efferent turition reflex (C-fiber mediated)
growth factor neurons
Altered Na+ channel
expression/function

BOO= Bladder outlet obstruction. Adapted from Steers WD. Rev Urol. 2002;4 (suppl 4): S7-S18
Table 6. Prevalence of urinary symptoms related to age. Men. Prostates < 20 g.

Age <49 50-59 60-69 70-79 80-84

No. subjects 44 52 37 22 13
Weak stream 30% 42% 54% 68% 77%
Urgency 9% 15% 16% 18% 23%
Frequency 11% 13% 19% 32% 38%
Nocturia 5% 13% 19% 32% 62%

Homma et al. 1994 [81].

Table 7. Prevalence of urinary symptoms related to age. Women.

Age <49 50-59 60-69 70-79 80-84

No. subjects 24 26 19 20 12

Weak stream 17% 19% 26% 40% 42%

Urgency 4% 15% 11% 30% 33%

Frequency 13% 15% 11% 30% 33%

Nocturia 8% 15% 26% 55% 58%

Homma et al. 1994 [81].

Figure 15. Prevalence of urinary symptoms in men with prostates < 20g (Homma et al 1994)

88
Figure 16. Prevalence of urinary symptoms in women (Homma et al 1994)
namic evidence of obstruction. The symptomatology
in these patients was related to detrusor overactivity
and low detrusor strength or speed (Coolsaet and
Block, 1986). However, age-matched men without
lower urinary tract symptoms have been found to
have a prevalence of detrusor overactivity between
25% and 63% (Andersen, et al., 1978; Jensen et al.,
1984). Interestingly, detrusor overactivity was
reported by Jones and Schoenberg (1985) to be pre-
sent in 38% of women over the age of 65. This obser-
vation is compatible with later observations which
report comparable IPSS symptom scores in aging
women to those in age-matched men (Lepor and
Machi, 1993; Chai, et al., 1993; Chancellor and
Rivas, 1993). Urodynamic studies fail to give a func-
tional explanation to this observation (Madersbach-
er, et al., 1999).
The ICS “BPH” Study (Donovan, et al., 1996) was
conceived because, as stated, “little evidence exists
to suggest which individual symptoms are related to
BPH, BPE, or BPO, and there is no clear concept of
which groups of symptoms should be used to identi-
fy or measure patients with these conditions.” It
should be noted that were the study to be titled
presently, the title would be different as views on the
use of the term “BPH” have changed. However, the
original name of the study has been retained, with
the thought being that everyone interested would
89
understand what the study was designed to investi-
gate. Ultimately, 1,256 patients >45 years of age who
presented to urology departments in twelve countries
with symptoms and possible BPO were recruited. A
substudy was performed of a population based group
of men, in which all ambulatory men age 40 years or
over registered with a rural general practice in the
United Kingdom were invited to complete the ques-
tionnaire, and this resulted in a sample of 423 indi-
viduals. The results are shown in Table 8. In the ICS
“BPH” study the general pattern of a positive associ-
ation with age is not evident, except for the symp-
toms of nocturia and urgency incontinence in the ICS
“BPH” patients. In the community sample, there was
an expected age gradient for the majority of urinary
symptoms. The authors speculate that the increasing
incidence of nocturia is due to the increasing occur-
rence of nocturnal polyuria secondary to occult car-
diac failure. They further speculate that the increase
in urgency incontinence is probably due to the rela-
tionship between detrusor overactivity and age. The
ICS “BPH” patients considered their symptoms to be
more bothersome much more frequently than those
in the community sample. From the standpoint of
symptomatology, it is particularly interesting to
examine the prevalence of the symptoms in the com-
munity sample of registered general practice patients
who were not consulting a urologist. It is of course
possible that many or most of these patients had
Table 8. Prevalence (%) of symptoms in the ICSmale questionnaire by age for the patients in the ICS-BPH study and for a
community sample, with tests of significance across the age groups for each of the samples separately

ICS-BPH patient (n=1256) Community sample (n=423)

<60 60-69 70+ p.value <60 60-69 70+ p. value
Symptom years years years years years years

Terminal dribble 96 94 91 0,018 79 78 73 0,63

Hesitancy 90 85 79 <0,001 53 47 49 0,61
Intermittency 90 90 84 0,018 44 53 53 0,22
Urgency 67 76 77 0,007 44 51 64 0,025
Post micturition dribble 69 69 65 0,30 44 40 42 0,83
Weak stream (words) 94 94 93 0,81 30 37 52 0,006
Weak stream (diagram) 87 89 88 0,72 21 53 60 0,003
Incomplete emptying 82 83 77 0,047 32 35 34 0,83
Frequency (hours) 71 70 69 0,83 29 43 34 0,049
Repeated urination 73 76 64 <0,001 24 28 27 0,71
Strain to continue 77 71 63 0,001 23 22 25 0,91
Urge incontinence 36 46 56 <0,001 13 26 41 <0,001
Dysuria 45 44 38 0,087 22 15 13 0,14
Strain to start 74 61 57 0,001 18 17 12 0,50
Bladder pain 48 43 35 0,001 15 14 19 0,70
Nocturia 66 74 79 <0,001 7 15 43 <0,001
Frequency (times) 51 48 43 0,10 11 15 12 0,58
Stress incontinence 12 14 18 0,088 8 14 14 0,16
Always weak stream 40 46 45 0,39 6 9 10 0,42
Misc incontinence 16 20 22 0,14 4 9 12

BPH/BPE/BPO (singly or in any combination).
However, until this is proven, one can only conclude
that such storage symptoms as urgency, frequency,
and nocturia are compatible with a diagnosis of
BPH/BPE/BPO but by no means specific or even
strongly suggestive of any of these.
Thomas, et al. (2005) followed neurologically intact
men diagnosed with detrusor underactivity during
voiding who opted initially for no specific treatment.
Of the ones who attended for repeat assessment and
who had not died in the interim, 84% remained
untreated with a mean follow up time of 13.6 years.
Initially, 20% of these also had urodynamic DO : at
follow up, this increased to 48%. However, the
symptom of urgency, present initially in 26% of men,
increased to only 34%. The mean age of presentation
was 57.5 years and at follow up 70.9 years. Thomas,
et al. (BJUI 2005) also followed a group of men ini-
tially diagnosed with bladder outlet obstruction who
opted for a conservative approach and attended for
repeat assessment. The mean follow up time was
13.9 years in those who had not died in the interim.
The urodynamic indices of obstruction and the spe-
cific voiding symptoms did not change. Nocturia
increased from a mean of 1.7 to 2.0 (p=0.022), but
the percentage of men reporting symptoms of urgen-
cy, frequency and urinary urgency incontinence did
not change significantly. However, the occurrence of
detrusor overactivity on urodynamic study, increased
from 35% to 70% (p<0.001). The mean age of pre-
sentation was 56.9 years and in follow up 70.8 years.
Thomas, et al. (2004), looked also at the natural his-
tory of lower urinary tract dysfunction following
transurethral resection of the prostate for bladder
outlet obstruction (Figure 17). They followed a pop-
ulation 60.5 years of age at presentation and 74.1
years at follow up. The mean follow up time was

90
 Pre-operative (n=137)

55 OAB (41%) 82 No (59%)

TURP with long-term follow-up

48 OAB* 7 No OAB 39 OAB* 43 No OAB

87 OAB
*p< .0001.
Mean follow-up time, 13.5 years.
Mean time since surgery, 12.6 yrears Post-operative
Figure 17. Long-term effect of transurethral prostate resection (TURP) on OAB. Thomas AW, et al BJU Int. 2000;85
(Suppl 3):57-68

14.3 years and mean time since surgery was 13.0
years. Although, there was significant resolution of
DO in the short term, at follow up, 64% of patients
demonstrated DO compared with 40% at original
presentation. Interestingly, only 31% complained of
urgency, compared with 51% at presentation. Their
observations would all support the association of at
least DO with aging but, oddly enough, less so with
the reported symptom of urgency. The reappearance
of DO following outlet ablation also is compatible
with a neurologic phenomenon, i.e., regrowth or re-
establishment of sensory afferents in the prostatic
urethra or prostate itself or perhaps of a central ner-
vous system change with age?
IV. NOCTURIA
1. INTRODUCTION
Nocturia is defined as the complaint that the individ-
ual has to wake at night one or more times to void
(Van Kerrebroeck et al, 2002). In view of the high
prevalence especially in elderly people it still is con-
sidered sometimes as a normal part of ageing
(Chasens, 2003). As such, nocturia is an important
but often still neglected element of LUTS in male
patients. However, where voiding once at night still
might have no major impact on sleep and as a conse-
quence quality of life, nocturia episodes of two or
more may significantly affect quality of life. More-
over in the majority of patients, the symptom of noc-
turia has a multifactorial pathophysiological back-
ground that complicates the analysis and hence the
therapeutic approach as multi-component therapy
may be necessary (Abrams and Wein 2002).
2. PREVALENCE AND IMPACT
Nocturia is a common symptom in men with an
increasing incidence from 50 years onwards (Schat-
zl, 2000).
The prevalence ranges from 10% in the general pop-
ulation above 20, but will rise to 16% above 40, 29-
60% at age 50 or more and will reach up to 55% in
men over 70 reaching 70-91% for those age 80+
years. There may be differences among different
countries depending probably on the local habits and
toileting facilities (Van Dijk, 2002). The increasing
prevalence is largely due to age-related conditions
that underlie the pathophysiology of the condition.
The symptom has also been associated with several
chronic medical conditions, such as hypertension,
diabetes, and cardiovascular disease (Rembratt et al
2003).
Especially in frail elderly people with gait and bal-
ance disorders and other risk factors, the risk for falls
is increased by the necessity to wake up at night to
void (Stewart, 1992). Nocturia also has been shown

91
to have adverse effects on quality of sleep (Asplund,
1992) and as a consequence on quality of life
(Asplund, 2005). Especially the first part of sleep is
very important and hence the decrease of the hours
of undisturbed sleep until the first nocturia episode
appears to be an important contributing factor in the
impact on quality of life (Jennum, 2002).
The complaint of nocturia is often not only bother-
some for the individual, but also for the partner.
In older men, the symptom of nocturia often occurs
together with other LUTS and/or other symptoms in
the framework of the overactive bladder syndrome.
However, the symptom of nocturia as such does not
suggest a specific diagnosis, although benign pro-
static obstruction is a major cause of nocturia (John-
son, 2003).
3. PATHOPHYSIOLOGY
The pathophysiology of nocturia, especially in elder-
ly males, is often multifactorial and related to a com-
bination of two or more of the primary causes, all of
which increase with age. Three major causes can be
identified: a primary sleep disorder, polyuria (24
hour or nocturnal) and low voided volumes, usually
as a component of overactive bladder syndrome or
prostatic obstruction (Weiss, 2000).
• Although elderly people spend more time in bed,
the total sleep time decreases and reduces sleep
efficiency. Also older people have more frequent
awakenings during the night and have difficulties
falling asleep again (Stanley, 2005). Furthermore,
sleep disordered breathing and sleep apnoea have
been associated with nocturia and nocturnal
incontinence in the elderly (Umlauf, 2004). The
exact mechanisms however are still unknown.
• Polyuria, especially nocturnal polyuria, is a major
cause of nocturia. The proportion of 24-hour urine
produced at night increases with age (Miller,
2000). Whereas in young healthy individuals, the
proportion of urine produced at night is less than
30%, this percentage can increase up to 50% in
the frail elderly (Rembratt, 2003). The nocturnal
urine production can be increased due to mobili-
sation of excess volume caused by peripheral
oedema related to venous insufficiency and/or
congestive heart failure. However there is some
evidence that an abnormality in the secretion
and/or action of arginine vasopressin at night
plays a role in this phenomenon (Asplund, 1991).
• In older men, benign prostatic obstruction, often
92
in combination with detrusor overactivity, results
in reduced voided volumes and increased micturi-
tion frequency. This occurs due to the combina-
tion of incomplete bladder emptying, and involun-
tary detrusor contractions, reducing the volumes
voided.
• Hence an increase in the frequency of nocturnal
micturitions is a well-established element of
LUTS in males (Johnson et al 2003). Therefore
although LUTS suggestive of BPO is considered
an independent risk factor for nocturia, other inde-
pendent age-related changes in the bladder may
contribute to nocturia in older men (Homma et al
2002).
4. DIAGNOSTIC ASSESSMENT
A specific algorithm (Figure 18, Wein 2002) based
on pathophysiological mechanisms has been devel-
oped by the ICS Standardisation Committee (Van
Kerrebroeck et al 2002).
As a nonspecific cause, sleep disorders must be men-
tioned and should be excluded or treated prior to fur-
ther lower urinary tract evaluation. As the symptom
of nocturia can be the consequence of a too high
urine production with 24 hour polyuria, nocturnal
polyuria or a combination of both, drinking
behaviour should be studied and preferably recorded
in terms of the amounts and types of fluid, as well as
timing of drinking. Since bladder problems must be
considered as a third contributing factor, the analysis
of nocturia may be complex.
The cornerstone to further analysis is the completion
of a frequency-volume chart with the length of night
time stated, that is the period in bed with the inten-
tion to sleep, until waking with the intention of aris-
ing (Saito, 1993). It is obvious that the time spent in
bed will be relevant to the total number of nocturia
episodes. It can also be useful to have a look at the
timing of nocturia episodes since this may relate to
the pathophysiological background. Increased
venous return tends to produce nocturia episodes ear-
lier during the night while some form of sleeping dis-
orders or bladder problems may rather cause nocturia
episodes in the second part of sleep.
History taking of other urinary symptoms and medi-
cation used are important elements to elucidate the
problem.
In view of the increasing incidence of the symptom
with age, one can question whether nocturia in elder-
ly men is part of the normal aging process. However
 Nocturia
Is it bothersome ?
NO
Active
Sleep Bladder
disturbance storage
probleme
Nocturnal
polyuria
Figure 18. Approach to differential diagnosis of patients with nocturia
not all men above a certain age will develop noc-
turia.
The bother and impact on quality of life (QoL) will
depend on the individual but in general bother will
increase as the number of nocturnal voids increases
(Asplund, 1992). Scoring systems may be used to
quantify the impact on quality of sleep or the overall
quality of life. A recently developed nocturia-specif-
ic quality of life score (N-QOL) may be a useful tool
in this respect (Abraham et al, 2004) and has become
one of the modules of the International Consultation
on Incontinence Questionnaire (ICIQ) (Avery et al
2004)
5. TREATMENT
In view of the bother and impact on quality of life,
treatment for nocturia must be considered with the
aim to at least relieve the severity/frequency of the
symptom by reducing or abolishing the nocturia
episodes.
Treatment of nocturia in males must be based on the
identification of all potential pathophysiological
mechanisms involved. No specific data are available
YES
Establish cause
Polyuria Psychological Behavioural
24-hour
polyuria
on combined interventions, but it is obvious that a
combination of several therapeutic approaches may
be beneficial. These include behavioural strategies,
therapy for medical and sleep disorders, drug thera-
py or any combination of these.
Evidence is lacking on the effects of behavioural
strategies such as altering/reducing fluid or sodium
intake, or leg elevation for oedema. Modifiying fluid
and food intake that might lead to altering urination
at night might equally affect the impact of nocturia
on sleep and minimize the risks for example, of falls.
Timing of antidiuretic therapy in the afternoon may
reduce volume overload at night by evacuation of
urine before going to bed to sleep (Reynard et al).
Data are lacking on the effect of treatment for sleep
apnoea with continuous positive airway pressure on
nocturia, but the condition must be treated because
of the potential side effects. There is also a place for
other treatments of disturbed sleep.
Several options for specific drug therapy for nocturia
are available. If detrusor overactivity is one of the
main contributing factors, antimuscarinic therapy
should be considered. Currently limited data are
available as to the impact of LUTS/BPO treatment
93
on the relief of nocturia. There is some indication
that the combination of an alpha-adrenoreceptor
antagonist in combination with a 5 alpha-reductase
inhibitor may be preferable (Johnson et al 2003). In
one study similar results, in terms of effect on noc-
turia, were published for the alpha1-AR antagonist
(tamsulosin) and surgical treatment (Yoshimura et al
2003).
An important number of publications present the
beneficial results of exogenous AVP (desmopressin
or DDAVP) for the treatment of nocturia. Also, in a
large group of men, significant results have been
published showing a significant reduction in nocturia
episodes and increases in mean duration of first
night-time sleep episode (Mattiasson et al 2002). A
major concern related to DDAVP treatment in elder-
ly patients may be the possibility of fluid retention
and hyponatremia. However with strict biochemical
control this may be a very effective therapy for both-
ersome nocturia.
V. VOIDING SYMPTOMS
The term voiding symptoms refers to those symp-
toms experienced by the patient during micturition :
slow stream, splitting or spraying of the stream,
interrupted stream (intermittency), hesitancy, strain-
ing to either initiate, maintain or improve the urinary
stream and terminal dribble (Abrams, et al 2002).
The term “obstructive symptoms” and “prostatism”
are still sometimes misused, but in modern termi-
nology the descriptive terms voiding symptoms as
part of Lower Urinary Tract Symptoms should be
used (Abrams, 1994).
A distinction should be made between storage symp-
toms and voiding symptoms, the latter related to the
time that the individual is evacuating urine. As there
is a poor relation between these voiding symptoms
and obstruction it is advised to no longer refer to
these symptoms as “obstructive”. The term “empty-
ing symptoms” is equivalent to voiding symptoms.
Voiding symptoms can be related to bladder outlet
obstruction, impaired detrusor contractility or a com-
bination of the two. In most individual patients it is
impossible to relate symptoms to pathophysiological
mechanisms or to the urodynamic findings. In terms
of objective urodynamic assessment, statistically sig-
nificant, but clinically insignificant correlations
between symptoms and urodynamic parameters of
obstruction, could only be established for the symp-
94
toms of hesitancy and weak stream (Abrams et al
1978). Postvoid dribble is so common among men
without prostatic problems that it is of little value as
a discriminator, and is not a voiding symptom, but
should be included with feeling of complete empty-
ing as a post-micturition symptom. Straining is a
symptom with little relation to obstruction (Reynard
1995). The overall conclusion in most of the relevant
literature is that voiding LUTS cannot predict which
pathology is present. Hence from symptoms alone, it
is not possible to diagnose bladder outlet obstruction
nor any of the other pathophysiological mechanisms
(Sirls 1996). However, scoring systems have been
based on these symptoms in community populations
(Brasso et al 1994).
The lack of significance of voiding symptoms is not
surprising as, in the case of limited bladder capacity,
voiding symptoms can be the consequence of small
volume voids. Moreover in patients with detrusor
overactivity, a suppressed involuntary contraction
may result in voiding symptoms because of the
inability to generate a voluntary detrusor contraction
in an attempt to empty the bladder. In this instance
slow flow results from a small voided volume.
Therefore, similar voiding symptoms may occur in
situations of overactive detrusor as well as of under-
active detrusor.
C. PATIENT ASSESSMENT
This section on clinical assessment includes:
• History taking, frequency-volume charts and
symptoms scores
• Physical examination
• Urinalysis
• Biochemical testing
• Postvoid residual urine
• Imaging of the lower urinary tract
• Endoscopy of the lower urinary tract
I. HISTORY & PHYSICAL
EXAMINATION
The American Urological Association (AUA Prac-
tice Guidelines Committee, 2003), the European
Association of Urology (Madersbacher, et al., 2004)
and the 5th International consultation on BPH
(Resnick, M., 2001) highly recommend that a
detailed medical history should be taken focusing on
the urinary tract and aiming at identifying condi-
tions, other than benign and malignant disorders of
the prostate which may be responsible for LUTS.
Such a recommendation is based on experts’ opinion
and no evidence to support such policy can be found
in the peer-review literature other than the guidelines
themselves. Possible causes of urinary symptoms
include benign disorders of the bladder, such as acute
bacterial cystitis, squamous metaplasia of the blad-
der, bladder stones, etc) (Badawi and Langbein, S.,
2005; Cruz, 1999; Kojima, et al., 1997; Porru, et al.,
2005) and urethral disorders such as urethral stenosis
(Serrano-Brambila, et al., 2003), malignant condi-
tions of the urinary bladder (urothelial tumours) and
conditions outside the LUT such as CNS (multiple
hyschemic lesion of the brain) (Seim, et al., 2005)
and spinal cord (lumbar disc protrusion) (Yamanishi,
et al., 1998). The symptomatic diagnosis of any of
the described conditions inside and outside the LUT
does not necessarily establish a cause-and-effect
relationship with LUTS as more than one pathologic
condition may coexist in the pathophysiology of the
storage and voiding symptoms. The evidence of co-
morbidities may be of importance not only in the
diagnostic phase but also when management and
treatment of LUTS is considered. [Level of evidence
4, Grade of recommendation D].
II. FREQUENCY-VOLUME CHARTS
Frequency-volume charts (FVC) have become an
important part of the evaluation of LUTS. Most
experts would agree that these charts provide invalu-
able information about a number of symptoms
including urinary frequency, urgency, incontinence
episodes, and voided volume. In fact some symp-
toms, like nocturia, cannot be properly evaluated
without a chart. Frequency-volume charts are critical
for the distinction between nocturnal overactive
bladder and nocturnal polyuria, two common causes
of nocturia. Despite this the structure, content and
duration of chart keeping for the evaluation of
MLUTS has not been standardised. There are a num-
ber of parameters that can be assessed by the FVC,
including: total number of voids 24/hours, total num-
ber of daytime (awake) voids, total number of night-
time voids, total fluid intake, total voided volume,
maximum, minimum and mean voided volume,
number of urgency episodes, and number of inconti-
95
nence episodes. Although, if data on urgency and
incontinence episodes is requested then the ICS
(Abrams et al 2002) would determine the instrument
as a bladder diary.
FVCs have been shown to be reproducible and more
accurate when compared with the patient’s recall
(Larsson, et al, 1992; McCormack, et al, 1992;
Wyman, et al, 1998; Blanker, et al, 2000; Groutz, et
al, 2000). For example, it has been shown that for
nocturia, 51.5% of men were inaccurate in their esti-
mation of the number of episodes per night (Jaffe, et
al, 2002). Furthermore, men who perceived their
nocturia as more severe, tended to overestimate their
nocturnal voiding frequency, and those who per-
ceived their nocturia as less severe, tended to under-
estimate it (Jaffe, et al, 2002). However, recommen-
dations for diary length in men vary considerably,
including 24 hours (Gisolf, et al, 2000), 3 days
(Robb, 1985), or 7 days (Russell, et al, 1994;
Abrams, et al 1996). This inconsistency may be
explained by the fact that previous investigations
have analyzed only the reproducibility and correla-
tion of data.
Homma et al (2002) determined that the optimal
length of a diary varies according to the parameter
assessed and the precision and sensitivity required.
In addition, if one is trying to assess change, the
baseline parameter (e.g. number of voids, inconti-
nence episodes) will affect the length of the diary
needed to detect a certain change. They concluded
that a 7 day diary is a reasonable option for most
patients with incontinence. Ku, et al (2004) conclud-
ed that a 7-day diary may be satisfactorily main-
tained by patients with incontinence and LUTS, and
is a valid tool for symptom evaluation. However,
record keeping for 7 days was found to increase
patient burden and they suggest that the number of
days required to evaluate voiding symptoms should
be reduced.
The majority of information collected on FVCs or
bladder diaries has been used to establish baselines
or to study patients with OAB or incontinence.
Gisolf, and colleagues (2000) reported on the relia-
bility of frequency volume charts to study men with
LUTS suggestive of BPO. Patients reported on fre-
quency volume charts for 3 periods of 24 hours. The
authors found correlations between diary data and
IPSS questions pertain to frequency and nocturia.
They also found that data obtained from a single 24-
hour diary was no different that that obtained from
three 24-hour diaries.
Most studies have used paper diaries to collect infor-
mation. Quinn, at al (2003) compared the use of elec-
tronic and paper diaries in a crossover study on
patients with OAB. They concluded that the compa-
rability of data collection, suggested that the elec-
tronic diary is an appropriate alternative to a paper-
based method for assessing the symptoms of OAB,
while ease-of use ratings appeared to support the
electronic diary as an acceptable alternative.
III. SYMPTOM SCORES
Symptom scores have been used in male LUTS for a
variety of purposes:
• to assess symptom severity
• to examine the relationships between clinical
measures/tests results and scores from symptom
and quality of life questionnaires
• to predict the response to treatment
• to assess the outcomes of treatment
Specific symptoms scores have been evaluated and
are discussed below:
• IPSS Symptoms and QoL impact of LUTS
• ICIQ-SF Symptoms and QoL impact of urinary
incontinence
• ICIQ-MLUTS Symptoms and bother
of LUTS and UI
• Dan PSS Symptoms and bother
of LUTS and UI
• OAB-q Symptoms and QoL impact of
OAB
Over the past two decades symptoms scores have
become a routine part of the evaluation of lower uri-
nary tract symptoms (LUTS). Symptoms scores have
been used to quantify LUTS in terms of both preva-
lence and severity, verify the influence of LUTS
upon quality of life, including sexual function, and
determine the therapeutic efficacy of various treat-
ments. In addition it is important that symptom
scores have a wide applicability across a number of
different cultures and languages. In an ideal setting,
symptoms scores should also help to determine the
underlying etiology of LUTS (e.g. bladder outlet
obstruction, detrusor overactivity, impaired detrusor
contractility, etc.) however this is made difficult by
the fact that different conditions can produce similar
or even identical symptoms. A number of different
96
symptom scores have been proposed to assess the type
and severity of LUTS associated with BPO. Each has
advantages and disadvantages, and it is clear that the
worldwide use of such indices has helped in evaluat-
ing symptoms, treating patients, and communicating
findings globally. Furthermore, attempts to develop
new and better indices are constantly improving our
understanding of LUTS and the conditions that cause
them. Three questionnaires with a high level of psy-
chometric validity and reliability, are the International
Prostate Symptom Score (IPSS), the International
Consultation on Incontinence Questionnaire Male
LUTS module (ICIQ-MLUTS), previously known as
the ICSmale questionnaire now known as the ICIQ-
MLUTS, and the Danish Prostate Symptom Score
(DAN-PSS). Although each was designed with the
same purpose, only 5 symptoms are common to all 3
: incomplete emptying, urgency, decreased stream,
frequency and nocturia.
1. THE INTERNATIONAL PROSTATE SYMPTOM
SCORE (IPSS)
The IPSS is the most commonly used tool to evalu-
ate LUTS suggestive of BPO. In 1992 Barry et al.
reported that the American Urological Association-7
(AUA-7) Symptom Index was a valid short ques-
tionnaire useful in the diagnostic work-up of voiding
symptoms (Barry et al 1992). Subsequently it was
adopted by the World Health Organization (WHO)
and renamed the International Prostate Symptom
Score (IPSS) after adding a disease-specific quality
of life score (Mebust et al 1991). The IPSS was
developed to examine how patients with “BPH” per-
ceived their symptoms and how symptoms affected
their lives. It was also created as a tool to give clini-
cians a uniform and reproducible method of assess-
ing symptoms and facilitate comparisons of results in
clinical studies (O’Leary et al 1992). Initially the
goal was to develop a short, practical, self-adminis-
tered, clinically sensible index with excellent psy-
chometric properties to capture the severity of uri-
nary symptoms related to “BPH” (Barry et al 1992).
The committee (the American Urological Associa-
tion Measurement Committee) reviewed previously
published indexes as well as unpublished indexes
from pharmaceutical companies conducting research
on treatments designed to alleviate BPO, and devel-
oped a list of questions which covered all symptom
domains that they felt were appropriate. Only
patients who investigators felt clearly had “symp-
tomatic BPH” were enrolled in the initial testing of
the questionnaire. After a second validation study
using a shorter, revised questionnaire which con-
tained questions that correlated with global bother
questions, the committee decided on the seven ques-
tion where each symptom was rated as 0-5 based on
increasing severity.
The IPSS includes seven questions covering incom-
plete emptying, frequency, intermittency, urgency,
weak urinary stream, hesitancy, and nocturia. Each
question can be answered on a scale of 0 to 5 (rang-
ing from “not at all” to “almost always”).The symp-
tom index is the sum of the seven scores and, there-
fore, ranges from 0 to 35 points. Additionally, one
question concerning the patient’s quality of life with
LUTS may be answered on a scale of 0 (“delighted”)
to 6 (“terrible”). Statistically, the index was shown to
be internally consistent, and highly reliable and to
accurately discriminate “BPH patients” from con-
trols. Furthermore, symptoms were able to be classi-
fied as mild (AUASS < 7), moderate (AUASS 8-19),
and severe (AUASS >20 severe) based on sensitivi-
ty cutoffs for “BPH patients” and specificity cutoffs
for controls (Barry et al 1991).
The IPSS has subsequently been used routinely in
clinically practice and has been used extensively in
clinical studies to evaluate the prevalence of LUTS
and “symptomatic BPH” (Tuncay et al 2003: Ander-
sson et al 2004) and also to assess the affects of var-
ious pharmacological, minimally invasive and surgi-
cal treatments for LUTS /BPO. It has many advan-
tages as it is self-administered (and thus efficient,
less time consuming and without interviewer bias),
sensitive to change and generalizable to different
populations and socio-economic groups (Netto and
Lima 1995: Netto et al 1997; Quek et al 2002; Gan-
pule et al 2004). In addition, in cases where self-
administration is not possible (visual impairment and
illiteracy) interviewer administration is an accept-
able substitute, however the mode of administration
should remain consistent in a given patient (Netto
and Lima 1995: Barry et al 1995; Plante et al 1996;
Cam et al 2004). IPSS scores increase with age as
would be expected. Young asymptomatic men (age
50 or less) tend to have low scores (Moon et al 1997;
Mueller et al 2005). However, with increasing age
IPSS has been shown to increase even in men with-
out voiding complaints suggesting that mild to mod-
erate LUTS may be considered a “normal” conse-
quence of aging and do not necessarily cause patients
to complain (Van Haarst et al 2005).
The IPSS has been shown to be sensitive to change.
Barry, et al (1995 b) calculated the clinically signifi-
cant changes in the score by examining patients’ rat-
ing of treatment which ranged from markedly, mod-
97
erately or slightly improved, through unchanged to
worse. Those who had no improvement had a reduc-
tion of 0.7 points; those who rated slight improve-
ment had a mean reduction of 3.0; moderately
improved reduced by 5.1 points; and markedly
improved reduced by 8.8 points. A much greater
decrease in symptoms was necessary to elicit the
same self-rating of improvement among patients
who started with higher baseline levels, thus minimal
perceptible difference were powerfully influenced by
baseline scores. A change of at least 3 points is con-
sidered indicative of a meaningful change.
One of the major criticisms of the IPSS is the fact
that it is not disease or condition specific. While it is
a useful tool for judging the severity of LUTS sug-
gestive of BPO, and evaluating therapeutic outcomes
(compared to baseline in individual subjects) it is
not, however, a diagnostic tool for benign prostatic
obstruction (de la Rosette, et al, 1998). LUTS are
multifactorial and bladder outlet obstruction, motor
and sensory abnormalities of the detrusor, impaired
detrusor contractility, urethral function, habits and
lifestyle are all potential causes of the same or simi-
lar symptoms. Multiple studies have shown that the
IPSS is not correlated with urodynamic obstruction
(Nitti et al, 1994; Yalla, et al, 1995; van Venrooji, et
al, 1995; Ko, et al, 1995; Sirls, et al, 1996; Maders-
bacher, et al, 1997; Eckhardt, et al,1997). It also cor-
relates poorly with free urinary flow rate, prostate
size, and the amount of post void residual urine
(Barry, et al 1993). In addition, the IPSS is not
strongly correlated with prostate volume as deter-
mined by transrectal ultrasonography (Madersbach-
er, et al, 1997; Yano et al, 2004]). Aged-matched
women have similar scores as men (Lepor and
Machi, 1993; Chancellor and Rivas, 1993; Chai, et
al, 1993), another indication that the IPSS is not dis-
ease or condition specific. Furthermore it has been
shown to accurately describe LUTS, to be a good
indicator of the degree of bother and the effect on
quality of life of LUTS ON WOMEN! (Scarpero, et
al, 2003).
Another criticism of the IPSS is that it does not
assess the symptom of urgency incontinence, one of
the most bothersome of the LUTS suggestive of
BPO. Urgency incontinence is an important symp-
tom, particularly in regard to therapeutic outcomes in
BPO patients. The prevalence of this symptom was
also reported as common by the ICS-“BPH” study
group and was higher in men with bladder outlet
obstruction than in those without (de la Rosette, et al,
1998).

CONCLUSIONS
There is level 1 evidence to suggest that the IPSS
is a useful tool to assess LUTS suggestive of BPO
and to assess change from baseline after treat-
ment. The IPSS is sensitive to change, and the
larger the change, the more is the impact on both-
er. There is also level 1 evidence that the IPSS it
not disease or condition specific and that the
symptoms that are measured are not necessarily
associated with BPH, BPE, or BPO. Finally, one
other shortcoming of the IPSS is that it does not
include the symptom of urgency incontinence, a
prevalent and highly bothersome symptom in men
with LUTS with or without BPO.
Recommendation: Grade A
2. THE INTERNATIONAL CONSULTATION ON
INCONTINENCE QUESTIONNAIRE: ICIQ
MALE LUTS (ICIQ-MLUTS, PREVIOUSLY
ICS MALE)
The ICSmale questionnaire resulted from the Inter-
national Continence Society “Benign Prostatic
Hyperplasia (ICS”BPH”) study” (Donovan, et al,
1996; Witjes, et al, 1997; Abrams, et al, 1997; de la
Rosette, et al, 1998; Donovan, et al, 2000). Unlike
the IPSS which compared patients with “clinically
defined BPH” to non-urological control patients, in
order to evaluate the ability of the questionnaire to
discriminate, the ICSmale questionnaire (now
renamed the ICIQMLUTS as part of the ICIQ mod-
ular questionnaire: www.iciq.net). was assessed by
comparing patients visiting urological clinics who
had urodynamically proven bladder outlet obstruc-
tion with community based men. When the ICSmale
was initiated, it was intended that a scoring system
would be devised in terms of relationships with uro-
dynamically confirmed bladder outlet obstruction
(Abrams, et al, 1997). However, early investigations
indicated that this would not be possible because
only the symptom of urgency incontinence had any
statistically significant correlation and that was with
detrusor overactivity, even with the power of study
due to a relatively large number of patients (1,271)
(de la Rosette, et al 1998). This is similar to what has
been found with the IPSS, even though the ICSmale
questionnaire was derived from patients who had
urodynamically investigated bladder outlet obstruc-
tion. This led the authors to conclude that: “there are
objective methods that quantify both urine flow rate
and bladder outlet obstruction. In addition, there are
valid and reliable methods to quantify the presence
98
of LUTS. These methods measure different aspects
of the clinical condition that should be viewed sepa-
rately in the evaluation and treatment decision of the
patient presenting with LUTS [de la Rosette, et al
1998].” Unlike the IPSS, the ICIQ MLUTS (long
form ICSmale) questionnaire does assess a number
of incontinence symptoms.
The ICIQMLUTS long form questionnaire contains
22 questions on 20 urinary symptoms, and, for most
questions, the degree of bother that the symptom
causes (Donovan, et al, 1996). It has exhibited
acceptable levels of validity, reliability and sensitiv-
ity to change following a range of treatments includ-
ing surgery, minimally invasive therapies and drug
treatments (Abrams, et al 1997; Donovan, et al,
1999;Vandonink, et al 2003). After factor analysis,
the long version has now been largely replaced by a
scored short-form the ICIQMLUTS formerly termed
the ICSmale-SF (Donovan, et al 2000). It also con-
tinues to be used to assess LUTS in men and the
results of minimally invasive therapies and drug
treatments (Joshi, et al 2002; Joshi, et al, 2003a;
Joshi, et al, 2003b;Gacci, et al, 2003). The ICIQM-
LUTS consists of 14 questions; 5 assessing voiding
symptoms, 6 assessing incontinence symptoms and 1
question each on frequency, nocturia, and quality of
life (Donovan, et al 2000). The ICIQMLUTS may be
divided into a voiding subscore (ICSmaleVS) and an
incontinence subscore (ICSmaleIS). Thus it is pri-
marily a questionnaire for the assessment of the
occurrence and bothersomeness of a wide range of
LUTS in men.
The scientific committee which met at the end of the
1st International Consultation on Incontinence in
1998 supported the idea that a universally applicable
questionnaire should be developed, that could be
widely applied both in clinical practice and research.
The hope was expressed that such a questionnaire
would be used in different settings and studies and
would allow cross-comparisons, for example,
between a drug and an operation used for the same
condition, in the same way that the IPSS has been
used. An International Consultation on Incontinence
Questionnaire (ICIQ) Advisory Board was formed to
steer the development of the ICIQ, and met for the
first time in 1999. The project’s early progress was
discussed with the Board and a decision made to
extend the concept further and to develop the ICIQ
Modular Questionnaire. The first module to be
developed was the ICIQ Short Form Questionnaire
for urinary incontinence: the ICIQ-UI Short Form.
The ICIQ-UI Short Form has now been fully validat-
ed and published (Avery, et al, 2004). Given the
intention to produce an internationally applicable
questionnaire, requests were made for translations of
the ICIQ-UI Short Form at an early stage, for which
the Advisory Board developed a protocol for the pro-
duction of translations of its modules. The ICIQ-UI
Short Form has been translated into 30 languages to
date. In addition to the ICIQ-UI Short Form, twelve
modules have been adopted which are direct
(unchanged) derivations from already published
questionnaires. As described above, the ICIQ-
MLUTS is derived from the ICSmaleSF.
CONCLUSION
The ICIQMLUTS long-form (ICSmale) and the
ICIQMLUTS (ICSmale-SF) have a high level of
psychometric validity and reliability. The ICIQ-
MLUTS is derived from the ICSmale-SF, and has
a 10 point bother question after each symptom
question. There is level 1 evidence to suggest that
the ICIQ-MLUTS is a useful tool to assess LUTS
suggestive of BPO and to assess change from
baseline after treatment. Furthermore, it does take
into account symptoms of incontinence and it may
be divided into voiding and incontinence sub-
scores. It has not yet had the same widespread use
in clinical practice to date as has the IPSS.
Recommendation: Grade A
3. THE DANISH PROSTATE SYMPTOM SCORE
(DAN-PSS)
This questionnaire was designed in Denmark to mea-
sure the presence and severity of LUTS and, in a sep-
arate assessment, to measure the degree to which
men are bothered by each urinary symptom (Hald, et
al, 1991; Meyhoff, et al, 1993). The DAN-PSS was
initially intended for use in “the BPH patient” with-
out serious complications such as recurrent urinary
tract infections, bladder stones, renal impairment,
acute or chronic urinary retention etc.” The question-
naire consists of 12 questions pertaining to a variety
of LUTS including hesitancy, weak stream, incom-
plete bladder emptying, straining to void, frequency,
nocturia, urgency, dysuria, post void dribbling, stress
and urgency incontinence. Each question is graded
from 0 (not present) to 3 (e.g. highest level of sever-
ity or always). For each symptom, the patient is then
asked how much of a problem the symptom is (0- no
problem; 1-small problem; 2- moderate problem; 3-
severe problem). A composite score is achieved by
99
the multiplication of the ‘symptom’ by the ‘bother’
score, with a total range of 0 to 108 (Hald, et al,
1991; Meyhoff, et al, 1993). The DAN-PSS has
excellent test-retest reliability, content and construct
validity and is able to discriminate between patients
with LUTS suggestive of BPO and those without
(Brasso, et al 1994; Hansen, et al, 1995). The DAN-
PSS has also been shown to be appropriately respon-
sive to change after surgery and medical therapy
(Hansen, et al, 1994; Hansen, et al, 1995; Pannek, et
al, 1998). A computer version of this questionnaire
has been validated and patients are said to appreciate
the new version more than the paper version (Flyger,
et al, 2001).
The DAN-PSS may be subdivided into an “obstruc-
tive” and an “irritative” part. Schou, et al claimed
that with a cutoff point of 6 for the “obstructive” part
the DAN-PSS is able to discriminate men with blad-
der outlet obstruction from men without significant
obstruction (Shou, et al, 1993). However, a subse-
quent study showed no correlation of the DAN-PSS
(or “obstructive” subscore) with obstruction mea-
sured by standardized pressure-flow analysis (Pan-
nek, et al, 1998). Furthermore that study showed that
neither the preoperative DAN-PSS nor the IPSS
score could sufficiently predict the success or failure
of transurethral prostate resection.
CONCLUSION
The DAN-PSS is a psychometrically valid and
reliable tool for the assessment of LUTS sugges-
tive of BPO. It is unique from other indices in that
it multiplies the severity of symptoms by the
degree of bother. Thus severe symptoms with no
bother will contribute zero to the total score. It
considers a variety of symptoms including incon-
tinence. There is limited level 1 evidence to sug-
gest that the DAN-PSS is a useful tool to assess
LUTS suggestive of BPO and to assess change
from baseline after treatment, with most studies
coming from Denmark.
Recommendation: Grade B.
4. SYMPTOM SCORES – SUMMARY
A variety of symptoms scores have been described to
assess patients with LUTS suggestive of BPO. The I-
PSS, ICIQ-MLUTS (long and short forms), and Dan-
PSS have been the most tested and found to be repro-
ducible, valid, reproducible, and sensitive to change
from therapy. The IPSS has been the most widely
used (in many countries and languages), but neglects
the symptom of urgency incontinence, a symptom
that produces significant bother. The ICIQMLUTS
(ICSmale-SF) is slightly longer, but takes into
account the symptom of urgency incontinence, and
in fact may be divided into voiding and incontinence
subscores. To date, it has not been as widely used as
the IPSS, but may see more widespread use as part of
the ICIQ Modular Questionnaire. The DAN-PSS has
been mostly used in Denmark. Because LUTS are
multifactorial, none of the symptoms scores are con-
dition specific and none are able to consistently pre-
dict obstruction. This has led to the conclusion that
these valid and reliable methods, to quantify the
presence and severity of symptoms and the objective
methods that quantify urine flow rate and bladder
outlet obstruction, measure different aspects of the
clinical condition, and should be viewed separately
in the evaluation and treatment decision of the
patient presenting with LUTS (Eckhardt, et al,
2000). Symptom scores and a functional assessment
provide the optimal way to appreciate the “total pic-
ture” of the male with LUTS.
IV. PHYSICAL EXAMINATION
A general physical examination with a specific atten-
tion to the presence or absence of a distended blad-
der, excoriation of the genitals secondary to urinary
incontinence, evidence of urethral discharge and a
focused neurological examination is also highly rec-
ommended. Digital rectal examination (DRE) of the
prostate is currently performed to excluded the pres-
ence of locally advanced prostate cancer, although its
specify and sensitivity is low (Chodak, et al., 1988),
to evaluate anal sphincter tone which is often
decreased in neurogenic patients (Agarwal and
Rosenberg, M. L., 2003) and to estimate prostate size
although DRE is known to underestimate prostatic
volume as compared with trans rectal ultrasound or
magnetic resonance imaging (Roehrborn, et al.,
2001). Prostate volume has been recently associated
with the risk of BPH progression (McConnell, et al.,
2003)and response to treatment (Boyle, et al., 1996).
Occasionally tumours of the anal canal can be diag-
nose while performing DRE of the prostate.
In conclusion, the level of evidence for recommend-
ing DRE in the diagnostic workup is weak consider-
ing the causative role of benign prostatic enlarge-
ment (BPE) for LUTS [Level of evidence 4, grade of
recommendation D], a higher level of evidence
100
exists for the estimation of prostate volume in the
managing LUTS patients [Level of evidence 1,
Grade of recommendation A]
V. URINALYSIS
Urinalysis is not a single test, complete urinalysis
includes physical, chemical, and microscopic exam-
inations. Dipstick urinalysis is certainly convenient
but false-positive and false negative results may
occur [19]. It is considered an inexpensive diagnos-
tic test able to identify patients with urinary tract
infection (UTI) as indicated by the presence of leu-
cocyte esterases and nitrites, although infection may
exist in the absence of pyuria and, in the elderly pop-
ulation, pyuria may develop in the absence of UTI
[19]. Microscopic haematuria can be easily identi-
fied by dipsticking because of the presence of
haemoglobin. The detection of haematuria is impor-
tant because the condition is associated with a 4-5%
risk of diagnosing urological disorder or malignancy
within 3 years [20]. Because of the high prevalence
of urinary tract infection (UTI) and the increase of
LUTS in the presence of UTI, all guidelines on the
management of patients with LUTS suggestive of
BPO, and urinary incontinence, endorse the use of
urinalysis in primary care management [Gerber et al
1997; Roehrborn et al 2001]. [Level of evidence 4,
Grade of recommendation A].
VI. BIOCHEMICAL TESTING
1. SERUM CREATININE
Epidemiological studies in community dwelling men
have shown the absence of any association between
BPO / BPE / BPO and chronic kidney disease (Rule,
et al., 2005) suggesting that screening for renal func-
tion is not justified in patients with LUTS (Rule, et
al., 2005). Such recommendation has been recently
endorsed by the American Urological Association in
their guidelines on “BPH” (AUA Practice Guidelines
Committee, 2003). Diabetes or arterial hypertension
appear to be the most important cause of elevated
serum creatinine in men with proven BPO and renal
failure (Gerber, et al., 1997). Recently, data from the
MTOPS study showed that the risk of developing de
novo renal failure in men with LUTS is low (less
than 1 %) suggesting that is not necessary to monitor
renal function in patients with LUTS / BPO
(McConnell, et al., 2003). Nevertheless, most nation-
al and international guidelines (Madersbacher, et al.,
2004; Roehrborn, et al., 2001) still recommend mea-
suring serum creatinine judging that the cost of miss-
ing a diagnosis of renal failure out weighs the expen-
diture of screening for renal function (Gerber, et al.,
1997). [Level of evidence 4, Grade of recommenda-
tion D]
2. PROSTATE SPECIFIC ANTIGEN
There is no consensus as to the measurement of
prostate specific antigen (PSA) in patients with
LUTS. The rationale for measuring PSA is twofold:
to screen for prostate cancer (Noel, 2000), and to
measure a parameter with prognostic value for the
progression of BPH and the response to treatment
(Boyle, et al., 1996; McConnell, et al., 2003).
Screening for prostatic cancer is a major reason why
men over 50 of age will consult their family doctor
or a urology clinic. Prostate Specific Antigen (PSA)
has been primarily used in the diagnosis and treat-
ment of prostatic cancer since its introduction in the
1980s; however it is also produced by benign pro-
static epithelial cells and many patients with LUTS /
BPO might have a raised PSA. The question as to
whether PSA is a proxy for prostate volume, as sug-
gested in LUTS patients, or a marker for prostate
cancer is unresolved. Evidence to support both views
can be found in the peer-review literature. A recent
paper from Catalona’s group suggests a relationship
between initial PSA level and subsequent prostate
cancer detection with a stepwise increase in cancer
detection rate (from <1% to 58%) in patients with
<1.0 ng/ml, 1.1-2.5, 2.6-4.0, 4-1-10.0 and >10 ng/ml
PSA value in over 26.000 patients enrolled in a
screening programme (Antenor, et al., 2004). In the
same year, Thompson published data on prostate
cancer prevalence from the prostate cancer preven-
tion trial (Thompson, et al., 2004) confirming a step-
wise increase in the risk of having a prostate cancer
in patients with serum PSA from ≤0.5 to 4.0 ng/ml
but showing the limitation of the current threshold of
4.0 ng/ml. Change of PSA threshold from 4.0 to 2.0
ng/ml has been proposed but no consensus exists yet
(Wilson and Crawford, E. D., 2004). Therefore the
discussion on the clinical benefit of PSA testing for
prostate cancer screening is not settled yet (Craw-
ford, 2005; Stamey, et al., 2004). All guidelines sug-
gest a cautious use of PSA in the diagnostic workup
of patients with LUTS because of the low specificity
of PSA for the diagnosis of prostate cancer (Noel,
2000) although it remains the best available tool for
prostate cancer screening (Crawford, 2005). When
101
PSA is considered as a screening tool for prostate
cancer, most guidelines suggest that it is used only in
patients with a life expectancy of 10 year or longer
(AUA Practice Guidelines Committee, 2003; Mader-
sbacher, et al., 2004). The European Urology Associ-
ation (Madersbacher, et al., 2004), the American
Urological Association guidelines (AUA Practice
Guidelines Committee, 2003) on “BPH” suggested
that the benefit and risks of PSA testing should be
discussed with the patient. PSA testing is recom-
mended in men with LUTS and a life expectancy of
over 10 years in whom the diagnosis of prostate can-
cer would change the management of patient’s void-
ing symptoms. The committee on initial evalution of
LUTS of the 5th WHO International Prostate Con-
sultation also supported this practice (Chatelain et al
2001).
Serum PSA is also a surrogate of prostate volume.
The Longitudinal Baltimore Study of Aging showed
evidence for a clear increase in the risk of prostate
enlargement in each cohort (from 40 to 69.9 years)
with increasing serum PSA levels (Wright, et al.,
2002). PSA is also a strong predictor of the risk of
acute urinary retention and the need for surgery in
men with LUTS (McConnell, et al., 2003). Laniado
et al (2004) has also recently tested the hypothesis
that PSA level could be used to predict the presence
or absence of bladder outlet obstruction, evaluated
by pressure flow studies. In patients with LUTS,
those with a PSA more than 4 ng/ml are significant-
ly more likely to have some degree of BOO. Con-
versely patients with PSA less than 2 ng/ml have a
33% risk of BOO (Laniado, et al., 2004).
The level of evidence for PSA as a screening tool for
prostate cancer, as a proxy for prostate volume and a
prognostic parameter for BPE progression is high
[Level of evidence 2, Grade of recommendation B].
VII. POST-VOID RESIDUAL URINE
Interestingly, PVR tends to increase with age sug-
gesting a progressive voiding dysfunction (Rule, et
al., 2005). In daily practice, PVR is often used to
assess patients presenting with LUTS, although the
pathophysiology of elevated PVR is not generally
well understood and its interaction with BOO and
detrusor underactivity is complex.
The standardization of terminology of lower urinary
tract functions defines post void residual (PVR) as
“the volume of urine left in the bladder at the end of
micturition” providing a qualitative description with-
out addressing the issue of normal and abnormal val-
ues. The rationale for measuring post voiding resid-
ual (PVR) urine in men with LUTS is twofold: to
diagnose significant residual urine volume/chronic
urinary retention as a possible cause of symptoms,
and to treat high residual urine volumes as they are
considered to be associated with an increased risk of
urinary tract infection and to an increased risk of uri-
nary retention.
No consensus exists as to the relation between PVR
and UTI. In the standard patient the evidence is con-
troversial (Abrams P et al 2001; Bosch, 1995), and
the negative role of large residuals has been largely
derived from experience in paediatric, elderly, dia-
betics and neurogenic patients (Beylot, et al., 1982;
Grosshans, et al., 1993; Lidefelt, et al., 1989; Mac-
Gregor and Williams, C. J., 1966; Merritt, 1981).
Large residual urine has been considered a bad prog-
nostic factor for disease progression although, in the
standard patient, the evidence suggest that renal fail-
ure, acute retention and UTIs are uncommon in men
with large, chronic residuals (Bates, et al., 2003). No
factors are available to identify patients, with signif-
icant residual urine, who are at risk for progression
(Bates, et al., 2003).
Following the described evidence, both the 5th Inter-
national Consultation on BPH and the AUA define
measurement of PVR as a optional test in primary
care management for the standard patient (AUA
Practice Guidelines Committee, 2003; Chatelain, C
et al 2001) although the test is recommended in some
national and international guidelines (Madersbacher,
et al., 2004; Roehrborn, et al., 2001). No data are
available to define normal versus abnormal PVR val-
ues, the International Consultation on BPH defined a
range of 50 to 100 ml as the lower threshold to define
abnormal PVR (Abrams et al , 2001). Both the AUA
and the EAU guidelines suggest a threshold of 300
ml to identify patients at risk of unfavorable outcome
following LUTS / BPO treatment (AUA Practice
Guidelines Committee, 2003; Madersbacher, et al.,
2004).
Post voiding residual can be measured by in-and-out
catheterization (preferably under ultrasound control)
to confirm that the bladder is empty (Stoller and Mil-
lard 1989)or by ultrasonography (Holmes, 1967).
More recently, a dedicated ultrasound system has
been developed for automatic measurement of PVR,
thereby improving the accuracy over catheterization
(Coombes and Millard, R. J., 1994; Marks, et al.,
1997) which has been largely abandoned in clinical
practice.
102
The level of evidence for the measurement of post
voiding residual in the standard patient with LUTS is
weak and it is mainly based on experts’ opinion
[Level of evidence D, Grade of recommendation D]
VIII. IMAGING
Imaging of the upper and lower urinary tracts has
been used for several years as part of the diagnostic
assessment of men with LUTS related to BPO (de
Lacey, et al., 1988). Nowadays the routine use of
upper urinary tract imaging by means of intravenous
urography or renal ultrasound has not been consid-
ered as a first line test in most LUTS / BPO diagno-
sis guidelines. Imaging can be used to screen for
upper and lower urinary tract disorders (hydrone-
phrosis, lithiasis, neoplasms, diverticula, etc.), and to
assess prostate morphology and size. However,
many urologist do not take images of the upper uri-
nary tract routinely because tumours and kidney
stones or failure are no more frequent in men with
LUTS related to BPO than in healthy men (Thorpe
and Neal, D., 2003). However renal ultrasound
should be considered as the imaging modality of the
upper urinary tract in patients with LUTS and an his-
tory of upper urinary tract infection or urolithiasis, or
haematuria or renal insufficiency (Roehrborn, et al.,
2001). Lower urinary tract imaging should be per-
formed to assess prostate size and shape, asymp-
tomatic bladder neoplasms, diverticula, stones and
wall thickness when clinically indicated.
Prostate volume can be estimated from the suprapu-
bic approach with sufficient accuracy. However, the
advantage of transrectal versus suprapubic ultra-
sound (TRUS) imaging is the possibility of evaluat-
ing prostate morphology and transitional zone index
(TZI). Choi et al (Choi, et al., 2002) showed an high-
er mean TZI value and IPSS value in Korean men
compared with Caucasian and Hispanic cohorts, they
confirmed a relationship between TZI and LUTS and
suggested the possible relationship between the
higher TZI observed in Korean men (despite a lower
mean prostate volume) and the greater severity of
LUTS in this population.
At present there is no evidence to recommend TRUS
as a valuable tool for detecting early prostatic cancer
or to exclude prostate cancer in men presenting with
LUTS, and it should be used to guide accurate nee-
dle placement during transrectal prostatic biopsy
(Brawer et al 2001). Currently prostate ultrasound
(transrectal or transabdominal) should be considered
as optional test in the management of patients with
LUTS / BPO. It may be an appropriate test when
minimally invasive therapy or surgical operations are
considered.
The size and shape of the prostate and the presence
of an intravesical lobe clearly evaluated by ultra-
sound should be considered when selecting patients
for transurethral microwave heat treatment (TUNA)
or other minimally invasive therapy as well as for the
selection of transurethral prostatic incision (TUIP)
versus transurethral prostatic resection (TURP)
(AUA Practice Guidelines Committee, 2003). Mag-
netic resonance imaging or computer tomographic
images are alternative methods for lower urinary
tract imaging and have somewhat greater precision
than transrectal or transabdominal ultrasonography,
but their higher cost and the lower availability of
machines limits their usefulness and their use in the
community setting (Jacobsen, et al., 2001). Three
dimensional ultrasonography is under investigation
and preliminary data suggests that it is superior to 2-
D TRUS in the prediction of the resected weight at
TURP(Kanao, et al., 2004).
BLADDER WALL THICKNESS AND BLADDER
WEIGHT
The observation of detrusor/bladder hypertrophy in
the aging male is a thousand years old (Abu Ali Al-
Hussain Ibn Abdallah Ibn Sina (981 – 1037 AD) but
only “recently” in 1810, did Hunter relate bladder
hypertrophy to obstruction.
Bladder wall thickness (BWT) is a variable that has
been used to assess BOO non-invasively. The postu-
lated rationale is that prostatic obstruction is associ-
ated with detrusor hypertrophy leading to increased
bladder wall thickness (Elbadawi, et al., 1993). Ani-
mal models confirm that detrusor hypertrophy
decreases after release of obstruction (Saito, et al.,
1996). However, detrusor hypertrophy and increased
BWT may be related to detrusor overactivity also.
Furthermore, an increase in BWT may result not
only from smooth muscle hypertrophy but also from
the increase in fibrous tissue and collagen that occurs
with both age and obstruction (Inui, et al., 1999).
BWT is currently measured by ultrasonography and
suffers the limitations of such technique. A suprapu-
bic approach is currently used in males and a
transvaginal one in females. In a given patient, the
value of BWT also depends on bladder distension.
As the bladder is filled the bladder wall is stretched,
thus reducing BWT (Kaefer, et al., 1997).
Beyond a certain volume the variation of BWT for a
103
given change of bladder volume may be lower than
the resolution of the imaging technique. To over-
come this a bladder thickness index can be calculat-
ed, which standardises BWT with respect to bladder
volume. Alternatively BWT can be measured at a
fixed bladder (150ml) (Manieri, et al., 1998).
Ultrasound measurements of BWT appears quite
promising, but the technique has not been thorough-
ly tested. The correlation between BWT and BOO is
of interest and may also have some clinical validity;
it certainly served as a proof of concept of the rela-
tion between morphology and function in this area.
Further research is needed to understand whether
ultrasound measurement of BWT may be a valuable
parameter to monitor the effect of LUTD on the uri-
nary bladder. At present, measurement of BWT
remains a promising research issue of limited use in
clinical practice unless automated ultrasound sys-
tems are made available reducing interobserver vari-
ability. The level of evidence for the imaging of
upper and lower urinary tract is weak and it is main-
ly based on experts’ opinion [Level of evidence 3,
Grade of recommendation C]
IX. ENDOSCOPY OF THE LOWER
URINARY TRACT
Endoscopy of the lower urinary tract provides infor-
mation regarding comorbidities of the urinary blad-
der and urethra which can be responsible for LUTS
or may change the management of patients with
prostate disorders. As far as the prostate is con-
cerned, endoscopy provides as estimation of prostate
size by evaluating prostate length, morphology of the
prostate and of the bladder neck. Because of the low
prognostic value of bladder endoscopy for the diag-
nosis of BOO (Shoukry, et al., 1975), the test
remains optional in all the reports examined (AUA
Practice Guidelines Committee, 2003; Chatelain et al
2001; Madersbacher, et al., 2004; Roehrborn, et al.,
2001). So far this test is not recommended in the ini-
tial evaluation of patients with LUTS but is usually
appropriate in men with a history of microscopic or
gross haematuria, urethra stricture, bladder cancer, or
prior lower urinary tract surgery. It can also be used
as an optional test to identifies whether surgery or
another form of invasive therapy was suitable in men
with severe LUTS (AUA Practice Guidelines Com-
mittee, 2003). It should not be performed in patients
scheduled for watchful waiting or medical therapy.
The level of evidence for the use of endoscopy in the
standard patient with LUTS is weak and it is based
on a single study [Level of evidence 3, Grade of rec-
ommendation D]
D. URODYNAMICS
I. INTRODUCTION
Urodynamics may be performed for various reasons.
In clinical research the main aim is to gather knowl-
edge about the diseases encountered: i.e. to ensure
that medical practice is knowledge-based. For clini-
cal urodynamic assessment the main aim of urody-
namics is to guide therapy and improve outcomes: its
ability to do this has to be judged from the evidence
provided by trials and cohort studies. When a condi-
tion is first widely encountered, there is a phase in
which clinical research is crucial in order to generate
new knowledge. For example, following the
widespread expansion in the indications for radical
prostatectomy, when the reasons for post-operative
urinary incontinence were imperfectly understood,
many articles dealing with clinical research into the
mechanisms and risk factors for incontinence were
published. Once the etiology had been established,
the debate shifted to whether routine clinical urody-
namics should be limited to selected difficult cases
or performed more widely. Because urodynamics
remains the only way of establishing objectively the
pathophysiological situation, urodynamic evaluation
always remains necessary in, at least, the difficult
cases.
Since the last International Consultation on “BPH”
(Abrams et al 2001), there has been some evolution
of views about the urodynamic evaluation of lower
urinary tract symptoms (LUTS) in men with possible
benign prostatic obstruction. This topic is updated in
the present report, which is based mainly on publica-
tions from 2000 onward. Recent efforts to improve
non-invasive methods of urodynamic measurement,
so as to reduce patient burden and make urodynamic
evaluation more practical, are reviewed more exten-
sively. Prostate cancer and its sequelae were not con-
sidered in any of the previous consultations on
prostate problems. In this report therefore the field of
urodynamic investigation and assessment, as per-
formed before and after prostate cancer and its treat-
ment, is reviewed for the first time at an Internation-
104
al Consultation. We have attempted to include all rel-
evant publications without regard to date.
Men in middle or old age present with lower urinary
tract symptoms (LUTS) that may be, but are not nec-
essarily, related to prostatic changes such as benign
or malignant enlargement and obstruction. LUTS
may be due to dysfunction anywhere in the compli-
cated mechanical and neural control system that
allows normal function and comprises lower urinary
tract function. The aim of urodynamics – according
to most textbooks – is to reproduce the symptoms
while making measurements that will reveal their
cause. Because the number of possible causes is in
principle very large, and urodynamics is currently
quite limited in its power to reveal them, it is fre-
quently useful to go beyond the mere reproduction of
the symptom and to document the complete function
of the LUT in both filling and voiding phases. Thus
for example, if cystometry is performed to ascertain
the cause of incontinence, and if incontinence is
indeed demonstrated during the filling phase, it is
still wise to complete filling and examine the voiding
phase also, because unsuspected abnormalities may
contribute to the incontinence, or may reveal urethral
obstruction, poor voiding, elevated residual urine, or
possible neuropathy, and may change the interpreta-
tion of the symptoms, alter the presumed diagnosis,
or change the choice of treatment.
For a comprehensive description of how urodynam-
ics is performed and interpreted the last Internation-
al Consultation should be consulted (Abrams et al
2001). In this chapter we shall focus on the urody-
namic assessment of voiding and in particular the
diagnosis of bladder outlet obstruction (BOO).
II. DIAGNOSING BLADDER OUTLET
OBSTRUCTION: PRESSURE-
FLOW STUDIES
1. INTRODUCTION
It is now accepted that, although symptomatic man-
agement of LUTS is important, obstruction associat-
ed with benign prostatic enlargement (BPE) is equal-
ly important, since it may lead to disease progression
and occasionally cause harmful effects on the blad-
der and the kidneys (Flanigan et al 1998; Lu et al
2000; Brierley et al 2003). Thus assessing bladder
outlet obstruction (BOO) is an important part of the
evaluation of men with LUTS. The currently accept-
ed ‘gold standard’ measure of BOO is the pressure-
flow study (PFS) of voiding (Abrams et al 2001,
Abrams et al 2002). In fact pressure-flow studies are
the basis of the definition of obstruction and there-
fore remain the only objective means of establishing
or ruling it out.
2. PRESSURE-FLOW STUDIES
For a pressure-flow study, intravesical pressure
(pves) and abdominal pressure (pabd, usually
obtained intrarectally) are measured during voiding,
simultaneously with the flow rate in the external
stream. The detrusor pressure (pdet) is calculated by
subtracting pabd from pves. The results of three typ-
ical studies are shown in Figures 19, 20 and 21.
The PFS contains information about urethral resis-
tance (i.e. possible obstruction) and detrusor contrac-
tility. Several fundamental classes can be distin-
guished.
Urethral resistance classes:
• low detrusor pressure and normal flow rate =
unobstructed
• high detrusor pressure and low flow rate =
obstructed
Detrusor contractility classes:
• low detrusor pressure and low flow rate = weak
detrusor contraction (detrusor underactivity)
• high flow rate at high detrusor pressure = abnor-
mally strong detrusor contraction
Numerous ways of making these descriptions quan-
titative have been suggested. The International Con-
tinence Society recommends judging obstruction (in
men) from the nomogram shown in Figure 20, (Grif-
fiths et al 1997). A point representing the value of the
maximum flow rate Qmax and the corresponding
detrusor pressure pdet.Qmax is plotted on the nomo-
gram, and falls into one of 3 regions, unobstructed,
obstructed or equivocal, consistent with the urethral
resistance classes just described. The equivocal
‘grey’ zone allows for normal physiological variation
and measurement errors.
Even without the ICS nomograms, a patient can be
placed in one of the three zones by calculating the
bladder outlet obstruction index (BOOI, Lim and
Abrams 1999) :
BOOI = pdet.Qmax – 2 Qmax, with pdet.Qmax in
cm H2O and Qmax in ml/s:
• unobstructed: BOOI ≤ 20 cm H2O
105
• equivocal: BOOI = 20 to 40 cm H2O
• obstructed: BOOI ≥ 40 cm H2O
Other variables (e.g URA [Griffiths et al 1989]
DAMPF [Schafer 1995]) also provide a continuous
classification of urethral resistance or obstruction.
Partly because of the natural variability of voiding
studies, they have not proved noticeably more useful
in practice than the simple ICS nomogram.
3. RELIABILITY OF URODYNAMICS IN MEN
WITH LUTS
a) Variability and reproducibility of urodynamic
measurements
In the previous consultation (Abrams et al 2001) it
was concluded that random variations of about 9-14
cm H2O in pressure measurement, and about 0.4-2
ml/s in maximum flow rate occur. In repeated stud-
ies during the same session there is usually a sys-
tematic decrease of up to 4 cm H2O in detrusor pres-
sure and 0.4 ml/s in maximum flow rate. These vari-
ations have little clinical importance: they cause only
10-16% of patients to change classification on the
ICS or similar nomogram, and in all but about 1%
the change is only by 1 class (e.g. from equivocal to
unobstructed or from obstructed to equivocal). A ure-
thral catheter appears to be associated with slight
changes in flow rate, although it is not certain that
these changes are due just to the catheter. A catheter
of size 8 French gauge seems to be acceptable.
More recently, Klausner et al [2002] examined the
effect of catheter size on assessment of bladder out-
let obstruction, in 31 pts with LUTS suggestive of
BPO. Using 5 French and 10 French catheters in ran-
dom order, they observed that the 10 French catheter
caused a decrease in Qmax and an increase in pdet.
Qmax indicating a detectable obstructive effect over
and above that of a 5 French catheter. On the
Abrams-Griffiths nomogram, 10 of the 31 pts (32%)
were categorized as obstructed with the 10 French
catheter but not with the 5 French. Overall 17 of the
31 went from a less to a more obstructed category
when the 10 French catheter was used. The authors’
conclusion was that 10 French catheters should be
avoided because of their obstructive effect.
Some centers perform pressure-flow studies with
their patients standing, and others with them seated.
Unsal and Cimentepe [2004] compared flow rates
and residual urine in the 2 positions, in 44 men with
LUTS suggestive of BPO and 44 healthy men. No
 Figure 19 A. typical pressure-flow
study in an unobstructed individu-
al. Satisfactory data quality is sug-
gested by similar fine straucture in
the pves and pabd signals and by
satisfactory cough tests before and
after voiding. However, regular
waves in pabd indicate rectal con-
tractions.. The resulting periodi-
cally negative values for pdet
should be viewed as artefacts. The
green circles mark the maximum
flow rate Qmax and the detrusor
pressure at maximum flow, pdetQ-
max

Figure 20. Pressure-flow study in

an obstructed individual. Qmax is
low and pdetQmax is elevated to
over 100 cm H2O (see red circles),
indicating bladder outlet obstruc-
tion. The negative value of the
abdominal pressure before voiding
suggests a slight artefact due to
incorrect levelling of the transduc-
ers

Figure 21. Pressure-flow study

with intermediate values of maxi-
mum flow rate and detrusor pres-
sure at maximum flow (yellow cir-
cles). Small rectal contractions are
visible in pabd and therefore also
in pdet as downward deflections

106
significant position-dependent differences in the
maximum or average free flow rate, or in PVR mea-
sured by ultrasound, were found. A limitation is that
the order of the observations was not clearly
described, so that there may be a confounding order
effect.
In 1999 Tammela et al [1999] reported on pressure-
flow studies of 3 consecutive voids in 216 men with
symptoms possibly associated with benign prostatic
obstruction. All were measured with no catheter pre-
sent in the urethra. The mean value of the detrusor
pressure at maximum flow rate (pdet. Qmax)
decreased significantly in successive voids, from 71
to 66 to 63 cm H2O. Correspondingly, the proportion
of patients classified as obstructed by the Abrams-
Griffiths nomogram fell from 67 to 64 to 59%.
Kranse and Van Mastrigt [2003] in 131 unselected
male patients, observed less pronounced systematic
variations from one pressure-flow study to the next,
but considerable random variability. In 35% of
patients the classification of obstruction based on the
ICS nomogram changed between measurements.
They investigated the possible causes of this vari-
ability by ingenious statistical methods and conclud-
ed that it was not due to random measurement noise
but to real physiological changes in bladder and ure-
thral function. They pointed out that the variability of
pressure-flow studies was therefore not a disadvan-
tage, but a reinforcement of their importance as the
only means to study bladder outlet resistance, detru-
sor contractility, and their physiological variations.
Using their results, if one amalgamates the unob-
structed and equivocal classes on the ICS nomo-
gram, as is often done, and takes the second test as
the standard, then the sensitivity and specificity for
obstruction of the first test are 81% and 83% respec-
tively and the overall accuracy is 82%. These figures
represent the intrinsic variability of obstruction.
(Similar figures would be obtained if the first test
were taken as the standard.) Similar calculations
based on data of Sonke et al [2000] yield an overall
accuracy of 83%, and sensitivity and specificity of
74% and 86% respectively. These figures are very
similar to those of Kranse, despite criticism of the
technical quality of the measurements (see editorial
comments following Sonke article [2000]).
Two recent studies have reported on the variability in
men of other urodynamic variables. Ockrim et al
(2001)compared variability of the observation of
detrusor overactivity in 60 men with LUTS (mean
age 67 y) and 35 men with spinal cord injury (mean
107
age 39 y). In men with LUTS the apparent preva-
lence of detrusor overactivity decreased from 72% to
63% to 48% in three successive filling cystometries,
performed on the same occasion. Similarly, the mean
maximum detrusor pressure during detrusor overac-
tivity decreased from 41 to 34 to 25 cm H2O. Blad-
der volume at first, normal, and strong desire to void
and cystometric capacity all increased significantly
from the first to the third cystometry, by 14 – 25 ml.
These observations of systematic changes in succes-
sive cystometries are consistent with those in neuro-
logically normal women [Griffiths, et al., 2005].
Unfortunately the random intra-subject variations
were not reported, but they are probably even larger
than the systematic ones [Griffiths, 2005]. In con-
trast, in men with spinal cord injury, none of these
variables changed significantly in successive cys-
tometries, except possibly for maximum detrusor
pressure during overactivity, which showed a barely
significant decrease of 4 cm H2O (5%). Thus, for
example, detrusor overactivity was observed in
100% of the spinal-cord injured men in all 3 cys-
tometries, while the mean cystometric capacity was
310, 308 and 307 ml respectively. Similar consistent
results were obtained by Ho et al [DATE] examined
the reproducibility of 2 consecutive urodynamic
studies in a neurologic population.
To summarize, in neurologically intact men there is
both systematic and random variability of urody-
namic variables, which is due to real physiological
changes in the behaviour of bladder and urethra. The
variability is much less pronounced in those with
serious neurological disease at spinal level, suggest-
ing that supraspinal control is responsible for much
of the normal variability.
b) New interpretations of urodynamic measure-
ments
Some new mathematical approaches to the interpre-
tation of studies of pressure and flow, based on com-
puter manipulation of urodynamic variables, have
been proposed. [Porena et al 2003; Valentini et al
2003] They are intended to reproduce more closely
the underlying physiology than existing methods, but
it is not yet clear how well they succeed in this nor
whether they will offer more reliable interpretation.
4. DETRUSOR CONTRACTILITY IN MEN WITH
LUTS
Detrusor contraction strength during voiding (an
aspect of detrusor contractility) can be judged from
another nomogram due to Schäfer (Figure 23) On
the basis of pdet.Qmax and Qmax it classifies con-
traction strength in one of 4 classes, from very weak
to strong (later subdivided to yield a finer gradua-
tion). Again the same classification can be obtained
by calculating the bladder contractility index (BCI,
Abrams 2004), also known as projected isovolumet-
ric pressure PIP; or the detrusor coefficient DECO,
which is almost identical (Tan et al 2004).
BCI = pdet.Qmax+ 5Qmax, with pdet.Qmax in cm
H2O and Qmax in ml/s:
• very weak: BCI ≤ 50 cm H2O
• weak: BCI = 50 to 100 cm H2O
• normal: BCI = 100 to 150 cm H2O
• strong: BCI ≥ 150 cm H2O
It is now widely recognized that impaired detrusor
contractility can cause poor flow rate, incomplete
emptying, and corresponding symptoms, even in the
absence of urethral obstruction,[Abrams, et al.,
2001; Griffiths, 2004] and that this is especially like-
ly in the frail elderly. [Resnick and Yalla, 1987]
A detrusor contraction of normal strength can pro-
duce either a high detrusor pressure or a high flow
rate (depending on the urethra), but not both at once.
A weakly contracting detrusor can produce neither a
high flow rate nor a high detrusor pressure. Thus to
assess detrusor contraction strength both pressure
and flow rate have to be considered. It is particular-
ly important to understand that a low detrusor pres-
sure does not necessarily represent a weak detrusor
contraction unless the flow rate at that moment is
also low. As described above, the simplest method of
assessment is to calculate the bladder contractility
index (Abrams 2004) or DECO (Tan, et al 2004) dur-
ing voiding at the moment of maximum flow, given
above:
Equivalently the values of pdet.Qmax and Qmax can
be plotted on a nomogram that shows the strength
categories (Figure 21).
Detrusor contraction strength can be estimated more
reliably by measuring the isovolumetric detrusor
pressure during a mechanical stop test,[Tan et al
2003; Tan, et al 2004] i.e. by eliminating the possi-
bility of flow altogether.
Another aspect of contractility is the ability to sus-
tain the detrusor contraction until the bladder is
empty. Failure to do so leads to residual urine, and
indeed Zhang et al [2003] have suggested that, in
men with suspected BPO, residual urine volume is
108
more closely related to a weak detrusor contraction
than to urethral obstruction. The prevalence of weak
detrusor contraction has not been much studied, but
Thomas et al [2004] found that among a large series
2066 of neurologically intact men with LUTS, 224
showed detrusor underactivity (defined as a detrusor
pressure at Qmax < 40 cm H2O, with Qmax <
15 ml/s). In a series of 196 patients with and without
prostatic obstruction, treated or otherwise, they
found no evidence to suggest that detrusor contrac-
tility declined in long-term obstruction, nor to sug-
gest that relieving the obstruction surgically
improves the contractility. [Al-Hayek, et al 2004]
Overall, however, research activity in the field of
detrusor contractility remains limited, presumably
because there is no obvious pharmacological way to
improve poor contractility. Discovery of a drug that
noticeably improved detrusor contraction would rev-
olutionize this field.
5. WHY URODYNAMIC PRESSURE-FLOW STUD-
IES ARE NOT MORE WIDELY PERFORMED
In spite of the above, urodynamic pressure-flow stud-
ies are not widely performed in routine clinical prac-
tice. One reason is the perceived invasiveness and
morbidity of urodynamics. [Porru et al., 1999] A sec-
ond is the perceived lack of clinical utility in improv-
ing outcomes – for example by better patient selec-
tion. In addition, assessment by methods of this sort is
strongly influenced by costs and reimbursement.
The objective morbidity of urodynamic studies is
low [Klingler et al., 1998; Bombieri et al., 1999;
Porru et al., 1999] although temporary dysuria is
common (33 to 76%). Bacteriuria is found in up to
8% and symptomatic infection in 0.5 - 4%. Mild
macroscopic haematuria (6%) [Porru et al., 1999]
and post-investigational urinary retention (5% in
men with obstruction, Klingler et al., 1998) have also
been reported. Subjective morbidity may be due to
factors such as embarrassment, which might make
the test not only unpleasant, but also unreliable.
Scarpero et al [2005] reported on the expectations
and experience of 78 men and 88 women undergoing
urodynamic testing. Men expected little or no embar-
rassment and most (90%) found the test better than
they had expected or the same. More older than
younger individuals found it better than expected.
Thus the patient population with prostate problems –
predominantly older males – is in fact the group that
finds urodynamic testing the least troublesome.
Figure 22. ICS pressure-flow nomogram: showing the three pressure-flow curves from figures 9, 10 and 11.

