Benha University Hospital, Egypt

Email:elnashar53@hotmail.com
Aboubakr Elnashar
 Define
Ectopic (outside the uterus)
endometrial glands & stroma.

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 Prevalence
5% of women in the
reproductive age group.
25% of infertile women.
50% of chronic pelvic pain.

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Age At Diagnosis
> 45 < 19
36 45 3% 6%
15% 19 25
24%

26 35
52%
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 Sites
Pelvic Extra pelvic
Uterine= Adenomyosis Umbilicus.
(50%). Scars (Lap.).
Extrauterine: Lungs & pleura.
- Ovary 30%
Others.
- Pelvic peritoneum 10%.
- F. tube.
- Vagina.
-Bladder & rectum.
- Pelvic colon.
- Ligaments.

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 Types

I. Superficial peritoneal lesions

Typically located on the pelvic organs or pelvic
peritoneum.
Classic bluish or blue-black powder-burn lesion
resembles the endometrium and may be
associated with hemosiderin deposits.
Non-classic lesions:
clear and red flame-like lesions or white lesions.
Endometriosis can also be found in the base of a
peritoneal defect called an Allen-Masters window.

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II. Endometrioma (Endometriotic Cyst)
>90% are pseudocysts [formed by invagination of the ovarian
cortex, which is sealed off by adhesions]
(Brosens et al, 2003).
Characterized by:
fibrosis
retraction of the cortex,
islands of glandular endometrial tissue
organized blood clots.
The remainder of the cyst wall:
Smooth
lined by a thin endometrial-like tissue that consists of surface
epithelium and highly microvascularized stroma.
There is no evidence that endometriotic tissue invades the
ovarian stroma; however, large multilocular cysts frequently
combine endometriomas with a hemorrhagic corpus luteum
or lutein cyst.
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III. Deep endometriosis
Define: Endometriosis infiltrating deeper than 5mm.
It is very active
Includes
1. Rectovaginal lesions
2. Infiltrative forms of bowel, ureters, bladder.
It originates intraperitoneally rather than
extraperitoneally.

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Pathogenesis:
intraperitoneal seeding of regurgitated endometrial cells, which
collect and implant in the most dependent portions of the
peritoneal cavity and the anterior& posterior cul-de-sac,
trigger an inflammatory process leading to adhesion of
contiguous organs with creation of false peritoneal bottoms
Treatment:
Drugs induce temporary quiescence of active deep lesions
Progestins should be considered as first-line medical treatment
for temporary pain relief.
Surgery is the final solution.
Mirena
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Ovarian Endometriosis:
Usually bilateral.
Two forms:
1- Multiple spots on the surface of the ovary.
2- Endometriotic (Chocolate) cysts
can reach the size of a fetal head, but is rarely
larger.
usually difficult to remove the cysts intact out of
surrounding adhesions.

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 Pathogenesis
I- Endometrial implantation:
Retrograde.
Vascular & lymphatic.
Mechanical.
II- In situ development:
Coelomic metaplasia.
Induction.
III- Immunological.
IV- Composite.

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Donnez et al (2003)

Red lesions= early endometriosis

Black lesions= advanced endometriosis
White lesions are believed to be
- healed endometriosis or
- quiescent or latent lesions.

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Pathogenesis Hypothesis (Donnez et al, 2003)

Early - quiescent or
endometriosis Red lesions latent lesions .

White lesions
Advanced
Black lesions
endometriosis

Healed
White lesions endometriosis

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Atypical (subtle) E:
Incidence:
More common than the classic dark blue-black
lesions in adolescents.
Common in age < 25 yr.
Types:
Red
White
Symptoms: like that characterize classic E.

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Significance:
1. Paraphysiological or self-limiting condition
which exist in all reproductive women as a
results of retrograde menstruation.
2. Biochemically & morphologically more active
than the classic lesions {synthesize more PG
F2}
Treatment:
E. does not itself demand treatment unless it is
causing, or it is likely to cause symptoms
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 Risk factors
(Odukoya & Cooke, 1996)
I- Associated:
First or second degree relation.
Menstrual cycle < 27 days.
Menstrual duration > 7 days.
Genital outflow obstruction.
II- Inconclusive:
Obesity,
Exercise,
Age at menarche,
uterine retroversion.
III- Not associated:
Age,
Race,
Social class,
duration of marriage,
ICUD,
Miscarriage. Aboubakr Elnashar
 Factors associated with a reduced risk
{reduced estrogen levels}
(ACOG, 1999) :
Menstrual disorders
Decreased body-fat content
Smoking.

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 Classification
The revised American Fertility Society
(rAFS) (1985)was produced to
standardize the documentation of
findings in patients who have pelvic pain
& endometriosis.
Staging Involves:
1. Location
2. Depth of Disease,
3. Extent of Adhesions.
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Endometriosis < 1cm 1-3cm >3cm

Superficial 1 2 4

Deep 2 4 6

R Superficial 1 2 4

Deep 4 16 20

L Superficial 1 2 4

Deep 4
Aboubakr Elnashar 16 20
POSTERIOR Partial COMPLETE
CULDESAC
OBLTTERATION 4 40
< 1/3 Enclosure 1/3-2/3 > 2/3 Enclosure
ADHESIONS Enclosure

R Filmy 1 2 4
Dense 4 8 16
L Filmy 1 2 4
Dense 4 8 16
R Filmy 1 2 4
Dense 4 8 16
L Filmy 1 2 4
Dense 4 Elnashar
Aboubakr 8 16
Revised AFS (1985)
Stage I (minimal) 1 5.
Stage II (mild) 6 15.
Stage III (moderate) 16 40.
Stage IV (severe) > 40.

