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SECTION 16

UROLOGIC DISORDERS
Edited by Cecily V. DiPiro

79
Chapter

Benign Prostatic Hyperplasia

• Benign prostatic hyperplasia (BPH), a nearly ubiquitous condition, is the most com-
mon benign neoplasm of American men.

PATHOPHYSIOLOGY
• Three types of prostate gland tissue: epithelial or glandular, stromal or smooth mus-
cle, and capsule. Both stromal tissue and capsule are embedded with α1-adrenergic
receptors.
• The precise pathophysiologic mechanisms that cause BPH are not clear. Both intra-
prostatic dihydrotestosterone (DHT) and type II 5α-reductase are thought to be
involved.
• BPH commonly results from both static (gradual enlargement of the prostate) and
dynamic (agents or situations that increase α-adrenergic tone and constrict the
gland’s smooth muscle) factors. Examples of drugs that can exacerbate symptoms
include testosterone, α-adrenergic agonists (eg, decongestants), and those with
significant anticholinergic effects (eg, antihistamines, phenothiazines, tricyclic anti­-
depressants, antispasmodics, and antiparkinsonian agents).

CLINICAL PRESENTATION
• Patients present with a variety of signs and symptoms categorized as obstructive or
irritative. Symptoms vary over time.
• Obstructive signs and symptoms result when dynamic and/or static factors reduce
bladder emptying. Patients experience urinary hesitancy, urine dribbles out of the
penis, and the bladder feels full even after voiding.
• Irritative signs and symptoms are common and result from long-standing obstruction
at the bladder neck. Patients experience urinary frequency, urgency, and nocturia.
• BPH progression may produce complications including chronic kidney disease, gross
hematuria, urinary incontinence, recurrent urinary tract infection, bladder diver-
ticula, and bladder stones.

DIAGNOSIS
• Includes careful medical history, physical examination, objective measures of bladder
emptying (eg, peak and average urinary flow rate and postvoid residual [PVR] urine
volume), and laboratory tests (eg, urinalysis and prostate-specific antigen [PSA]).
• On digital rectal examination, the prostate is usually but not always enlarged (>20 g),
soft, smooth, and symmetric.

TREATMENT
• Goals of Treatment: The goals are to control symptoms, prevent progression of com-
plications, and delay need for surgical intervention.
• Management options include watchful waiting, drug therapy, and surgical interven-
tion. The choice depends on severity of signs and symptoms (Table 79–1).
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TABLE 79–1 Categories of BPH Disease Severity Based on Symptoms and Signs
Disease AUA Symptom
Severity Score Typical Symptoms and Signs
Mild ≤7 Asymptomatic
Peak urinary flow rate <10 mL/s
PVR urine volume >25–50 mL
Moderate 8–19 All of the above signs plus obstructive voiding symptoms and
irritative voiding symptoms (signs of detrusor instability)
Severe ≥20 All of the above plus one or more complications of BPH

AUA, American Urological Association; BPH, benign prostatic hyperplasia; PVR, postvoid residual.

• Watchful waiting is appropriate for patients with mild disease (Fig. 79–1). Patients
are reassessed at 6 to 12 month intervals and educated about behavior modification,
such as fluid restriction before bedtime, avoiding caffeine and alcohol, frequent emp-
tying of the bladder, and avoiding drugs that exacerbate symptoms.
PHARMACOLOGIC THERAPY
• Pharmacologic therapy is appropriate for patients with moderate BPH symptoms and
as an interim measure for patients with severe BPH.
• Pharmacologic therapy interferes with the stimulatory effect of testosterone on pros-
tate gland enlargement (reduces the static factor), relaxes prostatic smooth muscle
(reduces the dynamic factor), or relaxes bladder detrusor muscle (Table 79–2).
• Initiate therapy with an α1-adrenergic antagonist for faster onset of symptom relief.
Select a 5α-reductase inhibitor in patients with a prostate gland more than 40 g.
Consider combination therapy for symptomatic patients with a prostate gland more
than 40 g and PSA of 1.4 ng/mL or more (1.4 mcg/L).
• Consider monotherapy with a phosphodiesterase inhibitor or use in combination
with an α-adrenergic antagonist when erectile dysfunction and BPH are present.
• Agents that interfere with androgen stimulation of the prostate are not popular in the
United States because of adverse effects. Luteinizing hormone–releasing hormone
agonists leuprolide and goserelin decrease libido and can cause erectile dysfunction,
gynecomastia, and hot flashes. Antiandrogens bicalutamide and flutamide cause
nausea, diarrhea, and hepatotoxicity.

Mild
Watchful waiting
symptoms

α-adrenergic antagonist, phosphodiesterase


With erectile inhibitor, or both
dysfunction

α-adrenergic antagonist
Moderate Small prostate
BPH
symptoms and low PSA

5 α-reductase inhibitor or
Large prostate and 5 α-reductase inhibitor + α adrenergic
increased PSA antagonist

Predominant irritative α-adrenergic antagonist + anticholinergic


voiding symptoms agent

Complications of Minimally invasive surgery or prostatectomy


Severe symptoms
BPH

FIGURE 79–1.  Management algorithm for benign prostatic hyperplasia (BPH).