Figure 23. The voids of Figures 9, 10 and 11 classified for detrusor contractility by the Schäfer nomogram. The position of
the maximum flow point (coloured dots) in the 4 bands indicates the strength of the contraction (VW = Very Weak, W = Weak,
N = Normal, S = Strong). The strengths for these 3 voids are Normal, Normal and Weak respectively

109

III. PRESSURE FLOW STUDIES :
RELATIONSHIP WITH OTHER
MEASUREMENTS
1. INTRODUCTION
Because of the above drawbacks to invasive urody-
namics, attempts have been made to assess BOO
non-invasively. Various methods have been used
both singly and in combination. Single measures can
be broadly divided into 4 categories :
• Symptoms and symptom scores
• Ultrasound derived parameters including prostate
size and shape
• Uroflowmetry
• Non-invasive bladder pressure measurements
(via a penile cuff or a condom catheter).
What can reasonably be expected of non-invasive
surrogate measures of obstruction? Pressure-flow
studies (PFS) themselves are not perfect. Repeated
measurements in one subject give quite variable
results, especially in patients with an intact nervous
system, who form the majority of those with LUTS.
Clearly the association of any surrogate with
obstruction can never be better than the association
of one pressure-flow determination with another in
the same patient. The intrinsic accuracy of classifica-
tion appears to be about 80% [Sonke et al., 2000;
Kranse and Van Mastrigt, 2003], limiting sensitivity
and specificity to about 80% if both are maximized
simultaneously.
In this section the various tests will be reviewed with
the aim of obtaining the sensitivity and specificity of
each test in predicting BOO, although frequently
only a correlation coefficient is provided. As far as
possible, positive and negative predictive values are
avoided since they are affected by the prevalence of
BOO, which may vary considerably across the stud-
ies assessed. It has to be realised that the sensitivities
and specificities quoted assume that PFS have 100%
accuracy, which stated above is not the case!
Male patients with LUTS are one of the commonest
problems seen in the urology clinic. Although the
symptoms are commonly associated with benign
prostatic obstruction (BPO), symptoms may be relat-
ed to an ageing bladder or a combination of BPO and
aging. Other types of bladder outlet obstruction, due
for example to bladder neck hypertrophy or urethral
110
stricture, may also cause LUTS. In the assessment of
patients with LUTS the initial step is to differentiate
LUTS suggestive of BPO from LUTS not associated
with BPO. This is often done by digital rectal exam-
ination although its accuracy in assessing the size of
the prostate is poor. [Meyhoff et al, 1981] Prostate
size can be measured more accurately with transrec-
tal or transabdominal ultrasound. [Loeb et al., 2005]
Patients without BPE have been defined as having a
prostate volume of less than 20 ml (grams), [Gar-
raway et al., 1993] but this certainly does not mean
that prostates larger than 20 ml are necessarily
obstructive, nor that prostates smaller than 20 ml are
necessarily non-obstructive. [Hirayama et al., 2002]
2. SYMPTOMS AND SYMPTOM SCORES
As the earlier section on LUTS, their Aetiologies and
Assessment demonstrated, LUTS and, in particular,
voiding symptoms, lack any worthwhile specificity
for BPO. This has been confirmed in large trials such
as the International Continence Society- “BPH”
study [de la Rosette et al., 1998] and summarised by
the last International Consultation on BPH. [Abrams
et al., 2001].
Eckhardt et al (2001) examined a cohort of 565 men
with LUTS suggestive of BPO. 301 men (53%, 66 ±
7 years of age) had obstruction, and 264 men (47%,
66 ± 8 years of age) had no clear obstruction on con-
ventional criteria (Schäfer grade ≤ 2, equivocal or
unobstructed on ICS nomogram). Obstruction grade
was not associated with symptoms, but decreased
contractility, reduced bladder capacity and detrusor
overactivity were weakly associated with some
symptoms. All associations were weak, even when
statistically significant in this large group, and no
correlation coefficient exceeded 0.2 in magnitude.
Symptom scores are reviewed earlier in this chapter
and, like individual symptoms, have weak associa-
tions with urodynamically proven BPO.
In spite of their weak relationship with urodynamic
parameters, in particular obstruction, because symp-
tom scores such as IPSS can be assessed easily and
non-invasively they are still useful tools. However,
neither individual symptoms nor symptom scores
should be used for the diagnosis of BPO or as the
only guide for further management of patients with
LUTS. To do so may lead to undertreatment of
patients with BPO or overtreatment of those without
it (Level 3 evidence, but Grade A recommendations
due to the large volume of evidence).
3. ULTRASONIC ASSESSMENT OF THE PROSTATE
TRUS is the imaging modality used most frequently
to assess prostate volume and it is more accurate than
DRE [Loeb, et al., 2005]. MRI provides an even
more accurate estimation of prostate volume and can
more easily detect drug-induced changes in volume.
[al-Rimawi et al 1994].
The relationship between total prostate volume and
BOO has been investigated in several studies. A ret-
rospective study involving 521 patients showed a
weak but statistically significant correlation of
prostate size and BOO (r=0.32, p<0.001). [Rosier
and de la Rosette, 1995] The sensitivity and speci-
ficity for BOO of a prostate volume greater than 40
ml were 49% and 32 % respectively. In another study
of 525 patients there was a similarly weak correla-
tion between prostate volume and BOO (r=0.28,
p<0.001). [Eckhardt et al, 2001].
With the failure of total prostate volume alone to
diagnose BOO, attempts have been made to diagnose
BOO using the prostate shape and relative propor-
tions of the different zones of the prostate. The zonal
anatomy of the prostate consists of 3 zones: a central
zone, a transitional zone (TZ) and peripheral zone.
[McNeal, 1988] The transitional zone is the major
site for the development of benign prostatic hyper-
plasia (BPH) leading to BPE, and is affected to a
greater extent than the peripheral zone by medical
treatment with finasteride [Tempany et al., 1993] and
dutasteride, [Roehrborn et al, 2002] with corre-
spondingly greater effect on Qmax. [Tewari et al,
1995; Roehrborn et al., 2002]
TZ index (the ratio of TZ volume to total prostate
volume) is more strongly correlated with symptoms
(r =0.75, p=0.001) and Qmax (r=-0.71, p=0.001)
than prostate volume alone, but it is only moderately
correlated with a critical measure of obstruction
(detrusor pressure at Qmax; r=0.43), [Kaplan et al,
1995] and several investigators have concluded that
it is not clinically useful for judging obstruction.
[Lepor et al., 1997; Witjes et al., 1997; Kurita et al.,
1998]
a) Prostate shape
Though size is important, shape may be equally or
more important in predicting BPO. One way of
assessing it is by using transrectal ultrasound
(TRUS) to measure the anterior / posterior and the
transverse diameter and to calculate the “presumed
circle area ratio” (PCAR). The PCAR represents
how closely the transverse ultrasound image of the
111
prostate approaches a circular shape.
The ratio tends toward one as the prostate becomes
more circular. The PCAR showed a stronger correla-
tion with BOO than TZ index (r=0.487, P<0.0001,
versus r = 0.331, P<0.005). The sensitivity and speci-
ficity for BOO of a PCAR value > 0.8 were 77% and
75% respectively, [Kojima et al., 1997] only a little
smaller than the limit imposed by intrinsic variability
of obstruction. It has been shown by Watanabe et al
(1975) that when the ratio is greater than 0.75, BPO
is likely. Similar findings were seen in a smaller study
[Desai, 1999]. It seems clear that the more circular
the prostate the more likely there is to be BOO.
In conclusion, these measures do show a consistent
and definite, although weak, correlation with the
diagnosis of BOO (see above). The relative size of
the transition zone and the “circularity” of the
prostate appear to improve the association with
BOO, although the level of evidence (3) is not suffi-
cient to allow a recommendation for the routine use
of TRUS to assess prostate volume or shape to be
used for the diagnosis of BOO/BPO.
b) Intravesical prostatic protrusion on transabdom-
inal ultrasound
Intravesical Prostatic Protrusion (IPP) is another way
of using prostate shape to predict BPO. The postulat-
ed rationale is that, as the prostate enlarges, it pro-
trudes into the bladder, distorting the proximal ure-
thral funnelling and leading to BOO. [Ohnishi et al,
1985] IPP is usually measured by transabdominal
ultrasound in the mid-sagittal plane. [Yuen et al,
2002] IPP is the distance from the tip of the protrud-
ing prostate to the base at the circumference of the
bladder. [Chia et al, 2003; Tan and Foo, 2003], see
Figure 24.
It is graded according to severity: grade 1 (≤ 5mm
protrusion), grade 2 (5-10mm) or grade 3 (>10mm)
[Chia et al, 2003]. As the measurement of IPP is
affected by bladder volume, it is suggested that it
should be measured at a comfortably full bladder
volume of 100 to 200ml. [Yuen et al, 2002]. The
test/retest reliability of this technique has not been
published to date.
The relationship of IPP to BOO is such that, as the
IPP grade increases, the severity of BOO also
increases. In one study, 79% of patients with IPP
grade 1 were not obstructed, but 94% of patients
with IPP grade 3 were obstructed. [Chia et al, 2003]
The positive predictive value of IPP grade 3 for BOO
was 94%, while the negative predictive value was
Figure 24. Transabdominal ultrasound sagittal view: measuring from the tip to the base of the prostate in a comfortably full
bladder. YH Tan, KT Foo J of Urol 2003; 170: 2339-2341
79%. IPP was an independent predictor of BOO. Its
sensitivity and specificity for BOO were 76% and
92% for grade 3, 17% and 53% for grade 2, and 7%
and 56% for grade 1 respectively. High grade IPP
seems also to be a good predictor of failure of
catheter trial in patients with acute urinary retention.
[Tan and Foo, 2003]
Intravesical prostate protrusion is a new method
being developed to predict BOO/BPO. It appears
promising but the level of evidence is not yet suffi-
cient to justify a recommendation for its routine use.
c) Other ultrasound based methods :
Post void residual
PVR is often used to assess patients presenting with
LUTS, although the pathophysiology of elevated
PVR is not generally well understood and its interac-
tion with BOO and detrusor underactivity is com-
plex. Elevated PVR (usually defined as PVR >
100ml) is commonly observed in patients with BOO
[Ball et al 1981], although one third of BOO patients
do not have significant residual urine [Turner-War-
wick et al 1973]. Thus, in patients with BOO, PVR
tends to decrease after surgery [Neal et al 1989].
Like other urodynamic parameters, PVR is quite
variable in any given subject [Bruskewitz et al
1982]. In one study however [Chia et al 2003] PVR
> 100 ml showed values of sensitivity and specifici-
112
ty (75% and 91% respectively) that approach the
limit set by intrinsic variability of obstruction.
Elevated PVR may also reflect detrusor underactivi-
ty [van Mastrigt and Rollema 1992; Zang at al 2003].
The interaction of BOO, (impaired) detrusor con-
tractility and PVR was recently investigated in 131
patients. This showed that there was only a weak cor-
relation between BOO and PVR. This result is not
surprising since elevated PVR is a consequence of
BOO, and therefore not all patients with BOO will
have developed an elevated PVR. By combining
measurements of detrusor contractility and BOO,
PVR mat be reasonably accurately predicted [Kranse
and van Mastrigt 2003]. PVR is most useful clinical-
ly in conjunction with other measurements, such as
uroflowmetry [Abrams et al 2001].
Bladder Wall Thickness / Weight
An additional problem is the effect of the volume in
the bladder on BWT. As the bladder is filled the
bladder wall is stretched, thus reducing BWT [Kae-
fer et al 1997]. To overcome this, a bladder thickness
index can be calculated, which standardizes BWT
with respect to bladder volume. Alternatively BWT
can be measured at a fixed bladder volume (150ml)
[Manieri et al 1998]. The mean BWT measured in
this way at 3 sites was moderately strongly correlat-
ed with obstruction as measured by the A – G num-
ber (r = 0.6724, p<0.0001). In 58 patients with a
BWT greater than 5mm, 88% were obstructed on
pressure-flow studies. The specificity for BOO of a
value of BWT>5mm was 92%; however, the sensi-
tivity was only 54%.
A similar way to eliminate the effect of variable
bladder filling volume is to calculate the ultrasound-
estimated bladder weight (UEBW, Kojima et al
1996), which has a standard deviation of + 5 grams
(12%) in repeated studies. In a group of 65 patients
there was a significant correlation of UEBW with
urodynamic parameters of obstruction (r = 0.478,
p<0.0001 for AG number; r = 0.543, p<0.0001 for
Schäfer grade) [Kojima et al 1997]. With a cut-off
value UEBW >35 g, the sensitivity of the test for
obstruction was 85% with a specificity of 87%.
These values are as good as those of pressure-flow
studies themselves, suggesting that this is an excel-
lent method. In the group of 33 patients undergoing
prostatectomy the UEBW changed from a mean of
53 g, pre-surgery, to less than 35 g, 12 weeks after
surgery [Kojima et al 1997]. Nevertheless, there are
patients with substantially increased UEBW who are
not obstructed [Kojima et al 1997] because, like
BTW, UEBW defines bladder wall thickening but
not the cause, which may not necessarily be prostat-
ic obstruction.
Thus these ultrasound-based methods appear quite
promising (level of evidence 3), but they have not
been thoroughly tested and will always have the dis-
advantage that they provide only an indirect assess-
ment of obstruction. It should be noted, however,
that these methods may measure the sequelae of pos-
sible obstruction, indicating that the obstruction, if
present, is clinically severe. No recommendation is
possible for their routine use in LUTS patients.
4. UROFLOWMETRY
a) Conventional uroflowmetry
Uroflow measurement is the least invasive urody-
namic assessment. It gives an objective and quantita-
tive indication of voiding dysfunction. Its limitation
is that it does not distinguish a low flow rate due to
prostatic obstruction from low flow due to poor
detrusor contractility [Chancellor et al 1991]. Fur-
thermore, obstructed patients with high detrusor
pressures can maintain a normal flow rate.
Uroflowmetry results show a considerable variation
in the maximum flow rate (Qmax) measured on
either the same or different days. [Feneley et al 1996]
The specificity of maximum flow rate for BOO
depends on a number of factors, for example the vol-
ume voided and the value of Qmax used. In a large
113
study the specificity and sensitivity for BOO of
Qmax of less than 15 ml/s were 38% and 82%
respectively. [Reynard et al 1998] Thus this value of
Qmax is too non-specific to be useful. For Qmax
< 10 ml/s the sensitivity and specificity were 70%
and 45% respectively. The limitation of this
approach remains therefore the poor sensitivity of
this value of Qmax(10 ml/s).
In general, the sensitivity and specificity of Qmax do
not approach the limits set by the intrinsic variabili-
ty of BOO. Single centre smaller studies have sug-
gested a higher specificity of up to 90 % for Qmax,
of < 10 ml in particular with multiple flows. [Nielsen
et al, 1994; Poulsen et al., 1994; Reynard et al,
1996]. Therefore, for uroflowmetry to play a part in
the diagnosis of BOO/BPO, the measurements need
to be multiple. In this circumstance, the level of evi-
dence 2 allows a recommendation, Grade B, for the
reliable diagnosis of BOO, but only when Qmax is
less than 10ml/s (Table 9).
Table 9. The specificity, sensitivity and positive predictive
value for BOO of two different values of Qmax.
Qmax (ml/s)
<10 <15
Specificity 70 38
Sensitivity 47 82
PPV 70 67
b) Penile compression release index.
Interruption of flow by manual pinching of the penis,
followed by release, leads to a surge in flow followed
by a steady state, just as in the cuff technique,
described below [Sullivan and Yalla, 2000]. The
penile compression release (PCR) index is defined as
((Qsurge – Qsteadystate)/Qsteadystate X 100). The
PCR index differed in obstructed, non obstructed,
detrusor underactivity and detrusor overactivity
groups and a cut-off value of 100% could diagnose
BOO with a sensitivity and specificity of 91% and
70% respectively [Sullivan and Yalla, 2000].
If a penile cuff (see below) was used to calculate the
PCR, a cut-off value of 160% gave a sensitivity and
specificity of 78% and 84% for BOO. [Harding et
al., 2004] These values approach the limit set by the
intrinsic variability of BOO.
5. NON-INVASIVE URODYNAMIC PRESSURE
MEASUREMENT
Over the past decade a number of ingenious ways
have been described for measuring the bladder pres-
sure associated with voiding in a non-invasive way.
The principle underlying these techniques is the
measurement of isovolumetric bladder pressure; this
allows a low free flow rate, due to obstruction, to be
distinguished from a low flow rate due to detrusor
underactivity. The penile cuff and the modified con-
dom method are the 2 principal methods. Both rely Condom catheter
on the assumption that there is a continuous column
of fluid from the bladder through the urethra to the
point where flow is interrupted, so that the fluid pres- Pressure
sure at the point of measurement is the same as the transducer
pressure within the bladder, thereby recording its iso-
volumetric value. Outlet closed
manually
a) Condom catheter method during voiding
For the external condom method [Schäfer et al,
1994; van Mastrigt and Pel, 1999] the patient voids
Figure 25. Modified condom catheter for noninvasive mea-
through a condom catheter (see Figure 25 below). At surement of bladder pressure during voiding.
maximum flow, the catheter is blocked and the iso-
volumetric pressure is measured. In a study of 75
patients, who underwent both pressure-flow studies Cuff inflation unit and
and the condom method, there was a 25 % technical pressure transducer
failure rate. Several strategies for analysing the data
were used and the best method (using Qmax also)
showed a sensitivity for BOO of 64% with a speci-
ficity of 79%. [Pel et al., 2002]. These are rather dis-
appointing values, markedly inferior to the limits set
by the variability of real pressure-flow studies. Penile cuff

In initial trials the isovolumetric pressure was not

always attained, especially in obstructed patients, or
those with low flow rates (< about 5 ml/s). [Gommer
et al., 1999; Pel and van Mastrigt, 1999]. Recent
improvements [Pel and van Mastrigt, 2001] have led
to better reproducibility [Huang et al., 2004; van
Mastrigt et al 2004] so that this method now has an
overall accuracy of 90% in diagnosing obstruction,
although only when the obstructed and equivocal
groups on ICS nomogram were combined. However,
the accuracy of agreement is only 67% for ICS
obstructed group alone, [Pel et al., 2002] a value that
should be compared with accuracies of 82 to 83% for
pressure-flow studies themselves. Van Mastrigt’s
group has shown that this method can usefully be
applied in epidemiological studies of large popula-
tions to gain information about bladder and urethral
function that would otherwise be inaccessible
[Chung at el 2005].
b) Penile cuff
The penile cuff is a flexible inflatable cuff that is
placed around the shaft of the penis (Figure 26
below). [McRae et al 1995]. Two methods of use
Flow meter
Figure 26. Penile cuff inflated during voiding to measure
isovolumetric bladder pressure.
have been suggested: the deflation and the interrup-
tion technique. For the deflation technique [Gleason
et al, 1997] the penile cuff is used to occlude the ure-
thra before voiding. The patient is instructed to void
into a flowmeter and the cuff is deflated slowly by
the patient (by pressing a button) when the urine is
felt in the urethra. Once a flow rate of greater than
1ml/s is detected by the flowmeter, the cuff is deflat-
ed rapidly.
For the interruption technique, an automatically
inflated penile cuff *(modified paediatric blood pres-
sure cuff) is used to interrupt the flow after voiding
has commenced. [Griffiths et al 2002] The cuff pres-
sure when the flow stops is presumed to be equal to

114
the bladder pressure. Once the flow has stopped, the
cuff is rapidly deflated and there is a surge of urine
after which the inflation cycle can be repeated.
Simultaneous invasive urodynamics showed that the
isovolumetric detrusor pressure was reliably estimat-
ed by this method, although the mean cuff pressure
over-estimated the bladder pressure by 14.5 +/-
14cm H2O [Griffiths et al., 2002]. The test/retest
variability was 0 (SD 20.3 cm H2O) in patients with
a voided volume of at least 150ml. [McIntosh et al.,
2004]. The interobserver agreement in the analysis
of the results was good. [Drinnan et al., 2003] The
majority of patients (80%) preferred the cuff to inva-
sive urodynamics.
In order to diagnose BOO with this technique a mod-
ification of the ICS nomogram has been suggested.
Alternatively a diagnostic parameter N (= pcuff –
6.4* Qmax + 0.35 PCR) can be used (PCR is defined
above); N > 100 indicates obstruction. A further
study of the outcome of TURP using the modified
ICS nomogram is in progress. Preliminary results
show that preoperative assessment using the nomo-
gram improves the outcome.
In conclusion, in spite of technical pitfalls [Blake
and Abrams, 2004] and the fact that it measures
intravesical and not detrusor pressure, non-invasive
urodynamic pressure measurement, especially if
combined with the PCR index and maximum free
flow rate, promises to provide a reasonably reliable
method of diagnosing BOO (Level 3 evidence).
However it remains unclear whether the extra com-
plications required are worth the relatively small
improvement in diagnostic accuracy over
uroflowmetry (no recommendation possible, as yet).
c) Doppler techniques
- DOPPLER ULTRASOUND TECHNIQUES
Doppler ultrasound, developed for measuring blood
flow velocity, can be used to measure urine flow
rates greater than 3ml/s. [Ozawa et al., 1998] The
technique measures urine flow velocity (V1) in the
prostatic urethra, the site of the flow-controlling
zone. The patient takes up a sitting position and the
probe is positioned perineally by a robotic arm. In a
small group of patients with and without BOO, the
functional cross-sectional area (calculated by divid-
ing maximum flow rate by maximum flow velocity,
as determined by Doppler), was lower in the group
with BOO (mean 0.31cm2 SD+/-0.16) than the con-
trol group (0.78cm2 +/-0.23) (p = 0.006). [Ozawa et
al., 1998] Subsequently the flow velocity (V2) in the
membranous urethra was added to the measurements
115
and the velocity ratio V1/V2 was calculated. A veloc-
ity ratio greater than 1.6 showed a sensitivity of 60%
and a specificity of 100% for the diagnosis of
obstruction as shown by pressure-flow studies.
[Ozawa et al, 2000] A further small study showed
that the velocity ratio decreased after alpha blocker
therapy, although V2 was more strongly associated
with the change in symptom IPSS after treatment
(r=0.584). [Watanabe et al., 2004]
- DOPPLER RESISTIVE INDEX
In animal models, detrusor blood flow has been
shown to be reduced in obstruction. [Lin et al, 1995]
In a pilot study, average detrusor arterial blood flow
was measured with color Doppler at 3 sites in the
bladder and the resistive index, an index of change in
blood flow was calculated (RI = Vmax-Vmin/
Vmax). There was a significant difference between
the values of RI in obstructed and unobstructed
patients. The overall accuracy for predicting BOO
was 86% but the predictive value was low (57%),
[Belenky et al., 2003] presumably because other fac-
tors also affect the change in blood flow. In men with
LUTS, RI measured transrectally showed only a
weak correlation with the Abrams-Griffiths number
(BOOI; r=0.330, p<0.05).
In conclusion, the reliability of the Doppler urody-
namic test appears reasonable, but there is large
inter-rater variability in the calculation of the veloci-
ty ratio. [Ding et al., 2000] Moreover, Doppler uro-
dynamics requires expensive and specialised equip-
ment and a cooperative patient who is able to void in
the sitting position. The Doppler Resistance Index is
an interesting technique but there is insufficient evi-
dence to reach any conclusion at present.
6. COMBINATIONS OF SINGLE MEASURES
Because of the shortcomings of individual non-inva-
sive parameters for diagnosing BOO, many different
combinations have been investigated.
Qmax and total prostate volume (PV) can be used
to estimate bladder outlet obstruction index. [Ockrim
et al., 2001] Data from 384 men suggest that esti-
mated bladder outlet obstruction index = antilog10
(2.21- 0.5 log Qmax + 0.18 log PV). In 42% of the
population, an estimated BOOI index of greater than
40 showed a sensitivity of 92 % for obstruction or
equivocal obstruction. Using Qmax alone provided a
sensitivity of 86% of predicting BOO, but could be
used in only a minority of the study population
(17%) [Note: this is NOT the BOOI described in the
ICS report 2002 (Abrams et al)].
The combinations of AUA symptom score and
Qmax with the highest specificity for BOO were
determined in 134 patients. [Schacterle et al, 1996]
With Qmax < 10 ml/s and AUA score > 20, speci-
ficity and sensitivity for obstruction were 98 % and
38%. Conversely, with Qmax > 15 ml/s and AUA
score < 10, specificity for no obstruction was 98%
but sensitivity was only 22%. Only 20% of the pop-
ulation studied were categorised as obstructed or
unobstructed using this approach. If prostate vol-
ume (> 40 grams) was added to the algorithm,
[Steele et al, 2000] specificity increased to 100% but
sensitivity remained only 26%, and the population
diagnosed remained low at 20%.
Qmax, PV and relative residual volume (post-void
residual volume as a percentage of pre-void bladder
volume) can be used to calculate a bladder outlet
obstruction number (BOON) as follows: [van Ven-
rooij and Boon, 1996]
BOON = prostate volume (from TRUS, in ml) – 3 *
Qmax + (0.25 * relative residual volume).
In a population of men with LUTS, the majority
obstructed on urodynamics, a value of BOON > -2
diagnosed 50% of men with BOO (Schäfer grade ≥
2), with a sensitivity of 90%. However for Schäfer ≥
3 (equivalent to obstructed on ICS nomogram) the
discrimination between obstruction and no obstruc-
tion disappeared. The equation was later refined [van
Venrooij et al, 2004] to use voided volume instead of
relative residual volume.
Qmax, prostate volume and PVR have been com-
bined in a simple categorical nomogram to determine
the probability of obstruction. [Madersbacher et al.,
1997] The method has not been validated in an inde-
pendent set of patients.
Qmax, prostate volume, PVR and voided volume
[Rosier et al., 1996] were measured in 871 elderly
patients and used to obtain a ‘clinical score’ (in
which Qmax was the most strongly weighted) to help
in the diagnosis of BOO. A score of greater than 11
gave a sensitivity of 80% but a specificity of only
53% for BOO.
Qmax, flow pattern, PVR, prostate volume, void-
ed volume, TZ index and median lobe enlarge-
ment, as measured in 324 Taiwanese men, were used
to construct a clinical prostate score to diagnose
BOO. [Kuo, 1999] A score of 3 or greater had a sen-
sitivity of 87% and a specificity of 61% for BOO.
However in the population studied, the majority
(54%) would still require urodynamics to determine
the presence of BOO. The generalisability of the
116
results to non-Asian populations is uncertain.
Intravesical prostatic protrusion (IPP) and
Doppler ultrasound appear to offer high sensitivity
and specificity for obstruction. Intravesical prostatic
protrusion (IPP) and Doppler ultrasound were
recently compared with pressure-flow studies in 30
patients. [Nose et al., 2005] Combination of these
parameters, with the same cut-off values, gave a sen-
sitivity of 100%(5/5) with a specificity of
91%(10/11). [Nose et al., 2005] These impressive
values are obtained by post hoc selection of the cut
points in a small population and appear to exceed the
limits set by the limited reproducibility of pressure-
flow studies themselves (see above). Taken separate-
ly, the sensitivities of IPP (grade 3) and velocity ratio
(> 1.6) for diagnosing BOO were 90%(9/10) and
100%(11/11) respectively. They require independent
testing and confirmation in a larger population.
IV. CLINICAL UTILITY OF NON-
INVASIVE MEASUREMENTS
Of the many non-invasive parameters available cur-
rently for assessing obstruction in patients with
LUTS, which are the most useful clinically? Only a
few of them achieve both a high specificity and sen-
sitivity for BOO (Table 10). The best in this respect
seem to be ultrasound-estimated bladder weight;
intravesical prostatic protrusion (grade 3); penile
cuff test + PCR index; cuff test + PCR index +
Qmax; and intravesical prostatic protrusion + veloc-
ity ratio. Many however have not been widely tested
outside the centres where they were developed. A
problem with all of them is that the majority of
patients presenting with LUTS are not ascribed with
certainty to any diagnostic group (e.g. patients with a
mid-range flow rate, moderately sized prostate
and/or moderate symptoms). In contrast the extremes
of the population are generally easy to categorize
(e.g., patients with large prostate, low Qmax and
severe symptoms), but for these such methods repre-
sent no improvement over clinical experience.
To address this problem it has been proposed that a
3-way classification system based on ultrasound
findings (e.g., IPP), bothersomeness of symptoms,
and flowrate/residual urine should be used [Chia and
Foo, 1999]. This enables patients’ status to be classi-
fied as mild (no bothersome symptoms and no sig-
nificant obstruction), moderate (bothersome symp-
toms but no significant obstruction) or severe (sig-
nificant obstruction, irrespective of symptoms).
Treatment can be tailored accordingly.
Table 10. Non-invasive methods for diagnosing bladder outlet obstruction.

117
Table 10. Non-invasive methods for diagnosing bladder outlet obstruction.

118
Further research is required to provide evidence that
these methods will reduce the need for pressure-flow
studies. Moreover, to be clinically useful, the param-
eter must not only accurately predict obstruction, but
it must also be easy to measure. It is always more dif-
ficult to do a functional measurement than a static
measurement, but uroflowmetry is a non-invasive
functional measurement with 90% accuracy in the
diagnosis of BPO when properly performed and if
Qmax is less than 10ml/s [Abrams et al, 1995]. It is
also more physiological and less invasive than other
“non-invasive” methods such as the condom
catheter, the penile cuff and Doppler ultrasound,
which, although slightly less invasive than conven-
tional urodynamics, may require the attendance of
the investigator. Moreover, the current “non-inva-
sive” urodynamic methods are no more accurate than
free uroflowmetry in assessing BPO. It is more
important to rule out BPO in equivocal patients than
to prove its presence, as surgical intervention in
patients without BPO has relatively poor results.
Currently only conventional urodynamic studies can
rule out obstruction with confidence.
The situation may be different for the ultrasound-
based methods of assessing obstruction, provided
that their sensitivity and specificity is maintained in
wider practice. With ultrasound readily available in
the clinics, enabling tests such as those listed above
to be performed, the need for urodynamics before
surgical intervention may be reduced to those with
obstruction that remains equivocal after non-inva-
sive (ultrasound) assessment.
V. PATHOPHYSIOLOGY OF
DETRUSOR OVERACTIVE AND
BLADDER OUTLET OBSTRUCTION
It has long been argued that urethral obstruction is
responsible for the relatively high prevalence of
detrusor overactivity found in men with LUTS, and
in particular for its post-operative decrease, and there
is some animal evidence to support this. Neverthe-
less the pathophysiological link between obstruction
and detrusor overactivity is still not entirely clear,
and a number of recent papers have examined this
problem.
Knutson et al [2001] studied a cohort of 162 men
with LUTS suggestive of BPO, without other dis-
eases that might affect bladder function. All were
assumed to have bladder outlet obstruction (BOO),
but it was classified as ‘mild’ in 15%. They showed
119
that 55% had pure BOO (judged from the obstruction
parameter DAMPF[Schäfer, 1995]), while the
remainder had DO+BOO. Those with DO+BOO
were older, had higher s-PSA, voided smaller vol-
umes and were more severely obstructed, although
there was no significant difference in Qmax or post-
void residual urine. There was a strong association
between DO and BOO (P= 0.008). They suggested
that this indicates that BOO is a progressive disease
that may contribute to the development of DO.
Eckhardt et al [2001] examined 565 men with LUTS
suggestive of BPO. 53% had obstruction with Schae-
fer grade III or higher, equivalent to obstruction on
the ICS nomogram. 465 (82%) showed detrusor
overactivity. Detrusor overactivity (especially if pre-
sent both supine and standing) showed a significant
positive association with grade of obstruction.
Wadie et al [2002] studied 459 men with LUTS. 24%
showed detrusor overactivity (with amplitude >15
cm H2O). Detrusor overactivity was positively asso-
ciated with severity of obstruction: Schaefer grade
[mean ± SD] was 3.4 ± 1.5 and 2.9 ± 1.5 in those
with and without detrusor overactivity, respectively.
This association, although statistically significant
(P= 0.004), still implies that there is a great deal of
overlap in obstruction grade between those with and
without detrusor overactivity.
All the above suggest that detrusor overactivity is
associated with bladder outlet obstruction. In appar-
ent contrast, Eckhardt et al [2001] compared 14 older
(≥50 y) male volunteers without LUTS with 465
older patients with LUTS. They found that 6 of the
14 volunteers (43%) showed detrusor overactivity,
while 259/565 patients with LUTS (46%) showed it.
Thus the incidence of detrusor overactivity was sim-
ilar in volunteers and patients. In spite of the differ-
ence in LUTS, however, there was only a modest dif-
ference in obstruction: 5/14 volunteers (36%) and
301/565 patients (53%) were obstructed. These
observations therefore remain consistent with the
hypothesis that detrusor overactivity and bladder
outlet obstruction are associated.
Hirayama et al [2003] investigated the etiology of
detrusor overactivity in LUTS. They performed an
ice water test in 2 groups of patients: 127 men with
LUTS, without neurological disease, age > 50 y,
IPSS ≥ 8, QOL index ≥ 2; and 20 neurological
patients as controls. In an ice water or bladder cool-
ing test, cold water is rapidly infused into the blad-
der. [Fall, et al 1995] A positive result (provocation
of involuntary detrusor contraction) is believed to
indicate pathological involvement of C-fibre affer-
ents in the voiding reflex. In this study 14/20 neuro-
logical patients (70%) showed a positive ice water
test, suggesting (as expected) that C-fibre afferents
were involved in the abnormal voiding reflex. How-
ever, 35/127 LUTS patients (27%) also showed a
positive ice water test, and all 35 showed detrusor
overactivity during regular cystometry also. They
also had more severe bladder outlet obstruction and
smaller volume at strong desire to void than those
with a negative ice water test. These observations
seem to suggest abnormal involvement of C-fibre
afferents in LUTS patients with severe obstruction.
Dinis et al [Dinis, Silva, Ribeiro et al., 2004] were
able to check the involvement of C-fibres directly.
They examined the effect of C-fibre desensitization
with a single intravesical administration of resinofer-
itoxin (50nM solution). 12 patients with storage
LUTS were treated. The IPSS decreased from 20 to
10 at 3 months and more. Urge incontinence was
abolished in 4/6 patients with this symptom. Bladder
volume at first desire to void and maximum cysto-
metric capacity both increased. Voiding itself, as
reflected in uroflow and PVR, was not altered. Thus
this observation is not only consistent with the
involvement of C-fibres in detrusor overactivity, but
it also suggests a potentially useful treatment.
To summarize, detrusor overactivity in LUTS
patients is associated with severity of obstruction,
and it appears to have a neurological component, as
shown by the involvement of C-fibre afferents in the
voiding reflex.
VI. WHEN IS OBSTRUCTION
SIGNIFICANT CLINICALLY?
In this section we have focused on the non-invasive
diagnosis of obstruction defined ultimately in urody-
namic terms. In practice however it would be more
satisfying to determine whether such methods can
diagnose obstruction of clinically relevant severity.
In assessing severity, it can be argued that actual
obstruction is more important than symptoms.
Although symptoms affect quality of life, obstruc-
tion, if not relieved in time, may lead to progression
of the disease and affect organ function. In less
developed parts of the world, obstruction still limits
lifetimes.
Until recently, attention was paid only to the back-
pressure effects of obstruction on the kidneys. More
120
recent studies have suggested that bladder outlet
obstruction affects bladder function, leading to struc-
tural changes also. Because the changes may eventu-
ally become irreversible, some would argue that
management should be directed towards early relief
of significant obstruction. [Flanigan et al., 1998; Lu
et al., 2000; Brierly et al., 2003]
When is the level of obstruction clinically signifi-
cant? Is the ICS definition of obstruction, based on
pressure-flow studies, clinically significant? If the
BOOI > 40, does the patient need more aggressive
treatment such as surgical relief of obstruction? If
not, at what level of obstruction would surgical relief
be indicated? There are no evidence-based studies to
suggest when surgical relief is indicated. However
many papers have shown that, if there is no evidence
of obstruction on pressure-flow studies, the results of
surgical relief are not as good. [Porru et al., 2002];
Thomas, 2004].
In clinical practice, it is important to know when sur-
gical intervention is indicated in the management of
BPO. Obstruction can vary from mild to severe, and
not all patients with a urodynamic diagnosis of
obstruction require surgery, especially in this era of
5-alpha reductase inhibitors. Going back to the basic
principles of clinical practice, if obstruction is affect-
ing the function of the organ, then more aggressive
treatment such as surgical relief is indicated. Analo-
gously, for the eye, in glaucoma, if the intra-ocular
pressure is affecting vision, then it is clinically sig-
nificant and requires more aggressive treatment.
Similarly, in clinical shock, the exact level of the
blood pressure is not as important as the hourly urine
output, which reflects the effect of the low blood
pressure on perfusion of the kidneys. If the hourly
urine output is poor then shock is clinically signifi-
cant. Clinical shock is not defined by the exact level
of the blood pressure. Thus in real life practice, it is
more important to assess the effects of prostatic
obstruction than the exact degree of obstruction,
whether using conventional urodynamic studies or
the non-invasive methods described in this section.
This argument suggests that tests could be selected
for their ability to assess potential changes in bladder
function and structure. The two basic functions of the
bladder are storage and emptying. If the storage
function is affected by BPO, there will be inability to
store urine, manifested clinically by frequency and
urgency and voiding of small volumes. If the empty-
ing function is affected then there will be persistent
residual urine. Suitable tests (some but not all dis-
cussed above) are:
a. Measurement of voided volume
This can be done easily and non-invasively by ask-
ing patients to keep a voiding diary.
b. Measurement of residual urine
c. Measurement of bladder weight
This can be done with transabdominal ultrasound.
Increased weight signifies a structural change.
d. Measurement of bladder blood flow (detrusor
resistive index)
Can be measured with Doppler ultrasound. Unre-
lieved obstruction may lead to decreased bladder tis-
sue perfusion and may eventually cause irreversible
harm to the structure and function of the bladder.
e. Ultrasound of kidneys for hydronephrosis
Patients with minimal symptoms despite pronounced
obstruction may rarely have bilateral hydronephro-
sis, as they seek treatment late. Measurement of
serum creatinine is not sensitive enough to detect this
complication until the kidneys have lost significant
function. As surgeons we need to detect this compli-
cation early and the best clinical tool is transabdom-
inal ultrasound. In less developed countries of the
world, chronic retention of urine with bilateral
hydronephrosis, and impaired renal function in about
6%, is still a common urological problem. [Lim et al,
1999]. However, this argument would logically
demand the screening of the whole older male popu-
lation, which is likely to remain impractical.
CONCLUSION
Many of the newer non-invasive methods that have
been suggested are not very sensitive or specific for
detecting BOO, and uroflowmetry – an old method –
remains surprisingly good (Grade B recommenda-
tion). The non-invasive methods of measuring blad-
der pressure, although ingenious, have yet to prove
their usefulness in the clinic. They may be useful for
evaluating bladder function in epidemiological stud-
ies.
Ultrasound-based methods provide quantitative and
objective measurements that are promising for mak-
ing therapeutic decisions in clinical practice,
although their reliability and applicability need to be
independently tested in centres outside those
involved in their development.
121
VII. URODYNAMICS IN
PROSTATE CANCER
The following will be reviewed: the urodynamic sit-
uation in men with a diagnosis of prostate cancer,
prior to any treatment; the changes after treatment,
judged prospectively; whether pre-operative urody-
namics can predict outcome (e.g. continence or
incontinence); the mechanism of post-treatment
incontinence; and the clinical utility of urodynamics
in prostate cancer.
1. URODYNAMICS IN UNTREATED PROSTATE
CANCER
Understandably, only limited urodynamic studies
have been reported prior to treatment in men with a
diagnosis of prostate cancer. Because such men may
be identified either by screening or by symptomatic
presentation, the prevalence of urodynamic abnor-
malities such as obstruction may be quite variable in
different centers with different patient populations. It
is usually suggested that the possible abnormalities
are similar to those in benign prostatic obstruction :
urethral obstruction and detrusor overactivity. The
age ranges of the patients are usually similar (though
quite wide).
a) Urethral obstruction
Urethral obstruction implies that the urethral resis-
tance to flow is abnormally elevated, as revealed
during voiding by a relatively low flow rate at a rel-
atively high detrusor pressure (see Figure 18).
Obstruction may be due to urethral overactivity (fail-
ure to relax during voiding) or to structural abnor-
malities (e.g. a stricture, or perhaps prostatic enlarge-
ment). A number of methods of assessing obstruction
have been developed, all giving somewhat similar
results except in borderline cases. The International
Continence Society [Griffiths et al., 1997] recom-
mends that the maximum flow rate (Qmax) and the
detrusor pressure at maximum flow (pdet.Qmax)
should be recorded in ml/s and cm H2O respective-
ly. A classification of obstruction can then be derived
from the ICS obstruction nomogram or the bladder
outlet obstruction index (BOOI).
In a study of urine flow rates [Masters and Rice,
2003], among 125 men examined prior to radical
retropubic prostatectomy for prostate cancer, 38%
had a maximum flow rate of 10 ml/s or less. Com-
parison with flow rates in benign disease (Table 9)
suggests that the majority of these 38% had bladder
outlet obstruction caused by an enlarged prostate.
Presumably most of the remaining 62% had relative-
ly slight prostatic obstruction, or none.
Direct assessment of obstruction by invasive urody-
namic measurements prior to surgery is rare. Perhaps
developments in non-invasive urodynamics will
allow this gap to be filled in the future.
b) Detrusor overactivity and bladder compliance
Detrusor overactivity is a urodynamic observation
characterised by involuntary detrusor contractions
during the filling phase which may be spontaneous
or provoked. Characteristically it is associated with
symptoms such as urgency and frequency of micturi-
tion and urgency incontinence. It is not a diagnosis
but a urodynamic observation, the cause of which is
sometimes clear (e.g. a neurological disease such as
multiple sclerosis) but often is obscure. For example,
it has been argued that detrusor overactivity may be
caused by urethral obstruction, and this is discussed
further below. In other cases there is no obvious
cause at all and the detrusor overactivity is called
idiopathic. Sometimes it may even be a normal vari-
ant.
The incidence of detrusor overactivity during filling
cystometry has been noted in 5 studies. Constantinou
and Freiha [1992] examined 29 patients with a mean
age of 63 years, prior to surgery for prostate cancer.
16/29 patients (55%) demonstrated detrusor overac-
tivity, with quite high maximum detrusor pressures
(59 ± 28 cm H2O [mean ± SD]). Golomb et al [1999]
reported on 20 patients with a diagnosis of prostate
cancer. Detrusor overactivity with detrusor pressures
exceeding 15 cm H2O was demonstrated in 12/20
patients (60%). Kleinhans et al [1999] studied 66
patients in the week before surgery for prostate can-
cer. Detrusor overactivity was observed in 21/66
(32%). Aboseif et al [1994] evaluated 92 men (mean
age 64 years) prior to prostate cancer surgery. 19/92
showed detrusor overactivity (21%). Hammerer et al
[1997] examined 82 patients pre-operatively. Detru-
sor overactivity was observed in 14/82 (17%). The
incidence of pre-operative detrusor overactivity
averaged over these 5 studies is 28%, with quite
high detrusor pressures being reported during filling.
The normal bladder is highly compliant: i.e. during
artificial filling the detrusor pressure rises by at most
10 or 15 cm H2O while the bladder is filled to a vol-
ume of about 500 ml. If natural filling by diuresis is
used the pressure rise is still smaller. A steeper pres-
sure rise (in the absence of detrusor overactivity)
implies abnormally low compliance – a “stiff” blad-
122
der wall. Low compliance appears always to reflect
pathology. An association between low compliance
and urethral obstruction has been reported but is
uncertain.
c) Urethral pressure
Urethral pressure is the fluid pressure needed to just
open the closed (collapsed) urethra. It can be mea-
sured in various ways (slow perfusion of liquid,
small balloon, or catheter mounted transducer, which
each have characteristics and artifacts that require
careful attention. Its value varies from point to point
along the length of the urethra. A plot of urethral
pressure against distance, measured along the urethra
from the bladder neck, is called a urethral pressure
profile. The profile parameters most commonly
reported are maximum urethral pressure and maxi-
mum urethral closure pressure (maximum urethral
pressure minus intravesical pressure), measured
supine. The maximum urethral pressure reflects the
action of the striated urethral sphincter, not the
prostate, and would be expected to have normal val-
ues in most patients with prostate cancer. Thus Ham-
merer et al, [1997] examining 82 prostate cancer
patients pre-operatively, found that the mean maxi-
mum urethral pressure was 90 cm H2O : within the
normal range. John et al, [2000] in 34 prostate can-
cer patients examined pre-operatively, found a max-
imal urethral closure pressure of 49 ± 10 cm H2O,
perhaps a little lower than normal.
2. URODYNAMICS AFTER TREATMENT OF
PROSTATE CANCER: PROSPECTIVE STUDIES
There are relatively few systematic prospective stud-
ies of the urodynamic situation after cancer treat-
ment. The majority of studies have focused mainly
on the changes produced by surgery, or on the risk
and mechanism of incontinence. Consequently sur-
prisingly little is known of the situation in the major-
ity of patients – those who do not become inconti-
nent or who quickly regain continence after surgery.
Such knowledge is essential to provide the basis for
informed medicine. Ideally systematic study of the
effect of each treatment option is required, including
radical prostatectomy and radiation treatments. The
following references provide the only available
knowledge.
a) Detrusor overactivity
As seen above, detrusor overactivity is moderately
common preoperatively, although it does not usually
lead to incontinence. An important question is
whether it is equally, more, or less common after
treatment for prostate cancer, since a weakened
sphincter mechanism may not be able to control
urine loss if the detrusor is overactive. The reports
are not entirely consistent; furthermore, the numbers
in each study are small.
Golomb et al 1999] showed that among 12/20
patients who demonstrated detrusor overactivity pre-
operatively, only 2 manifested urgency incontinence
after prostate surgery. The postoperative incidence of
detrusor overactivity was not reported, but would
appear to be lower than preoperatively. Hammerer et
al, [1997] examined 82 patients pre- and post-opera-
tively. Detrusor overactivity increased to 41% after
surgery, from 17% pre-operatively. Do et al [2002]
and Choo et al [2002] performed urodynamics pre-
and post-radiotherapy in 15 patients. There were no
significant changes in detrusor overactivity. In fact
the amplitude of detrusor overactivity can remain
quite high postoperatively (mean 49 cm H2O) [Con-
stantinou and Freiha, 1992]
b) Urethral obstruction
The urodynamics of urethral obstruction are dis-
cussed above.
Radical prostatectomy would be expected to remove
any bladder outlet obstruction caused by a malig-
nantly enlarged prostate, unless a urethral stricture or
stenosis were to develop. Radiation therapy may
increase obstruction in the short term, if swelling and
inflammation develop.
Kumar et al [2004] suggested that, in a group of 50
men with prostate cancer and moderate or severe
LUTS preoperatively, there were significant
improvements postoperatively in maximum flow
rate (11.3 ml/s to 27.3 ml/s at 3 months) and PVR (63
ml to 24 ml), as well as in symptoms. In 8 men with
mild LUTS (16% of the group) the symptomatic
improvement was much less. This suggests that
some men who are not highly obstructed preopera-
tively remain so and receive less symptomatic bene-
fit than those who are highly obstructed to start with.
Constantinou and Freiha [1992] found that, in 13
post-operative patients, the maximum flow rate was
13 ± 2 ml/s and maximum voiding detrusor pressure
was 39 ± 4 cm H2O. These values are within normal
ranges, suggesting that the most severe outlet
obstruction has been removed by surgery. Montorsi
et al [1993] found that, in 150 patients after radical
prostatectomy, mean maximum uroflow was 16.9 ±
1.3 ml/s and PVR was 11 ± 2 ml. 22% were still
123
obstructed post-operatively, by a stricture in 12%
and because of ‘denervation’ in 10%. According to
Masters and Rice, [2003] in 125 men, mean maxi-
mum flow rate post-operatively was 17 ml/s, rising
to 24 ml/s at 20 months. This high value suggests
that urethral obstruction has been removed by the
surgery. Strictures or stenoses developed in 20% and
were treated, partly explaining the gradual improve-
ment in flow post-treatment, although improvement
occurred even in men with no stenoses.
Taken together, these studies suggest that the major-
ity of pre-operative outlet obstruction (presumably
prostatic in origin) is removed by radical prostatec-
tomy, but that a certain amount of obstruction
remains or develops de novo (stenosis or stricture),
and gradually resolves either spontaneously or with
treatment over the following year or so.
Do et al [2002] performed urodynamics pre- and 3
months post-treatment by external beam radiothera-
py in 15 patients. This therapy caused no significant
change in bladder outlet obstruction, although there
was a significant decrease in PVR. Henderson et al
[2002] found that 27/100 patients had to use a
catheter after prostate brachytherapy treatment or
suffered acute urinary retention. This seems to have
been due mainly to urethral obstruction (new or pre-
existing) post-treatment.
c) Urethral pressure and other parameters
Because of anatomical propinquity, radical prostate-
ctomy is likely to produce significant weakening of
the striated urethral sphincter, by damage directly to
the muscle or through damage to its innervation. Pre-
sumably the damage is more serious in those who
suffer from post-surgery incontinence, but an impor-
tant question is, how serious is it in those who have
no problem with incontinence? In other words, is
radical surgery always accompanied by sphincter
damage, or is it possible to avoid damage, at least in
some patients?
Hammerer et al [1997] examined 82 patients. Pre-
operative mean maximum urethral pressure was 90
cm H2O, decreasing to 65 cm H2O post-operatively.
John et al [2000] measured a number of urodynamic
parameters in 34 patients pre- and post-operatively.
Maximal urethral closure pressure was 49 ± 10 cm
H2O preoperatively and became significantly lower
postoperatively. At 6 weeks it was significantly
lower in incontinent (11 ± 9 cm H2O) than in conti-
nent patients (35 ± 6 cm H2± 6 cm H2O and 42 ± 9
cm H2O, respectively. Posterior urethral electrosen-
sation also was reduced after surgery (i.e. the thresh-
old for sensation was higher), more so in incontinent
patients than continent.
These observations suggest that damage to the ure-
thral striated sphincter and its innervation is exten-
sive even in patients who are continent post-radical
prostatectomy. Thus initially there is intrinsic
sphincter deficiency (see section 2.4.1), which seems
to recover slowly in the months following surgery.
Choo et al [2002] studied urodynamic changes after
radiotherapy for prostate cancer in 15 patients. They
found that, in the supine position, bladder capacity
had decreased by 100 ml. The bladder volumes at
first sensation of filling and at normal desire to void
also decreased. These observations suggest that, after
radiation therapy, sensations referable to the bladder
became stronger.
d) Incontinence after radical prostatectomy
Urinary incontinence is the complaint of any invol-
untary leakage of urine. For a full definition in a
given context, factors such as frequency and severi-
ty need to be specified. Incontinence is both common
and troublesome after surgery for prostate cancer.
The reported incidence after radical prostatectomy
varies greatly, from 5% to over 60% [Hunskaar et al.,
2002]. It depends on the surgical technique, the def-
inition of incontinence and how it is quantified,
[Grise and Thurman, 2001; Peyromaure et al, 2002]
who performs the evaluation of the incontinence
(physician or patient) [Donnellan et al, 1997;
McCammon et al, 1999] and (because of sponta-
neous regression) the time between the surgery and
the evaluation. However, at 12 months post-surgery
the prevalence of incontinence is probably about 15-
20%. [Hunter et al, 2004]
e) Incontinence after radiation treatment
Henderson et al [2002] report no incontinence after
radiation/brachytherapy treatment, in a total of 100
patients. Choo et al [2002] report that 4 of 17 patients
suffered from urgency incontinence before radiother-
apy for prostate cancer and were still incontinent
afterwards. Three patients developed de novo urgen-
cy incontinence after treatment.
3. CAN PRE-OPERATIVE URODYNAMICS PRE-
DICT POST-OPERATIVE PROBLEMS?
Kleinhans et al [1999] examined 44 patients eight
months after radical prostatectomy, out of 66 exam-
ined preoperatively. 16% were continent at 6 months,
124
and 98% after a year. Detrusor overactivity seen pre-
operatively was not responsible for any case of
incontinence post-operatively. No preoperative blad-
der function parameters predicted post-operative
incontinence.
Golomb et al [1999] observed detrusor overactivity
(amplitude > 15 cm H2O) pre-operatively in 12/20
patients. Only 5 of these 12 complained of urgency
incontinence post-surgery. 5 of the original 20 had
mild stress incontinence. There was no significant
association between pre-operative detrusor overac-
tivity and post-operative incontinence.
In an earlier but larger study, Aboseif et al [1994]
came to a different conclusion. 92 men were divided
into 2 groups on the basis of pre-operative urody-
namics – with and without detrusor overactivity.
After 1 year, the incidence of incontinence was 3%
in the group without detrusor overactivity versus
39% in the other group. This result suggests that pre-
operative abnormalities in bladder function can
affect the post-operative situation.
John et al [2000] measured different variables and
found that, in 34 patients, preoperative urethral sen-
sory threshold (determined electrically) was not
related to the severity of post-operative incontinence.
Thus these reports are not entirely consistent, leaving
it open as to whether post-operative incontinence can
be predicted preoperatively. However, the predictive
value of any urodynamic measurement does not
appear to be high.
4. MECHANISM OF POST-OPERATIVE INCONTI-
NENCE
a) Types of incontinence
The 2 principal types of urinary incontinence are
stress and urgency incontinence.
Stress urinary incontinence (the symptom) is the
complaint of involuntary leakage on effort or exer-
tion, or on sneezing or coughing. The corresponding
urodynamic observation, noted during filling cys-
tometry, is urodynamic stress incontinence. It is
defined as the involuntary leakage of urine during
increased abdominal pressure, in the absence of a
detrusor contraction. In women, stress incontinence
is common and is believed to reflect a mechanical
defect which may be either weakness of the pelvic
floor, allowing the bladder base to become hypermo-
bile, or weakness (deficiency) of the intrinsic ure-
thral sphincter mechanism. In men, hypermobility is
almost unknown and stress incontinence is relatively
rare. If stress incontinence is observed it almost
inevitably implies intrinsic sphincter deficiency.
Urgency urinary incontinence (the symptom) is the
complaint of involuntary leakage accompanied by or
immediately preceded by urgency. The correspond-
ing urodynamic observation is detrusor overactivity
incontinence, which is incontinence due to an invol-
untary detrusor contraction. In a patient with normal
sensation, urgency is likely to be experienced just
before the leakage episode. Thus the observation of
involuntary detrusor contraction (detrusor overactiv-
ity) suggests the possibility of urgency incontinence,
which is proven if detrusor overactivity incontinence
occurs during urodynamics.
In principle, the incontinence encountered after treat-
ment of prostate cancer might be of either the stress
or the urge type. One of the objectives of clinical
research in this area has been to establish the relative
importance of these two types, with a view to pre-
vention and to selection of optimum treatment.
b) Radical prostatectomy
Many papers have been published on this topic. The
better ones compare urodynamic parameters in con-
tinent and incontinent patients post-radical prostate-
ctomy; that is, they seek variables whose changes
mediate continence or incontinence. The majority
however merely look for abnormalities in inconti-
nent patients that appear to account for the inconti-
nence.
Presti et al [1990] compared urodynamics in 24
incontinent and 13 continent patients after radical
prostatectomy. They found differences in: functional
profile length (2.1 vs 3.6 cm, P<0.001); maximum
urethral closure pressure (39 vs 74 cm H2O,
P < 0.001); and maximum urethral closure pressure
during voluntary sphincter contraction (107 vs 172
cm H2O, P < 0.002). Detrusor overactivity was only
weakly associated with incontinence. On fluo-
roscopy, ‘tubularization’ of the proximal urethra
above the striated sphincter was seen in continent
patients only.
John et al [2000] examined 34 patients, of whom
82% were continent at 6 months. The urethral senso-
ry threshold was not only raised post-operatively, as
reported above, but was worse in those with inconti-
nence. So-called ‘pressure transmission’ (probably
the ratio of pressure changes near the striated sphinc-
ter to those in the bladder, on straining) was dimin-
ished after surgery, and more so in incontinent than
continent patients. Maximal urethral closure pressure
125
became significantly lower postoperatively and was
significantly lower in incontinent than in continent
patients.
Bamshad et al [1999] measured retrograde perfusion
pressure in patients after prostatectomy. Although
not a standard measurement, retrograde perfusion
pressure (the fluid pressure needed to slowly perfuse
the urethra retrogradely from external meatus to
bladder) should be equal to the maximum urethral
pressure if carefully performed. There were 3 groups
of subjects. Group 1 (n = 14) had received no opera-
tion; group 2 (n = 11) were continent post-radical
prostatectomy; group 3 (n = 18) were incontinent
post- radical prostatectomy with a normal filling cys-
tometrogram. Perfusion pressure was 101 ± 16 cm
H2O [SD] in group 1, 78 ± 17 cm H2O in group 2,
and 37 ± 12 cm H2O in group 3. Perfusion pressure
in group 3 was thus much smaller than in the other 2
groups, and significantly so (P <0.0001 and P
<0.001, respectively). The mean ages in the 3 groups
were 60, 68 and 72 y respectively, and appear unlike-
ly to account for the differences in perfusion pres-
sure.
Taken together, the above comparisons of inconti-
nent and continent patients suggest that intrinsic
sphincter deficiency (due to sphincter damage and/or
denervation) is an important contributor to post-
prostatectomy incontinence and that it may have, at
least in part, a neurogenic basis. This seems to imply
that (urodynamic) stress incontinence is predominant
and detrusor overactivity is somewhat less impor-
tant, although if present it will certainly contribute to
the incontinence.
The following papers deal with observations in
incontinent patients only. Some are difficult to clas-
sify as they use terms that are non-standard or use
them in non-standard ways. For example, does
‘urgency incontinence’ mean the symptom urgency
incontinence (so not a urodynamic observation), or
does it mean that the authors observed leakage on
urodynamics associated with involuntary detrusor
contraction (that is, detrusor overactivity inconti-
nence)?
Chao and Mayo [1995]examined 74 men incontinent
after radical prostatectomy eight years post-surgery.
42 (57%) showed sphincter weakness; in 29 (39%)
either detrusor overactivity or decreased bladder
compliance was observed in addition to sphincter
weakness; in only 3 (4%) was detrusor overactivity
seen alone.
Desautel et al [1997] examined 39 male patients
incontinent after prostatectomy, which was a radical
prostatectomy in 35. Sphincter damage was the sole
cause of incontinence that could be found in 23
(59%) and it was a major contributor in 14 (36%).
Detrusor overactivity and low bladder compliance
were observed in 15 patients (39%). They concluded
that intrinsic sphincter damage (deficiency) account-
ed for the vast majority of post-radical prostatectomy
incontinence, but bladder dysfunction needed to be
identified and treated as well.
Winters et al [1998] examined 65 patients inconti-
nent after radical prostatectomy and 27 after TURP.
The predominant finding was sphincter incompe-
tence (intrinsic sphincter deficiency as shown by
leakage during Valsalva at pressures from 12 -120
cm H2O) in 85 pts (92%). Detrusor overactivity
(said to be either phasic or ‘tonic’) was observed in
34 pts (37%) but was the sole observable cause of
incontinence in only 3/92 pts (3%). They concluded
that sphincter deficiency was the most common
cause of incontinence, but bladder dysfunction could
coexist with it and might occasionally be the only
observable cause.
Ficazzola and Nitti [1998] examined 60 patients with
post-radical prostatectomy incontinence at least 6
months post-surgery. Intrinsic sphincter deficiency,
as shown by leakage on elevated abdominal pressure
during Valsalva, was seen in 54 patients (90%).
Detrusor overactivity was seen in 24 and reduced
compliance in 3 (27 total = 45%). In spite of this
bladder dysfunction, intrinsic sphincter deficiency
was observed to be the sole cause of incontinence in
40 patients (67%); intrinsic sphincter deficiency and
bladder dysfunction were the joint cause in 14
(23%); and bladder dysfunction alone was the cause
in only 2 (3%).
Groutz et al [2000] examined 83 men incontinent
after radical prostatectomy. They found sphincter
weakness in 73 (88%). Detrusor overactivity was
observed in 28 (34%) but it was found to be the main
cause of incontinence in only 6 (7%). They encoun-
tered occasional bladder outlet obstruction or detru-
sor underactivity on voiding (2% together), which
may have contributed to incontinence in unknown
ways.
McCallum et al [2001] reported on 16 patients with
longstanding incontinence (14 to 33 months, median
22 months) after radical prostatectomy. Half of the
subjects showing urodynamic stress incontinence
also showed either detrusor overactivity or low com-
pliance, which presumably contributed to the severi-
ty of the incontinence.
126
Gomha and Boone [2003] examined 61 patients with
incontinence after prostatectomy (radical prostatec-
tomy in 58 cases). Urodynamic stress incontinence
was present in all patients. There was concomitant
urgency/urgency incontinence (detrusor overactivi-
ty?) in 48%.
Pfister et al [2002] measured urethral pressures in 20
patients with incontinence after radical prostatecto-
my. They divided sphincter function into 3 compo-
nents (baseline, adrenergic, and voluntary), mea-
sured separately, that, in principle, might be differ-
ently affected by surgery. The most striking effect of
surgery was on the component sensitive to alpha-
adrenergic blockade, while the voluntary component
(the increase on voluntary sphincter contraction) was
hardly affected, if at all. This seems to confirm that
damage to some aspects of sphincter innervation
makes an important component to post-prostatecto-
my incontinence.
The above papers suggest that sphincter weakness
(intrinsic sphincter deficiency or sphincter damage,
possibly due to neuropathy) is the predominant cause
of post-radical prostatectomy incontinence, and that
detrusor dysfunction (detrusor overactivity or low
bladder compliance) is rarely the sole cause but can
exacerbate its severity. There is no clear evidence
either that pre-existing detrusor overactivity, or low
compliance persisting after surgery, predisposes to
more severe or more probable incontinence, or that
these abnormalities arise de novo after surgery. Pre-
sumably, however, one or both of these scenarios
must be the case.
5. CLINICAL UTILITY OF URODYNAMICS IN
PROSTATE CANCER
Consistent with the observations reported above, there
is no evidence that performing urodynamics pretreat-
ment will improve outcomes of surgery. Post-opera-
tively, incontinence improves spontaneously in most
men, so that conservative management (perhaps sup-
plemented by pelvic muscle exercises) while awaiting
return of continence is adequate for several months. In
fact, nursing support and education without actual
therapy may be the best management [McGlynn et al.,
2004]. Regular monitoring of flow rates is advisable,
as diminishing flow may signal stricture or stenosis
that should be treated. This is equally important after
radiation treatment. In those with persistent inconti-
nence, say at one year, impaired sphincter function is
the most common cause but there is still no evidence
that performing urodynamics will hasten the return of
continence. However, it appears logical to try to
understand the causes of incontinence at this stage, by
urodynamic investigation, and in particular to estab-
lish whether detrusor dysfunction (overactivity or low
compliance) is contributory, as in this case pharmaco-
logical treatment might be tried. Level of evidence =
4 (expert opinion), grade of recommendation C.
VIII. RECOMMENDATIONS:
WHAT URODYNAMICS SHOULD BE
DONE, AND WHEN?
1. URODYNAMICS IN PATIENTS WITH LUTS
SUGGESTIVE OF BENIGN PROSTATIC
OBSTRUCTION
1. Pressure/flow studies remain the only means of
establishing or ruling out the presence of BOO
2. Non-invasive methods of assessing obstruction are
not yet able to fill that role, although some may
ultimately be able to do so
3. The filling phase of micturition should also be
assessed, as symptomatic detrusor overactivity
may have a bearing on the outcome of treatment
(Grade of recommendation C).
4. Patients being submitted to TURP, with its atten-
dant risks, should have a definitive diagnosis of
outlet obstruction (Grade of recommendation B).
5. If pressure-flow studies are not planned prior to
invasive treatment, then the patient should be
made aware of the diagnostic limitations of
uroflowmetry (Grade of recommendation B).
6. In the research setting, pressure-flow studies of
possible obstruction in men with LUTS are essen-
tial to reveal biological mechanisms, increase sta-
tistical power and reduce the number of men “at
risk” from novel treatments for BOO.
2. URODYNAMICS IN PATIENTS WITH PROSTATE
CANCER (PRE- AND POST-TREATMENT)
1. Comprehensive urodynamics should be performed
if there is urinary incontinence that persists for >6
months after surgical treatment of prostate cancer
and does not respond to conservative management
/ treatment. The aim should be to determine the
type of incontinence (eg urodynamic stress incon-
tinence) and any exacerbating factors (eg detrusor
overactivity) [Grade of recommendation C].
2. Periodic monitoring of urine flow during the recov-
ery period post-surgery may help in early detection
of stricture [Grade of recommendation D].
127
E. PREDICTING OUTCOME
AFTER THERAPY
Benign prostatic enlargement (BPE) is a common
condition among older men and may lead to benign
prostatic obstruction [Hong et al 2003]. Clinical
manifestation of benign prostatic obstruction (BPO)
includes lower urinary tract symptoms (LUTS), and
impairment of urinary flow with a negative impact
on Quality of Life (QoL). European and Internation-
al “Benign Prostatic Hyperplasia” treatment guide-
lines have stated that watchful waiting is recom-
mended for patients with mild symptoms, medical
treatment for patients with mild to moderate symp-
toms, and BPO-related invasive therapy for those
with moderate to severe symptoms [Mochtar et al
2005]. Many authors are researching parameters that
could accurately predict the results of these three
treatment modalities, and thereby reduce the num-
bers of men who experience a negative outcome
from BPO treatment.
I. WATCHFUL WAITING
One of the treatment alternatives for LUTS sec-
ondary to BPO is watchful waiting (WW). Mochtar
et al [2005] investigated the prognostic role of
prostate-specific antigen (PSA) level and prostate
volume (PV) for the need for benign prostatic
obstruction (BPO)-related invasive therapy among
patients treated with WW. Increasing PSA levels pro-
duced an increase in the 5-year cumulative risk of
invasive treatment: 8%, 9%, and 15% for a PSA level
of less than 1.5, 1.5 to less than 3.0, and 3.0 to 10.0
ng/mL, respectively. The hazard ratio for the highest
compared with the lowest PSA strata was 2.7. An
increasing PV also increased the 5-year cumulative
risk from 8% to 11%, a hazard ratio of 1.0. These
results suggest that PSA is a significant prognostic
factor for invasive therapy among patients on watch-
ful waiting but not prostate volume [Mochtar et al
2005]. Knutson et al [2001] studied 37 men with
LUTS and suspected BOO with urodynamics and
transrectal ultrasound and followed the patients for 4
years. They found that the prevalence of detrusor
overactivity increased with BOO, and the failure rate
of WW was higher in the more obstructed patients
and significantly higher in those with more severe
obstruction. Thus, by including urodynamics when
investigating patients with BOO, it seems possible to
predict the failure rate according to the patients’
obstruction grade [Knutson et al 2001].
There is level 3 evidence that higher PSA and
BOO levels predict failure from WW.
 II. MEDICAL TREATMENT
Treatment with alpha-blockers and 5 alpha-reductase
inhibitor provides an improvement in symptoms,
uroflowmetric parameters and QoL indices in
patients suffering from BPO [Hong et al 2003]. Cur-
rently, alpha-blockers are first-line drug therapy for
BPO [Mimata et al 2002].
Hong et al [2003] evaluated 437 men over 50 years
of age with LUTS, treated with alpha-blocker and /or
5 alpha-reductase inhibitor. After three months of
medical treatment, failure was considered if a
decrease of less than 30% in IPSS and QoL index
was observed; Qmax increased less than 2mL/s from
the initial visit;, the post void residual urine volume
was greater than 100 mL;, or when patients were not
happy to continue with medical treatment [Hong et al
2003]. These are not validated criteria, but some
authors have used these measures to identify treat-
ment failure. Medical treatment failure occurs in
22.9% of patients and the causes are: insufficient
efficacy (44%), development of acute urinary reten-
tion (33%) and adverse events associated with med-
ication (27%) [Hong et al 2003].
Failure was associated with older age, higher IPSS
score and larger prostate volume. According to sta-
tistical analysis the best cutoff values for predicting
medical treatment failure are an IPSS of over 21 and
a prostate volume over 32 cm3.
The probability of medical treatment failure in
patients with symptom scores above 21 is 27% (12
months), 38% (24 months) and 40% (36 months). In
those with scores below 21 is 15% (12 months), 16%
(24 months) and 16% (36 months). If the prostate
volume is over 32 cm3 the probability of medical
treatment failure is 24% (12 months), 33% (24
months) and 34% (36 months) and in those with vol-
umes below 32 cm3 is 12% (12months), 15% (24
months) and 16% (36 months) [Hong et al 2003].
Mochtar et al [2005]treated 389 patients with alpha-
blocker and observed that higher PSA values (4-10
ng/mL) and larger PV (greater than 30 cm3) resulted
in a greater risk of invasive therapy.
There is level 3 evidence that prostate volumes,
and higher levels of IPSS, can predict the risk of
invasive therapy in patients on medical treatment
for BPO.
128
III. ACUTE URINARY RETENTION
It is now widely accepted that giving an alpha adren-
ergic antagonist increases the success rate of a trial
without catheter (TWOC) in men with BPO after a
first episode of acute urinary retention (AUR), and
up to 62% of patients will have a successful TWOC
after receiving alpha blocker [McNeill et al 2003]. In
other, somewhat older, studies, after 5 to 7 years fol-
low-up, 80 to 84% of the patients who had previous-
ly experienced AUR ultimately needed surgery
[Craigen et al 1969, Breum et al 1982]. Klarskov et
al [1987] reported that the factors that predicted pre-
served voiding ability after a successful TWOC are a
retention volume of less than 500 mL and a Qmax
over 5mL/s. McNeill et al [1999], in a prospective
trial, randomized 81 patients with a first episode of
AUR related to benign prostatic obstruction, to
receive either sustained-release alfuzosin or placebo
for 48 hours. Thirty four patients had a successful
TWOC (22 on alfuzosin, 12 placebo, p= 0.03).
Twenty six had a further episode of AUR or surgery
during the 6-year follow-up. Size of the prostate
assessed by digital rectal examination was the only
factor with a significant effect on the long-term out-
come [McNeill et al 2004].
Historically, the standard management of a man with
acute urinary retention (AUR) caused by benign pro-
static obstruction was early prostatectomy. Recent
data suggest that these patients can be managed with
alpha-blockers and that prostate size can predict
those who will subsequently require invasive thera-
py.
There is level 3 evidence that prostate size influ-
ences the success of TWOC.
IV. SURGICAL TREATMENT
Transurethral resection of the prostate is the gold
standard treatment modality for BOO [Madersbach-
er 2004]. Although effective, TURP has considerable
morbidity and also its overall cost per year is signif-
icant [ Rodrigues et al 2001]. Therefore, to minimize
unnecessary operations, predicting the outcome after
TURP is important. It has been shown that one third
of the men with LUTS do not have bladder outlet
obstruction and 5 to 35% of the patients with LUTS
do not have symptoms improvement after TURP
[Kanik et al 2004].
Javle et al [1998] studied 53 patients who were suit-
able candidates for TURP, assessed by IPSS,
uroflowmetry, ultrasonography (prostatic size and
residual urine volume) and pressure flow study
before and 3 months after surgery. TURP outcome
was significantly better in patients with unequivocal
obstruction and normal detrusor contractility. Treat-
ment failure occurred in 80% of patients with equiv-
ocal obstruction and impaired detrusor contractility,
and 100% of the unobstructed group. Urodynamic
grading of obstruction and detrusor contractility pre-
dicted treatment outcome with a sensitivity of 87%,
specificity 93% and positive predictive value of 95%
[Javle et al 1998]. Accordingly, Rodrigues et al
[2001] evaluated the TURP outcome in 253 patients
and observed that the entire obstructed group demon-
strated marked improvement compared to the nonob-
structed group (p = 0.018). In addition, the more
severely obstructed cases had greater clinical benefit
compared to those with little or no obstruction. Fur-
thermore, the nonobstructed subjects did not show
any clinical or subjective improvement after
transurethral prostatic resection (p = 0.24). Other
studies also show that performing urodynamics pre-
operatively helps to predict the degree of symptom
relief, decreasing bother and increasing well-being
after transurethral prostate resection [van Venrooij et
al 2002].
Van Venrooij et al [2002] re-evaluated 93 patients, 59
obstructed and 34 unobstructed or equivocal, 6
months after TURP and observed that reductions in
symptoms and bother in the unobstructed and equiv-
ocal men were about 70% of those reductions in the
obstructed men, thus indicating that equivocal and
unobstructed man also benefit from TURP [van Ven-
rooij et al 2003]. In a prospective study, 95 men
scheduled for TURP were assessed using the IPSS
and pressure-flow studies. It was observed that the
flow rate and degree of obstruction influenced the
improvement in flow rate but not in symptoms after
TURP. Symptom improvement was only related to
the initial level of symptoms. In a multivariate anal-
ysis, only age was an independent predictor of the
outcome variables of flow rate and symptoms [Hak-
enberg et al 2003].
The relationship among urodynamic parameters,
treatment outcome, symptom relief and patient satis-
faction are still the subject of controversy. The Inter-
national Prostate Consultation 2001 recommends
pressure-flow studies to evaluate patients, not only
before invasive therapy, but also when a precise
diagnosis of bladder outlet obstruction is important.
129
Detrusor underactivity (DUA) is a cause of lower
urinary tract symptoms in a significant minority of
men. Thomas et al [2004] followed 22 patients with
DUA who had a TURP with a mean follow-up after
surgery of 11.3 years and observed no significantly
sustained reductions in any symptoms. Comparison
with 58 age-matched patients with DUA who
remained untreated showed no significant advantage
of surgical intervention in the long-term evaluation.
On the contrary, there was more chronic retention in
those who had had surgery. Some authors have
investigated noninvasive methods for predicting
bladder outlet obstruction (BOO). Netto et al [1996]
compared IPSS with pressure-flow studies in 227
patients. Of the patients with a severe symptom score
92 (82.9%) had bladder outlet obstruction, compared
to 62 (53.4%) with a moderate symptom score. The
authors concluded that when the total IPSS is greater
than 28 or the “obstructive” symptom score is greater
than 15, a pressure-flow study can be avoided. Steele
et al [2000] demonstrated that the association of
IPSS, flow rate and prostate volume reliably predict-
ed BOO in patients with maximum urine flow rates
of 10 or less mL per second, prostate volumes of 40
g or larger and IPSS greater than 20. Conversely, the
combination of IPSS, flow rate and residual urinary
volume could not predict BOO in the study of Porru
et al [2002].
In summary, obstructed patients fare better after
surgery than non obstructed ones. Non invasive
methods are been evaluated and may have a role in
identifying BOO, avoiding the need for a full urody-
namic evaluation. These results strengthen the argu-
ment for a routine preoperative urodynamic assess-
ment (Level of evidence 3, grade of recommendation
B).
V. DETRUSOR OVERACTIVITY AND
BLADDER OUTLET OBSTRUCTION
The clinical presentation (OAB) of detrusor overac-
tivity (DO) is often similar to BOO. The prevalence
of OAB and DO increases significantly with age, in
a similar fashion to BOO. The rate of DO also
increases with increasing grade of obstruction, but
has no impact on other LUTS [Vesely et al 2003]. To
distinguish between BOO and DO, cystometry and
pressure flow study are necessary. In 162 patients
with LUTS and suspected BOO the urodynamic
evaluation demonstrated DO in 45% of the cases and
55% normal storage phase [Knutson et al 2001]. In
this study, patients with BOO and DO were older,
had a higher PSA, voided smaller volumes, and were
more obstructed. Prostate volume (measured by
transurethral ultrasound), Qmax, IPSS, and PVR did
not predict whether the patients had combined BOO
+ DO or not. Another study also observed that
patients with BOO and DO were older (p < 0.05) and
had a higher IPSS [Lee et al 2004].
After 3 months of treatment with doxazosin, 35% of
the patients with BOO and DO reported a symp-
tomatic improvement ([Lee et al 2004].In those
patients with no response to alpha blockers, 73%
improved after adding tolterodine. Acute urinary
retention developed in 3.3% treated with the alpha
blocker and anticholinergic drugs. Combination
treatment with an alpha-blocker (tamsulosin) plus an
anticholinergic (tolterodine) improves quality of life
in patients with bladder outlet obstruction and con-
comitant detrusor overactivity [Athanasopoulos et al
2003].
Detrusor overactivity (DO) in men with evidence of
bladder outlet obstruction due to benign prostatic
enlargement typically resolves in about two thirds of
patients after TURP. Twelve males (mean age 80
years,) with symptoms of OAB, were studied by 24-
hour monitoring of incontinence and videourody-
namic examination, before and after TURP [Gorm-
ley et al [1993]. Preoperatively, all patients showed
detrusor overactivity, which resolved postoperative-
ly in only one patient, a significantly smaller propor-
tion than that consistently reported in younger
patients. In the geriatric population, detrusor overac-
tivity and urgency incontinence may be the result of
age-associated changes and not secondary to
obstruction [Gormley et al 1993].
Detrusor overactivity can be classified in three pat-
terns: I - continual sporadic detrusor contractions; II
– a single episode of detrusor contraction occurring
at volume of < 160 mL with saline leaking around
the urethral catheter; III – a single episode of con-
traction at bladder volume > 160 mL [Kageyama et
al 2000]. Cystometric patterns can predict the post-
operative course. Twenty patients with BOO and DO
underwent TURP and cystometry was carried out
between 3 and 6 months after operation. Most pat-
tern I patients had persisting DO, whereas DO disap-
peared after surgery in pattern III patients, and pat-
tern II patients had an intermediate outcome.
For patients with the combination of severe BOO and
severe DO, no straightforward and safe treatment
exists due to the risk of persistent urgency inconti-
130
nence after TURP [Knutson et al 2002]. To predict the
outcome after TURP for persistent urgency inconti-
nence a biodegradable polyglycolic acid stent can be
used [Knutson et al 2002]. After this stent was insert-
ed into the prostatic urethra, 68% of the patients
noticed minor or no leakage and they later had a
TURP with good results. A biodegradable polyglycol-
ic acid stent may be a new tool to test the risk for post-
TURP urgency incontinence in patients with com-
bined BOO and severe OAB [Knutson et al 2002].
There is considerable level 3 evidence for the
advantages of perfoming urodynamics (UDS)
prior to surgical treatment in men presenting
with LUTS. UDS can predict failure by demon-
strating detrusor underactivity, the absence of
obstruction and the presence of DO as a cause of
LUTS.
VI. ACUTE URINARY RETENTION
AND SURGERY
In patients with acute urinary retention, pressure-
flow studies are useful in predicting the surgical out-
come. Old age, absence of detrusor overactivity,
inability to void during the pressure-flow study and a
maximum detrusor pressure < 20 cmH2O are associ-
ated with a poor outcome after prostatectomy
[Dubey et al 2001].
There is level of evidence 3, evidence for UDS pre-
dicting the outcome of TURP after AUR.
VII. PREDICTIVE/PROGNOSTIC
VALUE OF URODYNAMICS
A potentially important application for urodynamics
is prognosis and prediction of the outcome of treat-
ment or of no treatment. Adequate predictive power
might guide choice of the best treatment or might
help in counselling patients about the likelihood of
success of any given treatment (see Table 10). Since
the last consultation on “BPH” [Abrams et al 2001],
where it was suggested that urodynamics has some
but not strong predictive value for the outcome of
treatment, there has been considerable activity in this
field. Two recent reviews by Homma [2001] and
Clemens [2003 ]reinforce the view of the last con-
sultation. A third review [Bhargava et al 2004] con-
cluded that conventional urodynamic studies are use-
ful in providing preoperative information about
detrusor function, and to exclude patients less likely
to benefit from prostate surgery. Despite this, some
regard the need for performing urodynamic evalua-
tion routinely, before transurethral resection of the
prostate, as still controversial (Table 11). However,
the risk of operating on patients who will not benefit
has to be balanced against the risk of not operating
on patients who will benefit, although there may well
be treatment methods as beneficial but less risky than
TURP in unobstructed patients, such as drugs.
There has been considerable work on a variety of
“non-invasive” methods of diagnosing BOO; how-
ever, these require further work before one or more
can be recommended as routine tests. Level 3 evi-
dence exists for tests that will predict the outcome of
watchful waiting, drugs and a trial of catheter after a
retention episode (see Table 12). However, the
weight of evidence and the safe nature of these treat-
ments means that we will not yet give a recommen-
dation for UDS in these groups.
Although almost all evidence for the advantages
of UDS prior to invasive therapy for BPO is Level
3, the quantity of evidence allows a Grade B rec-
ommendation.
F. RESEARCH QUESTIONS
1. What components of filling/storage symptomolo-
gy are susceptible to intervention?
2. Do all interventions act on all components of fill-
ing/storage (ie desire to void, urgency, warning
time, urgency-free interval) in the same way?
3. Do successful treatments for overactive bladder
prolong deferment time, or simply prolong the
refractory period (ie decrease the number of
episodes of urgency) or can they eliminate urgen-
cy altogether?
4. Are there subsets of patients with overactive blad-
der, and do the subsets give any insight into patho-
physiology or response to treatment (ie presence
or absence of DO ; if DO, phasic or terminal)?
5. From what structure or structures does the sensa-
tion of urgency emanate?
6. Are there differences in the symptom of urgency
and its clinical features in men as contrasted to
women?

Table 11. Studies evaluating whether urodynamic studies (pressure flow) are necessary to predict the outcome of
transurethral resection of the prostate

Author Year Number of patients Are UDS necessary ?

Ignjatovic I. 1997 48 “Only in inconclusive cases”
Javle P. 1998 53 Yes
Pannek J. 1998 25 No
Rodrigues P. 2001 253 Yes
van Venrooij G.E. 2002 93 Yes
Porru D. 2002 45 Yes
Kanik E.A. 2004 54 No
Thomas A.W. 2004 22 Yes

Table 12. An overview of predicting outcome after therapy

Treatment Parameters Predictive Ability
Watchful Waiting Urodynamics PSA Severe obstruction and higher PSA predict
treatment failure
Medical Treatment Prostate volume Higher volume predicts treatment failure
Medical Treatment after Acute Prostate size Retained Smaller prostates, retained volume < 500 ml
Urinary Retention volume Qmax and Q max > 5 ml/s predict the ability to
void
Surgical treatment Urodynamics Obstruction predicts better results
Surgical treatment after Acute Urodynamics Age Old age, inability to void and Pdet < 20
Urinary Retention cmH2O predict a poor outcome
OAB + BOO Urodynamics Severe OAB predicts urinary incontinence
after TURP for BOO

131
7. Are there differences in the sensation of urgency
due to a known neurologic cause, as opposed to
those with so-called idiopathic detrusor overactiv-
ity?
8. Is there any correlation between prostate size,
pressure-flow indices of obstruction and prostate
configuration and any filling/storage or
voiding/emptying symptoms?
9. Does the symptom of urgency always imply detru-
sor overactivity? In other words, we need investi-
gations to look at what the pathophysiology of
urgency is. In some cases, when it is associated
with urgency incontinence, it is obviously related
to an involuntary detrusor contraction. In other
cases, it is clearly related to an involuntary detru-
sor contraction which can be aborted by inhibition
of the contraction exerted by various manouevres
at various levels, anywhere from the supraspinal
area to the local inhibitory reflex arch initiated by
pelvic floor musculature contraction. In some
instances, however, it does not seem related to
DO.
10. Can urgency exist as a discrete symptom during
filling/storage with no detrusor overactivity?
11. Can urgency really be initiated from receptors in
the urothelium? If so, what are these receptors
and what are the possible pharmacologic avenues
of inhibition?
12. Once urgency is established, does neuroplastici-
ty occur; in some patients, do these changes per-
sist even after the initial stimulus has been
removed? If so, are there any methods to reduce
or remove these abnormal pathways covered
under the term “plasticity” that leads to persis-
tence of the inappropriate sensation during fill-
ing/storage? The few experimental models which
exist are interesting but far from proof that these
occur clinically.
13. Can non-invasive methods of urodynamics pre-
dict outcome from treatment ?.