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ASRM classification (1996)
The only difference between the 1985 rAFS
classification & 1996 ASRM classification is that the
latter includes information on the morphologic
appearance of the disease.
Red: red, red-pink & clear lesions
White: white, yellow-brown, peritoneal defects,
subovarian adhesion
Black: black & blue lesions.
Denote percent of total described as R .%, W .%
and B .%. Total should equal 100%.

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Atypical

Red Red yellow Clear

White Defect White

Typical
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Black Blue
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Aboubakr Elnashar
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 CLINICAL PICTURE
Common symptoms:
Infertility.
Pain
Pelvic pain.
Dysmenorrhea (Crescendo=progressive)
Dysparunia.
Dyschasia.
Dysuria
Less common symptoms:
Heamaturia, rectal pain,
urgency, heamoptysis,
coetaneous nodules, hyperprolactinaemia.
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Infertility:
E should be suspected in
infertile females.
Suspicion is heightened when
there are also dysmenorrhea
&
dysparunia.
.
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Mechanism of infertility (Prentice, 2001)

I- Advanced disease:
Mechanical interference with
ovulation, ovum pick up,
Tubo-ovarian adhesion,
Severe pelvic adhesions &
Distorted tubal anatomy.
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II- Minimal & mild disease:
1. Coital problems: dysparunia.
2. Altered peritoneal environment:
increase volume of peritoneal fluid,
increase proportion of activated macrophages
(phagocytosis of sperms, decreased sperm motility &
embyotoxicty).
3. Altered foliccular maturation:
lutenized unruptured follicle,
anovulation,
luteolysis caused by prostaglandin F2
No evidence that they are more common in E.

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Chronic Pain:
The severity of pain is not
correlated to the extent of E but to
the site & the depth (Demco, 1998)
Midline disease is more painful
than lateral disease (Konickx, 1994)

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 Acute Abdominal Pain
{Rupture of an endometrioma, usually at
menstruation}.
Differential Diagnosis:
1. Disturbed ectopic
2. PID
3. Acute appendicitis.
Careful analysis of past and present history
suggests the diagnosis of endometriosis.
Laparoscopy is usually needed to reach the
diagnosis.

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Dyschasia
Pain during defecation occurs
when there is involvement of the
rectovaginal septum
It is particularly noticeable during
menstruation.

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Dysmenorrhea
E should be considered in women who develop
dysmenorrhea after years of pain-free cycles.
Pain
1. May be diffuse in the pelvis
localized to one side or
felt in the rectum.
2. Comes on gradually for few days before the
period, but is more severe during menstruation
(Crescendo).
3. Later on it may persist during most of the cycle.

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Deep-seated dyspareunia:
Douglas pouch.
Uterosacral ligament .
Rectovaginal 'septum
Fixed retroversion flexion.

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Sings:
Pelvic tenderness,
Nodules in the cul-de-sac,
Adnexal mass,
Uterine fixity,
Nodules along the uterosacral ligament.

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Adolescent Endometriosis
(Reese et al's 1996)
Symptoms %
Pelvic pain. 95

Dysmenorrhea. 94

Irregular menses. 25
Deep dyspareunia 29
Abdominal pain & 43
nausea
Constipation and 3
diarrhea

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A history of E in the family should prompt further
questioning & raise the index of suspicion (Attaran
and Gidwani, 2003)
Laparoscopic evaluation of the pelvis commonly
reveals atypical, endometriotic lesions.
Microlaparoscopic evaluation may be
recommended in those cases
(Nazhate et al 2000)

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Diagnosis
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Diagnosis is very difficult (Taylor ,2003):
Most women become accustomed to
painful menstrual cycles at an early age.
Even with extensive E, it is possible to
have minimal symptoms or none at all.
The presentation is so variable and there
is considerable overlap with other
conditions such as irritable bowel
syndrome and pelvic inflammatory disease
(RCOG 1999)
Physicians have few diagnostic-usually
invasive- tools. Aboubakr Elnashar
Diagnosis is usually delayed:
It takes a average of 4 years from the
time a woman has her first symptom,
to the time she discusses it with her
doctor.
It takes average of 9 years from the time
she first experiences symptoms, until a
diagnosis of E is finally made.
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Methods of diagnosis:
Invasive diagnosis
I. Laparoscopy
II. Microlaparoscopy.
Non invasive diagnosis.
I. Therapeutic .
II. Imaging: U/S, MRI
III. Endometrial nerve fibers
IV. CA 125
V. Other.
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 Laparoscopy
Gold standard' diagnostic test
Advantages
(RCOG Grade B evidence lll)

1. Excludes other conditions e.g. ovarian

cancer
2. Treatment of E.

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 Disadvantages.
1. Requirement for surgery and anesthesia.
2. Risk of major complications
(e.g. bowel perforation)
Diagnostic laparoscopy: 0.06%
operative laparoscopy: 1.3% in (Harkki-Siren et al, 1999)
3. Visual inspection might
not prove to be E on histological analysis.
not detect deep E.