132

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 CHAPTER 5

Committee 6

New Medical Developments in the

Management of LUTS in Adult Men

Chairman
C. CHAPPLE (UK)

Members
W. ARTIBANI (ITALY),
R. BERGES (GERMANY),
S. KAPLAN (USA),
M. C.MICHEL (THE NETHERLANDS),
P. PERRIN (FRANCE),
D. PREZIOSO (ITALY),
M. TAKEDA (JAPAN),
T.L. TAMMELA (FINLAND),
P. TEILLAC (FRANCE)

Consultant
MO. BELAL (U.K)

143
 CONTENTS

A. INTRODUCTION D. PHYTOTHERAPY

B. HORMONAL APPROACHES I. INTRODUCTION

TO THE TREATMENT OF
BENIGN PROSTATIC II. SERENOA REPENS EXTRACTS
OBSTRUCTION
III. PYGEUM AFRICANUM
I. INTRODUCTION
IV. HYPOXIS ROOPERI /
II. THE ROLE OF STEROID PHYTOSTEROLS
HORMONES
V. URTICA DIOICA
III. ENDOCRINE CONTROL OF (STINGING NETTLE)
PROSTATE GROWTH
VI. POLLEN EXTRACT

C. ADRENOCEPTOR VII. PUMPKIN SEEDS

ANTAGONISTS (CUCURBITAE PEPONIS SEMEN)

I. INTRODUCTION VIII. CACTUS FLOWER EXTRACTS

(OPUNTIA)
II. UROSELECTIVITY
E. SYNTHETIC POLYENES
III. α1-AR SUBTYPES AND α1-AR
ANTAGONISTS IN THE I. MEPARTRICIN
TREATMENT OF BPH
F. NEW MEDICAL
IV. PHARMACOKINETIC DEVELOPMENTS IN THE
CONSIDERATIONS MANAGEMENT OF LUTS IN
ADULT MEN
V. CLINICAL STUDIES
I. OVERACTIVE BLADDER

II. NOCTURIA

REFERENCES

144
 New Medical Developments in the
Management of LUTS in Adult Men
C. CHAPPLE
W. ARTIBANI, R. BERGES, S. KAPLAN, M. C.MICHEL, P. PERRIN, D. PREZIOSO, M. TAKEDA,
T.L. TAMMELA, P. TEILLAC
A. INTRODUCTION
Lower urinary tract symptoms (LUTS) suggestive of
benign prostatic obstruction (BPO)—previously
referred to as “symptomatic benign prostatic hyper-
plasia (BPH)” —are common in the ageing male.
The term LUTS/BPO will be used in this review to
refer to the symptomatic man with LUTS presumed
to be associated with BPO. Approximately 25% of
men over 40 suffer from LUTS, and the prevalence
of this condition rises with age [1] (Figures 1-2).
Figures 1-2.
145
No LUTS [2] are disease specific and hence diag-
nostic of BPO. Therefore appropriate evaluation of
the symptomatic patient relies upon comprehensive
evaluation. This begins with a careful clinical histo-
ry augmented by the use of a validated symptom
score such as the International Prostate Symptom
Score (IPSS), combined with a physical examination
including a digital rectal examination and the subse-
quent appropriate use of a serum PSA and transrectal
ultrasonography, in appropriate patients to exclude
malignancy. The quantification of BPO relies on the
judicious use of urodynamics, incorporating a flow
rate, transabdominal ultrasound (for post micturition
residual volumes) and pressure flow studies in
selected patients; i.e. where the flow rate is inade-
quate or equivocal or there is a large residual (sug-
gesting possible detrusor underactivity); or in those
with other features in the history suggestive of a
more complex clinical situation (young age, previous
neurological history, failed surgery). A major prob-
lem in the contemporaneous literature is the absence
of an adequate internationally accepted and applied
definition for ‘BPH’; in the remainder of this review
since this is a review relating to clinical practice and
hence symptomatic patients presumed to have histo-
logical BPH which has resulted in bladder outlet
obstruction, hence the term LUTS/BPO will be used.
No more than ten years ago, surgery and watchful
waiting were the only widely accepted management
options for LUTS suggestive of benign prostatic
obstruction (LUTS/BPO). There has been an enor-
mous decline in the popularity of surgery and it is
now clearly apparent that medication is the most fre-
quently used treatment modality for LUTS/BPO.
Arguably, this has therefore been the most major
change in urological clinical practice in the last
decade. Operative intervention is increasingly con-
sidered rather radical from the patient’s perspective,
and not surprisingly many patients feel reluctant to
undergo surgery, and prefer a less invasive interven-
tion such as medical therapy, before contemplating
surgery. Indeed whilst few absolute indications for
surgery still exist, the number of patients undergoing
operations for BPO has decreased by around 60% in
the USA over the last decade [3] and similar trends
are evident across Europe. This trend has been
encouraged not only by increased patient awareness
of the availability of effective contemporary pharma-
cotherapy, but has also been encouraged by an
increased awareness of the complications of surgery,
in particular, that it can be associated with significant
morbidity such as irreversible incontinence and loss
of sexual function with subsequent impairment of a
patient’s quality of life.
Medical therapies to treat LUTS/BPO include α1-
adrenoceptor antagonists (which relax the smooth
muscle in the prostate), 5α reductase inhibitors (RIs)
(which shrink the glandular component) and phy-
totherapeutic agents which may have multiple mech-
anisms of action – often poorly defined,
Today, α1-adrenoceptor (AR) antagonists are the
most widely used medical therapy and are thought
directly and indirectly affect smooth muscle tone –
the neural or so called ‘dynamic’ component of BPO.
5α−RIs (finasteride, dutasteride) are another medical
treatment option for LUTS/BPO which reduce pro-
static mass and therefore the mechanical or ‘static’
component of BPO. In the last ten years four direct
comparative studies between α1−AR antagonists and
finasteride including their combination have been
published, the results of these and their implications
for therapy are discussed. Another group of com-
pounds, the phytotherapeutic agents act via various
mechanisms – many as yet poorly defined. This
review critically assesses the existing literature relat-
ing to the medical management of LUTS/BPO. We
will principally emphasise the literature based on
randomized controlled trials with rigidly enforced
selection criteria and acknowledge that this intro-
duces potential bias which may not reflect real life
clinical practice.
With any pharmacotherapy for LUTS/BPO there are
a number of general points which need to be consid-
ered:
1. Data on the long-term safety and efficacy of ther-
apy, patient compliance and therefore willingness
to continue with therapy is important. There is a
little literature base on placebo controlled studies
extending out beyond 3 months. Little prospective
146
long-term epidemiological work has been carried
out to date. Ultimately it is the perceived long-
term ‘clinical effectiveness’ of therapy (represent-
ing the synthesis between efficacy, safety and tol-
erability), which underlies the usefulness and
cost-effectiveness of any therapy. Adequate
prospectively acquired comparative epidemiolog-
ical data on the long term efficacy, tolerability and
compliance with pharmacotherapy for
LUTS/BPO does not at present exist.
2. Outcome measures and measures of disease pro-
gression (considered in detail by the Roehrborn
committee). Contemporary literature relating to
the evaluation of LUTS/BPO relates principally to
both the objective and subjective quantification of
voiding dysfunction, with limited reference to
storage disorders. Consequently, the evidence
based literature is anchored on objective assess-
ments utilizing flow rates, with a limited amount
of synchronous pressure/flow data, and subjective
assessment utilizing the International Prostate
Symptom Score (IPSS). The IPSS has 4 questions
relating to voiding symptoms and 3 to storage
symptoms. Review of the literature clearly reveals
that storage symptoms are those that are the most
troublesome to patients, although the IPSS does
not include the important symptom of urgency
incontinence. Clearly assessment of the impact of
therapy on both storage and voiding symptoms
must be addressed in future studies . This review
will consider the literature base on the use of phar-
macotherapy for both storage and voiding symp-
toms seen in the ageing male traditionally consid-
ered under the term LUTS/BPO.
3. Surprisingly, there is little robust information in
the existing literature base on the subject of cost
effectiveness and cost benefit. With the ageing of
the population world wide, it is essential that ade-
quate data on cost effectiveness and cost benefit
are accrued in the future. The results of such anal-
yses are likely to differ by country due to the dif-
ferent cost structure in various health care sys-
tems.
4. The subject of targeting of therapy based on mor-
phology has been raised in the past (See Figure 3).
5. The interpretation of data derived from studies is
not standardized:-
a. With reference to the criteria relating to baseline
values
b. Relating to the change from baseline values that
occurs during the placebo run in phase, prior to
starting “active “ therapy

Figure 3
c. In interpreting data , in particular it is important to
consider the ‘size of the treatment effect’ and
relate this to its clinical importance and relevance.
6. It is important prior to considering the potential
role of pharmacotherapy to note that the placebo
response in LUTS/BPO is notoriously high. For
example, the AHCPR report estimated a mean
probability of symptomatic improvement in 98,
88, 80, 57, 67, 74, 42 and 45% for open prostate-
ctomy, TUR-P, TUIP, balloon dilatation, finas-
teride, α1−AR -blockade, watchful waiting and
placebo [4]. Placebo effects have been reported
out to 5 years and post-treatment.
7. It must be remembered that untreated LUTS/BPO
does not necessarily progress, even to 13 years.
Indeed, Isaacs has reviewed the contemporary lit-
erature and provided a metanalysis of existing
studies to show that that 16% of those with LUTS/
BPO had no changes in symptoms and 38% were
better with a follow up ranging 2.6 - 5 years [5]. A
policy of watchful waiting is therefore a very
appropriate choice in patients with mild or moder-
ate symptoms. Whilst the probability of disease
progression in these patients remains uncertain,
nevertheless we know from studies to date that the
progression is slow[6]. It is (maybe) prudent for
patients to be periodically monitored to check that
there is no significant deterioration.
8. Since the efficacy of surgery is superior to phar-
macotherapy in the treatment of LUTS /BPO it is
often used as the “standard” against which to
compare other therapies. The 6th International
Consultation on “BPH” [7] has recommended that
the absolute indications for surgical intervention
in LUTS/BPO patients should be urinary reten-
147
tion, recurrent gross haematuria due to benign
prostatic enlargement (BPE), renal failure or blad-
der stones due to bladder outlet obstruction
(BOO), large bladder diverticula, or recurrent uri-
nary tract infections due to BOO. Where ‘relative’
indications for surgery exist, strict guidelines for
appropriate patient management have not yet been
established due to a lack of adequate follow-up
data and the heterogeneity of study results. Thera-
py should therefore be tailored to the individual
patient, taking account of their symptomatology,
comorbidity, and ‘informed’ expectations.
9. The existing literature base suggests that pharma-
cotherapy doesn’t lead to relief of obstruction as
assessed on pressure flow assessment.
RECOMMENDATIONS
There is a lack of :-
• Data on the long-term safety and efficacy of
therapy, patient compliance and therefore
willingness to continue with therapy is
important.
• Long-term data from real life practice
• Information on cost effectiveness and cost
benefit.
The interpretation of data derived from studies
is not standardized:-
• With reference the criteria defining baseline
values
• Relating to the change from baseline values
that occurs during the placebo run in phase
prior to starting active therapy
• In interpreting data:-
• it is important to consider the size of the
‘treatment effect’ and relate this to its
clinical importance and relevance.
• remember that there is a high placebo
response in BPH/LUTS.
• untreated BPO does not necessarily
progress
Level 1 Grade A

B. HORMONAL APPROACHES
TO THE TREATMENT OF
BENIGN PROSTATIC
OBSTRUCTION
I. INTRODUCTION
Clearly histological BPH is of heterogeneous aetiol-
ogy (hormones, ageing, growth factors and stromal-
epithelial interactions), in pathology (epithelium and
smooth muscle) and in pathophysiology (mechanical
obstruction, dynamic smooth muscle contraction and
detrusor function); still it is an androgen-dependent
process in which oestrogens may play a synergistic
role. Many treatment strategies to inhibit androgen
production/action in the prostate have been devised
and tested. Oestrogen inhibition is less well studied.
Of particular interest has been the possibility of hor-
monal approaches being able to reverse or even pre-
vent the hyperplastic process itself.
II. THE ROLE OF STEROID
HORMONES
The development of the BPH clearly requires a com-
bination of testicular androgens and ageing [8-10].
Although the role of androgens as the causative fac-
tor for BPH is debated, they undoubtedly have at
least a permissive role. Men castrated before puber-
ty do not develop BPH. Furthermore, patients with a
variety of genetic diseases that inhibit androgen pro-
duction, or androgen action, have impaired if not
absent prostatic growth. In addition, clinical studies
using a variety of androgen withdrawal therapies
have clearly shown that regression of established
BPE can occur. However, even castration (medical
or surgical) fails to restore the enlarged hyperplastic
gland to a normal volume. Once BPE is established,
androgen withdrawal alone may be insufficient to
return the number of prostate cells - especially stro-
mal cells - to normal. Partial involution may be
insufficient to relieve urodynamic obstruction.
The principal prostatic androgen is dihydrotestos-
terone (DHT). Although not elevated in BPE, DHT
levels in the prostate remain at a normal level with
ageing, despite a decrease in the plasma testosterone
[11]. DHT binds to specific receptors in the cyto-
plasm which translocate to the nucleus, where they
148
are critical to the role of androgens in stimulating
both normal and hyperplastic prostatic growth [10].
In other androgen-dependent tissues, for example in
penis, androgen receptor levels are down-regulated
after puberty, thus limiting further androgen-depen-
dent growth. This maintenance of androgen recep-
tors in the prostate permits androgen-dependent
growth even in the face of the age-related declines in
plasma testosterone [3]. Androgen receptor levels
may not be elevated in BPH or BPE [12,13] but they
are maintained at normal levels.
The rationale for androgen withdrawal in the treat-
ment of BPO is based upon two hypotheses. First, a
critical level of prostatic androgen is required to main-
tain the enlarged hyperplastic state. Second, androgen
withdrawal will result in significant involution in pro-
static size, thus reducing outflow resistance. However,
androgen withdrawal in humans does not appear to
return the hyperplastic prostate to a normal state. This
observation does not necessarily invalidate the andro-
gen hypothesis, but rather shows that the pathophysi-
ology of BPH/BPE is multifactorial.
Oestrogens may play a role in the pathogenesis of
BPH/BPE. In the dog, where oestrogens act syner-
gistically with androgens to produce experimental
BPH/BPE [14,15], oestrogen is involved in induc-
tion of the androgen receptor [16]. Oestrogen may, in
fact, “sensitise” the ageing dog prostate to the effects
of androgen [14]. The canine prostate contains an
abundance of high affinity oestrogen receptors. In
the dog, oestrogen treatment stimulates the stroma
causing an increase in the total amount of collagen
[17,18]. It was shown that the patterns of oestradiol-
17ß or DHT, plus oestradiol-17ß (E2) - induced
increases in activities of catechol oestrogen synthase,
and of other drug metabolising enzymes, were con-
sistent with the postulated free radical generation by
redox cycling of catechol oestrogen specifically in
the prostate [19].
The proposed role of oestrogens in the development
of human LUTS/BPO has been reviewed in detail
[20-22]. Serum oestrogen levels increase in men
with age, absolutely or relative to testosterone levels.
III. ENDOCRINE CONTROL OF
PROSTATE GROWTH
Testosterone is the principal circulating androgen. In
men, it is secreted primarily by the testes, with the
adrenal glands providing a minor contribution. To be
maximally active in the prostate, testosterone must
first be converted to DHT by the enzyme 5α-reduc-
tase. Studies in rats have demonstrated that at equiv-
alent androgen concentrations in the prostate, DHT
is about twice as potent as testosterone [23]. Howev-
er, DHT also has a greater affinity for the androgen
receptor than testosterone [24], permitting it to accu-
mulate in the prostate when circulating testosterone
levels are low [25]. This dual action of 5α-reductase
in androgen physiology explains the critical impor-
tance of this enzyme in stimulating prostate growth.
It also explains why DHT concentrations in the
prostate remain high in elderly men, in spite of the
fact that serum testosterone concentrations decrease
with age.
The concentration of testosterone in blood is about
10 times higher than that of DHT. From animal data,
it is clear that circulating testosterone and DHT enter
equally well into the prostate, and both can serve as
precursors for intraprostatic DHT [25]. However,
because of its low concentration in blood, DHT is
unlikely to have a major role as a circulating andro-
gen or as a precursor to intraprostatic DHT. In the
prostate, nearly all testosterone is converted to DHT
by 5α-reductase. Because testosterone is more abun-
dant in blood, circulating DHT has a minor role in
normal prostate physiology. This is best demonstrat-
ed in men with 5α-reductase deficiency, who have
near normal circulating levels of DHT, but small
prostate glands throughout life [26].
α-REDUCTASE INHIBITORS
1. 5α
The mechanism of androgen action varies in differ-
ent tissues, but in the majority of androgen target tis-
sues either testosterone or DHT binds to a specific
androgen receptor to form a complex that can regu-
late gene expression. DHT is essential for prostate
development and growth, the development of the
external genitalia and male patterns of facial and
body hair growth or male-pattern baldness. DHT is
synthesized from testosterone via the enzyme 5-α-
reductase [27-29].
Two isoenzymes of 5α-reductase have been discov-
ered [30] (Table 1). Type 1 is present in most tissues
of the body where 5α-reductase is expressed, and is
the dominant form in sebaceous glands. The overall
functional role of type 1 5 α-reductase is unclear,
because no one with a genetic deficiency of this
enzyme has been discovered. Its predominance in
sebaceous glands suggests that it has a role in the
development of acne. Female type 1 knock-out mice
have delayed parturition, indicating that this isoen-
149
zyme is critical for normal initiation of labour in
mice [31,32]. However, the relevance of this obser-
vation for humans is unknown, and such mice appear
otherwise normal. Type 2 5 α-reductase is the domi-
nant isoenzyme in genital tissues, including the
prostate.
Table 1. 5 α-reductase isoenzymes
Type 1 Type 2
Chromosome: 5 Chromosome: 2
KM = 10 µM KM = 0.4 µM
pH optimum = 6.5 - 9.0 pH optimum = 5.5
Skin, sebaceous glands, liver; Prostate and genital
organs;
lower level in the prostate lower levels in other
organs
Mutations: not known Mutations: Male
pseudohermaphroditism
The notion that 5α-RIs could be useful in the treat-
ment of androgen related disease emerged in the
early 1970’s as the genetic phenotype of 5α-reduc-
tase type 2 deficiency was described and the role of
DHT as the primary mediator of androgen action in
many tissues was demonstrated. The clinical pheno-
type of 5 α-reductase deficiency was first described
in the 1960s when it was termed “pseudovaginal per-
ineoscrotal hypospadias”. Affected subjects were
noted to have a 46 XY karyotype, normally differen-
tiated testes, male internal ducts, and ambiguous
genitalia. These patients have non-palpable prostates
as adults, despite otherwise normal virilisation at
puberty. Two patient cohorts with this inherited form
of male pseudohermaphroditism caused by deficient
DHT production were described by Walsh et al. [33]
and Imperato-McGinley et al. [34].
The structural features of steroids which are impor-
tant for inhibition of human foreskin 5 α-reductase
activity were first investigated by Hsai and Voight 25
years ago and their conclusions still form the basis
for understanding the structure-activity-relationships
in this class: a 3-oxo-∆4,5 structure is preferred as
well as a 17ß but not a 17α substituent [5,36]. A
number of compounds have been identified as
inhibitors of 5 α-reductase, including both steroidal
inhibitors, MK-906, finasteride [37], SKF 105687,
epristeride [38], dutasteride (a dual 5 α-RIs) [39].
Only finateride and dutasteride have reached clinical
practice.
a) Pharmacology and mechanism of action lipophily of dutasteride the two drugs differ in their
plasma elemination time. Dutasteride has a long
Boths finasteride and dutasteride lead to a reduction
plasma elemination half life for 5 (1-7) weeks under
of DHT in serum and prostate tissue due to the inhi-
steady state conditions [51] compared to 6-8 hours of
bition of the 5 α-reductase enzymes [40-45]. Finas-
finasteride [41,45]. This leads to the recommenda-
teride solely inhibits type 2 whereas dutasteride
tion that men receiving dutasteride therapy should
inhibits both type1 and type 2 enzymes [46].
not donate blood within 6 months of their last medi-
The type 2 isoenzyme is the predominant form in cation to avoid dutasteride contaminated blood being
genital tissue it is clear that the majority of DHT syn- donated to pregnant women.
thesized in the prostate derives from this enzyme.
As 5 α-RIs inhibitors reduce DHT concentration in
The same is known for serum DHT. About 80% of
the prostate, they also alter PSA concentration in
serum DHT synthesized derives from testosterone
serum of treated patient. It is now well established
conversion through type 2, only 20% are synthesized
form multiple clinical trials, that dutasteride and
by type 1 [47]. Reduction of serum DHT-concentra-
finasterde both lower PSA-values by 50% in mid
tion provided by dutasteride (90-93%) exceeds that
term {42,52]. However, after long term treatment,
of finasteride (70%) [48]. However, 5mg daily
the PSA lowering effect may slightly exceed that of
administration of finasteride reduces DHT-concen-
50% as shown from the prostate cancer prevention
tration in the prostate by 85-90% [49,50]. The
trial.
intraprostatic DHT-concentration at the therapeutic
0,5mg dose of dutasteride is unknown. In men treated with finasteride, multiplying PSA by
2 and using normal ranges for untreated men pre-
Finasteride and dutasteride are both 4-azasteroids.
serves the usefulness of PSA for prostate cancer
The chemical name of finasteride is N-tert-Butyl-3-
detection. Use of an upper limit of normal for last
oxo-4-aza-5α-androst-1-en-17ß-carboxamid with
PSA of 2.0 ng/ml for finasteride and 4.0 ng/ml for
dutasteride being an analogue thereof with a substi-
placebo yielded similar sensitivity (66% versus 70%,
tution of the tert-Butyl-group of finasteride through
P=0.6), higher specificity (82% versus 74%,
a 2,5-bis(trifluormethyl)phenyl-group in dutasteride
P<0.0001), and a higher likelihood ratio (3.6 versus
(Figure 4), making dutasteride a more lipophilic
2.7, P < 0.05) for finasteride than for placebo (53). In
agent with loss of type 2 enzyme specificity. Oral
addition it appears from data derived from PCPT that
bioavailability (finasteride: 63 %; dutasteride: 60 %)
due to volume reduction, treatment with 5 α-RIs
and time to reach maximum plasma concentrations
may enhance cancer detection.
are equal (finasteride: Tmax = 1-2 hours; dutasteride:
Tmax = 2-3 hours). Mostly due to the greater
To interpret an isolated PSA value in a man
treated with either agent for 6 months or more,
the PSA value should be doubled for compari-
son with normal values in untreated men.

b) Treatment for symptomatic LUTS suggestive of

BPO with 5 α-RIs, evidence from clinical trials:
1. FINASTERIDE
The efficacy and safety of finasteride in men with
LUTS/BPO has been demonstrated in several large-
scale, randomised, placebo-controlled Phase III stud-
ies consisting of a double blind duration between 1
and 5 years (Table 2) [54-65] and has been summa-
rized in numerous meta-analysise [66-84]. Addition-
al evidence comes from a large scale double blind
trial over 7 years comparing finasteride versus place-
bo and its ability to prevent prostate cancer [85].
Figure 4. Hormonal approaches to the Treatment of
Benign Prostatic Enlargement and Benign Prostatic
Obstruction

150
 Table 2. Randomized clinical phase III trials (with more than 100 pt. in each study arm) conducted with finasteride versus placebo for the treatment of symptomatic LUTS/BPH.
Studies comparing finasteride eather to other drugs or their combination, or trials conducted with less than 100 indiviuals randomized in each treatment arm, or study duration
below 1 year, are not listet. (pla.=placebo, fin.=finasteride, PV: prostate volume, Qmax, maximum urinary flow rate, pt.=score points).

151
 Table 2. Randomized clinical phase III trials (with more than 100 pt. in each study arm) conducted with finasteride versus placebo for the treatment of symptomatic LUTS/BPH.
Studies comparing finasteride eather to other drugs or their combination, or trials conducted with less than 100 indiviuals randomized in each treatment arm, or study duration
below 1 year, are not listet. (pla.=placebo, fin.=finasteride, PV: prostate volume, Qmax, maximum urinary flow rate, pt.=score points).

152
$ p<0,001 compared to placebo. * cohort originally randomized to placebo and switched to finasteride in open extension. § cohort originally randomized to finasteride and continued with finasteride in open
extension.

1. Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS et al.: The effect of finasteride in men with benign prostatic hyper-
plasia. The Finasteride Study Group. N Engl J Med. 327: 1185-91, 1992.
2. Stoner E: Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology. 43: 284-92; discussion 292-4, 1994.
3. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. The Finasteride Study Group. Prostate. 22: 291-9, 1993.
4. Andersen JT, Ekman P, Wolf H, Beisland HO, Johansson JE, Kontturi M, Lehtonen T and Tveter K: Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study.
The Scandinavian BPH Study Group. Urology. 46: 631-7, 1995.
5. Nickel JC, Fradet Y, Boake RC, Pommerville PJ, Perreault JP, Afridi SK and Elhilali MM: Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized con-
trolled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. Cmaj. 155: 1251-9, 1996.
6. Marberger MJ: Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. PROWESS Study Group. Urology. 51: 677-86, 1998.
7. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ et al.: The effect of finasteride on the risk of acute urinary retention and the
need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 338: 557-63, 1998.
8. Roehrborn CG, Bruskewitz R, Nickel JC, McConnell JD, Saltzman B, Gittelman MC, Malek GH, Gottesman JE, Suryawanshi S, Drisko J et al.: Sustained decrease in incidence of acute urinary retention
and surgery with finasteride for 6 years in men with benign prostatic hyperplasia. J Urol. 171: 1194-8, 2004
These studies demonstrated that treatment with
finasteride induced a significant decrease in symp-
tom score compared to placebo after one year of
treatment (-21% vs. –2% respectively [56,61,62],
which was confirmed in 2-year double-blind studies
(mean 17%, range 13-22% [58,63,64] and long-term
placebo-controlled trials over a study period of 4
years [86]. Three and 5 year open-label studies also
showed a reduction in symptom severity [83,87,88].
A meta-analysis of six RCTs demonstrated that the
effect of finasteride treatment on symptom improve-
ment depends on baseline prostate volume. Finas-
teride treatment is most effective in men with large
prostates ≥40gms [84].
Several RCTs have demonstrated that finasteride
reduces prostate volume by 20% (range 15-23%). All
placebo-controlled studies that lasted more than 1
year indicate that the prostate volume decreased dur-
ing the first year, with no further decrease thereafter
[56-58, 61-63, 86, 89]. In the open-label studies the
largest reductions in prostate volume were also noted
during the first year of finasteride therapy, leading to
a decrease of around 27% after 3 and 5 years
[83,87,88].
Several placebo controlled trials demonstrated that
finasteride induces an increase in Qmax varying
between 1,8 and 2ml [56-58, 62-64, 86, 89]. A five-
year open extension of an initial double-blind period
showed a mean improvement of approximately 13%
in Qmax in patients treated with finasteride 5mg/day
[88]. Similar to symptom improvement, the effect of
finasteride on Qmax also depends on prostate vol-
ume with finasteride being most effective in men
with large prostates [84].
Long-term placebo-controlled studies with finas-
teride in large number of patients have demonstrated
that finasteride reduces the occurrence of AUR from
2.7% to 1.1% in 4000 patients within 2 years [90],
from 2.5 to 1.0% in 2900 patients within 2 years [64]
and from 6.6% to 2.8% in 3040 patients within 4
years [59,86]. However, the frequency of AUR was
comparable to placebo (1%) in a one-year finasteride
trial in 750 patients [62]. Both in a community-based
and primary care study, the incidence of AUR was
similar between finasteride (0.6 and 0.2%) and
placebo (0.7 and 0.4%) [61,91]. In addition to that,
placebo-controlled clinical trials have shown that
finasteride reduces the risk for surgery from 6.5% (in
2109 placebo patients) to 4.2% in 2113 finasteride
patients treated for 2 years [90] and from 5.9% to
3.5% in 2900 patients treated for 2 years [64]. In the
4-year placebo-controlled Prostate longitudinal effi-
153
cacy and safety study (PLESS) study the risk for
surgery with finasteride was reduced from 10% to
5% [59,60].
Several studies have investigated the effect of finas-
teride on obstructive parameters in pressure flow
studies. In a 12 months placebo controlled trial,
Finasteride caused a moderate but significant
decrease (-8.1 cm. water) in detrusor pressure at
maximum flow (p <0.05 versus placebo) [89] Of the
finasteride treated cases 75% were obstructed and
25% equivocal at baseline compared to 67% and
33% respectively at month 12. These results were
confirmed by others where the percentage of patients
obstructed by the Abrams-Griffiths classification
decreased from 76.2% at baseline to 66.7% after 1-
year finasteride treatment and to 59.6% after 2
years[92]. In general, the urodynamic effects of
finasteride are only small or moderate in amplitude.
2. DUTASTERIDE:
The efficacy and safety of dutasteride in men with
symptomatic BPO has been demonstrated in an anal-
ysis of three, large-scale, randomised, placebo-con-
trolled Phase III studies each consisting of a double
blind phase of two years and an open extension of
additional 2 years (ARIA3001, ARIA3002 and
ARIB3003, Table 3). Date from these trials have
been summarized in 2 meta-analysis [93,94].
These studies have shown a significant but moderate
decrease in AUA-SI symptom score, a reduction in
prostate volume of about 25 %, and a marginal
improvement of maximum flow rate of 1 ml/s,
respectivly, during the double blind phases of 12
months [28,39,79-81]. At 24 months, to calculate the
primary outcome parameter “incidence of acute uri-
nary retention” results from these 3 trials were
pooled and a relative risk reduction of 0.43 over
placebo was demonstrated[95,96, 97-99].
The effect of dutasteride on symptom improvement
was the largest in patients with a large transition zone
index TZI [100]. also, men with prostates in the 2
upper TZI-tertiles had statistically significantly
fewer incidences regarding AUR and surgery. How-
ever, dutasteride did not have a differential effect on
transition zone volume (TZV) or peripheral prostate
volume (PV). Total PV, TZV and peripheral PV were
reduced by approximately 26% after 2 years of
dutasteride treatment [101].
In these trials, the effect of dutasteride on the emo-
tional consequences of LUTS/BPO was assessed
using a new questionnaire, the BPH-Psychological
 Table 3. Randomized clinical phase III trials conducted with dutasteride for the treatment of symptomatic LUTS/BPH.

154
 Table 3. Randomized clinical phase III trials conducted with dutasteride for the treatment of symptomatic LUTS/BPH.

155
1. Roehrborn C G, Boyle P, Nickel J C, Hoefner K and Andriole G: Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology.2002;60: 434-441.
2. O'Leary M P, Roehrborn C, Andriole G, Nickel C, Boyle P and Hofner K: Improvements in benign prostatic hyperplasia-specific quality of life with dutasteride, the novel dual 5alpha-reductase inhibitor. BJU Int.2003;92: 262-266.
3. Roehrborn C G, Marks L S, Fenter T, Freedman S, Tuttle J, Gittleman M, Morrill B and Wolford E T: Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology.2004;63: 709-715.
4. Debruyne F, Barkin J, van Erps P, Reis M, Tammela T L and Roehrborn C: Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol.2004;46:
488-494; discussion 495.
5. data made publik from investigator at www.gsk.com
6. Andriole GL and Kirby R. Safety and Tolerability of the Dual 5 alpha Reductase Inhibitor
Dutasteride in the Treatment of Benign Prostatic Hyperplasia. European Urology 44 (July 2003) 82-88
7. Efficasy of dutasteride and finasteride for the treatment of benign prostatic hyperplasia: results of the one year enlarged prostate indernational comparative study (EPICS). Gilling PJ, Tammela TL, van Erps P. Promed Urology, Tauranga, New
Zealand BJU Intl 95(s1): 12; Abstr: U051 2005
8. Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S and van Vierssen Trip O B: Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur
Urol.2003;44: 461-466.
Well-being (BPWB) questionnaire (5 questions on
embarrassment, frustration, feeling down, worry and
the desire that symptoms would improve). Compared
to placebo, 2-year dutasteride treatment statistically
significantly improved psychological well-being.
Improvements were significant from 12 months of
treatment onwards [102].
Of the 4,325 LUTS/BPO patients a total of 2,340
continued with open-label dutasteride treatment for
another 2 years. In the 1,188 patients who had
already received dutasteride in the placebo-con-
trolled study, the total AUA-SI further improved in
the open-label study. In the 1,152 patients who had
previously received placebo, there was also a further
improvement in total AUA-SI score when they were
switched to dutasteride in the open-label study. How-
ever at 4 years, the improvements in the original
placebo groups were, smaller than in the original
dutasteride group [99].
In addition to these published trials, one randomized
direct comparison trial of 12 months dutasteride ver-
sus finasteride including an additional 12 months
open extention phase has been conducted (ARI
40001, table 3), of which only safety data have been
published so far in peer reviewed journals [95], the
outcome data have been made public however on the
investigators web site and as abstract in one scientif-
ic conference [103]. In this trial, none of the outcome
parameters (change of prostate volume, Qmax and
AUA-SI) were statistically different in each treat-
ment group [104].
Furthermore, one small randomized, double blind,
placebo controlled trial of 6 months duration direct-
ly assessed obstructive parameters derived from
pressure flow studies. Neither the primary outcome
parameter pDet(Qmax) nor any of the other
secondary outcome parameters have been statistical-
ly significant compared to placebo. Again, data from
this trial were made public only on the investigators
web site [104].
c) Effect of 5α-reductase treatment on overall dis-
ease progression
The Medical Therapy Of Prostatic Symptoms
(MTOPS) study looked into the progression of 3047
LUTS/BPO patients who were treated for an average
of 4.5 years with placebo, the α1- AR antagonist
doxazosin, the 5α-RI finasteride and their combina-
tion [105]. The primary parameter in the MTOPS
study was the effect of treatment on overall clinical
progression defined as symptomatic progression
156
(defined as total I-PSS ≥ 4 points), or the develop-
ment of AUR, urinary incontinence, urinary tract
infections or urosepsis or renal insufficiency. Finas-
teride reduced the risk of overall clinical progression
from 16.6% (placebo) to 10.2% [105]
d) Side effects during treatment with 5 a-reductase
inhibitors
Finasteride and dutasteride are generally well toler-
ated with the most prevalent adverse events being
sexual function related, the highest incidence being
reported in the first year of therapy. 5α-RIs such as
finasteride and dutasteride induce adverse events
related to sexual dysfunction such as impotence,
decreased libido and abnormal ejaculation. However,
these side effects are rare compared to traditional
anti-androgen treatment and mostly appear in the
first year of treatment in up to 5 % of patients
(Tables 4 and 5).
However, the question has been raised about the
advantages of dutasteride over finasteride, especially
with regard to the risk of breast cancer induction and
of prostate cancer prevention or induction of high
grade prostate cancer.
There were 3 cases of breast cancer reported during
the ARIA3001/2 and ARIB3003 clinical trials, one
with placebo and two with dutasteride (after 10
weeks and 11 months of treatment) [119]. In the
MTOPS study there were 4 cases of breast cancer
with finasteride. In contrary, in the PLESS study
there were no cases of breast cancer with finasteride
and 2 with placebo, while in the Prostate Cancer Pre-
vention Trial there was 1 case of breast cancer with
finasteride and one with placebo [106,107]. Taken
together these data do not point to a major effect on
the risk of breast cancer induction with either drug.
The EPICS (Enlarged Prostate International Com-
parator Study) was a randomized double-blind
active-controlled trial that compared 12 months of
dutasteride and finasteride therapy in 27 European
countries.
The study was conducted to fulfill European regis-
tration requirements. The primary objective of the
study was the change in baseline prostate volume at
1 year. Safety and tolerability data were also
obtained. Patients with BPE or BPO (N= 1630) were
randomized to receive either dutasteride 0.5 mg once
daily (n=813) or finasteride 5.0 mg once daily
(n=817) for 12 months. Of the patients randomized,
1454 completed the 12-month double-blind phase
(719 dutasteride and 735 finasteride) [104].
Table 4. Study withdrawals and adverse events in randomized clinical phase III trials (with more than 100 pt. in each study
arm) conducted with finasteride versus placebo for the treatment of symptomatic LUTS/BPH. Studies comparing finasteride
eather to other drugs or their combination, or trials conducted with less than 100 indiviuals randomized in each treatment arm,
or study duration below 1 year, are not listed. (pla.=placebo, fin.=finasteride, AUR: acute urinary retention).

1. Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS et
al.: The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med. 327: 1185-91, 1992.
2. Stoner E: Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology. 43: 284-92;
discussion 292-4, 1994.
3. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. The Finasteride Study Group. Prostate. 22: 291-9, 1993.
4. Andersen JT, Ekman P, Wolf H, Beisland HO, Johansson JE, Kontturi M, Lehtonen T and Tveter K: Can finasteride reverse the progress of
benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH Study Group. Urology. 46: 631-7, 1995.
5. Nickel JC, Fradet Y, Boake RC, Pommerville PJ, Perreault JP, Afridi SK and Elhilali MM: Efficacy and safety of finasteride therapy for benign
prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two
year Study. Cmaj. 155: 1251-9, 1996.
6. Marberger MJ: Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter
study. PROWESS Study Group. Urology. 51: 677-86, 1998.
7. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ et al.: The
effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia.
Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 338: 557-63, 1998.
8. Roehrborn CG, Bruskewitz R, Nickel JC, McConnell JD, Saltzman B, Gittelman MC, Malek GH, Gottesman JE, Suryawanshi S, Drisko J et
al.: Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperpla-
sia. J Urol. 171: 1194-8, 2004.

157
Table 5. Study withdrawls and adverse events (AE’s) in the ARIA3001 randomized clinical phase III trial conducted with
dutasteride for the treatment of symptomatic LUTS/BPH representative for all ARIAxxxx studies. (As numbers for with-
drawals and AE’s do not differ in all other ARIAxxxx trials, they are not been listed here).

1. Roehrborn C G, Boyle P, Nickel J C, Hoefner K and Andriole G: Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2
(dutasteride) in men with benign prostatic hyperplasia. Urology.2002;60: 434-441.
2. O'Leary M P, Roehrborn C, Andriole G, Nickel C, Boyle P and Hofner K: Improvements in benign prostatic hyperplasia-specific quality of
life with dutasteride, the novel dual 5alpha-reductase inhibitor. BJU Int.2003;92: 262-266.
3. Roehrborn C G, Marks L S, Fenter T, Freedman S, Tuttle J, Gittleman M, Morrill B and Wolford E T: Efficacy and safety of dutasteride in
the four-year treatment of men with benign prostatic hyperplasia. Urology.2004;63: 709-715.
4. Debruyne F, Barkin J, van Erps P, Reis M, Tammela T L and Roehrborn C: Efficacy and safety of long-term treatment with the dual 5 alpha-
reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol.2004;46: 488-494; discussion 495.
5. data made public from investigator at www.gsk.com
6. Andriole GL and Kirby R. Safety and Tolerability of the Dual 5 alpha Reductase Inhibitor
Dutasteride in the Treatment of Benign Prostatic Hyperplasia. European Urology 44 (July 2003) 82-88
7. Efficacy of dutasteride and finasteride for the treatment of benign prostatic hyperplasia: results of the one year enlarged prostate
international comparative study (EPICS). Gilling PJ, Tammela TL, van Erps P. Promed Urology, Tauranga, New Zealand BJU Intl 95(s1):
12; Abstr: U051 2005
8. Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S and van Vierssen Trip O B: Alpha-blocker therapy can be withdrawn in the majority
of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur Urol.2003;44: 461-466.

Table 6. Summary of drug-Related Adverse Events after 1- appeared to be as safe as finasteride for patients with
year of dutasteride or finasteride [104] BPO.
Dutasteride Finasteride e) Effect of 5 αreductase inhibitors on BPE-related
0.5 mg daily 5 mg daily
haematuria and reduction of blood loss after TUR-P
N=813 N=817
Any adverse event 17% 20% Several studies have confirmed the benefit of finas-
teride in limiting hematuria arising from benign pro-
Sexual adverse
static enlargment [108-119]. The role of vascular
event % 11% 14%
Gynecomastia endothelial growth factor (VEGF), a potent stimula-
tor of angiogenesis, and microvessel density have
Impotence 7% 8% been independently evaluated in trying to establish
Decreased libido 5% 6% the mechanisms of the decreased bleeding observed
Ejaculation in patients treated with finasteride [120].
disorders 1% 1% Haemorrhage is a significant complication of TUR-P
Gynecomastia 1% 1% which may result in blood transfusions and increased
morbidity. The potential of finasteride to reduce
Although fewer drug-related sexual adverse events blood loss after TUR-P was evaluated in several
occurred in patients receiving dutasteride than finas- small randomised, placebo-controlled trials [121-
teride, there were no significant differences between 124]. In total 160 patients have been treated prior to
the two drugs (17% in the dutasteride group com- TUR-P. Some of these studies reached statistical sig-
pared with 20% in finasteride-treated patients). The nificance, mainly with the parameter Hb loss/g
most frequent drug-related adverse events were sex- resected tissue. Administration of finasteride prior to
ual in nature and are listed in Table 6. TUR-P might be useful to reduce blood loss and
related complications, especially for high-risk
Few adverse events led to patient withdrawal from patients. Similar data were shown when finasteride
the study (5% of dutasteride patients and 4% of was administered prior to open prostatectomy.
finasteride-treated patients) [104]. Thus, dutasteride (Fig.1) [57].

158
f) 5 alpha-reductase inhibitors and Prostate cancer
The normal range for serum PSA concentrations
applicable to men with BPO treated for 12 months
with a 5-mg daily dose of finasteride is shifted down-
ward by 50%. The range 0.0 to 4.0 ng/ml for untreat-
ed men with BPO corresponds to the range 0.0 to 2.0
ng/ml for finasteride-treated men. Hence, to interpret
serum PSA in a man who has been taking finasteride
for at least 12 months, the clinician can multiply the
serum PSA concentration by two and consider it as in
an untreated man with BPO. A serum PSA increase
of 1.0 ng/ml over a 6- to 12-month period in place-
bo-treated men with BPO, corresponds to a 0.5 ng/ml
increase from months 6 to month 12 among finas-
teride treated men with BPO [125].
In men treated with finasteride, multiplying PSA by
2 and using normal ranges for untreated men pre-
serves the usefulness of PSA for prostate cancer
detection. Use of an upper limit of normal for last
PSA of 2.0 ng/ml for finasteride and 4.0 ng/ml for
placebo yielded similar sensitivity (66% versus 70%,
P=0.6), higher specificity (82% versus 74%,
P<0.0001), and a higher likelihood ratio (3.6 versus
2.7, P < 0.05) for finasteride than for placebo [126].
Both agents reduce serum PSA values to similar
extents. Dutasteride reduces total serum PSA con-
centration by approximately 40% following 3
months of treatment and approximately 50% follow-
ing 6,12,and 24 months of treatment. This decrease is
predictable over the entire range of PSA values,
although it may vary in individual patients. Howev-
er, since the ratio of free to total PSA is not signifi-
cantly altered, PSA may still be used as a screening
tool for the detection of prostate cancer. To interpret
an isolated PSA value in a man treated with either
agent for 6 months or more, the PSA value should be
doubled for comparison with normal values in
untreated men.
Prostate cancer was diagnosed in 4.7% of men on
finasteride and 5.1% on placebo (P = 0.7). Elevated
PSA prompted diagnosis in 35% of cases on finas-
teride and 34% on placebo. The area under the
receiver operating characteristic curve for last PSA
was 0.84 on finasteride and 0.79 on placebo
(p=0.07). Use of an upper limit of normal for last
PSA of 2.0 ng/ml for finasteride than for placebo
[126].
However, finasteride also reduces serum PSA in men
with known prostate cancer [127,128]. In some
patients, ultimately diagnosed with prostate cancer,
the serum PSA did not increase in longitudinal fol-
159
low-up [129]. Little is known about the effect of
finasteride on unbound or free serum levels of PSA.
Such information would be important since percent-
age free PSA may substantially improve the cancer
specificity of PSA testing. The mean percent free
PSA (13 to 17% at baseline) was not altered signifi-
cantly by finasteride or placebo [130]. Certainly,
finasteride-induced suppression of the serum total
PSA does not appear to be a useful test to discrimi-
nate cancer from benign disease [127].
Since it has been suggested that, as DHT may be
implicated in the development and progression of
prostate cancer, then the use of a 5 α-RI might help .
The Prostate Cancer Prevention trial has randomised
18,882 men 55 years or older with a normal digital
rectal examination and a PSA <3.0ng/ml to finas-
teride 5mg/day or placebo treatment for 7 years and
compared the prevalence and grade of histologically-
proven prostate cancer. [106]. Prostate cancer was
detected in 803 of the 4368 men (18.4%) in the finas-
teride group with data for the final analysis as con-
trasted to 1147 of the 4692 men (24.4%) in the place-
bo group – a 24.8% reduction in prevalence. In con-
trast, tumours of Gleason grades 7-10 were more
common in the finasteride group, 6.4% of the 4368,
men as compared to 5.1% of the 4692 men on place-
bo. They concluded that finasteride prevents or
delays the appearance of prostate cancer but this ben-
efit and the improvement in urinary symptoms must
be weighed against sexual side effects. The apparent
increase in prevalence of prostate cancer in the finas-
teride treated group appeared to be related to an over
detection of high grade cancers due to prostate vol-
ume reduction in the finasteride treated group. Nev-
ertheless, at present, the results of this study remain
the subject of continuing controversy.
g) Finasteride and alpha-blocker combination
therapy
The initial experience with combining alpha-
blocker and 5-alpha-reductase therapy was not
promising. The effects of finasteride and
alpha-blockers have been compared in the Veterans
Affairs Co-operative Studies “Benign Prostatic
Hyperplasia” Study Group [131]. Terazosin (10 mg
daily), finasteride (5 mg daily) and the combination
of both drugs in 1229 men with LUTS/BPO was
assessed. The mean changes from baseline in the
symptom scores in the placebo, finasteride, tera-
zosin, and combination therapy groups at one year
were decreases of 2.6, 3.2, 6.1 and 6.2 points, respec-
tively (P > 0.001 for the comparisons of both tera-
zosin and combination therapy with finasteride and
with placebo). The mean changes at one year in the
peak urinary-flow rates were increases of 1.4, 1.6,
2.7 and 3.2 ml per sec., respectively (P <0.001 for the
comparisons of both terazosin and combination ther-
apy with finasteride and with placebo). Finasteride
had no more effects on either measure than placebo.
In the placebo group, 1.6 percent of the men discon-
tinued the study because of adverse effects, as did
4.8 to 7.8 percent of the men in the other three
groups. The authors concluded that in men with
BPH, terazosin was an effective therapy, whereas
finasteride was not effective and that combination
with terazosin was no more effective than terazosin
alone [131].
From this Veterans Affairs Cooperative Group
study, it could be concluded that one year of com-
bination therapy was no more effective than
monotherapy with an alpha-blocker in improving
symptoms or flow rates and substantially
increased the cost of treatment.
In a European study (randomized, double-blind,
multicenter trial involving 1051 patients with
LUTS/BPO, alfuzosin given at a dose of 5 mg twice
daily and finasteride 5mg once daily were compared
with both drugs combined for 6 months. Primary
efficacy criteria were symptomatic improvement
(International Prostate Symptom Score: IPSS) and
maximum flow rate (Qmax). Safety was assessed by
monitoring adverse events. In this 6-month trial,
alfuzosin was more effective than finasteride, with
no additional benefit in combining both drugs [132].
The PREDICT study randomized 1,089 patients to
placebo, finasteride, doxazosin, or the combination
for 1 year [133]. The results show that α1-AR
antagonists are more effective than finasteride in
reducing symptom score. In the studies which
involved a placebo, finasteride did not perfom better
than placebo, and the combination of finasteride and
an α1-AR antagonist was no more effective than the
α1-AR antagonist alone. Data from the PREDICT
study also suggested that finasteride was no more
efficacious than placebo when adjusting data for
prostate size using surrogate measures such as
prostate specific antigen and digital rectal examina-
tion [133].
The recently published Medical Therapy of Prostatic
Symptoms (MTOPS) study has changed our thinking
regarding combination therapy [105]. More than
3000 men were randomized to receive either place-
bo, doxazosin (alpha-blocker), finasteride (5α-RI),
or both. The principal outcome was clinical pro-
160
gression - defined as either an increase of at least 4
points in AUA symptom score, or urinary retention,
incontinence, renal insufficiency, or recurrent UTI.
Other dependent variables included maximum uri-
nary flow rate, serum PSA, and incidence of invasive
therapy. After a median 4.5 years of follow-up, the
median change in AUA symptom score was -4 for
placebo, -6 for doxazosin, -5 for finasteride, and -7
for combination therapy. All differences were statis-
tically significant. Clinical progression, which was
mostly due to increasing AUA symptom score,
occurred in 4.5 per 100 patients per year in the place-
bo group. Doxazosin and finasteride reduced the risk
of progression by 39% and 34% respectively, and
while significantly different from placebo, the differ-
ence between the two agents was not. Combination
therapy caused a 66% risk reduction of clinical pro-
gression compared to placebo, and this was signifi-
cantly different from the other three arms.
Secondary analysis showed that prostate volumes
greater than 40cc and serum PSA >4.0 ng/ml pre-
dicted a better response to combination therapy.
Looking specifically at AUR , the risk reduction for
doxazosin, finasteride, and combination therapy was
31%, 67%, and 79% respectively.
Finasteride and combination therapy also reduced
the risk of invasive procedures by 64% and 67%
respectively, but there was no significant effect of
doxazosin compared to placebo. We must of course
weigh against these findings the additive side effect
profile accruing from combination therapy.
The following conclusions can be drawn from the
MTOPS data:
1 Combination therapy is the most effective medical
treatment to produce symptomatic improvement
and to slow disease progression. Although this
conclusion is different from previous trials of
combination therapy, the data is actually consis-
tent. Similar to the Veterans Affairs Cooperative
Group study, at one year follow-up in the MTOPS
trial there was no difference in symptoms between
finasteride and placebo or between combination
therapy and doxazosin alone. However, with
longer follow-up to four years we see the effect of
finasteride compared to placebo, and the overall
benefit of combination therapy.
2 An alpha-blocker alone can reduce clinical pro-
gression, as defined by symptom deterioration.
Although it delayed the time to acute urinary
retention, doxazosin did not significantly decrease
 its cumulative incidence as compared to placebo,
nor did it have any effect on the incidence of sur-
gical procedures.
3 With a clinical progression rate of 4.5 per 100
patients per year in the placebo group, we can
accurately counsel patients with LUTS that over 5
years their risk of progression is approximately 20
percent without treatment.
4 Finally, although doxazosin and finasteride are the
best tested agents in combination therapy and, in
the absence of any head-to-head trials comparing
different agents used in combination,we can con-
clude that all alpha-blockers and 5α-RIs should be
equally effective in combination [134].
5 Preliminary evidence suggests that histological
examination of prostatic biopsies taken in this
study have shown the presence of chronic inflam-
matory schanges within the prostate which may
have a significant impact on clinical outcome,
(Roehrborn CG personal communication)
Comments
Overall, the results of 5α-reductase therapy have
fallen somewhat short of initial expectations, proba-
bly because the following obstacles will be faced by
any inhibitor of 5α-reductase:
• heterogeneity of the disease;
• coincidental concurrence of human BPO and
symptoms unrelated to prostatic obstruction ;
• the role of residual, or rising testosterone levels in
maintenance of prostate size;
• the possibility that the essential developmental
role of DHT in the prostate is not mirrored by
regression of theenlarged, hyperplastic gland on
removal of DHT support.
Randomised, placebo-controlled trials have demon-
strated the benefit of both finasteride and dutasteride
over placebo in men with LUTS/BPO due to clinical-
ly enlarged prostates secondary to BPH. In the over-
all study population, the magnitude of benefit is
modest; however, approximately one-third of
patients have clinically significant improvement. The
drug is less effective in men with LUTS/BPO without
significantly enlarged prostates.
Given their minimal side-effects, both finasteride
and dutasteride should be considered to be an
acceptable treatment option in men with clinically
enlarged prostates. Studies have suggested durabili-
ty of initial treatment response out to nearly six
years. Available data show that finasteride has a pre-
161
ventative influence on the progression of the disease
over time. It significantly reduces clinically signifi-
cant endpoints such as acute urinary retention and
surgery. To date, there are no data to suggest that
finasteride masks the detection of prostate cancer
but it may affect its incidence The combined block-
ade of both type 1 and 2 5 ?-reductase has not shown
additional clinical benefits in the pathophysiology of
benign prostatic hyperplasia relative to the inhibi-
tion of only one type of the enzyme.
RECOMMENDATIONS:
• Randomised, placebo-controlled trials have
demonstrated the benefit of 5α α-RIs over
placebo in men with clinically enlarged
prostates above 30- 40cc secondary to BPH.
(Level 1 Grade A)
• Randomised, placebo-controlled trials have
demonstrated the benefit of 5αα-RIs over
placebo in men treated for LUTS/BPO
(Level 1 Grade B)
• Placebo controlled data for finasteride out to
over 5 years and for dutasteride out to 2
years have confirmed the durability of the
treatment response. (Level 1 Grade A)
• The efficacy and tolerability of both finas-
teride and dutasteride is identical. (Level 1
Grade B)
• The magnitude of systematic benefit is
greater than placebo but consistently small-
er than seen with α1-AR antagonists. (Level
1 Grade A)
• Other aspects of therapy relating to preven-
tion of progression in volume increase,
reduction of the risk of retention and the
development of cancer, are considered by
other committees.
• The efficacy of combination therapy with
α-RIs and α1-AR antagonists is greater
5α
than either agent alone. (Level 1 Grade B)
• The clinical utility of this combination ther-
apy should take account of the balance
between cost efficacy and additional side
effects. (Level 1 Grade B)

• If one assumes a class effect:
• all combinations of an α1- AR and a
5 α-RI would be equally effective.
• the combination of doxazosin and finas-
teride is the best tested regarding safety
and efficacy
2. ANDROGEN WITHDRAWAL
True antiandrogens, which block the action of testos-
terone and DHT in the prostate, should be distin-
guished from agents that impair androgen produc-
tion. Classification of treatment by mechanism of
action is of some value in predicting relative side-
effects: interventions that impair Testosterone pro-
duction are usually associated with sexual dysfunc-
tion. Certain hormonally-active compounds used for
the treatment of BPO exhibit both anti-androgen and
androgen ablation activities.
a) Surgical Castration
Recommendation: Surgical castration may be effec-
tive for the treatment of BPO, but the invasiveness
and risk of the procedure preclude its use.
b) Medical Castration: GnRH analogues
Recommendation: GnRH therapy has shown benefit
in the treatment of BPO. However, cost, sexual dys-
function, decreased bone density and hot flashes pre-
clude the use of these drugs in routine cases.
c) Progestational Agents
Recommendation: Progestational agents have evi-
dence of efficacy for the treatment of BPO. One clin-
ical trial shows that one agent in this class (CMA)
has an efficacy similar to finasteride. However,
undesirable androgen withdrawal side effects (e.g.
impotence, decrease of bone density) limit the
widespread use of progestational agents.
d) Androgen Receptor Antagonists
Recommendation: Data strongly suggest that the
side-effects of current androgen receptor antagonists
(gynaecomastia, hepatotoxicity, diarrhoea) outweigh
any potential benefit in the treatment of BPO.
3. OESTROGEN WITHDRAWAL
There is evidence which suggests that oestrogens
play some role in the development of BPH. The rel-
ative importance of oestrogens compared to andro-
gens or other growth stimulatory factors in the
prostate is uncertain. A variety of preliminary clin-
cial studies have been conducted to determine
162
whether anti-oestrogen-like approaches have clinical
utility in the treatment of BPO. Only aromatase inhi-
bition, however, has been studied in detail.
RECOMMENDATION:
The rationale for aromatase inhibitor therapy
in the treatment of BPO is based solely on ani-
mal studies. Randomised clinical trials have
failed to show benefit. Therefore, aromatase
inhibitor therapy is currently not a recom-
mended treatment option.
C. ADRENOCEPTOR
ANTAGONISTS
I. INTRODUCTION
The effect on smooth muscle tone is dependent on
the release of noradrenaline (NA) from adrenergic
nerves, the amine stimulating α1-ARs on smooth
muscle of the prostatic stroma, bladder neck and ure-
thra. Storage symptoms, on the other hand, have
been associated with bladder dysfunction secondary
to outlet obstruction. However, there is no convinc-
ing evidence for direct links between the size of the
prostate, BOO, and LUTS; [135].
α1-AR antagonists improve both LUTS and flow
rate in BPH patients [136]. Since prostatic and ure-
thral α-ARs are considered to mediate the dynamic
component of obstruction, and since a direct rela-
tionship between the amount of prostatic smooth
muscle and dynamic obstruction (as assessed by the
response to α1-AR blockade) has been demonstrated
[137], it is logical to assume that these receptors
mediate at least part of the symptoms.
On the other hand, many patients who have under-
gone prostatectomy, which should relieve obstruc-
tion, still experience persistent storage symptoms
[138]. Since α1--AR antagonists can have beneficial
effects on the LUTS even in the absence of outlet
obstruction [136], mechanisms outside the prostate
involving α1--ARs may be involved in the patho-
genesis of, particularly storage symptoms. LUTS can
be caused by a number of factors (Table 7) and
beside the prostate, there are several possible sites of
action of α-AR antagonists (Table 8).
Table 7. Possible mechanisms for the development of
LUTS /BPO
• Anatomical and neural changes in the smooth muscle of
the LUT (hypertrophy, denervation)
• Alterations in the bladder urothelium affecting afferent
neurotransmission
• Altered central processing of afferent information
• Defects in efferent neurotransmission
Table 8. Possible sites of action of α-AR in BPO
• Prostatic stroma – smooth musculature
• Detrusor, trigone, urethra smooth musculature
• Detrusor, trigone, urethra urothelium
• Ganglia
• Spinal and/or supraspinal structures within the central ner-
vous system
Meanwhile, however, it has become clear that the
effects of alpha-blockers on BOO are moderate at
best, [139] and are insufficient to explain the
improvement in symptoms, particularly storage
symptoms. Therefore, newer concepts highlight a
possible involvement of α1-ARs in the bladder
and/or spinal cord as possible mediators of α-block-
er-induced symptom relief [140, 141] but the specif-
ic mechanisms of such effects need to be defined.
Moreover, it is clear that the alpha-blocker effects on
BOO are mediated predominantly, if not exclusively,
by α1A-ARs; while it has been speculated that clin-
ical effects on the bladder and spinal cord could
involve a1D-ARs: this needs to be verified.
Further information relating to the recent evi-
dence relating to pharmacological mechanisms
are reviewed in the specific committee dealing
with pharmacology
II. UROSELECTIVITY
Drugs which decrease outlet resistance, without
affecting blood pressure, would obviously be of ther-
apeutic interest. There have been several reports of
the effects of α1-AR antagonists decreasing urethral
resistance in animals [142]. Indeed, such animal
models can be used to determine the potency and
selectivity of α1-AR antagonists for the prostate
163
over other parameters such as blood pressure. In sev-
eral such models, the potency order of effects of var-
ious α1-AR antagonists on the pressures in the ure-
thra has been defined. This has then been related to
blood pressure changes in the same animal [142].
Although such models may predict effects on, for
example, flow rate in humans, they also have limita-
tions, and the results may be both species and assay-
dependent [143]. Thus, results obtained in one ani-
mal species may differ from those obtained in anoth-
er, and it has not been established which animal
model is the most relevant for effects in humans.
Since side effects, that may be dose-limiting clinical-
ly, are not always cardiovascular, but may be from
the central nervous system, e.g, drowsiness and
dizziness, and since such effects cannot always be
studied in animals, animal models may not ade-
quately predict clinical usefulness.
Considering this, a clinically relevant definition of
uroselectivity can only be made in man. Such a def-
inition of uroselectivity is the one previously sug-
gested by the 3rd International Consultation on
Benign Prostatic Hyperplasia [144]: ”desired effects
on obstruction and LUTS related to adverse effects”.
III. α1-AR SUBTYPES AND α1-AR
ANTAGONISTS IN THE
TREATMENT OF BPH
The efficacy of α1-AR antagonists for improving
flow rate and for treatment of LUTS in BPH patients
has been well documented [136]. Among the α1-AR
antagonists currently in common clinical use for
treatment of BPH, only tamsulosin has some selec-
tivity for the α1A-AR subtype [142. Whether this
pharmacological selectivity has clinical relevance,
remains to be determined, in particular, If the
prostate, bladder, and spinal cord are important sites
for α1-AR antagonists, it seems that α1A-and/or
α1D-ARs should be more important than α1B-ARs.
This may give a therapeutic advantage for drugs with
relatively low affinity for α1B-ARs, since these
receptors seem to be important for regulation of
blood pressure. Whether an α1-AR antagonist
should have a preference for α1A- or α1D-ARs, or
both, is still a matter of speculation. Since it appears
that α1A-AR antagonism is more important for flow
rate increase than for symptom relief (see above),
and the role for α1D-AR antagonism for symptom
relief has not been defined, the most advantageous
subtype selectivity profile for an α1-AR antagonist
is yet to be established.

IV. PHARMACOKINETIC
CONSIDERATIONS
The pharmacokinetic characteristics (absorption, dis-
tribution, metabolism, excretion) of the different α1-
AR antagonists may contribute to differences in
effects and side effects. However, this is a field that
has been incompletely explored. The rationale for
introducing controlled (slow) release preparations is
to change the absorption characteristics to obtain a
sustained plasma concentration over 24 h, which can
reduce dosing to once daily and/or improve tolera-
bility (avoiding high peaks in plasma concentration).
In recent years, new formulation of alfuzosin (alfu-
zosin XL) [145], doxazosin (doxazosin GITS) [146
and tamsulosin (tamsulosin OCAS) [147] (have been
introduced. Although the new formulations tended to
have maintained efficacy but a somewhat better tol-
erability, the clinical relevance of such improve-
ments remains unclear. Differences in distribution
between the α1-AR antagonists may be of impor-
tance. If effects on the CNS are responsible for some
of the adverse effects, e.g., asthenia and dizziness,
these effects should be more frequent with drugs
which have good penetration into the CNS. Howev-
er, this has not been established. Drugs which seem
to have a high diffusion into prostatic tissue [148,
149] (should be expected to have better effect on
flow rate than other α1-AR antagonists: this does not
seem to be the case.
V. CLINICAL STUDIES
Since the last review carried out by this Committee
there have been few new developments of major
clinical importance in the field of α1-AR antagonist
therapy for BPO. The following will focus on aspects
which have evolved since the 5th “BPH” consulta-
tion report [150] , i.e. the effects of new formulations
of known alpha-blockers, comparative studies
between alpha-blockers and the long-term effects of
alpha-blockers.
It has been suggested that in patients with both
LUTS/BPO and hypertension, non-α1-AR subtype
selective agents would be advantageous, since both
diseases could be treated by one drug. Information
on the long-term treatment of hypertension with an
α1-AR antagonist [151], has led to α1-AR antago-
nists not being recommended as a first line treatment
164
for hypertension in several countries. However, this
should not influence treatment of BPO. In patients
with BPO and hypertension, α1-AR antagonists
remain a first-line treatment for BPH. However,
associated hypertension and cardiovascular diseases
should be treated independently according to estab-
lished guidelines.
Blood pressure reductions, particularly orthostatic
hypotension, dizziness and asthenia are typical side
effects in the use of alpha-blockers. They involve
predominantly α1-ARs in blood vessels and in the
central nervous system. Both tissues express all three
α1-AR subtypes. Hence, selectivity for one or more
of them may contribute somewhat to tolerability of
some alpha-blockers, but pharmacokinetic aspects
also appear to play an important role. These include
drug enrichment in urogenital tissues [149, 152] as
well as smooth pharmacokinetic profiles (long time
to reach maximal plasma concentrations, small ratio
between maximal and trough plasma concentrations,
long half lives) seen with modified/ extended/slow
release formulations [146,153, 154].
The present review focuses on the four alpha-block-
ers which are globally available for the treatment of
BPO, i.e. alfuzosin, doxazosin, tamsulosin and tera-
zosin. Other alpha-blockers, which are available
only in few countries (e.g. indoramin or naftopidil),
have only been tested on a limited scale (e.g. pra-
zosin) and/or those that are still in clinical develop-
ment (e.g. sidolosin), will not be discussed in detail.
New formulations, allowing agents to be prescribed
once a day, have been developed. It has been sug-
gested that some of these formulations have provid-
ed a better side-effect profile because of a more con-
trolled release of agents within the gastrointestinal
tract. For several of the above drugs, new formula-
tions with smoother pharmacokinetic profiles have
been introduced in recent years. Alfuzosin was orig-
inally marketed in a thrice daily immediate release
formulation, since then twice daily sustained release
(alfuzosin SR) [155] and once daily extended release
(alfuzosin XL) [154] forrmulations have been intro-
duced. In addition to the original once daily immedi-
ate release formulation of doxazosin, a once daily
gastrointestinal therapeutic system (GITS) formula-
tion with slower release (doxazosin GITS) has been
introduced [146]. While the originally marketed
once daily modified release tamsulosin version
already represented a modified release formulation, a
once daily oral controlled absorption system formu-
lation with even slower release (tamsulosin OCAS)
has been introduced [147]. The new formulation of
alfuzosin has involved an increase in the total rec-
ommended daily dose (from 7.5 to 10 mg), whereas
the recommended total daily dose of doxazosin (4-8
mg) and tamsulosin (0.4 mg) has not changed. Ran-
domized, double-blind studies directly comparing
the old and the new formulations have demonstrated
that they did not alter the overall efficacy of alfu-
zosin [45], doxazosin [146] and tamsulosin [147].
The extent of improvement, even where it reached
statistical significance, was only small and may not
be noticeable clinically in the majority of patients.
The efficacy of alpha-blockers in relieving LUTS
has primarily been assessed by their ability to reduce
validated symptoms scores (most often the Interna-
tional Prostatic Symptom Score, IPSS) and by their
ability to increase the maximum free urine flow rate
(Qmax). Multiple placebo-controlled, randomized,
double-blind studies, of adequate size and duration,
exist for all four major alpha-blockers (i.e. alfuzosin,
doxazosin, tamsulosin and terazosin). The outcomes
of these studies have been summarized in a system-
atic review [156]. which has recently been updated
[157]. Moreover, the efficacies of tamsulosin [158]
and of terazosin [159] have been reviewed by the
Cochrane Collaboration. (Table 9, 10 and Figures 4
and 5).
The aggregate of the data yields level 1 evidence to
support the efficacy of alpha-blockers as a class in
relieving both storage and voiding symptoms associ-
ated with BPO. A comparison of the results from
placebo-controlled RCT’s and open-label studies
suggests that the RCT’s may somewhat underesti-
mate the true efficacy of the alpha-blockers, possibly
due to the symptom improvement occurring during
the single-blind placebo run-in phase, preceding ran-
domisation, in most studies [160].
Indirect comparisons of placebo-controlled studies
for the individual alpha-blockers had already indicat-
ed that they have similar efficacy when adequately
dosed [156,157]. In this context, adequate dose
refers to 2.5 mg thrice daily for the immediate
release formulation of alfuzosin, 5 mg twice daily for
the sustained release formulation of alfuzosin, 10 mg
once daily for the extended release formulation of
alfuzosin, 4-8 mg once daily for both the immediate
release and the GITS formulation of doxazosin, 0.4
mg once daily for both the modified release and the
OCAS formulation of tamsulosin and 5-10 mg once
daily for terazosin. Somewhat smaller doses are used
for some of these drugs in several Asian countries,
but little published information supports the ratio-
165
nale for lower dosing in specific ethnic groups. Mul-
tiple direct comparative studies have confirmed the
similar efficacy of the various alpha-blockers. Thus,
direct comparative studies have been reported for
alfuzosin vs. doxazosin [161], alfuzosin vs. tamsu-
losin [162, 163], alfuzosin vs. terazosin, [163] doxa-
zosin vs. tamsulosin [164], doxazosin vs. tera-
zosin[165] and tamsulosin vs. terazosin [166, 167,
168, 163]. While some studies, often involving small
patient numbers, have reported greater efficacy of
one drug compared to another [161, 164, 167], the
majority of studies confirms similar efficacy for all
of the alpha-blockers in relievingLUTS.
Several direct comparative clinical studies have
demonstrated similar tolerability of various formula-
tions of alfuzosin and the modified release formula-
tion of tamsulosin [162,163], and this was supported
by clinical pharmacology studies into their vascular
effects [169]. In contrast, several direct comparative
clinical studies have demonstrated greater tolerabili-
ty with tamsulosin than with terazosin [166, 167,
168]; a direct comparative study between tamsulosin
and doxazosin did not report such differences but
may have had insufficient sensitivity due to small
patient numbers [164]. The differences in tolerabili-
ty between tamsulosin and terazosin appear to relate
to a differential effect on the vasculature. This is sup-
ported by several clinical pharmacology studies
demonstrating a greater vascular antagonism and/or
greater orthostatic reactions with terazosin than with
tamsulosin [170, 171, 172]; similar differences were
also reported for the comparison of doxazosin with
tamsulosin [173]. A recent systematic review of car-
diovascular side effects of alpha-blockers in high-
risk patients (i.e. those with cardiovascular comor-
bidities, anti-hypertensive comedications or con-
comitant use of phosphodiesterase inhibitors) also
indicates greater tolerability of tamsulosin as com-
pared to doxazosin and terazosin [174]. A notable
exception from the above is the phenomenon of
abnormal ejaculation. RCT’s have repeatedly report-
ed this more frequent with tamsulosin than with
placebo; its incidence is considerably less than 10%
at 0.4 mg tamsulosin but may increase with 0.8 mg
tamsulosin [175,176, 177]. On the other hand, no
such differences have been seen in the placebo-con-
trolled studies with other alpha-blockers. Neverthe-
less, two direct comparative studies between tamsu-
losin and alfuzosin involving more than 100 patients
per group each have failed to detect significant dif-
ferences in abnormal ejaculations between the two
drugs [162]. While it had originally been assumed
that the abnormal ejaculation seen with tamsulosin
Table 9. Placebo-controlled studies with α1-AR antagonists

@: number of randomized patients in the placebo and presented dosage groups

#: for Qmax after 12 weeks
&: IR: immediate release, SR: sustained release, XL: prolonged release, GITS: gastrointestinal therapeutic system
*: pooled analysis

166
A B

C D

Figure 4. Effect of α1-AR antagonists on total symptom score (a,b) and Qmax (c,d) in placebo-controlled studies. Total num-
ber of patients in all studies included for total symptom score: alfuzosin n=2,208; terazosin n=3,229; doxazosin n=3,947; tam-
sulosin n=1,331; Qmax: alfuzosin n=2,208; terazosin n=3,393; doxazosin n=1,777; tamsulosin n=2,066.

A B

Figure 5. Percentage of patients that discontinued due to AEs (4a,b)in placebo-controlled studies

167
Table 10. Direct-comparative studies between α1-AR antagonists

*: The dose for alfuzosin was titrated from 2.5 mg b.i.d. during the first 2 weeks to 2.5 mg t.i.d. during the last 10 weeks where-
as the 0.4 mg dose of tamsulosin was used throughout the whole study without dose titration.
**: The dose for terazosin was titrated from 1 mg for the first week, 2 mg for the second week and 5 mg from the third week
onwards.
#: Administration according to prescribing information in most European countries: terazosin was administered in the evening
after dinner and titrated from 1 mg for the first week, 2 mg for the second week and 5 mg for 1 day whereas tamsulosin was admin-
istered after breakfast and the 0.4 mg dose was used throughout the whole study without dose titration.
##: The dose for alfuzosin was titrated from alfuzosin 2.5 mg b.i.d to alfuzosin 5 mg b.i.d. for the remainder of the study. Tam-
sulosin was administered at 0.4 mg o.d. throughout the study without dose titration.
@: placebo-controlled

represents retrograde ejaculation, recent studies
demonstrate that it rather represents a reduced ejacu-
latory volume [178, 179]; the functional mechanism
underlying this, i.e. whether it is α1-AR-mediated,
remains unclear.
The present data indicate that the general tolerability
of α-blockers is good but somewhat better for those
used solely in the treatment of LUTS/ BPO (i.e. alfu-
zosin and tamsulosin) than for those primarily devel-
oped for hypertension treatment (i.e. doxazosin and
terazosin), primarily due to reduced cardiovascular
side effects (level 2 evidence). Abnormal ejaculation
may occur more frequently with tamsulosin than
with other alpha-blockers.
Due to the high prevalence of erectile dysfunction in
LUTS/BPO patients, comedication with α1-AR
antagonists combined with phosphodiesterase ( PDE
V) inhibitors such as sildenafil, tadalafil or varde-
nafil is likely to occur. Since both drug classes have
vasodilating properties, such combinations can lead
to enhanced blood pressure reductions, and a recent
systematic review of corresponding studies confirms
this [174]. Hence, the FDA-approved prescribing
information states that sildenafil should not be used
in doses exceeding 25 mg within 4 h of taking an α1-
AR antagonist, and advises caution in the combina-
tion of tadalafil or vardenafil with α1-AR antago-
nists.
RECOMMENDATION
There is insufficient evidence to recommend
that the combination of phosphodiesterase
inhibitors and an α AR antagonist has any
advantage over monotherapy with α-blocker
therapy alone.
Level 4 Grade C
The average patient being diagnosed with BPO has a
remaining life expectancy of 15-20 years. Therefore,
an ideal treatment should have demonstrated durabil-
ity over such a time span. To date, the efficacy of α-
blockers has been studied for time spans of up to 4-
6 years. Most such studies were open-label exten-
sions of earlier RCT’s. Such studies have demon-
strated sustained symptom relief over at least 4 years
for doxazosin [180] and tamsulosin [181]. More
importantly, 4-year randomized, placebo-controlled
data for doxazosin have recently been obtained as
part of the MTOPS study [105]. This study demon-

168
strated sustained symptom improvement relative to
placebo over the entire observation period. While
doxazosin prevented the overall LUTS/BPO pro-
gression as defined in this study, it had no statistical-
ly significant effect on the occurrence of AUR or
progression to surgery at study end.
In conclusion, taken together, the available data pro-
vide level 1 evidence that alpha-blockers as a class
are significantly more effective than placebo in the
treatment of LUTS, and such efficacy is maintained
for more than 4 years.
It is clear that there appears to be a discrepancy
between the ability for α1-AR antagonists to relieve
symptoms when compared to the relief of BOO and
consequent improvement in urodynamic parameters
such as flow rate. Whilst an improvement in flow
rate may be to some extent counteracted as a conse-
quence of lowering the voiding pressure resultant
from a significant improvement in outlet resistance,
nevertheless the improvements of flow rate which
are recorded in the literature appear to be substan-
tially less than those to be expected from the degree
of concomitant symptomatic relief. It is clear that
other pathophysiological mechanisms do need to be
identified to explain the observed drug effects.
The epidemiological data relating to the use of these
agents in clinical practice is as yet scanty and this is
also an area which needs to be urgently addressed in
future studies.There is no convincing evidence that
new formulations of existing alpha-blockers result in
clinically relevant improvements of efficacy or that
any drug within this class is more effective than
another member of this group.
RECOMMENDATIONS
The efficacy of α-AR antagonists on symp-
toms has been demonstrated in placebo con-
trolled studies out to 5 years.
(Level 1 Grade B)
The benefit of α1-AR antagonists is not relat-
ed to prostate size.
(Level 1 Grade A)
The efficacy of all α1-AR antagonists is simila
(Level 1 Grade A)
The tolerability of alfuzosin and tamsulosin is
similar and better than the other agents.
(Level 1 Grade A)
169
Randomised, placebo-controlled trials have
demonstrated the benefit of α1-AR antagonists
over placebo and finasteride in men with
LUTS, with regard to symptom improvement.
(Level 1 Grade A)
D. PHYTOTHERAPY
I. INTRODUCTION
There is interest in phytotherapy of BPO/LUTS, par-
ticularly within the framework of complementary
medicine. The fundamental question, however, is to
critically assess the evidence-base supporting the use
of phytotherapy.
Plant extracts are complex mixtures of various
agents and are in a sense unique, as the extraction
procedures differ from company to company and the
exact compositions of the preparations vary and are
only partially chemically defined. Therefore, the
product of one company may be different from that
of another with regard to specific formulations and
their potentially active effective components, even if
the preparations originate from the same plant. In
addition, an extract from one plant, for example saw
palmetto, could have different mechanisms of action,
efficacy, bioavailability and pharmacodynamics,
compared to an extract made from stinging nettles,
the African plum tree, pollen extract, pumpkin seeds
or cactus flower extracts.
Therefore, the different preparations from the vari-
ous producers with their recommended doses each
have to be submitted to separate evaluation, as the
results of basic research and clinical trials cannot
automatically be transferred from one product to
another. It is therefore essential that each individual
manufacturer of plant extracts should perform sepa-
rate scientific studies and placebo-controlled clinical
trials, to allow an adequate assessment and evalua-
tion of their individual product(s) in comparison to
placebo with adequate long term follow up.
Comparative, placebo-controlled studies with other
phytotherapeutic preparations as well as with 5α RIs
and alpha AR blockers, in addition to a placebo arm,
are essential.
Although more than 30 different plant species can be
identified as components of the these products, most
of the phytotherapeutic agents used are extracted
from the roots, seeds, bark or fruits of the plants list-
ed in Table 11. Some products stem from a single
plant only (monopreparations); others are combina-
tion preparations of two or more plants.
The number of identified components in plant
extracts is increasing (Table 12). For many of the
agents the suggested mechanisms of action are pure-
ly hypothetical, lacking scientific proof and evidence
in man. For others, there are conflicting data in the
literature, for example relating to the inhibitory
effect on 5α- reductase activity.
A major problem of many in vitro and experimental
studies is that supraphysiologic doses were used
which were many times higher than the doses rec-
ommended for clinical use. There is little data on the
pharmacodynamics and bioavailability of most
preparations. Some of the ingredients of plant
extracts are probably not absorbed at all and others
only minimally. Much of the existing literature base
with phytotherapy is based on parameters such as
nocturia and frequency with less reference to other
objective measures such as flow rates and post void-
ing residuals.
Table 11. Origin of phytotherapeutic agents used for the
treatment of LUTS secondary to BPH
• American dwarf palm/ (fruits of Serenoa repens/Sabal)
• Saw palmetto serrulata)
• African plum tree (bark of Pygeum africanum)
• South African star grass (roots of Hypoxis rooperi)
• Pine, Spruce (Pinus, Picea)
• Stinging nettle (roots of Urtica dioica)
• Rye (pollen of Secale cereale)
• Pumpkin (seeds of Cucurbita pepo)
• Cactus flower extracts (Opinfia)
170
Table 12. Main Components of plant extracts suggested to
be active
• Phytosterols (α-sitosterol)
• Phytoestrogens
• Fatty acids (lauric and myristic acid)
• Lectins
• Flavonoids
• Plant oils
• Polysaccharides
II. SERENOA REPENS EXTRACTS
1. INTRODUCTION
The most widely used plant extract is from the Amer-
ican dwarf palm, (Serenoa repens), formerly known
by the botanical name Sabal serrulata and colloquial-
ly as saw palmetto. The different extracts are mainly
comprised of free and esterified fatty acids, phytos-
terols, long chain alcohols, cycloartenol, lupeol,
lupenone and methylcycloartenol. However, since
the extraction procedures differ and the origin of the
plant differs, individual extracts differ in their final
composition.
A study was performed aiming at fully quantifying
the variations in commercially available Serenoa
repens extracts [204]To this end, 14 brands of
Serenoa repens were compared in terms of concen-
trations of free fatty acids, methyl and ethyl esters,
long-chain esters and glycerides. The analysis
revealed marked differences between brands despite
their common origin. The mean proportion of free
fatty acids ranged from 80.7% in one product to
40/7% in another analysed product. Methyl and ethyl
ester content ranged from 16.7% to 1.5%, while long
chain ester content ranged from 1.36% to 0.7%. The
disparity between the extracts indicates that any clin-
ical benefits derived may vary between products.
The most rigorously investigated plant extract to date
is a lipido-sterolic extract of Serenoa repens com-
posed of various compounds and commercialized
worldwide under the trademark Permixon .
2. MECHANISM OF ACTION
The possible mechanisms of action attributed to the
extract of Serenoa repens have been suggested to
fall into three main categories [205].
• Anti-androgenic activity
• Anti-proliferative activity
• Anti-inflammatory activity
2. CLINICAL STUDIES
a) Placebo controlled trials
Clinical studies performed with Permixon have sug-
gested clinical efficacy for the lipido-sterolic extract
of Serenoa repens, with improvements in symptoms
and urinary flow rate[206]. Overall, in placebo-con-
trolled trials, mean reduction from baseline in uri-
nary frequency at night ranged from 33 to 74% with
the extracts of Serenoa repens compared to 13 to
39% with placebo; corresponding day-time reduc-
tions ranged from 11 to 43% and from 1 to 29%.
Mean increase from baseline in maximum urinary
flow rate ranged from 26 to 50% with Serenoa
repens extracts versus 2 to 35% with placebo. Six of
the seven studies performed between 1983 and 1995
with a Serenoa repens extract show superiority over
placebo[207, 208, 209,210, 211, 212].
On the other hand in a trial published by Reece
Smith, no significant difference in any parameter
between a group of patients (n=33) who had taken a
Serenoa repens extract for three months and a place-
bo group (n=37) was found. However the number of
patients included in both arm was very small[208].
Most of these studies were carried out some time ago
and were often not performed in accordance with
modern guidelines.
b) Meta Analyses of clinical trials
Boyle undertook a meta-analysis [213]of thirteen
studies of Permixon: 7 placebo-controlled studies, 4
comparator studies and 2 large, open label studies,
involving 2857 men. No uniform symptom assess-
ment was used in those studies, so only data on
Qmax and nocturia were assessable. In all these tri-
als, the average placebo effect was associated with
an increase in maximum urinary flow rate of 0.5
ml/s. The estimated effect of the Serenoa repens
extract was a further increase of 2.2 ml/s. The place-
bo effect was associated with a reduction in the mean
number of night time urinations of 0.69 and the
effect of the product, a further 0.5 urinations over
and above this.
In addition to these 13 studies, another 4 trials were
recently available for an update of the meta-analysis,
including 4,820 men[214].The additional data
allowed the examination of the effect of Permixon on
I-PSS and revealed that, in addition to improving
maximum flow rate (2.28 ml/s above placebo) and
nocturia (1.0 above placebo), the drug caused a sig-
nificant fall in I-PSS (-4.7). Permixon in this analy-
sis produced similar effects to those described in
171
equivalent meta-analyses for terazosin[215]and
finasteride[216]. Those results have been confirmed
in a recent meta-analysis published by the Cochrane
Library including a total of 21 randomized controlled
trials lasting 4 to 48 weeks and involving 3139
patients [217]. 18 trials were double-blinded and
treatment allocation concealment was adequate in 11
studies. Compared with placebo, Serenoa repens
improved urinary symptom scores, symptoms and
flow measures. The weighted mean difference
(WMD) for the urinary symptom score was –1.41
points. The WMD for nocturia was –0.76 times per
night and 1.86 ml/s for maximum urinary flow rate.
The authors suggested that Serenoa repens provides
mild to moderate improvement in urinary symptoms
and flow measures. However, this meta-analysis is of
limited value since Saw Palmetto products from 11
different manufacturers were used in these trials and
some included mixtures of various phytotherapeutic
preperations.
c) Comparative Studies
In a comparative 6-month double-blind study con-
ducted on 1,098 men, Serenoa repens (Permixon)
160mg twice daily showed equivalent efficacy to
finasteride 5 mg once daily in the treatment of men
with mild or moderate LUTS [218]. At the end of the
study mean total I-PSS had decreased by 37% in the
Permixon group and 39% in the finasteride group. In
addition to improvement in symptom scores, patient
self-rated Quality of Life score improved in 69% of
Permixon recipients and 73% of finasteride recipi-
ents. Both treatments were associated with an
improved maximum urinary flow rate. Results of a
questionnaire on sexual function demonstrated that it
was modestly improved among men receiving Per-
mixon compared to deterioration in those treated
with finasteride.
A recent one year double-blind, randomized study
compared the efficacy and tolerability of Permixon
320mg/day and tamsulosin 0.4mg/day (the
PERMAL study) [219]. Conducted in 11 European
countries this. 704 patients were randomized to treat-
ment : 350 to Permixon and 354 to tamsulosin.
After one year of treatment, analysis of the primary
efficacy variable, the mean change from baseline in
I-PSS total score, showed no statistically significant
difference between the two groups : a decrease of
–4.4 points. At week 6, the decrease in symptoms
was slightly greater in the tamsulosin group than in
the Permixon group but this difference was not sta-
tistically significant (p=0.09). Full activity was
achieved for tamsulosin at 3 months and maintained
until the final visit. For Permixon, continuous
improvements were observed throughout the dura-
tion of the study. No differences were observed
between the treatment groups at 12 months in terms
of storage symptoms, -1.7 and –1.5 and voiding
symptoms, -2.8 and –2.9 for Permixon and tamsu-
losin respectively.
d) Tolerability
Data from clinical trials in men with BPO receiving
Permixon 320mg / day indicate that this drug is well
tolerated by most patients [206]. Overall, 3% and 2%
of patients, respectively reported adverse events in
two large non-comparative trials of 592 and 500 men
receiving the drug for 3 months [220,221]. All com-
plaints, which were spontaneously reported, were
minor gastrointestinal problems such as nausea, and
resolved when Permixon was taken with meals.
None of the patients had to discontinue therapy
because of adverse events. Similar results were
demonstrated in a 1-month placebo controlled study
of 176 patients [212].
e) Conclusion
The Permixon extract of Serenoa repens, which has
been extensively studied in the field of BPO, has
been suggested to have superior efficacy against
placebo and equal efficacy to finasteride and tamsu-
losin.
Unfortunately there is a lack of modern well pow-
ered placebo controlled studies and its principal
mode of action still remains to be established. Since
not all brands of Serenoa repens are equal, the dif-
ferences, in terms of final composition and activity,
prevent a direct comparison of the various phy-
totherapeutic preparations even though they origi-
nate from the same plant.
III. PYGEUM AFRICANUM
1. ORIGIN, SUGGESTED MECHANISMS OF
ACTION
An extract of the african plum tree, Pygeum
africanum, is mainly used in France (Tadenan®), but
also in the US where it is sold as a dietary supple-
ment . The chloroform extract contains phytosterols,
short- (lauric and myristic) and unsatured long chain
(oleic and linoleic) fatty acids. In vitro data suggest
that the extract with the trade name Tadenan® is
thought to exert an inhibitory effect on b-FGF and
172
EGF-induced prostate fibroblastic proliferation and
displays anti-inflammatory activities by inhibition of
the production of chemotactic leucotries and other 5-
lipoxygenase metabolites and may have a protective
effect on the cellular membrane: also suggested to be
one of the main potential mechanisms of action for
Pygeum africanum. [222], Experimental studies by
Choo [223,224] and Constantinou [225,226]
described that the plant extract selectively reduces
DHT-stimulated prostate growth.
2. CLINICAL STUDIES
The clinical effects of the Pygeum africanum extract
(Tadenan®), suggesting efficacy, were demonstrated
in placebo-controlled [227-231] and in open studies
[232, 233] using both subjective and objective
assessment criteria.
However, these studies were performed years ago
and do not meet the strict guidelines recommended
by the International Consultation Conferences. A
review has been presented by this committee during
the previous conference in 1997 [222]. No placebo-
controlled studies with Tadenan ® have been pub-
lished since the last Consultation Conference. Some
new data from uncontrolled studies are available
[234-238]. The recent trials lack a placebo group and
thus do not meet the strict guidelines recommended
by the International Consultation Conferences.
3. COMPARATIVE TRIALS
In 1996, Abbou [239] reported the results of a ran-
domized trial comparing Alfuzosin to an extract from
Pygeum africanum: 331 patients completed the 8
week study. Alfuzosin was more effective than
Pygeum africanum with regard to maximum flow
rate, decrease of residual urine and improvement of
storage symptom score .
4. META-ANALYSIS
A systematic review and quantitative meta-analysis
has been performed on the studies of the therapeutic
efficacy and tolerability of Pygeum africanum in
men with symptomatic BPO; where it was used
either alone or in combination with other phytother-
apeutic agents, with a control group who received
placebo or other pharmacological therapy, and where
the treatment duration was at least 30 days.
Compared with placebo in 6 studies, P. africanum
provided a moderate improvement in urological
symptoms and flow rate. Nocturia was reduced by
19% and residual urine volume by 24%; maximum
urine flow was increased by 23%. Adverse effects
due to P. africanum were mild and similar to place-
bo. The overall dropout rate was 12% and was simi-
lar for P. africanum (13%), placebo (11%), and other
controls (8%; P = 0.4 versus placebo and P = 0.5 ver-
sus other controls) [240].
However, the literature on P. africanum for the treat-
ment of BPO is limited by the short duration of stud-
ies and the variability in study design, the type of
phytotherapeutic preparation, and the nature of
reported outcomes. Further research is needed using
standardized preparations of P. africanum to deter-
mine its long-term effectiveness and ability to pre-
vent complications associated with BPO.
IV. HYPOXIS ROOPERI /
PHYTOSTEROLS
1. ORIGIN, SUGGESTED MECHANISM OF
ACTION
Although ß-sitosterol and other phytosterols are con-
tained in most plant extracts used for the treatment of
LUTS/BPO, some manufacturers suggest that
ß-sitosterol is the major active component and there-
fore specify their preparation by a high (main) con-
tent of the ß-sitosterol fraction. Most of these prepa-
rations derive from the species Hypoxis rooperi
(South African Star Grass), Pinus (pine) or Picea
(spruce).
ß-sitosterol has been suggested to have an inhibitory
effect on cyclo-oxygenase and lipoxygenase, inter-
fering with prostaglandin metabolism and thereby
exerting anti-inflammatory effects. A stimulating
effect on transforming growth factor (TGF- ß) as an
apoptosis inducer is also reported [241-246]. How-
ever, whether these effects play a relevant role in
BPO remains uncertain.
2. CLINICAL STUDIES
Most of the earlier studies were open or retrospective
[247].
A study, with a phytosterol preparation (Harzol ®
that contains mainly beta-sitosterol and smaller
amounts of sitosterol, campesterol, stigmasterol and
several other sterols) extracted from the plants
Hypoxis rooperi, Pinus or Picea showed a positive
effect which was, superior to placebo [242,248].The
improvement observed in the treatment group, com-
pared to the placebo group, was statistically signifi-
cant for the modified Boyarski Score, IPSS, QoL
173
score, flow maximum rate and residual urine. Berges
et al recently published the results of an 18-month
follow-up of that study [243] and reported that the
patients who continued taking Harzol® maintained
“their benefit”.
The beneficial effect of another preparation (Azupro-
stat®),which also mainly contains ß-sitosterol has
been evaluated in another study [249-251]. The ori-
gin of the product is not mentioned by the company.
After 6 months of therapy with Azuprostat® (65 mg
phytosterol bid), there was a significantly greater
improvement detected in the treatment group com-
pared to the placebo group for IPSS (5.4 points),
QoL Score (0.9 points) maximum flow rate (4.5
ml/sec) and decrease of residual urine (33.5 ml). Side
effects were minimal in both studies. The results of
both studies with phytosterols, as the suggested main
active component, are interesting but await confir-
mation by other authors.
3. METANALYSIS
In 1999, Wilt T et al, reported a review on four dou-
ble blind trials comprising a total of 519 men. Three
studies used nonglucosidic beta-sitosterols and one
used a preparation that contained only beta-sitos-
terol-beta-d-glucoside. He concluded that these trials
were limited by short treatment duration and lack of
standardized beta-sitosterol preparations. Their long-
term effectiveness, safety and ability to prevent the
complications of BPO are unknown [252].
V. URTICA DIOICA
(STINGING NETTLE)
1. ORIGIN, SUGGESTED MECHANISM OF
ACTION
Extracts from the roots of the stinging nettle (Urtica
dioica) have been widely used in Germany. There are
16 different preparations.
The roots of the stinging nettle contain a complex
mixture of water-and alcohol-soluble compounds
including lectins, phenols, sterols and lignans.
Extraction procedures vary from company to compa-
ny using methanol, ethanol or exhaustive percolation
with hot water. Numerous potential pharmacological
mechanisms have been suggested [253-257]. Hirano
et al. [253] suggested suppression of prostatic cell
metabolism and growth by inhibition of membrane
Na+,K+ -ATPase and Hryb [254] postulated that the
binding of SHGB to its receptor on prostatic mem-
branes might be modulated.
2. CLINICAL STUDIES
The data of two double blind placebo-controlled
studies performed more than 10 years ago are incon-
clusive because of low patient numbers and only 8
and 9 weeks trial duration [258,259].
VI. POLLEN EXTRACT
1. ORIGIN, SUGGESTED MECHANISM OF
ACTION
The pollen extract “Cernilton®” is prepared from a
few plants growing in Southern Sweden and is avail-
able as a registered pharmaceutical in some Euro-
pean countries (Switzerland, Austria, Germany,
Spain, Greece), Japan, Korea and Argentina.
[260,261]
The preparation is obtained by microbial digestion of
pollen followed by extraction with water and an
organic solvent. The total extract consists of a water-
soluble and a fat –soluble fraction. Studies to dis-
cover the mechanisms of action suggested several
possible effects
2. CLINICAL STUDIES
No additional randomized placebo-controlled studies
have been reported since the last International Con-
sultation when the conclusion reached was that the
Cernilton® trials analyzed were limited by short
duration,limited number of enrollees, gaps in report-
ed outcomes, and unknown quality of the prepara-
tions.
VII. PUMPKIN SEEDS
(CUCURBITAE PEPONIS SEMEN)
The seeds of pumpkin contain a sweet tasting oily
substance, mainly composed of linolic acid, delta-5 –
and delta-7-sterols, tocopherol, selen, magnesium
and carotinoids. The extract is suggested to have an
antiandrogenic and antiphlogistic mechanism of
action [262].
A published randomized, placebo-controlled double-
blind trial of 476 patients, of 12 months duration
showed a significantly greater reduction of IPSS
(6.8) compared to the placebo group (-5.6) while the
other parameters (Qmax,QoL,Pvol,PVR) did not
change in either of the groups [263].
174
VIII. CACTUS FLOWER EXTRACTS
(OPUNTIA)
Aqeous and organic solvent extracts of dried cactus
flower powder have been described to have a broad
spectrum of activity, including inhibition of both
Type I (foreskin fibroblast ) and Type II (human
prostate hyperplastic cells) 5α-reductase activity,
inhibition of aromatase and antioxidant activity. The
authors postulate that, as cactus flower has simulta-
neus 5α-reductase and aromatase inhibitory activity,
[264].
There are no reports of any controlled clinical trials
with cactus flower products
E. SYNTHETIC POLYENES
I. MEPARTRICIN
1. SOURCE AND SUGGESTED MECHANISMS OF
ACTION
Mepartricin, marketed in several countries under the
trade name Ipertrofan or Iperplasin, is not a plant
extract but a semisynthetic polyene substance isolat-
ed from a streptomyces strain. The final preparation
is a mixture of closely related identified polyenic
structures. In the doses used, it is not absorbed after
oral administration and is well tolerated. Mepartricin
reportedly acts by interrupting the enterohepatic cir-
culation of oestrogens. Mepartricin binds to oestro-
gens in the intestine, inhibits their re-absorption, thus
decreases the blood oestrogen concentration and
thereby diminishes oestrogen-induced growth stimu-
lation of the prostate [265-268]. Mepartricin, dose
dependently, inhibited the estradiol-induced increase
of prostate weight, of hydroxyproline content and of
the activity of growth factors in its soluble fraction
[269-271]. The androgen receptors, too, were signif-
icantly reduced, although with a non linear dose-
response relationship.
In a controlled study in LUT/BPO-patients, treated
for 30 days, a highly significant decrease of serum
concentration of estrone, estradiol and estriol has
been reported [272].
2. CLINICAL STUDIES
Short term open label studies have suggested clinical
efficacy for mepartricin. The results of a multicentre
double-blind randomized, placebo-controlled trial
were published by Denis et al.[273-275]. 98 patients
were included in each group, follow-up was 6
months. There was evidence of a more rapid and sig-
nificant (p=0.006) decline in the mean IPSS of
patients treated with Mepartricin than in controls.
The mean increase in maximum flow rate (ml/sec) of
treated patients relative to controls and determined at
6- months, showed a significantly different
(p=0.053) linear trend between the groups .
Whilst a review of the results of 23 clinical studies
performed with mepartricin was published by
Boehm et al. [276], suggesting clinical efficacy and
good tolerability for mepartricins; this needs to be
confirmed by adequately powered, longer term
placebo controlled studies.
F. NEW MEDICAL
DEVELOPMENTS IN THE
MANAGEMENT OF LUTS IN
ADULT MEN
LUTS and in particular, those of OAB, increase in
prevalence with increasing age amongst both men
and women. (Figures 6-10).
Weak stream, incomplete emptying, show an age-
related increase in prevalence among men, but not
among women. LUTS occur with high prevalence in
the background population, but they do not always
cause trouble.
I. OVERACTIVE BLADDER
1. INTRODUCTION AND ASSESSMENT OF
PATIENTS
BPO is one of the most common diseases of aging
men, interfering with normal daily activities and
sleep patterns [277]. Voiding symptoms (such as
slow stream, intermittency, hesitancy, straining or
terminal dribbling) and post-micturition symptoms
(feeling of incomplete emptying and post-micturi-
tion dribble) are classically related to BPO, although
are not associated with obstruction [278,279]. A per-
centage of patients as high as 50% can experience
however, storage symptoms [280] which significant-
ly bother patients, their quality of life.
175
There is clearly detrusor dysfunction manifest as
storage symptoms are seen in patients with BOO.
There is clearly a disparity between the accepted
norms for the appropriate assessment of patients with
voiding and storage symptoms. The existing litera-
ture base in the field of LUTS/BPO has relied on the
use of the IPSS and flow rates and post –void resid-
uals. In contrast in the assessment of OAB, other
measures such as frequency volume charts are com-
monly used. Clearly the appropriate assessment of
patients must incorporate a combination of both sets
of measures.
RECOMMENDATIONS
• Lower urinary tract symptoms relating to
voiding (LUTS) are not disease specific and
hence diagnostic of BPO or BOO.
• Appropriate assessment of the symptomatic
patient relies upon comprehensive evalua-
tion.
• A major problem in the contemporaneous
literature is the absence of an adequate
internationally accepted and applied defini-
tion for ‘BPH’
• When evaluating therapy we need to:-
• Identify and standardise robust outcome
measures pertinent to the condition -
LUTS, OAB, BPO, BOO….
• With reference to what is most bother-
some to patients
Level 1 Grade A
• The management of OAB component of
LUTS in men is of potential interest .
• We would recommend that specific mea-
sures developed for the assessment of OAB
should be applied to this disease area.
• The IPSS has only 3/7 questions dealing with
storage symptoms – one documents nocturia
Level 1 Grade B
2. MATERIALS AND METHODS
Our aim was to review the available evidence con-
cerning the use of anticholinergic drugs, alone or in
combination with alpha-blockers, in the patients with
LUTS due to BPH/BPE/BPO and concomitant over-
active bladder syndrome (OABS).The review of the
literature was performed using MEDLINE through a
Figures 6-10

176
complex search strategy including both “free text”
and “MeSH” (Medical Subject Heading) protocols.
Specifically, the MeSH search was conducted with
the use of the following terms retrieved from the
MeSH browser provided by MEDLINE at
www.pubmed.org: “Prostatic Hyperplasia”, “Adren-
ergic alpha-Antagonists”, “Cholinergic Antago-
nists”. Multiple “free text“ searches were performed
applying singularly the following terms through all
the fields of the records: “Antimusc*”, “Oxybu-
tynin”, “Tolterodine”, “Propiverine”, “Trospium”,
“Emepronium”, “Propantheline”, “Darifenacin”, and
“Solifenacin”. Subsequently, the following search
limits were employed: Humans, gender (Male).
Nineteen records were selected from the MEDLINE
search and the authors reviewed their abstracts. They
agreed on the selection of six papers concerning the
topic of the review. Moreover, the Cochrane database
of systematic review was browsed for records
regarding BPH and the abstract books of both AUA
and EAU annual meetings from 2000 to 2004 were
hand-searched for studies concerning the topic of the
review. In addition, other significant studies cited in
the reference lists of the selected papers were con-
sidered.
All the papers were defined according to the grade of
evidence as stated by Phillips and Sackett [281].
Meta-analyses of randomized clinical trials (RCTs)
constitutes the highest evidence (level 1), followed
by an adequately sampled single randomized clinical
trial (level 1) and observational studies (level 2).
Lower grade of evidence was provided by surgical
series (level 4). Among the selected papers, there
was only one published RCT. All the other studies
were prospective series, reviews or congress
abstracts.
3. RESULTS
Two-hundred twenty-one patients were randomized
(2 to 1) to tolterodine 2 mg twice daily for 3 months
(149 patients) or placebo (72 patients) [282, 283].
There were no significantly differences in the
changes of both Qmax (-0.7 ml/sec) and PdetQmax
(-7 cm H2O) due to tolterodine but the antimus-
carinic drug caused a statistically significant increase
in the post-void residual urine volume (+25 ml),
compared to placebo. However, this finding had lim-
ited clinical significance. Similarly, only two patients
(one in each arm) experienced acute urinary reten-
tion [282,283]. This study, although underpowered
might suggest that anticholinergic drugs can be safe-
ly used in patients with BOO without causing urinary
retention. This study did not suggest any significant
177
beneficial clinical effect on patients’ symptoms,
although it was designed only as a safety study.
In another randomized clinical trial performed by
Athanasopoulos et al [284], after a seven-day run-in
period with tamsulosin therapy, the authors random-
ized 50 patients with urodynamically proven mild to
moderate BOO (according to Schafer’s nomogram)
and concomitant detrusor overactivity to either sin-
gle drug therapy with tamsulosin (0.4 mg once a day)
or a combination of tamsulosin (same dosage) and
tolterodine (2 mg twice a day). After 3 months of
therapy, the patients were evaluated through a quali-
ty of life score (the Greek version of the Urolife
“BPH” quality of life 9 questionnaire) and a urody-
namic study. The clinical characteristics of the
patients in the two arms were overlapping. In both
groups, similar improvements in the maximum flow
rate and volume at the first detrusor contraction were
shown. Only the combination therapy arm demon-
strated a statistically significant reduction in maxi-
mum detrusor pressure during micturition and maxi-
mum pressure of the detrusor contraction during the
filling phase of the pressure-flow study. No data,
however, was reported on the effect on storage
symptoms, but, quality of life scores in 6 out of 9
domains were significantly better in the combination
therapy group. Tolterodine did not appear to increase
the post-void residual urine. and no acute urinary
retention was reported, however, two patients
stopped anticholinergic because of xerostomia and
two other ones (one in each arm) stopped alpha-
blockers because of orthostatic hypotension [284].
In 2004 Lee et al [285] published a prospective study
where a combination therapy with doxazosin and
tolterodine was used in 60 patients with LUTS who
had not improved after doxazosin monotherapy
[285]. All the patients had undergone a pressure-flow
study, which had shown the presence of detrusor
overactivity in 44 of them. Six of the 16 (37.5%)
patients without detrusor overactivity and 24 out 68
(35%) of those with detrusor overactivity showed
significant improvement in the IPSS after combina-
tion therapy. On the other hand, the use of tolterodine
was associated with xerostomia in 16 patients (27%)
but only in 2 of them this side-effect was so severe to
discontinue the drug. Similarly, tolterodine therapy
was stopped in 2 patients because of acute urinary
retention (3.3%) [285].
A cohort of 43 men who had previously failed alpha
blocker therapy and where subsequently treated with
tolterodine extended-release (4 mg once a day) for 6
months has been reported [286]. Comparing baseline
and 6-month data, the authors found statistically sig-
nificant reductions in daytime (from 9.8 to 6.3 per
day) and nighttime frequency (from 4.9 to 2.9 per
night), with AUA symptom index decreasing from
17.3 to 11.2. Moreover, Qmax increased from 9.8 to
11.7 ml/sec, while post-void residual urine decreased
from 97 to 75 ml.
In a multicentre study, Okada et al [287] assessed the
impact of propiverine on both storage and voiding
symptoms in 35 patients non-responsive to alpha
blockade. The authors showed significant decreases
in IPSS values (from 20.4 to 15.8, p<0.05), due to
better scores to the IPSS questions 2, 4, and 7 (those
assessing storage symptoms). Furthermore a higher
Qmax and voided volume resulted as did a more
favourable quality of life score [287].
Table summarizes the figures from the retrieved
studies (Table 13).
4. DISCUSSION
Although the presence of storage symptoms is
extremely common in patients with BOO only a few
published papers specifically addressed this issue.
Only a single randomized controlled trial has been
published [284], while the other retrieved studies
were prospective series [285], reviews, or congress
abstracts [282,283,286,287].
The randomised study published by Athanasopoulos
et al. [284] although underpowered suggest that
anticholinergic therapy can be safely used in the
patients with BOO and detrusor overactivity. How-
ever, the study has to be criticised on a number of
counts; small sample size with only 25 patients treat-
ed in each arm; short study follow-up period and lim-
Table 13. Summary of the data on the effect of the antimuscarinic drugs in male patients with LUTS/ BPO.
To: Tolterodine; Ta: Tamsulosin; Do: Doxazosin; Pro: Propiverine; P: Placebo; α-block..: α-blockers; PVR: post-void residual
urine; Inc. AUR: Incidence of acute urine retention increased; Q of L score: quality of life score; NA : not assessed;
NS : not statistically significant.
178
ited follow-up data. the randomization criteria were
not described and it was unblinded; also there was a
lack of a third arm with tolterodine mono-therapy.
Although a statistically significant advantage was
demonstrated in the combination therapy arm, it was
clearly shown that allocation bias and the absence of
blinding could overestimate the efficacy of a treat-
ment by up to 40% [288]. Hence, according to Jadad,
who reported a score to assess the quality of RCTs
based on their methodological design, that RCT has
to be considered a low quality study (score=0) (289).
According to the Evidence-based Medicine criteria,
a low-quality RCT provided only a level 2b of evi-
dence and grades “B” of recommendation [281].
Furthermore, the studies reported by Lee, Kaplan,
and Okada [285-287] are all prospective case-series
(level 4 of evidence and grades “C” of recommenda-
tion) [281].
It has been postulated that the safe use of antimus-
carinic drugs is due to these drugs mainly acting by
decreasing urgency and increasing bladder capacity
during the storage phase, when there is no activity in
the efferent parasimpatic nerves. Hence, it has been
hypothesized that these drugs act on the afferent
nerves which initiate the micturition reflex, by the
slow tonic release of acetylcholine from afferent
nerves or, maybe, from the urothelium [290]. More-
over, being competitive antagonists, the action of
these drugs may be reduced during the voiding
phase, when there is a massive release of acetyl-
choline [291].
To date, both AUA and EAU guidelines on “BPH”
[277,292] do not consider this category of drugs in
the management of the patients with LUTS due to
BPO. The NHMRC guidelines on the management
of uncomplicated lower urinary tract symptoms in
men [293,294] suggest that men with predominantly
storage symptoms who request pharmacological
intervention could be offered a trial of an anticholin-
ergic agent. However, this suggestion is based solely
on expert opinion.
The limited data available highlights the need to plan
larger and better designed RCTs with the intent to
appropriately assess long-term safety and efficacy of
either monotherapy with antimuscarinics or combi-
nation therapy with alpha blockers .
5. RECOMMENDATIONS
BPO is one of the most common diseases of aging
men, interfering both directly on normal activities of
daily living and indirectly via an effect on sleep pat-
terns. Although voiding and post-micturition symp-
toms are classically associated with BPO; it must be
remembered that as many as 50% of patients experi-
ence significant storage symptoms and these are
often the most bothersome to them, producing sig-
nificant impairment of quality of life.
We recommend further evaluation of the poten-
tial for an empirical approach to the initial
treatment of male OAB symptoms. This
approach would rely on careful assessment of
storage symptoms, a physical examination, and
urinalysis.
• If BPO is suspected based on symptom
assessment or uroflowmetry, an α1-receptor
antagonist would be prescribed as first line
therapy.
• In men with enlarged prostates, use of a 5α α-
reductase inhibitor may also be appropriate.
• Addition of an antimuscarinic would be con-
sidered for patients with a normal urinalysis
and no PVR of note whose symptoms do not
respond sufficiently to either therapy.
• Preliminary data suggests that when used
alone or in combination with α1-receptor
antagonists, antimuscarinic agents relieve
male storage symptoms without increasing
the risk for urinary retention in patients with
comorbid BPO.
179
• At present, it must be concluded that the
existing literature is based on pilot studies
using urodynamic criteria for patient selec-
tion that do not necessarily represent real life
practice. On the whole these studies are not
placebo-controlled and/or not adequately
powered.
Combination therapy with an anticholinergic
and an α1-receptor antagonist in men with
OAB and with suspected BPO is an interesting
potential direction in pharmacotherapy that
requires testing in well-designed clinical trials
before it can be recommended for routine clini-
cal use.
• OAB symptoms are more bothersome than
voiding LUTS in men and may occur in the
presence or absence of BPO.
• The treatment of OAB in the absence of BPO
should be as suggested by the 3rd ICI
Level 1 Grade A
• The management of OAB occurring in the
presence of BPO is the subject of ongoing
research
• Antimuscarinic therapy as solo therapy
can not be recommended for routine use
Level 2 Grade B
• Combination therapy of an antimus-
carinic and alpha blocker may be effica-
cious
Level 2 Grade B
II. NOCTURIA
1. INTRODUCTION
Nocturia is a very common problem among elderly
men and often a reason for urological consultation
[295]. Nocturia has been poorly studied and, , has
only recently been classified according to its aetiolo-
gy and pathogenesis. Nocturia may be attributed to
nocturnal polyuria (nocturnal urine overproduction),
diminished nocturnal bladder capacity, or a combi-
nation of the two. Multiple factors may result in noc-
turia, among which are pathological conditions such
as cardiovascular disease, diabetes mellitus, lower
urinary tract obstruction, anxiety or primary sleep
disorders, and behavioural and environmental factors
Distinction between these conditions is made by a
simple arithmetic analysis of the 24-hour voiding
diary.
Based on a review of the current state of knowledge,
this article presents a scheme for the classification
and treatment of patients suffering from loss of sleep
resulting from nocturnal micturition is presented
[296].
With the increase in the mean age of the general pop-
ulation, the number of individuals with LUTS and in
particular nocturia, is likely to increase and must be
considered when resources are allocated for medical
care [297,298].
2. DEFINITION, EPIDEMIOLOGY, AND QOL IN
NOCTURIA
The storage symptom of nocturia is defined as the
complaint that the individual has to wake at night
one or more times to void, each void being preceded
and followed by sleep [299]. Nocturia is a very com-
mon problem among elderly men and is often a rea-
son for urological consultation [300,295]. The preva-
lence of nocturia is positively correlated with age,
and is higher in men than in women in the age group
of 60 years or older [301]. According to a health sur-
vey data of 1247 women (age 49.8 +/- 13.5 years)
and 1221 men (age 48.5 +/- 11.9 years), the percent-
age of individuals with nocturia of two or more times
increased constantly with age: less than 30 years,
3.1% of women and 3.4% of men; 30 to 59 years,
7.2% of women and 5. 7% of men; and 60 years old
or older, 26.7% of women and 32.4% of men. Noc-
turia is almost equally present in both sexes, and the
incidence and severity increase constantly from early
adolescence to senescence. Approximately 10% of
the general population (older than 20 years) have
nocturia of two or more times, which impairs the
quality of life in two thirds [302].
Voiding symptoms were almost identical in both
sexes until the 5th decade, thereafter they increase
significantly in men but not in women. ‘Urgency’
and ‘frequency’ are more bothersome to older indi-
viduals, but ‘nocturia’ and voiding symptoms were
almost equally bothersome to younger and older par-
ticipants ( 303,304 ).
In an otherwise healthy and professionally active
group of individuals, waking at night to void signifi-
cantly diminishes their overall well-being, vitality
and productivity, leading to a significant level of
indirect and intangible costs [305]. Impairment of
both somatic and mental health is associated with
increased nocturnal voiding. Sick-leave is more
common in association with more nocturnal voids
[306].
180
3. THE MULTIFACTORIAL AETIOLOGY OF
NOCTURIA (Figure 11)
There are several common causes of nocturia which
may exist singly or in combination. The circadian
pattern of urine production is maintained in healthy
people until the age of 60 years, after which a greater
proportion of 24-h urine production occurs at night
[307]. This shift in the relative proportions of urine
produced during the day and night-time does not
affect the total volume of urine produced over a 24-
h period [308,309]. Nocturia may be due to the 24
hour overproduction of urine (olyuria) or to the noc-
turnal overproduction of urine (nocturnal polyuria).
Decreased nocturnal voided volumes have 2 com-
mon causes: the presence of residual urine, or a
decrease in bladder capacity due to involuntary
detrusor contractions characteristic of detrusor over-
activity. There was no correlation between the num-
ber of nocturnal voids and known and treated hyper-
tension, angina pectoris, congestive heart failure or
diabetes mellitus. The number of nocturnal voids is
highly correlated with both urgency and inconti-
nence indicating detrusor overactivity as a causative
factor [310]. Since nocturia is clearly associated with
a number of factors; multiple approaches are needed
to the treatment of patients with nocturia [311].
Figure 11
a) Polyuria
Polyuria is defined by the ICS as the measured pro-
duction of more than 2.8 litres of urine in 24 hours in
a 70-kg adult [299]. This is based on the upper limit
of urine production being 40 ml per kg bodyweight
per 24 hours. The commonest cause is habitual
excessive fluid intake , rather than for any medical
reason. However, an increased total urine produc-
tion can be due to disease: a common cause of
polyuria is diabetes mellitus, which may give rise to
a glucose-induced osmotic diuresis [312]. In the
much rarer disease, diabetes inspidus, the kidney
either fails to respond to the presence of arginine
vasopressin ( AVP ), or else the secretion of AVP may
be impaired [25]; consequently large amounts of
urine are secreted.
b) Nocturnal polyuria
Nocturnal polyuria has been defined as night-time
production of urine that is either 33 % of the total 24-
h urine volume [314,315] or >0.9 ml/min, with an
age dependant relationship [316].
The hormone AVP is responsible for regulating urine
production. In healthy adults, the release of AVP into
the circulation follows a diurnal pattern, with peak
blood concentrations occurring during the hours of
sleep [317,318]. The rhythm appears to be linked to
the wake-sleep cycle rather than to the time of day
[317] and is established during childhood. With
advancing age, the nocturnal secretion of AVP
becomes blunted, resulting in similar day-night time
blood levels of AVP [319] and hence to an increase
in night-time urine production. Another hormone
that is likely to play a role in the altered renal sodi-
um handling of elderly people is atrial nariuretic hor-
mone (ANH).
The action of ANH on the kidney, leads to natriure-
sis and diuresis, (blood ANH levels increases with
age [320].
It is evident that an increase in night-time urine
excretion, causing individual to rise and void, is part
of the normal ageing process. Nocturnal polyuria is
believed to be account for at least 50-65 % of cases
of nocturia [307,309].
c) Reduced bladder capacity
In older men BPO commonly coexists with detrusor
overactivity resulting in reduced voided volumes and
increased micturition frequency due to a significant
PVR [321]. An increase in the frequency of noctur-
nal micturition is also as well-established symptom
of LUTS suggestive of BPO for the same reason
[322]. Indeed, LUTS/BPO is considered as an inde-
pendent risk factor for nocturia [323].
Homma et al. [324] suggested that not only BOO,
but also independent age-related changes in the uri-
nary tract may contribute to nocturia in older men
181
[324]. However, nocturia correlates significantly
with LUTS and BPO [325]. Indeed, Yoshimura et al.
reported in their study that 71 % of the men who
were diagnosed with LUTS and BPO had at least two
nocturnal voids, which is much higher than commu-
nity-based studies where a much lower prevalence of
nocturia (>=2) of 25-45 % is reported in older men
[325]. Other factors that may be involved in the
pathology of detrusor overactivity include activation
of muscarinic receptors, patchy denervation of the
detrusor, and changes on the central nervous system
[326]. A gradual deterioration in the function of the
central nervous system may also contribute to blad-
der dysfunction, particularly bladder hypersensitivi-
ty or detrusor overactivity. Neurological disease (for
example, Parkinson’s disease), may also cause an
increase in urinary frequency and nocturia,
d) Sleep disorder
Nocturia is widely prevalent and increases with age,
affecting men and women equally. Incremental
increases in the number of voids/night have further
negative effects on sleep, symptom bother, and
HRQoL [327].
Adequate sleep is a basic requirement for good
health. Adults generally require 7 to 8 hours of sleep
per night. Sleep deprivation is associated with a
decreased ability to perform tasks controlled by the
frontal lobe, such as planning, concentration, motor
performance, and high-level intellectual skills. Con-
stant poor-quality sleep can also cause excessive
daytime sleepiness, depression, and immune func-
tion compromise. In addition, continued sleep dis-
ruption has been associated with an increased risk for
mortality [328].
Older adults with severe sleep-disordered breathing
have a greater number of nocturia episodes. Sleep
disordered breathing is an important differential
diagnosis in the evaluation of older patients with
nocturia [329]. Pathological nocturia is common in
obstructive sleep apnea-hypopnea syndrome
patients. The strongest predictors are age and select-
ed polysomnographic variables reflecting obstruc-
tive sleep apnea-hypopnea sydrome severity [330].
Nasal continuous positive airway pressure reduces
obstructive sleep apnea and nocturia and improves
quality of life of elderly patients [331,332]. The
apnea hypopnea index was calculated as the sum of
apneas and hypopneas divided by hours of sleep. In
subjects with elevated the apnea hypopnea index
(> 15), nighttime urine production and ANH excre-
tion are elevated [333]. The measurements are usu-
ally performed in a sleep laboratory.
e) Depression
Major depression has previously been found to be
associated with increased nocturnal micturition.
Twice as many men and women treated with SSRIs
as those not so treated had two or more nocturnal
voids, after adjusting for major depression and age
[334].
f) Serum factors, nutrients, smoking, and
hypertension
Rohrmann and associates reported that the role of
metabolic abnormalities in the aetiology of LUTS
including nocturia [335]. They found that greater cir-
culating concentrations of vitamin E, lycopene, and
selenium, antioxidant micronutrients that are sup-
ported in published reports as protecting against
prostate cancer, were observed also to be inversely
associated with LUTS. The effect modification of the
association with vitamin C by cigarette smoking
warrants additional examination [336]. Dietary ele-
ments may also have an important role in the devel-
opment of diseases causing LUTS. Direct effects of
food components may likewise influence the occur-
rence of LUTS including nocturia [337]. Smoking
increases the prevalence of LUTS. The similarity in
the odds ratios of these symptoms between current
and former smokers suggests that changes caused by
smoking occur long term or the pathological process
resulting in symptoms starts early in smokers. The
decreased risk of LUTS after the cessation of smok-
ing suggests that the process is reversible but recov-
ery is a long-term process [338]. Elderly obese men
with urgency at night should be questioned about
snoring, and that micturition frequency and volume
charts should be completed by such men, particular-
ly before deciding to operate [339]. Nocturnal
polyuria and essential hypertension may share some
of the same pathophysiological determinants. Specif-
ically, a defect in the nitric-oxide pathway may lead
to a resetting of the pressure-natriuresis relation in
the kidney with sodium retention, and a compensato-
ry nocturnal natriuresis. This suggestion is consistent
with evidence that ageing and essential hypertension
are both associated with defects in the nitric-oxide
pathway. This hypothesis has obvious therapeutic
implications [340].
4. DIAGNOSING THE CAUSE OF NOCTURIA:
History-taking, physical examination, and laboratory
tests are necessary to exclude polyuria and nocturia
resulting from certain diseases, including those asso-
ciated with oedema (i.e. congestive heart failure and
renal disease), reduced renal concentrationg capacity
182
(i.e. diabetes inspidus and renal insufficiency), and
bladder storage symptoms resultant from bacterial
cystitis, painful bladder syndrome, bladder calculi or
bladder cancer. An accurate diagnosis of nocturia
requires careful questioning of the patient, including
details of bladder storage and voiding symptoms,
which may suggest detrusor overactivity or BOO.
Other factors, such as fluid intake, medications, neu-
rological disorders and nocturnal apnoea, may make
an accurate diagnosis difficult and must also be
examined. The frequency of nocturia is reliably self-
reported by patients [52] but in order to reveal the
underlying cause, frequent volume charts have been
found to be particularly useful in documenting clini-
cal data. Poor agreement between subjectively esti-
mated nocturnal frequency and chart-determined
nocturnal frequency has been demonstrated.
Nocturia due to polyuria can be detected by using a
FV chart. In these patients, a 3-day FV chart is suf-
ficient to detect nocturia not a polyuric and seems
therefore to be a valuable tool in evaluating patients
with LUTS referred for potential BPO [314, 342-
344].Nocturia is a result of a mismatch between noc-
turnal urine volume and largest voided volume,
rather than abnormal values of either. The treatment
of nocturia should be directed at one or both of these
factors, depending on the findings from the 3-day
frequency-volume chart of the individual [345].
In a well-defined group of men with LUTS sugges-
tive of BPO, filling cystometric capacities were
strongly associated with maximal and mean voided
volumes derived from frequency-volume charts. The
presence of detrusor overactivity during filling cys-
tometry did not significantly affect voided volumes,
or nocturia [346].
Except for nocturia, older men had lower voiding
scores on the IPSS. Prostate volume and obstruction
grade were not, but low detrusor contractility and
low capacities were, associated with the symptom
index. The presence of an overactive bladder and/or
residual volume was poorly correlated with the
symptom index or quality-of-life score [347].
The ICSmaleSF represents a comprehensive, con-
cise, valid and reliable instrument for evaluating men
with LUTS. Unlike other questionnaires in the field
it contains sub scores for the domains of voiding and
incontinent symptoms as well as the separate consid-
eration of frequency, nocturia and impact on daily
life. It will become the tool of choice for the com-
prehensive evaluation of treatment of men with
LUTS associated with benign prostatic disease
[348].
5. RECOMMENDATIONS FOR TREATING NOC-
TURIA POLYURIA
There are two main therapeutic options for
treating noctural polyuria: antidiuretic agents
(retention of water until a more appropriate
time for voiding) and diuretic agents (prevent-
ing water accumulation by forcing water out of
the system before the early sleeping hours).
The 3rd ICI committee also evaluated publica-
tions on drugs affecting urine production( 349).
LOOP DIURETICS
They found insufficient evidence to allow them
to make any recommendations about the use of
the loop diuretics, bumetanide and frusemide,
in nocturia.
DESMOPRESSIN
Desmopressin is the only analogue of vaso-
pressin (antidiuretic hormone) that is current-
ly available. Desmopressin is an antidiuretic
agent, but unlike vasopressin, it does not
directly affect the cardiovascular system. The
ICI committee highly recommended the use of
desmopressin for treating nocturnal polyuria,
because there was clear evidence for its effica-
cy in children with nocturnal enuresis, and in
adults ( 349) with nocturia resulting from noc-
turnal polyuria. Desmopressin may be associ-
ated with an increased risk of developing
hyponatraemia and water retention, so care
should be taken when desmopressin is used in
older patients (over 65 years).
Desmopressin, a synthetic antidiuretic hormone ana-
logue, is the only drug currently approved for the
treatment of nocturia associated with nocturnal
polyuria or multiple sclerosis (MS). Compared with
vasopressin, desmopressin has a longer lasting and
more potent antidiuretic effect and is devoid of vaso-
pressor and uterotonic effects. In two large, ran-
domised, double-blind phase III trials in adults with
nocturia associated with nocturnal polyuria, 3 weeks
of oral desmopressin therapy was significantly more
effective than placebo in reducing the mean number
of nocturnal voids and in normalizing the rate of noc-
turnal urine production. Beneficial effects of desmo-
pressin on nocturia were maintained or increased in
patients completing 10 or 12 months of further treat-
ment in a non-blind extension of short-term trials. In
randomized, double-blind trials in MS patients with
nocturia, nasal desmopressin reduced the mean num-
183
ber of nocturnal voiding episodes by 31-54%. In
both patient populations, desmopressin increased the
initial sleep period or mean maximum period of
uninterrupted sleep by approximately 2 hours, an
outcome significantly greater than that achieved with
placebo. In trials of 6 weeks or less duration in adults
with nocturia, desmopressin was generally well tol-
erated. Most desmopressin-related adverse events
were transient and mild or moderate in severity.
Clinically significant hyponatraemia was reported in
approximately 5% and required withdrawal from
studies in 3% or less of patients [350]. A long-term
study shows that desmopressin is a generally well
tolerated and effective treatment for nocturia [351].
Desmopressin was well tolerated in elderly patients
with nocturia, but the results suggest that serum sodi-
um should be measured before and after a few days
of treatment [352]. Orally administered desmo-
pressin is an effective and well-tolerated treatment
for nocturia in men. Desmopressin is also an effec-
tive treatment for nocturnal polyuria in some elderly
men. However, it can cause fluid retention and
should not be given to patients with cardiac failure.
Those undergoing treatment must be closely moni-
tored [353]. Desmopressin was effective in reducing
nocturnal diuresis and nocturnal voids in polyuric
elderly subjects, with no significant adverse events
or inconvenience to the patient. The length of unin-
terrupted sleep was also improved [354].
• New drugs for the treatment of nocturia in men
(Table 14)
Botulinum A toxin injections into the detrusor have
a significant and comparable, but temporally limited,
effect in idiopathic and neurogenic detrusor overac-
tivity resistant to anticholinergic treatment [355].
Fourteen of 31 patients with refractory (OAB) and
nocturia improved with oral gabapentin. Gabapentin
was generally well tolerated and can be considered in
selective patients when conventional modalities have
failed although the evidence base is very limited
[356].
Melatonin treatment is associated with a significant
nocturia response rate, improvement in nocturia
related bother, and a good adverse effect profile, in a
single study. However, it is uncertain whether the
observed changes in this study are clinically signifi-
cant [357].
Loxoprofen can be an effective and useful treatment
option for patients with BPO complaining of refrac-
tory nocturia. Further placebo-controlled studies are
required [358].
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ity of life versus age, prostate volume, and urodynamic param-
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348 Donovan JL. Peters TJ. Abrams P. Brookes ST. de aa Rosette JJ.
Schafer W.: Scoring the short form ICSmaleSF questionnaire.
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349 Abrams P, Khoury S, Wein A, eds. Incontinence, 2nd Interna-
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350 Cvetkovic RS. Plosker GL. Desmopressin: in adults with noc-
turia.Drugs. 65:99-107; 2005.

194
 CHAPTER 6

Committee 7

New Minimally Invasive and Surgical

Developments in the management of BPO

Chairman
J. DE LA ROSETTE (THE NETHERLANDS)

Members
S. BABA (JAPAN),
G. BADLANI (USA),
M. ELHILALI (CANADA),
S. GRAVAS (GREECE),
R. MUSCHTER (GERMANY),
S. NAITO (JAPAN),
N. R. NETTO (BRAZIL)

195
 CONTENTS

INTRODUCTION V. PROSTATE INJECTABLES

I. TRANSURETHRAL RESECTION 1. EFFICACY OF TEAP

OF THE PROSTATE (TURP)
2. COMPLICATIONS
3. RE-INTERVENTION RATE
II. LASER
VI. PROSTATIC STENTS
1. TYPES OF LASER FIBERS
1. PERMANENT STENTS
2. TYPES OF LASERS AND SURGICAL
TECHNIQUES 2. BIODEGRADABLE AND TEMPORARY STENTS
III. MICROWAVE 3. UROLUME REMOVAL
THERMOTHERAPY
4. COMPLICATIONS OF PERMANET STENTS
1. TRANSURETHRAL MICROWAVE 5. DISCUSSION
THERMOTHERAPY (TUMT)

2. WATER-INDUCED THERMOTHERAPY, VII. OVERALL CONCLUSIONS

(WIT™)
REFERENCES
IV. TRANSURETHRAL NEEDLE
ABLATION OF THE PROSTATE

1. TUNA THERAPY

196
 New Minimally Invasive and Surgical
Developments in the management of BPO
J. DE LA ROSETTE,
S. BABA, G. BADLANI, M. ELHILALI, S. GRAVAS, R. MUSCHTER, S. NAITO, N. R. NETTO
INTRODUCTION
Benign prostatic obstruction (BPO) and its related
lower urinary tract symptoms (LUTS) are a common
problem that has an impact on daily activity and qual-
ity of life. It may lead to serious outcomes, including
urinary tract infection (UTI), hematuria, bladder
stones, hydronephrosis, renal insufficiency and uri-
nary retention [1]. Transurethral resection of the
prostate (TURP) has been the reference standard for
the treatment of BPO over the past 30 years, however,
the intraoperative and postoperative morbidity of
TURP has been the driving force behind the develop-
ment of several minimally invasive treatments of
symptomatic BPO [2-4].
Several minimal invasive treatments (MIT) have
reached the surface in the arena of instrumental treat-
ments for BPO. These therapies include the use of
different modalities in the minimalY invasive
approach to overcome BPO. Although the use of
197
electro resection has dominated the surgery of BPO,
more recently, different energy sources have chal-
lenged TURP. On the one hand microwaves and laser
techniques have matured during the past years,
whereas needle ablation, stents and injectables are at
present under evaluation. Within the coming years it
will be decided whether they pass the test of time and
are accepted both by the urological community and
regulatory authorities.
Figure 1 illustrates that the number of publications
on MIT is rapidly increasing, thus reflecting the
increased interest and use of these new technologies.
The numerous options available use different princi-
ples and result in different ablative abilities. In fig-
ure 2 the full spectrum of MIT for BPO is presented:
an increased ablative power results in an increased
relief of BPO. But besides improvement of objective
and subjective parameters, a whole range of factors
may influence the choice of MIT. The ‘perfect’ MIT
option balances in a favourable way the different
issues that need to be addressed (see Figure 3).
Figure 1. Number of publications on minimal invasive
treatments per year

Figure 2. Spectrum of MIT for BPO and ablative qualities
Figure 3. Factors influencing the outcome of therapy
In this chapter we have reviewed the different instru-
mental techniques available to treat BPO and we
have provided recommendations.
One should, however, keep in mind that ‘new’ by
definition implies that there are limited long term
data on some of the technologies considered by the
committee. Moreover, the power of the data is limit-
ed by the number of patients included, as compared
to drug studies. Also, durability may be an issue
since the committee feels that for making any rec-
ommendation one needs at least 3-5 year data.
198
I. TRANSURETHRAL RESECTION
OF THE PROSTATE (TURP)
Together with Open Prostatectomy the by far most
common surgical procedure for BPO is Transurethral
(Electro-) Resection of the prostate (TURP). Histor-
ically this developed from lithotomy and lithotripsy
of bladder calculi secondary to bladder outlet
obstruction, which has been done since the sixteenth
century without any knowledge of the etiology and
pathophysiology of the condition, using instruments
inserted into the urethra. Development of the early
resectoscope depended on many scientific advances,
such as the cystoscope, the incandescent lamp, and
the vacuum tube which made possible the develop-
ment of an electrosurgical unit for coagulation and
cutting of tissue. Modern transurethral resection is
based on improved materials and engineering, fiber
optic light sources, rod lens systems, video cameras,
and high-tech electro surgery generators. Open
prostatectomy was also improved by developments
in modern surgery, such as anesthesia, blood transfu-
sion, and antibiotics. To date, open surgical tech-
niques have used the retropubic, perineal and supra-
pubic transvesical approaches.
Certain complications of BPO are generally consid-
ered a definite requirement or absolute indication for
surgical intervention. These complications are acute
refractory urinary retention, recurrent urinary tract
infection, recurrent hematuria, bladder stones, and
renal insufficiency secondary to BPO.
Although TURP continues to be the operation most
commonly done for benign disease of the prostate
and the reference standard for treatments utilized in
the management of BPO-related LUTS, the number
of TURP’s performed declined by 52% between
1989 and 1995 (Holtgrewe, AUA Health Policy
Brief). This decline, which is documented worldwide
in several countries, represents the impact of newer
medical treatments as well as the availability of less
invasive interventional treatments. The morbidity
and mortality of TURP, although considered accept-
able, still exists. However, TURP achieves excellent
clinical results with a low retreatment rate.
TURP is usually referred to as the “Gold Standard”
or more recently ‘reference standard’. However, sup-
porting this reputation by data isn’t easy, because
most reports on major series of patients were pub-
lished decades ago. In spite of expected improve-
ments because of recent technological and medical
progress, there are few more recent publications.
And hence little data can be found in the literature
detailing minor and early side effects, such as post-
operative storage symptoms, long-term results and
retreatment rates of larger patient cohorts. It is equal-
ly surprising that the technique for TURP is not well
standardized (see Figure 1). Several different tech-
niques used to perform the procedure can be found in
textbooks. Generally, all have in common that the
adenomatous tissue needs to be resected completely
down to the capsule. Whether this is always done in
reality is a matter for discussion. Furthermore, no
experimental or clinical data are available to give
evidence that the complete resection of the adenoma
is necessary and superior to a somehow standardized
incomplete resection. Although it has been known
for years that the presence of BPO, or the degree of
prostate enlargement, does not correlate to the
degree of bladder outlet obstruction and LUTS, it
remains unknown why TURP with complete
removal of the adenoma works in the majority of
patients. Finally, in contrast to the subjective feeling
of most urologists judging TURP, even the most
recent publications demonstrate a constant relevant
overall complication rate and in particular a require-
ment for blood transfusion in a high percentage, as
well as a significant number of unsatisfied patients.
Most clinical data regarding symptom and quality of
life improvement, improvement of urinary flow rates
(Table 1) and residual urine volumes, and other
parameters such as pressure-flow-studies, come from
TURP groups in prospective randomized studies
comparing so-called minimally-invasive procedure
with TURP. Only few of such studies contain long-
term results and retreatment rates for longer than 5
years.
Intraoperative complication rates of TURP can also
be obtained from such studies, in addition some cur-
rent publications investigating these complication
specifically are also available.
In recent years, several modifications of TURP have
been introduced, most of them trying to improve
hemostasis (see Figure 2). In this context some stud-
ies were performed in which BPO patients were pre-
treated before TURP with finasteride. Data are avail-
able on a limited number of such patients, showing
encouraging results.
199
Open prostatectomy certainly removes more com-
pletely all adenomatous tissue and achieves the best
clinical results with the lowest retreatment rate; how-
ever, it is highly interventional and has a consider-
able morbidity and mortality. On the other hand
TURP in patients with very large glands (i.e., 100 g
or larger) can be associated with significant fluid
absorption, intraoperative bleeding, and intraopera-
tive and immediate postoperative complications.
Therefore, the open procedure is usually reserved for
patients with larger glands (i.e., >80 g). The decision
whether to do a TURP or open prostatectomy
depends on the urologist’s training and surgical skills
in resecting larger glands. Open surgery has a proven
good effect on obstruction and symptoms with 80%
completely asymptomatic [24] and a reoperation rate
of 2% within 5 years [25]: however, the transfusion
rate is very variable (0.3-100%). Other complica-
tions include secondary bleeding in 4%, bladder
neck stricture in 5-7%, and retrograde ejaculation in
75%.
Comparative studies of TURP and open adenomec-
tomy to prostate volumes >50g (resected weight)
showed a shorter hospitalization and lower early
complication rate for TURP, but with a higher rate of
late complications. No significant differences
regarding Qmax and residual urine volume were
found [26]. In another study [27] it was reported that
improvements in objective and subjective parame-
ters were significantly better in open prostatectomy.
In a prospective randomized study [28] 9% of
patients of the open prostatectomy group and 15% of
the TURP group were dissatisfied with their clinical
outcome.
CONCLUSION:
• TURP is the reference instrumental treatment
modality
BUT:
• Outcome data on TURP are outdated and
scarce
• There is significant variability in clinical out-
comes
• There is questionable standardization
• The development of bipolar is still inadequate-
ly studied
Table 1. Treatment Outcomes From Recent Studies on Transurethral Resection of the Prostate

IPSS Qmax
Study Baseline Postoperative Baseline Postoperative
Anson et al. [6] 18.2 5.1 10.0 21.8
Borboroblu et al. [8] 23.8 6.4 nd nd
Carter et al. [9] 19.8 5.9 nd nd
Cowles et al. [10] 20.8 7.5 9.5 16.5
Dixon et al. [12] 20.5 7.7 8.8 14.7
Fay et al. [13] 22.5 8.6 8.8 18.9
Francisca et al. [11] 20.8 3.2 7.9 23.5
Gilling et al. [14] 23.0 4.3 9.1 20.4
Kabalin et al. [16] 18.8 6.4 9.0 21.2
Kaplan et al. [17] 18.3 6.1 8.3 19.6
Karanjavala et al. [17] 19.0 4.5 9.5 19.7
Keoghane et al. [15] 19.4 6.5 11.4 12.7
Keoghane et al. [18] 20.2 7.0 9.0 14.0
Küpeli et al. [19] 21.6 5.2 9.2 19.7
Mottet et al. [5] 23.7 4.7 7.7 17.6
Muschter et al. [20] 21.1 3.5 8.9 25.6
Oesterling et al. [21] 24.0 8.6 8.8 20.8
Patel et al. [22] 23.3 3.2 7.5 22.6
Uchida et al. [23] 21.3 3.3 8.0 21.1

Figure 1. Examples of different resection techniques. Figure 2. Examples of different resection loops.

200
 delivery of greater energy and the vaporization of
II. LASER larger amount of tissue. The interstitial fibers have a
diffuser tip that is inserted directly into the prostatic
Laser prostatectomy as described initially in 1986 tissue causing coagulative necrosis while sparing the
was a novel way to treat patients with LUTS, and urethra from injury.
became popular after 1990 when the side-firing fiber
was introduced [29]. Four types of laser have been 2. TYPES OF LASERS AND SURGICAL
used for treatment of LUTS secondary to BPO; TECHNIQUES
Neodymium: Yttrium Aluminum Garnet (Nd: YAG),
a) Visual laser ablation of the prostate (VLAP)
the Holmium: YAG (Ho: YAG), the Potassium
Titanyl Phosphate: YAG (KTP: YAG) and the diode In 1992, Costello and associates were the first to
laser. report using Nd: YAG laser for the treatment of BPO
[29]. This procedure utilized a side firing fiber in a
The ideal type of laser light for the treatment of
no contact mode (see Figure 1). Tissue effects are
LUTS secondary to BPO is the one that has a high
largely based on the power setting (40 to 60 W in
degree of incisional and vaporizing properties allow-
most studies), duration of the treatment (30 to 120
ing clean removal of prostatic tissues, has the ability
seconds), and the distance between the fiber tip and
to coagulate blood vessels in the prostatic fossa, and
the prostate. In most series, four quadrant areas of
is not significantly absorbed by fluid. The laser tech-
laser treatment (2, 4, 8, and 10 o’clock) are used in
niques include coagulation, vaporization, resection
patients with prostatic urethral lengths of 2.5 to 4 cm
and dissection depending on the wavelength, power,
or less [32]. In larger prostates sextant spots were
and type of emission (continuous or pulsed). Cur-
described. In an attempt to avoid retrograde ejacula-
rently, many laser procedures use distinctly different
tion Nau et al [33] started the coagulation effect 1 cm
surgical techniques and the broad term ‘laser prosta-
distal to the bladder neck with a scanning motion
tectomy’ is quite ambiguous if the exact technique is
radially or longitudinally. The advantages of the
not elaborated upon [30].
VLAP include simplicity of the procedure and a
haemostatic effect, which means it can be used safe-
1. TYPES OF LASER FIBERS
ly in anticoagulated patients [34]. It also carries no
Several types of fiber systems are used in the treat- risk of dilutional hyponatremia or TUR syndrome
ment of BPO including: bare fibers; right-angle [35]. A number of randomized trials comparing
fibers, contact tip, and interstitial fibers [31]. A vari- VLAP to TURP were reported. In a multicenter
ety of right-angled delivery systems are used in non- study, Cowles et al [36] ( level 1 evidence ) random-
contact laser procedures. The laser energy is passed ized 115 patients to TURP (n=59) or VLAP (n=56)
along the laser fiber and then reflected or refracted. and found that the operative and hospitalization
Reflective fibers utilize a 6 to 7.5 F gold or gold-plat- times were shorter in the VLAP group. The improve-
ed alloy dish that is glued to the end of the fiber [32]. ment in symptom score was 48% and 64% in the
The Urolase fiber is composed of a bare fiber that VLAP and TURP arm, respectively. The Qmax
ends in an open metal cavity with a prism. This sys-
tem allows application of laser to certain areas of the
prostate for a fixed period of time (30-60 sec). The
air refraction fibers include a bare fiber ending in a
plastic enclosed cavity in which the laser energy is
bent by air refraction and exists through a small aper-
ture in order to decrease the fiber damage by treated
tissues. The advantages of this type include higher
power density with narrower beam. Also the fiber
can be dragged through the entire prostate and allows
the choice of coagulation or vaporization treatment
[39]. Contact fiber tips are composed of fused silica
quartz or synthetic sapphire, which, when placed
directly against the prostate, produce intense thermal
energy and immediate removal of tissue. Contact Figure 1. Example of side fire laser treatment
fibers have been improved over the years to allow

201
increased by 59.5 % and 73.7% in the VLAP and
TURP group, respectively. The long-term results
were reported to be durable. McAllister et al [37]
reported on 5-year follow-up of patients who under-
went VLAP and TURP. The authors found that 8 of
51 patients (16%) in the TURP group required reop-
eration, compared with 18 of 47 patients (38%) in
VLAP. The subjective and objective outcome of
VLAP was similar to that of TURP, with the results
of both treatments maintained at 5 years. The other
reported complications of VLAP include storage
symptoms for 1 to 2 months, and urinary retention in
up to 30.4% of patients requiring longer catheteriza-
tion for up to several weeks [36]. Retrograde ejacu-
lation rates varied from 27% to 33%, with loss of
potency in 4.3% [36-38]. The EAU does not recom-
mend VLAP as a first line surgical treatment for
BPO patients, but indicate that it may have a role in
the treatment of a high-risk patient group [39].
b) Contact Nd: YAG Laser Vaporization
In this approach the laser is applied in contact mode
using a sapphire contact tip that converts the laser
light into heat whereby the high temperature induces
vaporization and immediate removal of some tissue.
This results in immediate relief of obstruction, early
catheter removal, rapid improvement of voiding
symptoms and decreases the postoperative retention
and storage symptoms. The disadvantages of this
approach include the inability to ablate large glands
and less effective hemostasis compared with the non-
contact approach.
In a randomized trial Keoghane et al [40] compared
the symptom improvement and Qmax in 72 contact
laser treated patients and 76 patients who underwent
TURP. At 3 months the results were quite compara-
ble (symptoms score decreased from 19.9 to 9.6 in
the laser group and from 19.4 to 7.5 in the TURP
group and maximum flow rate improved from 11.8
to 21.3 ml/sec in the laser group and from 11.4 to
21.8 ml/sec in the TURP group). They reported an
update at 36 months in 43 and 44 patients showing a
similar long-term outcome [41].
The reported 7-year follow up of the patients in this
study confirmed the durable effect of the treatment in
the two groups and the re-operation rate after TURP
and laser treatments was 6% and 7%, respectively
(Level 1) [41]. Keoghane et al [42] reported on the
long term results of Oxford Laser Prostatectomy
Trial. The authors found that the voiding outcomes
were equally maintained after TURP and contact
laser prostatectomy and the re-operation rate were
202
similar (18% in laser group and 14% of TURP
patients) [41,42] (level 1).
c) Interstitial Laser Coagulation of the prostate
(ILC)
In 1991 Hofstetter introduced ILC of the prostate
[43]. In this technique, Nd: YAG, a diode or holmi-
um laser fibers are placed directly into the prostatic
adenoma (see Figure 2). The fiber is fitted with a
special diffuser tip or used as a bare fiber placed per-
cutaneously through the perineum or directly
through a cystoscope. The Nd: YAG laser fiber is left
in position for 10 minutes at 5 to 10 W. The diode
laser requires a 3-minute treatment at each location
starting at 20 W and decreasing to 7 W in the “turbo
mode”. The aim of this technique is to preserve the
urethra, thus preventing tissue sloughing with less
storage symptoms than seen with other laser tech-
niques.
Figure 2. Example of interstitial laser coagulation
Martenson and de la Rosette [415] reported a com-
parative study between ILC and TURP in 30 and 14
patients, respectively with 2 years follow up. The
retreatment rate for the ILC group was 21% com-
pared to 7% in the TURP group, no incontinence was
documented in either group, with one patient in the
TURP group developing a urethral stricture. The
authors found that when using a temperature sensing
system, the objective results of laser treatment
improved and seem to be more durable. The storage
symptoms are frequent and long post-operative
catheterization is required for up to one month in
some studies. To achieve immediate relief of
obstruction, some authors perform a limited resec-
tion of the coagulated tissues immediately after ILC
[46].
A multicenter randomized trial at six U.S hospitals
comparing TURP (n=35) with ILC (n=37) was pub-
lished by Kursh et al. [47]. At 2-years follow up, the
Qmax improved by 81% in the TURP group (from
9.1 to 16.5 ml/sec) and by 51% in the ILC group
(from 9.2 to 13.9 ml/sec). The improvement in AUA
symptom index was 70% in the TURP group and
63% in the ILC group. The ILC group had a signifi-
cantly shorter hospital stay and a better sexual func-
tion score. The urinary tract infection rate in ILC
group was 20%, the retreatment rate was 16% and no
decrease in PSA was noted at 2 years [23]. Floratos
et al [48] reported on long-term follow up (34 to 53
months) after VLAP (n=107), contact laser (n=30),
and ILC (n=53). The retreatment rate was higher in
ILC group than other groups (41% vs 14%). Similar
retreatment rate (35%) within 8 years after ILC was
reported by Terada et al. [49].
The future of ILC technique in the treatment of BPO
is debatable. The unacceptable re-operation rate,
delayed improvement and longer catheterization
time support the AUA guidelines which do not rec-
ommend ILC as a treatment option. The EUA guide-
lines suggest using the ILC only in the treatment of
high-risk patients [39,44,50].
d) Photoselective Vaporization of the Prostate
(PVP)
The potassium Titanyl phosphate:YAG (KTP) laser
is based on the technique of passing Nd: YAG laser
light through a KTP crystal. This halves the wave-
length of the emitted laser to 532 nm and doubles its
frequency. The emitted light is a visible green light,
which is strongly absorbed by red tissues and
hemoglobin; this means that a blood rich organ such
as the prostate gland is an excellent target. Based on
these qualities, its name (photoselective vaporization
of the prostate) was coined [51].
In 1997 Malek et al [52] developed the technique of
high power KTP laser vaporization using the 60 W
setting at the Mayo clinic. This pilot study of 10
patients assessed the safety and efficacy of the pro-
cedure in the outpatient setting. (Level 3) At 24
hours the Qmax improved from 8 to 19.4 ml/sec, and
none of the treated patients developed dysuria,
hematuria or required re-catheterization. In 2000,
Malek et al [53] reported a 2 years follow-up of 55
patients with pre-operative prostate volumes as large
as 90 cc (mean prostate volume 43cc) who under-
went 60 W KTP laser vaporization of the prostate. At
2 years follow-up there was an 82% improvement in
the mean symptom score and a 278% mean improve-
203
ment of Qmax, from 8 to 29.1 ml/sec. Recently an 80
W KTP laser generator was developed. Hai and
Malek [54] reported the first pilot study of 10
patients who underwent 80 W KTP laser vaporiza-
tion of the prostate. Te et al [55] reported the first
multicenter study of 139 patients with a mean
prostate volume of 54.6 cc who underwent 80 W
KTP laser vaporization of the prostate with a 12-
month follow-up. The mean operative time was 38.7
minutes, the mean catheterization time was 14 hours
and 32% of patients required no post-operative
catheterization, thus making PVP a cost-effective
procedure. There was an 82% improvement in symp-
tom score, 190% improvement in Qmax, and 37%
reduction in prostate volume. The postoperative
complications included dysuria (9.4%), transient
hematuria (8.6%), transient urge incontinence
(6.5%) recatheterization (5%), retrograde ejaculation
(36%) bladder neck contracture (1.4%) and urethral
stricture (0.7%). Sandhu et al [56] reported on 64
men with a mean prostate volume of 101 cc who
underwent PVP. The mean operative time was 123
min and 62 out of 64 patients were discharged with-
in 23 hours.
Long-term results demonstrated sustained improve-
ment in voiding parameters. Of 84 patients who
underwent PVP, Malek and Kuntsman [57] reported
80% improvement in symptom score and 170% to
250% improvement in the Qmax after 5 years fol-
low-up, with no need for re-operation.
e) Holmium: YAG laser
Holmium: YAG (Ho: YAG) is a multifunction surgi-
cal laser that has multiple applications in urology
such as incision of urethral and ureteral stricture
[58], lithotripsy of urinary calculi [59], ablation of
superficial urothelial tumours [60], bladder neck
incision (BNI) [61] and ablation, resection and enu-
cleation of the prostate [62]. The excellent haemo-
static properties of holmium laser result in a mostly
bloodless field and decrease or eliminate the need for
bladder irrigation [63]. Holmium laser works
through thermal energy that allows the use of physi-
ologic irrigants such as normal saline which elimi-
nate the risk of dilutional hyponatremia and TUR
syndrome [64].
Initially, the Ho: YAG laser was used in combination
with ND: YAG laser to vaporize and coagulate pro-
static tissue in a technique known as Combination
Endoscopic Laser Ablation of the Prostate (CELAP).
[65]. However, the addition of Ho:YAG laser does
not improve the longer catheterization time, storage
symptoms, delayed improvement and high
recatheterization rate (26%) caused by the ND: YAG
laser [66].
Now, with more clinical experience, the high power
Ho: YAG laser is used alone for ablation, resection
and enucleation of the prostate due to its excellent
incisional, ablative and haemostatic properties [67].
1. HOLMIUM LASER BLADDER NECK INCISION
This technique uses holmium laser energy to perform
a single or bilateral incision of the bladder neck [66].
Cornford et al [61]. reported the results of holmium
laser incision of the bladder neck in 100 men with
prostate glands less than 30 gm. IPSS decreased
from 19.2 to 3.7 at 6 weeks and remained improved
at 2 years. Qmax increased from a mean of 9.79 to
19.23 and 18.27 ml/ sec at 6 weeks and 2 years,
respectively. The authors confirmed that the holmi-
um: YAG laser allows transurethral prostatic incision
to be performed without the need for postoperative
catheterization and without significant perioperative
complications.
2. HOLMIUM LASER ABLATION OF THE PROSTATE
(HOLAP)
Holmium Laser Ablation of the Prostate (HoLAP) is
a simple procedure and suitable for small to moder-
ate sized prostates but it is not efficient and is tedious
for treating larger prostate glands and also generates
no tissue specimen for histopathological analysis
[68,69]. Currently, HoLAP is being revisited as an
easy to learn procedure which is comparable to the
KTP prostate ablation. Vaporization of the prostate
usually starts at the bladder neck using the side firing
laser fiber to make a BNI at 5 and 7 o’clock, then the
laser fiber is gently moved over the surface of the lat-
eral lobes towards the apex of the prostate, proximal
to the verumontanum. Circumferential vaporization
of the obstructive tissue at the bladder neck and both
lobes creates a TURP-like defect.
Mottet et al [70] (level 1 evidence) reported a pros-
pective Randomized Catheter Trial (RCT) compar-
ing HoLAP and TURP in men with prostate size <60
ml. The subjective and objective improvement in the
HoLAP group was similar to that obtained with
TURP at 1-year follow up. The advantages of
HoLAP over TURP included less bleeding, shorter
hospital stay, and shorter catheter times without the
need for any irrigation.
Tan et al [71] reported a 7-year follow-up of 34
patients who underwent HoLAP. There was an 83 %
improvement in Qmax and 47% decrease in AUA
204
score with a re-operation rate of 15% and recatheter-
ization in 9% of patients. At the McGill University
Health center (MUHC) similar results were obtained
in 80 patients who underwent HoLAP. They demon-
strated a 64% improvement in Qmax, 51% decrease
in IPSS and 67% decrease in PVR at 5 years com-
pared to pre-operative values.
HoLAP is an easy technique with a short learning
curve but the procedure is rather slow [68].
3. HOLMIUM LASER RESECTION OF THE PROSTATE
(HOLRP):
This procedure is similar to the standard TURP.
Resection of the prostate is achieved by using the
end firing Ho: YAG laser fiber. The procedure is
started with bilateral incisions to define the depth
and amount of tissue to be removed. The two inci-
sions are joined just in front of the veru montanum to
undermine the median lobe and detach it back into
the bladder. Incisions at the 1 and 11 o’clock position
are needed to define the upper margin of the lateral
lobes excision. The lobe is peeled off the surgical
capsule until only a bridge of tissue remains at the
bladder neck. Then the lobe is cut into small peaces
to facilitate their removal with a modified resecto-
scope loop or Ellik evacuator [62, 72].
In 1996 Gilling et al [62] reported the results of the
initial 84 patients who underwent HoLRP. The mean
AUA symptom score improved from 21.3 pre-opera-
tively to 4.1 at 3 months. The mean Qmax increased
from 7.5 to 19.3 ml/sec at 3 months post-operatively.
Only 2 patients’ required bladder irrigation for hema-
turia and 5% of patients’ required recatheterization.
The authors concluded that, the HoLRP technique
produces a cavity identical in appearance to TURP
with a relatively bloodless procedure that results in a
short catheter time, immediate symptom relief and
minimal storage symptoms. Similar results were
confirmed by other larger studies that demonstrated
that HoLRP has equivalent or even better results than
TURP [73].
Mackey et al [74] reported their results of HoLRP in
96 patients with mean prostate volume of 52 cc (10-
200 cc). The mean operative time, the catheterization
time and hospital stay was 43 min, 1.5 and 1.1 days,
respectively. They suggested that the HoLRP tech-
nique is equivalent to TURP and can be performed as
day case surgery and can be used safely in a fully
anticoagulated patient with a large prostate. In 1999
Gilling et al [75] (level1) published the results of a
prospective randomized trial with 1-year follow-up
of patients assigned to HoLRP (n=61) and TURP
(n=59). The improvement in flow rate and symptoms
score was similar but the operating time was longer
in the HoLRP group, however the nursing contact,
catheter time (20 vs 37.2 hours) and hospital stay
(26.2 vs 47.5 hours) were significantly shorter than
the TURP group. At 12 months, 8.3% of the HoLRP
group and 10.6% in the TURP group had deteriora-
tion in their level of potency compared to the pre-
operative level. Retrograde ejaculation developed in
96% and 86% of the HoLRP and TURP groups,
respectively. Re-operations included 1 bladder neck
incision in the HoLRP group and 2 bladder neck inci-
sions and 2 revisions in the TURP group. The report-
ed stricture rate was similar in each group (9.9 and
9.8%). No perioperative blood transfusion was need-
ed in the HoLRP group while 6.6% of patients in the
TURP group required blood transfusion. The long-
term results showed no significant difference
between the two groups in terms of symptom score
or flow rate at 2 years and 4 years follow up [76, 77,
78].
Fraundorfer et al [79] reported a comparison
between HoLRP and TURP in terms of cost effec-
tiveness. HoLRP offers a 24.5% cost saving over
TURP and 93 procedures annually would cover the
initial and maintenance cost of the laser machine.
The 2 major critiques of the HoLRP procedure are
the longer operative time than TURP (average 16
minute) and the resulting difficulties with pathologi-
cal interpretation of the resected small pieces of the
adenoma that may have been affected by thermal
damage [80].
These drawbacks have been overcome with the
development of a transurethral morcellator that
allows complete enucleation of the adenoma in a
new technique known as Holmium Laser Enucle-
ation of the Prostate (HoLEP).
4. HOLMIUM LASER ENUCLEATION OF THE
PROSTATE (HOLEP):
Holmium Laser Enucleation of the prostate (HoLEP)
is the most recent step in the evolution of holmium
laser prostatectomy (see Figure 3).
Refinement of the holmium laser technique and
development of an efficient tissue morcellator have
led to the true anatomic enucleation of a prostatic
adenoma of any size. Ho: YAG laser fiber acts like
the index finger of the surgeon during an open
prostatectomy peeling the median and lateral lobes
off the surgical capsule. In contrast to TURP, HoLEP
is equally suitable for small, medium sized and large
Figure 3. Example of Holmium laser enucleation of the
prostate
prostate glands with a similar clinical outcome that is
independent of the prostate size [81].
The steps of the technique has been described in
detail elswere [82, 83]. Briefly, the two-lobe tech-
nique starts with a 5 or 7-o’clock incision with enu-
cleation of one lateral lobe which is followed by the
median and remaining lateral lobe enucleation as a
single unit into the bladder. The three-lobe technique
is suited for a large gland with a large median lobe.
In 1998 Fraundorfer and Gilling [84] reported the
first 14 patients treated with HoLEP where, the mean
ultrasound volume of the prostate was 98.6 cc (55-
200 cc). The mean total operating room time was 98
min (64-190). At 1 month, the mean Qmax was 25.2
ml/sec and the mean AUA score was 7.2. Gillling et
al [85] subsequently reported their preliminary expe-
rience with 64 patients who had undergone HoLEP
combined with intravesical morcellation. The mean
pre-operative prostate volume was 75.3 cc. The
mean laser time and morcellator time was 46.9 and
10.5 minutes respectively.
In 2000 Gilling et al [86] reported on 43 patients
with pre-operative prostate volume >100 g, the mean
catheter time was 19.7 hours, and the mean hospital
time was 28.4 hours. One patient required readmis-
sion for evacuation of tissue fragments. The authors
concluded that the holmium: YAG laser can be used
to enucleate the adenoma of a large prostate in more
or less the same way the surgeon’s finger does dur-
ing open prostatectomy.

205
Moody and Lingeman [64] reported the initial U.S
experience with 61 patients who underwent HoLEP.
The laser time was 77 minutes and morcellation effi-
cacy was 2.3 g/min. The complications were stress
incontinence observed in 13 patients, and bladder
neck contracture in 2 patients. Prostatic capsule per-
foration and bladder mucosal injuries occurred in 1
and 5 patients, respectively.
The authors attributed these complications to the
learning curve. Two patients were unable to void
postoperatively and were placed on intermittent self-
catheterization. Kou et al [87] reported on 108
patients with a mean prostate volume of 63 cc. All
the outcomes parameters were decreased significant-
ly with 91.7% and 85% decrease in PSA and prostate
volume. The dramatic reduction of PSA after HoLEP
confirms a nearly complete removal of adenoma.
Vavassori et al [88] reported 2 years follow-up of
196 patients who underwent HoLEP.
The improvement of voiding outcome is durable for
2 years with a 2.5% reoperation rate, bladder neck
contracture and urethral stricture developed in 0.5%
each. The authors reported bladder mucosal injuries
in 6.6%, perforation in two patients (1 capsular and
1 bladder perforation) storage symptoms in 23% and
transient stress incontinence in 7.1%. Another study
reported the morbidity of 206 patients undergoing
HoLEP; whereby the transfusion rate was 1%, cap-
sular perforation 1.5% and bladder mucosal injury
rate 1.9%. The recatheterization rate was 7.8% and
bladder neck contracture and urethral stricture
occurred in 3.9% and 2.4%, respectively [89].
One of the advantages of HoLEP is that it has no size
limitation, with significant improvement of the
symptoms and flow rate regardless of the size of the
prostate. The rate of blood transfusion, catheteriza-
tion time and hospital stay did not depend on the
prostate size either [90, 91]. The classical treatment
of large prostates used to be limited to either staged
TURP or open prostatectomy, both of which are
associated with significant morbidity. Now, HoLEP
allows the patients with large prostates who tradi-
tionally required open prostatectomy, to be treated
endoscopically [86, 92].
Randomized comparative trials (level 1 evidence)
have shown similar results for HoLEP and tradition-
al surgery used to treat BPO. Tan et al [93] found that
HoLEP is superior to TURP for relieving bladder
outlet obstruction. HoLEP is also superior to TURP
with less bleeding, amount of tissue removed,
decreased catheter time and hospital stay [94, 95].
206
There was no blood transfusion needed in the
HoLEP group in contrast to the TURP group where
the transfusion rate was 3.3%. In another study Mon-
torsi et al [96] found that HoLEP and TURP were
equally effective with similar rate of complications
at 1 year follow-up. The erectile function did not
show a decrease from baseline in either group. There
was no TUR syndrome in the HoLEP group, versus
in 2.2% of patients in the TURP group.
Transient urge incontinence was reported in 44% and
38% of the HoLEP and TURP groups, respectively.
This complication is usually short term and self-lim-
iting. Urethral stricture occurred in 1.7% in HoLEP
group and 7.4% in the TURP group.
Kuntz et al [97] reported that the AUA symptom
scores improved 13-fold in the HoLEP and more
than 5 fold in the TURP group, however, the maxi-
mum flow rate improved about 5-fold in each group.
Mean PVR decreased by 98% in the HoLEP and
88% in the TURP group. Of sexually active patients,
74% in the HoLEP group and 70.3% in the TURP
group had retrograde ejaculation. The operative time
of HoLEP was 25% longer than TURP, but this is
because Kuntz used the electrocautery loop to frag-
ment the tissue in most of the HoLEP cases at the
beginning of their study, until the tissue morcellator
became available.
The operative time was longer than TURP, which
seems to be due to the significant learning curve of
HoLEP, which is the main problem of the HoLEP
procedure. It is difficult to compare operative time in
HoLEP and conventional surgery, as the prostate size
influences the mean operative time.
In the experience at the MUHC, HoLEP requires
longer training than TURP and the operator became
comfortable with the HoLEP technique after a mean
of 20 to 30 cases with moderate size prostates [98].
Some authors suggest that learning HoLEP is equiv-
alent to learning TURP because it is a mostly blood-
less procedure with good visibility, however close
supervision of an experienced urologist is a prereq-
uisite for success [93].
A randomized study comparing HoLEP and trans-
vesical prostatectomy (Kuntz et al [99, 100]) found
that both procedures are equally effective with less
perioperative morbidity in the HoLEP group. The
blood transfusion rate was 13% in open prostatecto-
my group and zero in the HoLEP group (level 1 evi-
dence).
Unlike HoLRP, there are no thermal tissue artifacts
in the enucleated specimen in the HoLEP procedure
which improves the histological assessment com-
pared to TURP [101] HoLEP has the advantage of
safely treating (critically ill) patients and anticoagu-
lated patients, with low perioperative morbidity
regardless of the prostate size [102]. This justifies the
suggestion that HoLEP is the modern gold standard
alternative to TURP and open prostatectomy. It
appears to be at least as effective as the traditional
surgery of BPO in terms of its short and long- term
efficacy and low perioperative complications [103].
MICROWAVE THERMOTHERAPY
Thermotherapy uses high temperatures to produce
coagulation necrosis of prostatic tissue, attempting to
achieve results with heat that are similar to those
achieved by TURP but inducing a lower morbidity.
Microwaves delivered via the transurethral route
have been the dominant means used to heat prostatic
tissue, but hot water (Water-Induced Thermotherapy)
has also been used for the same goal.

SUMMARY 1. TRANSURETHRAL MICROWAVE

Over the last decade, several minimally invasive
treatments have been introduced to challenge the
standard TURP in the treatment of symptomatic
BPO. Laser therapy is one of the most document-
ed alternatives. The improvement in laser technol-
ogy has led to the development of promising treat-
ment options.
The long catheterization time and severe storage
symptoms with delayed improvement, resulted in
abandoning VLAP as a treatment option. Further-
more contact laser and interstitial laser coagula-
tion of the prostate are not considered as first line
treatments of BPO and are only used in high-risk
patients. KTP laser has produced promising
results as a challenge to TURP but a randomized
control trial with long-term follow-up is still
needed.
Holmium laser provides several applications in
urology and its use in the treatment of BPO is con-
sidered a true challenge for TURP, as well as to
open prostatectomy. HoLEP has the same or even
better results than the traditional surgery, with low
morbidity, regardless of the prostate size and it is
being promoted as the new gold standard for treat-
ment of BPO.
THERMOTHERAPY (TUMT)
TUMT uses a special transurethral catheter with a
microwave antenna that transmits heat into the
prostate with the eventual goal of destroying tissue
by achieving temperatures that exceed the cytotoxic
threshold and inducing cell death. More specifically,
heating in excess of 45°C results in coagulation
necrosis. In addition, apoptosis has been observed, at
temperatures lower than those inducing necrosis.
Brehmer and Svensson [104] investigated the feasi-
bility of using heat to induce apoptosis in human pro-
static stromal cells. Several temperatures and expo-
sure times were tested. Exposure of the cultured cells
to 47°C for 1 hour achieved the most extensive apop-
tosis (76% of the cells). In addition, it was reported
that apoptosis was observed in a variety of cell sys-
tems at temperatures lower than those inducing
necrosis [105] (see Figure 1).

CONCLUSION:
• HoLEP ≈ is equivalent to TURP/Adenomecto-
my
• HoLEP has the disadvantage of a long learning
curve.
Figure 1. Example of TUMT principle
• Resurgence of vaporization techniques (green
light and holmium side fire ablation) need to be
better studied.