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Technique:
2 port approach
Inspection of D pouch, us lig, pelvic side walls,
anterior surface of the ovary (adhesions) To ensure
complete evaluation, inspection of the pelvis in a
clockwise or counterclockwise fashion.
Biopsy if there is doubt. It is not a routine

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 Findings:
Peritoneal
Typical E: black-blue, powder-burn appearance.
Diagnosis in most cases is simple, without the need
for a biopsy.
Atypical (Subtle = Non-pigmented) E: E lesions that
lack the typical black-blue, powder-burn
appearance
Diagnosis: more difficult with standard laparoscopy
Other laparoscopic procedures or
biopsy may be necessary to confirm diagnosis
(Martin,1999)
Endometrioma Aboubakr Elnashar
Atypical

Red Red yellow Clear

White Defect White

Typical
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Black Blue
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1-Near-contact: magnifies the peritoneal area
(Redwin,1987)
2-Peritoneal blood painting: flowing erythrocytes
outline surface irregularities
(Redwin,1987)
3-Examined from different angles and at different
degrees of illumination to see vesicles or whitish
lesions.
4-Direct vision:
Although the resolution of cameras has improved, it
is still not comparable to that of direct vision
(Nezhate et al, 2000)

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5. Laparoscopic visualization through lactated Ringer
or normal saline
(Laufer,1997) .

Vesicular lesions are no longer falsely interpreted as

light reflection .
6. Bubble test:
The posterior cul de sac is irrigated with short bursts
of saline under controlled pressure. Development
of dense soap like bubbles for at least 5 s
indicates a positive test. {increased level of
triglycerides in peritoneal fluid}
(Amer A & Omar M., 2002)
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Accuracy
Visual diagnosis of endometriosis is unreliable.
5467% of suspected endometriotic lesions are
confirmed histologically
18% of patients clinically suspected to have
endometriosis have no evidence of endometriosis
on pathology
(Walter et al, 2001)
a positive finding on laparoscopy will be incorrect
in half of the cases
(Wakes et al, 2004)

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In these circumstances, peritoneal lesions
inflammatory changes,
hemangiomas,
foreign body reaction,
mesothelial hyperplasia
hemosiderin deposits
Biopsy of normal-appearing peritoneum has
revealed endometriosis in
6% of women with no visible lesions and
25% of asymptomatic infertile women
(Balasch et al, 1999).

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Directed biopsy (Brosen, 1994)
E in
90% of typical &
40% of atypical cases.
Endometrioma:
The appearance most commonly associated
with positive histology:
irregular brown or red mottling on the surface
of white capsule.
old hemorrhagic corpus luteum:
uniform brown appearance

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Laparoscopic visualization of peritoneal lesions
alone is of limited accuracy, and if a diagnostic
laparoscopy is performed, confirmatory biopsies of
peritoneal lesions, even atypical ones, will be of
value (SOGC, 2010).
The lesions most likely to be histologically
confirmed as endometriosis are
generally large
mixed-color lesions
in the culde sac or on the uterosacral ligaments
(Stegmann et al, 2008)
On histopathology, the diagnosis requires the presence of two or more
of these histologic features:
endometrial epithelium
endometrial glands
endometrial stroma Aboubakr Elnashar
hemosiderin-laden macrophages (ACOG, 1999)
Is laparoscopy required before medical
management of pelvic pain?
(SOGC, 2010)
not always necessary .
{1. Management of the pain is required whether or
not endometriosis is the cause.
2. All the management strategies for E are relatively
general strategies to decrease inflammatory
conditions in the pelvis}

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E can be strongly suspected
severe dysmenorrhea unresponsive to NSAID
with pelvic tenderness and nodularity on palpation
of the uterosacral ligaments and rectovaginal
septum, or
US: endometrioma.
: In these situations, laparoscopy for diagnosis is
not necessary before medical treatment.
Laparoscopy should be performed only if the
surgeon is prepared to vaporize or excise lesions if
endometriosis is discovered {surgical management
provides long-term pain relief for up to 50%}
(Abbott et al, 2003)

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II. Microlaparoscopy

Less invasive

Out patient procedure

Local anesthesia
Pain mapping.
For adolescent E.

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Non Invasive Diagnosis

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I. Diagnosis by therapeutic trials:
1. Pain suggestive of E +
Woman not trying to conceive +
No pelvic mass
Therapeutic trial of
COCs (monthly or tricycling) or
Progestogen without performing a diagnostic
laparoscopy
(RCOG 1999)

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2. Chronic pelvic pain
{Moderate to severe
at least 6 m,
unrelated to menstruation
unrelieved by NSAI & antibiotics} +
Clinically suspected E +
Clinical response to GnRha (Depot leuprolide
acetate 3.75 mg monthly for 3 m)
Can diagnose E (Ling, 1999).

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 GnRH agonist is an appropriate therapy of
chronic pelvic pain, even in the absence of
surgical confirmation of E, provided that a
detailed initial evaluation fails to demonstrate
some other cause of pelvic pain
(ACOG Recommendations Grade (B)

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II. Imaging
1. Transvaginal ultrasound
first-line investigational tool for suspected E
help diagnose endometriomas, bladder lesions,
and deep nodules such as those in the
rectovaginal septum.
Findings:
1. Anechoic to echogenic cysts
2. Masses containing multiple septations & solid
tissue (Morane &Older, 1996)
3. Cysts with low-level echoes: The commonest
finding (95%)
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Cysts with low-level echoes
(Patel et al, 1999)
Endometrioma 95%
Hemorrhagic cyst 50%
Teratoma 18%
Malignant neoplasm 12%
Benign neoplasm 6%

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 Unilocular Adnexal mass with diffuse
low-level internal echoes (Patel et al,1999)

No Wall Wall Nodularity

Nodularity
regional No
hyperechoic bright characteristic
wall foci = echo = feature.
6 w Follow- Endometrioma Teratoma
up US MRI or Doppler
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Multilocular Adnexal mass with diffuse
low-level internal echoes (Patel et al,1999)

Hyperechoic No hyperechoic
wall foci wall foci
No neoplastic Neoplastic
features features
= Endometrioma MRI or Doppler
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2. Transrectal ultrasound
Detect
rectal involvement in E
depth of infiltration by E,
lesions on the posterior bladder wall
but it has not been shown to be superior
to transvaginal ultrasound.