207
It has also been proposed that induced necrosis dis-
rupts periurethral alpha-adrenergic receptors, result-
ing in denervation of the smooth muscle cells [106].
These findings may be responsible for the increased
urinary flow after TUMT. Recently, it was demon-
strated that TUMT increased the sensory threshold
(evoked by electrical stimulation) in the posterior
urethra by 30%, resulting in the alleviation of storage
symptoms [107]. During the last decade, numerous
studies have been published presenting the clinical
results from the application of TUMT for the treat-
ment of LUTS associated with BPO. These studies
have used different devices and energy protocols,
have had different follow-up periods and response
criteria, and have differed in patient selection. The
steadily increasing number of publications on TUMT
is suggestive of the method’s acceptance and the
efforts made to optimize the treatment outcome. The
identification of the deficiencies of the first-genera-
tion devices, mainly the limited and often interrupt-
ed energy delivery, contributed to their further evo-
lution regarding heat distribution, treatment time,
energy, and monitoring of the treatment effect. Many
TUMT devices with different technical specifica-
tions and treatment protocols have been evaluated.
Bolmsjo et al [108] reported substantial differences
in heating profiles between devices with different
microwave antenna designs.
However, at present time there is not enough critical
data to support the hypothesis that TUMT challenges
TURP, further studies that provide high quality of
evidence are needed.
a) Clinical outcomes-efficacy
Hoffman et al [109] combined all evidence from ran-
domized controlled trials evaluating the efficacy and
safety of microwave thermotherapy in treating men
with LUTS and BPO, in order to quantify the thera-
peutic efficacy. This excellent systematic review pro-
vides level 1 evidence and represents a cornerstone
on which we can build our recommendation on the
efficacy of TUMT in the management of BPO. Over-
all, 540 patients were randomized in the six eligible
randomized studies, including 322 to TUMT and 218
to TURP. Patients included in the studies had moder-
ate to severe LUTS, with decreased Qmax and mod-
erately enlarged prostates. Studies generally exclud-
ed men with very large prostates (>100 g), prominent
median lobes and in urinary retention. These exclu-
sion criteria are similar to those used in other surgi-
cal studies of BPH treatment, suggesting that the pre-
sent results are generalizable. Treatment was offered
by different TUMT devices and software including
208
Prostatron (Prostatsoft 2.0 and 2.5) and ProstaLund
Feedback.
The mean (range) age was 67.8 (65-70) years, base-
line symptom score 19.5 (15.7-21.3), baseline Qmax
8.6 (7.9-10.1) ml/sec and prostate volume
44.5 (33.9-52.7) ml, and did not differ by treatment
group. Two studies followed patients for 6 months
and 4 studies provided a 12-month follow-up. The
proportion of patients who completed follow-up
ranged from 85 to 100%. Five studies found signifi-
cant decreases in urinary symptoms and significant
increases in Qmax between baseline and follow-up
for both TURP and TUMT, while Ahmed et al [110]
found that TUMT did not improve Qmax.
TUMT was somewhat less effective than TURP in
reducing LUTS. The pooled mean symptom score
for men undergoing TUMT decreased 65% in
12 months (from 19.4 to 6.7), compared with 77%
(19.6 to 4.5) in men undergoing TURP. Weighted
Mean Differences (WMD) were calculated with
95%CI for the between treatment differences in
pooled means. WMD for the symptom score at the
follow-up for all six studies was 1.83 (3.09 to 0.58),
favouring TURP. TURP led to greater improvement
in Qmax than TUMT; the pooled mean Qmax for
men undergoing TUMT increased by 70% (7.9 to
13.5 ml/sec), and by 119% (8.6 to 18.7 ml/sec) in
men undergoing TURP. The WMD for Qmax at the
follow-up was 5.37 (4.226.51) ml/sec, favouring
TURP. The mean Qmax after TUMT was usually
<15 ml/sec, since only two studies reported a mean
post TUMT Qmax greater than 15 ml/sec. In con-
trast, five studies reported that TURP achieved a
mean Qmax >15ml/sec. Three studies [111,112,113]
evaluated the effect of treatment on QOL using the
eight IPSS question. The pooled mean QOL score for
men undergoing TUMT decreased by 58.5% (4.1 to
1.7) and by 63.4% (4.1 to 1.2) in men undergoing
TURP. Although QOL significantly improved after
both TUMT and TURP, there were no significant dif-
ferences between treatments.
The urinary symptom scores (WMD 1.83) and Qmax
(WMD 5.37 ml/sec) significantly favoured TURP at
the follow-up. However, the mean urinary symptom
scores for TUMT patients almost always decreased
from the moderate-to-severe symptom range to the
mildly symptomatic range. Analytical results are list-
ed in Table 1 [114, 115, 116, 117, 118, 119].
Gravas et al performed a pooled analysis of 3 studies
of ProstaLund Feedback TUMT with 12-month fol-
low-up [120]. They combined 2 randomized studies
comparing PLFT to TURP and an open label study
with no comparative group. It should be noticed that
the study by Wargell et al [113] has also been includ-
ed in the systematic review by Hoffman et al. The
authors underlined that inclusion and exclusion crite-
ria of the 3 studies were identical and this fact
reduced any selection bias. They tested noninferiori-
ty of PLFT (183 patients) compared to TURP (65
patients) using a Confidence Interval (CI) approach.
The responder rate was 85.3% and 85.9% in the
PLFT and TURP group, respectively. One-sided 95%
CI analysis showed noninferiority of PLFT as com-
pared to TURP. A responder was defined as a patient
that following treatment had an IPSS of 7 or less,
and/or 50% or greater improvement in IPSS from
baseline, and/or Qmax of 15ml/sec or more, and/or
50% or greater improvement in Qmax from base-
line. In the PLFT group there was a marked decrease
from a mean IPSS of 20.9 at baseline to 6.4 at the 12-
month visit (69% decrease). Mean IPSS was
decreased from 20.7 at baseline to 7.1 at the 12-
month visit after TURP. The 1-sided CI (95%) for the
ratio of IPSS between the PLFT and TURP group
(1.06) suggested noninferiority of PLFT compared to
TURP. In the PLFT group the mean Qmax value
improved from 7.7 ml/sec at baseline to 16.1ml/sec
at the 12-month follow-up visit, corresponding to a
109% increase. In the TURP group, Qmax increased
from a mean value of 7.5ml/sec at baseline to 18.6
ml/sec 12 months after treatment. The 1-sided lower
CI (95%) was slightly below the 0.8 limit (0.760),
suggesting that noninferiority of PLFT as compared
to TURP did not reach the predetermined level. The
bother score reduction in the two groups (70.9% for
PLFT and 64.0% for TURP) was not significantly
Table 1. Clinical outcome of randomized controlled trials (RCT), Hoffman’s systematic review and pooled data of PLFT
Treatment
different. These pooled data indicate that PLFT
seems to have an efficacy that in terms of IPSS and
responder rate is noninferior to TURP (Table 1).
The position of TUMT against medical therapy for
the management of LUTS with BPO, has also been
evaluated. Djavan et al presented a randomized
prospective comparison of targeted TUMT and
alpha-blockade with terazosin [121]. In this random-
ized study with 103 patients, the authors demonstrat-
ed that the clinical outcomes of TUMT were signifi-
cantly greater than those achieved by terazosin. The
mean IPSS improved significantly from baseline by
6 months in both groups, with a greater improvement
in patients after TUMT, where the IPSS was 38%
lower than that in the terazosin group; 78.4% of the
TUMT group had a ≥50% improvement in the IPSS,
compared with 32.7% of terazosin recipients. The
Qmax increased significantly from baseline in both
groups by 6 months and remained stable thereafter; it
was 19.8% higher after TUMT than with terazosin.
The percentage of TUMT patients having a ≥50%
increase in Qmax at 6 months (64.7%) markedly
exceeded that in the terazosin group (9.6%). The
mean QOL declined significantly in both groups at 6
months, with scores 38% lower after TUMT than
with terazosin. Furthermore in an update of the pre-
vious study, patients have been followed-up for 18
months [122]. The significant between-group differ-
ences observed at 6 months in the mean IPSS, Qmax,
and QOL score were maintained at 18 months, at
which time the improvements in these three outcome
measures were significantly greater (p <0.0005), by
35%, 22%, and 43%, respectively, in the microwave
group compared to the terazosin group. Patients were
judged to have failed TUMT if they required further

IPSS Qmax(ml/s)
STUDY TUMT TURP TUMT TURP
Baseline Post Baseline Post Baseline Post Baseline Post
Ref 86 18.5 5.3 18.4 5.2 10.1 9.1 9.5 14.6
Ref 90-92 11.2 2.7 13.3 0.9 8.0 12.3 7.9 17.7
Ref 93,94 18.3 5.0 16.7 3.4 9.3 17.1 9.3 19.3
Ref 87, 95 20.1 7.6 20.8 3.2 9.6 15.2 7.9 23.5
Ref 88 20.5 9.5 21.3 6.8 9.1 13.2 9.6 20.6
Ref 89 21.0 7.2 20.4 7.1 7.6 13.3 7.9 15.2
Review of RCT 19.4 6.7 19.6 4.5 7.9 13.5 8.6 18.7
Pooled PLFT 20.9 6.4 20.7 7.1 7.7 16.1 7.5 18.6

209
therapy, e.g. TURP. Patients on terazosin were clas-
sified as treatment failures if they discontinued their
medication because of either ineffectiveness or side
effects. By 18 months, 21 patients had failed tera-
zosin therapy, in 13 because it was ineffective and in
8 because of side effects. Subsequent to terazosin
failure, 19 of these patients underwent TUMT and 2
TURP. Three patients failed TUMT by 18 months
and proceeded to surgery. The rate of treatment fail-
ure at 18 months in the terazosin group (41%) sig-
nificantly exceeded that of the TUMT group (5.9%).
b) Durability – The test of time
The burning question for thermal-based treatment is
how good the results remain in a long-term perspec-
tive. Stated differently, how durable are the achieved
clinical outcomes?
It will be attempted to give a reply to these questions
using evidence of varying levels of quality. There is
a lack of any systematic review or meta-analysis of
randomized controlled studies, therefore the prepon-
derance of data presented in this section consists of
level 2 and 3 evidence. No randomized or other stud-
ies with a follow-up >2 years have been published.
In most studies the attrition rate was significant, thus
less than half of the initial group of patients treated is
analyzed at 4-5 years. In addition, the analyses are
done in those patients who remain in the study and
are likely to represent the best data (responders).
Despite these flaws, these types of studies remain the
best data available. Retreatment rate, defined as the
percentage of any additional therapy given for the
primary treatment failure, may serve as a measure of
durability.
Historically the Low-Energy TUMT has been aban-
doned due to the disappointing durability of its
effects. At 5 years after TUMT with the Prostasoft
2.0, 41% of the patients had received instrumental
retreatment, and 17% were being retreated with med-
ication [123]. More recent studies confirm the limit-
ed durability of clinical outcome obtained by lower-
energy programs, with a retreatment rate as high as
84.4% after 5-year follow-up [124,125,126].
In the randomized study with the longest available
follow-up by Floratos et al [111], the results of 36
month follow-up were presented. One hundred and
fifty-five patients were randomized to receive either
high-energy TUMT with software version 2.5 or
undergo transurethral resection. Improvement in
Qmax of the TUMT group from 9.2 ml/sec retreat-
ment to 15.1 ml/sec, 14.5 ml/sec and 11.9 ml/sec at
1-, 2 and 3 years, respectively, was reported, whilst
210
the IPSS symptom score improved from 20 to 8, 9
and 12, respectively. These data indicate that the
level of improvement is durable up to 3 years. The
retreatment rate for TUMT and TURP (including
medication for primary treatment failure) was 19.8%
and 12.9%, respectively. It is important to underline
the different causes of retreatment. Retreatment was
offered to the TUMT patients because of primary
treatment failure, while in the TURP group, retreat-
ment included reintervention mainly because of ure-
thral strictures, bladder neck sclerosis, meatal steno-
sis, but rarely, treatment failure. Similarly, d’ Ancona
et al [117] found a retreatment rate of 26% and 4.7 %
for TUMT and TURP in their randomized study with
a mean follow-up of 30 months. Improvement in
terms of IPSS and Qmax was significant and
remained stable during follow-up. The relatively
longer-term outcomes still favoured TURP in both of
these studies.
Recently, Wagrell et al [127] presented the 3-year
results of a prospective randomized multicenter
study comparing TUMT with ProstaLund Feedback
Treatment (PLFT, the Core-Therm device) toTURP.
At 36-month follow-up, the average value for the
PLFT group was 8.2, 1.2, and 11.9 ml/sec for IPSS,
QOL, and Qmax, respectively. The corresponding
values for the TURP group were IPSS 5.0, QOL 1.0,
and Qmax 13.5 mL. The degree of improvement was
in the same range as that observed after 12 and 24
months for both groups. These data suggest that at 3
years clinical results obtained with PLFT and TUMT
were comparable to those seen after TURP.
Trock et al [128] performed a pooled analysis of 6
multicenter studies of cooled thermotherapy with
comparable baseline measures. In total 541 patients
were pooled and data showed an improvement of
55%, 53% and 51% in AUA symptom score, QOL
and Qmax after TUMT, respectively. A slight
decrease was observed at 48 months since subjective
and objective improvement remained durable (43%,
50% and 35%, respectively).
However, given the low morbidity of TUMT, a high-
er risk of retreatment may be a reasonable trade-off
for patients with LUTS attributable to BPO. In Table
2 retreatment rates of long-term studies are present-
ed [129,130,131].
c) Morbidity (side effects-complications)
Morbidity of treatment remains one of the main con-
siderations for both clinicians and patients. One of
the commonly used arguments for the application of
TUMT as an alternative to TURP for BPO is its low
Table 2. Retreatment rate of long-term TUMT studies
Study Patients (n)
D’ Ancona [117] 31
Floratos [111] 78
Thalmann [130] 200
Miller [129] 150
Gravas [131] 213
morbidity. Pooled data of the available randomized
studies comparing TUMT and TURP regarding mor-
bidity have been published recently. Hoffman et al
systematically reviewed the adverse events of
TUMT and TURP that were reported in randomized
controlled trials. Morbidity variables are presented
as the percentage of adverse events (ratio of events to
pooled subjects). The authors also estimated the rate
of retreatment due to treatment failure or strictures
during the follow-up.
These data were reported as the number of events per
person per year of follow-up. De la Rosette et al
[132] and Walmsley and Kaplan [133] pooled data
from available randomized studies of the two inva-
sive treatments for the management of BPO. In these
studies values of each morbidity variable are
expressed as estimated mean value of the pooled
analysis. The range of mean values of the studies is
also provided. This solid body of high quality evi-
dence is presented in Table 3 and 4.
Catheterisation time, incidence of dysuria/urgency
and urinary retention were in favour of TURP. The
incidence of hematuria, clot retention, transfusions,
TUR syndrome, erectile dysfunction, retrograde
ejaculation and urethral strictures is reported to be
significantly less for TUMT than for TURP.
Having pooled data of 3 studies (2 randomized and 1
open label without a control arm) of PLFT TUMT,
Gravas et al [120] reported that serious adverse
events (SAE) probably or possibly related to the
treatment occurred in 6.0% of the patients (11/183)
in the PLFT group, including post-operative hemor-
rhage, urethral disorder (perforation with hematuria
occurred prior to treatment during the catheterization
and TUMT was not performed), fever, urinary incon-
tinence, thrombosed hemorrhoids, urethral stricture,
FU (months) Retreatment Rate (%)
30 26.0
36 19.8
42 21.5
60 29.3
48 29.1
urinary retention (2 cases), vertigo, sepsis, and epi-
didymitis. This SAE rate was higher in the TURP-
group, where 15.4% of the patients (10/65) present-
ed SAEs probably or possibly related to the treat-
ment including gout, delirium, sepsis, post-operative
hemorrhage (2 cases), hematuria (3 cases), urinary
tract infection, orchitis and urethral stricture. The
difference between groups was significant
(p=0.035).
In the same study the mean post-treatment catheter
time was on average 16.0 (±10.9) days for the PLFT
group, while for the TURP groups the mean catheter-
ization time was markedly shorter (3.1 ±3.7 days), a
finding that was expected due to the two different
types of intervention (coagulation vs. resection of
prostate).
One important complication that was not reported in
clinical trial reports was thermal injury. Although
USA Food and Drug Administration has recognized
that TUMT is safe and effective, it issued a warning
regarding unexpected procedure-related complica-
tions, due to 16 reported severe thermal injuries,
including 10 resulting in fistula formation and 6
resulting in tissue damage to the penis or urethra
[134].
Among the factors that may have contributed to the
occurrence of these complications, the FDA included
improper placement of the microwave catheter and
inadequate monitoring of the patient during treat-
ment.
The reported low morbidity and the absence of any
need for spinal or general anesthesia make TUMT a
true outpatient procedure, representing an excellent
option for patients at high operative risk (American
Society of Anesthiologists class 3 or 4) who are
unsuitable for an invasive treatment.
211
Table 3. Morbidity following TUMT and TURP (pooled data of randomized controlled studies)

de la Rosette [132] Walmsley [133] Hoffman [109]

Variables TUMT TURP TUMT TURP TUMT TURP
Hospitalization time (days) 0 4 0 2.8 - -
Catheterization time (days) 13.7 3.6 - - - -
Urinary Tract Infections (%) 14.6 13.1 9 6 17.7 13.9
Dysuria (%) - - 51 15 31.2 13.1
Hematuria (%) - - 2 100 3.9 5.9
Retention (%) - - 15 5 23.9 6.9
Clot retention (%) - - - - 0.5 4
Transfusions (%) - - 1.5 8 0 5.7
TUR syndrom (%) - - - - 0 6.1
Erectile Dysfunction (%) 4.4 9.3 8.7 10 5.7 13.9
Retrograde ejaculation (%) 19.8 63 20 65 22.2 57.6

Table 4. Reintervention/Retreatment following TUMT and TURP (pooled data of randomized controlled studies)

de la Rosette [132] Walmsley [133] Hoffman [109]

Variables TUMT TURP TUMT TURP TUMT TURP
Reintervention <30 days % 0 7.4 - - - -
Retreatment >30 days % 18.7 12.2 - - - -
a) Strictures-meatal /bladder
neck stenosis 0.7 9.6 2 7 0.006 0.006
b) Treatment failure 18 2.6 18 2.6 0.075 0.010

RECOMMENDATIONS-
FUTURE PERSPECTIVE:
The best available clinical data suggest that
TUMT is an effective treatment for BPH that can
be delivered to outpatients and has fewer adverse
events than TURP. However, TURP offers greater
improvements in symptom scores and Qmax
resulting in a smaller number of patients requiring
retreatment for BPO. Further research is needed to
evaluate the long-term effectiveness and safety of
TUMT and to determine which devices and ener-
gy settings are most effective. Our future efforts
should be focused on the development of new pro-
tocols and direct comparator trials to investigate
differences between similar therapeutic interven-
tions, development of standard definitions of treat-
ment failure and retreatment rates, determination
of cost-effectiveness through randomized clinical
studies, and incorporation of numerical findings
into daily clinical practice.
CONCLUSION:
TUMT:
• Has good clinical outcomes that seem durable
• Has low morbidity
• Is outpatient based and under local analgesia
• Is an option when instrumental treatment is
indicated (except when absolute indication for
surgery exists)
2. WATER-INDUCED THERMOTHERAPY,
(WIT™)
WIT was developed as a minimally invasive treat-
ment option for the interventional management of
LUTS due to BPO. The concept is to produce heat-
induced coagulative necrosis and secondary ablation
of the obstructing hyperplastic tissue. The source of
thermal energy is heated water circulated in a propri-

212
etary closed-loop system, which includes a specially
designed catheter. During WIT, the conductive heat
is distributed evenly around the cigar-shaped treat-
ment balloon (see Figure 2).
Currently limited data are available for the evalua-
tion of WIT in the management of LUTS and BPO.
Evidence comes mainly from a single international,
uncontrolled, multicenter trial demonstrating symp-
tom reduction and safety. In this prospective interna-
tional study [135] and its subsequent updates
[136,137], 125 patients were enrolled at 8 study cen-
ters and evaluated both short term (3, 6, and 12
months) and long-term (24 and 36 months) follow-
up. In addition a single-center experience has been
published [138]. Breda and Isgro treated patients
with and without retention using two different proto-
cols including a “standard” with a temperature set-
ting of 60°C and balloon inflation to 50F and an
“enhanced” with balloon inflation to 60F and a treat-
ment temperature of 62°C. The overall failure rate
was 23% with a mean follow-up of 10 months. The
remaining available data have only been reported in
abstract form. [139,140]. Clinical efficacy of WIT in
terms of IPSS, QOL and Qmax are presented in
detail. (see Table 5).
Published studies have not reported significant mor-
bidity. The duration of indwelling catheterization
Table 5. Clinical outcome of WIT studies
213
was as follows: 45.5% of patients were catheter free
after 1 week (the minimum required by the protocol),
30.5% after 2 weeks, and the remaining 24.0% after
3 to 5 weeks. Adverse events included prolonged (>1
month) or excessive dysuria (11.2%); epididymitis
(3.2%); prolonged (>1 month) or excessive hema-
turia (22.4%); transient impotence (1.6%); transient
urinary urge incontinence (2.4%); culture-confirmed
bacteriuria or urinary tract infection (32.8%); ure-
thral pain (4.8%); proctitis (0.8%); and urinary reten-
tion subsequent to the post-treatment catheterization
period (12.0%) [132]. The effect of WIT on sexual
function has been studied by Muschter et al. [141]
No patient suffered from newly occurring permanent
erectile dysfunction or retrograde ejaculation. Inter-
est in sex, sexual activity, and other measures were
not affected or were slightly improved by WIT. In
general during follow-up, no serious morbidity has
been reported. Breda and Isgro preferred a more gen-
eral description of the adverse events reporting
minor storage symptoms. None of the patients com-
plained of urinary incontinence, retrograde ejacula-
tion or erectile dysfunction. One case of acute pro-
statitis was reported [138].
Data regarding durability are also preliminary. In the
only long-term series by Muschter et al [135-137], it
was reported that the treatment failure rate of WIT,

Figure 2. Example WIT procedure
requiring subsequent TURP was 5.6%, 9.6% and
11.2% after 12, 24 and 36 months, respectively. On
an intention-to-treat basis, which counts all patients
lost to follow-up and unrelated deaths as treatment
failures, the percentages are higher: 10.4% after 12
months, 23.2% after 24 months and 36% after 36
months.
It seems that WIT acts as an improved transurethral
incision of the prostate with some degree of cavity
formation, since the procedure has also been associ-
ated with statistically significant post-treatment
prostate shrinkage (median 3.2 cc) at 12 months
compared with baseline [135].
For the evidence-based approach to a critical evalua-
tion of WIT, it is obvious that randomized studies
against one of the reference standards (including
medical therapy or TURP) are required.
CONCLUSION:
• Remains investigational
214
IV. TRANSURETHRAL NEEDLE
ABLATION OF THE PROSTATE
In patients who are unwilling to remain on medica-
tion, in whom medical therapy has failed or who are
unsuitable candidates for surgery, several minimally
invasive therapies have been developed, including
transurethral microwave therapy [142], interstitial
laser therapy [143], water induced thermotherapy
[144], and transurethral needle ablation of the
prostate (TUNA) [145,146,147].
1. TUNA THERAPY
TUNA therapy uses low-level radiofrequency (RF)
energy that is delivered by needles into the prostate
and that produces localized necrotic lesions in the
hyperplasic tissue. The inner region of the prostate is
selectively ablated with temperatures approaching
90-100°C while the prostatic urothelium is preserved
[145,148].
The TUNA system (Vidamed, Menlo Park, Calif)
consists of a special catheter attached to a generator.
At the end of the catheter there are two needles that
are withdrawn into two adjustable shields made from
Teflon. (See Figure 1) The needles are advanced into
the prostatic tissue and can be placed accurately into
the required position. The generator produces a
monopolar RF signal of 490 kHz, which allows
excellent heat penetration and uniform tissue distri-
bution of heat [145,148].
The procedure is performed with the patient in the
lithotomy position under topical anesthesia with 2%
intraurethral lidocaine. The best result is achieved by
applying a penile clamp for 10 minutes and giving
intravenous sedation if required [145].
The TUNA catheter is advanced under vision with
the 0-degree fiberoptic telescope. The exact position
of the needle tip within the prostate can be visualized
by transrectal ultrasound. The thermal lesion may
extend up to 5 to 6 mm beyond the position of nee-
dle deployment with lesions measuring up to 20 x 10
mm [148].
At the end of the procedure, either a urethral catheter
may be left in overnight or the patients can go home
after they have voided and feel that they are empty-
ing their bladder, without a catheter.
In general, improvement in symptoms is seen fairly
early (within 2 weeks) and is usually complete with-
in 6 weeks following TUNA treatment [149].

Figure 1. Example of TUNA treatment
The advantage of TUNA is that it can be delivered
under topical anesthesia to patients with symptomat-
ic BPO and is an attempt to minimize operative risk
and reduce postoperative sequela and the need for a
long recovery period, while optimizing the therapeu-
tic benefit.
a) Clinical Results
The initial clinical evaluation of TUNA therapy was
conducted in the early 1990s in Europe [150,151]
and in the USA in 1994 [152]. Results from a multi-
center, randomized trial comparing TUNA and
TURP led to the approval of the procedure by the
Food and Drug Administration in 1996 [145]. Subse-
Table 1. Worldwide results of Transurethral Needle Ablation (TUNA) of the Prostate with 12-month follow-up
215
quently there have been several clinical studies of
TUNA therapy reported, showing significant
improvement in the symptom score (Table 1). There
is a wide variety in the number of patients in each
series and in the length of follow-up. It can be noted
that most are open series, with a minority of ran-
domized studies. The size of studies varies from 10
to 188 patients, and, in many cases, the number of
patients, followed up for a long period of time is less
than 50% of the original sample, which makes it dif-
ficult to draw definitive conclusions [148].
The overall average improvement in symptom score
is 58% at 1 year (546 patients in 10 series), 60% at 2
years, and 66% at 3 years. The improvement in the
maximum flow rate (Qmax) reported improved flow
rates in the range of 60% to 80% (77% at 1 year, 82%
at 2 years and 92% at 3 years). These results were
significant when compared with baseline and surpass
the expected placebo effect of 30% [149].
b) Trials comparing TUNA to TURP (Table 2 and 3)
In a non-randomized prospective study the standard
TURP was compared with other minimally invasive
treatments in 212 patients, including TUNA therapy.
TURP achieved the highest decrease of prostate vol-
ume (48.8%), the best increase of maximum flow
rate (75.3%) and the largest decrease of residual vol-
ume (89.8%) in comparison to other methods [165].
Table 2. Trials comparing transurethral needle ablation with transurethral resection of prostate
Table 3. Detrusor pressures following Transurethral Needle Ablation (TUNA) of the prostate
In another prospective study comparing TURP to
minimally invasive treatments, the TURP group
achieved the best results according to IPSS and
Qmax. In up to a quarter of the patients, a secondary
TURP was performed within the first 2 years after
“less invasive” procedures, including TUNA therapy
[166].
In the United States a randomized clinical trial with
a 1 year follow up compared TUNA to TURP [145].
A total of 65 patients were treated by TUNA and 56
by TURP. The symptom score improved from 24.7 to
11.1 (13.6 symptom units) in the TUNA group
against 23.3 to 8.3 (15.0 symptom units) in the
TURP group. The maximum urinary flow rate
improved from 8.7 to 15.0 ml/sec (6.3 ml/sec) in the
TUNA group and from 8.4 to 20.8 ml/sec (12.4
ml/sec) in the TURP group. The treatment was found
to be effective and safe. The complication rate of
TUNA was low in both the short and the long
term.The most commonly reported adverse events
were bleeding (32.3%), urinary tract infection
(7.7%), and urethral stricture (1.5%). There was no
reported change in the sexual function in patients
treated by TUNA. In the TURP group there was a
high incidence of retrograde ejaculation.
216
In conclusion, compared to TURP, TUNA is an effi-
cacious minimally invasive treatment for symp-
tomatic BPO with few side effects [145].
The results of 5 year follow-up of the United States
randomized clinical trial were presented [167]. Fol-
lowing treatment, significant improvement from
baseline occurred in symptom score, higher for
TURP than for TUNA (statistically significant in the
first 4 years). The two groups demonstrated a signif-
icant improvement in maximum urinary flow rate
(greater for TURP patients). TUNA showed signifi-
cantly fewer adverse events than TURP. The TURP
group reported 41% retrograde ejaculation, while the
TUNA group reported none. However, in the TUNA
group 14% required further intervention with addi-
tional treatment (TURP), against only 2% in the
TURP cohort. The results of this study demonstrate
stable treatment outcomes after 5 years of follow up
and suggest that TUNA is an attractive treatment
option for men with LUTS due to BPO. While the
TURP improvement was superior, TUNA showed
lower adverse events [167].
Another randomized clinical trial comparing TUNA
with TURP analyzed 59 patients [168]. Improve-
ments in Qmax, post voiding residual volume (PVR),
IPSS and the QOL score were statistically significant
for both groups at 3 and 18 months of follow-up. The
increase in the mean Qmax of the TURP group was
higher than that in the TUNA group, whereas no sig-
nificant differences were found between the two
groups regarding improvements in IPSS and QOL
scores. There were no complications associated with
the TUNA procedure, while after TURP 16 patients
suffered from retrograde ejaculation, 4 from erectile
impairment, 2 from urethral stenosis and 1 from uri-
nary incontinence [168].
c) Meta-analysis
A recent meta-analysis [169] analyzed the data from
two randomized trials [167,170], two non-random-
ized protocols [159,166] and 10 single-arm studies
conducted on TUNA [153,155,156,159,171,
172,173,174,175]. The meta-analysis was based on
the difference in the mean score at the end of the
study from baseline. In almost all studies the patients
recruited had severe lower urinary tract symptoms
and a mean IPSS of more than 20 before treatment.
The effect of TUNA was a decrease of the mean
IPSS by 50% from baseline at 1 year after treatment.
This effect maintained up to 5 years. The Qmax
increased by 70% from baseline after 1 year in virtu-
ally all studies and approached or exceeded 15
ml/sec. Although there was a tendency for the Qmax
to decline slightly over time, the mean Qmax 5 years
after treatment was more than 50% improved com-
pared to baseline.
When only the two randomized trials are considered,
the mean decline in IPSS was 11.6 after TUNA and
15.7 after TURP (difference statistically significant).
The effect of TUNA therapy on Qmax (+7.0 ml/sec)
was smaller than that of TURP (+11.6 ml/sec= statis-
cally significant) [169].
This meta-analysis shows that TUNA is an effective
and minimally invasive treatment for men, even
with severe symptoms. There is a significant
improvement in symptoms and flow rate after 1 year
which persists for at least 5 years. TUNA therapy
would appear to be an alternative to surgery and an
attractive option for men who do not wish to under-
go long-term medical therapy, for men who are poor
candidates for surgery or those concerned about the
side-effects of TURP [169].
d) Adverse effects
The most common post-treatment complication
reported after TUNA is urinary retention, ranging
from 13.3% to 41.6%. The retention is transient (12-
48 hours) in the majority of patients [148,149]. A
217
mild degree of transient macroscopic hematuria is
noted in most patients for a period of 24 hours and
does not require specific treatment [149].
Other common adverse event reported are storage
symptoms, occurring in about 40% of patients in the
early post treatment period. These are mild and tran-
sient in nature, usually lasting 1 to 7 days and rarely
more than 2 to 4 weeks [148,149].
Postoperative urinary infection and epididymitis
occur rarely (0% to 3.1%). The risk of infection is
minimized by maintaining urine sterile preoperative-
ly by the use of antibiotics [149].
Urethral strictures may occur in 0% to 1.5% of
patients and are related to instrumentation of the ure-
thra. The risk of urethral stricture is smaller than
after standard TURP [149].
Sexual dysfunction is rare after TUNA and urinary
incontinence was not reported in any series [148,
149].
e) Re-Operation
Although a 14% requirement for re-operation due to
the lack of efficacy of the primary treatment with
TUNA may seem low, it occurred within 2 years
[161,167]. In addition, the 12.7% incidence reported
by other authors also occurred within a 2 year period
[159].
f) Indications
The patient most likely to benefit from TUNA would
be the one who has lateral lobe enlargement and a
prostate of 60g or less [171]. Patients with larger
prostates, purely bladder neck hypertrophy, or medi-
an lobe enlargement are not ideal patients to receive
this kind of treatment. However, they can be treated
by rotating the TUNA catheter so that the needles
will point posteriorly, with special care being taken
in assessing the depth of their penetration into the
prostate [148].
CONCLUSIONS
TUNA:
• Has good clinical outcomes that seem durable
• Has reported low morbidity
• Is outpatient based and performed under analge-
sia/anesthesia
• Is an option when instrumental treatment is indi-
cated (except when absolute indication for
surgery exists)

V. PROSTATE INJECTABLES
Ethanol and Botox have been described as possible
agents for injection into the prostate. No data have
been published yet on the latter.
Transurethral Ethanol Ablation of the Prostate
(TEAP) is defined as a minimally invasive
transurethral procedure to effectively treat patients
with symptomatic BPO, by injecting anhydrous
ethanol into the periurethral prostatic nodule under
continuous urethroscopic irrigation. (see Figure 1)
Microscopically, the ethanol injection created a uni-
formly demarcated line of tissue necrosis, which did
not extend to the capsule of the prostate or to the
sphincter [176]. The integrity of the prostate capsule
is said to act as a relative barrier to ethanol diffusion,
and systemic absorption of ethanol is apparently
minimal.
Several articles on intra prostatic ethanol injection
have been published [177,178,179,180].
Figure 1. Example of TEAP treatment
1. EFFICACY OF TEAP
After TEAP, IPSS and QOL score decreased signifi-
cantly at 1 month and these improvements were sus-
tained for 12 months (Table 1, 2). However, Goya et
al [195] followed 17 patients for longer than 3 years
(median follow-up for 4.3 years), and reported
durable improvements in only 59%.
With regard to the maximum flow rate, an increase
of 35% was seen 3 months after TEAP (Table 3) and
the effect was mostly sustained through 12 months.
The post-void residual volume seems to be decreased
by TEAP [180,184,195], but this change has not
been remarkable in some studies [182].
2. COMPLICATIONS
Plante et al [192] reviewed the complications of
TEAP among 200 patients from 15 countries. Most
patients do well with catheter removal 3 days after
the procedure. Overall more than 90 % of patients
were able to void 96 hours after TEAP [192]. The
most common reported adverse events were storage
symptoms (21.5%), urinary retention (17.5%) and
hematuria (13%), most of which resolved without
intervention by one month post TEAP. Urinary
incontinence, erectile dysfunction and retrograde
ejaculation occurred in less than 5% of the time over-
all. Bladder necrosis was reported in three cases
including one case requiring urinary diversion.
3. RE-INTERVENTION RATE
The reported re-intervention rate ranged from 7%
after one year [194] to 26% after 3 years after TEAP
[195]. TEAP conversion to TURP within 6 months
was reported in 10 % of the deep injection group and
15% in superficial injection group [186]. If the
reported case series are continuously observed for
another 4 years, the re-treatment rate may increase
further.

Table 1. Changes in IPSS (AUA) after TEAP (mean)

No Pts. Preop 3 months 6 months 12 months
Plante et al [182] 5 23.4 12.2 11.4 13.8* *p<0.05
Ditrolio et al [183] 13 22.4 5.6 5.8 5.9
Gutierrez Aceves [191] 118 21.2 10.3* 9.9* 10.7* *p<0.001
Grise et al [194] 93 20.6 10.3* 10.7* 10.3* *p<0.05
Goya et al [195] 29 21.8 10.4* 10.8* 9.6* *p<0.001
Average 258 21.2 10.1 10.1 10.3
Number of patients indicates those followed through the final evaluation.

218
Table 2 Changes in QOL score after TEAP (mean)
No Pts. Preop 3 months 6 months 12 months
Plante et al [182] 5 4.0 1.6 2.2 2.8* *p<0.05
Gutierrez-Aceves [191] 116 4.4 2.2* 2.1* 2.1* *p<0.001
Grise et al [194] 93 4.4 2.2* 2.3* 2.1* *p<0.05
Goya et al [195] 29 5.0 2.6* 2.7* 2.3* *p<0.001
Average 245 4.4 2.2 2.2 2.1
Number of patients indicates those followed through the final evaluation.

Table 3. Changes in Maximum Flow Rate (ml/sec.) after TEAP (mean)

No Pts. Preop 3 months 6 months 12 months
Plante et al [182] 5 9.9 13.8* 13.0* 1 3.1* *p<0.05
Ditrolio et al [183] 13 5.7 11.7 11.7 11.9
Gutierrez-Aceves [191] 130 9.3 11.9* 13.2* 13.7* *p<0.001
Grise et al [194] 90 9.9 13.4* 13.4* 13.4* *p<0.05
Goya et al [195] 29 8.3 12.5* 12.9* 13.6* *p<0.001
Average 267 9.2 12.5 13.2 13.5
Number of patients indicates those followed through the final evaluation.

SUMMARY VI. PROSTATIC STENTS

One year follow up data from 5 case-series reports
(evidence level 3) demonstrate similar success
rates regarding improvements in IPSS, Qmax and
QOL score. TEAP is effective, at least for one year,
and might be a suitable option in patients with co-
morbidities who are unfit to undergo TURP. With
regard to durability, one year data only have limit-
ed value. A longer term result suggests a continued
decline in success rate by 26%. Further follow-up
for another 3-5 years is required before this proce-
dure is considered to be a reasonable alternative
treatment for BPO.
The local toxicity in the form of spreading necro-
sis warrants further research in establishing the
safe injection site before it can be recommended
and it can be put to regular clinical use.
CONCLUSION
Remains investigational.
Urinary drainage catheters function by passive blad-
der drainage whereas urethral stents, whether tempo-
rary or permanent, work on the principle of active
drainage requiring a detrusor contraction. Urethral
stents may act as substitutes for indwelling catheters,
ideally replacing them and thus reducing the risks
seen with catheters, such as infection, hematuria and
overall discomfort. The ideal stent can be placed or
removed atraumatically, has a high radial force, and
can be used as a bridge before more permanent ther-
apy in those not presently medically stable or at high
surgical risk, or after procedures after which urinary
retention can occur in the short term, such as
microwave thermotherapy or brachytherapy. Stents
can be temporary or permanent. Permanent stents are
biocompatible allowing epithelialization and are
therefore subject to less complications, whereas tem-
porary stents do not epithelialize. Temporary stents
can be either biostable or biodegradable. A stent
must not extend beyond the bladder neck into the
bladder, should cause no local tissue reaction, must
be easy to place and remove, and should allow

219
endoscopy through it. However, in reality both types
are subject to misplacement, migration, poor tolera-
bility due to the exacerbation of lower urinary tract
symptom (LUTS) and encrustation.
1. PERMANENT STENTS
The following permanent stents will be discussed:
the Urolume, the Memotherm, the Titan.
The original justification for permanent stents for
BOO secondary to BPO was in men at high surgical
risk. Several early reports outline short-term success
(18 months) in these men [198,199] with success
both in men with severe voiding symptoms and in
those in frank retention. A result of these reports was
the development of multicenter trials evaluating the
use of permanent stents in men with BPO who were
otherwise healthy. These included the North Ameri-
can UroLume Study Group [200], and the European
Multicenter Study [201]. Two-year follow-up in
these studies revealed significant and durable
changes in the following: decrease in symptom
score, post void residual volume and increase in
maximum flow rate in men with and without urinary
retention. Voiding symptoms were alleviated best,
whereas men with storage symptoms had the most
difficulty tolerating the stents. Sexual activity and
spontaneous voiding returned to normal in most of
those previously in retention. Complete epithelializa-
tion was noted in the majority at 12 months. Stent
removal was performed in 17 (13%) and 21 (15.5%)
patients at two years in both trials, mainly due to
intractable detrusor overactivity, stent encrustation,
stent migration, recurrent outlet obstruction, perineal
pain and urinary incontinence. Common complica-
tions that did not necessitate stent removal and were
managed conservatively included hematuria,
hematospermia, UTI, urgency, retention, and stric-
ture.
The stent with the longest follow-up is the UroLume
endourethral prosthesis (American Medical Systems,
Minnesota, USA). It is a woven tubular mesh com-
posed of a nonmagnetic stainless steel alloy that is
biocompatible and inert.
Initial long-term follow up in the multicenter North
American trial for BPO included 10 study sites
involving 126 patients who underwent stent place-
ment in 1990-92 [200].
A post approval study [203] of 32 patients had fur-
ther follow-up beyond the closure of the original
study date of July 1997. Maximum flow at baseline
compared to 10 years showed a return to baseline
220
10.0/10.1 (n=9), however Madsen-Iverson scores
remained above baseline, 13.8/5.8 (n=16). Tissue
reaction remained unchanged in 14 appearing with
no/mild changes, while 1 had moderate change. Six
patients had stent explantation between 7 to 10 years,
due to worsening of voiding symptoms, tissue over-
growth, prostate enlargement outside the stent,
encrustation, and hematuria [203]. Four additional
patients died, all from non-stent related events.
The Memotherm stent (Bard, Covington, GA, USA)
is a permanent stent, and unlike the UroLume, is
made from a nitinol alloy that is thermosensitive,
biocompatible and flexible. Between 1993 and 1996,
123 patients considered poor operative candidates
but necessitating TURP received the stent [205].
Mean prostate volume was 40 ml. Only 77 (62.6%)
patients were able to void pre-operatively, with the
remainder in retention and 27 (22%) demonstrating a
weak/absent detrusor contraction. Mean age was
77.6 years. One, two, and four year follow up was
achieved in 52, 26 and 4 patients respectively. Forty-
four patients (36%) died during follow-up unrelated
to stent placement. Eleven patients became immobi-
lized from other morbidity and required catheteriza-
tion. Average follow up was only 12.2 months, and
therefore no generalizations could be made about
long term follow up. Baseline characteristics for
IPSS, QOL, Qmax and PVR were 24, 4.5, 7.4 ml.sec,
and 154 ml respectively. At 1, 2, and 4 years, IPSS,
QOL, maximum flow rate, and residual urine were:
8.8/7.6/5.7, 1.9/1.5/1.4, 13.0/16.4/14.8 ml/sec and
31/14.8/5.0 ml, respectively.
The authors observed that their complication rate and
retreatment rate exceeded that experienced at equal
time points from early UroLume data where voiding
symptoms were transient (2-3 weeks) [200], and
obstruction was absent or mild [199].
The TITAN Intra-prostatic Stent (Boston Scientific,
Watertown , MA, USA) is a pure titanium mesh tub-
ing with an internal diameter of 33 French, and is
deployed under direct cystoscopic vision. Kaplan
[206] reported on 144 patients with moderate to
severe symptoms enrolled between 1991 and 1993
with mean follow up of 17.6 months, and mean age
of 73.5 years. At 24 months, Madsen-Iverson symp-
tom score improved from 16.3 to 6.2 (p<0.001)
(n=19) and Qmax increased from 5 to 12 ml/sec
(p<0.01). Cystoscopy revealed “varying degrees of
epithelial covering and no evidence of encrustation”
at intervals of 1 and 12 months. Eight patients
required removal and redeployment due to poor posi-
tioning, 28 (19%) had the stent explanted for migra-
tion or treatment failures, 15 died, and 4 withdrew or
were lost to follow up. Anticipated adverse reactions,
most commonly storage symptoms (4%) resolved by
4 weeks. No comments were given on the number of
stents requiring tissue resection secondary to tissue
reaction.
2. BIODEGRADABLE AND TEMPORARY STENTS
In this section data on the biodegradable stents, and
non biodegradable stents, the Spanner, the Conticath
and the Prostacoil will be presented.
Biodegradable stents are composed of poly-lactic
acid and glycolic acid, and have a presumed advan-
tage for temporary management of BOO in high sur-
gical risk patients, where the stent would not need to
be removed a later date [187]. They are self-expand-
ing, promote little encrustation, and have an outer
diameter between 21-24 French. They have been
used in conjunction with minimally invasive thera-
pies such as interstitial laser coagulation and
microwave. However, strength retention time may be
short, degradation is inconsistent, and the stents may
cause worsening flow from obstructing fragments
and are expensive [183]. At this time none are cur-
rently commercially available.
A number of small case studies involving a variety of
temporary non biodegradable stents exist. Earlier
generation stents were coils that were subject to a
high rate of migration and encrustation. In addition,
they would frequently worsen the voiding symptoms
they were meant to alleviate. Herein we report the
devices with the largest and latest series.
The Spanner (AbbeyMoor Medical, Minnesota,
USA) is a temporary stent that resembles the proxi-
mal 4-6 cm of a Foley catheter and is designed to
relieve BOO, improve voiding efficacy and maintain
the bladder as a reservoir. The proximal end has a
balloon similar to a Foley preventing distal migra-
tion, a urine port to allow drainage and a distal
anchor that sits in the bulbar urethra attached by a
suture spanning the external sphincter. A retrieval
suture extends distally and is cut just proximal to the
fossa for later removal. It is inserted with an inser-
tion device. When pulling on the retrieval string the
proximal balloon deflates allowing the stent to be
removed. In the largest case series, thirty men with
mean age of 68 years, of which 5 were in retention,
had the Spanner inserted under local anesthesia
[208]. Position was confirmed with a radiograph.
Maximum flow rate, voided volume, residual vol-
ume and IPSS were measured. Mild urgency, stress
221
and/or urge incontinence, and perineal discomfort
developed in approximately 1/3 of cases, but
resolved within two weeks. No patients dropped out
of evaluation which was performed after placement,
at 24 hours, 4 days, and every seven days thereafter.
Significant changes were seen with maximum flow
increasing from 8.2 to 11.6 ml/sec (p<0.001), PVR
from 312 to 112 ml (p=0.004), and IPSS 22.3 to 7.1
(p<0.001). Voided volume only demonstrated a 1%
improvement. Upon removal no significant encrusta-
tion was noted.
A group of 5 patients with severe LUTS after [I-125]
brachytherapy for prostate cancer underwent Span-
ner placement an average of 40 days after implant.
[189]. All patients had previously failed medical
therapy. Mean age was 64 years, mean IPSS before
and after brachytherapy were 5.4 and 25.2 respec-
tively. Post-Spanner IPSS at 5 days decreased to 14.6
(p<0.03). Two patients requested stent removal at 1
week due to discomfort, while the other three had
symptoms treated with tolterodine and continued
with the stent for 30 days until planned removal. The
two patients who had stent removal then developed
acute urinary retention and were then managed with
intermittent catheterization until voiding resumed at
7 and 10 days. The best Qmax improved from a
mean of 13.9 ml/sec before brachytherapy to 23.2
ml/sec after the Spanner was inserted (p<0.03). The
three who completed the course of treatment found
that their urinary symptoms reverted to pre-stent lev-
els after removal. Despite improvement in IPSS and
flow rate, all had dysuria/pain from the stent that the
authors attributed to radiation urethritis in the imme-
diate post-treatment period.
A multicenter pilot study enrolled 64 patients with
post-operative or temporary urinary retention who
were treated with ContiCath (ContiMed Minneapo-
lis, MN, USA), a temporary stent similar in concept
to the Spanner [210]. A 20 French prostatic segment
is anchored in the bladder with a proximal curl
inserted with a trochar. The narrowed segment that
passes the external sphincter ends with a long suture
taped to the meatus that is used for later removal.
The stent is not hollow but has 3 deep grooves that
allow urine passage along side the stent. Sixty-one
patients with stents placed were divided into three
groups: group 1 (37) included those with non-neuro-
pathic retention and retention less than 1 week;
group 2 (19) included those with non-neuropathic
retention with retention longer than 1 week; group 3
(5) included neuropathic retention with retention
longer than 1 week. After insertion, the onset of
spontaneous voiding was recorded, and then patients
were reassessed at 24 hours, and then every week
until it was removed at 28 days. Within 3 hours, 34
(89%) in group 1 resumed spontaneous voiding
regardless of the reason for retention (microwave,
brachytherapy, general anesthesia). Eight (24%)
experienced symptoms requiring removal including
urgency, leaking, migration and pain. Of the 24
patients in both groups 2 and 3, only 3 (12.5%)
resumed voiding within 3 hours of placement. Flow
rates and residual urine were not recorded. The
authors concluded it to be useful in only those with
non-neuropathic causes of retention less than one
week.
The Prostacoil (Instent, Eden Praire, MN, USA) is a
newer generation temporary prostatic coil stent made
of nitinol and was designed to overcome the short-
coming of frequent migrations (up to 75%) seen with
earlier prostatic coils [192]. Prior to insertion the
Prostacoil has a diameter of 17 French that expands
up to 30 French once in situ. Wound on a delivery
catheter it is composed of 3 parts: a prostatic urethral
body, a trans-sphincteric head, and a bulbar anchor
head. In addition it allows endoscopy through it into
the bladder. 65 patients with moderate to severe
BOO treated by Prostacoil insertion have been
reported [209]. Of these, 37 patients had the stent
removed between 3-12 months when fit for TURP,
while 27 continued to void “without difficulty”
through the stent. One required removal for urgency,
5 required repositioning, and 14 had temporary
dysuria and perineal pain. Advantages included ease
of placement and removal and instrumentation if
necessary.
Another example of a spiral prostatic stent is the
Horizon prostatic stent. Two designs of this stent,
differing in shape, have been the subject of study: the
hourglass-shaped [216] and the bell-shaped [217]
prostatic stent. Both designs are made of nitinol
coiled wires with a temperature based memory for
the shape and can be inserted in an outpatient setting,
under local anesthesia, using a gun-shaped delivery
system.
The hourglass-shaped stent has an increasing diame-
ter towards both ends of the stent. The stent was test-
ed in 35 patients with LUTS due to BPO [196]. In 5
patients, insertion of the stent failed, mainly because
of anatomical limitations. After all placement proce-
dures minimal temporary haematuria was observed.
Spontaneous voiding was achieved in all patients,
with immediate significant improvements in voiding
parameters and symptom scores. At 14 days and at 3,
222
6, and 12 months, the stent was still in situ in 73%,
40%, 33% and 23% of the patients, respectively. The
main reason for removal of the stent was migration
(93%), in most cases towards the bladder. Due to the
high migration rate, the hourglass-shaped stent was
not suitable for clinical practice. An explanation for
this was sought in the design of the stent. Therefore,
the successor of the hourglass-shaped stent was
designed with an increasing diameter towards the
distal end only (bell shape) with the aim of prevent-
ing migration.
The efficacy, safety and durability of the bell-shaped
nitinol stent were assessed in 108 patients with
LUTS due to BPO [227]. Stents were successfully
inserted in 97% of the cases. Spontaneous voiding
was achieved in all patients, with significant
improvements in voiding parameters and symptom
scores. Significant improvements, however, are only
maintained for a period of 1-3 months. The main
complications were haematuria (19%), urge inconti-
nence (22%) and migration into the bladder (15%).
At 1, 3, 6, 12, 18, 24 and 30 months after insertion,
the stent was still in situ in 85%, 54%, 36%, 31%,
26%, 22%, and 18% of the patients. The primary rea-
son for removal of stents was worsening of symp-
toms. Upon removal, many stents appeared to have
tilted within the prostatic urethra. This phenomenon
could have been a contributory factor with respect to
the worsening of symptoms after 1-3 months.
Although the bell-shaped prostatic stent showed
improved migration rates compared to the hourglass-
shaped stent, for widespread clinical application
improvements in stent design are essential.
3. UROLUME REMOVAL
Once epithelialized, for intact endoscopic removal,
the overlying urothelium must be resected. The most
common method [214] of resection is preformed
with a low monopolar cutting current using a stan-
dard resectoscope. Pure cut is used and resection is
performed in smooth sweeping strokes. Small gullies
are created on either side of the UroLume in the soft
tissue. Longitudinal compression is performed to
free it from the prostatic base, and a forceps can then
grasp and pull out the stent. As reported above, most
explantations are performed within the first one or
two years for incorrect stent positioning and/or
migration, when the learning curve for stent place-
ment is the steepest. A secondary method [215] for
stent removal once all tissue has been resected is
placement of a 0.038 inch guide wire through the
stent into the bladder, removing and replacing the
endoscope sheath next to the wire, then advancing
the stent into the bladder. The other end of the wire
is retrieved and both wire ends are pulled to pull the
stent into the sheath and out of the patient.
4. COMPLICATIONS OF PERMANENT STENTS
Hematuria and urgency can occur during stent place-
ment and may persist until epithelialization is com-
plete, however they are frequently mild and self-lim-
iting. Catheterization should be avoided before 4-8
weeks to allow for epithelialization to occur, so that
if drainage is required, a suprapubic tube may be
placed.
Urinary retention can occur from clots, but often is
secondary to chronic retention from detrusor failure,
or from obstructing apical tissue that may necessitate
a second overlapping stent. This can be assessed by
transrectal ultrasound.
Stress urinary incontinence will clearly occur if the
stent overlaps the external striated sphincter, also, it
appears that the stent can promote urge incontinence
due to prostatic irritation. Stent repositioning may be
necessary. Anti-cholinergic medication can address
detrusor overactivity which is usually self-limiting.
Urothelial obstruction is benign in nature and occurs
as a reaction to foreign body placement, yet tends to
subside after 6-12 months. Although uncommon, if
tissue ingrowth is severe, resection is necessary.
Perineal pain is usually self-limiting but has lead to
stent explantation. Irradiated prostatic urothelium is
expected to be more sensitive and may not tolerate
the stent despite apparent successful voiding.
The critical moment for permanent stent placement
is its release from the delivery mechanism. Precise
evaluation of the contour and length of the urethra is
necessary to properly select the appropriate stent
size, but also permits proper stent expansion without
too much shortening. Stent placement just distal to
the bladder neck will allow epithelialization and
avoid encrustation while still providing its intended
relief of obstruction. Overlap of the bladder neck
into the bladder is more apt to occur at the 12 o’clock
position due to the oblique angle the prostatic urethra
forms with the bladder.
5. DISCUSSION
The high rate of early removal of the UroLume,
caused initial apprehension about the usefulness of
the device. Many urologists avoided placement in
order to avoid the potential need for manipulation
and removal. Explantation rates were clearly higher
within the first 2 years of placement, reflecting the
learning curve. Adoption of stent placement in uro-
logic practice should begin with live proctoring and
careful patient selection, as well as appropriate
informed consent.
Proper initial positioning is important to minimize
later difficulties, however, the cylindrical stent will
often not uniformly conform to the assymetric pro-
static urethra. This may lead to poor epithelialization
and/or migration. Delayed epithelialization can lead
to stent encrustation although only mild encrustation
was often noted when exposed. Tissue reaction was
more prominent in trial patients treated for BPO,
with adenomatous obstruction within the stent, yet
the retreatment rate for those patients at 10 and 12
years was minimal. Dropout rates were high, often
due to patient death, as expected in an elderly popu-
lation with comorbidies, and from explantation, so
that only a fraction of those originally enrolled in the

Table 1. Summary of long-term evidence in the literature on urethral stents for BPO. M: Multicenter, P: Prospective, C: case
series

Author Stent Type Follow-up Study type Level of Evidence

Osterling [200] Urolume Permanent 7 yrs M, P, C 3
AMS [203] Urolume Permanent 10 yrs M, P, C 4
Masood [204] Urolume Permanent 12 yrs P, C 3
Gesenberg [205] Memotherm Permanent 4 yrs P, C 3
Kaplan [206] TITAN Permanent 2 yrs M, P, C 3
Corica [208] Spanner Temporary 57 days P, C 3
Henderson [209] Spanner Temporary 30 days P, C 3
Corujo [211] ContiCath Temporary 28 days M, P, C 3
Yachia [213] Prostacoil Temporary 365 days P, C 3

223
post-approval study of the North American trial
[203] and Masood et al. [204] were available for fol-
low-up. It appears that those that survived the treat-
ment had few adverse events, yet with a shrinking
denominator, definitive conclusions can not be
made. For optimal outcomes patient selection must
include accurate urethral measurement, exclusions of
patients who had radiation or TURP, and patients
with inadequate detrusor function on preoperative
studies. Permanent urethral stents are a suitable alter-
native for patients who are at too high a risk for
TURP as the stent can be placed in less than 1/2 hour
and under local or regional anesthesia, yet its use
should be avoided in healthy men who can tolerate
TURP or minimally invasive heat therapy. Moreover,
with the rise in popularity of heat therapies for BPO
in men who are high surgical risks and in men with
BPO in general, the pool of available patients for
permanent stents is likely to diminish. Stenting of the
prostate is reasonable and effective but it does not
seem likely that randomized trials of permanent
stents versus TURP or heat therapies will be the most
efficient use of time or resources. The Memotherm
does offer the unique opportunity to become a hybrid
stent that can act as a permanent stent where indicat-
ed, yet can be removed in a technically unchalleng-
ing manner similar to a temporary stent, if necessary.
Further investigations in patients with the definitive
indications for BOO treatment and for relief of tem-
porary retention would be useful. Complication and
retreatment rates were higher than with UroLume,
but possible device modifications may address these
discrepancies. The TITAN offers no advantage over
the UroLume and requires the extra step of balloon
inflation to maximally expand the stent, and leaves
the impression of inferior epithelialization compared
to UroLume. The available studies do indicate a
place for temporary stents in relieving short-term
obstruction from non-neurogenic causes such as
after minimally invasive heat therapies for BPO, and
brachytherapy. Their ease of placement and removal
warrants further investigation in those with larger
glands that undergo these procedures in order to pre-
dict which patients would prospectively benefit from
prophylactic stent placement. In addition, the added
cost of the device must be proven to decrease ulti-
mate costs of out-patient or emergency room patient
visits from post-procedure acute retention episodes
in order to justify usage.
An inexpensive biodegradable stent that does not
obstruct during degradation and whose degradation
is predicable would be the ideal solution for relief of
temporary obstruction.
224
CONCLUSION
• Long term data (multicenter) for safety and
efficacy for permanent stents exist, but the
clinical use of permanent stents is limited.
• There is clinical use for temporary stents,
which have potential, but they have not yet
been adequately evaluated.
VII. OVERALL CONCLUSIONS
A systematic review of the literature was conducted
to evaluate the efficacy and safety of a range of MIT
for BPO. The MEDLINE and Cochrane Library
from 1992 through 2002 was searched to identify
studies of 3 months or greater in duration and with at
least 10 subjects in each treatment arm. The data
were also extracted on study design, subject and
treatment characteristics, adverse events, urinary
symptoms and urinary flow. The following treat-
ments were reviewed in table 1 and table 2. Details
of the number of studies included as well as number
of patients, clinical data and data on follow up dura-
tion are presented. We can observe that the baseline
data of the patients treated with the different MIT are
within the same range regarding age, prostate vol-
ume, IPSS symptom score, QOL parameter and
uroflow parameters.
In Figure 1, 2 and 3 the follow up of the symptom
scores, QOL scores and uroflow parameters are pre-
sented. It is interesting to observe that at first glance
the symptomatic improvements and the QOL
improvements more or less follow the same pattern,
with a more pronounced improvement in the more
ablative techniques. The durability, however, seems
to be similar for the different therapies. A similar
trend is observed for the flowmetry changes. The
improvements for most therapies seem to be durable
whereas significant better outcomes are achieved
with more ablative technologies.
In table 3 and 4, the morbidity of the different ther-
apies is presented. Urinary retention is more often
seen following heat therapies and consequently, in
these patients, a higher level of urinary infections is
observed. Macroscopic hematuria is observed in
most therapies but it is obvious that TURP has the
highest transfusion rate. The highest rate of adverse
events is also found for TURP in respect to urethral
strictures, urinary incontinence and sexual dysfunc-
tion. Last but not least, the urological community is
 Figure 1. Baseline and follow-up
QOL score (IPSS)

Figure 2. Baseline and follow-up

maximum urinary flow (ml/s)

Figure 3. Baseline and follow-up

post void residual (ml)

225
Table 1. Outline of different treatments versus data on studies included for analysis

174 studies (255 treatment arms)

Treatment Treatment arm subjects Average duration (M) Maximum Duration (M)
HIFU 12 459 12.7 33
ILCP 9 280 11.0 48
TUMT 66 6679 13.7 60
TUNA 17 736 12.7 24
TURP 59 3679 16.4 72
TUVP 37 1519 10.1 36
VLAP 43 2010 13.2 72
HoLEP 12 1713 10.8 28
Total 255 17072 - -

Table 2. Outline of different treatments versus baseline parameters

Subjects background in each treatment arm
Treatment Age P. Vol (ml) IPSS QOL Qmax (ml/s) PVR (ml)
HIFU 62.0 38.8 20.8 4.8 8.5 109.2
ILCP 67.6 46.4 22.3 4.6 7.5 106.8
TUMT 67.4 44.3 19.2 4.3 8.8 95.3
TUNA 69.2 48.5 20.8 4.5 8.3 127.7
TURP 67.7 43.3 21.1 4.5 8.4 108.5
TUVP 68.4 43.9 20.7 4.6 8.4 103.9
VLAP 68.8 42.7 21.4 4.3 7.9 171.7
HoLEP 67.5 42.4 21.6 4.5 8.1 110.2
Average 67.7 43.6 20.6 4.5 8.3 113.5

facing challenges regarding morbidity and costs

IN SUMMARY WE CAN CONCLUDE
reflected in catheter duration and hospital stay. The
THAT:
balance here is in favour of less ablative technologies
with respect of hospital stay but less favourable for • The efficacy of TURP is greater than the effi-
catheter duration. cacy of MIT. However: HOLEP is equal to
TURP
The key issue that needs to be addressed is: which is
the best choice of instrumental therapy? We feel that • The morbidity of TURP is higher than the
there is not one straightforward answer to that ques- morbidity of MIT
tion. One needs to balance on the one hand the clin- • The durability of TURP is longer than the
ical outcomes, morbidity and technical improvement durability of MIT
of these technologies. On the other hand there are
obvious patients’ preferences as well as doctors pref-
erences that may guide the eventual choice of thera-
py.

226
Table 3. Outline of different treatments versus side effects
Adverse events (1)
Treatment Retention Transfusions Hematuria Urinary tract infection
HIFU 29.4% 0.2% 11.2% 2.5%
ILCP 18.3% 0.0% 7.6% 14.0%
TUMT 7.1% 0.0% 11.5% 4.0%
TUNA 27.4% 0.2% 14.1% 7.4%
TURP 2.5% 3.9% 4.6% 2.4%
TUVP 4.0% 0.2% 2.5% 1.8%
VLAP 14.7% 0.4% 2.3% 4.6%
HoLEP 3.4% 0.1% 3.1% 0.4%

Table 4. Outline of different treatments versus adverse events

Adverse events (2)

Treatment Stricture Incontinence Erectile dysfunction
HIFU 0.6% 0.0% 0.0%
ILCP 0.3% 0.1% 0.7%
TUMT 0.1% 0.1% 0.2%
TUNA 0.6% 0.0% 0.0%
TURP 3.4% 1.4% 1.1%
TUVP 1.7% 0.9% 1.5%
VLAP 0.9% 0.2% 0.4%
HoLEP 4.3% 1.2% 0.0%

prospective study of endoscopic laser ablation versus

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233
234
 CHAPTER 7

Committee 8

Prevention of Progression and Adverse

Outcomes in BPH/BPE/BPO

Chairman
C. ROEHRBORN (USA)

Members
J. EMBERTON (U.K),
F. GIULIANO (FRANCE),
Y. HIRAO (JAPAN),
A. JARDIN (FRANCE),
M. O’LEARY (USA),
F. KEUPPENS (BELGIUM),
R. ROSEN (USA)

235
 CONTENTS

I. INTRODUCTION VI. PREDICTORS OF PROGRESSION

OR OUTCOMES

II. DEFINITON OF PROGRESSION 1. SYMPTOMS, BOTHER, QUALITY OF LIFE

AND OUTCOMES AND SEXUAL FUNCTION

1. PROGRESSION 2. URINARY FLOW RATE

2. OUTCOMES 3. PROSTATE VOLUME

3. TYPES OF PREVENTION 4. AUR AND SURGERY

III. EVIDENCE FOR PROGRESSION VII. PREVENTION OF

AND OUTCOMES (Table 3) PROGRESSION AND OUTCOMES

1. POPULATION-BASED LONGITUDINAL 1. PRIMARY PREVENTION

STUDIES 2. SECONDARY PREVENTION
2. REGISTRIES AND SIMILAR DATABASES
3. CLINICAL PRACTICE STUDIES VIII. PREDICTORS OF EFFECTIVE-
NESS OF PREVENTION OF
4. PLACEBO/SHAM GROUPS FROM CONTROL PROGRESSION AND ADVERSE
CLINICAL TRIALS OUTCOMES
5. EFFECT OF SELECTION BIAS

IV. METHODOLOGICAL ISSUES IX. SUMMARY AND CONCLUSIONS

AND DEFINITION OF
PROGRESSION
REFERENCES
1. THRESHOLDS OF IMPROVEMENT VERSUS
GLOBAL SUBJECTIVE ASSESSMENT (GSA)
2. PLACEBO EFFECT VERSUS REGRESSION TO
THE MEAN: INTERPRETATION AND EXTRAP-
OLATION

V. EVIDENCE FOR PROGRESSION

AND ADVERSE OUTCOMES IN BPH

1. EVIDENCE FOR PROGRESSION OF DIRECT

HEALTH OUTCOMES
2. INDIRECT/PROXY HEALTH OUTCOMES
3. THE TRANSITION BETWEEN HEALTH
STATES OR OUTCOMES

236
 Prevention of Progression and Adverse
Outcomes in BPH/BPE/BPO
C. ROEHRBORN
J. EMBERTON, F. GIULIANO, Y. HIRAO, A. JARDIN, M. O’LEARY , F. KEUPPENS , R. ROSEN
I. INTRODUCTION
The concept of lower urinary tract symptoms
(LUTS) and benign prostatic hyperplasia (BPH) as a
chronic progressive disease is relatively new. Histor-
ically, the emphasis of medical care for BPO on the
part of both physicians and health care providers has
been solely on the improvement of symptoms and
acute treatment of outcomes, such as urinary reten-
tion with the subsequent need for surgery. This
should not be surprising as urology as a specialty
concerns itself principally with the treatment and
management of acute illnesses, rather than disease
prevention and chronic disease management or mod-
ification. In contrast, other medical specialties have
long embraced the concept of disease prevention and
disease modification, possibly leading to earlier and
more successful long-term management. Examples
of such programs in other therapeutic areas are the
effort to prevent coronary artery disease, myocardial
infarctions, and strokes by long-term management of
serum cholesterol, or the disease management pro-
grams for diabetes mellitus. The actual events pre-
vented in many of these examples are obviously
more significant and potential lethal compared to the
potential outcomes in LUTS and BPH, limiting the
relevance of such comparisons.
Two developments in particular have led to a recon-
ceptualization of the progression and management of
BPH in this regard. For one, long-term follow-up
data from population-based studies became available
suggesting that in fact, both symptom severity and
other signs and markers of BPH show evidence of
progression over time. Secondly, long-term, random-
237
ized, placebo-controlled trials were conducted to
study the effect of 5alpha-reductase inhibitors on
LUTS, which revealed additionally that this class of
drug may also be capable of preventing clinically rel-
evant outcomes, such as acute urinary retention
(AUR) and the need for subsequent prostate surgery.
For the purpose of this chapter we attempt to replace
the often misused term “BPH” with the more appro-
priate terminology as outlined in the consensus doc-
ument at the end of this volume which differentiates
the following terms:
• Benign Prostatic Hyperplasia (BPH) is reserved
for the histological pattern the phrase describes.
• Benign Prostatic Enlargement (BPE) is used
when there is gland enlargement. It is usually a pre-
sumptive diagnosis based on the size of the prostate.
• Benign Prostatic Obstruction (BPO) is used
when obstruction has been proven by pressure-flow
studies or is highly suspected from flow rates, and if
the gland is enlarged.
Prevention of progression, and disease management
represent new concepts in BPE/BPO management
from a urological perspective. Not surprisingly, there
is a knowledge gap between specialists, i.e., urolo-
gists, and primary care providers as well as patients,
and secondly, that the specific parameters as to when
preventive therapy might be indicated are not, as yet,
well defined. A recent survey suggested that most
urologists are aware that alpha-adrenergic receptor
blockers are effective in treating bothersome urinary
symptoms, while 5alpha-reductase inhibitors are
effective in arresting the progression of the disease
and reducing prostate size. However, when primary
care providers were asked the same question con-
cerning symptom alleviation versus progression of
disease, they were far less able to distinguish effects
of 5alpha-reductase inhibitors and alpha-blockers
(Figure 1A and B). When patients were asked in the
same survey, 72% of the patients stated that they
were concerned about long-term outcomes, even
more so than about acute symptom relief, and 73%
of the queried men were willing to take at least one
tablet daily to reduce the long-term risk of surgery,
the amount of reduction, however, being not speci-
fied in the questionnaire (Roehrborn 2005).
Djavan et al., assessed 472 European urologists by
means of a 15-item questionnaire regarding their
A
B
Figure 1 A, B. Perceived efficacy of medication as used by
urologists versus primary care physicians regarding reduc-
tion in prostate size, arresting progression, and improve-
ment in symptoms (base n=100 urologists and 100 primary
care doctors) (Roehrborn 2005)
238
views on BPH progression, etc. (Djavan, Nickel et
al. 2002). On a scale from 0 to 10, with 10 being
extremely important, improvement of the patient’s
overall quality of life was rated at 9.0 with relief of
LUTS at 8.5. Prevention of long-term complication
was rated a little lower at 7.6, whereas reduction in
prostate volume was only rated at 3.5. When asked
about their concern with preventing BPO-related
changes, deterioration of patients’ quality of life and
urinary retention were both rated equally at 8.6.
When asked about their confidence in certain risk
factors as reliable predictors of progression, the
highest rating was given to reduction in urinary flow
rate being an important risk factor for progression.
Seventy-seven and 79% of urologists believed in,
and used evidence of a reduced flow rate as an
important risk factor, and the overall rating for this
variable was 7.2. Increases in post-void residual
urine and LUTS severity was rated slightly lower, as
was urodynamic evidence of obstruction. Two fac-
tors that were found to be significantly related to pro-
gression in randomized, control trials, namely
increase in prostate volume and elevated serum PSA,
were given ratings of importance of only 5.5 and 3.5,
while an increase in age was rated in importance as
4.0, despite the fact that the Olmsted County Study
of Urinary Symptoms in Men documented that pro-
gression of BPO is strongly related to age.
These observations suggest a need for a more precise
definition of progression and outcomes in LUTS and
BPH/BPE/BPO, increased awareness of the accumu-
lating evidence for LUTS and BPE/BPO being a pro-
gressive condition with long-term outcomes, a deep-
er understanding of what baseline factors may be
predictive of progression and outcomes, and ulti-
mately, what the evidence and results are associated
with efforts to prevent both progression and out-
comes. Lastly, progression of LUTS has many caus-
es which become more important with advancing
age. Prior to initiation of treatment it is therefore
important to attempt to identify these causes for the
most targeted treatment.
II. DEFINITON OF PROGRESSION
AND OUTCOMES
It is important first to have consensus on terminolo-
gy and definitions. This is the nomenclature and def-
initions used throughout this chapter.
1. PROGRESSION
We refer to progression as a transition within the
same health state in the direction of a worsening or
increase in severity, or to a higher level of threat for
an outcome to occur. For example, consider a patient
who during the course of observation, worsens from
an IPSS score of 12 to an IPSS score of 17 points, or,
whose urinary flow rate deteriorates from 15 to 9
ml/sec. This patient can be considered as having pro-
gressed in their symptoms or symptom score within
the same specific health state.

2. OUTCOMES
Outcomes are defined as a transition from one health
state to another. For example, consider a patient who
urinates normally and develops AUR, i.e., inability
to void at all. This patient has transitioned from the
health state of ‘normal urination’ to the disease state
of “urinary retention”. For the purpose of this chap-
ter we will consider for the most part only adverse
outcomes, ie changes from a more to a less desirable
health state.
It is important to differentiate both theoretically and
in practice, this progression in outcomes as both can
be measured and analyzed in various ways. Classifi-
cation into evidence-based categories of outcome is
an important corollary of this definition.
3. TYPES OF PREVENTION
For purposes of the current chapter, we define pre-
vention along the timeline of the progression of
LUTS and BPH/BPE/BPO (Figure 2). As men age,
histological benign prostatic hyperplasia develops in
the prostate beginning approximately at the age of 40
and increasing relentlessly for each decade of life,
ultimately reaching almost 100% prevalence by age
80 or 90. At the same time, the prostate begins a
steady pattern of growth, also roughly beginning at
about age 40, and continuing throughout a man’s
adult life. LUTS although these may develop early in
life, are likely not related to BPH, but possibly to
issues such as bladder dysfunction, urethral stricture
disease, infectious diseases, or other causes. LUTS
secondary to BPH increases in severity, also, begin-
ning at about age 40 and increasing steadily with
advancing age.
a) Primary Prevention
Primary prevention is defined as the a priori preven-
tion of histologic benign prostatic hyperplasia and
associated LUTS. There is very little evidence avail-
able regarding the primary prevention of BPH. This
evidence stems from two sources, namely a congen-
ital abnormality characterized as a deficiency in the
Figure 2. Timeline of progression demonstrating growth of
the prostate, development of LUTS, and benign prostatic
hyperplasia (BPH over time with opportunities for primary,
secondary, and tertiary or post-event prevention)
5 alpha-reductase type II enzyme leading to a condi-
tion known as pseudovaginal perineoscrotal
hypospadias, an under development of the prostate,
and from our knowledge of men castrated prior to
puberty to serve as eunuchs in the courts of the
Ottoman empire and forbidden city of the Chinese
empire (Wagenseil 1927; Walsh, Madden et al. 1974;
Wilson, Harrod et al. 1974; Imperato-McGinley
1991; Imperato-McGinley, Gautier et al. 1992; Wil-
son and Roehrborn 1999) .Results of these studies
will be presented in detail in a later section.
b) Secondary Prevention
Far more common and in everyday practice are
efforts at secondary prevention, implying that pre-
vention of progression events after the condition has
been diagnosed or treated; i.e., preventing further
worsening of symptoms, flow rate, prostate growth
increases, etc., in men already diagnosed with benign
prostatic enlargement and obstruction. Late sec-
ondary or tertiary prevention can be referred to as the
prevention of future progression or outcomes after an
outcome has already taken place. An example for
this would be a patient developing acute urinary
retention, being given an alpha-adrenergic receptor
blocker, and then a trial without catheter in hopes of
re-establishing normal urination.
d) Direct Versus Indirect or Proxy Outcome Vari-
ables
There are several types of outcomes that can be cat-
egorized as direct health outcomes versus proxy or

239
indirect health outcomes. Direct health outcomes
are those that can be immediately perceived by the
patient and have a direct impact on his life or the
quality of his life. Indirect or proxy health outcomes
are those that cannot be immediately perceived by
patients and do not have a direct impact on the
patient. An example in the area of LUTS and BPO
would be a patient who develops AUR. The inability
to void and the pain associated with it are direct
health outcomes. However, the slow growth of the
prostate over years triggering the acute urinary reten-
tion event is an indirect outcome as it is not noted by
the patient and has no immediate impact until the
final event of AUR occurs.
e) Efficacy or Outcome Variables
It is further necessary to define different types of
efficacy or outcome variables (Figure 3). Continu-
ous variables are those that are measured along a
continuous scale. Examples in the field of LUTS and
BPO are the IPSS Score ranging from 0 to 35 points,
the maximum urinary flow rate ranging from 0 theo-
retically to infinity, but more realistically to 50
ml/sec, a serum PSA ranging from 0 or undetectable
to theoretically infinity, prostate size ranging from
very small glands to glands over 200 grams, etc.
In contrast, categorical outcomes are outcomes that
Figure 3. The IPSS Score is a continuous variable running from 0 to 35 points. A division into mild, moderate, and severe
symptoms converts this into a categorical outcome. A division into patients with mild symptoms as requiring no treatment ver-
sus those above 7 points requiring treatment converts the IPSS Score into a dichotomous outcome.
240
can be divided in certain categories. For example,
scores on the IPSS scale of 7 or less points are
defined as mildly symptomatic, while men scoring
from 8 to 18 points are referred to as moderately
symptomatic, and those above 19 points are defined
as severely symptomatic. Categorical outcomes rep-
resent health states, and changes between the cate-
gories can be viewed as outcomes, while changes
along a continuous variable can only be viewed and
analyzed as a progression event. This minor concep-
tual difference can make a large difference in which
outcomes are viewed as primary and what effect
sizes will be needed to achieve significance in clini-
cal trials.
A dichotomous efficacy variable is one variable for
which there are only two states, yes or no, and an
example for this would be the status of urinary reten-
tion being present or not present.
It is important to note that from an analytical point of
view, categorical and dichotomous variables can be
viewed as distinct health states, and analyzed as a
probability of changing from one health state to
another, while continuous variables can only be ana-
lyzed as changes along the dimension of the contin-
uous variable, and are typically expressed as changes
in means or medians.
There is a need for better defined categorical out-
comes in BPO/LUTS research, and it would be
advantageous for future health care researchers to
have clearer understanding of what constitutes opti-
mal categorization of outcomes utilized. For exam-
ple, it would be good to understand what constitutes
a small, moderately, or markedly enlarged prostate, if
and when these categories could be tied to significant
probabilities of outcomes. If, for example, we would
know that a prostate of 40 or more grams in size has
a greater probability of creating AUR episodes, it
would be important to quantify the probability of a
patient moving from a small to moderately or
markedly enlarged prostate in that risk group over
time. Similar examples can be drawn for other con-
tinuous variables, such as IPSS score, Bother score,
“BPH” Impact Index, Sexual Function question-
naires, flow rate parameters, prostate size, and serum
PSA.
A final concept for consideration is the role of static
versus dynamic predictor variables. For example,
a patient who presents to a health care provider with
a symptom score of 20 points and a quality of life
score of 4 points (range 0 to 6) may be placed on
medical therapy. The treatment decision is based on
the observed static (baseline) variables at the time of
presentation.
On the other hand, if this same patient after a tempo-
rary improvement eventually progresses, and is re-
evaluated a year later with a symptom score of 22
points, and a quality of life score of 5 points, he may
be referred for surgical treatment. In this case, how-
ever, the change in treatment plan is based on a
dynamic change in variables. As it turns out, the
majority of treatment decisions in daily practice are
made based on changes and patterns of dynamic
changes and variables, rather than on static baseline
variables. In essence, a health care provider seeing
patients with LUTS and BPH has only one chance to
base recommendations and treatment decisions on
static variables, namely when he sees the patient for
the first time as a new encounter. At subsequent vis-
its, she or he will make clinical decisions based not
only on the baseline variables, but more likely on the
dynamic changes taking place regarding the patient’s
age, symptom severity, changes in prostate size,
serum PSA and others. A pertinent example is the use
of PSA velocity in the diagnosis of prostate cancer
and the management of patients with PSA recur-
rences after curative treatment.
241
III. EVIDENCE FOR PROGRESSION
AND OUTCOMES (Table 3)
The evidence base for LUTS and BPH/BPE/BPO
being a progressive condition associated with long-
term outcomes stems from a variety of studies, each
type of study having methodological advantages and
disadvantages. Advantages and disadvantages of
specific types of research designs are as follows:
1. POPULATION-BASED LONGITUDINAL
STUDIES
• No predefined selection criteria.
• Excellent ability to study the natural history of the
condition.
• Fewest biases of any study design.
• Hawthorne effect which states that a population
may behave differently when observed compared
to when it is not observed.
• No ability to study the effect of an intervention.
2. REGISTRIES AND SIMILAR DATABASES
• Limited selection criteria are applied.
• Good ability to study the natural history.
• Ability to study the effect of an intervention.
• Ability to study dynamic changes and variables as
trigger points for treatment initiation and changes.
• Limited biases.
• Hawthorne effect.
3. CLINICAL PRACTICE STUDIES
• Some selection criteria apply as the study takes
place in a physician’s or health care provider’s
office.
• Reduced ability to study the natural history.
• Ability to study the effect of intervention.
• Biases are common.
4. PLACEBO/SHAM GROUPS FROM CONTROL
CLINICAL TRIALS
• Strong selection criteria are applied.
• Limited ability to use the placebo or sham groups
of a proxy for the natural history of the disease.
• Best ability to study the effect of an intervention.
• Censoring of patients limits universally.
• Lack of generalizability of the data.
5. EFFECT OF SELECTION BIAS
The effect of selection biases on the ability of the
study design to answer questions regarding the natu-
ral history is worthy of a more detailed discussion.
Figure 4 A through D highlights the issue. Let’s
assume that the possible universe of men with LUTS IV. METHODOLOGICAL ISSUES AND
and BPO that can be studied ranges in age from 40 to DEFINITION OF PROGRESSION
100 years. The possible range of symptom score
ranges from 0 to 35, etc. (4 A). Figure 4 B would There are several methodological issues relating to
show a typical selection bias for a population-based the definition of progression and the interpretation
study. For various reasons, patients above the age of of progression measures, some of which are dis-
80 may not be included due to the fact that their life cussed in the following paragraphs.
expectancy is not long enough to warrant their par- 1. THRESHOLDS OF IMPROVEMENT VERSUS
ticipation in a long-term study. For one reason or
another, patients with a PSA of over 10 may also be
GLOBAL SUBJECTIVE ASSESSMENT (GSA)
excluded. A registry (4 C) may further restrict Other than for the most obvious dichotomous out-
patients to those with a flow rate and symptom score comes, such as urinary retention present - “yes”, or -
within certain parameters, may not allow patients “no”; there are surprisingly few established criteria
with excessively large prostate and may not allow and changes in defined variables that are accepted as
patients who had already undergone a minimally validated measures of disease progression. One such
invasive or surgical treatment for their condition. example is a negative change in the IPSS score, for
The most severe restrictions or selection biases are which there is at least limited evidence. However, the
applied to patients participating in either medical or magnitude of the progression effect is not well estab-
surgical interventions as shown in Figures 4 D and lished at this time. Hardly any evidence exists for the
E. It is clear from this observation, that our ability to effects of progression on other continuous variables.
comprehend and predict the natural history of the
Baseline values can effect or influence perception of
disease is severely restricted based on these funda-
outcomes. For example, Barry et al. demonstrated in
mental selection biases.
1995 that depending on baseline symptom severity
If we learn from the placebo-control group of a med- (moderate versus severe), patients perceived an
ical treatment trial that peak maximum urinary flow improvement of 7.4 versus 15.3 points from baseline
rate is a strong predictor of future episodes of urinary IPSS values as “marked” improvement (Barry, Willi-
retention, this knowledge can be applied only to the ford et al. 1995). A slight improvement was noted if
specific patient population studied, i.e., patients who the change was 1.9 versus 6.1 points. Patients per-
presented originally at the age of 50 to 80, with a ceived worsening of their condition if the symptom
symptom score from 10 to 30 points, a PSA of under score increased by 3.3 versus 1.2 points in moderate
10 ng/ml, and most importantly, a maximum urinary and severe patients, respectively. Similar observa-
flow rate between 5 and 15 ml/sec. tions were made regarding the “BPH” Impact Index
While this is an important aspect of selection bias, (range 0 to 13 points) (Table 1). There are other stud-
which narrows the observation spectrum and poten- ies utilizing a similar approach to demonstrate the
tial generalizability of findings, another important
consequence is the ability to study correlations Table 1. Mean absolute changes in IPSS Score and BPH
between parameters. It is an acknowledged truism in Impact Index as they relate to levels of self-rated global
all areas of medicine that correlations are best stud- subjective assessment in categories of marked, moderate,
slight improvement versus no improvement versus symp-
ied in groups of patients with the fewest selection
tom worsening. (Barry, Williford et al. 1995)
biases. For example, it is a well-established fact that
blood pressure magnitude is a strong predictor of
patients suffering a cerebrovascular accident (CVA).
However, when focusing only on a very limited
range of blood pressure scores, this correlation may
lose its significance. Similarly, in LUTS and BPO
studies, it is best to study correlations between age,
symptom score, flow rates, prostate size, and PSA in
relatively unrestricted populations, while in the
severely restricted populations found in some arms
of a clinical trial, , there may not be a demonstrable
correlation . Different study populations are likely to
be found in population survey studies, registry stud-
ies and clinical trials, each with different selection
biases as below.
242
A B

C D

Figure 4 A – E. Demonstration of the selection bias.

Patient population can be defined by age, IPSS, QMAX,
TRUS volume, PSA, and treatments chosen. In the ideal
setting, if no selection criteria are applied, no bias occurs.
In population-based studies of LUTS and BPH, men are
chosen over the age of 40, and oftentimes, other criteria
are applied. In registries, again, age, but also symptom
severity criteria are often applied limiting the generaliz-
ability. In controlled clinical trials, in addition, symptom
score, flow rate, and prostate size criteria are applied lim-
iting the generalizability similar to controlled medication
trials in which again age, symptom score, flow rate, and
other parameters are strictly controlled.

243
relationship between changes in the symptom score
and the global subjective assessment or self-rating of
symptom relief. One such example is the HYCAT
trial (Roehrborn, Oesterling et al. 1996) As Figure 5
demonstrates, excellent relief of symptoms by self-
rating is dependent on the change in the symptom
score from baseline, but also depends on the absolute
values of the baseline symptom score. For example,
for patients at baseline with a score of 15 points, a 9-
point improvement represents excellent improve-
ment, but for those starting with a symptom score of
30 points, a 23-point improvement would represent
an excellent improvement. Similarly, poor relief of
symptoms is associated with a 1-point worsening
versus a 3-point improvement for patients starting at
15 and 30 points, respectively.
Another example comes from the ALFUS study
(Figure 6) (Roehrborn 2001). In this multi-center
clinical trial, patients were asked to rate their satis-
faction with treatment outcome following treatment
with an alpha-blocker on a visual analogue scale
(VAS) ranging from 0 to 100. Arbitrarily, the VAS
scale was divided in five categories ranging from
much better (80 to 100) to much worse (0 to 20). As
shown in Figure 6, patients with a baseline symp-
tom score of 10 points associated worsening with
virtually no change in their symptom score, and a
much worse condition of their illness with an
increase in 2 to 3 points. Those starting with a base-
line score of 20 perceived the same changes at – 2
and + 1 and 0 points, while those starting at 30
points, perceived worsening even if their symptom
score improved by 4 points and perceived much
worse outcomes than expected at a –2 point improve-
ment. It is interesting to note that the same associa-
tion between change scores from baseline and base-
line values, and global subjective assessment mea-
sures cannot be shown for changes in the urinary
flow rate. (Figure 7). As one can see, patients are not
able to relate objectively measured changes in their
urinary flow rate with perceived changes in the
strength of their urinary stream. This is an important
finding since it suggests that maximum urinary flow
rate changes are not relevant to patients’ perception
of change, at least not in the observed range of
changes with current medical treatment modalities
for BPO.
The relationship between patients’ self-rating of
change and overall outcomes has been examined in
the VA Coop study reported by Barry et al, the
HYCAT study, and recently, the ALFUS study. Each
of these studies have shown that patients can relate
global assessment of relief of symptoms to numeri-
244
cal changes in symptom scales and other outcome
scores. However, it must be noted that for patients
beginning treatment at very different points on the
symptom severity scale, different thresholds of
response, and different amounts of changes are need-
ed for patient’s to perceive an improvement versus
no change, or a worsening in their symptoms. This
introduces a second issue, with the definition of a
single threshold as evidence for worsening. As Fig-
ure 8 clearly illustrates, the room for improvement is
greater when patients start with a higher baseline
symptom score, while the room for worsening is
greater when the patients start with a lower baseline
symptom score. In the MTOPS trial, a 4-point wors-
ening was predefined as evidence for symptomatic
worsening based on data published by Barry et al.
Figure 8 would suggest, that a worsening in symp-
tom score by 4 points or greater is likely to occur less
often in patients starting out with high or very high
levels of IPSS scores at baseline. The experimental
evidence to prove this point comes from the MTOPS
study. Paradoxically, the probability of a 4-point
worsening in the symptom score is higher in all four
treatment groups, particularly for patients starting at
low-moderate levels of IPSS scores, versus those
pateints beginning the study with more severe symp-
toms. Clearly, this observation limits the applicabili-
ty of a categorical threshold of IPSS score worsening
as the definition of progression, if this is applied
regardless of the baseline IPSS score. The degree of
change is affected by the baseline level, The change
required is not the same for all patients, i.e., patients
along a spectrum of possible baseline symptom
scores. In turn, it is very likely that this observation
is also true for other continuous variables with a
finite continuous measurement scale, i.e., not an
open ended scale.
2. PLACEBO EFFECT VERSUS REGRESSION TO
THE MEAN: INTERPRETATION AND EXTRAP-
OLATION
The last theoretical point to consider is the so-called
“placebo effect” that is observed in nearly all place-
bo or sham control groups regarding both subjective,
and objective measures, direct and indirect parame-
ters of change. A significant component of the place-
bo effect consists of a unilateral regression to the
mean induced by artificially imposed thresholds at
screening or baseline assessment, and which are typ-
ically used as a component of the inclusion or exclu-
sion criteria. This use of the measure as a component
of the inclusion critieria for the study introduces a
source of bias or artifact, and limits the informative
 Figure 5. Relationship between baseline and
mean change in symptom score with self-rating
of symptom relief in the 12-month HYCAT trial.
(Unpublished data from the HYCAT trial
(Roehrborn, Oesterling et al. 1996; Roehrborn,
Oesterling et al. 1996))

Figure 6. Baseline IPSS Score with a change in

IPSS Score stratified in quintiles of visual ana-
logue score question regarding the expectation of
the treatment regarding from much better to
much worse than expected.

Figure 7. aseline maximum flow rate versus

change in maximum flow rate stratified by
response of the patients regarding the strength of
their stream ranging from much stronger to
much weaker stream. There is no discernible pat-
tern of relationship identifiable.

245
 explanation is that patients with a score of 7 or less
points were excluded at the first observation, but not
at the second observation. Thus, the natural variabili-
ty of the symptom score resulted in more patients
tending to have an “improvement” compared to a
worsening in their symptom score from the first visit
to the second, and thus, a unilateral regression to the
mean takes place. (Figure 9). When applying the
entry criteria more stringently, such as a symptom
score of greater than 15 points, the difference
between the means could be 22.0 versus 20.6 for an
“improvement” of 1.4 points (p=0.026) (Table 2).
Similar “improvements” can be induced for the BPH
Impact Index and the Quality of Life score. Even the
maximum urinary flow rate, perhaps the most objec-
Figure 8. This cartoon shows the problems of choosing a tive measure of improvement, will shown this effect
fixed numerical worsening in symptoms versus a fixed when increasing threshold levels applied at baseline
numerical improvement in symptoms as evidence for clini-
will induce an “improvement” of 1.5 to 1.7 ml/sec
cal improvement. Due to the symptom score running from
0 to 35, there is a “glass ceiling” effect, which limits the when the threshold applied is lowered from less than
opportunity for patients in the higher symptom score 15 ml/sec to less than 10 ml/sec at baseline.
ranges to experience worsening, while they have a greater In all controlled, clinical trials, the selection bias
potential for improvement.
applies at baseline. This introduces a unilateral
regression to the mean artifact, which makes it diffi-
value of placebo or sham control groups regarding
cult to study the natural history and/or progression of
the natural history, progression, and outcomes of the
continuous variables in placebo or sham groups of
disease. In fact, the so called “placebo effect” may be
control clinical trials. This regression to the mean
one of the most inherently confounded effects in
artifact adds to the true placebo effect, also referred
medical science, thus offering little if any meaning-
to as a doctor, clinic, or “white coat” effect, while the
ful information about the actual role of placebos.
quantitative contribution of each element can not
In one typical study, for example, a group of 145 vol- under normal circumstances be assessed.
unteers were asked to perform two flow rate record-
ings and fill in the IPSS, BPH Impact Index, and Figure 10 shows an example of regression to the
Quality of Life question twice within one month mean occurring in the placebo group in the 4-year
without any interim interventions. There were only
Table 2. Regression to the mean artifact. Depending on the
very small differences in these parameters between severity and restrictiveness of the criteria applied, an artifi-
the first and the second assessment, as anticipated. cial “regression to the mean” improvement from 0.4 to 1.4
The mean IPSS score was 12.0 and 11.7 at assess- points can be produced without any active interventions.
ment 1 and 2 (p=0.27) and the maximum flow rate (Sech, Montoya et al. 1998)
17.6 versus 17.5 (p=0.72). The correlation between
the first and the second symptom score was r=0.892
(p<0.0001) (Sech, Montoya et al. 1998)
If this experiment had been a clinical trial, it is likely
that flow rate or IPSS thresholds would have been
applied to the population after the first flow rate mea-
sure or symptom score assessment. When applying
increasingly stringent enrollment criteria to the first
assessment, a unilateral regression to the mean would
be anticipated. For example, if at baseline, only
patients with moderate levels of disease would be
allowed to proceed into the study and ipso facto to the
second measurement point (i.e., patients >7 points
IPSS), the mean score at the first assessment was
17.8, but at the second assessment, it was 16.8 for a
difference of nearly 1 point (p=0.035). The obvious

246
 Figure 9. Effect of regression to the mean. If
only patients are chosen who score on the initial
assessment more than 12 points, several of those
patients will experience an artificial improve-
ment in their symptoms even without any treat-
ment at a second assessment point. Of all
patients, many will experience either an increase
or decrease in the symptom score, however, due
to the artificial restriction, at assessment no. 1
the trend will be for a reduction, i.e., improve-
ment in the score on the second assessment.
(Sech, Montoya et al. 1998)

A B

Figure 10 A – C. Regression to the mean artifact. Figure

10 A shows a unilateral regression to the mean plus the
true placebo effect after which the symptom score slightly
deteriorates back to baseline. In Figure 10 B, the initial
regression to the mean artifact is eliminated showing just
the slight worsening over time in the placebo group of the
PLESS trial. Figure 10 C shows the actual data regarding
prostate volume in the placebo group. As there is no
threshold applied, there is no regression to the mean
effect and the natural history is visible in terms of
increase in prostate volume (original data adjusted from
(McConnell, Bruskewitz et al. 1998))

247
PLESS trial. At approximately six months, patients progression, although these measures should always
in the placebo group seemingly improved by 1.5 be viewed as indirect/proxy outcomes.
points (Figure 10A). This likely represents a compo-
Concerning outcomes, (i.e., transitions from one
nent of true placebo effect, but also a likely large
health state to another, as defined above), the evi-
degree of regression to the mean artifact. If one
dence base is strongest for acute urinary retention
aimed to study the natural history or disease progres-
(AUR), and the associated or subsequent need for
sion in the placebo group, one would need to begin
invasive therapy by either minimally invasive surgi-
the observation period at approximately six months
cal intervention (MIST) or direct surgical interven-
after baseline. To eliminate the artifact, it would be
tions. Other transitions between health states or cat-
necessary to alter the Y axis to reflect the true base-
egories within health states would be changes from
line as a starting point, or 0 point value for the symp-
one category of IPSS Score to another, development
tom score. Figure 10 B shows how this can lead to a
of urinary tract infections, renal failure, bladder
different assessment of the natural history of LUTS
stone occurrences, incontinence episodes, etc. One
symptoms in the placebo group of PLESS. It is
of the most common outcomes is that of health or
important to note, however, that the regression to the
health care-seeking behavior. With this, we mean to
mean artifact only applies to those parameters where
say that a patient may decide that his symptoms have
a threshold is applied at baseline. In the PLESS
worsened to a point that he is now prepared to seek
study, no threshold was applied to the baseline
medical care. Unfortunately, however, such health or
prostate volume and prostates of all sizes were
health care-seeking behavior is not adequately docu-
enrolled. Therefore, in the absence of a specific
mented in the current literature, and cannot be
inclusion criterion for this measure, or an artificial
derived from placebo controlled or sham-control
threshold for inclusion, the prostate volume increas-
treatment groups. The only study designs that permit
es over time appear to reflect the true natural history
a true investigation of health or health care-seeking
at shown in Figure 10 C.
behavior are the longitudinal, population-based stud-
ies of which there are preciously few available for
review.
V. EVIDENCE FOR PROGRESSION
The key studies supporting LUTS and
AND ADVERSE OUTCOMES IN BPH BPH/BPE/BPO as a progressive condition are listed
in Table 3). There are several population-based
The evidence for LUTS and BPH/BPE/BPO as a cohort studies that have longitudinal follow-up over
progressive disease and for long-term outcomes can variable periods of time, and in addition, there are a
also be divided into direct versus proxy/indirect substantial number of placebo-control groups and
health progression events as well as outcomes. Fur- practice studies that allow certain types of progres-
thermore, the sources for the evidence can be divid-
ed into those derived from population-based studies Table 3. Key study supporting key population based on
versus placebo/sham-control groups with all the placebo groups supporting BPH as a progressive condition.
appropriate caveats mentioned in the previous sec-
tions.
When assessing the evidence for progression, i.e.,
the transition of a patient within a given health state,
one can search for evidence that symptom severity
and frequency, bother, BPH impact, disease-specific
quality of life, sexual function, sleep disturbances,
and many other subjective measurable direct health
outcomes show evidence of worsening or deteriorate
over time. Concerning indirect/proxy outcomes, we
can consider evidence that urinary flow rate, post-
void residual urine, urodynamic studies, and others
deteriorate or worsen over time. In addition, growth
of the prostate gland as well as changes of serum
PSA over time might be considered as evidence for

248
sion events to be studied with the caveats listed in the
above section.
1. EVIDENCE FOR PROGRESSION OF DIRECT
HEALTH OUTCOMES
While the most desirable way of measuring progres-
sion of direct health outcomes such as symptom
severity and frequency would be an accounting of
the proportion of men who over a stated period of
time progressed from one health state to another, this
evidence is less available. It is indeed more common
for the outcomes analysis to be presented in a semi-
quantitative way, indicating broadly whether or not
symptoms have worsened over time. A good exam-
ple for this is the Scottish prospective community-
based study conducted in 217 men from Forth Valley,
Scotland, and published by Lee et al (Garraway,
Collins et al. 1991; Garraway, EB et al. 1993; Lee,
Russell et al. 1996). Figures 11 shows the changes in
urinary symptom and bother status between baseline
and three years of follow-up. From this report, it is
evident that, by and large, significant increases
occurred in mean symptom and bothersome levels
for nocturia, urgency, dribbling, intermittency, and
incomplete emptying. However, there was a high
level of variability or fluctuation in the occurrence of
the symptoms. At the same time, the bother associat-
ed with these symptoms in general increased, but
again, there was a considerable degree of fluctuation
associated with varying symptoms listed. An obvious
shortcoming of this type of analysis is the fact that it
does not allow us to quantify the worsening for a
given patient, to assess the probability of a given
Figure 11. hanges in urinary symptoms and bother status
between baseline in three years in Scottish community-
based study. (Lee, Russell et al. 1996)
249
patient to experience such worsening, and to assess
the subjective correlates of symptom worsening over
time.
The Olmsted County study provides a numerical
estimate for the average annual increase in the IPSS
Score in a cohort of community dwelling men in
Olmsted County, Minnesota (Jacobsen, Girman et al.
2001). After 42 months of follow-up, the mean slope
of the annual increase was 0.18 points/year, with a
standard deviation of 1.22. The average annual
change increased from 0.05 points/year among men
in their 40s to 0.44/year among men in their 60s lev-
eling off for men in their 70s. If one were to assume
an approximately linear increase for a man starting
out in his early 60s, this would translate into a 4.4-
point increase spanning a decade in a given man’s
life. Figure 12 (Jacobsen, Girman et al. 1996)
depicts the progression of symptoms observed over
four years stratified by decade of life suggesting the
age dependency of the numerical increase or pro-
gression of symptoms in community dwelling men.
A slightly different picture emerges when examining
men already diagnosed with LUTS. Djavan et al.
(Djavan, 2004 #19807) followed a group of 397 men
presenting to a urology clinic with mild symptoms
defined as scoring less than 8 points on the IPSS
Score. These men were followed for four years
beginning with a watchful waiting protocol and were
reevaluated every three months for 48 months total
time. The authors assessed the cumulative incidence
of clinical progression defined as worsening of the
IPSS with migration from mild to moderate (IPSS 8
to 18 points) or severe symptoms (IPSS 19 to 35
Figure 12. Progression of IPSS Score stratified by age over
four years in the Olmsted County study. (Jacobsen, Gir-
man et al. 1996)
points). The likelihood of transitioning from one
health state to another was 6, 13, 15, 24, 28, and 31%
at 6, 12, 18, 24, 36, and 48 months, respectively. This
is graphically shown in Figure 13.
Data from community-based longitudinal studies
regarding changes in subjective parameters such as
bother, BPH Impact Index, sexual function assess-
ment, etc., are not readily available. Concerning pro-
gression in subjective parameters from placebo-con-
trol groups, the best study for evaluating these effects
is the four-year randomized, placebo-controlled
study comparing finasteride with placebo (PLESS
study) (McConnell, Bruskewitz et al. 1998). Howev-
er, due to the fact that patients were screened at study
entry to have moderate LUTS, there is a noticeable Figure 13. Probability of progressing from mild to moderate
“placebo” or regression to the mean effect observed and severe symptoms from 6 to 48 months in men originally
during the first six months of this study. As discussed treated with watchful waiting starting with mild symptoms.
(Djavan, Fong et al. 2004)
above, thereafter, the symptom score shows a trend
towards worsening, however, any interpretation of
such changes over time is based on an artificial reset-
ting of the baseline to approximately a six month
time point of follow-up and thus, is scientifically less
valid. The limitations of using outcomes observed in
a placebo arm of randomized, clinical trials of BPO
in this regard was highlighted by the report of
Roberts et al., who found substantially fewer out-
comes in the placebo arm of the MTOPS study, com-
pared to the Olmsted County community study
cohort (Roberts, Lieber et al. 2005).

2. INDIRECT/PROXY HEALTH OUTCOMES

Indirect or proxy measures may provide additional
data on the progression of disease. One of the most
commonly used physiological or proxy measures of
benign prostatic obstruction is the urinary flow rate.
In the cross-sectional results of the Olmsted County
study, a consistent decrease of approximately
2%/year across all age groups was seen. However,
when analyzing these data by decade of life, men in
their 40s had a 1.3%/year decrease, whereas those in
their 70s had a 6.5%/year increase. The authors
attribute this effect to the baseline selection factors
that influence differences between the cross-section-
al and longitudinal estimates (Roberts, Jacobsen et
al. 2000). (Figure 14).
Virtually all BPO treatment studies utilized maxi-
mum urinary flow rates as an inclusion criterion, and
thus, an inevitable regression to the mean artifact
markedly diminishes our ability to learn much about
the natural history or likely deterioration of the max-
imum flow rate in placebo-control groups.
Other indirect/proxy measures of interest for study-
Figure 14. Decrease of maximum urinary flow rate by
decade of life and within each decade of life by year of fol-
low-up from the Olmsted County study. (Roberts, Jacobsen
et al. 2000)
ing BPE progression is the assessment of prostate
volume, typically by transrectal ultrasonography
(TRUS) or magnetic resonance imaging (MRI).
While there is no widely accepted volume threshold
above which a man can be diagnosed with BPE, it is
evident that men with BPH tend to have larger
prostate volumes than those without. Furthermore, a
number of cross-sectional studies demonstrate that
prostate volume is related, in turn, to age. Prostate
volume in the Olmsted County Community study
increases approximately 0.6%/year (Corica, Jacobsen
et al. 1999; Rhodes, Girman et al. 1999; Rhodes, Gir-
man et al. 2000). However, in the longitudinal study

250
of the clinic population in the Olmsted County, the
average volume increase was in the order of
1.6%/year. This did not vary by age, but the trend was
greater among men with larger prostates at baseline
compared to those with smaller baseline prostates.
The rate of increase was greater than estimated from
the baseline cross-sectional data, but similar to the
autopsy-based estimates (Berry, Coffey et al. 1984).
A sub-parameter or component of prostate volume,
namely the transition zone or central zone volume
was found to increase on average by 2.3%/year, and
this increase does not appear to differ by age. In an
earlier publication from the Olmsted County study,
the mean overall annual growth rate was estimated at
0.6 cc/yr over the observation period of 3.5 years.
The increase ranged from 0.4 cc in men aged 40 to
59 years, to 1.2 cc in men aged 60 to 79 years of age
(Corica, Jacobsen et al. 1999).
In contrast, men participating in the PLESS trial and
being treated with placebo experienced an annual
growth of 1.8 cc/yr over four years with a range from
1.45 in men 50 or 60 to 2.4 cc in men 70 to 79 years
of age. The patients in the PLESS trial had a larger
baseline prostate volume and thus, these data are
consistent with the observation from the Olmsted
County study that baseline prostate volume is a reli-
able predictor of future prostate growth (McConnell,
Bruskewitz et al. 1998).
3. THE TRANSITION BETWEEN HEALTH
STATES OR OUTCOMES
a) Acute Urinary Retention (AUR) and Surgery
There are a variety of population-based studies avail-
Table 4 . Acute urinary retention episodes in population-based studies.
251
able from which the overall prevalence and the annu-
alized incidence rate of AUR episodes can be calcu-
lated. Similarly, data from several long-term place-
bo-controlled studies permits us to calculate the
probability for an individual patient to experience
urinary retention and the need for associated or sub-
sequent surgery. Generally, the available literature on
this topic approaches the subject using analyses by
baseline risk factors, and a more detailed discussion
of the predictors of progression can be found in the
relevant section. Table 4 lists a number of watchful
waiting studies, TURP versus watchful waiting stud-
ies, and other studies including the Olmsted County
that allow for calculation of incidence rates.
The incidence rate is expressed as AUR
episodes/1000 patient years of follow-up, and ranges
widely from 3.7 to 130. In the most carefully con-
ducted study of this type – the Olmsted County
study, the incidence rate is 6.8/1000 patient years,
with a 95% confidence interval of 5.2 to 8.9
(Craigen, Hickling et al. 1969; Birkhoff, Wiederhorn
et al. 1976; Ball, Feneley et al. 1981; Wasson, Reda
et al. 1995; Barry, Fowler et al. 1997; Jacobsen,
Jacobson et al. 1997; Meigs, Barry et al. 1999)
Figures 15 and 16 lists the cumulative incidence of
AUR and surgery in the placebo arms of controlled
BPO trials. While the incidence rates for each of
these outcomes varies greatly from study to study, it
is evident that these incidence rates are generally
higher than those in the population-based studies or
in the watchful waiting cohort shown in Table 4. The
reasons for these differences are obvious, namely
that the patient in the placebo arms of controlled tri-
Figure 15. Cumulative incidence of acute urinary retention
in placebo arms of controlled BPH trials of two and four
year’s duration.
als are typically diagnosed by a physician with BPE,
thus, are more symptomatic, and likely to have an
enlarged prostate gland at baseline. This affects the
overall risk for both AUR and prostate surgery.
(Andersen, Nickel et al. 1997; McConnell, Bruske-
witz et al. 1998; Roehrborn, Boyle et al. 2002;
McConnell, Roehrborn et al. 2003)
When assessing the overall risk of progression and
adverse outcomes, it should be stressed that in most
studies, the risk for AUR or surgery increased in a
linear fashion over time. An example of this trend is
shown in Figure 17 from the PLESS study
(McConnell, Bruskewitz et al. 1998). The probabili-
ty of either surgery or AUR as an outcome is shown
to increase in a linear fashion in the placebo group,
beginning at the start of the study to the end point at
four years. Similar observations can be made from
the dutasteride phase III trials (Roehrborn, Boyle et
al. 2002; Debruyne, Barkin et al. 2004; Roehrborn,
Marks et al. 2004).
Based on findings in the Olmsted County Communi-
ty study, it does not appear that symptomatic wors-
ening or prostate growth occurs in a linear fashion
over time. However, certain conclusions regarding
the likelihood of progression and developing certain
clinical outcomes over time can be drawn.
Consider a 60-year-old man with no prior diagnosis
of LUTS or BPE/BPO, who presents to a health care
provider with a prostate size of 30 ml, a 10-point
baseline score on the IPSS, an annual risk of pro-
252
Figure 16. Cumulative incidence of surgery in placebo arms
of controlled BPH trials of two and four year’s duration.
gression of 1 ml volume increase of his prostate, and
a 0.2-point increase in his symptom score. The annu-
al risk of AUR for this individual is approximately
1%, with the annual risk of requiring any form of
treatment of 3%, and the risk for surgery of 1%.
Assuming a linear risk, this same patient at the age of
80 might have increased his prostate size by 20 ml to
50 ml, and have a symptom score from 10 to 14
points. The cumulative risk of AUR would be 20%
with a cumulative risk for overall treatment to 60%
and the risk for surgery 20%. (Figure 18 A). In con-
trast, a 60-year-old man already diagnosed with
LUTS or BPH might be assumed to start out with an
already enlarged prostate gland of 50 grams and a
higher symptom score of 15 points.
The annual increase in the prostate size might be 2
ml for a total volume increase of 40 ml to an end vol-
ume of 90 ml at the age of 80. Similarly, the symp-
tom score might worsen from 15 to 19 points,
although the overall risk of AUR and surgery appears
to be higher in patients diagnosed with BPE, leading
to a cumulative risk of 40% for AUR, and 60% for
surgery. (Figure 18 B).
Clearly, these predictions are based on generalized
assumptions presupposing a linear risk of progres-
sion for all direct and indirect/proxy health out-
comes, as well as for the risk of urinary retention and
surgery. This assumption of linear progression has
not been established for all risk factors; although by
and large, it appears that linearity can be assumed at
least for the risk of urinary retention or surgery.
Figure 17. The risk of AUR and surgery in placebo-treated patients in the four-year PLESS study is linear. (McConnell,
Bruskewitz et al. 1998)

A B

Figure 18 A -B. A and B demonstrate annual changes and changes over 20 years for 60-year-old men with no diagnosis of
BPH or LUTS (A) and with diagnosed BPH and LUTS (Figure 18 B) based on annual changes in size, symptoms, risk of AUR,
and surgery as reported in the literature.

253

VI. PREDICTORS OF PROGRESSION
OR OUTCOMES
While the previous section analyzed the evidence for
progression and outcomes, in this section we will
consider the evidence for potential baseline predic-
tors of disease progression and outcomes. These pre-
dictors are in general factors that can be assessed at
baseline, i.e., at the first encounter of the patient with
the health care provider in either population-based
studies or placebo-controlled trials.. The analysis of
outcome predictors has been extensive, and has
focused on both direct as well as indirect or proxy
health outcomes, subjective and objective outcome
variables, health progression events, and clinical
outcomes such as health care-seeking behavior,
AUR, and the need for surgery.
1. SYMPTOMS, BOTHER, QUALITY OF LIFE
AND SEXUAL FUNCTION
One study assessing longitudinal changes and LUTS
in African-American men is the Flint Men’s Health
Study (Sarma, McLaughlin et al. 2004). The proba-
bility sample of 369 black men aged from 40 to 79
years residing in Genesee County, Michigan, without
prior history of prostate cancer or surgery participat-
ed in prostate cancer screening. Of these men, 175
Figure 19. Longitudinal changes of LUTS severity and black Americans in the Flint study. (Sarma, McLaughlin et al. 2004)
254
agreed to participate in a follow-up of over four
years. The mean IPSS score at baseline and four
years of follow-up were 7.1 and 7.0 points, respec-
tively, i.e., no overall change was observed. Howev-
er, men in their 40s had a decrease of –0.42 points,
while men in their 70s, an increase of 2.1 points. Of
those men reporting none or mild symptoms at base-
line, 26.4% reported moderate to severe symptoms at
follow-up. This is a clinically significant increase.
Conversely, of those who had moderate to severe
symptoms at baseline, 44.8% had none or mild
symptoms at follow-up, while 55.2% remained in the
moderate category or progressed to severe symp-
toms. Figure 19 shows the percent of men experi-
encing either one or more-point increase versus three
or more-point increase in IPSS scores, and corre-
sponding decreases in scores by decade of life. It is
evident that older men are more likely to experience
a 1 or 3-point increase, compared to a decrease in
IPSS scores, and vice versa in younger men. The
authors examined predictors of progression versus
regression in the IPSS Score, and in addition to age,
prostate size at baseline was a significant predictor of
progression. The odds ratio for a progression of the
AUA Symptom Score over time for men with a base-
line prostate volume of over 30 ml was 1.52, with a
non-significant confidence interval from 0.69 to
3.38.
The earlier study by Djavan et al (Djavan, Fong et al.
2004) also examined the risk of progression versus
non-progression, stratified by pre-defined baseline
parameters. In this study assessment, transition zone
volume, “obstructive symptoms” sub-score, and
serum PSA, were found to be significant predictors
of progression from the mild category, to having
moderate or severe symptoms. Higher baseline val-
ues of serum PSA, transition zone volume, and high-
er “obstructive symptoms” sub-scale scores were all
seen in those men progressing, versus those not pro-
gressing. (Table 5). Interestingly enough, age was
not a factor in the Vienna study (Djavan et al.,) while
it played a significant role in the Flint study, as well
as in the well-known Olmsted County study, where
symptom progression over time was more pro-
nounced in men in their 60s, compared to men in
their 40s and 50s, and flattened out almost complete-
ly for men in their 70s.
Table 5. Predictors of symptomatic progression of men with
wide symptoms in a watchful waiting study. Serum PSA,
transition zone volume, and obstructive symptom score are
significant predictors of progression. (Djavan, Fong et al.
2004)
Despite the limitations in generalizing about pro-
gression effects from results of placebo groups in
clinical trials, ,we have recently examined findings
from the placebo group in the four-year PLESS
study, which can be used to assess predictors of the
natural history and progression of symptom severity,
bother, interference of daily activities, as well as sex-
ual function and general health perception (Bruske-
witz, Girman et al. 1999; Roehrborn, Boyle et al.
1999). As shown in Figure 20 A and C, there is a
255
consistent placebo/regression to the mean effect of
similar magnitude and proportion regardless of PSA
stratification. However, after this initial effect is
taken into account, distinct differences emerge
between those men in the lowest tertile of PSA,
namely from 0 to 1.3 mg/ml, versus those in the
intermediate (PSA 1.4 to 3.2 ng/ml) or in the higher
PSA tertiles (PSA 3.3 to 12.0 ng/ml). The general
trend seen is that men in the lowest PSA tertile main-
tained a placebo/regression to the mean effect, in
terms of symptom severity, bother, and interference
with activities. These men also experienced the least
change over time in their sexual activity, sexual fre-
quency, and general health perception. However,
men in the intermediate to higher PSA category and
intermediate to high PSA tertile, after the initial
placebo/regression to the mean artifact phase, sub-
jects showed a deterioration of symptoms, bother,
interference with activity score, and a progressive
decline in sexual activity, sexual frequency, and gen-
eral health perception over the four years follow-up
period.. Despite the limitations of analyzing natural
history phenomena in this placebo group, it is strik-
ingly evident that higher PSA values at baseline pre-
dict an accelerated return of symptom severity, both-
er, and interference score compared to the baseline
levels, i.e., an accelerated and worsened natural his-
tory of the disease, compared to those men starting
out with lower PSA values.
The only controlled trial which truly assesses the risk
of symptom progression, based on a priori definition,
was the Medical Therapy of Prostatic Symptoms or
MTOPS study (McConnell, Roehrborn et al. 2003).
In this study, progression was defined as an increase
in four or more IPSS points from baseline, as veri-
fied twice within a two-week window, or the devel-
opment of urinary retention, recurrent urinary tract
infections with an infection-free interval, develop-
ment of socially unacceptable incontinence, or
development of renal failure secondary to BPO. Pro-
gression to a surgical intervention for BPO was not
defined as integral to the primary outcome. When
stratifying the risk of symptomatic worsening by
four or more points in the placebo group, Figure 21
demonstrates that the risk of symptomatic progres-
sion decreases significantly for men with baseline
PSAs of less than 1.4 ng/ml compared to those with
a PSA in the intermediate or higher range. Similarly,
the risk of symptomatic progression nearly doubles
for those men with baseline prostate volumes by
transrectal ultrasound of > 40 ml, versus those with
baseline values < 40 ml.
A B

C D
Figure 20 A - D. tratification of the PLESS placebo group in PSA tertiles. It is evident, that the patients in the lowest PSA tertile
experience a regression to the mean/placebo improvement and maintain that improvement in symptom score over the four years
in terms of their symptom score (A), bother score (B), interference with activity score (C), and sexual function (C). The patients
in the intermediate and higher PSA categories experience initial placebo/regression to the mean effect and then a worsening
towards baseline. Figure D shows sexual activity, frequency, and general health stratified in PSA tertiles. Again, it is evident that
the greatest decrease in these three parameters is experienced in the men with the highest PSA tertile at baseline.

Figure 21. Association of baseline PSA and prostate volume

in convenience tertiles in the MTOPS trial and symptomat-
ic progression, i.e., (greater than 4-point worsening). A sig-
nificant difference exists between men with prostate vol-
umes less than 40 and over 40 ml.

256
2. URINARY FLOW RATE
Clear evidence for the rate of decline in urinary flow
rate comes from the Olmsted County Study. This
study established a consistent decrease in maximum
flow rate of 2%/year across all age groups in the
cross-sectional results. The annual change in this
variable based on longitudinal follow-up ranged
from 1.3%/year decrease for men in their 40s, to a
rate of 6.5% decrease for men in their 70s.
Similar to the above-described results of the placebo
group in the PLESS study, maximum urinary flow
rate changes can also be stratified in that study by
PSA tertiles (Roehrborn, McConnell et al. 1999).
(Figure 22). As is evident, men in the lowest PSA
tertile in the placebo group of PLESS experienced a Figure 22. Stratification by serum PSA tertiles of peak uri-
mild improvement in the maximum maximum flow nary flow rates in the placebo group of the PLESS study.
Men in the lowest PSA tertile experience ongoing improve-
rate of about 1 ml/sec. Those in the middle tertile
ment in their flow rate, while men in the intermediate tertile
experienced an initial placebo (or regression) effect, experience no change over time, and those in the highest
but then a return to baseline, while those in the high- tertile, an actual deterioration in flow rate.
est PSA tertile experienced initially no change and
then a sustained deterioration of the maximum uri-
nary flow rate by –1 ml/sec. The phase III dutasteride
studies (Roehrborn, Boyle et al. 2002) found a simi-
lar relationship between baseline serum PSA scores,
and changes in maximum urinary flow rate for the
placebo group. (Figure 23). While in this study only
patients with a PSA > 1.5 ng/ml were included, there
is a trend towards decreasing placebo/regression to
the mean effects over two years, with the subjects in
the highest PSA quartile (i.e., > 6.0 ng/ml) showing
no change in maximum flow rate over the course of
the study.

3. PROSTATE VOLUME
Detailed analyses are available regarding changes in
prostate volume and predictors thereof from a num-
ber of studies. In the Olmsted County study, a
detailed analysis of annualized percent volume
increases stratified by various baseline parameters
was performed (Table 6) (Jacobsen, Jacobson et al.
1997). As is evident, the median percent volume
increase is nearly identical for men in their 40s com-
pared to men in their 70s, and independent of peak
urinary flow rate, as well as mild versus moderate to
severe baseline symptoms. However, greater increas-
es in prostate volume are observed for men with larg-
er prostate volumes, as well as for those with higher
serum PSA values at baseline (Roberts, Jacobsen et
al. 1997; Rhodes, Girman et al. 2000).
The placebo group of the four-year PLESS study
also permitted an analysis of predictors of prostate
growth over time, with the usual caveats to be con-
Figure 23. Relationship of baseline PSA with mean abso-
lute changes in maximum flow rate at two years in the
placebo group of the dutasteride phase III trials.
sidered (Roehrborn, McConnell et al. 2000). Figure
24 demonstrates the percent change of prostate vol-
ume stratified by PSA tertiles versus decade of life
(men in their 50s, 60s, and 70s). As is evident, men
in the lowest PSA tertile show a volume growth of
7.4% over four years for an annualized growth of
1.9%, compared to those in the intermediate PSA
category of 16.2% (for an annualized growth of
4.1%), and those in the highest PSA category 22%,
resulting in an annualized growth of 5.5 points in this
group. Of note, the stratification by age in the place-
bo group yields considerably smaller differences,
i.e., age does not play as much of a role in men

257
Table 6 – Part I and II. Categorical percent volume increase over one year in the prostate stratified by age, maximum urinary
flow rate, symptom severity, prostate size, and baseline serum PSA. Only larger prostates and higher serum PSAs at baseline
predict a greater numerical prostate volume increase over time (data from the Olmsted County study).(Rhodes, Girman et al.
1999)
Part I
Figure 24. Predictors of prostate growth in the PLESS
placebo group. This stratification by PSA tertile (left), and
age (right) demonstrates the percent volume increase over
four years in PLESS. Men with highest PSAs have a 22%
volume increase, while those with low PSAs, a 7.4%
increase. The stratification by decade of life is much less
pronounced ranging from 12 to 16.6%. (Roehrborn,
McConnell et al. 2000)
already diagnosed with BPE in predicting future
prostate volume increases, compared to the baseline
PSA score. A striking example for this can also be
seen in a quartile PSA analysis of the relationship
between baseline PSA and the median percent of
change in transition zone volume at two years in the
placebo group of the dutasteride study. (Figure 25).
The median percent change ranges from 0.8 for an
258
Part I I
annualized increase of 0.4%, to an increase of 10.4%
(for an annualized increase of 5.2%). This occurs in
the highest quartile of men with a PSA of > 6.0
ng/ml. Comparing results of the PLESS placebo
group with those of the dutasteride placebo group, in
the highest PSA stratum, the annualized volume
increase is 5.5 versus 5.2%, a very similar and thus,
seemingly reproducible rate.. When considering this,
it appears that over a 10-year period, a man starting
out with LUTS and BPE and a PSA at 4 or above,
may experience up to a 50% increase in prostate vol-
ume or, for an example, an increase from 40 to 60 or
60 to 90 ml.
Figure 26 shows the total prostate volume, the abso-
lute and percent changes in prostate volume in the
placebo group of the MTOPS study (McConnell,
Roehrborn et al. 2003). The prostate volume at base-
line increases substantially for all men in this age
group. However, neither the absolute nor the percent
change over the five-year observation period differed
substantially for men in their 50s, 60s, or 70s. This
data corroborates the findings from the PLESS study
suggesting, that in placebo-control groups, prostate
volume increases over time are more influenced by
baseline PSA compared to baseline age. This may be
related to the selection criteria applied at baseline
and population selection biases, as discussed above.
In contrast, baseline serum PSA again in the MTOPS
study proves to be a powerful predictor of future
prostate growth in regards to both the total volume
and the transition zone volume. (Figure 27). In the
 Figure 25. Relationship of baseline PSA with a median
percentage of change in transition zone from two years in
the Dutasteride phase III study.

Figure 26. Total prostate volume (yellow), percent

change in prostate volume (green) and total prostate vol-
ume absolute change in red stratified by decade of life in
MTOPS. Baseline prostate volume is higher in older
men, however, neither percent nor absolute changes are
different between men in their 50s, 60s, and 70s.

Figure 27. Change in total prostate volume and transi-

tion zone volume (yellow and red) stratified by baseline
PSA quartiles in the MTOPS study placebo group. In the
lowest quartile, the total prostate volume is either 5 ml or
1 ml/year, while in the highest quartile, it increases to 15
ml or 3 ml/year.

259
lowest PSA quartile, an overall increase in prostate
volume of 5 ml (or an annualized increase of 1 ml) is
observed, while in the highest PSA quartile, the over-
all increase is in the range of 15 ml, or 3 ml/year.
Similar, although numerically smaller, changes in
size are observed for the transition zone.
Barry et al. followed 500 potential candidates for
elective prostatectomy who were treated medically
in five North American urology practices over a peri-
od of four years. Complete data were obtained on
371 “survivors”. Over the follow-up period, 10, 24,
and 39% of patients originally presenting with mild,
moderate, and severe baseline symptoms had under-
gone surgery, while 27, 31, and 27% of those were
receiving medical therapy. This resulted in 63%,
45%, and 33% of patients who had discontinued
treatment at four years (Barry, Fowler et al. 1997)
(Table 7).
Another investigation of health care-seeking behav-
ior for men with urinary symptoms comes from the
Olmsted County study (Jacobsen, Girman et al.
1995). In the clinic study of 475 men, this study
found that men with moderate to severe symptoms
were 3.4 times as likely to have sought medical care
in the previous year compared to those with mild
symptoms. Men with enlarged prostates of over 40
ml were 3.9 times as likely to have sought health care
and men with maximum urinary flow rates of under
10 ml/sec were only slightly more likely to have
sought health care. Seventy-six percent of men who
sought medical care had prostate enlargement,
reduced maximum flow rates, or moderate to severe
symptoms, while only 55% of men who did not seek
health care had mild symptoms, normal prostate vol-
umes, and normal maximum flow rates. This sug-
Table 7. Outcomes of natural history of BPH as diagnosed
by US urologists stratified by mild, moderate, and severe in
terms of referral for surgery, medical therapy, or no thera-
py. (Barry, Fowler et al. 1997)
260
gests that clinical, physiological, and anatomical
measures of LUTS and BPE/BPO did not adequate-
ly distinguish men who sought medical care for their
urinary symptoms from those who do not. On the
other hand, investigators in the Olmsted County
study, (Roberts et al.,) reported that men who were
significantly embarrassed or worried about their uri-
nary function were more likely to have sought med-
ical care for their symptoms compared to those who
were not. . The association between health care-seek-
ing behavior and embarrassment or concern was
especially strong among men with little or no bother
associated with their urinary symptoms (Roberts,
Rhodes et al. 1994). The role of psychological pre-
dictors of health-care seeking or other outcomes war-
rants further investigation.
4. AUR AND SURGERY
In reviewing predictors for acute urinary retention
(AUR) and surgical intervention for LUTS and pre-
sumed or proven BPO, significant and well-analyzed
data are available from population-based studies, as
well as cohort designs and placebo-controlled stud-
ies.
Arrighi et al. reported in an early study in 1990, that
the need for surgery was strongly dependent on base-
line factors such as change in size and force of
stream, sensation of incomplete emptying, and
prostate enlargement as noted on DRE (Arrighi, HA
et al. 1990) (Figure 28). In population-based stud-
ies, it has been known for sometime that age is a
strong predictor of the incidence of AUR (Meigs,
Barry et al. 1999) (Figure 29), as data analyzed by
Meigs et al. from the Physicians’ Health Study clear-
ly demonstrates.
In the Olmsted County study, the relative risk of
AUR and treated significantly for men in their 70s
compared to younger men, for men with moderate to
severe symptoms compared to those with mild symp-
toms, and for men with a reduced maximum urinary
flow rate of less than 12 ml/sec (Jacobsen, Jacobson
et al. 1999). (Figure 30).
The focus on psychological factors (e.g., worry/dis-
tress) as predictors of health care seeking behavior,
observed in the Olmsted County study, was assessed
further in the VA Cooperative Study comparing a
cohort of moderately symptomatic men, and ran-
domizing them to either immediate TURP or watch-
ful waiting (Flanigan, Reda et al. 1998). Over time,
it was observed that the patients with high baseline
bother scores crossed over from watchful waiting to
a TURP in a significantly higher proportion com-
pared to those with low bother scores at baseline.
(Figure 31).
Figure 28. Need for surgery by baseline risk factors and pres- Figure 29. Incidence of acute urinary retention stratified
ence or absence of prostatic enlargement. . (Arrighi, HA et al. by decade of life in population-based studies. (Meigs,
1990) Barry et al. 1999)

Figure 30. Relative risks of acute urinary

retention stratified by baseline parameters
(age, symptom severity, maximum urinary flow
rate). (Jacobsen, Jacobson et al. 1997)

Figure 31. Risks of watchful waiting in

patients crossing over to TURP stratified by
bother. It is evident that patients with high
bother more commonly cross over to surgery.
(Flanigan, Reda et al. 1998)

261
An informative analysis of the role of baseline vari-
ables in predicting the risk for medical or surgical
treatment overall, or for needing a TURP, can be
seen again in findings from the well-known Olmsted
County study. The risk for treatment in this study
was increased for men in their 50s, 60s, and 70s
compared to those in their 40s, and for those with
moderate to severe symptoms, compared to those
with mild symptoms. Furthermore, a reduced urinary
flow rate, prostate volume over 30 grams, and a PSA
of over 1.4 predict an increased risk for treatment
compared to those with a normal flow rate, small
prostate volume, and a low serum PSA. (Figure 32)
(Jacobsen, Jacobson et al. 1999). Age plays a major
role as seen in Figure 33, which shows the cumula-
tive incidence of overall treatment and TURPs strat-
ified by age. It is noteworthy, that the risk of overall
treatment as well as the risk for surgical treatment
appears to be linear, i.e., predictable over time.
Extensive information regarding baseline predictors
of the risk for retention or surgery comes from three
placebo-control arms of the dutasteride phase III
studies, the PLESS study, and the MTOPS study. In
dutasteride phase III studies, patients were enrolled
who had a baseline prostate volume of over 30 ml
and a baseline serum PSA of greater than 1.5 ng/ml.
The relationship of baseline PSA with the proportion
of patients experiencing AUR and/or requiring BPH-
related surgery is shown in Figure 34 A and B. The
incidence rate of AUR increases from 1.6 to 9%,
while the proportion of subjects requiring BPH-relat-
ed surgery from 2.9 to 7.5% stratified in quartiles of
serum PSA (Roehrborn, Boyle et al. 2002;
Debruyne, Barkin et al. 2004).
Figure 35 A and B shows the cumulative incidence
of progression events in the placebo-control group of
the four-year PLESS study (Roehrborn, Boyle et al.
1999). Of note, prostate volume was measured by
MRI only in a subset of 10% of patients. The tertile
analysis groups these patients according to prostate
volume (40 to 41 grams, 42 to 57 grams, and 58 to
220 grams), while the PSA tertiles have been
described above. As is evident from the figure, the
risk of spontaneous retention, precipitated retention,
or the combined spontaneous plus precipitated or
total AUR rate, as well as the risk of surgery increas-
es with both increasing prostate volume as well as
increasing serum PSA tertiles. The overall risk of
surgery or AUR reaches 22% in the highest prostate
volume group, and 20% in the highest PSA tertile,
while it is only 11% and 8% in the lowest volume
and PSA tertile groups, respectively. Figure 36
262
shows that the risk of AUR or surgery is indeed
increased in a linear fashion with increasing serum
PSA. The higher the PSA threshold along the X axis,
the greater is the risk for both urinary retention or
surgery, suggesting again that this is a linear risk and
that all thresholds chosen are artificial. In line with
this interpretation, there is no obvious break point
between patients at low versus high risk (See Figure
36).
Additional information regarding the risk of AUR
stratified by baseline prostate volume and serum
PSA comes from the MTOPS study (McConnell,
Roehrborn et al. 2003) As Figure 37 shows, the risk
of AUR increases with increasing serum PSA and
specifically, doubles with a PSA of greater than 4.0
ng/ml compared to those with a lower PSA. The risk
of AUR increases although much less noticeably
with an increase in prostate volume from less than 20
to over 20 ml.
A comprehensive evaluation of clinical predictors of
spontaneous urinary retention across pooled data of
placebo-treated patients in clinical trials was report-
ed by Roehrborn et al.(Roehrborn, Malice et al.
2001). More than 110 variables were considered
individually and in combination as predictors of
AUR using the logistical regression analysis and
classification and regression tree method (CART)
with a split-sample approach. Data from over 5000
patients were included in the analysis. A five-vari-
able model including the baseline parameters of
serum PSA, symptom problem index, maximum uri-
nary flow rate, frequency of urination less or equal to
two hours, and urinary hesitancy was found to per-
form best, however, it performed only slightly better
than serum PSA alone as a predictor of spontaneous
AUR. In the combined data set, the area under the
curve for the receiver operating characteristics was
0.706 for the five-variable model and 0.709 for PSA
alone. The overall algorithm including all parameters
yielded an AUC value of 0.754. This study clearly
demonstrates that PSA, at least in patients in clinical
trials diagnosed with LUTS and BPE, is indeed the
most powerful predictor of spontaneous AUR.
As discussed earlier, many decisions in clinical prac-
tice are made based on changes in variables or
dynamics predictors during periods of observation.
Data regarding dynamic variables or changes of vari-
ables during follow-up are extremely rare, although
in clinical practice they probably constitute the most
common reason for a change in therapeutic regi-
mens. A recent analysis of a real life practice study
suggested that, in addition to a previous episode of
 Part I

Part II

Figure 32 – Part I and II. Baseline variables and

risks for BPH treatment stratified by age, symp-
tom severity, maximum urinary flow rate, prostate
volume, and serum PSA. Men over the age of 50,
those with more than with moderate or severe
symptoms, peak urinary flow rate under 12 ml,
prostate size over 30 ml, and serum PSA greater
than 1.4 experience greater risks for treatment in
the Olmsted County study. (Jacobsen, Jacobson et
al. 1999)

Figure 33. BPH treatment and TURP, BPH

treatment (left) and TURP treatment (right)
stratified by age in the Olmsted County
study. Older men experience more treat-
ment and are more commonly referred for
TURP. (Jacobsen, Jacobson et al. 1999)

263
 A B

Figure 34 A - B. Relationship of baseline PSA with the proportion of subjects experiencing AUR and BPH-related surgery in
the Dutasteride phase III studies placebo group.

A B

Figure 35 A -B. Cumulative incidence of progression events in PLESS stratified by MRI volume tertiles in the placebo group
and by PSA tertile (B). Patients with larger prostate volumes and higher serum PSA values have a greater likelihood of pro-
gression compared to patients with lower PSA and prostate volume. (data from PLESS study (Roehrborn, McConnell et al.
1999)

264
Figure 36. Cumulative incidence of AUR (left) and surgery (right) stratified by baseline PSA threshold in the placebo group
of PLESS. The risk for AUR and surgery increases nearly linearly with increase in serum PSA. (data from PLESS study
(Roehrborn, McConnell et al. 1999)

Figure 37. Association of baseline PSA and prostate vol-

ume and risk of acute urinary retention in the placebo
group of MTOPS stratified by convenience tertiles. The risk
of progression increases dramatically when the PSA is over
4, and for patients with prostate volumes over 20 grams.

265
AUR, a rise in the IPSS score or the bother score
under treatment were the most powerful predictors of VII. PREVENTION OF
future episodes of AUR and BPO-related surgery, PROGRESSION AND OUTCOMES
and in fact, more powerful than either age, baseline
PSA, or baseline IPSS and bother score. (Figure 38)
Considering evidence for prevention of progression
(Emberton et al. AUA and EAU abstract). This is an
and outcomes, we refer to the initial discussion
important observation, which warrants replication
regarding primary versus secondary prevention, and
and further investigation.
early secondary versus late-secondary or tertiary pre-
Table 8 (Sections 1 and 2) lists the evidence for pro- vention.
gression/outcomes in population studies and place-
bo-control groups in clinical trials, as well as the evi- 1. PRIMARY PREVENTION
dence for predictors of progression. The tables list
Primary prevention implies that the development of
the types of predictors studied across the top row,
a disease and its complications is prevented entirely,
and the outcome variables or parameters of progres-
while secondary prevention refers to the prevention
sion down the left-hand side of the table. In general,
of further symptomatic deterioration of worsening of
there is reasonably good concordance in the evidence
the condition. Late secondary or tertiary prevention
for progression from population-based studies and
may refer to the prevention of an outcome after an
placebo groups, although the evidence of progres-
initial event has already taken place (e.g. AUR).
sion from placebo-control groups is limited by the
Obviously, in the area of LUTS and BPH, the litera-
described regression to the mean artifact. Regarding
ture on prevention is concerned mostly with sec-
predictors of progression, however, good to excellent
ondary or tertiary prevention, although primary pre-
evidence is available from both population studies,
vention in this condition is not only theoretically
as well as placebo-control groups for many of the
possible, but may also be practically achievable.
potential predictors and reported outcomes. Notably
missing from this list is evidence for the role of uro- It is known that androgen action is required for the
dynamic studies in predicting progression and out- development of the prostate during androgenesis.
comes. This is likely due to the invasive nature of Growth of the prostate and the development of BPH
urodynamic testing. do not occur in men with mutations of the androgen

Figure 38. Risk factors for AUR or BPH surgery in a clinical practice study setting (n=4287 patients). Previous history of
AUR, but also changes in symptom score under treatment and bother score under treatment are the most significant predic-
tors of AUR and surgery emphasizing the importance of dynamic changes in variables.

266
Part I

Part II

Table 8 – PART I - II. Evidence for progression/outcomes and predictors of progression/outcomes in population-based stud-
ies (Part I) and placebo groups (Part II). The evidence is rated for each of the parameters listed in the first column for both
population-based studies and placebo group, and for the predictors in the various columns. (Jacobsen, Jacobson et al. 1999)

267
receptor with profoundly affected function. (Wilson
and Roehrborn 1999) or in men with congenital defi-
ciency of the 5alpha-reductase type II referred to as
male pseudohermaphroditism.(Imperato-McGinley
1991) Ultrasonography was performed on male
pseudohermaphrodites with a 5alpha-reductase type
II deficiency and the results compared to age-
matched controls. In addition, six of these patients
underwent MRI studies of the prostate, as well as
their heterozygote fathers. The prostates of the male
pseudohermaphrodites appeared as a plate-like soft
tissue structure posterior to the urethra on both imag-
ing modalities. The prostate volume was significant-
ly smaller (approximately .01% compared to the vol-
ume of age-matched controls). The biopsies per-
formed on two of such affected individuals revealed
stromal tissue only. These results correlate with
undetectable serum PSA levels in affected subjects,
suggesting an atrophic epithelium or lack of epithe-
lial differentiation altogether. There was no differ-
ence, however, in the prostate size between the het-
erozygous fathers and age-matched controls.
The effect of pre-pubertal castration on the prostate
has been examined in several populations. It has
been shown, for example, that the prostate becomes
atrophic in eunuchs serving in the Ottoman Court
who were castrated prior to puberty. (Hikmet et al,
New York Academy of Med, 1901). In addition, the
prostate was found to be very small or non-palpable
in a group of eunuchs serving at the Imperial Court
in the Forbidden City in Beijing, China. Autopsy on
a single 40-year-old eunuch castrated and emasculat-
ed prior to puberty revealed a 4-gram prostate size
gland 8. Digital rectal examination on 26 eunuchs
with a mean age of 72 and duration of castration of
54 years revealed a non-palpable prostate in 21 of 26
(81%) of affected individuals (Wu and GU, EORTC
Genitourinary Group, 1991).
These observations indicate that primary prevention
of BPH is indeed possible by either pre-pubertal cas-
tration, or by a congenital deficiency of the 5alpha-
reductase type II enzyme leading to a significant
deficiency of dihydrotestosterone at the pivotal time
of the development of the prostate and later on,
development of BPH. Incidentally, prostate cancer
has also not been reported in either the eunuch group
or in the individuals affected with the 5alpha-reduc-
tase type II deficiency syndrome.
2. SECONDARY PREVENTION
a) Symptoms, Bother, Quality of Life
In contrast to primary prevention, secondary preven-
268
tion has been extensively studied and is a well-docu-
mented strategy in the field of LUTS and BPE/BPO.
When looking at disease progression as a transition
within one health state, it is evident that the preven-
tion of progression of symptoms, bother, interference
with daily activities, quality of life, sexual function,
and other direct outcomes are difficult to quantify
and analyze. The same is true for the indirect or
proxy health outcomes, such as changes in maximum
urinary flow rate, post-void residual urine, urody-
namics, growth of the prostate, and PSA changes
over time. The reason for this is a lack of evidence to
suggest what margin of change should constitute
clinical progression, with the exception of the afore-
mentioned threshold of worsening in IPSS scores.
For the other progression events, a clearly defined
margin of change is needed which would constitute
true progression. This leaves only two choices for the
interpretation of evidence related to progression, and
the prevention thereof.
Progression could be defined as a worsening by any
margin of change on any of the continuous scales,
and conversely the absence of any worsening on
these parameters could be defined as prevention of
progression.
The definition could be limited to those instances
where clear thresholds have been established, such
as in the case of the IPSS Score.
The only trial in which the prevention of a prede-
fined progression event is adequately addressed is
the MTOPS trial. When faced with this difficulty, the
vast majority of the urological literature has focused
on symptom score, quality of life score, “BPH”
impact indices, and maximum urinary flow rate.
These are typically reported an an improvement of
these scores from baseline, rather than prevention of
progression in these scores. The recently published
guidelines of the American Urological Association
offers a comprehensive overview of the improve-
ment in the IPSS Score, the maximum urinary flow
rate, and the quality of life score achieved with all
medical therapies, minimally invasive therapies, and
surgical interventions. (http://auanet.org/guidelines/
bph.cfm). Figure 39 a-c shows the average improve-
ment shown with various medical therapies at 3 to 9
months, 10 to 16 months, and >18 months duration,
the average improvement maximum urinary flow
rate and the average improvement in the quality of
life score. Figure 40 A – C shows the range of
observed symptom scores, quality of life scores, and
maximum urinary flow rate improvement with med-
ical therapy, minimally invasive therapies, and surgi-
 A

Figure 39 A, B, C. Average improve-

ment in symptom score for various
medical therapies, peak urinary
flow rate, and quality of life score
according to the AUA Guidelines.
(AUAPracticeGuidelinesCommittee
2003)

269
 A

Figure 40 A, B, C. Range of
observed improvements in
symptom score (A), flow rate
(B), and QOL (C) for medical
therapy, minimally invasive
therapy, and surgical therapy
stratified by duration of follow-
up from the AUA Guidelines.
(AUAPracticeGuidelinesCom-
mittee 2003)

270
cal therapies, again, taken directly from the AUA
Guidelines. (http://auanet.org/guidelines/bph.cfm)
b) Serum PSA
If one were to consider an increase in serum PSA
over time as evidence of progression of BPE, then
the reversal of such, namely a decrease in serum PSA
could be considered a prevention of progression.
Clearly, an increase in serum PSA can only be con-
sidered an indirect or proxy health outcome and thus,
a decrease in the serum PSA cannot be construed as
being directly beneficial to the patient. However,
there is substantial evidence linking the decrease in
serum PSA to a decrease in prostate volume, in turn,
linking this change to clinically relevant outcomes
such as the prevention of AUR and surgery (see later
in this section). The class of drugs, 5alpha-reductase
inhibitors contains two compounds, namely finas-
teride, which inhibits exclusively the type II of the
5alpha-reductase isoenzyme, and dutasteride, which
inhibits both type I and type II of the 5 alpha-reduc-
tase isoenzymes. Both drugs prevent the conversion
of testosterone to dihydrotestosterone and thereby
reduce circulating serum dihydrotestosterone (DHT)
by 70% (finasteride) and 90% (dutasteride). As a
result of this, prostate volume decreases and serum
PSA is reduced by a median of 50% over time.
This decrease in serum PSA has been shown for
finasteride to be maintained over a period of obser-
Figure 41. Serum PSA decrease by about 50% is sustained over six or more years under treatment with 5alpha-reductase
inhibitor, finasteride.
271
vation of up to six years. (Figure 41).(Roehrborn,
Bruskewitz et al. 2004). Dutasteride reduces total
serum PSA to a similar degree at least over an obser-
vation period of 12 months. In addition, serum free
PSA is reduced by approximately 50% as well, leav-
ing the ratio of free to total PSA more or less
unchanged. (Figure 42). (Roehrborn, Andriole et al.
2002). The effects of dutasteride and finasteride on
serum PSA have been studied in a head-to-head com-
parison trial (EPIC) (http://ctr. gsk.co.uk/Summa-
ry/dutasteride/studylist.asp). In this study, finasteride
and dutasteride reduced serum PSA by –45 and 46%,
respectively, at 3 months, by –53 and 54%, respec-
tively, at 12 months (median percent change from
baseline). It has been shown that the reduction in
serum PSA actually increases over time, i.e., there is
a further reduction in serum PSA, at least with dutas-
teride over time. Whether or not this relates to any
clinically meaningful changes or not is an unresolved
question.
c) Prostate Volume
Another indirect/proxy outcome is an increase in
prostate volume, as discussed in previous sections.
Conversely, a reduction in the prostate volume could
be considered a prevention of progression. The
5alpha-reductase inhibitors, finasteride and dutas-
teride, have again been shown to reduce prostate vol-
ume over a period of 3 to 6 months by approximate-

Figure 42. Dutasteride reduces total PSA by approximate-
ly 50% and, also, free PSA by approximately 55%. The
ratio of free to total PSA is preserved.
ly 15 to 30%. As Figure 43 A and B shows, the
reduction does not change significantly from an
observation period of 6 months to an observation
period of 48 months. This has been verified for both
finasteride and dutasteride in a multitude of placebo-
controlled clinical trials.
The reduction in prostate volume has been sustained
over a period of at least 6 years as published by
Lowe et al., (Lowe, McConnell et al. 2003) for finas-
teride. It is reasonable to assume that a similar sus-
tained decrease in prostate volume would apply to
dutasteride. Until recently, it had been assumed that
the effect on prostate volume induced by the 5alpha-
reductase inhibitor drugs would be more pronounced
on the transition zone as it is assumed to be the
source of BPE. However, data recently presented by
Marks et al., suggests that the effect on the transition
zone is identical, as well as on the peripheral zone of
the prostate (Marks 2005). (Figure 44 A and B). The
dutasteride phase III trials allow an assessment of the
changes in total prostate volume (PV), transition
zone volume (TZV), and peripheral zone volume
(PZV). Figure 44 A shows that there is a simultane-
ous decrease in transition zone and peripheral zone
volume combining for a significant decrease in total
prostate volume. Figure 44 B suggests that the tran-
sition zone index, which is the ratio of TZV over PV
remains unchanged from baseline to 24 months at
approximately 0.5. Overall, this suggests that the
effect of 5alpha-reductase inhibitors is identical on
peripheral and transition zone volume.
Another question of interest is whether or not base-
line prostate volume or baseline serum PSA might
predict changes in the opposing factor, namely
whether baseline serum PSA would predict changes
in prostate volume or whether prostate volume
272
would predict changes in serum PSA. Figure 45
demonstrates that in fact, baseline serum PSA pre-
dicts the degree of volume increase in the placebo
treated patients, with those patients in the higher
PSA categories having greater increases in prostate
volume over time (Figure 45). An analysis of sever-
al controlled studies performed with finasteride
allows a definite answer to these questions. Figure
46 shows the two-year change in prostate volume by
serum PSA categories. As is evident, prostate volume
decrease remains steady at around 20%, whether or
not the baseline serum PSA is in the 0 to 0.5 range,
or in the 8 to 10 range. In the placebo-treated patients
(open circles), there is an increase in prostate volume
noted, which ranges from 5 to maximally 20% over
the same time period. Figure 47 shows the change in
serum PSA by baseline prostate volume in six cate-
gories. The decrease in total serum PSA is strictly
volume dependent, i.e., patients with larger prostate
volumes tend to have a higher serum PSA, and thus,
do have a larger absolute decrease in serum PSA.
The percent reduction in serum PSA, however, is not
affected by prostate volume. This figure also illus-
trates that patients with larger prostate volumes have
a greater increase in serum PSA when treated with
placebo (open circle). Figure 48 shows the percent
volume changes in control clinical trials for the
placebo and alpha-blocker group (the latter one only
referring to the doxazosin group in the MTOPS trial).
Due to the regression to the mean artifact, there are
no substantial changes noted in prostate volume at 6
months in both trials in which it was reported. At 12
months, either a decrease or an increase was noted.
At 24 months, the majority of studies report an
increase in prostate volume in the placebo groups,
and all studies reporting data out to 48 months report
an increase in prostate volume between 10 and 25%.
Of note, an increase in prostate volume in the
MTOPS study is identical for the placebo and the
doxazosin group. The increase in transition zone vol-
ume in the phase III dutasteride studies is identical to
the increase in the total prostate volume in the dutas-
teride studies at 24 months.
The issue of volume increases as evidence for pro-
gression and the reversal thereof as evidence for pre-
vention of progression can therefore be summarized
as follows:
• Alpha-blockers do not affect the natural growth
history of the prostate as evidenced in the MTOPS
and VA Cooperative trial.
• The 5alpha-reductase inhibitors, finasteride and
dutasteride, reduce the prostate volume by 15 to
30% over a period of treatment of 24-48 months.
 A

Figure 43 A -B. Baseline and follow-up volumes in controlled clinical trials with 5"-reductase inhibitors ranges from 3 to 48
months. Figure 43 B shows the percent volume reduction, which ranges from 15 to 30% across the various trials and various
time points starting at six months.

273
Figure 44 A. utasteride affects total prostate volume, transition zone volume, peripheral zone volume to the same degree. There
is no differential effect on peripheral versus transition zone volume.

Figure 44 B. Transition zone index, i.e., the ratio of transition zone volume to prostate volume remains unchanged over 24
months of treatment with dutasteride.

274
 Figure 45. Change in prostate volume at
year 4 in MTOPS for the four treatment
groups (McConnell, Roehrborn et al.
2003)

Figure 46. Two-year changes in prostate

volume stratified by serum PSA for
patients treated with finasteride (closed
circles) and placebo (open circles).
There is no difference in prostate vol-
ume changes in finasteride-treated
patients stratified by baseline serum
PSA.

Figure 47. Two-year change in PSA by

prostate volume (closed circles, finas-
teride) and (open circles, placebo). The
absolute decrease in PSA increases with
increase in prostate volume as those
prostates have a higher baseline serum
PSA.

275

Data from the EPIC study suggests that the reduction
in prostate volume at 12 months is nearly identical,
namely 26.3% versus 26.7% for finasteride, and
dutasteride, respectively. The shrinkage of prostate
volume affects both peripheral and transition zone
volume to the same degree. The reduction in prostate
volume is maintained to six years and likely longer.
The percent reduction in prostate volume is not
dependent on baseline size or baseline serum PSA.
d) Relationship Between Baseline Parameters and
Likelihood/Magnitude of Improvement Versus Pro-
gression
There is some evidence that the improvement in
symptoms and maximum urinary flow rate, and pre-
sumably other parameters such as bother score, inter-
ference with daily activity score, and quality of life,
is dependent on baseline parameters such as prostate
size or serum PSA, at least when treatment with
5alpha-reductase inhibitors are studied. An early
observation by Boyle et al. suggested that finasteride
is more effective than placebo in improving symp-
toms and urinary flow rate in men with larger glands
at baseline. (Figure 49 A and B). As is evident from
these figures, the placebo effect (in orange) decreas-
es with increasing prostate size, both in terms of
symptom score and in terms of urinary flow rate.
Simultaneously, the effect of finasteride increases
slightly leading to a greater net benefit of finasteride
over placebo (Boyle, Gould et al. 1996). A similar
analysis was performed for symptom score improve-
ment and flow rate improvement, this time stratify-
ing patients into six categories of PSA ranges). (Fig-
276
Figure 48. Percent volume changes in
controlled clinical trials with placebo
and alpha-blockers. Due to the regres-
sion of the mean effect, not in all tri-
als is a volume increase noticeable.
However, in the pivotal 24 and 48-
month studies, significant volume
increases are observed with both
placebo and alpha-blockers.
ure 50 A and B). Again, the placebo effect decreas-
es with increasing serum PSA reflecting an acceler-
ated natural history, while the finasteride effect
increases slightly leading to a greater net drug bene-
fit.
In a similar manner, the data from the MTOPS study
support the notion that patients with larger glands at
baseline respond more favorably to 5alpha-reductase
inhibitors. Figure 51 shows the changes from base-
line in terms of maximum urinary flow rate, IPSS
score, BPH impact index, and quality of life score for
patients treated in the MTOPS trial with placebo,
doxazosin, finasteride, and combination therapy.
Figure 51 A shows the improvements for patients
with total prostate volume under 20 ml, transition
zone volume under 10 ml, or a serum PSA of less
than 1.4 ng/ml. As is evident, in this group of patients
with small glands and low PSA, the alpha-blocker,
doxazosin, is associated with greater improvement
that placebo or finasteride alone, but is equal to com-
bination therapy. Figure 51 B shows the same anal-
ysis repeated in patients with a total prostate volume
of over 40 grams or a transition zone volume of over
20 grams, or a total serum PSA of greater than 4.0
ng/ml. In this instance, the alpha-blocker still is
superior to placebo, but the margin is less pro-
nounced. Surprisingly, finasteride performs as well
or slightly superior to the alpha-blockers, but combi-
nation therapy performs superior to both single arm
therapies. This analysis from the MTOPS study sug-
gests the interpretation that, for patients with small
glands and lower serum PSA values, alpha-blocker
therapy alone is sufficient to treat symptoms, bother,
 A

Figure 49 A, B. Meta-analysis of
finasteride one-year study. This meta-
analysis shows the average changes in
peak flow rate and quasi-IPSS Score
(A and B) with finasteride and place-
bo stratified by baseline prostate vol-
ume. It suggests that the placebo
effect decreases with increasing
prostate size, and that the finasteride
effect slightly increases leading to a
greater therapeutic benefit. (Boyle,
Gould et al. 1996)

A B

Figure 50 A, B. Finasteride one-year study meta-analysis for peak flow rate and quasi-IPSS Symptom Score. When stratified
by serum PSA, the placebo-treated patients experience less improvement in peak flow rate and symptom score, while the finas-
teride-treated patients experience greater improvement with higher PSAs, thus, increasing the therapeutic benefit.

277
A
Figure 51 A, B. Changes from baseline to end-of-study for maximum flow rate, IPSS Score, BPH Impact Index, and Quality of
Life Score for placebo, doxazosin, finasteride, and combination therapy-treated patients in the MTOP study. Figure 51 A shows
the changes for patients with a prostate volume of under 20 grams, a transition zone volume of under 10 grams, and for a PSA
under 1.4 ng/mL. The efficacy of doxazosin is superior to placebo and finasteride in comparison to combination therapy.

Figure 51 B. The data are shown for patients with prostate volumes over 40 grams, transition zone volumes of over 20 grams,
and serum PSA of over 4.0. In this case, the efficacy of doxazosin and finasteride is virtually identical, and the combination
therapy is superior in improving these longitudinal outcomes.
278
BPH impact, and improve the maximum urinary drug benefit. Similarly, the net drug benefit can be
flow rate, while in patients with larger glands and expected to increase with increasing prostate volume,
higher PSA values, combination therapy is superior. transition zone volume, transition zone index, and
The beneficial effect of the combination therapy serum PSA. Conversely, with alpha-blockers, the net
must be weighed against the side effect, particularly drug benefit can be shown to decrease with increasing
the sexually related adverse event seen with several prostate volume and serum PSA.
of the drugs used.
The only study addressing prevention of symptom
A strikingly similar observation concerning the rela- progression in an a priori fashion is the MTOPS
tionship of improvement in symptoms, BPH impact, trial. In this study, symptom progression was defined
and maximum urinary flow rate to baseline prostate
characteristics can be made in the dutasteride phase
Table 9. The net decrease in AUA Symptom Score at 24
III trials. When stratifying the patients into those months in the Dutasteride phase III trials is greatest in
with a prostate volume less than 40 ml, a PSA less those patients in the higher prostate volume tertiles, and in
than 3.0 ng/ml, and a transition zone volume of les the higher transition zone index tertiles. The benefit may be
than 25 ml, and comparing them with those with a as low as 0.9 points between placebo and dutasteride, but
TRUS volume over 40 ml, PSA over 3.0 ng/ml, and may also be as high as 3.5 in those patients with a transi-
a transition zone volume of over 25 ml, it is evident tion zone index of greater than 0.55.
that the margin of improvement, i.e., the net drug
benefit, is significantly greater for all three groups in
all three outcome parameters. (Figure 52 A and B).
Table 9 shows the net improvement in IPSS Score at
24 months in the dutasteride phase III trials stratified
by total prostate volume tertiles and by transition zone
index tertiles. As shown, the greatest net improvement
in AUA symptom index is achieved in patients with
the highest PSA tertile and the highest prostate vol-
ume tertile. The least effect is achieved in patients in
the lowest tertile of prostate volume, and the lowest
PVI tertile. Taken together, these observations strong-
ly suggest that when treating patients with 5alpha-
reductase inhibitors, baseline prostate volume, and
serum PSA is a powerful predictor of the expected net

Figure 52 A, B. Shows the difference between placebo and dutasteride for AUA Symptom Index, BPH Impact Index, and max-
imum urinary flow rate in the Dutasteride phase III studies for patients with a total prostate volume of less than 40 grams,
serum PSA less than 3, and transition zone volume of less than 25 versus those with a total prostate volume of over 40 grams,
PSA greater than 3.0, and transition zone volume greater than 25. The marginal benefit increases significantly in these larg-
er prostates with higher baseline PSA.

279
 as a worsening from baseline by 4 or more points on
the IPSS score, and this worsening had to be verified
within two to four weeks by repeat administration of
the IPSS score. Overall, a 4-point symptom worsen-
ing was the most common progression event in the
MTOPS trial. (Figure 53). Symptomatic progression
was prevented by both single arm therapies with
finasteride and doxazosin. Although numerically dif-
ferent from one another, there were no statistical dif-
ferences between the ability of finasteride or doxa-
zosin to prevent symptomatic worsening. However,
combination therapy was statistically superior to
both single arm therapies and to placebo in terms of
prevention of symptomatic worsening.
Figure 54 A, B. Symptom worsening in the MTOPS study stratified by prostate volume and convenience tertiles show the four
treatment groups and stratified by serum PSA in figure 54 B. (McConnell, Roehrborn et al. 2003)
280
Figure 54 A and B provides a stratified analysis of
the cumulative incidence of symptomatic worsening
based on baseline volume (Figure 54 A) and serum
PSA (Figure 54 B). The analysis provides evidence
for the following conclusions. In the placebo group,
the risk of symptomatic progression increases with
increasing prostate volume, as well as increasing
serum PSA. The alpha-blocker, doxazosin, prevents
symptomatic progression for patients with small,
intermediate, and large prostate volumes, as well as
for patients with low, intermediate, and high serum
PSA. Finasteride prevents symptom progression best
in patients with prostate volume of over 40 grams,
and in those with a serum PSA of greater than 1.4
Figure 53. Cumulative incidence
of symptomatic worsening
defined as a greater than 4-point
increase in the MTOPS study or
before-treatment group. (Mc
Connell, Roehrborn et al. 2003)
ng/ml. Combination therapy is effective in prevent-
ing symptom progression in patients of all prostate
sizes and all serum PSA levels. However, combina-
tion therapy is truly only superior to doxazosin in
terms of symptom progression for a prostate volume
>40 ml and a PSA of >4.0 ng/ml.
f) AUR and Surgery
Clearly, AUR and surgery are the most significant
outcomes of LUTS and BPE/BPO due to their
impact on the patient’s personal life, the potential for
further complications, and the health care costs asso-
ciated with the treatment thereof. The first report
regarding the possible prevention of acute AUR or
surgery was published in 1997, a meta-analysis of
three studies comparing finasteride with placebo in
men with BPE/BPO over 24 months (Andersen,
Nickel et al. 1997). Figure 55 A and B shows the
reduction in the risk of AUR and the need for surgery
in these studies. Overall, a reduction of approximate-
ly 50% in the rate of retention and surgery was
observed. Table 10 shows the three studies con-
tributing to this analysis, namely the SCARP,
PROSPECT, and PROWESS studies, as well as a
combined analysis.
Table 10. Risk reduction of AUR and need of surgery in
either/or in three two-year studies and the combined meta-
analysis based on 4222 patients.
The next study published was the Proscar Long-
Term Efficacy and Safety study or PLESS study.
(McConnell, Bruskewitz et al. 1998) In the PLESS
study, finasteride when compared to placebo induced
a reduction in risk of AUR of 57% and a reduction in
risk of surgery of 55%.. Figure 56 shows that the
risk of AUR and surgery is linear and that finasteride
resulted in a statistically significant reduction in the
risk over time. The MTOPS study allowed a com-
parison between single arm therapies with finas-
teride and doxazosin as well as combination therapy
to placebo (McConnell, Roehrborn et al. 2003). Fig-
281
ure 57 A shows the cumulative incidence of AUR
and Figure 57 B shows the cumulative incidence of
BPE/BPO invasive therapy. As is evident from Fig-
ure 57 A, there is a steady increase in the risk of
AUR in the placebo group. Finasteride reduces this
risk significantly compared to placebo, but con-
tributes markedly to the risk reduction with combi-
nation therapy. Treatment with the alpha-blocker,
doxazosin, delayed the risk of urinary retention by
about two years, but ultimately did not significantly
reduce the risk. In fact, the slope of the two curves
(doxaxosin and placebo) parallel each other follow-
ing a delay of about 2 to 2.5 years. Regarding inva-
sive therapy, Figure 57 B demonstrates that the
alpha-blocker, doxazosin, does not alter the risk of
surgery at all, but finasteride reduces the risk signif-
icantly and contributes entirely to the risk reduction
observed with combination therapy. Table 11 shows
the actual reduction in risks for the combined two-
year studies, the PLESS study, and the MTOPS
finasteride, doxazosin, and combination therapy arm.
As is evidenced, combination therapy reduced the
risk of AUR by 81% and the risk of surgery by 67%,
which is superior to monotherapy with finasteride.
Doxazosin reduced the risk of AUR by 35%, but did
not affect the risk of surgery.
Additional data are available from the phase III
dutasteride studies (Roehrborn, Boyle et al. 2002). In
this analysis, patients were included who at baseline
had a serum PSA of greater than 1.5 ng/ml and a
prostate volume of over 30 ml. This led to a study
population with a relatively high serum PSA and rel-
atively large prostate volumes. Figure 58 A and B
shows the pooled data from the three phase III trials
regarding the risk of AUR (Figure 58 A) and the risk
of surgical intervention (Figure 58 B). Table 12 adds
the risk for AUR and surgery observed in the dutas-
teride phase III trials, and the risk reduction, which is
nearly identical to the risk reduction with finasteride,
namely 57% for the risk of AUR and 48% for the risk
of surgery, compared to the data shown in table 12,
which only reflects finasteride vs placebo data.
Figure 59 A and B assesses the changing risk of
AUR after the placebo-treated patients are converted
to active drug in an open label extension of the dutas-
teride phase III trials (Figure 59 A) or the open label
extension of the PLESS trial (Figure 59 B). As is
evident, the placebo group, which up to the open
label extension had more than twice the risk of AUR,
after being converted to open label drug, adjusts to
the ongoing baseline risk of the dutasteride and
finasteride group, respectively. The same is true for
 Figure 55 A , B. Reduction in the
incidence of AUR (55 A) and
surgery (55 B) in the meta-analy-
sis of finasteride two-year study
for finasteride versus placebo.
(Andersen, Nickel et al. 1997)

Figure 56. Reduction in

the risk of AUR and the
need of surgery (left and
right) in the four-year
PLESS study. (Mc Con-
nell, Bruskewitz et al.
1998)

282
Figure 57 A, B. Cumulative incidence of AUR (A) and surgery (B) over four years in MTOPS for the four treatment groups.
(McConnell, Roehrborn et al. 2003)

283
Figure 58 A , B. Pooled data from the three phase III trials with dutasteride showing the risk of AUR (Figure 58 A) and the
risk of surgical intervention (Figure 58 b) in the placebo versus dutasteride arms (Roehrborn, Marks et al. 2004)

284
 Table 11. Risk reduction of AUR and need
of surgery in patients with BPH. Combined
analysis of two-year data three-year finas-
teride study, four-year PLESS study, and
four-year MTOPS study for finasteride,
doxazosin, and combination therapy.

Figure 59 A , B. Acute urinary retention.

Following conversion to open-label
dutasteride, the placebo group assumes
the baseline risk of the dutasteride
group (59 A). Similarly, after conversion
to open-label finasteride in the four-year
PLESS study, the placebo group
assumes the baseline risk of finasteride
group (59 B). (Roehrborn, Marks et al.
2004) (Roehrborn, Bruskewitz et al.
2004)

285
BPO-related surgery where the risk in the placebo
group after switching to open label drug is converted
to the baseline risk of the active drug group. (Figure
60 A and B). This suggests that the risk reduction
achieved with 5alpha-reductase inhibitors takes
effect regardless of the time in a patient’s life in
which the drug is introduced, i.e., independent of the
disease progression or natural history of BPH/
BPE/BPO for the individual patient. .
While these data are all derived from randomized,
placebo-controlled trials, there are other large
datasets published in the literature supporting the
reduction in the risk of AUR or surgery, particularly
with the use of 5alpha-reductase inhibitors.
Boyle et al., published results of a two-year follow-
up from a large cohort of patients observed in gener-
al practices in the United Kingdom and treated with
either alpha-blocker or 5alpha-reductase inhibitors
(Boyle, Roehrborn et al. 2004) Figure 61 shows the
unadjusted Kaplan-Meier survival from first initia-
tion of treatment to either surgery or AUR stratified
by first treatment with either an alpha-blocker (blue)
or a 5alpha-reductase inhibitor (red). The difference
at two years was significantly in favor of a risk
reduction with 5alpha-reductase inhibitors. When the
Hazard ratio for 5alpha-reductase inhibitors was set
at 1.0 as a reference, it was 1.89 (1.44 – 2.48 95%
CI) for alpha-blockers. Souverein et al. performed a
retrospective cohort study amongst 1430 men over
the age of 45 who were registered with general prac-
titioners in the Netherlands. They found that there
was no difference in the risk of prostatic surgery
between patients on medical treatment and watchful
waiting. Patients using a 5alpha-reductase inhibitor
at any stage had a statistically significant reduced
risk of surgery compared to those using an alpha-
blocker only with an adjusted Hazard ratio of 0.35
(0.13 – 0.96 95% CI). (Figure 62). (Souverein,
Erkens et al. 2003) There is a retrospective analy-
sis of observational data from the general practice of
the research database (UK GPRD). This cohort con-
tains 4500 patients with LUTS suggestive of
BPOaged over 50 years who were prescribed either a
5alpha-reductase inhibitor (finasteride) or an alpha-
blocker as initial therapy for symptoms between
1996 and 1999. Patients prescribed an alpha-blocker
were significantly more likely to experience AUR
(Hazard ratio 2.32) or surgery (Hazard ratio 1.78)
than patients prescribed 5ARI. These differences
were sustained with sensitivity analysis.
Clifford et al. utilized also a population from the
United Kingdom General Practice Research
286
Database (GPRD) and analyzed a total of 61,364
men with LUTS suggestive of BPO without a record
of prostate cancer of which 14,195 were treated with
either an alpha-blocker or finasteride. They observed
that the incidence of LUTS increased linearly from
the age of 45 to 85, and the prevalence increased
from 3.5 to 35% for men in their 40s and 80s. Dur-
ing the observation period, they observed a progres-
sive increase in the interval between first diagnosis
and prostatic surgery. This interval was found to be
significantly longer for medically treated patients
than those receiving no medical therapies. The inter-
vals between the initiation and failure of medical
therapy were shorter for patients receiving the older
alpha-blockers, indoramin and prazosin, than those
receiving specific medications for LUTS such as
tamsulosin, alfuzosin, terazosin, doxazosin, and the
5ARI, finasteride, used as a reference (Figure
63).(Clifford, Logie et al. 2000),
VIII. PREDICTORS OF EFFECTIVE-
NESS OF PREVENTION OF
PROGRESSION AND ADVERSE
OUTCOMES
Much effort has been devoted to analyzing baseline
parameters that might predict whether or not a given
patient would benefit from efforts to prevent either
progression or adverse outcomes. Much of this atten-
tion has focused on the patient’s age, baseline
prostate volume, and serum PSA, as it has been
shown that prostate volume and serum PSA in treat-
ment studies are powerful predictors of progression
and outcome events. Mochtar et al. analyzed the
prognostic role of serum PSA and prostate volume
for the risk of invasive therapy for BPO in men treat-
ed with either watchful waiting or alpha-blockers
(Mochtar, Kiemeney et al. 2005) He found that under
watchful waiting, the Hazard ratio increased from
2.7 for men with a PSA of greater than 3.0 compared
to those with a PSA of less than 1.5. For alpha-block-
ers, the Hazard ratio increased to 2.8 for the same
threshold of PSA. TRUS volume was not a powerful
predictor of invasive therapy in the watchful waiting
group, but was so in the alpha-blocker group where
the Hazard ratio was 1.8 if the prostate volume was
greater than 30 grams compared to those men with a
prostate volume of less than 30 grams. (Figure 64).
Analyses of serum PSA and prostate volume as pre-
dictors of progression, as well as their impact on the
 Figure 60 A, B. BPH-related surgery.
After converting to open-label dutas-
teride, the previously placebo-treated
patients assume the baseline risk of the
dutasteride population (60 A) and, simi-
larly, after converting to open-label
finasteride, the previously treated place-
bo patients assume the baseline risk of
the finasteride-treated patients in the
PLESS study (60 B). ). (Roehrborn,
Marks et al. 2004) (Roehrborn, Bruske-
witz et al. 2004)

Figure 61. AUR or surgery in patients

treated with 5ARI (red) and alpha-
blocker (blue) in a general practitioner’s
database. (Boyle, Roehrborn et al. 2004)

287
 Figure 62. Hospital admission for
BPH treatment for patients treated
with 5ARI and alpha-blocker showing
the proportion of patients remain free
of prostate surgery. (Souverein,
Erkens et al. 2003)

Figure 63. Survival from first BPH/LUTS therapy to

treatment failure for various medical interventions.