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3. CT:
has been replaced by MRI
poor specificity
high radiation dose
An important role for the CT scan with contrast is to
detect ureteral involvement and possible renal
insufficiency.

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 MRI
Indications: (Funt et al, 2002):
1. Indeterminate
2. Poorly visualized
3. Inadequately localized lesions
Relies on:
Detection of pigmented hgic lesions: signal
characteristics vary according to the age of
hge.

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Advantages:
1. Greater sensitivity. Detect 75% of mild disease
(Stratton et al, 2003).
MR And Endometriosis
2. Evaluation of deep lesions
3. superior to ultrasound in diagnosing rectosigmoid
lesions and endometriosis of the bladder.

Disadvantages:
Not readily available
Expensive.

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Aboubakr Elnashar
III. Endometrial nerve fibers
Appropriate marker (Fatheima et al, 2011)
an increased number of nerve fibers in the
endometrium of women with endometriosis
compared to women without endometriosis.
These nerve fibers are reported to be primarily
small unmyelinated sensory C fibers in the
functional layer of endometrium, which
are identified by their staining with PGP9.5, VIP,
and substance P, but not with neurofilament.

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(A) Absence of nerve fibres in the functional layer of
endometrium in adenomyosis but no endometriosis.
(B) Small unmyelinated C nerve fibres (black arrows) in the
functional layer of endometrium in a woman with peritoneal
endometriosis (immunohistoclinical staining with protein
gene product 9.5 and fast Aboubakr
red chromogen.
Elnashar
IV. Serum markers:
limited value as a screening test as well as a
diagnostic test.
Useful marker for monitoring treatment
no individual serum marker has been found
to specifically correlate with the symptoms of
endometriosis, and many of them are
present in other conditions.

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V. Other:
1. Cystoscopy (for bladder endometriosis)
2. sigmoidoscopy or colonoscopy (for transmural
bowel lesions),
3. ultrasound-guided fine needle aspiration
(FNA: for endometriosis in the rectosigmoid,
rectovaginal septum, or in abdominal scars).
4. IVP, barium study

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 D.D.
1. Ovarian cysts*.
2. Pelvic inflammatory disease .
3. Other causes of nodularity in Douglas pouch:
tuberculous peritonitis
metastases of ovarian cancer.
4. Causes of haematuria,
bleeding per rectum and
acute abdominal pain
if the patient is presented by one of these
symptoms.
5. Asymmetrical enlarged uterus.
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*Cysts With Low-level Echoes +

Characteristic Features

Endometrioma
Hyperechoic wall foci (in 35%)

Hemorrhagic cyst :
Lacelike internal echoes (in 40%)

Teratoma
Regional bright echoes ( in 97% )
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*Endometrioma Vs Malignancy
(Brown et al 1998)

Suggestive of malignancy:
1. Mural thickening
2. Wall nodularity
3. Septations > 3 mm
4. Papillary projections
The most significant predictor of malignancy:
Solid component within an ovarian mass

Aboubakr Elnashar
Aboubakr Elnashar
Medical treatment
of endometriosis
Prof Aboubakr Elnashar

Benha university hospital

elnashar53@hotmail.com
Aboubakr Elnashar
 Contents
Lines of treatment and treatment
strategy
Non hormonal
Hormonal
New treatments
Evidence based recommendations

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Depend on:
1. Age
2. Presenting symptoms
3. Reproductive status
4. Fertility demands
5. Stage
6. Previous response to
treatment. Aboubakr Elnashar
Lines of treatment

A- Symptomatic:
PG inhibitors
ART
Psychotherapy.

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B- Hormone (Medical) suppression:
Conventional
New drugs

C. Surgical:
Conservative:
Diathermy, laser vaporization,
excision,
Ov cystectomy, presacral
neurectomy
Radical:
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Hysterectomy & ovarian removal.
Treatment strategy
1. Endometriosis & pain (RCOG,2000) :
a. Medical:
NSAID: may be effective.
COC, progestagens, danazol & GnRHa:
equal in relieve pain associated with E.
Prescribe the safest & cheapest.
b. Surgical:
Effective for many women.
Some women fail to respond
{incomplete excision or
post-operative disease recurrence}.
Aboubakr Elnashar
 Aboubakr Elnashar
(SOGC, 2010)
2. Endometriosis & infertility:
Medical:
No value.
{results in 6 mo. of contraception which further
delays pregnancy.}
Minimal or mild E:
Ovarian stimulation & IUI is more effective than
either no treatment or IUI alone

Surgical:
Minimal or mild:
Laparoscopy: destruction or ablation of the E
implants & lysis of adhesions
Moderate to Severe:
Surgical treatment may improve fertility
Aboubakr Elnashar but RCT
Aboubakr Elnashar
 Medical treatment
I. Non hormonal
NSAIDs

II. Hormonal

Conventional: New
LNG-IUD
COC GnRHan
Progestagens, Aromatase inhibitors
GnRHa SERM
Danazol Progesterone antagonist
SPRM
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Angiogenesis inhibitors
Immunomodulatory drugs.
 I. NSAIDs
Useful in women trying to conceive
ibuprofen (Sapofen)
naproxen (Naprosyn).
Mefenamic acid (Ponstan)
Start 2 d before menstruation
Similar efficacy
Gastric irritation.

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 Cyclooxygenase-2 (COX-2).
Celebrex
Vioxx
Not more effective (than naproxen or ibuprofen)
lower risk of gastric ulceration
high cost
(Mahutte & Arici, 2003)

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 II. Hormonal
Conventional
Rationale:
E. Implants:
estrogen, progesterone & androgen receptors
at a lower concentration than eutopic endometrium.

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Is laparoscopy required
before medical management
of pelvic pain?
(SOGC, 2010)
Not always necessary .
{1. Management of the pain is
required whether or not E is
the cause.
2. All managements aim to
decrease inflammatory
conditions in the pelvis}

Aboubakr Elnashar
E can be strongly
suspected
Severe dysmenorrhea
unresponsive to NSAID+
on palpation of the uterosacral
ligs and rectovaginal septum:
tenderness and nodularity OR
US: endometrioma.

: In these situations,
laparoscopy for diagnosis is
not necessary before medical
treatment.
Aboubakr Elnashar
Laparoscopy should be
performed only if the surgeon
is prepared to
vaporize or
excise lesions
{: long-term pain relief for up
to 50%}
(Abbott et al, 2003)

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Diagnosis by therapeutic
trials:
1. Pain suggestive of E +
Woman not trying to conceive +
No pelvic mass
COCs (monthly or tricycling) or
Progestogen for 3 cycles
(RCOG 1999)

Clinical response
can diagnose E
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2. Chronic pelvic pain
{Moderate to severe
at least 6 m,
unrelated to menstruation
unrelieved by NSAI & antibiotics}
+
Clinically suspected E +
GnRha (monthly for 3 m)
Clinical response
can diagnose E (Ling, 1999).

Aboubakr Elnashar
GnRHa
An appropriate therapy of
CPP, even in the absence
of laparoscopic
confirmation of E,
provided that a detailed
evaluation fails to
demonstrate other cause
(ACOG Recommendations Grade (B)

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Indications of medical treatment
.
Suspected endometriosis
Confirmed endometriosis
.
1. Dysmenorrhea, dysparunia & pelvic pain
associated E.

2. Temporary relief of pain in women awaiting for IVF

3. After surgical treatment who need long-term

management.

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Indications of long term medical therapy
1. Severe symptoms with little palpable findings
2. Recurrence after conservative surgery.

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 Results:

1. Volume of the disease: similar for

all forms
2. Pain: equally effective
3. Subsequent pregnancy rates:
similar for all forms
4. Recurrence rates: similar
5. Infertility: no improvement

The various agents: are

comparable in terms of efficacy
Choice is determined by Elnashar
Aboubakr cost & side
effects.
 Aim:
(A) Pseudopregnancy :
1. Combined contraceptive pills
2. Progestins {avoid oestrogen's
side effects}
(B) Pseudomenopause (induction
of amenorrhoea)
1. Danazol.
2. Gn RH analogues.

Aboubakr Elnashar
 1. Combined oral contraceptives

Mechanism of action:
pseudopregnancy
Decidual transformation of both normal & ectopic
endometrium followed by gradual necrosis &
absorption of the decidual cells.

Dose:
Initially, a trial of continuous or cyclic for 3 months.
With pain relief, continue for 6-18 months.

Aboubakr Elnashar
Aboubakr Elnashar
Continuous administration:
more beneficial in terms of pain relief.
{preventing withdrawal bleeding prevent retrograde
menstruation}

Aboubakr Elnashar
Side effects:

BTB:
More common with continuous than with cyclic tt
Treated with conjugated estrogen 1.25 mg or
estradiol 2mg for 1 w.

Other estrogen induced side effects:

Nausea & vomiting
weight gain
DVT.

Aboubakr Elnashar
Efficacy:

OCP Vs GnRHa (Cochrane library, 2005).

No significant difference in the relief
of dyspareunia or non-menstrual
pain

With OCP:
More Headaches and wt gain
Less Hot flushes, insomnia &
vaginal dryness

Aboubakr Elnashar
OCP is first line therapy in the management of E.
1. Effective as GnRHa
2. With E: an increased risk of epithelial ovarian
cancer: COCPs protect against this.
3. Can be taken indefinitely
(SOGC, 2010)

Aboubakr Elnashar
 2. PROGESTAGNES
Mechanism of action:
decedualization & subsequent atrophy of the
endometrial tissue.
Suppression of the ovarian activity.

Aboubakr Elnashar
 Dose:
Continuously:
Progestagens given in the luteal phase are not
effective

Preparation Name Dose

MPA Provera 30mg/d

DMPA Depo provera 150mg/1- 3 mo, IM.
Noreethisterone acetate Primoult nor 10-20 mg/d.
Dydrogestrone Duphaston 20 mg/d
Dienogest Visanne 2mg/d

Aboubakr Elnashar
Side effects:
Irregular bleeding:
Common
Treated with estrogen for 7d
Wt gain
Fluid retention,
Depression.
Adverse effect on lipoprotein High doses

Aboubakr Elnashar
Efficacy:
Norethindrone acetate
effective in most patients for relieving
dysmenorrhea and chronic pelvic pain.
positive effect on calcium metabolism: relatively
good maintenance of BMD.
BTB: 50%
Negative effects on serum levels of high-density
lipoprotein cholesterol.

Aboubakr Elnashar
MPA:
like danazol can relieve the symptoms of E
effective in the treatment of painful symptoms
(Cochrane library, 2005).
First choice for medical T.T. of E.
{more cost effective & fewer side effects}.