Figure 64. Prognostic role of

serum PSA and prostate volume
for the risk of invasive therapy in
men on alpha-blocker and
watchful waiting stratified by
PSA and prostate volume stratifi-
cation, and by alpha-blocker ver-
sus watchful waiting. (Mochtar,
Kiemeney et al. 2005)

288
effectiveness of treatment with finasteride on pre- Table 13. Risk of AUR and BPH-related surgery stratified
vention of progression and adverse outcomes were by prostate volume tertiles and PVI tertiles from the Dutas-
reported in the PLESS study. (McConnell, Bruske- teride phase III trials. The odds ratio of placebo versus
dutasteride is shown. Patients in the highest PSA tertile
witz et al. 1998) (Figure 65 a-d). The adverse out- have the highest risk of AUR or surgery compared to those
comes that were analyzed were spontaneous AUR, in the lower prostate volume and lower PVI tertiles.
precipitated AUR, and BPO-related surgery. In the
placebo group, the incidence of spontaneous AUR
increased from 1.4 to 7.6% from the lowest to the
highest PSA tertile, while the incidence of precipitat-
ed AUR increased from 1.5 to 4%, and the incidence
of surgery from 6.2 to 14.6%. In the finasteride treat-
ment group, the incidence changed from 1.3 to 1.4
for spontaneous, from 0.6 to 2.4 for precipitated, and
from 3 to 5.4% for surgery. The risk reduction for
spontaneous AUR was therefore 7% in the lowest
PSA tertile, 48% in the middle PSA tertile, and 77%
in the highest PSA tertile. For surgery, it increased
from 51 to 74%, and for the combined outcomes,
AUR or surgery from 44 to 60%. Similar findings
can be obtained regarding stratification by MRI-
measured prostate volume although only 10% of the
patients underwent prostate size measurement by
MRI and thus, the division in tertiles yields less
reproducible results. Figure 66 demonstrates that the
risk reduction for either AUR or surgery increases
>4.0ng/mL. Figure 67 A demonstrates that AUR
because of the rapid increase in the risk for AUR
occurs with increasing frequency in the placebo
with surgery in the placebo group, and the relatively
group with increasing volume. In the smallest
stable risk for both outcomes in the finasteride
prostates, all three active drug treatments prevent
group, while the baseline serum PSA is increasing.
episodes of retention, while in the intermediate size
(Roehrborn, McConnell et al. 1999)
group, the alpha-blocker, doxazosin, reduces the risk
The odds ratios of patients in the placebo group to by 50%. However, in the largest glands over 40
experience either AUR or BPO-related surgery com- grams, the alpha-blocker is ineffective and only the
pared to patients treated with dutasteride over two 5ARI or combination therapy reduces the risk of
years in the dutasteride phase III trials is shown in retention. Figure 67 B shows a similar analysis for
Table 13. It shows the risk stratified by prostate vol- serum PSA, demonstrating again the reduction in
ume and by transition zone index. Patients in the risk for alpha-blockers in the low and intermediate
highest transition zone index had an odds ratio of groups, but not in the highest PSA categories where
6.17 compared to those in the lowest transition zone only the 5ARI and combination therapy were able to
index, while patients with the largest prostate vol- reduce this risk. Figure 67 C and D shows the same
ume and the highest transition zone index had an analysis for BPO treatment and basic therapy strati-
odds ratio of 3.29 to experience either AUR or BPO- fied by volume and by PSA. The alpha-blocker, dox-
related surgery. As is evident in this table, prostate azosin, in this case is ineffective in preventing inva-
volume and specifically, the volume of the transition sive therapy for BPH for any volume size category,
zone, or the transition zone index, are powerful pre- while the 5ARI in combination therapy reduce the
dictors not only of progression and outcomes, but risk for all sizes and all PSA values.
also of the ability of 5alpha-reductase inhibitors to Figure 68 shows the BPO-related adverse outcomes
prevent such outcomes and progression events. in the Prostate Cancer Prevention Trial. (Thompson,
A similar analysis is shown in Figure 67 A through Goodman et al. 2003). In this trial, BPO-related
D for the MTOPS study. Here, stratification is by adverse outcomes were measured as the patients
serum PSA and prostate volume in tertiles of prostate were either treated with placebo or finasteride. The
volumes less than 20, 20 to 40, and over 40 grams, relative risk for a diagnosis of BPE or BPO being
and serum PSAs of less than 1.4, 1.4 to 3.9, and made was 0.6 in the finasteride compared to the

289
A B

C D
Figure 65 A - D. Incidence of outcomes in the placebo versus finasteride-treated patients over four years in PLESS. Sponta-
neous AUR (65 A), spontaneous and precipitated AUR (65 B), BPH-related surgery (65 C), and incidence of AUR or surgery
(65 D). (Roehrborn, McConnell et al. 1999)

Figure 66. Cumulative incidence of AUR

or BPH-related surgery over four years in
PLESS stratified by baseline PSA thresh-
old. The risk increase is linear and the
magnitude of risk reduction is greater in
patients with higher PSA baseline values.
(Roehrborn, McConnell et al. 1999)

290
A B

C D

Figure 67 A – D. Prostate volume (A and B) and PSA (B and C) dependency of AUR (A and B) and surgery (C and D) in the
four treatment groups of the MTOPS trial. (McConnell, Roehrborn et al. 2003)

Figure 68. BPH-related outcomes

in PCPT with absolute and relative
risk reduction.

291
placebo group for a risk reduction of 40%. The risk
reduction for AUR was 33% and for TURP 46%.
Table 14 presents an informative comparison of crude
annualized progression events in the PCPT, MTOPS,
PLESS and Dutasteride phase III trials. As is evident,
a major difference between these trials was the base-
line serum PSA and prostate volume in the men
enrolled. It ranged from a PSA of 1.5 to 4.0, and a
prostate volume from 33 to 54 ml. The crude annual-
ized progression event for AUR and surgery are also
depicted in this table. As is evident, the AUR events in
the placebo group increased from 0.9 to 2.1%, and the
surgery events from 0.23 to 2.1% per year.
Figure 69 A and B plots the annualized AUR (A)
and surgery (B) endpoints for the placebo and
5alpha-reductase inhibitor-treated patients by plot-
ting the individual studies and the mean serum PSA
and prostate volumes on the X-axis, and the annual
incidence of AUR (A) and surgery (B) along the Y-
axis. Two observations are striking from this analy-
sis. First, the annual incidence of AUR and surgery
increases significantly in those studies with higher
serum PSA and larger prostate volume, and, second,
a gap between the placebo and 5alpha-reductase
inhibitor-treated patients increases with increasing
PSA and prostate volume for both outcomes.

Figure 69 A , B. Comparison of annualized endpoints. AUR stratified by PSA and TRUS mean baseline values along the “X”
axis (69 A), surgery by mean PSA and TRUS baseline along the “X” axis (69 B).

292

Several conclusions can be drawn as follows:
• Alpha blockers appear to delay AUR overall and
to prevent it in patients with smaller glands
• 5 ARIs prevent episodes of retention with the RR
being 50-60% overall
• Alpha blockers do not appear to prevent surgical
intervention
• 5 ARIs prevent surgical intervention with RR
being 50-60 % overall
• Combination therapy does not add to the preven-
tion of AUR or treatment intervention
• Larger glands/higher PSA are associated with
greater baseline risk, and thus greater risk reduc-
tion
While it appears that prostate volume and serum
PSA are reasonable predictors of progression and
outcomes in men with BPO treated with placebo ver-
sus medical therapy, it is clear that a multivariate
analysis, or a nomogram taking into consideration
multiple baseline parameters may be even more use-
ful to practicing physicians. Such effort is shown in
Figure 70 A and B. Slawin et al. analyzed the symp-
tom score, BPH Impact Index, prior treatment with
an alpha-blocker, prostate volume, PSA, maximum
urinary flow rate, and dutasteride therapy and uti-
lized these parameters to predict the probability of
AUR and/or surgical intervention within two years in
the dutasteride phase III trials. Nomograms of this
type have been developed for other outcomes utiliz-
ing other baseline parameters, most notably in the
treatment of prostate cancer. Once transferred to an
electronic calculator, PDA, etc., these algorithms
might be used by practicing physicians to enter
whatever baseline data are available, and thereby to
293
Table 14. Comparison of accrued annualized
progression events in PCPT, MTOPS, PLESS,
and Dutasteride phase III trials. Baseline PSA
and prostate volumes are shown as are annual-
ized AUR and surgery events in the placebo and
5ARI (finasteride or dutasteride) groups.
calculate the risk of a given patient experiencing
symptom progression, retention, or a need for
surgery over a given period of time. Figure 71 shows
a snapshot from a Web site www.oncovance.com
where physicians can enter baseline parameters, and
predict the likelihood of a person developing either
AUR or surgery based on data from the MTOPS
trial. It is possible that future efforts such as these
will help physicians and other health care providers
caring for patients with LUTS suggestive of BPO in
the complex decision making process, if and when
preventive efforts are available, and associated
expenses are indicated or not.
IX. SUMMARY AND CONCLUSIONS
A careful examination of the literature suggests that
there is significant evidence for LUTS and
BPH/BPE/BPO, at least in many patients, being a
progressive condition leading to worsening of symp-
toms, bother, interference with quality of life, deteri-
oration of flow rate, urodynamic parameters and oth-
ers, over time, and ultimately, to adverse outcomes
such as urinary retention and the need for surgical
intervention. From population-based studies and
placebo-controlled arms of randomized clinical tri-
als, such evidence can be obtained for worsening of
these parameters as listed in Table 15. There is also
significant evidence available regarding the preven-
tion of such progression and outcomes. Much of this
evidence is derived from randomized, placebo-con-
trolled trials and thus, it can be rated as an evidence
level I and grade A (Table 15).
Despite the considerable knowledge accumulated
over time, we do believe that there are significant
research gaps and priorities that are derived from our
analysis of the literature, and in our attempt to sum-
 A

Figure 70 A, B. Nomogram approach to predicting BPH progression. Baseline statistical analysis, various parameters proved
to be predictive of BPH progression. The data can be expressed by a nomogram where for each baseline parameter the
patient is assigned a certain point. The number of total points is established at risk for progression.

294
Figure 71. Example of a BPH progression nomogram on the Oncovance Web site.

Table 15. Rating of evidence and recommendations for prevention of BPH progression and outcomes derived from data in
population-based studies and placebo groups for various parameters and various treatments.

295
marize the available literature and to make recom-
mendations regarding the prevention of progression
and outcomes. These research recommendations are
briefly as follows.
• Better understanding of relationships between
changes in continuous variables and subjective
perception of worsening/improvement
• Conversion of transition within health states to
transition between health states by converting
continuous outcomes into categorical or dichoto-
mous outcomes
• Better understanding of the role of dynamic
change in variables as predictors, and their impact
on health care seeking behavior
• Cost/benefit effectiveness as well as benefit to risk
analyses to determine thresholds for initiation of
therapies to prevent progression and adverse out-
comes
• Population based studies and placebo control
groups provide level 2 / 1 evidence that LUTS/
BPH/BPE/BPO is a progressive condition
- Symptoms, bother, QoL, Qmax, Volume,
PSA, AUR, treatment intervention
• Population based studies and placebo control
groups provide level 2 / 1 evidence for the role of
baseline and dynamic factors to predict progres-
sion
- Age, Symptom and bother severity, Qmax,
Volume, PSA
• We recommend against initiating treatment to pre-
vent progression/outcomes in men with low risk
(young, PSA < 1.5, Vol < 25-30 ml) [1 A]
296
Our final recommendations in regards to prevention
of progression and adverse outcomes in men with
LUTS and BPH/BPE/BPO are summarized as fol-
lows. The available literature allows us to recom-
mend strongly against initiation of any preventive
treatment efforts to prevent progression/outcomes in
men who are at low risk for such progression and
outcomes. In general, these men are young, have a
low serum PSA (less than 1.5 ng/mL), and a prostate
volume (less than 25 to 30 ml). This recommenda-
tion carries a level I grade A.
The initiation of treatment to prevent progression or
outcomes in men who are at higher risk, as defined
by the parameters listed above, requires a considera-
tion of the relative risks in each individual patient,
and an analysis of the benefit to risk ratio based on
the relative risks and the adverse events associated
with the treatment, and certainly, consideration of the
socio-economic circumstances of the individual, the
society in which he resides, and the health care deliv-
ery system and available resources.
While there is evidence for strong recommendation
level I, these circumstances must be taken into con-
sideration in each case, which results in our opinion
in an overall grade B recommendation.
Figure 72 shows graphically the problem that the
health care provider faces when making recommen-
dations for the prevention of progression or out-
comes. When we manage a patient who falls some-
where across a spectrum of increasing risk of pro-
gression and adverse outcomes along the X axis, we
have to acknowledge that the risks and costs associ-
ated with the treatment to prevent such outcomes is
Figure 72. Across the “X” axis, the
patients are based on various baseline
parameters experiences an increased
risk of progression of outcomes. At the
same time, however, the side effects,
costs, and other negative attributes of
the potential treatments to prevent these
outcomes remains stable across the
entire spectrum of increasing risks.
Thus, for each intervention and in each
patient, and in each health care system,
there presumably is a point by which the
benefits of prevention of risks outweighs
the harms at which point prevention of
progression and outcomes become a
reasonable strategy.
constant across the spectrum of risks (red bar). How-
ever, inasmuch as the risk increases from left to right,
the potential benefit of preventing the risk of pro-
gression and adverse outcomes increases also from
left to right. (Green triangle). For every patient, in
each and every situation and circumstance with a
given set of baseline parameters, in a given society
with a given health care system, and available
resources, there is a breakpoint at which the benefit
of preventing progression and adverse outcomes out-
weighs the risks and costs associated with the treat-
ment to prevent progression and adverse outcomes.
This would be the point at which it becomes cost-
effective and, therefore, both economically and ethi-
cally feasible and reasonable to engage in a strategy
to prevent progression and adverse outcomes in such
patients. However, at present, it is impossible to state
where exactly this break-even point is in each case,
and as stated above, it depends on many other
parameters that should be assessed by the individual
health care providers and the individual patient situ-
ation.
The initiation of treatment to prevent progression or
outcomes in men with higher risk requires
• Consideration of relative risk in the individual
patient
• Benefit to risk ratio based on the relative risk of
the individual patient and adverse events
• Consideration of socio-economic circumstances
of the individual, society and health care delivery
system
• While there is level 1 evidence, the listed circum-
stances must be taken into consideration resulting
in an overall 1B recommendation
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 CHAPTER 8

Committee 9

New therapeutic targets in BPH and LUTS

(Research priorities)

Chairman
K-E ANDERSSON (SWEDEN)

Members
F CRUZ (PORTUGAL),
H KLOCKER (AUSTRIA),
M WYLLIE (U.K),
O YAMAGUCHI (JAPAN)

299
 CONTENTS

I. INTRODUCTION X. VITAMIN D3 RECEPTORS

II. SUBTYPES OF XI. NITRIC OXIDE DONORS

α1-ADRENOCEPTORS

XII. PHOSPHODIESTERASE
INHIBITORS
ΙΙΙ. β3-AR AGONISTS

XIII. RHO-KINASE
IV. MUSCARINIC RECEPTORS

XIV. CYCLOOXYGENASES/
PROSTANOID RECEPTORS
V. PURINOCEPTORS

XV. OTHER AGENTS

VI. VANILLOID RECEPTORS
1. GABAPENTIN

2. ALTERNATIVE STRATEGIES - COMBINATIONS

VII. BOTULINUM TOXIN
3. TARGETS WITHIN THE CENTRAL NERVOUS
SYSTEM

VIII. ENDOTHELIN RECEPTORS

XVI. CONCLUSIONS

IX. ANGIOTENSIN RECEPTORS REFERENCES

300
New therapeutic targets in BPH and LUTS
(Research priorities)
K-E ANDERSSON,
F CRUZ, H KLOCKER, M WYLLIE, O YAMAGUCHI
I. INTRODUCTION
For many years, medical treatment of the lower uri-
nary tract symptoms (LUTS) associated with or sug-
gestive of benign prostatic hyperplasia (BPH) has
been based on mainly three types of agents, α1-
adrenoceptor (AR) antagonists [1, 2], 5α-reductase
inhibitors, [3-5] and phytotherapy. [6-8] Despite con-
tinued efforts, few new drug classes have been added
to the therapeutic armamentarium. This is probably
due to the fact that the pathophysiology of LUTS is
multifactorial and that treatment targets are difficult
to clearly define. It has not been established whether
the most relevant target is within the prostate or
whether extra-prostatic sites are more important [9].
However, focus has shifted from the prostate to the
bladder as the source of some of the lower urinary
tract symptoms, and as a therapeutic target [10, 11]
(Figure 1). This has created a renewed interest in
drugs used for treatment of the overactive bladder
(OAB), characterized by urgency, frequency and
urgency incontinence, i.e., equivalent to LUTS [12].
Increasingly, combinations of drugs are being evalu-
ated in clinical trials and are being prescribed “off
label” by physicians.
Some potential targets for future drugs, and some
alternative treatment strategies, are reviewed in this
chapter.
II. SUBTYPES OF
α1-ADRENOCEPTORS
It is well documented that the currently used α1-AR
antagonists are effective for treatment of LUTS asso-
301
ciated with or suggestive of BPH [1, 2]. Whether or
not treatment can be improved, either by increasing
efficacy beyond that of existing drugs, reducing
adverse effects, or both, has still not been deter-
mined, but is looking increasingly unlikely. Since
targeting the predominant α1-AR (α1A/L) in the
prostate has not resulted in more effective drugs, [13]
interest is now focussing on the α1-ARs (α1D) in the
bladder [14, 15]. α1-ARs (Figure 2) may have
effects on different locations in the bladder: the
detrusor smooth muscle, the detrusor vasculature,
the afferent and efferent nerve terminals and intra-
mural ganglia.
The inter-relationship between the α1-ARs in the
human detrusor and the pathophysiology of LUTS is
unclear. Most investigators agree that there is a low
expression of these receptors [16]. In human detru-
sor studies Malloy et al. [17] found that 2/3 of the
α-AR mRNA expressed were α1D, while there were
no α1B, and 1/3 were α1A. In the rat detrusor, the
α1-AR distribution was different: the α1A-AR was
predominating, 1/3 were α1D-AR, and there were
very few α1B-AR. The subtype ratio was relatively
consistent throughout the detrusor [18].
A change of subtype distribution may be produced
by outflow obstruction. Hampel et al. [18] reported
that there was a change in the obstructed bladder
from α1A-AR to α1D-AR mRNA predominance. In
humans, as described above, there is already an
α1D-AR predominance in the normal detrusor,
implying that a change in a similar direction as in the
rat would be of minor importance, provided that the
overall number of receptors did not increase. Indeed,
Nomiya and Yamaguchi [19] have demonstrated that
this was not the case. They confirmed both the low
expression of α-AR mRNA in normal human detru-

sor, and that there was no upregulation of any of the
ARs with obstruction. Functionally, a similar situa-
tion was apparent. Nomiya and Yamaguchi [19]
found a small response to phenylephrine at high drug
concentrations with no difference between normal
and obstructed bladders. Overall, in the obstructed
human bladder, there seems to be no evidence for α-
AR upregulation or change in subtype, although this
finding was challenged by Bouchelouche et al., [20]
who found an increased response to α1-AR stimula-
tion in obstructed bladders. Whether or not this
would mean that the α1D-ARs in the detrusor mus-
302
Figure 1. Different bladder conditions
which can result in lower urinary
tract symptoms (LUTS)
Figure 2. α-Adrenoceptor subtypes.
The predominating subtype in the
human bladder is the α1D receptor.
cle are responsible for detrusor overactivity or OAB
is unclear. Nakamura et al. [21] showed that the blad-
der of α1D-AR KO mice did not develop overactiv-
ity when stimulated with acetic acid. Chen et al. [22]
studied micturition in α1D-AR KO mice and clearly
showed that these mice have a larger bladder capac-
ity and voided volumes than their wild type controls,
supporting an important role for the α1D-AR in the
control of voiding (Figure 3). However, it was not
possible to draw any conclusions from their data
about the location of the α1D-ARs receptors
involved in micturition control. As discussed by

Chen et al., [22] the α1D-ARs in the detrusor and
their levels of expression may not always be relevant
for the functional importance of this receptor sub-
type.
Sugaya et al. [23] investigated the effects of intrathe-
cal tamsulosin (blocking α1A/D ARs) and naftopidil
(blocking preferably the α1D ARs) on isovolumetric
bladder contractions in rats. Intrathecal injection of
tamsulosin or naftopidil transiently abolished these
contractions. The amplitude of contraction was
decreased by naftopidil, but not by tamsulosin. It was
speculated that in addition to the antagonistic action
of these agents on the α1A-ARs of prostatic smooth
muscle, both agents (especially naftopidil) may also
act on the lumbosacral cord (α1D-ARs?). This
observation is of particular interest considering the
findings that in the human spinal cord, α1D-AR
mRNA predominated overall [24]. Ikemoto et al.
[25] gave tamsulosin and naftopidil to 96 patients
with BPH for 8 weeks in a crossover study. Whereas
naftopidil monotherapy decreased the I-PSS for stor-
age symptoms, tamsulosin monotherapy decreased
the I-PSS for voiding symptoms. However, this dif-
ference (which was suggested to depend on differ-
ences in affinity for α1-AR subtypes between the
drugs) could not be reproduced in a randomized head
to head comparison between the drugs [26]. Based
on available evidence, it therefore cannot be con-
cluded that the α1D-ARs on the detrusor muscle is
an important therapeutic target. This does not
exclude that α1D-ARs located elsewhere in the blad-
der (i.e., the vasculature; Das et al. [27]) or in other
structures, might be of importance.The role of α1-
303
Figure 3. Changes in
urodynamic parame-
ters in mice lacking
the α1D receptor.
ARs located in the bladder vasculature was investi-
gated in an experimental model of urethral ligation in
the rat [27]. The α1-AR antagonist doxazosin was
shown to increase blood flow to the bladder (Figure
4). This effect, which presumably depended upon a
reduction in the resistance of bladder vasculature,
reduced the severity of the responses to partial outlet
obstruction, including the increase in bladder weight
and the decrease in detrusor contractile response
[27].
The expression of α1-AR was investigated in the
transitional zone of 28 prostates with BPH [28].
Twelve (43%) were α1A-AR dominant, whereas 16
(57%) were α1D-AR dominant. The implications of
these findings to the selection of α1-AR antagonist
was further investigated. Curiously, naftopidil was
shown to provide significant advantage in the treat-
ment of α1D-AR dominant BPH patients [28].
The importance of the α1D-ARs for the generation
of LUTS and the potential advantages of α1D-AR
receptor blockade in the treatment of LUTS cannot
be assessed until a drug with appropriate subtype
selectivity becomes available for clinical evaluation.
ΙΙΙ. β3-AR AGONISTS
The detrusor muscle contains β-ARs, and 3 subtypes
(β1, β2, and β3) have been identified in most species
(Figure 5). Functional evidence for a role of the β3-
AR in human detrusor suggests that the relaxation
induced by adrenergic stimulation is mediated main-

ly through β3-AR activation [29-31]. Recent studies,
using real-time RT-PCR, have revealed a predomi-
nant expression of β3-AR mRNA in human detrusor
muscle [19, 32]. Thus, of the 3 subtypes of mRNA,
97% was represented by the β3-AR and only 1.5%,
and 1.4% by the β1-AR and β2-AR, respectively. If
the amount of subtype mRNA reflects the population
of receptor protein, then the β3-AR is the most abun-
dant in the human detrusor. Supporting an important
role of β3-ARs, selective β3-AR agonists effectively
relaxed isolated detrusor muscle from both normal
and neurogenic bladders [19, 30, 31, 33, 34] (Figure
6).
The in vivo effects of β3-AR agonists on bladder
function have been studied in animal models. It has
been shown that compared with other agents (includ-
ing antimuscarinic agents), β3-AR agonists increase
304
Figure 4. α1-Adrenoceptor blockade
increases blood flow in both normal
and obstructed rat detrusor.
Figure 5. Distribution of adrenocep-
tor subtypes.
bladder capacity with no change in micturition pres-
sure and the residual volume [29, 35-37].
Thus, the above results suggest the β3-ARs as a
potentially useful target for drugs intended for the
treatment of OAB, including storage symptoms sec-
ondary to outflow obstruction.
IV. MUSCARINIC RECEPTORS
Storage symptoms, including urgency, frequency and
urgency incontinence may be related to bladder dys-
function secondary to e.g., increased outflow resis-
tance in BPH, but also to several other disorders
[38]. Since muscarinic receptors mediate the main
part of bladder contraction in many species, and par-

ticularly in humans, it seems reasonable to assume
that changes in their function can be related to LUTS
[39]. Both M3 and M2 receptors may be involved in
bladder contraction and micturition control. M3
receptors are primarily responsible for detrusor con-
traction both in the normal and overactive bladder.
The role of the M2 receptors may increase in bladder
pathologies including changes associated with pro-
static obstruction [16]. A role for the M1 receptor in
prostatic cell proliferation has been suggested [40]
However, the development of infravesical obstruc-
tion in men with BPH did not seem to be related to
upregulation or altered binding affinity of mus-
carinic receptor receptor binding sites [41].
In humans, no direct contractile effect on prostatic
smooth muscle of acetylcholine or carbachol was
found by Hedlund et al. [42]. However, Abdel-
khalek et al. [43]. found that strips of muscle from
both the anterior capsule and prostatic urethra could
be contracted by acetylcholine, and the investigators
speculated on their role in the pathophysiology of
BPH/LUTS. Muscarinic receptors may also be
involved in the control of adrenergic activity and
may thus also influence LUTS initiated from the
prostate. More probable is that muscarinic receptors
are involved in LUTS emanating from the bladder
Antimuscarinics are still the most widely used treat-
ment for urgency, frequency and urgency inconti-
nence [12, 44]. Based on urodynamic studies, detru-
sor contractility increases initially with the grade of
305
Figure 6. Relaxant effects of non-
selective and β3-adrenoceptor-selec-
tive agonists in strips from normal
and obstructed human detrusor.
obstruction in order to guarantee an optimal voiding
despite an increased outlet resistance. If the main
mechanism of action of antimuscarinics used for
treatment of OAB were reduction of detrusor con-
tractility, treatment with theses drugs might be
expected to result in increasing amounts of residual
urine even to the extent of producing complete reten-
tion. However, antimuscarinics act mainly during the
filling phase, and in the doses recommended for
treatment of OAB, there is little effect on detrusor
contractility [44]. The implication is that muscarinic
receptors on other structures than the detrusor may
be involved in LUTS generation [44]. On this basis
it would not be unreasonable to consider these struc-
tures as potentially important targets for antimus-
carinic drugs. Historically, the effect of antimus-
carinics has been studied primarily in patients with
OAB without BOO. In chronic obstruction, the mor-
phological, biochemical and functional changes
together with detrusor denervation make it reason-
able to assume that blocking the muscarinic recep-
tors in a damaged bladder can lead to a decompensa-
tion of the detrusor. However, at least two studies of
antimuscarinics [45, 46] in patients with BOO have
challenged, to a certain extent, these assumptions.
Additional studies on safety and efficacy of antimus-
carinics in patients with BOO are needed to assess
their usefulness. An important question is whether
any of the currently used antimuscarinic agents are
more efficacious or safer than the others, or whether
an antimuscarinic with particular properties (target-
ing preferentially afferent mechanisms) would be
advantageous in the treatment of LUTS. M2 recep-
tors were demonstrated in afferent fibers [47] and
their blockade was shown to inhibit nociceptive sen-
sory transmission. In addition, M2 receptors were
shown to occur in urothelial cells in close association
with sub-urothelial sensory nerves. [48] Both M2 and
M3 receptors [49] and their mRNA [50] have been
demonstrated in the human urothelium/suburotheli-
um with the same ratio M2/M3 as in the detrusor
[49]. In a recent experimental study Kim et al. [51]
suggested that antimuscarinic agents applied intrav-
esically could be effective in treating overactive
bladder by blocking muscarinic receptors in bladder
afferent pathways. Nevertheless, at the present stage
of knowledge, the clinical relevance of these find-
ings is not known.
V. PURINOCEPTORS
ATP can be released by distension of the bladder,
[52, 53] and released ATP may be able to activate
the micturition reflex (Figure 7). Supporting this
view, ATP, given intravesically induced pronounced
detrusor overactivity in unanesthetized rats and mice
[54].
The ATP receptor P2X3 is expressed on small diam-
eter primary sensory neurons, [55-57] but also in the
urothelium of rats and humans, [57] which suggests
306
a role in sensory processes. Vlaskovska et al. [53]
demonstrated release of ATP proportional to the
extent of bladder distension in both normal and P2X3
receptor deficient mice, and found good evidence for
a major sensory role for urothelially released ATP
acting via P2X3 receptors on a subpopulation of
pelvic afferent fibers. P2X3-deficient mice exhibited
a marked reduction in urinary frequency as shown by
cystometry, which revealed decreased voiding fre-
quency, increased bladder capacity and voiding vol-
ume, but normal bladder pressures [58] (Figure 8).
Thus, P2X3 receptors seem to be critical to the nor-
mal physiological regulation of afferent pathways
controlling volume reflexes [52, 53, 59].
In studies of human bladder, P2X2 receptors were
not seen to co-localize exclusively with sensory
nerve fibers containing calcitonin gene-related pep-
tide [57]. In particular, in the suburothelium, non-
neuronal P2X3 receptor immunoreactivity was
demonstrated near so-called “interstitial cells” or
“myofibroblasts” [57]. These observations show that
the sensory process is more complex than previously
thought and emphasize the potential role of a newly
described layer of suburothelial myofibroblasts [58,
59]. Electron microscope studies have also shown
that these cells make close appositions with C-fiber
nerve endings [59]. Thus, myofibroblasts interpose
between urothelium and afferent nerve endings.
Their intimate association with nerves suggest that
they may respond to ATP released from the urotheli-
um, and may influence afferent nerve function [60].
Figure 7. Substances generated and
released from the urothelium may
directly or via interstitial cells stimu-
late afferent nerves in the suburothe-
lium. It may be speculated that such
stimulation can be involved in the
generation of lower urinary tract
symptoms (urgency, frequency,
urgency incontinence). ACh=acetyl-
choline; NO=nitric oxide;
ATP=adenosine triphosphate;
PGs=prostaglandins

Most probably, a cascade of mediators, released from
the urothelium and the suburothelial plexus of nerves
in response to bladder distension, can initiate or
depress activation of the bladder [63]. The firing of
suburothelial afferent nerves, and the threshold for
bladder activation, may be modified by both
inhibitory (e.g., NO) and stimulatory (e.g., ATP,
tachykinins, prostanoids) mediators. These mecha-
nisms can be involved in the generation of detrusor
overactivity, causing urgency, frequency and urgen-
cy incontinence, and thus seem to be potential targets
for pharmacological intervention.
O´Reilly et al. [64] examined the role of P2X recep-
tors in female patients with idiopathic detrusor over-
activity. Bladder biopsies were obtained from the
patients and from age and sex matched controls with
a urodynamically proved stable bladder. In the
patients, detrusor P2X2 receptors were significantly
(50%) elevated, while other P2X receptor subtypes
were significantly decreased. A purinergic compo-
nent of nerve mediated contractions was not detect-
ed in control female bladder biopsy specimens but
there was a significant component in overactive
bladder specimens. It was concluded that in patients
with idiopathic detrusor overactivity there is abnor-
mal purinergic transmission in the bladder, which
may explain symptoms. This pathway may be a
novel target for the pharmacological treatment of the
overactive bladder.
307
Figure 8. Urodynamic
changes in mice lacking
P2X3 receptors.
Which P2X receptor subtype is the most promising
to target for drugs meant for treatment of
OAB/detrusor overactivity has not been established.
Antagonists of P2X3 receptors are in development.
VI. VANILLOID RECEPTORS
Intravesical administration of capsaicin or resinifera-
toxin (RTX) — two members of the vanilloid fami-
ly—has been shown to increase bladder capacity and
decrease urge incontinence in patients with neuro-
genic, as well as nonneurogenic forms of detrusor
overactivity [65]. Vanilloids are exogenous ligands
of vanilloid receptor type 1 (TRPV1 or VR1), an ion
channel present in the membrane of type C primary
afferent nerve fibers innervating the bladder wall
[66] and the peri-urethral zone of the prostate gland
[67]. This receptor, which plays a key role in inflam-
matory pain perception and control of the micturition
reflex, [68] may be upregulated by nerve growth
factor (NGF), a neurotrophic molecule detected in
high concentrations in overactive detrusors generat-
ed by chronic bladder outlet obstruction [69]. Vanil-
loids, by reducing uptake of NGF through sensory
neurons, may counteract TRPV1 upregulation [65].
In addition, vanilloids decrease the response of
already expressed TRPV1 receptors, a phenomenon
known as desensitization [65].
Important sensory information from the prostate and
bladder is conveyed by C fibers. Local anaesthesia of
the prostatic urethra was shown to increase bladder
volume to first sensation to urinate and maximal
bladder capacity, and also to reduce or abolish detru-
sor overactivity, in patients with benign prostatic
enlargement [70, 71]. Likewise, intravesical lido-
caine was shown to reduce involuntary detrusor con-
tractions in patients with detrusor overactivity [72].
As lidocaine is more effective to anaesthetize C- than
Aδ-fibers the contribution of prostate and bladder C-
fiber input to abnormal detrusor activity is strongly
suggested.
The ice water test triggers a capsaicin-sensitive
spinal micturition reflex mediated by unmyelinated
C fibers in the bladder and urethra [73]. Chai et al.
[74] demonstrated a positive ice water test in 71% of
subjects with bladder outlet obstruction (12 of 17),
which was significantly higher than the 7% positive
ice water test rate in nonobstructed subjects (3 of
44). The authors suggested this to be caused by an
enhanced spinal micturition reflex, possibly due to
plasticity of bladder afferents after BOO. If this is the
case, intravesical treatment of patients with LUTS
associated with BOO with intravesical vanilloids, by
desensitizing C-fibers would be an interesting
approach. Two preliminary studies with intravesical
resiniferatoxin suggest that this may be the case [75,
76]. Dinis et al. [75] treated 12 males with a mean
prostate volume of 45 ml by instilling a 50 nM RTX
solution in 10% ethanol in the bladder during 30
minutes. RTX decreased by half the IPSS and QoL
score, 91% of the patients having reported at least a
25% improvement. Cystometries performed in these
patients showed that the mean volume at which
patients reported the first desire to void and urgency
to urinate increased by 90 % and 55 %, respectively.
Kuo [76] performed multiple low dose (10 nM) RTX
instillations in 20 patients with BPH and observed a
reduction in the total IPSS score of 6 points. In a
more detailed analysis, both studies concluded that
the decrease of the IPSS score was predominantly
due to an improvement of the storage symptoms. In
contrast, improvement of voiding symptoms was
marginal. Likewise, urodynamic parameters as max-
imum flow rate or post-voiding residual were not
changed by the intravesical administration of the
vanilloid [75, 76].
Another recent trial involving 18 BPH patients in
whom urgency incontinence due to detrusor overac-
tivity persisted in spite of having been submitted to
prostatectomy also indicated that RTX may improve
308
BPH associated storage symptoms [77]. RTX, 100
nM concentration, was instilled in the bladder in a
10% ethanol solution. In spite of being a subgroup
of patients particularly difficult to handle, 11 patients
(61%) improved due to either a decrease of 50% or
more in the number of urge incontinence episodes.
A randomized, placebo-controlled study is needed to
assess the therapeutic value of this approach.
VII. BOTULINUM TOXIN
Doggweiler et al. [78] injected botulinum toxin type
A into the rat prostate and found that the toxin
induced selective denervation and subsequent gener-
alized atrophy of the gland (Figure 9). Apoptosis
was seen diffusely throughout the gland.
Maria et al. [79] evaluated the therapeutic role of
botulinum toxin injection in 30 men with benign pro-
static hyperplasia in a randomized, placebo-con-
trolled study. The patients received intraprostatic
injections with a perineal needle inserted under ultra-
sound guidance. The control group received saline
solution and the treated group received 200 U of
botulinum toxin A. The outcome of each group was
evaluated by comparing the symptom scores, serum
prostate-specific antigen concentration, prostate vol-
ume, postvoid residual urine volume, and peak uri-
nary flow rates. Thirty consecutive patients were
enrolled. No local complications or systemic side
effects were observed in any patient. After 2 months,
13 patients in the treated group and 3 in the control
group had subjective symptomatic relief (P
<0.0007). In patients who received botulinum toxin,
the symptom score was reduced by 65% compared
with baseline values and the serum prostate-specific
antigen concentration by 51% from baseline. In
patients who received saline, the symptom score and
serum prostate-specific antigen concentration were
not significantly changed compared with the base-
line values and 1-month values (Figure 10). It was
concluded that botulinum toxin injected into the
prostate seems to be a promising approach for the
treatment of BPH.
In a prospective study, Kuo [80] evaluated the effec-
tiveness of prostate injection of botulinum A toxin in
BPH patients who were poor surgical candidates.
Ten patients with BPH and urinary retention or a
large postvoid residual urine volume received 200 U
botulinum A toxin injection into the transition zone
of the prostate under visual endoscopic control. The

clinical results and urodynamic parameters at base-
line and after treatment were compared. All patients
had an improvement in spontaneous voiding after
treatment. Of them, 8 had an excellent result (80%)
and 2 had an improved result. Both voiding pressure
and postvoid residual volume were significantly
decreased after treatment. The total prostate volume
was significantly reduced, and the maximal flow rate
was significantly increased after treatment. The max-
imal effects of botulinum A toxin appeared at about
1 week and were maintained at 3 and 6 months after
treatment. At 6 to 12 months of follow-up, no patient
309
Figure 9. Involution and apoptosis in
rat prostate after injection of
botulinum toxin.
Figure 10. Effects on AUA score,
prostate volume, prostate specific
antigen (PSA), and maximal flow
rate (Qmax) in patients with BPH
after intraprostatic injection of
botulinum toxin.
had had recurrence of urinary retention and the void-
ing condition in all patients remained at the post-
treatment status. No adverse effect was noted.
Another three non-randomized clinical trials recent-
ly reported to International meetings and involving
37 symptomatic BPH patients support these results
[81-83]. Prostates were injected with 100-150 UI
Botox under transrectal ultrasound control. A signif-
icant symptomatic improvement occurred, as shown
by a marked decrease in the IPSS score which could
be detected, at least in some cases, within one week
after injection and reached a maximum effect at one
month [81, 82]. Symptomatic improvement was
accompanied by a marked decrease in the prostate
volume and PSA serum levels [83].
These results are promising but further information
is required concerning e.g., doses, duration of effect,
effects on prostate size and PSA, and effects of
repeated injections, to properly assess this potential
treatment alternative. Randomized, sham-controlled
studies are urgently needed.
VIII. ENDOTHELIN RECEPTORS
Endothelins (ET-1, ET-2, ET-3) and ET (ETA, ETB)
receptors have been demonstrated both in the
prostate and bladder. Since ETs can initiate both
short-term (contraction) and long-term (mitogenesis)
events in targets cells in the bladder and urethra via
their receptors, they may be of importance in the
pathogenesis of LUTS.
In the prostate, ET-like activity is prominent in the
glandular epithelium, but not in the stroma [84]. ET
receptors have been demonstrated and characterized
in prostatic tissue by many investigators; [85-94] in
patients with BPH, the density of these receptors was
found to be increased [87, 88]. Mumtaz et al. [94]
used high affinity ETA and ETB -receptor-specific
radioligands to determine the density and distribu-
tion of ET receptor subtypes in prostatic tissues
obtained from patients with symptomatic benign
prostatic hyperplasia (BPH). They demonstrated
dense ETA and ETB receptor-binding sites in the
prostatic stroma. The ETB receptor-binding sites
were predominantly seen in the prostatic stroma,
whereas ETA receptor-binding sites were prominent
on the prostatic epithelium. ET-1, at sub-threshold
concentrations, significantly enhanced α1-AR recep-
tor-mediated prostatic smooth muscle contractile
responses. Confirming previous reports, [84, 89, 95,
96] ETs were found to contract prostatic smooth
muscle, and both ETA and ETB receptors were
involved.
Saenz de Tejada et al. [97] demonstrated ET-like
immunoreactivity in the transitional epithelium,
serosal mesothelium, vascular endothelium, smooth
muscles of the detrusor (nonvascular) and vessels,
and in fibroblasts of the human bladder. This cellular
distribution was confirmed in in situ hybridization
experiments. The authors suggested that ETs may act
as an autocrine hormone in the regulation of the
bladder wall structure and smooth muscle tone, and
that it may regulate cholinergic neurotransmission by
310
a paracrine mechanism. The density of ET receptors
was significantly lower in bladders from patients
with BPH than in men without this disorder [87, 88].
ET-1 is known to induce contraction in animal as
well as in human detrusor muscle [98]. The contrac-
tile effect of ETs seems to be mediated mainly by the
ETA receptor, and the ETB receptor could not be
linked to contraction. [99] However, in human blad-
der smooth muscle, ETs may not only have a con-
tractile action, but could also be linked to prolifera-
tive effects. Supporting this view, Khan et al. [100]
found that ETA and ETB receptor antagonists inhib-
ited detrusor and bladder neck smooth muscle cell
proliferation, and they suggested that ET-receptor
antagonists may prevent smooth muscle cell hyper-
plasia associated with partial bladder outflow
obstruction.
In rat urinary bladder, NANC neurotransmission is
facilitated by ET-1 via the ETA receptor, [101] and
in rat vas deferens ETs potentiated the postjunction-
al effects of ATP, acting at P2X receptors [102. Con-
sidering the potential role of purinergic transmission
in the pathogenesis of detrusor overactivity, [64]
such effects may be of importance in the pathogene-
sis of LUTS.
Many authors have suggested that ET may play a
pathophysiological role in bladder outlet obstruction
associated with BPH. ETs have a direct contractile
effect on prostatic smooth muscle, they may enhance
α1-AR receptor-mediated prostatic smooth muscle
contractile responses, and they may stimulate cell
proliferation. In the bladder, they may be implicated
in detrusor hypertrophy and its functional conse-
quences, including LUTS.
However, there is presently no clinical evidence
available that ET receptor antagonists are effective
against LUTS, or that they can influence the disease
process in BPH.
IX. ANGIOTENSIN RECEPTORS
Several mitogenic factors may induce proliferation
in the periurethral tissue of the prostate, including
angiotensin. Dinh et al. [103, 104] showed the exis-
tence of angiotensin receptors type 1 (AT1) in nor-
mal human prostate and BPH. Other work showed
elevated prostatic levels of local angiotensin-con-
verting enzyme (ACE) in BPH and that the expres-
sion of the AT1 receptor might be affected by this
[104, 105]. The intriguing question is what role Ang
II plays in prostate physiology and pathophysiology
(Figure 11).

Wennemuth and Aumuller [106] studied the occur-
rence of angiotensin I (AT1) and angiotensin II
(AT2) receptors in human primary cultures of the
prostate stromal compartment, and on human
prostate tissue-embedded in paraffin. They also
applied pharmacological tools in combination with
photometry experiments to characterize the physio-
logical activity of AT1 and AT2 receptors in prima-
ry human prostate cells. Only the AT1 receptor was
detected in Western blot analysis. Immunocytochem-
istry of primary human prostate cells showed that the
AT1 receptor was present in both the smooth muscle
type and the fibroblastic type. In the stromal com-
partment of human prostate tissue, immunoreaction
with antibodies against the AT1 receptor was
detectable. In human prostate cells a linear rise in
free intracellular calcium was elicited by angiotensin
II in concentrations of 10 µM. This effect could be
inhibited by losartan.
In the isolated human detrusor, Andersson et al.
[107] found that both angiotensin II and angiotensin
I caused concentration-dependent contractions. The
contractile effect was immediate, and was complete-
ly blocked by saralasin (blocking AT1 receptors), but
was not affected by pre-treatment of the preparations
with captopril or enalaprilate. A subsequent study
showed that the conversion of angiotensin I to
angiotensin II was produced not only by ACE, but
also by a serine protease [108]. Waldeck et al. [109]
characterized angiotensin II formation in human iso-
lated bladder by selective inhibitors of ACE and
human chymase. They confirmed that angiotensin II
is a potent contractile agent in the human isolated
detrusor muscle, and showed that the serine protease
responsible for angiotensin II formation in the
311
Figure 11. Generation and possible
effects of angiotensin II in the lower
urinary tract.
human bladder in vitro is human chymase or an
enzyme similar to human chymase.
In rats with partial bladder outflow obstruction treat-
ed with losartan, Persson et al. [110] found no evi-
dence for involvement of angiotensin II in develop-
ment of bladder hypertrophy. The effect of
angiotensin II on bladder smooth muscle tone was
minor but was mediated by stimulation of the AT1
subtype receptor. Palmer er al. [111] arrived at a sim-
ilar conclusion, showing that neither captopril nor
losartan significantly ameliorated the histological or
biochemical features of partial bladder outlet
obstruction in the rat.
Whether or not blockade of angiotensin II generation
or angiotensin receptors can block prostate growth or
has any positive effects on LUTS remains to be
established.
X. VITAMIN D3 RECEPTORS
Analogues of vitamin D3 were shown to inhibit BPH
cell proliferation and to counteract the mitogenic
activity of potent growth factors for BPH cells [112-
114]. Receptors for vitamin D were demonstrated in
rat and human bladder (Crescioli et al 2005), [115]
which makes it conceivable that the bladder may also
be a target for vitamin D. Experiments in rats with
bladder outflow obstruction [116] showed that one of
the analogues, BXL-628, at non-hypercalcemic
doses, did not prevent bladder hypertrophy, but
reduced the damage to the bladder smooth muscle
which occurs with increasing bladder weight. BXL-
628 has been selected for a phase II clinical trial in
patients with benign prostate hyperplasia.

XI. NITRIC OXIDE DONORS
In the human prostate, there is a dense nitrergic
innervation of the fibromuscular stroma, glandular
epithelium, and blood vessels. Particularly secretory
cells were found to be surrounded by a dense net-
work of NOS-containing nerve terminals [117-119].
In BPH, this nitrergic innervation is reduced [118].
NO and electrical stimulation of nerves relaxed nora-
drenaline-contracted preparations of human prostatic
smooth muscle; inhibition of synthesis of NO abol-
ished the electrically induced relaxations [119, 120].
These findings suggest that NO can be a regulator of
prostatic smooth muscle tone. However NO may
have effects not only on stromal smooth muscle, but
also on secretory cells and on vessels. Theoretically,
lack of NO may lower the threshold for afferent fir-
ing leading to detrusor overactivity and LUTS asso-
ciated with BPH. However, there is so far no clinical
evidence showing that this may be the case.
In male neuronal NOS (nNOS)-deficient mice, Bur-
nett et al. [121] found markedly dilated bladders with
muscular hypertrophy, findings compatible with
deficient urethral relaxation and increased outflow
resistance. Supporting that the bladder changes were
caused by disturbances in outflow relaxation, the
decrease in tension produced by low frequency stim-
ulation of nerves of isolated urethral preparations
from wild-type controls, was absent in preparations
from nNOS-deficient mice.
Evidence that baseline NOS activity prevents unin-
hibited bladder contractions also exists from urody-
namic studies performed in a fetal lamb model [122].
If the nitrergic nerves observed in the detrusor, and
particularly within and beneath the urothelium, are
afferent terminals, NO may be involved in the regu-
lation of the threshold for bladder afferent firing.
Supporting such a view, intravesical oxyhemoglobin,
a nitric oxide scavenger, induced detrusor overactiv-
ity in normal rats [123]. It was suggested that intrav-
esical oxyhemoglobin induced detrusor overactivity
by interfering with nitric oxide (NO) generated in the
urothelium or suburothelially, and that NO may be
involved in the regulation of the threshold for affer-
ent firing in the bladder. Inhibition of the L-argi-
nine/NO pathway by NOS inhibitors also lead to
detrusor overactivity and decreased bladder capacity
[124]. Furthermore, mice lacking cyclic GMP-
312
dependent protein kinase I (cGKI, PKG I) showed
detrusor overactivity characterized by decreased
intercontraction intervals and non-voiding bladder
contractions [125]. This further supports the view
that the L-arginine/NO pathway is involved in the
control of detrusor activity.
iNOS does not seem to be expressed in the normal
bladder, but enhanced expression is seen early after
BOO [126]. An enhanced function seen in bladders
from mice lacking iNOS after longer periods of
obstruction (5 weeks) in comparison to WT bladders
suggests that reactive nitrogen species-induced pro-
tein nitrosylation may be involved in the loss of con-
tractile function observed after more prolonged peri-
ods of obstruction [127]. Felsen et al. [128] showed
that pharmacological or genetic decreases in iNOS
resulted in amelioration of functional and fibrotic
changes in the bladder after partial BOO, suggesting
that NO contributes to the pathophysiology of BOO.
Gradini et al. [129] found that iNOS could not be
detected in normal prostate, while it was expressed
in the prostate of BPH patients, even in the absence
of prostatitis or systemic signs of an inflammatory
condition. Romih et al. [130] showed that in patients
with BOO, some superficial urothelial cells lacked
the asymmetric unit membrane, suggesting focal
compromise of the blood-urine permeability barrier.
In such relatively undifferentiated urothelial zones
there was an accompanying increase in the expres-
sion of iNOS, which marks perturbed urothelial dif-
ferentiation and may modulate bladder response to
the outlet obstruction.
In an open prospective study Klotz et al. [131] stud-
ied the effects of orally given nitrates on micturition
in 32 subjects. Fifteen patients suffered from
obstructive symptoms, and 17 had no subjective mic-
turition problems. In symptomatic patients, the
authors found a significant improvement of peak uri-
nary flow rates, IPS score and a significant decrease
of residual urine volume. No significant changes of
micturition parameters were found in asymptomatic
patients.
The usefulness of NO donors in the treatment of
LUTS remains to be established.
Use of NOS inhibitors to prevent the negative effects
of the increased iNOS expression in BOO is excit-
ing. However, further investigations are necessary to
explore the potential of this approach.

XII. PHOSPHODIESTERASE
INHIBITORS
Uckert et al. [132] characterized the PDE isoen-
zymes from human prostatic tissue by molecular
biology and protein chemistry, and also investigated
the effects of various PDE inhibitors on α1-AR
mediated tension in isolated human prostatic strips.
Reverse transcriptase-polymerase chain reaction
revealed messenger RNA transcripts encoding for
PDE 1, 2, 4, 5, 7, 8, 9 and 10 in the various anatom-
ical regions of the human prostate, including the
peripheral, central and transition zones. Except for
complementary DNA encoding for PDE 1C, comple-
mentary DNA fragments encoding for PDE 1A, 1B,
2A, 4A, 4B, 4C, 4D, 5A, 7A, 8A, 9A and 10A were
found at almost even ratios in the different histolog-
ical regions of the prostate. The hydrolytic activities
of PDE 4 and 5 were present in the cytosolic fraction
of prostatic tissue, whereas in the particulate fraction
only the hydrolytic activity of PDE 4 was detected.
α1-AR mediated tension in prostatic strip prepara-
tions was reversed by forskolin, sodium nitroprus-
side, and inhibitors of PDE 4 and 5. The authors con-
sidered their studies to support the possible use of
inhibitors of PDE 4 and 5 for treating urinary
obstruction secondary to BPH. Sairam et al. [133]
found that treatment with sildenafil appeared to
improve urinary symptom scores in men with ED
and LUTS in an open study, giving support to the
conclusion drawn by Uckert et al. [132]
Truss et al. [133, 135] demonstrated the presence of
five PDE isoenzymes in human detrusor and sug-
313
gested that the cAMP pathway and the
calcium/calmodulin-stimulated PDE (PDE 1) could
be of functional importance in the intracellular regu-
lation in this tissue in vitro. They also presented pre-
liminary clinical data with the PDE 1 inhibitor vin-
pocetine in patients not responding to standard
antimuscarinic therapy, which suggested a possible
role for vinpocetine in the treatment of urgency, fre-
quency, and urge incontinence [134]. The results of
a larger randomized, double-blind, placebo-con-
trolled, multicenter trial with vinpocetine showed a
tendency in favor of vinpocetine over placebo; how-
ever, statistically significant results were document-
ed for one parameter only [135].
To assess the value of PDE inhibition (PDE 4 and 5)
alone or in combination, further placebo controlled
randomized trials are required.
XIII. RHO-KINASE
In BPH/LUTS there seems to be an increased smooth
muscle activity contributing to the pathophysiology
and development of symptoms. This may be attribut-
ed to increased sympathetic activity and increased
stimulation of smooth muscle α-ARs. However, in
the pathophysiology of BPH/LUTS several other
contraction-mediating transmitters than noradenaline
may be involved such as endothelins, angiotensins
and prostanoids [136]. The question is whether or not
there is a common pathway through which the dif-
ferent contractile transmitters/mediators can mediate
contraction of the smooth muscle (Figure 12)?
Figure 12. Rho-kinase activation
increases the sensitivity to Ca2+ in
the smooth muscle of the lower uri-
nary tract by inhibiting myosin light
chain phosphatase (MLCP). Since
only phosphorylated myosin light
chains (MLC) can interact with actin
to produce contraction, inhibition of
Rho-kinase decreases the calcium
sensitivity of the contractile proteins
and the smoth muscle relaxes. IP3=
inositoltrisphosphate; CaM=calmod-
ulin; MLCK=myosin light chain
kinase.
During recent years, regulation of the myosin light
chain phosphatase (MLCP) has received much atten-
tion. One main pathway for inhibition of the MLCP
and inducing Ca2+-sensitisation involves a specific
kinase (Rho-kinase), which is activated by RhoA via
G-protein coupled receptors. [137-139] RhoA is a
small, GTP-binding protein, which regulates a wide
range of cellular processes including cytoskeletal
function, secretion and smooth muscle contraction.
Once activated, RhoA has several downstream tar-
gets, but for smooth muscle contraction the down-
stream target is Rho-kinase. Rho-kinase, in turn,
phosphorylates MLC phosphatase which results in
the loss of phosphatase activity. When MLC phos-
phatase activity is inhibited, the phosphorylated form
of MLC (i.e., MLC~P) is maintained and smooth
muscle remains contracted [137-139].
Rees et al.[140] showed that Rho-kinase is present in
the cytosol and located in the perinuclear region in
human and rat prostatic smooth muscle cells. Y-
27632 decreased the proliferation of human and rat
prostatic smooth muscle cells, and inhibited nora-
drenergic contractions elicited by electrical field
stimulation and exogenous phenylephrine in rat pro-
static strips.
Lindberg et al. [141] demonstrated an intense stain-
ing for RhoA in spontaneously hypertensive rats
(SHR) prostatic smooth muscle cells. In comparison,
immunoreactivity detected in prostatic smooth mus-
cle from Wistar Kyoto (WKY) control rats was
weaker in intensity amounting to 53 ± 4% of that
obtained in SHR (p<0.05). Western blot analysis ver-
ified upregulated expression of RhoA in prostates
from SHR compared to WKY. It was suggested that
the increased activity of the RhoA/Rho-kinase path-
way in prostatic smooth muscle from SHR may
explain why prostatic tissue from these animals
exhibit enhanced nerve-induced α1-AR-mediated
contractions.
If Rho-kinase is upregulated in the prostate and the
bladder in BPH, and contributes to increased smooth
muscle activity both in the prostate and the bladder,
this enzyme would be an interesting target for the
treatment of BPH/LUTS. Fasudil is currently the
only Rho-kinase inhibitor available for clinical use,
and it is approved in Japan for the prevention of
vasospasm in patients with subarachnoid hemor-
rhage [142]. Rho-kinase may represent a new target
aimed for treatment of BPH/LUTS and studies are
needed to define the therapeutic potential of Rho-
kinase inhibitors.
314
XIV. CYCLOOXYGENASES/
PROSTANOID RECEPTORS
Prostanoids (prostaglandins and thromboxanes) are
generated locally in both detrusor muscle and
mucosa, [143-144] and synthesis is initiated by vari-
ous physiological stimuli such as stretch of the detru-
sor muscle, but also by injuries of the vesical
mucosa, nerve stimulation, and by agents such as
ATP and mediators of inflammation, e.g., bradykinin
and the chemotactic peptide [136, 145-146].
Prostanoids are synthesized by cyclooxygenase
(COX) in the bladder [144]. This enzyme exists in
two isoforms, one constitutive (COX-1) and one
inducible (COX-2). It has been suggested that in the
bladder, the constitutive form is responsible for the
normal physiological biosynthesis, whereas the
inducible COX-2 is activated during inflammation.
Even if prostanoids cause contraction of human blad-
der muscle, [98] it is still unclear to what extent they
contribute to the pathogenesis of OAB/DO. More
important than direct effects on the bladder muscle
may be sensitization of sensory afferent nerves,
increasing the afferent input produced by a given
degree of bladder filling. Involuntary bladder con-
tractions can then be triggered at a small bladder vol-
ume. If this is an important mechanism, treatment
with COX inhibitors could be expected to be effec-
tive OAB/DO. However, clinical evidence for this is
scarce.
Cardozo et al. [147] performed a double-blind con-
trolled study of 30 women with DO using the nonse-
lective COX inhibitor flurbiprofen at a dosage of 50
mg 3 times daily. The drug was shown to have
favourable effects, although it did not completely
abolish DO. There was a high incidence of side
effects (43%) including nausea, vomiting, headache
and gastrointestinal symptoms. Palmer [148]) stud-
ied the effects of flurbiprofen 50 mg x 4 versus
placebo in a double-blind, cross-over trial in 37
patients with idiopathic DO (27% of the patients did
not complete the trial). Active treatment significant-
ly increased maximum contractile pressure,
decreased the number of voids and decreased the
number of urgent voids compared to baseline.
Indomethacin (non-selective COX inhibitor) 50 to
100 mg daily was reported to give symptomatic
relief in patients with DO, compared with
bromocriptine in a randomized, single-blind, cross-
over study [149]. The incidence of side effects was
high, occurring in 19 of 32 patients. However, no
patient had to stop treatment because of side effects.
Sprem et al. [150] administered ketoprofen (non-
selective COX inhibitor) intravesically once a day
for 4 weeks in a double-blind, placebo-controlled
cross-over study to 30 women with urodynamically
verified idiopathic DO. Both symptomatic and uro-
dynamic improvement was demonstrated. Eighteen
out of 30 patients became symptom-free after treat-
ment, and no side effects were observed.
Schroder et al. [151] investigated whether the PGE2
receptor EP1 was involved in the regulation of nor-
mal micturition, the response to intravesical PGE2
administration, and the development of bladder
hypertrophy and overactivity due to BOO. Moderate
BOO was created in EP1 receptor knockout
(EP1KO) mice and their wild type (WT) counter-
parts. After 1 week cystometry was performed in
conscious animals before and after PGE2 instillation.
Findings were compared to those in unobstructed
control animals. There was no difference between
unobstructed EP1KO and WT mice in urodynamic
parameters, but EP1KO mice did not respond to
intravesical PGE2 instillation, while WT mice
showed detrusor overactivity. The lack of EP1 recep-
tor did not prevent bladder hypertrophy due to BOO.
After BOO, WT mice had pronounced detrusor over-
activity, while this was negligible in EP1KO mice. It
was concluded that the EP1 receptor appears not to
be essential for normal micturition or the mediation
of bladder hypertrophy due to BOO, but to have a
role in the development of detrusor overactivity
caused by PGE2 and outlet obstruction.
Prevention and/or termination of inflammation and
infiltration with lymphocytes in the prostate repre-
sent another potential new treatment concept for
LUTS. Chronic inflammation is consistently associ-
ated with BPH and with precursor lesions of prostate
cancer as well [152-154]. There is good evidence
that this process lasting over years and decades, con-
tributes to the development of benign hyperprolifer-
ation and in consequence LUTS. Interesting new
therapeutic targets are therefore likely also to be
found among the regulators of chronic inflammation
of the prostate.
The predominating infiltrating cell type in inflamma-
tory BPH lesions were characterized to be activated
CD3+ T lymphocytes suggesting an autoimmune
response as the underlying mechanism [155-156].
Accompaning prostate autoantibodies in the serum
of BPH patients, directed for example against PSA
[157] support this hypothesis. The chronic activation
of infiltrating immune cells can cause tissue damage
315
and thus may contribute to the pathogenesis of
prostate diseases. Inflammatory infiltrates produce a
variety of cytokines among them substances with
autocrine stimulatory activity for prostate cells like
IL6 or IL8 that likely contribute to hyperproliferation
[158-161].
One potential class of drugs available for interfering
with inflammation and inflammatory effects on the
tissue are the non-steroidal anti-inflammatory drugs
(NSAIDs), and among them especially the COX-2
inhibitors. They are used as potent pain relievers in
diseases associated with inflammation and in addi-
tion are considered and tested as promising tumor
chemopreventive agents for cancers such as colon
and prostate cancer [162-163]. In the prostate high-
est level of expression of COX-2 were found in
tumor cells, thus the interest to use substances like
rofecoxib or celecoxib for chemoprevention of
prostate carcinogenesis and tumor progression [164].
However, COX-2 is also induced in BPH lesions and
smooth muscle cells of the prostate [165-166]. This
pattern of expression nourishes hope that COX-2
inhibitors might also be effective in BPH. So far
studies of COX-2 inhibitors in the treatment of
LUTS are scarce. Di Silverio et al. [167] tested a
combination of finasteride and the COX-2 inhibitor
refecoxib versus finasteride alone in forty-six con-
secutive men with LUTS and BPH. Especially dur-
ing the first weeks of therapy the improvement of
symptoms was significantly better in the combina-
tion group, later on this difference levelled-off. This
result is promising and would justify extension of
these studies. However, recent findings of cardiovas-
cular toxicity associated with prolonged use of COX-
2 inhibitors resulting in withdrawal of some of these
compounds from the market will make the conduct
of appropriately designed long term placebo con-
trolled studies very difficult.
XV. OTHER AGENTS
1. GABAPENTIN
Gabapentin was originally designed as an anticon-
vulsant GABA (y-aminobutyric acid) mimetic capa-
ble of crossing the blood-brain barrier [168]. The
effects of gabapentin, however, do not appear to be
mediated through interaction with GABA receptors,
and its mechanism of action remains controversial
[168]. It has been suggested that it acts by binding to
a subunit of the α2δ unit of voltage dependent calci-
um channels [169].
Gabapentin is also widely used not only for seizures
and neuropathic pain, but for many other indications,
such as anxiety and sleep disorders, because of its
apparent lack of toxicity.
In a pilot study, Carbone et al. [170] reported on the
effect of gabapentin on neurogenic detrusor overac-
tivity. These investigators found a positive effect on
symptoms and significant improvement in urody-
namic parameters after treatment with gabapentin,
and suggested that the effects of the drug should be
explored in further controlled studies in both neuro-
genic and non-neurogenic detrusor overactivity. Kim
et al. [171] studied the effects of gabapentin in
patients with OAB and nocturia not responding to
antimuscarinics. They found that 14 out of 31
patients improved with oral gabapentin. The drug
was generally well tolerated, and the authors sug-
gested that it can be considered in selective patients
when conventional modalities have failed. It is pos-
sible that gabapentin and other α2δ ligands (e.g.,
pregabalin and analogs) will offer new therapeutic
alternatives.
2. ALTERNATIVE STRATEGIES - COMBINATIONS
Combining the current α1-adrenoceptor antagonists
with other agents might theoretically provide
improved symptom relief. One such example is the
combination of α1-adrenoceptor antagonists with 5
α-reductase inhibitors, which has proven to improve
clinical outcomes and reduce the incidence of BPH
and LUTS progression measured as symptom wors-
ening, retention or progression to surgery [172].
Other combinations have also been tested with vary-
ing degrees of success. Traditionally muscarinic
receptor antagonists have been contradicted in
patients with BPH due to fears of urinary retention.
However, this dogma has been questioned recently,
[39] and several studies have been performed in
which a1-adrenoceptor antagonists are combined
with muscarinic receptor antagonists with promising
results [173-174].
As mentioned above, Di Silverio et al. [167] found
that combination with the COX-2 inhibitor rofecox-
ib and finasteride compared favourably to finasteride
alone in a short-term interval (4 weeks). It was
hypothesized that the association of rofecoxib with
finasteride induces a more rapid improvement in
clinical results until the effect of finasteride becomes
predominant.
Speculatively, other combinations can be suggested:
α1-adrenoceptor antagonists combined with ET-
316
receptor antagonists may potentially offer both short-
term and long-term benefits. Also a combination
between an α1-adrenoceptor antagonist and a Rho-
kinase inhibitor seems attractive.
3. TARGETS WITHIN THE CENTRAL NERVOUS
SYSTEM
Several CNS transmitters may modulate voiding, but
few drugs with a defined CNS site of action have
been developed for treatment of voiding disorders,
including LUTS associated or suggestive of BPH
[16, 175].
Drugs affecting γ-aminobutyric acid, opioid, sero-
tonin, noradrenaline, dopamine, or glutamatergic
receptors and mechanisms are known to influence
micturition, and potentially such drugs could be
developed for clinical use. However, a selective
action on the lower urinary tract may be difficult to
obtain. Recently, the inhibition of the intracellular
MAP kinase ERK 1, 2 signaling cascade (Figure 13)
in lumbosacral spinal cord neurones was shown to
reduce the frequency of reflex bladder contractions
in anaesthetised rats with cyclophosphamide-
induced chronic bladder inflammation (Figure 14),
but not in normal rats [176].
The selective effect of ERK1, 2 inhibitors, designed
to evaluate the role of this signalling cascade, on
bladder function is attractive as a therapeutic tool,
but future studies specifically focusing on bladder
changes accompanying chronic BOO are needed.
XVI. CONCLUSIONS
Theoretically, there may be several possibilities to
improve current medical treatment of LUTS associ-
ated with or suggestive of BPH (Figure 15; Table 1).
Subtype selective α1-AR antagonists (α1D?), β3-
AR agonists, muscarinic receptor antagonists (as sin-
gle treatment or in combination with α1-AR antago-
nists), ET-receptor antagonists (alone or together
with α1-AR antagonists), drugs acting at vanilloid
receptors, angiotensin receptors, vitamin D3 recep-
tors, and intraprostatic botulinum toxin all seem to
have a certain potential. Nitric oxide donors, PDE
inhibitors, iNOS inhibitors, Rho-kinase inhibitors,
COX inhibitors, drugs blocking purinoceptors, and
drugs like gabapentin, may offer new opportunities.
Drugs acting on targets within the CNS seem to have
a potential, but selective effects on LUTS may be
difficult to obtain.
 Figure 13. The ERK1/2
pathway in spinal cord
neurones stimulated by
bladder afferents.

Figure 14. The ERK 1/2

pathway in the spinal
cord can be activated by
physiologic bladder dis-
tension, an effect that
can be inhibited by the
mitogen-activated pro-
tein kinase kinase 1/2
(MEK 1/2) inhibitor
PD98059.

Figure 15. Possible new therapeutic principles in the

treatment of BPH/LUTS.

317
Table 1.
Treatment target Treatment Principle Evidence, Evidence,
preclinical clinical Comment
α1D-Adrenoceptor α1D-Adrenoceptor antagonist ++ ? Lack of drugs with sufficient
selectivity
β3-Adrenoceptor β3-Adrenoceptor agonists +++ ? Promising. Proof of concept trials
positive?
Muscarinic M2 Muscarinic M2 receptor Lack of drugs with sufficient
receptor antagonists + - selectivity
P2X3 receptor P2X3 receptor antagonists +++ ? Promising. Drugs under
development
TPRV1 receptor TPRV1 receptor agonists
(capsaicin, resiniferatoxin) +++ +++ Documented effects Practical
problems
TPRV1 receptor TPRV1 receptor antagonists ? - Theoretically interesting. No data
Botulinum toxin Botulinum toxin sensitive Documented effects
mechanisms +++ +++ Promising
Endothelin receptor / Endothelin receptor /
converting enzyme converting enzyme inhibitors ++ - Theoretically interesting
Angiotensin receptor / Angiotensin receptor /
converting enzyme converting enzyme inhibitors ++ - Theoretically interesting
Vitamin D3 receptor Vitamin D3 receptor agonists +++ + Under development. Promising?
Soluble guanylyl NO donors +++ ++ Documented effect (limited)
cyclase Adverse effects
iNOS iNOS inhibitors ++ - Theoretically interesting
Phosphodiesterases Phosphodiesterase inhibitors ++ ++ Promising. Limited clinical
evidence of effect
Rho-kinase Rho-kinase antagonists +++ - Theoretically interesting
Promising?
Cyclooxygenases Cyclooxygenase inhibitors +++ ++ Promising?
Prostanoid receptors Prostanoid receptor inhibitors +++ - Theoretically interesting
α2δ subunit of Promising? Documented effect
voltage- regulated limited
Ca2+ channels Gabapentin ++ ++
Central nervous Central nervous system Promising, but no positive proof
system mechanisms active drugs ++ + of concept studies

Grading
- Evidence lacking
? Evidence not yet available
Evidence, preclinical:
+ Effect suggested – limited evidence
++ Effect demonstrated in several models
+++ Effect demonstrated in relevant in vivo models
Evidence, clinical:
+ Effect demonstrated – clinical implications unclear
++ Effect demonstrated – limited information
+++ Effect demonstrated in controlled clinical trials

318

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324
 CHAPTER 9

Committee 14

Androgen Therapy in
Men at Risk for Prostate Disease

Chairman
C. SCHULMAN (BELGIUM)

Members
S. HORIE (JAPAN),
J.M KAUFMAN (BELGIUM),
C. MAHLER (BELGIUM)
A. MORALES (CANADA),
A. MORGENTALER (USA),
J. TOSTAIN (FRANCE)

325
 CONTENTS

I. POTENTIAL MOLECULAR VI. ANTIESTROGENS AND

EFFECT OF TESTOSTERONE SELECTIVE ESTROGEN
ADMINISTRATION ON THE RECEPTOR MODULATORS (SERMs)
PRECANCEROUS LESIONS
1. ANTIESTROGENS : CLOMIPHENE CITRATE
1. PROLIFERATIVE INFLAMMATORY ATROPHY
AND TAMOXIFEN
AND TESTOSTERONE
2. SELECTIVE ESTROGEN RECEPTOR MODULA-
2. TESTOSTERONE AND P27
TORS (SERMS)

II. ANDROGEN THERAPY AND VII. INDICATIONS AND

PROSTATE DISEASE CONTRAINDICATIONS FOR
TESTOSTERONE TREATMENT
1. INTRODUCTION
1. MANAGEMENT OF MEN WITH BPH AND
2. TESTOSTERONE REPLACEMENT THERAPY
SLOH.
AND BENIGN PROSTATIC HYPERPLASIA
2. MANAGEMENT OF MEN WITH SLOH AND AT
3. TESTOSTERONE THERAPY AND PROSTATE
RISK OF PROSTATE CANCER.
CANCER

4. PROSTATE CANCER PREVALENCE AMONG

MEN WITH LOW SERUM TESTOSTERONE
5. CONCLUSIONS
III. DEHYDROEPIANDROSTERONE
(DHEA) and DEHYDROEPIANDRO
STERONE SULFATE (DHEA-S).
RECOMMENDATIONS
(insofar as indications for androgen
substitution)
1. MONITORING – PROSTATE
2. PROSTATE AND BREAST SAFETY – I
3. PROSTATE SAFETY – II
4. PROSTATE SAFETY – III

IV. GROWTH HORMONE (GH)

RECOMMENDATIONS

V. SELECTIVE ANDROGEN
RECEPTOR MODULATORS (SARMs)

1. STEROIDAL ANDROGEN RECEPTOR MODULA-

TOR : MENT

2. NONSTEROIDAL SELECTIVE ANDROGEN

RECEPTORS MODULATORS

3. CONCLUSION ON SARMS

326
 Androgen Therapy in
Men at Risk for Prostate Disease
C. SCHULMAN
S. HORIE, J.M KAUFMAN, C. MAHLER, A. MORALES, A. MORGENTALER, J. TOSTAIN
I. POTENTIAL MOLECULAR
EFFECT OF TESTOSTERONE
ADMINISTRATION ON THE
PRECANCEROUS LESIONS
Currently the major concern for the therapy for male
late-onset hypogonadism is whether androgen
replacement affects the safety of prostate. This sec-
tion discusses the molecular aspects of the potential
effect of androgen replacement on the prostate of
aging male.
Prostate cancer is the absolute contraindication of
androgen replacement. However recent studies show
that low androgen milieu itself contributes to more
aggressive prostate cancer [1, 2, 3]. These findings
may invite speculation that androgen level in the
prostate might modulate the oncogenic process of
prostate cancer. To this date, there is no proof of evi-
dence that androgen replacement therapy does
increase the chance of prostate cancer. Thus the prac-
tical approach would be to discuss the potential
molecular effect of testosterone administration on
the precancerous lesions.
1. PROLIFERATIVE INFLAMMATORY ATROPHY
AND TESTOSTERONE
Several lines of evidence suggest that chronic
inflammation establishes a microenvironment for a
precancerous lesion of many types of malignancies
in humans, including prostate cancer. Inflammatory
cells produce an array of oxygen-containing muta-
genic chemicals, including superoxide, nitric oxide
(formation of peroxynitrite), hydrogen peroxide, and
hypochlorous acid [4, 5]. Oxygen radicals can cause
327
tissue damage, and moreover they can directly attack
DNA, which results in the accumulation of poten-
tially pro-mutagenic oxidized DNA bases, such as 8-
hydroxydeoxyguanosine [6]. Oxygen radicals are
now considered to have a place in the prostate car-
cinogenesis since several studies show that antioxi-
dants, such as carotenoid lycopene, vitamin E and
selenium, decrease oxidative genomic damage in
prostate cells, and may also reduce the risk of
prostate cancer [7,8,9]. When a tissue becomes dam-
aged as a result of inflammation, the consequent tis-
sue regeneration processes usually involve increased
cellular proliferation. De Marzo et al. proposed that
a prostatic lesion called proliferative inflammatory
atrophy is a precursor to prostatic intraepithelial neo-
plasia and prostate cancer) [10]. The frequent associ-
ation of lesions of proliferative inflammatory atro-
phy with chronic inflammation suggests that these
lesions arise as a consequence of the regenerative
proliferation of prostate epithelial cells in response to
injury caused by inflammatory oxidants [10]. Indeed
PIA lesions that are exposed to inflammatory oxi-
dants induce GSTP1 expression as a defense against
oxidative genome damage [11]. In aging males, the
tissue level of androgens decreases as the blood level
of testosterone does [12]. A thorough deprivation of
circulating androgens results in diffuse prostatic
atrophy. However whether partial decrease in andro-
gen signal triggers focal atrophy which may be relat-
ed to PIA remains unknown. Testosterone probably
has two opposite effects on the prostate with inflam-
mation. First of all, in relatively low androgen level,
testosterone has anti-inflammatory effects. For
example, in patients with hypogonadism, supple-
mentation of androgens reduces serum inflammatory
cytokines [13]. In an animal model, the inflammation
of the spontaneous nonbacterial chronic prostatitis of
rats is worsened by castration, and it is blocked by
replacement with testosterone [14,15,16]. Estrogen
induces exaggerated inflammation and activates
proinflammatory genes in the rat prostate [17], while
testosterone inhibits the inflammation [18]. These
experimental data indicate that testosterone may
have anti-inflammatory effect on the prostate with
low androgen milieu.
However, testosterone also has prooxidative effects
which lead to activate AP-1 and NF-kB [19]. AP-1 is
a transcriptional factor stimulating cell proliferation.
NF-kB is a pro-inflammatory molecule and plays
significant role in carcinogenesis. Furthermore,
testosterone also activates MAPK and PI3K-Akt cas-
cades, which contribute to cell proliferation [20].
These facts propose a serious question whether addi-
tion of testosterone to PIA, a potential precancerous
lesion of prostate cancer, further enhances inflamma-
tion, aberrant cell proliferation, and genetic instabil-
ity. In experimental carcinogenesis, short-term treat-
ment of rats with chemical carcinogens or chronic
treatment with testosterone produces a low incidence
of prostate cancer. Thus testosterone itself may not
be genotoxic enough to initiate carcinogenesis. How-
ever, combination of chronic treatment with testos-
terone following administration of carcinogens such
as N-methyl-N-nitrosourea (MNU) and 3,2’-
dimethyl-4-aminobiphenyl (DMAB) results in a high
carcinoma incidence. Testosterone markedly
enhances prostate carcinogenesis even at doses that
do not measurably increase circulating testosterone.
These data indicate that testosterone is a strong
tumor promoter for the rat prostate [21].
2. TESTOSTERONE AND P27
Testosterone exerts strong proliferative effect on
developing prostate epithelial cells. Prostate epitheli-
um chronically requires physiological levels of
androgens for their maintenance to avoid apoptosis
[22]. After castration, a majority of secretory cells of
the rat prostate are rapidly lost (60%–70% within 7
days of androgen deprivation). Androgen administra-
tion to mature castrated rats can trigger the regrowth
of the prostate gland, which will eventually return to
its original size [23]. However this regenerative pro-
cess is timely regulated since proliferation rates
decline to the baseline levels once the organ has
attained adult size despite further androgen treatment
[24]. At the same time that androgens exerts mito-
genic activity, androgens induce glandular differenti-
ation [25,26]. Recent study utilizing cDNA microar-
ray identified that androgen responsive genes are
328
involved in metabolism, chaperoning, trafficking,
cell cycle, apoptosis, protein synthesis, extracellular
matrix and scaffold, which are presumably involved
in prostate differentiation [27]. In this switch from
proliferation to differentiation, a cyclin kinase
inhibitor, p27, plays a significant role in controlling
the regrowth by limiting the proliferation of epithe-
lial cells and inducing their differentiation
[28,29,30]. p27 belongs to the Kip (Kip1) family of
CKIs and is involved in multiple fundamental cellu-
lar processes, including cell proliferation, cell differ-
entiation, and apoptosis. p27 was initially identified
as an inhibitor of cdk2/cyclin E complex activity,
and it was found to induce cell cycle arrest when
overexpressed in cultured cells [31]. Moreover,
p27Kip1 is a putative tumor suppressor gene that
appears to play a critical role in the pathogenesis of
several human malignancies, and its reduced expres-
sion has been shown to correlate with poor progno-
sis in cancer patients [32]. Androgens regulate the
expression of p27 in both normal and neoplastic
prostate epithelial cells. This regulation is dependent
on the androgen receptor and achieved through mod-
ulation of its specific degradation by the ubiquitin-
proteasome proteolytic system. p27 is widely
expressed in differentiated prostate secretory cells.
The expression of p27 is lost in cancer, PIN, and PIA
[33]. Especially, it is noteworthy that PIN features
hyperproliferative or intermediate state. The specific
mechanism by which androgens regulate p27 degra-
dation is unknown. However in the loss of p27, the
transitional process from proliferation and differenti-
ation would be disrupted, and androgen might direct
towards proliferation in precancerous and malignant
lesions. Back to 1964, Franks, LM et al. reported that
prostates in old mice showed the atrophy and hyper-
proliferation of epithelial cells. This atrophy was
reversed by the replacement of androgens. However,
androgens did not normalize the increased cell pro-
liferation [34].
Extrapolating this observation to patients who are
receiving androgens based on the findings of current
molecular biology, the administration of androgens
on the p27- or any other molecules that regulate cell
cycle- deficient prostate might further increase cell
proliferation and jeopardize for the progression of
prostate cancer. Currently there is no evidence on the
influence of androgen replacement on PIA. This
could be further clarified with clinical studies in
patients with long term androgen replacement and
having frequent prostate biopsies to observe the
change of pathology more closely even at lower
range of PSA.