Aboubakr Elnashar
DMPA
equivalent to leuprolide acetate in relieving pain.
effective in relieving pelvic pain in up to 75%
Very economical alternative

Aboubakr Elnashar
loss of BMD but not as much as leuprolide acetate
without addback.
Long-term use:detrimental to BMD.

Prolonged delay in resumption of ovulation (6-12 mo)

:not be given if pregnancy is aimed in the near future.

BTB: may be prolonged, heavy, and difficult to

correct {progestin effect can not be reversed quickly}.

An ideal indication: residual E after hysterectomy

with or without BSO when future conception and
irregular uterine bleeding are not issues.
Aboubakr Elnashar
Dienogest: Visanne
selective 19-nortestosterone and progesterone
activity. {strong progestational and moderate antigonadotrophic effects, but
no androgenic, glucocorticoid or mineralocorticoid
Activity}.
Effective as GnRHa (triptorelin 3.75 mg/4w)
Quality of life: slightly improved compared with
leuprolide acetate
Effective long-term treatment option
less hypoestrogenic side effects and little
changes in BMD: advantages in safety and
tolerability
Higher incidence of abnormal menstrual bleeding
patterns
Aboubakr Elnashar
Vercellini et al, 2011

For pain relief, OCs used continuously is a worthy

option in women with peritoneal and ovarian
lesions

NETA appears to be the preferable compound in

patients with rectovaginal disease.

For prevention of endometrioma recurrence, OCs

are extremely effective whether used continuously
or cyclically, as the mechanism of action seems to
be ovulation inhibition.
Aboubakr Elnashar
 3. GNRH AGONISTS
Produced by
Modification of the native GnRH decapeptide at 6 &
10 positions
Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
LHRH
Glp-His-Trp-Ser-Tyr-Ser(But)-Leu-Arg-Pro-Azgly-NH2
Goserelin
100 times more potent than natural LHRH

Aboubakr Elnashar
Mechanism:
After initial agonistic action (flare response),
down-regulation & desensitization of the
pituitary: hypogonadotrophic, hypogonadal
state.

Aboubakr Elnashar
Indications
GnRHa with HT addback
should be considered as 2nd
line treatment:
No response to CHCs or
progestins
Recurrence of symptoms
after initial improvement
(SOGC, 2010)

Aboubakr Elnashar
Types
Preparation Name Route Dose company PriceEP
Goserelin Zoladex SC 3.6 mg/4w Astrazenica 530
11.8mg/12w
Triptolerin Decapeptyl IM, SC CR: 3.75mg, Ferring 605
0.1mg then 0.05 mg 266(7syr)
Leuprorelin Lupron IM, SC 3.75 mg/4w Abbot 750
Lucrin IM, SC 11.25 mg/12 w 1550
2.8 ml, 1 ml daily 540
Buserelin superfact Nasal, SC 0.5 mg then 0.2 mg Sanofi

Nafarelin Synarel nasal 0.2 mg bid Pfaizer

Aboubakr Elnashar
 Site of injection:
anterior abdominal wall
Best route of absorption
and steady dissolution of
depot
The trunk area is less
sensitive than the thighs:
negligible pain on injection

Aboubakr Elnashar
Side effects:
GnRHa alone: symptoms of estrogen
deficiency
hot flushes
insomnia
Loss of libido,
vaginal dryness,
emotional instability, depression, headache.
loss of BMD, which is not always reversible.

Aboubakr Elnashar
Add-back therapy:
Aim:
To prevent demineralization of bone
& menopausal symptoms.
When:
GnRha should not be given as a
single agent for >6 ms.
GnRHa should not be used for any
length of time in the absence of HT
addback
(SOGC, 2010).

Aboubakr Elnashar
Rationale:
There is a threshold serum estrogen concentration that
is low enough that endometriosis is not stimulated but
high enough that hypoestrogenic symptoms are
prevented (Barbieri,1992).
GnRHa Endometriosis symptoms

Addback
Oestradiol

Menopausal symptoms

This concentration is the same as that achieved with

physiologic HT for menopausal women.
Aboubakr Elnashar
Estrogen-progestagen combination.
Tibilone (livial): 2.5 mg/d.
Bisphosphonates: Etidronate.

Aboubakr Elnashar
Efficacy:

GnRHa: Pain relief 85-100%

persisting for 6-12 months
after cessation of tt.
(Winkel et al,2005 )

GnRHa Vs other hormonal tt:

No difference with respect to pain
relief or reduction in E deposits
(Cochrane library, 2005).

Aboubakr Elnashar
 4. DANAZOL(Danocrine, Danol).

isoxazzole derivative of 17 ethinyltestosterone

It is an oral impeded or weak androgen
The golden age for danazol has passed:
No more effective than the other medications
Side effects
Expensive

Aboubakr Elnashar
Mechanism of action:
Inhibition of pituitary Gnt.
Inhibition of steriodogenesis in C. luteum.
It is metabolized to at least 60 products.
The multiple effects of these products is
high-androgen, low-estrogen environment that does
not support the growth of endometriosis &
amenorrhea prevents new seeding from the uterus
into peritoneal cavity.

Aboubakr Elnashar
Side effects:
Androgenic Hypoestrogenic
Wt gain atrophic vaginitis
fluid retention hot flushes
Fatigue muscle cramps
decreased breast size emotional liability.
small study raised the concern of
acne, oily skin, growth of facial an increased risk of ovarian cancer
hair
Hepatocellular damage
{metabolized in liver}
increased cholesterol & LDLP
& decreased HDLP.

The significant side effects limit its use

(Cochrane Reviews 2003)

Aboubakr Elnashar
Contraindications:
Liver disease.
Severe hypertension
congestive heart failure
impaired renal function.

Dose:
200mg 4 times daily for 6 mo.
< 800 mg daily is less effective.
low-dose regimens or vaginal administration
have been described.
Aboubakr Elnashar
Efficacy:
Recurrence in 1/3 of cases.
Success is greatest in cases of
peritoneal E.
Endometriomas > 1cm are less likely
to respond.
Effective in treating symptoms and
signs of E.
Useful to relieve pain & prevent
progress of the disease.

Aboubakr Elnashar
 New drugs
An ideal treatment:
Regression of the disease & symptoms
No adverse hypoestrogenic effects

Aboubakr Elnashar
Group Drugs
1. LNG-IUD Mirena
2. GnRHan Cetrorelix
3. Aromatase Anastrazole (Arimidex),
inhibitors Letrozole (Femara)
4. SERM Tamoxifen, Raloxifene
5. Progesterone Mifepristone, Onopristone
antagonist
6. SPRM Asoprisnil
7. Angiogenesis TNP470, Endostatin, Anginex,
inhibitors Rapamycin
8. Immunomodulatory Loxoribine, IFN- 2 , TNF-
drugs. inhibitors.
9. Others Matrix metalprotease, Doxycycline, 5-
Aboubakr Elnashar
fluorouracil, Thiazolidinediones
 1. levonorgestrel (IUD):
Mechanism of action:
Unclear
LNGIUD delivers significant amounts of
LNG into the peritoneal fluid: clearing up
the local effect on the endometriotic
implants

Aboubakr Elnashar
LNG-IUD
T-shaped
Release rate of LNG:
20 g/24 h during 1st y
slowly throughout the 5 y of use.
: Endometrial atrophy
Ovulation: usually not suppressed.
Contraception
Hypomenorrhea or
amenorrhea
Reduced dysmenorrhea

Aboubakr Elnashar
LNG-IUD
Treatment of choice for CPP-associated E in
women who do not wish to conceive.
1. Effective for at least 5 ys
2. Can be reapplied every 5 ys.
3. No modifications in estrogen levels
4. In the long term it is a low-cost therapy
5. Fewer SE than other progestogenic agents.

Aboubakr Elnashar
II. GnRH antagonists

Aboubakr Elnashar
Mechanism of action:
GnRHan
immediately block GnRH
effects
competing with endogenous
GnRH for pituitary binding
sites
suppress LH secretion in a
dose-dependent manner.

Aboubakr Elnashar
Studies:
3 mg of cetrorelix/w for 8 w
E2: suppressed to 50 pg/ml.
100%: symptom-free period during GnRH TT
50%: Regression
2nd look laparoscopy: Degree of E declined to a
mild stage
(Kupker et al, 2002).

Aboubakr Elnashar
 3. Armoatase inhibitors
Anastrazole (Arimidex): 1mg/d
Letrozole (Femara): 2.5 mg/d
Both are approved in USA for tt of breast cancer.

Aboubakr Elnashar
Mechanism of action in endometriosis
Estrogen is produced by 3 pathways
1. Hypothalamic-pituitary-ovarian pathway
2. Peripheral conversion
3. Locally within endometriosis.
GnRHa stops only 1st pathway
AI stop all 3 pathways
Decreasing aromatase in the brain: decrease LH&
FSH: decrease estrogen
Suppress ovarian & peripheral (e.g. adipose tissue)
estrogen production.

Aboubakr Elnashar
Aboubakr Elnashar
AIs:
1. Should be combined with a progestin or COCs or
GnRHa
2. Combinations of an AI with a progestin or COCs
is more popular {cheaper, fewer side effects}
3. No severe SE
4. AIs should be offered with severe pain despite
previous surgical& hormonal therapies.
4. Further research is required before
recommending the routine use of these agents.

Aboubakr Elnashar
 Evidence based
Recommendations

Aboubakr Elnashar
1. Combined hormonal contraceptives, ideally
administered continuously, should be
considered as 1st line agents. (I-A)

2. Administration of progestin alone orally,IM, or

SC may also be considered as 1st line therapy.
(I-A)

3. A GnRHa with HT addback, or the LNG-IUS,

should be considered 2nd line therapeutic
option. (I-A)

Aboubakr Elnashar
4. A GnRHa should be combined with HT
addback therapy from commencement of
therapy and may be considered for longer-term
use (> 6 months). (I-A)

5. While awaiting resolution of symptoms from

the directed medical or surgical treatments for
endometriosis, NSAIDs can be tried. (III-A)

Aboubakr Elnashar
4. SERM: Raloxifene has
Estrogen antagonist on the endometrium
(attenuates the growth)
Estrogen agonist on bone (preserve bone
mineral), but
Vasomotor symptoms limits its use

Aboubakr Elnashar
5. SPRM (asoprisnil):
Mixed agonistic & antagonistic.
It inhibits endometrial growth without
producing systemic progestational
effects

Aboubakr Elnashar
6. Pentoxifylline:
Multi-site immunomodulating drug
7. Mifepristone:
It has antiprogesterone & antiglucocorticoid
actions.
8. Endostatin (Becker et al, 2005)
angiogenesis inhibitor
suppressed the growth of endometriotic in
mice without any apparent negative effects
on fertility or reproduction,

Aboubakr Elnashar
 Endometriosis & miscarriage
RCT: miscarriage rate was in the normal range in
women with E who were not treated.
Implantation failure & early abortion: E does not
result in a higher rate of early pregnancy loss.