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II. ANDROGEN THERAPY AND
PROSTATE DISEASE
1. INTRODUCTION
One of the main concerns regarding testosterone
therapy is the possibility of causing or promoting
prostate disease, especially prostate cancer. This con-
cern originates from two historical observations:
Metastatic prostate cancer regresses with castration
or with pharmacologic lowering of serum testos-
terone to castrate levels, [1] and under experimental
conditions, normal and malignant prostate cells die
or regress in the absence of testosterone, and resume
growth with restoration of physiologic levels of
testosterone.
These observations have led to the concern that high-
er testosterone levels, via the use of testosterone
replacement therapy (TRT) may cause growth of
occult prostate cancer, converting these into clinical
cancers. Since benign prostatic hyperplasia is also
androgen-dependent, [1] there is an additional con-
cern that testosterone supplementation may cause
progression of benign prostatic hyperplasia and asso-
ciated lower urinary tract symptoms (LUTS).
Although these beliefs are widely held, clinical
results largely fail to support these concepts. Key
studies are briefly reviewed below.
2. TESTOSTERONE REPLACEMENT THERAPY
AND BENIGN PROSTATIC HYPERPLASIA
Eugonadal men who received supra-physiologic
doses of testosterone failed to demonstrate any
increase in PSA, [2] suggesting that there exists a
threshold, or saturation level for testosterone-depen-
dent stimulation of prostatic tissue. In contrast, sev-
eral studies have shown that TRT in hypogonadal
men does result in a rise in PSA and prostate volume
[3-6]. This increase is modest, at approximately
15%. Of interest is that the PSA and prostate vol-
umes rise to levels similar to those of eugonadal
men, [3] again suggesting a saturation point for stim-
ulation of prostate growth. Clinically, however, these
studies have shown no evidence for worsening of
voiding symptoms, with unchanged prostate symp-
tom scores. Urine flow rates and post void bladder
residual urine measurements were also unchanged,
and there has been no evidence that complications
such as urinary retention occurred more frequently
among TRT patients than for placebo control
patients.
330
Although this experience with TRT and BPH is reas-
suring, individuals with severe voiding symptoms
may note exacerbation of such symptoms with TRT.
Consideration should therefore be given to treatment
of LUTS prior to initiation of TRT in men with
severe voiding symptoms.
3. TESTOSTERONE THERAPY AND PROSTATE
CANCER
a) Clinical trials
Although there are no long-term, large-scale place-
bo-controlled clinical trials of TRT, the available
data fail to support the contention that TRT results in
a substantially increased risk of prostate cancer, or
cancer progression [7]. A compilation of TRT trials
revealed a cancer detection rate of 1%, which is sim-
ilar to detection rates in large-scale screening pro-
grams for prostate cancer [7].
Moreover, one year of TRT among hypogonadal
men at high risk for prostate cancer based on the
presence of high grade prostatic intraepithelial neo-
plasia (PIN) resulted in only one case of cancer
among 20 men (5%) [8]. The natural history of men
with PIN is the development of cancer in 25% over
three years. Although one must be cautious in com-
paring one-year to three-year data, it would certainly
appear that TRT failed to cause a substantially
increased rate of prostate cancer in a high-risk popu-
lation.
b) Population-based studies of endogenous testos-
terone levels and prostate cancer risk
In 2001 Hsing reviewed twelve prospective popula-
tion-based studies examining the relationship of
endogenous testosterone levels to prostate cancer
risk [9]. The hypothesis of such studies is that men
who develop prostate cancer would demonstrate
higher testosterone levels than men without cancer
based on frozen serum samples from years prior to
the clinical diagnosis of cancer. None of these twelve
studies showed that men who developed prostate
cancer had higher testosterone levels than men who
did not develop cancer.
Moreover, men with the highest testosterone levels
did not exhibit a greater risk of prostate cancer com-
pared to men with the lowest testosterone levels.
Although one study did claim an association for
higher testosterone and prostate cancer, [10]. this
result was obtained only after simultaneous adjust-
ment for four other hormones, representing a statisti-
cal manipulation that is unlikely to have clinical rel-
evance.
4. PROSTATE CANCER PREVALENCE AMONG
MEN WITH LOW SERUM TESTOSTERONE
If high testosterone is believed to represent a risk
factor for prostate cancer, then it follows that low
testosterone should be protective against prostate
cancer. However, this does not appear to be true.
Prostate biopsy performed in a group of 77 hypogo-
nadal men with normal digital rectal exam and PSA
<4.0 revealed cancer in 11 men, for a detection rate
of 14% [11]. This rate is similar to the 15% cancer
detection rate among men with PSA <4.0 in the
placebo arm of the Prostate Cancer Prevention Trial
who underwent biopsy as part of the study protocol.
[12]. Although cancer rates in that latter trial were
reduced by 25% among men receiving finasteride
(which lowers dihydrotestosterone), [13] this drug
does not substantially alter serum testosterone levels,
and thus one cannot draw any conclusions from that
study regarding the potential impact of TRT on
prostate cancer risk.
5. CONCLUSIONS
In the absence of large-scale, long-term clinical trials
of TRT, one must be cautious in assessing the risk of
TRT with regard to prostate cancer. Nevertheless,
the effect of testosterone on the prostate has been
investigated extensively, and from a variety of
research approaches. As noted above, normalization
of testosterone among hypogonadal men causes a
modest rise in PSA and prostate volume to levels
seen with eugonadal men, but no higher, and does
not impact voiding except in rare cases. Clinical tri-
als of TRT have shown a low prevalence of cancer
detection with treatment, and even high-risk popula-
tions fail to demonstrate any striking increase in can-
cer detection or progression. Moreover, multiple
studies have failed to show that higher endogenous
testosterone is a risk factor for subsequent cancer
development. Furthermore, the presence of low
testosterone does not appear to reduce this risk.
How does one resolve the lack of worrisome clinical
data with the original observations that prostate can-
cer regresses with castration? The answer is that
TRT is not the opposite of castration, since most
hypogonadal men presenting for treatment already
have substantially higher circulating testosterone
levels than castrates. Saturation of testosterone
receptors in cancer cells at hypogonadal levels would
explain why no further stimulation of prostate cancer
growth has been shown in clinical trials. This
hypothesis merits laboratory investigation.
331
Although it is possible that further research may ulti-
mately provide evidence that higher testosterone lev-
els or TRT increases prostate cancer risk, to date
there is no compelling evidence to support this con-
tention. Indeed, this belief flies in the face of the
inescapable, yet rarely acknowledged fact that
prostate cancer becomes prevalent at a time of life
when testosterone levels are in decline, and that clin-
ical prostate cancer is almost never seen during the
early decades of life when testosterone levels are
highest. As others have previously postulated, [14]
this observation leads to the possibility that long-
term studies may even show that TRT is protective
against the development of prostate cancer.
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Eur Urology 2004; 46:285-295.

III. DEHYDROEPIANDROSTERONE
(DHEA) and DEHYDROEPIANDRO
STERONE SULFATE (DHEA-S).
Serum levels of the adrenal androgen dehy-
droepiandrosterone (DHEA) peak in men in the 3rd
decade of life and thereafter decrease progressively
with age. This decreased secretion of DHEA and
DHEA-S by the adrenals is responsible for a parallel
decrease in androgen and oestrogen formation in
peripheral tissues by the steroidogenic enzymes
specifically expressed in each cell type in individual
target tissues [3]. The consequences of decreased
DHEA production are still matter of debate. Because
DHEA can serve as a precursor to more potent
androgens and estrogens, like testosterone (T), dihy-
drotestosterone (DHT), and oestradiol (E2), supple-
mental DHEA use may pose a cancer risk in patients
with nascent or occult prostate cancer.
ADRENAL ANDROGENS FUNCTION AS AN
ANDROGEN SOURCE WITHIN PROSTATE AND
ANDROGEN TARGET TISSUE
Up-to-date only a few studies have investigated the
effects of DHEA on the prostatic cell. Experiments in
male Wistar-Unilever rats demonstrated that non-
toxic doses of DHEA confer significant protection
against prostate carcinogenesis in rats. The efficacy
of delayed administration of DHEA suggested that
the compound confers protection against later stages
of prostate cancer induction and could suppress the
progression of existing preneoplastic lesions to inva-
sive disease [1].
Koh E. et al. [4] compared the ability of three human
prostatic cancer cell lines to metabolise the adrenal
androgens, DHEA, and androstenedione under living
culture conditions. Androgen-independent cell lines
PC-3 and DU145 and androgen-dependent cell line
LNCaP were investigated [2]. The findings show that
332
the adrenal precursor pool has the potential to con-
tribute to the regulation of prostatic cells. In anoth-
er study with steroid responsive human LNCaP
prostate cancer cells, containing a functional, but
mutated androgen receptor (AR) the effects of
DHEA were compared with those of T, DHT, and E2
on cell proliferation, and protein and/or gene expres-
sion of AR, PSA, IGF-I, IGF-I receptor (IGF-IR),
IGF-II, IGF binding proteins -2,3, and 5, (IGFBPs-2-
5), and oestrogen receptor-beta (ERbeta). Cell prolif-
eration assays revealed significant stimulation by all
four steroids. DHEA and E2- induced responses
were similar, but delayed and reduced, compared
with those of T and DHT.
Since the drug is unregulated and easily available as
over the counter “nutritional supplement” in some
countries, the use of DHEA should be considered to
have the same contraindications that apply to T
regarding prostate safety. Further studies of the
mechanisms of DHEA effects on prostate cancer
epithelial cells of varying AR status, as well as on
prostate stromal cells, will be required to discern the
implications of DHEA supplementation on prostatic
health.
REFERENCES
1. Rao KV, Johnson WD, Bosland MC, Lubet RA, Steele VE,
Kelloff GJ, McCormick DL Chemoprevention of rat prostate car-
cinogenesis by early and delayed administration of dehy-
droepiandrosterone. Cancer Res. 1999 Jul 1;59(13):3084-9
2. Arnold JT, Le H, McFann KK, Blackman MR. Comparative
Effects of DHEA Versus Testosterone, Dihydrotestosterone and
Estradiol on Proliferation and Gene Expression in Human
LNCaP Prostate Cancer Cells.Am J Physiol Endocrinol Metab.
2004 Nov 9
3. Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its trans-
formation into androgens and estrogens in peripheral target tis-
sues: intracrinology. Front Neuroendocrinol. 2001 Jul;22(3):185-
212
4. Koh E, Kanaya J, Namiki M. Adrenal steroids in human prostat-
ic cancer cell lines. Arch Androl. 2001 Mar-Apr;46(2):117-25.

IV. GROWTH HORMONE (GH)
Relatively few studies have examined the effects of
GH on the prostate. Prostate hypertrophy is found in
acromegaly and reduced size of the prostate in
patients with GH deficiency. Overall and cancer
mortality in acromegaly have been shown to corre-
late with the degree of GH control; if post therapy
GH is controlled, both the overall and cancer mortal-
ity do not appear to differ from that of the normal
population. Neither prostate nor breast cancers have
been consistently shown to have an increased preva-
lence in acromegaly, but larger prospective epidemi-
ological studies are required to study this further [1].
The effects of GH are transmitted through the
insulin-like growth factor 1 (IGF-1). Although IGF-
1 appears to exert a permissive effect on tumorigen-
esis, there is no clear evidence that tumour initiation
is triggered by IGF-1 in acromegaly. However IGF-
1 and its main binding protein, IGFBP-3, modulate
cell growth and survival, and are thought to be
important in tumour development. An evaluation of
21 studies comparing 3609 cases and 7137 controls
showed that circulating concentrations of IGF-I
might be associated with an increased risk of cancer,
whereas IGFBP-3 concentrations could be associat-
ed with a decreased cancer risk, but these associa-
tions were modest and varied between sites [2].
Although laboratory methods need to be standard-
ised, these epidemiological observations could have
major implications for assessment of risk and pre-
vention of cancer. In men below 59 years of age
however P. Stattin [3] found a significant rise in
prostate cancer risk with increasing IGF-1 levels.
This amounted to odds ratio of 1.67 for those with
the highest compared to the lowest levels. Even after
adjustment for IGFBP-3, the ratio remained at 1.47.
For men who were aged less than 59 years at recruit-
ment, the odds ratio was 4.12. Moreover, the odds
ratio for advanced cancer was 2.87 times greater in
men with the highest versus the lowest IGF-1 levels.
Thus the researchers conclude that the association
appears particularly strong “for IGF-1 measurements
made at a comparatively young age and for advanced
disease”.
GH has been shown to increase the rate of cell pro-
liferation in prostate cancer cell lines and the co-
expression of GH and GH receptor (GHR) mRNA
isoforms in the ALVA41, PC3, DU145, LNCaP
prostate cancer cells by reverse transcription poly-
333
merase chain reaction has been demonstrated.
Sequence analysis confirmed that these cell lines
express the pituitary form of GH mRNA and also the
placental mRNA isoform. The presence of GH and
GHR proteins in these cell lines by immunohisto-
chemistry was also shown [5]. Weiss-Messer et al.
[6] in a recently published study demonstrated
mRNA expression of GHR and of its exon 9-truncat-
ed isoform (GHR(tr)) in benign prostate hyperplasia
(BPH) and prostate adenocarcinoma patient tissues,
as well as in LNCaP, PC3 and DU145 human
prostate cancer cell lines. GH-induced activation of
signalling pathways, and its effects on AR protein in
LNCaP cells and the isoform-specific regulation of
GHR in prostate cancer patient tissues, suggest that
GH, most likely in concert with other hormones and
growth factors, may play an important role in pro-
gression of human prostate cancer.
Colao et al [4] investigated whether GH replacement
therapy in adult patients with GHD has adverse
effects on the prostate. The effects of 12-month GH
or GH plus testosterone replacement on prostate
pathophysiology in 24 adult patients with GHD (11
euandrogenemic and 13 hypoandrogenemic), com-
pared to 24 age-matched healthy controls were eval-
uated. GH replacement restored prostate size to nor-
mal in both young and elderly patients, with no
increase in prostate abnormalities. Prostate-specific
antigen (PSA) and free PSA did not change, whereas
PSA density was significantly reduced after treat-
ment in hypoandrogenemic patients. Because the
simultaneous treatment with GH and testosterone
induces an increase of prostate size by 50% of base-
line on average, care is suggested in elderly patients
with prostate hyperplasia to avoid any risk of
prostate symptoms. In these cases, GH replacement
might be performed sequentially to reduce the hyper-
trophic effect of combining GH and testosterone.
Very recent, as yet unpublished data from the KIMS
study database following more than 6400 patients
receiving GH replacement therapy showed a very
slightly increased rate of prostate cancer incidence,
but this might be biased by the relatively high age of
the treated patients (personal communication).
RECOMMENDATIONS
Surveillance for prostate cancer in elderly males with
high IGF-1, especially if also receiving testosterone
replacement therapy, is recommendable, by mea-
surement of serum PSA, rectal examination and/or
prostatic ultrasound [7].
However, GH administration is contraindicated in
the presence of any cancer to which prostate is not
an exception; as it is suspected to play a causal role
in CaP. It is prudent, therefore, to consider that the
same concerns and contraindications apply to GH as
to androgens in relation to prostate health.
REFERENCES
1. Webb SM, Casanueva F, Wass JA. : Oncological complications
of excess GH in acromegaly. Pituitary. 2002 Jan;5(1):21-5.
2. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM,
Egger M.: Insulin-like growth factor (IGF)-I, IGF binding pro-
tein-3, and cancer risk: systematic review and meta-regression
analysis. Lancet. 2002 Jul 27;360(9329):273-7.
3. Stattin P, Rinaldi S, Biessy C, Stenman UH, Hallmans G, Kaaks
R. High levels of circulating insulin-like growth factor-I increase
prostate cancer risk: a prospective study in a population-based
nonscreened cohort. J Clin Oncol. 2004 Aug 1;22(15):3104-12
4. Colao A, Di Somma C, Spiezia S, Filippella M, Pivonello R,
Lombardi G. Effect of growth hormone (GH) and/or testosterone
replacement on the prostate in GH-deficient adult patients. J Clin
Endocrinol Metab. 2003 Jan;88(1):88-94
5. Chopin LK, Veveris-Lowe TL, Philipps AF, Herington AC. Co-
expression of GH and GHR isoforms in prostate cancer cell lines.
Growth Horm IGF Res. 2002 Apr;12(2):126-36.
6. Weiss-Messer E, Merom O, Adi A, Karry R, Bidosee M, Ber R,
Kaploun A, Stein A, Barkey RJ. Growth hormone (GH) receptors
in prostate cancer: gene expression in human tissues and cell
lines and characterization, GH signalling and androgen receptor
regulation in LNCaP cells. Mol Cell Endocrinol. 2004 May
31;220(1-2):109-23.
7. Leroith D. Clinical guidelines for treatment with growth hor-
mone in the ageing male. 2001;4(Suppl 1): 44-45
V. SELECTIVE ANDROGEN
RECEPTOR MODULATORS (SARMs)
The term selective androgen receptor modulator
(SARM) was introduced by A. Negro-Vilar in 1999
to name synthetic androgen agonists targeting the
androgen receptor with a great degree of tissue selec-
tivity, designed to eliminate undesired side effects
(i.e. prostate stimulation, aggressive behavior…) and
to maintain or enhance the positive, protective
effects (i.e. anabolic) normally regulated by endoge-
nous androgens [17].
The complete action of testosterone on male sex
accessory organs, especially prostate and seminal
vesicles, depends upon its reduction to 5α-dihy-
drotestosterone (DHT) whereas the action on most
other tissues does not. Because DHT is a 6-7 times
334
more potent androgen than testosterone, its action on
proliferation is amplified in tissues where such
reduction occurs. Since DHT mediates several unto-
ward actions, including prostate diseases, the ideal
steroid for therapeutic androgen replacement in the
adult male would be, like SARMs, a potent testos-
terone agonist that does not undergo 5α-reduction to
DHT but can be aromatized to estradiol.
1. STEROIDAL ANDROGEN RECEPTOR MODULA-
TOR : MENT
The synthetic androgen 7α-methyl-19-nortestos-
terone (MENT) is believed to be more biopotent
overall than testosterone both because 19-nor-testos-
terone derivatives in general demonstrate this prop-
erty [12] and also because the 7α-methyl group in
MENT greatly enhances its binding affinity for the
androgen receptor and increases subsequent nuclear
retention [15]. In contrast to testosterone, MENT
shows no binding to sex hormone binding globulin
[13]. In a study on castrated rats, MENT was 4 times
more potent than testosterone in maintaining the
weights of ventral prostate and seminal vesicles but
was 10 times the effect of testosterone on the weights
of bulbocavernous plus levator ani muscles and 12
times that of testosterone in the suppression of
gonadotropin levels [11]. The physiologic half-lives
of MENT and testosterone are similar, suggesting
that the increased biological activity of MENT is not
determined by reduced clearance. The use of a 5α-
reductase inhibitor had no influence on the activity
of MENT, whereas cyproterone acetate, an antian-
drogen that competitively binds to the androgen
receptors, inhibited the action of MENT and testos-
terone on the prostate as well as on the muscle. The
response of seminal vesicles or kidney weights to
either testosterone or MENT replacement may differ
according to different animal strains [18]. Similar
results were obtained in non human primates in
which MENT has 10 times more antigonadotropic
and anabolic potency than testosterone, but is only 2-
3 times more potent at stimulating prostate growth
[5]. In the castrated male monkey, the minimal
testosterone dose required to suppress LH stimulated
prostate growth to twice normal size, whereas the
minimal MENT dose for LH supression maintained
approximately normal prostate size [5]. Moreover,
these effects were associated with unaltered HDL
and increased HDL2 [5]. In hypogonadal men previ-
ously treated with testosterone, prostate volume and
serum PSA were found to fall during MENT admin-
istration on a 24 weeks trial [2]. In the latter study,
according to MENT dosage, lean mass increased
whereas fat mass and serum leptin concentration
were shown to fall.
The effects of MENT on behavior seem not to be
uniform. The sexual behavior in male castrated rats
or mice, as judged on the percent of animals with
mounts and intromissions, is fully restored at a dose
between 1/2 and 1/20 of the effective dose of testos-
terone [16, 18]. In the castrated male hamster,
MENT is approximately 4 to 5 times more potent
than testosterone to sustain mating behavior [25],
equivalent to the relative binding affinities of MENT
and testosterone for the androgen receptor. In con-
trast, testosterone was much more effective than
MENT to restore aggressive behavior in male cas-
trated mice [18]. However, the relative contributions
of androgenic and estrogenic metabolites in male
sexual and aggressive behaviors cannot be general-
ized. In a short term study in hypogonadal men,
MENT was as effective as testosterone in improving
spontaneous nocturnal and waking erections, and
sexual interest [1]. The ability of MENT to provide
adequate support to sexual behavior and erectile
function was confirmed in a 24 weeks replacement
study [2] and in another one for contraceptive pur-
pose [23]. The effects on mood were less consistent
and partly conditioned by cultural differencies [1].
Thus, in a clinical setting, MENT may maintain
important androgenic, anabolic, antigonadotropic
and behavioral functions without hyperstimulation
of the prostate or promotion of aggressiveness. The
dose required for androgen replacement in human is
estimated to be 300-700µg/day, according to the
severity of hypogonadism and the tissue selectivity
[21]. This quantity could be delivered subdermally in
currently available sustained release formulations,
such as subdermal implants of MENT acetate, that
should last for up to 8-12 months [1, 20].
As with others androgen derivatives, it is unclear
how to determine with certainty androgen replace-
ment in the absence of an ability to measure serum
testosterone. Normal hemoglobin concentration and
hematocrit seemed to be sensitive markers of an ade-
quate androgen stimulus in a mid-term study in
hypogonadal men [2]. Part of the effect of testos-
terone on the maintenance of BMD in men is medi-
ated by conversion to estradiol. Although MENT is a
substrate for aromatase [14], it was shown that phys-
iological androgen replacement with MENT did not
provide adequate support to the skeleton with a fall
in BMD at the lumbar spine [2]. The high potency of
MENT as an androgen, by reducing the dosage
335
requirement, might become disadvantageous when
metabolism by aromatase is required. On the other
hand, aromatization end-products of MENT might
be less potent activators of estrogen receptors than
estradiol itself [2]. Obviously, more data are needed
to further evaluate the effects and long-term safety of
MENT.
2. NONSTEROIDAL SELECTIVE ANDROGEN
RECEPTORS MODULATORS
Although MENT is considered one of the first tissue-
selective androgens, some suggest to reserve the
acronyme SARM for androgens with a partial ago-
nist/antagonist profile like the classical selective
estrogen receptor modulator (SERM) raloxifène [6].
The steroidal compound mifepristone (RU34486)
has partial agonist and antagonist actions [3]. Non-
steroidol ligands have a better receptor selectivity
than steroidal ligands and demonstrate tissue-selec-
tive actions with diverse activity profiles that may
serve specific therapeutic needs. Nonsteroidal andro-
gens can neither be potentiated upon 5α-reduction
nor aromatized to estrogenic compounds. The tissue
selectivity of nonsteroidal androgen action may
depend upon ligand-induced AR conformation and
recruitment of a tissue-specific repertoire of coregu-
latory factors that function as coactivators or core-
pressors [4].
The tissue selectivity of nonsteroidal SARMs has
been demonstrated in animal models, with a partial
agonist action in prostate and seminal vesicles and a
full anabolic action in the levator ani muscle [26]. In
intact rats, the tissue selectivity of the SARM desig-
nated S1 decreased prostate weight with efficacy
similar to that of the 5α-reductase inhibitor finas-
teride without affecting the levator ani muscle or
altering the plasma levels of T, LH, or FSH [7].
When administered to orchidectomized rats,
LGD2226 [19] and S-40503 [8] showed an osteoan-
abolic effect with an increase of BMD and biome-
chanical strength of femoral cortical bone but no ele-
vation of prostate weight over the normal. Both
products also exerted anabolic activity on the levator
ani muscle [8, 19].
Thus, the strong agonist activity of tissue-selective
nonsteroidal androgens in DHT-independent tissues
could be used to help to reduce androgen depletion
syndromes and to treat muscle wasting, osteoporosis
and age-related frailty. However, the development of
these compounds is at an early stage, and no infor-
mation is yet available on the effects of these new
androgens in humans.
3. CONCLUSION ON SARMS
In theory, SARMs should be safer than testosterone
with regard to prostate hypertrophy and with regard
to stimulating the growth of incipient prostate can-
cer. But the results of the Prostate Cancer Prevention
Trial [22] raises an important question concerning a
possible useful physiological function mediated by
5α-dihydrosteroids that would not be subserved by
an androgen that resists 5α-reduction. The incidence
of prostate cancer in the finasteride group was
18.4%, as compared with 24.4% in the placebo
group. Moreover, the incidence of tumors with a
Gleason score 7-10 was 37.0% in the finasteride
group vs 22.2% in the placebo group [22]. The sec-
ond estrogen receptor (ER-β) may have a role in this
outcome [9]. ER-β is silenced in human cancers that
are not well differentiated [27] and knock-out mice
for ER-β show failure of the prostatic epithelium to
differentiate fully, whereas the epithelial cells con-
tinue to proliferate [10]. The natural ligand for ER-β
may be a steroid, 5α-androstane-3β,17β−diol (3 β-
androstanediol), a metabolite of DHT [24]. Imamov
et al. [9] suggest that finasteride, by blocking the
conversion of testosterone to DHT, inhibits the pro-
duction of 3 β-androstanediol, thus suppressing ER-
β and preventing the differentiation of epithelium,
accounting for the higher incidence of poorly differ-
entiated tumors in the finasteride group in the
Prostate Cancer Prevention trial. While the tissue
selectivity and prostate-sparing effect of SARMs
have been demonstrated in animal models, clinical
trials with SARMs suppressing endogenous testos-
terone and 5α-reduction to DHT should address this
potential major drawback in the future.
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1. ANDERSON R.A., MARTIN C.W., KUNG A.W., EVERING-
TON D., PUN T.C., TAN K.C., BANCROFT J., SUNDARAM
K., MOO-YOUNG A.J., BAIRD D.T.: 7Alpha-methyl-19-
nortestosterone maintains sexual behavior and mood in hypogo-
nadal men. J Clin Endocrinol Metab, 1999, 84, 3556-3562.
2. ANDERSON R.A., WALLACE A.M., SATTAR N., KUMAR
N., SUNDARAM K.: Evidence for tissue selectivity of the syn-
thetic androgen 7 alpha-methyl-19-nortestosterone in hypogo-
nadal men. J Clin Endocrinol Metab, 2003, 88, 2784-2793.
3. BERREVOETS C.A., UMAR A., BRINKMANN A.O.: Antian-
drogens: selective androgen receptor modulators. Mol Cell
Endocrinol, 2002, 198, 97-103.
4. BROWN T.R.: Nonsteroidal selective androgen receptors modu-
lators (SARMs): designer androgens with flexible structures pro-
vide clinical promise. Endocrinology, 2004, 145, 5417-5419.
5. CUMMINGS D.E., KUMAR N., BARDIN C.W., SUNDARAM
K., BREMNER W.J.: Prostate-sparing effects in primates of the
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potent androgen 7alpha-methyl-19-nortestosterone: a potential
alternative to testosterone for androgen replacement and male
contraception. J Clin Endocrinol Metab, 1998, 83, 4212-4219.
6. ELBERS J.M.H., GROOTENHUIS A.J.: New tissue-selective
androgens: perspectives in the treatment of androgen deficits.
Ann Endocrinol (Paris), 2003, 64, 183-188.
7. GAO W., KEARBEY J.D., NAIR V.A., CHUNG K., PARLOW
A.F., MILLER D.D., DALTON J.T.: Comparison of the pharma-
cological effects of a novel selective androgen receptor modula-
tor, the 5alpha-reductase inhibitor finasteride, and the antiandro-
gen hydroxyflutamide in intact rats: new approach for benign
prostate hyperplasia. Endocrinology, 2004, 145, 5420-5428.
8. HANADA K., FURUYA K., YAMAMOTO N., NEJISHIMA H.,
ICHIKAWA K., NAKAMURA T., MIYAKAWA M., AMANO
S., SUMITA Y., OGURO N.: Bone anabolic effects of S-40503,
a novel nonsteroidal selective androgen receptor modulator
(SARM), in rat models of osteoporosis. Biol Pharm Bull, 2003,
26, 1563-1569.
9. IMAMOV O., LOPATKIN N.A., GUSTAFSSON J.A.: Estrogen
receptor beta in prostate cancer. N Engl J Med, 2004, 351, 2773-
2774.
10. IMAMOV O., MORANI A., SHIM G.J., OMOTO Y., THULIN-
ANDERSSON C., WARNER M., GUSTAFSSON J.A.: Estrogen
receptor beta regulates epithelial cellular differentiation in the
mouse ventral prostate. Proc Natl Acad Sci U S A, 2004, 101,
9375-9380.
11. KUMAR N., DIDOLKAR A.K., MONDER C., BARDIN C.W.,
SUNDARAM K.: The biological activity of 7 alpha-methyl-19-
nortestosterone is not amplified in male reproductive tract as is
that of testosterone. Endocrinology, 1992, 130, 3677-3683.
12. KUMAR N., SUNDARAM K., BARDIN C.W.: Feedback regu-
lation of gonadotropins by androgens in rats: is 5 alpha-reduction
involved? J Steroid Biochem Mol Biol, 1995, 52, 105-112.
13. KUMAR N., SUVISAARI J., TSONG Y.Y., AGUILLAUME C.,
BARDIN C.W., LAHTEENMAKI P., SUNDARAM K.: Phar-
macokinetics of 7 alpha-methyl-19-nortestosterone in men and
cynomolgus monkeys. J Androl, 1997, 18, 352-358.
14. LAMORTE A., KUMAR N., BARDIN C.W., SUNDARAM K.:
Aromatization of 7 alpha-methyl-19-nortestosterone by human
placental microsomes in vitro. J Steroid Biochem Mol Biol,
1994, 48, 297-304.
15. LIAO S., LIANG T., FANG S., CASTANEDA E., SHAO T.C.:
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16. MORALI G., LEMUS A.E., MUNGUIA R., ARTEAGA M.,
PEREZ-PALACIOS G., SUNDARAM K., KUMAR N.,
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7 alpha-methyl-19-nortestosterone, an androgen that does not
undergo 5 alpha-reduction. Biol Reprod, 1993, 49, 577-581.
17. NEGRO-VILAR A.: Selective androgen receptor modulators
(SARMs): a novel approach to androgen therapy for the new mil-
lennium. J Clin Endocrinol Metab, 1999, 84, 3459-3462.
18. OGAWA S., ROBBINS A., KUMAR N., PFAFF D.W., SUN-
DARAM K., BARDIN C.W.: Effects of testosterone and 7 alpha-
methyl-19-nortestosterone (MENT) on sexual and aggressive
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19. ROSEN J., NEGRO-VILAR A.: New, non-steroidal, selective
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20. SUNDARAM K., KUMAR N., BARDIN C.W.: 7 alpha-methyl-
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subdermal implants in healthy men. Contraception, 1999, 60,
299-303.
22. THOMPSON I.M., GOODMAN P.J., TANGEN C.M., LUCIA
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23. VON ECKARDSTEIN S., NOE G., BRACHE V., NIESCHLAG
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2012.
VI. ANTIESTROGENS AND
SELECTIVE ESTROGEN
RECEPTOR MODULATORS (SERMs)
A diagnosis of primary gonadal failure is made when
a decreased serum level of testosterone is associated
with an elevated level of gonadotropin and, on the
other hand, normal or low level of gonadotropin in
the presence of a lowered serum level of testosterone
lead to a diagnosis of secondary or hypogonadotrop-
ic hypogonadism. In the latter group of patients, it is
necessary to exclude patients with hyperprolactine-
mia and patients with a structural lesion of the
hypothalamic-pituitary area.
However, a group of men exists who have a low
level of serum testosterone and normal or low levels
of prolactin and gonadotropin with no demonstrable
anatomic abnormality of the hypothalamus or pitu-
itary gland and no conditions known to cause hypog-
onadotrophic hypogonadism (physical stress, psy-
chotic illness, head injury, acute critical illness, alco-
hol intake, multiple medications…). This phe-
nomenon of testosterone levels that decline without
337
an increase in the gonadotropins has been reported to
be related to age. Secondary hypogonadism refers to
a low free testosterone level that is not compensated
for by an increase in LH secretion.
The normal LH and FSH responses to GnRH suggest
that the cause of reduced basal gonadotropins in the
presence of reduced testosterone is a result of inade-
quate stimulation of pituitary gonadotrophs by prop-
erly timed release of GnRH pulses [4].
1. ANTIESTROGENS : CLOMIPHENE CITRATE
AND TAMOXIFEN
Clomiphene [8] and tamoxifene [7] are believed to
stimulate endogenous production of GnRH by the
hypothalamus by their antiestrogen action, probably
reflecting the primacy of estrogen over testosterone
in the negative feedback regulation of male gonadal
function. In men with erectile complaints and sec-
ondary hypogonadism, administration of clomiphene
resulted in elevation of the levels of LH, FSH, and
free and total testosterone similar to that reported in
patients with intact pituitary and gonadal function [3,
4]. Clomiphene citrate was effective on both clinical
and biological data in hypogonadotrophic hypogo-
nadism induced by exercice in a male endurance ath-
lete [1] and by steroid abuse in a 30-year-old male
[9]. Tamoxifen had the same favourable effect in a
man with hypogonadism caused by sports activity
together with an impaired testicular function (cryp-
torchidy) [7]. The hypothalamus can be challenged
with 50-100mg of clomiphene citrate for 5-7 days [3,
9] and the treatment resumed to 25-50mg 3 times a
week [5].
2. SELECTIVE ESTROGEN RECEPTOR MODULA-
TORS (SERMS)
Recent data suggest that estrogen deficiency may
play an important role in age-related bone loss in
elderly men. Lasofoxifene, a selective estrogen
receptor modulator, has been shown to prevent bone
loss by inhibiting bone turn-over associated with
aging and orchidectomy in adult male rats [6]. Fur-
ther, lasofoxifene did not affect the prostate weight.
Raloxifen, a SERM with an agonist action on bone
without feminization, has been used during 6 months
in 50 aging men, showing an osteoanabolic effect in
patients with a low estradiol [2].
These results suggested that SERMs such as ralox-
ifène or lasofoxifene might be useful agents for the
prevention of osteoporosis in elderly men with some
degree of hypogonadism.
3. CONCLUSION ON SERMS
Endogenous testosterone elevation from antiestro-
gens stimulation in hypogonadotrophic hypogo-
nadism raises PSA levels as exogenous testosterone
does [5]. Determining PSA levels before and during
treatment with an anti-oestrogenic drug is therefore
strongly recommended.
REFERENCES
1. BURGE M.R., LANZI R.A., SKARDA S.T., EATON R.P.: Idio-
pathic hypogonadotropic hypogonadism in a male runner is
reversed by clomiphene citrate. Fertil Steril, 1997, 67, 783-785.
2. DORAN P.M., RIGGS B.L., ATKINSON E.J., KHOSLA S.:
Effects of raloxifene, a selective estrogen receptor modulator, on
bone turnover markers and serum sex steroid and lipid levels in
elderly men. J Bone Miner Res, 2001, 16, 2118-2125.
3. GUAY A.T., BANSAL S., HEATLEY G.J.: Effect of raising
endogenous testosterone levels in impotent men with secondary
hypogonadism: double blind placebo-controlled trial with
clomiphene citrate. J Clin Endocrinol Metab, 1995, 80, 3546-
3552.
VII. INDICATIONS AND CONTRAINDICATIONS FOR
TESTOSTERONE TREATMENT
In clinical practice there are only a few valid and
specific reasons not to consider treatment for men
with documented symptomatic late onset hypogo-
nadism SLOH. In fact, the case for treatment is com-
pelling, although some simply consider androgen
substitution to be a quality of life issue. In a retro-
spective historical review of castrati who lived
between the XVI and XIX Centuries, Nieschlag et al
[1] found that life expectancy among these 50 men
was not different than that of contemporary controls.
However, a recent retrospective study suggests a
contrary view: standardized mortality ratio was sig-
nificantly higher in men with untreated gonadotropin
deficiency as compared to those treated (with sex
steroids) and healthy controls [2] .
This section deals primarily with long-term andro-
gen treatment. As explained later, treatment should
not be instituted until a satisfactory work up has been
completed. It is also understood that this section
focuses on the adult male –the common victim of
both prostate diseases and hypogonadism- eligible
for androgen supplementation in whom androgen
deficiency has been clearly diagnosed.. The physi-
cian should be satisfied that the patient has signs and
338
4. GUAY A.T., BANSAL S., HODGE M.B.: Possible hypothalam-
ic impotence. Male counterpart to hypothalamic amenorrhea?
Urology, 1991, 38, 317-322.
5. GUAY A.T., PEREZ J.B., FITAIHI W.A., VEREB M.: Testos-
terone treatment in hypogonadal men: prostate-specific antigen
level and risk of prostate cancer. Endocr Pract, 2000, 6, 132-138.
6. KE H.Z., QI H., CRAWFORD D.T., CHIDSEY-FRINK K.L.,
SIMMONS H.A., THOMPSON D.D.: Lasofoxifene (CP-
336,156), a selective estrogen receptor modulator, prevents bone
loss induced by aging and orchidectomy in the adult rat.
Endocrinology, 2000, 141, 1338-1344.
7. NAESSENS G., DE SLYPERE J.P., DIJS H., DRIESSENS M.:
Hypogonadism as a cause of recurrent muscle injury in a high
level soccer player. A case report. Int J Sports Med, 1995, 16,
413-417.
8. SANTEN R.J., LEONARD J.M., SHERINS R.J., GANDY
H.M., PAULSEN C.A.: Short- and long-term effects of
clomiphene citrate on the pituitary-testicular axis. J Clin
Endocrinol Metab, 1971, 33, 970-979.
9. TAN R.S., VASUDEVAN D.: Use of clomiphene citrate to
reverse premature andropause secondary to steroid abuse. Fertil
Steril, 2003, 79, 203-205.
symptoms of SLOH and that the clinical picture is
supported by biochemical findings. The decision tree
summarizes in a practical way the views expressed
here. In general terms hormone replacement therapy
aims to substitute the deficient hormone with a per-
fect copy of the natural hormone, with a dose sched-
ule that generates physiological hormone levels over
24 hours of the day. Currently, it is not known
whether the treatment schedule should ideally mimic
the circadian rhythm of production of the deficient
hormones.
1. MANAGEMENT OF MEN WITH BPH AND
SLOH.
As with most clinical situations where evidence-
based guidelines do not exist, knowledge and good
medical judgment play a crucial role. From the con-
siderations on the effect of androgens on BPH, it is
clear that some modest increase in the volume of the
gland is to be expected after T treatment in a hypog-
onadal man. Men with modest residual urine vol-
umes and minimal symptoms of bladder outlet
obstruction due to BPH (I-PSS < 8) can be safely
treated with supplemental androgens. The situation
is less well defined in the moderate category (I-PSS
between 8-15). Obviously, a man with severe symp-
toms and significant residual volumes can be tipped
over into urinary retention by the administration of
T; therefore, ART is contraindicated. But the benefits
of ART should not be denied to a properly selected
candidate because of the presence of mild, stable
lower urinary obstructive symptoms. Treatment
should only be postponed in those with moderate to
severe obstructive symptoms until they have been
successfully treated according to well established
criteria [3].
2. MANAGEMENT OF MEN WITH SLOH AND AT
RISK OF PROSTATE CANCER.
Current standard of practice establishes categorically
that the administration of androgens is absolutely
contraindicated in men suspected of or harboring
prostate (and breast) cancer. This includes those with
an abnormal digital rectal examination (DRE) and/or
abnormal prostate specific antigen (PSA) in whom
the diagnosis of carcinoma has not been excluded
beyond doubt. However, a sub-clinical cancer can
easily escape detection [4]. The presence of prostat-
ic intraepithelial neoplasia (PIN) represents a major
dilemma for the urologist. The experience on this is
minimal and the information available limited to the
extreme. Although Rhoden et al [5] concluded that
ART “is not contraindicated in men with a history of
PIN” their study included only 75 men followed for
12 months. These results must be viewed with cau-
tion until further independent information is avail-
able.
The increasing use of T preparations has made the
issues involving ART and prostate cancer an impor-
tant area of controversy with immediate clinical con-
sequences. At present there are no studies available
to answer the question: does T administration induce
prostate cancer? This, beyond a doubt constitutes the
most important issue regarding safety in men receiv-
ing androgens. The IOM report [6], in its extensive
review of the situation regarding ART recommended
that prostate safety be considered a high priority in
future clinical trials. Unfortunately the IOM also rec-
ommended that small studies be conducted initially
to document the efficacy of T treatment and only
after efficacy has been confirmed, should the matter
of prostate safety -among other safety issues- be
addressed. This puts the clinician in a precarious sit-
uation when dealing with a man with SLOH. Obvi-
ously, it is inappropriate to wait for 15 or more years
339
until those important concerns are eventually settled.
As mentioned above, limited studies have already
clearly demonstrated efficacy of ART in the treat-
ment of most of the manifestations of SLOH (for a
recent and thorough review see reference [7]). In
many of these studies the changes induced in the
prostate gland have been assessed directly (digital
rectal examination, ultrasonography, biopsy) or by
surrogate measures (urine flow, post-micturation
residual volumes, PSA). All of those studies, howev-
er, are relatively small and lack sufficient power and
follow-up for definitive answers. In short, these
results although reassuring are far from definitive.
The increasing prevalence of localized CaP results in
a large number of men undergoing curative proce-
dures. Some of these men will present with SLOH.
This presents a truly challenging situation. Should
they receive androgen supplementation? If so when?
Let us start admitting that today’s physicians have an
ingrained desire for deterrence of T use in men with
a history of prostate cancer. However, if one such
man is considered cured and suffers from SLOH,
should he be denied treatment? The facts are
1) most men undergoing curative surgery for CaP do
not undergo simultaneous castration,
2) most men undergoing radical surgery have normal
serum T levels,
3) although not fully recognized, serum T levels
increase after radical prostatectomy and
4) early evidence is being presented indicating that
no detrimental effects have occurred in patients
receiving T after radical prostatectomy.
With these facts and a commitment for close follow-
up, the prudent treatment of SLOH with testosterone
supplementation appears warranted. Once again,
definitive evidence is simply not available.
RECOMMENDATIONS
(insofar as indications for androgen
substitution)
The following recommendations are adapted from
the Consensus Conference held in Paris in 2003 [8] .
They reflect the current state of knowledge but must
be seen as “work in progress”. As new and better
documented information becomes available the rec-
ommendations must be adapted to fresh realities.
They are provided only as a general guide with glob-
al applicability.
1. MONITORING – PROSTATE
In men over the age of 40 years, digital rectal exam-
ination (DRE) and determination of serum prostatic
specific antigen (PSA) are mandatory as baseline
measurements of prostate health prior to therapy
with androgens, every three (3) to six (6) months for
the first 12 months, and yearly thereafter. Transrectal
ultrasound guided biopsies of the prostate are indi-
cated only if the DRE or the PSA are abnormal.
2. PROSTATE AND BREAST SAFETY – I
Androgen administration is absolutely contraindicat-
ed in men suspected of harboring carcinoma of the
prostate or breast.
3. PROSTATE SAFETY – II
Men successfully treated for prostate cancer and suf-
fering from symptomatic hypogonadism may
become candidates for androgen therapy, after a pru-
dent interval, if there is no evidence of residual can-
cer. The risk and benefits must be clearly understood
by the patient and the follow-up must be particularly
careful. No reliable evidence exists in favor or
against this recommendation. The clinician must
exercise good clinical judgment together with ade-
quate knowledge of the advantages and drawbacks of
androgen therapy in this situation.
4. PROSTATE SAFETY – III
Androgen supplementation is contraindicated in men
with severe bladder outlet obstruction due to an
enlarged, clinically benign prostate. Moderate
obstruction represents a partial contraindication to
ART. After successful treatment of the obstruction,
the contraindication can be lifted.
340
REFERENCES
1. Nieschlag E, Behre HM: Clinical uses of testosterone in hypog-
onadism and other conditions. In: . Nieschlag E, Behre HM
(eds): Testosterone –Action.Deficiency.Substitution. Cambridge,
Cambridge University Press, 2004, pp 375-404
2. Tomlison JW, Holden N, Hills RK, Wheatley K, Clayton RN,
Bates AS, Shepperd MC, Stewart PM: Association between mor-
tality and hypopituitarism. Lancet 2001;357:425-431.
3. AUA Practice Guidelines Committee. AUA Guideline on Man-
agement of Benign Prostatic Hyperplasia (2003). Chapter 1.
Diagnosis and Treatment Recommendations. J Urol 2003;
170:530-547.
4. Curran MJ, Bihrle W III. Dramatic rise in PSA after androgen
replacement in a hypogonadal man with occult adenocarcinoma
of the prostate. Urology 1999; 53:423-424.
5. Rhoden EL, Morgentaler A. Testosterone replacement therapy in
hypogonadal men at risk for prostate cancer: Results of 1 year of
treatment in men with prostatic intraepithelial neoplasia. J Urol
2003; 170:2348-2351.
6. Testosterone: Action- Deficiency- Substitution. Nieschlag E,
Behre HM eds. Cambridge University Press. Cambridge, UK,
2004.
7. Zhang PL, Rosen S, Veeramachaneni R, Kao J, de Wolf WC,
Bubley G. Association between prostate cancer and serum testos-
terone levels. Prostate 2002; 53:179-82.
8. Morales A. Buvat J, Gooren LJ, Guay AT, Kaufman JM, Tan HM,
Torres LO. Endocrine aspects of sexual dysfunction. J Sex Med
1:69- 81, 2004.
 2006 6th International Consultation
on New Developments in Prostate
Co-Sponsored by
International Union Against Cancer and Prostate Diseases
Cancer (U.I.C.C)
International Consultation
on Urological Diseases
Recommendations of the International
(I.C.U.D.)
International Society of
Scientific Committee:
Urology (S.I.U)
* Evaluation and Treatment of
In collaboration with
American Urological
Lower Urinary Tract Symptoms (LUTS)
Association (AUA) in Older Men
Confederacion Americana
de Urologia (CAU)
European Association ◆◆◆
of Urology (EAU)
Urological Association
of Asia (UAA) J. McConnell, P. Abrams, S. Khoury, C. Roehrborn
and
H. Akaza, K.E. Andersson, M. Barry, L. Denis, C. Chapple, P. Gan,
The Major Associations
of Urology M. Murai, M. Resnick, J. de la Rosette, T. Schaeffer, J. Schalken
and the Members of the Committees.

INTRODUCTION
The 6th International Consultation on New Developments in Prostate Cancer
and Prostate Diseases met from June 24-28, 2005, in Paris, France, under the
co-sponsorship of the Union Internationale Contre le Cancer (UICC), to review
new developments in prostate cancer, lower urinary tract symptoms (LUTS),
benign prostatic disease, prostatitis and chronic pelvic pain syndrome (CPPS)
and other related fields.
The recommendations are based on a thorough review of the available literature,
and the global subjective opinion of recognized experts serving on focused com-
mittees. The individual committee reports were developed and peer-reviewed by
open presentation and comment. Final recommendations were then refined by the
Scientific Committee, consisting of the Chairmen of all the committees. The rec-
ommendations are graded whenever possible according to the International Con-
sultation level of evidence and grading system adapted from the Oxford system.
The recommendations apply only to the standard patient defined below. Patients
falling outside the definition of a standard patient may require diagnostic evalua-
tion and treatment beyond the scope of these recommendations.
These recommendations agreed upon in 2005 will be periodically re-evaluated in
the light of clinical experience and technological progress.

387
 1. Terminology and Definitions
Lower urinary tract symptoms (LUTS) include sto-
rage and/or voiding disturbances which are very
common in aging men.
LUTS may be due to structural or functional abnor-
malities in one or more parts of the Lower Urinary
Tract (LUT) which comprises of bladder, bladder
neck, prostate, distal sphincter mechanism and ure-
thra. It must also be remembered that LUTS may
result from abnormalities of either or both the per-
ipheral and central nervous systems which provide
neural control to the LUT. LUTS may also be secon-
dary to cardiovascular, respiratory or renal dysfunc-
tion or disease.
This Consultation endorses the previously recom-
mended nomenclature from the 5th International
Prostate Consultation (2000) and detailed in the
International Continence Society’s Terminology
Report published in 2002.
• LUTS is divided into
- Storage Symptoms which are experienced
during the storage phase of the bladder and
include daytime frequency and nocturia.
- Voiding Symptoms which are experienced
during the voiding phase
• Overactive Bladder Syndrome (OAB) is defined
as urgency with or without urge incontinence,
usually with frequency and nocturia.
• Detrusor overactivity (DO) is a urodynamic
observation characterized by involuntary detru-
sor contractions during the filling phase which
may be spontaneous or provoked.
• Benign Prostatic Hyperplasia (BPH) is reserved
for the histologic pattern the phrase describes.
• Benign Prostatic Enlargement (BPE) is used
when there is gland enlargement. It is usually a
presumptive diagnosis based on the size of the
prostate.
• Benign Prostatic Obstruction (BPO) is used
when obstruction has been proven by pressure-
flow studies or is highly suspected from flow
rates, and if the gland is enlarged.
388
• Bladder Outlet Obstruction (BOO) is the gene-
ric term for all forms of obstruction to the bladder
outlet (eg urethral stricture), including BPO.
Therefore, terms such as “BPH patient”, “sympto-
matic BPH”, “clinical BPH”, “drugs for BPH” and
“BPH treatment” are imprecise, cause confusion and
are not recommended.
The Physicians Desk Reference (PDR) lists as indi-
cation for alfuzosin and tamsulosin the “treatment of
the signs and symptoms of benign prostatic hyper-
plasia (BPH)”, and for finasteride and dutasteride
the “treatment of symptomatic benign prostatic
hyperplasia (BPH) in men with an enlarged prosta-
te”. It is clear from the above discussion that these
definitions are less than ideal. “Alpha blockers are
effective in treating LUTS, while 5-α reductase inhi-
bitors are effective in treating LUTS in men with
Benign prostate enlargement (BPE)” would be a
more appropriate listing of indications.
The standard (usual) patient is a man over the age
of 50 years consulting a qualified health care provi-
der for lower urinary tract symptoms (LUTS). These
symptoms may or may not be associated with an
enlarged prostate gland, bladder outlet obstruction
(BOO), or histologic benign prostatic hyperplasia
(BPH).
A qualified health care provider is a person (physi-
cian, physician assistant, nurse practitioner or other
mid-level provider) knowledgeable in diseases affec-
ting the urinary tract, in particular the prostate gland,
who has the expertise to perform the tests required as
an initial evaluation, and who has been trained and
has demonstrated competence in performing digital
rectal examination (DRE).
LUTS consensus recommendations do not apply
when other pathologies are known to be responsible
for the patient’s LUTS, such as prostate cancer or
other genitourinary tract malignancies, or due to
significant comorbidities (eg severe diabetes melli-
tus) or significant concomitant medications, prior
pelvic surgery or trauma. As well as being respon-
sible for the symptoms, these diseases/conditions
affect the proposed treatment in a manner not consis-
tent with the consensus recommendations.
 2. Diagnostic work-up of men presenting
with lower urinary tract symptoms (LUTS)
The following categorization was utilized to clas-
sify diagnostic tests and studies:
• A recommended test is a test that should be
done on every patient during the initial evalua-
tion.
• An optional test is a test of proven value in the
evaluation of selected patients. In general,
optional tests are done during a specialized eva-
luation usually performed by a urologist.
A. BASIC EVALUATION
RECOMMENDED TESTS
The basic evaluation should be done on every
patient presenting to a health care provider with
lower urinary tract symptoms (LUTS).
1. History
A relevant medical history should be obtained
focusing on the:
• nature and duration of reported genitourinary
tract symptoms,
• previous surgical procedures (in particular, as
they affect the genitourinary tract),
• general health issues, sexual function history,
• medications currently taken by the patient, and
• the patient’s fitness for possible surgical proce-
dures or other treatments.
2. Assessment of Symptoms and Bother
At least a semi-quantitative assessment of symp-
toms and bother is strongly recommended to
grade the severity of lower urinary tract symptoms
and to understand the patient’s degree of bother
caused by those symptoms.
Excellent quantitative assessment tools have been
developed and validated such as the International-
Prostate Symptom Score (IPSS) with Bother
Score (BS) (see page 14). Other questionnaires
include the DANPSS, the ICIQMLUTS and the
“BPH” Impact Index
3. Physical and Digital Rectal
Examination
• A focused physical examination should be per-
formed to assess:
- the suprapubic area to rule out bladder disten-
sion,
389
- overall motor and sensory function focused on
the perineum and lower limbs.
• A digital rectal examination (DRE) should be
performed to evaluate the anal sphincter tone
and prostate gland with regard to approximate
size, consistency, shape, and abnormalities sug-
gestive of prostate cancer.
4. Urinalysis
The urine should be analyzed using any of the wide-
ly available dipstick tests. These tests are done to
determine if the patient has hematuria, proteinuria,
pyuria, or other pathological findings (e.g., gluco-
suria, ketonuria, positive nitrite test etc).
Examination of the urinary sediment and culture is
indicated if the result of the dipstick is abnormal.
The results of urinalysis may guide further and
additional testing independent of the evaluation
for LUTS.
5. Serum Prostate-Specific Antigen (PSA)
The benefits and risks of PSA should be discussed
with the patient, including the possibility of false-
positive and false-negative results, the possible
complications of subsequent transrectal ultra-
sound guided-biopsy, and the possibility of a false-
negative biopsy. Given the uncertainties surroun-
ding prostate cancer detection, physicians must
use clinical judgment in determining which
patients should or should not undergo transrectal
ultrasonography and prostate biopsy in response to
a particular value of PSA.
Serum PSA is a reasonable predictor of prostate
volume in men with LUTS, and can be used in this
capacity in clinical decision making.
6. Frequency - Volume Chart
(Voiding Diary or Time and Amount
Voiding Charts)
Frequency-Volume Charts are particularly useful
when nocturia is the dominant symptom. The
time and voided volume is recorded for each mic-
turition over several 24-hour periods (usually 3)
and will help to identify patients with nocturnal
polyuria or excessive fluid intake, which are com-
mon in the aging male (a model of a chart is
reproduced on page 15).
 B. SPECIALIZED
EVALUATION
I. RECOMMENDED TESTS
1. Detailed Quantification of Symptoms
by Standardized Questionnaires
When patients present with LUTS, the use of a
short, self-administered questionnaire, in the
appropriate language, for the objective documen-
tation of symptom frequency from the patient’s
perspective is highly recommended.
Three short, patient-completed questionnaires are
recommended, the IPSS, and the ICIQMLUTS,
both of which include a single quality of life ques-
tion, and the DAN-PSS-1
a) The IPSS (Page 14) is used to assess the fre-
quency of three storage symptoms (frequency,
nocturia, urgency) and four voiding symptoms
(feeling of incomplete emptying, intermittency,
straining, weak stream).
The Bother Score assesses the degree of bother
associated with the seven questions queried in the
IPSS symptom severity score cited above.
The “BPH” Impact Index can be used with the
IPSS and has four questions asking how the symp-
toms affect the patient’s everyday life and interfe-
re with daily activities, thus capturing the impact
of the condition. This gives useful additional
information to the single QoL question “If you
were to spend the rest of your life with your urina-
ry condition just the way it is now, how would you
feel about that?”
b) The ICI-QMLUTS assesses the frequency and
bother of eight storage symptoms (frequency, noc-
turia, urgency, plus five questions on types of
incontinence: urgency, stress, unconscious enure-
sis and post-micturition dribble) and five voiding
symptoms (feeling of incomplete emptying, inter-
mittency, straining, weak stream, hesitancy).
Bother is evaluated using a 0 to 10 linear analog
scale. Additional ICIQ modules on QoL (ICIQM-
LUTSqol) and sexual function (ICIQMsex) can be
used with the ICIQMLUTS.
The advantage of ICIQMLUTS is that it reco-
gnizes and assesses symptoms due to causes other
than BPO in the pathogenesis of LUTS, such as
OAB.
390
2. Flow Rate Recording
Urinary flow rate measurement is useful in the ini-
tial diagnostic assessment and during or after
treatment, to determine response. Because of the
non-invasive nature of the test and its clinical
value, it is recommended as part of the specialized
evaluation, to be performed prior to embarking
on any active therapy.
Maximum urinary flow rate (Qmax) is the best
single measure, but a low Qmax does not distin-
guish between obstruction and decreased detrusor
contractility.
Because of the intra-individual variability and the
volume dependency of the Qmax, at least two flow
rates ideally, both with a volume > 150 ml of
voided urine, should be obtained. If such a voided
volume cannot be obtained by the patient, despite
repeated recordings, the Qmax results at the avai-
lable voided volumes should be considered.
3. Residual Urine
The determination of post-void residual (PVR)
urine is useful in the initial diagnostic assessment
of the patient and during subsequent monitoring
as a safety parameter.
The determination is best performed by non-inva-
sive transabdominal ultrasonography.
Because of the marked intra-individual variabili-
ty of residual urine volume, the test should be
repeated to improve precision, particularly if the
first residual urine volume is significant and sug-
gests a change in the treatment plan.
4. Pressure Flow Studies (PFS)
Recommended prior to invasive therapies in men
with a Qmax of greater than 10ml/sec. If Qmax is
< 10ml/sec obstruction is very likely and PFS are
not necessarily needed.
PFS are of proven value in the evaluation of
patients prior to invasive therapies, or when a pre-
cise diagnosis of BOO is important.
Pressure-flow urodynamic studies are the only
method with the potential to distinguish men with
a low urinary flow rate due to detrusor under- acti-
vity from those with bladder outlet obstruction.
This is done by relating the detrusor pressure at the
time of the maximum urinary flow rate to the maxi-
mum flow rate.
If patients are found not to have BOO, yet suffer
from severe LUTS, they are less likely to benefit
from invasive treatments, such as surgery, designed
 to relieve outlet obstruction. Consequently, it is
recommended that these patients have their symp-
toms treated in an appropriate fashion. Such treat-
ment can consist of therapy aimed at other under-
lying disease processes, including anticholinergics,
bladder behavioral training, biofeedback, etc.
The most important parameter of the pressure-
flow study is the detrusor pressure (pdet) at the
time of the maximum urinary flow rate (Qmax).
II. OPTIONAL TESTING
1. Imaging of the Prostate
by Transabdominal or Transrectal
Ultrasound (TRUS)
When residual urine is determined by transabdo-
minal ultrasonography with a machine generating
real-time B-mode images, prostate shape, size,
configuration, and protrusion into the bladder
may be simultaneously evaluated.
Outside this context, imaging of the prostate by
transabdominal or transrectal ultrasound (TRUS)
is optional in selected patients. The success of
certain treatments may depend on anatomical
characteristics of the prostate gland (e.g., hormo-
nal therapy, thermotherapy, stents, TUIP). When
such treatments are planned, transabdominal or
transrectal ultrasonography may be used to assess
prostatic size and shape.
In men with serum PSA levels elevated above the
locally accepted reference range, transrectal ultra-
DIAGNOSTIC TESTS
A. BASIC EVALUATION
RECOMMENDED TESTS
1. History
2. Assessment of Symptoms and Bother
3. Physical and Digital Rectal Examination
4. Urinalysis
5. Consideration of Serum Prostate-Specific
Antigen (PSA)
6. Frequency - Volume Chart (Voiding Diary)
391
sonography (TRUS) is the method of choice to
evaluate the prostate, and to guide a needle biop-
sy of suspicious areas, or to perform biopsies in an
attempt to rule out prostate cancer.
2. Imaging of the Upper Urinary Tract
by Ultrasonography or Intravenous
Urography (IVU)
Although imaging of the upper urinary tract is not
recommended as a routine procedure, imaging is
indicated in patients presenting with one or more
of the following signs or symptoms:
• history of or current upper urinary tract infec-
tion,
• hematuria (microscopic or macroscopic),
• history of urolithiasis,
• renal insufficiency (in this case, ultrasonogra-
phy is the preferred imaging study)
• recent onset nocturnal enuresis
3. Endoscopy of the Lower Urinary Tract
Endoscopic evaluation of the lower urinary tract is
not recommended in an otherwise healthy patient
with an initial evaluation consistent with BOO
although it has certain indications, as described
above for imaging.
There are treatment alternatives in which success
or failure depend on the anatomical configuration
of the prostate (e.g., TUIP, thermotherapy, etc.).
Endoscopy is recommended if considered helpful
when such treatment alternatives are contemplated.
B. SPECIALIZED EVALUATION
I. RECOMMENDED TESTS
1. Detailed Quantification of Symptoms by Stan-
dardized Questionnaires
2. Flow Rate Recording
3. Residual Urine
4. Pressure Flow Studies (PFS)
II. OPTIONAL TESTING
1. Imaging of the Prostate by Transabdominal
or Transrectal Ultrasound (TRUS)
2. Imaging of the Upper Urinary Tract by Ultra-
sonography or Intravenous Urography (IVU)
3. Endoscopy of the Lower Urinary Tract
 3. Treatment Recommendations
I. BASIC MANAGEMENT
Initial evaluation demonstrates the
A. presence of LUTS associated with one
or more of the following findings:
• DRE suspicious of prostate cancer
• Hematuria
• Abnormal PSA
• Pain
• Recurrent infection (infection should be assessed
and treatment started by the practitioner before
referral)
• Palpable bladder
• Neurological disease
These patients need to be referred to a specialist (urol-
ogist) for appropriate evaluation before advising treat-
ment.
Initial evaluation demonstrates the
presence of LUTS only, with or
B. without some degree of non-suspi-
cious prostate enlargement:
1. If the symptoms are not significantly botherso-
me to the patient, or if the patient does not want
treatment:
No further evaluation is recommended and the patient
is reassured and can be seen again if necessary. This
recommendation is based on the opinion that this cate-
gory of patients with non-bothersome LUTS is unlike-
ly to develop significant health problems in the future
due to their condition.
2. In patients with bothersome symptoms:
It is now recognized that LUTS has a number of differ-
ent causes which may occur singly or in combination:
Benign Prostatic Obstruction (BPO), Overactive Blad-
der (OAB), and Nocturnal Polyuria are amongst the
most important.
The physician can discuss treatment options with the
patient based on the results of initial evaluation with
no further tests being needed.
In primary care there should be a discussion of the ben-
efits and risks involved with each of the recommended
treatment alternatives (watchful waiting, medical treat-
ment, interventional therapy, surgical or non-surgical).
The choice of treatment is reached by a shared deci-
sion-making process between physician and patient.
a) If patient has predominant significant nocturia:
• If the patient gets out of bed to void 2 or more times
per night then he should be asked to complete a fre-
quency-volume chart (FVC) for 3 days.
392
The FVC chart will show polyuria when present. This
may be either 24-hour polyuria or nocturnal polyuria.
24-hour polyuria has been defined as about ≥ 3 liters
output. In practice, patients with symptoms are advised
to aim for a urine output of 1liter/24 hour.
Nocturnal polyuria is diagnosed when more than 33%
of the 24-hour urine output occurs at night. The patient
should be managed according to the nocturia algo-
rithm (see page 7). If his symptoms do not improve
sufficiently, he should be treated along the same lines
as men without predominant nocturia.
b) If the patient has no polyuria
If medical treatment is considered,
the physician can proceed with therapy based mainly
on:
1. ALTERING MODIFIABLE FACTORS SUCH AS:
• Concomitant drugs
• Regulation of fluid intake especially in the evening
• Lifestyle changes (avoid sedentary life) and
• Dietary advice (avoid dietary indiscretion, such as
excessive intake of alcohol and highly seasoned or
irritative foods).
2. PHARMACOLOGICAL TREATMENTS
(SEE PAGES 10-12)
The patient should be followed to assess treatment suc-
cess or failure and possible adverse events. The time
interval after initiation of therapy for the assessment of
treatment success varies according to the pharmacolog-
ical treatment prescribed. It is usually 2-4 weeks for
α-blocker therapy and 3 months for 5α reductase
inhibitor.
• If treatment is successful and the patient is satis-
fied, follow-up should be repeated approximately once
a year by repeating the initial evaluation as outlined
previously. The follow-up strategy will allow the physi-
cian to detect any changes that have occurred over the
past year, more specifically, if symptoms have pro-
gressed or become more bothersome, or if a complica-
tion has developed creating an imperative indication for
surgery.
• If treatment fails and the patient is not satisfied, the
patient should be referred to a urologist for further eval-
uation and possibly interventional treatment.
If interventional therapy is chosen,
the patient should be referred to the specialist.
 Basic Management of LUTS in Men
Recommended Tests:
- RELEVANT MEDICAL HISTORY Complicated
LUTS - ASSESSMENT OF LUTS LUTS:
CAUSE LITTLE OR SYMPTOM SEVERITY AND - SUSPICIOUS DRE
NO BOTHER BOTHER - HEMATURIA
- PHYSICAL EXAMINATION - ABNORMAL PSA
INCLUDING DRE - PAIN
- URINALYSIS 3
- INFECTION
REASSURANCE - SERUM PSA 1 - PALPABLE BLADDER
AND FOLLOW-UP - FREQUENCY - VOLUME CHART2 - NEUROLOGICAL
DISEASE

PREDOMINANT
SIGNIFICANT NOCTURIA
↓
BOTHERSOME LUTS
FREQUENCY-VOLUME CHART

Polyuria NO POLYURIA

Polyuria
1 24-hour output ≥ 3 liters
Standard Treatment
Lifestyle and fluid intake
is to be reduced4 - ALTER MODIFIABLE FACTORS
• DRUGS
• FLUIDE & FOOD INTAKE
Nocturnal polyuria
2 ≥ 33% output at night - LIFESTYLE ADVICE
- BLADDER TRAINING
Fluid intake to be
reduced Consider
desmopressin Drug Treatment5

1 When life expectancy is > 10 years and if the

diagnosis of prostate cancer can modify the FAILURE SUCCESS IN
management. RELIEVING
2 When significant nocturia is a predominant BOTHERSOME
symptom. LUTS:
3 Assess and start treatment before referral.
4 In practice, advise patients with symptoms to
aim for a urine output of about 1liter/24 hours CONTINUE
5 See pages 10-12. TREATMENT

SPECIALIZED MANAGEMENT

393

II. SPECIALIZED
MANAGEMENT
For Persistent Bothersome LUTS after
Basic Management
The specialist will use additional testing beyond
those recommended for basic evaluation:
• Frequency -Volume Chart
• Detailed LUTS questionnaire
• Urine flow studies
• Ultrasound estimate of residual urine
If storage symptoms predominate
A. (OAB) and no indication of BOO
Overactive Bladder (OAB) due to idiopathic
detrusor overactivity is the most likely cause if
there is no indication of Bladder Outlet Obstruc-
tion (BOO) from flow study and ultrasound esti-
mates of PVR. The treatment options of lifestyle
intervention, behavioral modification (bladder
training and pelvic floor muscle exercises) and
pharmacotherapy (antimuscarinic drugs) should
be discussed with the patient.
The best results are obtained by combined therapy
using all three modalities. Should improvement
be insufficient and symptoms severe, then newer
modalities of treatment such as botulinum toxin
and sacral neuromodulation can be considered.
If there is evidence of Bladder Outlet
B. Obstruction (BOO)
The treatment options should be discussed in the
categories of drug therapy or interventional proce-
dures.
1. IF DRUG THERAPY IS CONSIDERED:
Drug therapy decisions will be influenced by two
factors: coexisting overactive bladder (OAB)
symptoms and the size of the prostate or serum
PSA level.
a) Coexisting BOO+OAB symptoms
This condition has been treated with alpha blocker
and antimuscarinic combination therapy with
increasing evidence of safety and efficacy.
394
b) BOO symptoms predominant
α1-adrenergic blocking agents are the treatment of
choice for LUTS due to BOO. However, combina-
tion therapy with a 5α−reductase inhibitor has
shown the highest efficacy when the prostate is
enlarged and/or if the serum PSA is > 1.5 ng/ml.
The patient should be followed to assess treatment
success or failure and possible adverse events. The
time interval after initiation of therapy for the
assessment of treatment success varies according
to the pharmacological treatment prescribed. It is
usually 2-4 weeks for α-blocker therapy and at
least three months for 5 α- reductase inhibitors.
• If treatment is successful and the patient is sat-
isfied, the follow-up should be repeated approx-
imately once a year by repeating initial evalua-
tion as outlined previously. The follow-up strat-
egy will allow the physician to detect any
changes that have occurred over the past year,
more specifically, if symptoms have progressed
or become more bothersome, or if a complica-
tion has developed creating an imperative indi-
cation for surgery.
• If treatment fails and the patient is not satisfied,
reassess and consider other therapies.
2. IF INTERVENTIONAL THERAPY IS CONSIDERED
• If the patient elects to have interventional ther-
apy, and there is sufficient evidence of obstruc-
tion, e.g., Qmax < 10ml/s, patient and physician
should discuss the benefits and risks of the var-
ious interventions. TURP is still the “gold stan-
dard” for interventional treatment, but when
available, new interventional therapies could be
discussed. The techniques accepted for clinical
use are summarized in Table 1 (page 12).
• If the patient’s condition is not sufficiently sug-
gestive of obstruction, e.g. Qmax > 10 ml/s,
pressure-flow studies are indicated, as treat-
ment failure rates are somewhat higher in the
absence of obstruction. If interventional therapy
is planned without clear evidence of the pres-
ence of obstruction, the patient needs to be
informed of possible higher failure rates of the
procedure.
 Specialized Management for Persistent Bothersome LUTS
after Basic Management
Recommended Tests:
OAB - VALIDATED QUESTIONNAIRES
(STORAGE SYMPTOMS) - FVC (FREQUENCE-VOLUME CHART)
NO EVIDENCE OF BOO - FLOWRATE RECORDING
- RESIDUAL URINE

Evidence of BOO
- LIFESTYLE MIST
INTERVENTION DISCUSS RX OPTIONS
OR
- BEHAVIORAL SHARED DECISION
SURGERY OPTION
THERAPY
- ANTIMUSCARINICS
MEDICAL THERAPY
OPTION

FAILURE MIXED OAB

PREDOMINANT BOO
AND BOO

LARGER GLAND
REASSESS AND ANTIMUSCARINICS SMALL GLAND/
AND/OR HIGHER PSA 2
CONSIDER INVASIVE & AND/OR LOW PSA1
α-BLOCKERS +
THERAPY OF OAB α-BLOCKERS α-BLOCKERS
α-REDUCTASE INHIBITORS
5α
(BOTULINUM TOXIN
AND
NEUROMODULATION) FAILURE

OFFER MIST OR SURGERY TO PATIENT

Evaluation clearly suggestive of YES

OAB: Overactive Bladder
Obstruction ? (Qmax < 10ml/s)
BOO: Bladder Outlet Obstruction
MIST: Minimally Invasive NO
Surgical Treatment

1 PSA < 1.5 ng

Pressure-Flow Studies
2 PSA > 1.5 ng

NO Obstruction ?

YES
Treat appropriately. If inter-
ventional therapy is pursued,
patients need to be informed
of possibly higher failure rates
Proceed with
selected technique

395
 III. CRITERIA FOR ACCEP-
TABLE TREATMENT OPTIONS
For a treatment to be considered as an acceptable
option, it must meet the following criteria:
1. Effectiveness and safety of the treatment must
have been shown in trials according to the gui-
delines established by the International
Consultation on Prostate Diseases.
2. Any treatment of this disease should either
improve symptoms and/or prevent long-term
complications of the disease by either shrin-
king the enlarged prostate and/or reducing obs-
truction or by other modes of action.
3. The risk of morbidity and mortality associated
with treatment must be considered in the
context of the treatment:
New interventional treatments should be com-
pared to sham, similar treatments of proven
efficacy, or TURP.
Pharmacological treatments should be compa-
red to placebo, have minimal morbidity, be
acceptable to the patient, should not interfere
with the patient’s sense of well-being or his
quality of life and must not be unacceptably
hazardous to his health.
4. After a new treatment is considered as an
acceptable treatment option, long- term studies
should be conducted to demonstrate durability
and:
• Continued effectiveness and safety.
• Continued effectiveness relative to existing
treatment options.
• Cost-effectiveness related to existing and
emerging therapeutic options.
The results of such long-term studies could lead
to a treatment being firmly established in routine
practice, or to it being rejected as an unacceptable
option.
396
IV. ACCEPTABLE TREATMENT
OPTIONS
The patient must be informed of all available and
acceptable treatment options applicable to his cli-
nical condition and the related benefits, risks, and
costs of each modality.
LUTS associated with benign prostatic obstruction
can significantly affect the quality of life in aging
men, but are rarely life-threatening. Moreover, a
significant number of men with histologic BPH or
even gland enlargement (BPE) do not have disease
progression. Consequently, it is reasonable to dis-
cuss the benefits, risks, and costs of the available
treatment strategies with the patient and have the
patient actively participate in the choice of thera-
py (shared decision making). Some patients with
very bothersome symptoms might opt for surgery,
while other patients might opt for watchful waiting
or medical therapy, depending on their individual
views of benefits, risks, and costs.
A. WATCHFUL WAITING
Progression of LUTS, BPE and/or BPO in terms
of symptoms, future prostate growth, and long-
term complications has been shown to be more
likely in men with larger glands and higher
serum PSA levels (i.e, >1.5 ng/ml or greater).
Many men with smaller glands and/or lower
serum PSA may have minimal progression of their
symptoms over time. Moreover, the level of symp-
toms individual men may tolerate before being
bothered by them is highly variable.
For these reasons, watchful waiting is an accepted
management option for patients with mild, mode-
rate or even severe symptoms, as long as they are
not bothered by them and have not developed one
of the imperative indications for surgery (mainly
today upper tract dilatation and/or elevated creati-
nine).
If, after being adequately informed of the various
treatment options and their consequences, the
patient chooses watchful waiting as the preferred
form of management, he should be followed
approximately yearly by repeating the initial eva-
luation as outlined previously. This follow-up
strategy will allow the physician to detect any
changes that have occurred over the past year, spe-
cifically if symptoms have progressed or become
more bothersome, or if a complication has develo-
ped, creating an imperative indication for surgery.

B. MEDICAL THERAPY
Patients initiated on medical therapy should be
followed at appropriate intervals by repeating the
initial evaluation, assessing treatment success or
failure, and possible adverse events, and determi-
ning whether an alteration in treatment plan is
indicated. Once patients are stable on treatment,
follow-up intervals should be at least yearly.
Before deciding on a specific medical therapy, the
physician should discuss the benefits and risks of
the available drugs with the patient.
1. α-Adrenergic Receptor Antagonists
α-Blockade)
(α
• α1-AR antagonists are effective, improve qua-
lity of life, and have acceptable safety, as
documented in properly conducted randomi-
zed clinical trials.
• α1-AR antagonists are an acceptable treat-
ment option for “LUTS” patients with bother-
some symptoms, thought to be due to BPO,
who have not developed serious complica-
tions.
• The long-term efficacy and safety of treat-
ment with α1-AR antagonists have been docu-
mented in open-label extension investigations,
but continued study for example of cost-effec-
tiveness, is recommended.
• Clinical efficacy on symptoms and safety of
α1-AR antagonists cannot be reliably predic-
ted from preclinical data. However, effects on
flow may be predicted.
• The most advantageous subtype selectivity
profile for an α1-AR antagonist has not been
established.
• Clinical uroselectivity, as defined by the Inter-
national Consultation on “BPH”, (“desired
effect on obstruction and lower urinary tract
symptoms related to adverse effects”), is still a
valid concept.
• All clinically available α1-AR antagonists can
be associated with dizziness, asthenia, and
orthostatic hypotension, and have the potential
to lower blood pressure. The frequency of side
effects of α1-AR antagonists may vary bet-
ween individual agents and the choice of a par-
ticular α-blocker might be influenced by the
cardiovascular and sexual status of the patient.
Dizziness and asthenia may be mediated by
the CNS.
• Adequate head-to-head comparisons between
397
different α1-AR antagonists are still scarce,
making fair comparisons between different
agents difficult. More such studies are needed.
• The clinical action of α1-AR antagonist is
rapid. The treatment’s success is usually
assessed after 2-4 weeks of treatment.
• α1-AR antagonists are first-line medical treat-
ment for “BPO”.
• In patients with “BPO” and hypertension, α1-
AR antagonists remain a first-line treatment
for “BPO”. Associated hypertension and car-
diovascular diseases should be treated inde-
pendently according to established guidelines.
2. 5 α-Reductase Inhibitor ( 5 α−RIs) Therapy
• Of the available forms of hormonal therapy
(androgen ablation, antiandrogens, and 5α-
reductase inhibitors), only the 5 α-reductase
inhibitors have demonstrated both efficacy and
acceptable safety in properly conducted, ran-
domized clinical trials. 5 α−RIs are less effec-
tive with regard to symptom relief and flow
rate in men who do not have clinically enlarged
prostates. It is considered an acceptable first-
line treatment option in patients with clinically
enlarged prostates and bothersome symptoms
who have not developed serious complications.
• The long-term efficacy and safety of
5 α−RIs have been demonstrated in open-label
extension investigations, but continued study
for example, of cost-effectiveness, is recommen-
ded
• Available data show that 5 α−RIs have a pre-
ventive influence on the progression of benign
prostatic enlargement (BPE) and significantly
reduce clinically important endpoints such as
acute urinary retention and the need for surgery.
• 5 αRIs lower serum PSA, but this can be cor-
rected with sufficient clinical accuracy by mul-
tiplying the value by two. To date, there is no
evidence that 5 α−RIs mask the detection of
prostate cancer.
• The most common side effects of 5 α−RIs are
sexual adverse events (diminished ejaculation,
diminished libido and impotence).
• After initiation of therapy, the time interval for
the assessment of treatment success is at least
3 months.
3. Combination treatment C. INTERVENTIONAL THERAPIES

The combination of an α-adrenergic receptor Standard surgical approaches produce the most
antagonist and a 5 α-reductase inhibitor (combina- significant, long-term symptom improvement with
tion therapy) is a appropriate and effective treat- acceptable risks. However, there is increasing
ment for patients with LUTS associated with acceptance of minimally invasive therapies that
demonstrable prostatic enlargement produce variable degrees of symptom improve-
ment with risks that (in some cases) may be less
than surgery. Evidence of durability is lacking,
4. Alternative Treatments however, and it remains uncertain whether these
new technologies are more cost-effective in the
Alternative medical treatment for LUTS mainly long-term than standard surgery (e.g., TURP).
includes phytotherapeutic preparations and deriva-
tives of polyene substances. The use of alternati- The present status of the various available tech-
ve medical treatments for LUTS varies greatly in niques is summarized in Table 1.
different countries due to the evolution of treat-
Table 1: Clinically acceptable interventional
ment traditions and structures of the health care techniques (present state).
systems. In some countries, it is regarded as drug
treatment and partly or totally reimbursable, while Conventional and novel treatments for BPO and recom-
mendations about their use in international guidelines.
in others it is not reimbursed, but still considered
(A) acceptable; (A/R) acceptable with restriction
as drug treatment, or merely considered as a dieta-
ry supplement.
ICPD : International Consultation on Prostate Diseases
Most phytotherapeutic preparations are plant
Interventional Abbreviation ICBPH
extracts with different components, manufactured
therapies 2005
by different extraction procedures, which compli-
cates comparison of the various preparations even Transurethral TURP A
though they originate from the same plant. Pro- resection of
gress has been made towards isolation of various the prostate
components of these preparations and their pos- Open OP A
sible mechanism(s) of action. prostatectomy
Randomised clinical studies against placebo have Transurethral TUVP A
been conducted with one extract of Serenoa electrovaporization
Repens (Permixon extract) and suggest superior Laser-vaporization LV A
efficacy against placebo. Comparative studies of
Transurethral TUMT A
this extract with other medical treatments are not
microwave therapy
conclusive as these studies do not include a pla-
cebo arm. Other products (extracts from Pygeum Transurethral TUNA A
africanum, preparations containing high concen- needle ablation
trations of ß-sitosterol and mepartricin) have not Interstitial laser ILC A
been evaluated in adequate studies to draw signifi- coagulation
cant conclusions. Urethral stents A/R
Further studies according to the guidelines of the
International Consultation are needed. Long-term
follow-up is lacking. These studies are encoura-
ged, as the Consultation considers this approach
an interesting direction for further pharmaceutical
and clinical research.

398
 4. Standard Evaluation of
New Treatment in Clinical Trials
All new investigational drugs and devices inten-
ded for use in LUTS, BPE, BOO and/or BPO
should undergo rigorous testing in phase III clini-
cal trials of at least 12 months duration in which
they are compared with either standard treatments,
or placebo/sham treatments to document their effi-
cacy.
For commercial products, these trials may be
sponsored by patent holder/owner/device manu-
facturer/pharmaceutical industry; however, third
party monitoring of all trial-related source docu-
ments at each investigational site is mandatory to
avoid either real conflicts of interest or the appea-
rance thereof.
All new investigational drugs and devices should
undergo additional testing in phase IV clinical
trials to document efficacy over the long term (>12
months).
Additional recommended trial designs are com-
munity-based effectiveness and cost-effectiveness
trials.
All trials involving humans must follow the
Declaration of Helsinki Principles as revised by
the World Medical Association in October 2000*
and must be approved by an Institutional Review
Board (IRB) which may either be local or central.
All trials should be planned, administered and
conducted in close consultation with biostatisti-
cians to assure proper sample sizes and data ana-
lysis and interpretation.
Inclusion and exclusion criteria, outcomes and
efficacy parameters should be carefully chosen
with the anticipated effect of the drug or device to
be tested on the disease process in mind.
399
Rather than creating new symptom scoring instru-
ments, all investigators should make use of wide-
ly available, validated, and in many cases transla-
ted and additionally culturally and linguistically
validated instruments such as the I-PSS.
Regarding the reporting of trials in the peer-revie-
wed literature, worldwide accepted standards as
published in the Journal of the American Medical
Association (JAMA 272:1926-1931, 1994, JAMA
277:927-934, 1997) should be followed.
Reports should include a detailed listing of inclu-
sion/exclusion criteria, and a flow diagram detai-
ling how the participants pass through the various
stages of the trial (JAMA 272:1926-1931, 1994).
Outcomes, efficacy and safety parameters should
be reported in a clear and concise manner, avoi-
ding the combination of two or more parameters
into “global indices” and the reporting of propor-
tions of patients who achieve X% improvement in
parameter A and/or Y% improvement in parameter
B.
Absolute as well as percentage changes should
always be reported. If percentages and proportions
are reported, the absolute changes should also be
presented. All reported variables should be repor-
ted including measures of central tendency (mean,
median) and measures of variance (SD, SE or CI).
To relate improvements in symptoms and, bother,
quality of life scores to patients’ perceptions,
standardized global subjective assessment ques-
tionnaires, should be administered during several
of the follow-up visits in the pivotal trials.
Patient name :

DOB : ID : Date of assessment :

INTERNATIONAL-PROSTATE SYMPTOM SCORE (I-PSS)

Not at Less than Less than About half More than Almost
all 1 time half the the time half the always
in 5 time time

1. Over the past month, how often have you

had a sensation of not emptying your bladder 0 1 2 3 4 5
completely after you finished urinating ?

2. Over the past month, how often have you

had to urinate again less than two hours after 0 1 2 3 4 5
you finished urinating ?

3. Over the past month, how often have you

found you stopped and started again several 0 1 2 3 4 5
times when you urinated ?

4. Over the past month, how often have you 0 1 2 3 4 5

found it difficult to postpone urination ?

5. Over the past month, how often have you 0 1 2 3 4 5

had a weak urinary stream ?

6. Over the past month, how often have you 0 1 2 3 4 5

had to push or strain to begin urination ?

None 1 time 2 times 3 times 4 times 5 or more

times

7. Over the past month, how many times

did you most typically get up to urinate 0 1 2 3 4 5
from the time you went to bed at night
until the time you got up in the morning ?
Total I-PSS Score =

BOTHER SCORE DUE TO URINARY SYMPTOMS (BS)

Delighted Pleased Mostly Mixed Mostly Unhappy Terrible
satisfied about Dissatisfied
equally
satisfied
and
dissatisfied

1. If you were to spend the rest of your life

with your urinary condition just the way it 0 1 2 3 4 5 6
is now, how would you feel about that ?

Bother Score (BS) =

400
 Name Date
Please indicate the times you get up and go to bed
URINARY DIARY
EXAMPLE DAY 1 DAY 2
TIMES VOLUME URGENCY LEAKAGE ? DRINKS TIMES VOLUME URGENCY LEAKAGE ? DRINKS TIMES VOLUME URGENCY LEAKAGE ? DRINKS
OF URINE OF URINE OF URINE
PASSED PASSED PASSED

401
Total Total Total