Endometriosis & ovulation

The frequency of anovulation & luteal phase defects
is similar in women with & without E.

Aboubakr Elnashar
 Endometriosis & IVF
The presence of E does not generally impair
the results of IVF but it increases the risk of
infection.
It is preferable not to cauterize ovarian
endometrioma if IVF or ICSI is indicated for fear
of destruction of ovarian tissues.

Aboubakr Elnashar
SURGICAL

Aboubakr Elnashar
A- Conservative:
Aim :
Restore normal anatomical relationships
Excise or destroy as much of the E as possible
Prevent or delay recurrence
Even 1/10 of an ovary can be enough to preserve
function & fertility (Speroff, 1999).

Aboubakr Elnashar
Routes: Laparoscopy or laparotomy
Laparoscopy
Advantages:
Better visualization
Less tissue trauma & desiccation
Smaller incision, speedier postoperative
recovery.
Postoperative adhesions & complications
may be less than laparotomy
Results are equivalent or better than
laparotomy (Admson & Pasta, 1994)
Aboubakr Elnashar
Disadvantages:
In advanced E it may be extremely hazardous.
For gynecologist without level III training
laparotomy will be more appropriate.
Strict adherence to microsurgical principles:
Magnification
Minimal tissue trauma
Minimal exposed sutures
Meticulous hemostasis
Aboubakr Elnashar
Procedures:
1. Peritoneal implants:
Ablation (with unipolar or bipolar electrosurgery or
laser) or
Excision by sharp dissection.
Superiority of one method over another are not
substantiated (Sperof & Fritz, 2005)
2. Adhesions:
Excision is preferable to simple lysis because
adhesions will frequently contain
Aboubakr Elnashar
disease.
3. Ovarian endometrioma:
Wedge resection,
stripping,
drainage with & without ablation of the internal cyst wall.
The best is cystectomy or fenestration with ablation of the internal
cyst wall (Sperof & Fritz, 2005)
1. Residual deep ovarian disease is less likely than after
drainage alone
2. Reoperation rates are lower after drainage without ablation
3. Wedge resection is associated with marked postoperative
adhesions
4. Fenestration & ablation may preserve more functional ovarian
tissue
Aboubakr Elnashar
4. Dysmenorrhea & central pelvic pain:
Presacral neurectomy (PSN) &
Laparoscopic uterosacral nerve ablation (LUNA)
PSN= interrupting the sympathetic innervations of the
uterus at the level of the superior epigastric plexus.
LUNA= transecting the mid-portion of ut sac lig.
Risks:
injury to the ureters or bowel
bladder dysfunction.
RCT
These procedures add no significant benefit to
conservative surgery (Daniell et al 1995).
Aboubakr Elnashar
5. Deeply infiltrating rectovaginal E:
Extensive surgery
By the most skilled & experienced surgeons.

Often, a portion of the posterior

vagina must be excised, &
sometimes, a short segment of
rectum must be resected, followed
by anastomosis Aboubakr Elnashar
Results of surgery:
Pain
Mild E:
effectiveness is comparable to that of medical tt.
Endometriomas or deeply infiltrating disease:
Surgical tt offers better long term results.
The combined surgical approach (of laparoscopic laser
ablation, adhesiolysis and uterine nerve ablation) is
beneficial for pelvic pain associated with minimal, mild
and moderate endometriosis (Cochrane library, 2005)

Aboubakr Elnashar
Infertility:
Moderate to severe E: Surgical treatment
improves fertility
Minimal & mild: improvement to a modest
extent

Aboubakr Elnashar
Preoperative medical treatment:
No proven value except in deep disease
involving the cul-de sac or rectovaginal
septum.

Aboubakr Elnashar
Postoperative medical treatment:
Infertility:
It does not increase PR (Vercellini et al, 1998).
The highest PR following conservative surgery occur
in the first year & most doctors not use it.
Pain:
It delays recurrence (6 mo) of the disease &
symptoms & warrants consideration in extensive or
residual disease (Hrnestein, 1997)

Aboubakr Elnashar
Recurrence of E after surgery
E. tend to recur unless definitive surgery (TAH &
BSO) is performed.
Recurrence rate: 10-20% per year
Reasons of recurrence:
Microscopic E escaped detection
Incomplete treatment,
Reestablishment of primary disease.

Aboubakr Elnashar
B- Radical:
Indications:
Failure of hormonal tt &
conservative surgery is unnecessary or
unsuccessful
Hysterectomy& usually bilateral salpingo-
oophrectomy.

Aboubakr Elnashar
HRT after radical surgery
Estrogen & progestagen replacement therapy at
usual doses can be started immediately after
surgery with negliable risk of recurrence.

Aboubakr Elnashar
 Thank you

Benha University Hospital, Egypt

Email:elnashar53@hotmail.com

Aboubakr Elnashar
Aboubakr Elnashar
Pharmacological therapy for endometriosis is
inevitably a compromise.
Not all women using progestins will be relieved
from pain, not all will be satisfied with their
treatment, not all will continue it and not all will
avoid surgery. But at least two-thirds of them could
substantially ameliorate their health-related quality
of life, controlling the disease with marginal
associated morbidity. This appears to be a major
medical achievement, and as such should be
regarded.

Aboubakr Elnashar
Aboubakr Elnashar
Aboubakr Elnashar
Aboubakr Elnashar
Aboubakr Elnashar