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Benign Prostatic Hyperplasia   |   CHAPTER 79

TABLE 79–2 Medical Treatment Options for Benign Prostatic Hyperplasia


Category Mechanism Drug (Brand Name)
Reduces Blocks α1-adrenergic receptors in prostatic Prazosin (Minipress)
dynamic stromal tissue Alfuzosin (Uroxatral)
factor
Terazosin (Hytrin)
Doxazosin (Cardura)
Blocks α1A-receptors in the prostate Tamsulosin (Flomax)
Silodosin (Rapaflo)
Causes smooth muscle relaxation of prostate, Tadalafil (Cialis)
bladder neck, and prostatic urethra
Reduce static Blocks 5α-reductase enzyme Finasteride (Proscar)
factor Blocks dihydrotestosterone at its intracellular Dutasteride (Avodart)
receptor Bicalutamide (Casodex)a
Blocks pituitary release of luteinizing Flutamide (Eulexin)a
hormone
Leuprolide (Lupron)a
Blocks pituitary release of luteinizing
hormone and blocks androgen receptor Goserelin (Zoladex)
a

Megestrol acetate (Megace)a


Other Relaxes detrusor muscle of bladder Tolterodine (Detrol)
Oxybutynin (Ditropan)
Trospium (Sanctura)
Solifenacin (Vesicare)
Darifenacin (Enablex)
Fesoterodine (Toviaz)
a
Not FDA approved for treatment of BPH.

α-Adrenergic Antagonists
• α-Adrenergic antagonists relax smooth muscle in the prostate and bladder neck,
increasing urinary flow rates by 2 to 3 mL/sec in 60% to 70% of patients and reducing
PVR urine volumes.
• α1-Adrenergic antagonists do not decrease prostate volume or PSA levels.
• Prazosin, terazosin, doxazosin, and alfuzosin are second-generation α1-adrenergic
antagonists. They antagonize peripheral vascular α1-adrenergic receptors in addition
to those in the prostate. Adverse effects include first-dose syncope, orthostatic hypo-
tension, and dizziness. Alfuzosin is less likely to cause cardiovascular adverse effects
than other second-generation agents.
• Slowly titrate to a maintenance dose at bedtime to minimize orthostatic hypotension
and first-dose syncope with immediate-release formulations of terazosin and doxa-
zosin. Sample titration schedules for terazosin include:

Titration Schedules
Terazosin Slow Terazosin Quicker
Days 1–3: 1 mg at bedtime Days 1–3: 1 mg at bedtime
Days 4–14: 2 mg at bedtime Days 4–14: 2 mg at bedtime
Weeks 2–6: 5 mg at bedtime Weeks 2–3: 5 mg at bedtime
Weeks 7 and on: 10 mg at bedtime Weeks 4 and on: 10 mg at bedtime

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• Tamsulosin and silodosin, third-generation α1-adrenergic antagonists, are selective


for prostatic α1A-receptors. Therefore, they do not cause peripheral vascular smooth
muscle relaxation and associated hypotension.
• Tamsulosin is a good choice for patients who cannot tolerate hypotension; has severe
coronary artery disease, volume depletion, cardiac arrhythmias, severe orthostasis, or
liver failure; or are taking multiple antihypertensives. Tamsulosin is also suitable for
patients who want to avoid the delay of dose titration.
• Potential drug interactions include decreased metabolism of α1-adrenergic antago-
nists with CYP 3A4 inhibitors (eg, cimetidine and diltiazem) and increased catabo-
lism of α1-adrenergic antagonists with concurrent use of CYP 3A4 stimulators (eg,
carbamazepine and phenytoin).
• Reduce the dose of silodosin in patients with moderate renal impairment or hepatic
dysfunction.

5α-Reductase Inhibitors
• 5α-Reductase inhibitors interfere with the stimulatory effect of testosterone. These
agents slow disease progression and decrease the risk of complications.
• Compared with α1-adrenergic antagonists, disadvantages of 5α-reductase inhibitors
include 6 months of use to maximally shrink prostate, less likely to induce objective
improvement and more sexual dysfunction.
• Whether the pharmacodynamic advantages of dutasteride confer clinical advan-
tages over finasteride is unknown. Dutasteride inhibits types I and II 5α-reductase,
whereas finasteride inhibits only type II. Dutasteride more quickly and completely
suppresses intraprostatic DHT (vs 80%–90% for finasteride) and decreases serum
DHT by 90% (vs 70%).
• 5α-Reductase inhibitors may be preferred in patients with uncontrolled arrhythmias,
poorly controlled angina, use multiple antihypertensives, or cannot tolerate hypoten-
sive effects of α1-adrenergic antagonists.
• Measure PSA at baseline and again after 6 months of therapy. If PSA does not
decrease by 50% after 6 months of therapy in a compliant patient, evaluate the patient
for prostate cancer.
• 5α-Reductase inhibitors are in FDA pregnancy category X and are therefore con-
traindicated in pregnant women. Pregnant and potentially pregnant women should
not handle the tablets or have contact with semen from men taking 5α-reductase
inhibitors.

Phosphodiesterase Inhibitors
• Increase in cyclic GMP by phosphodiesterase inhibitors (PI) may relax smooth
muscle in prostate and bladder neck. Effectiveness may be result of direct relaxation
of detrusor muscle of bladder.
• Tadalafil 5 mg daily improves voiding symptoms but does not increase urinary flow
rate or reduce PVR urine volume. Combination therapy with α-adrenergic antagonist
results in significant improvement in lower urinary tract symptoms, increased uri-
nary flow rates, and decreased PVR volume.

Anticholinergic Agents
• Addition of oxybutynin and tolterodine to α-adrenergic antagonists relieves irrita-
tive voiding symptoms including urinary frequency, urgency, and nocturia. Start with
lowest effective dose to determine tolerance of CNS adverse effects and dry mouth.
Measure PVR urine volume before initiating treatment (should be less than 250 mL).
• If systemic anticholinergic adverse effects are poorly tolerated, consider transder-
mal or extended-release formulations or uroselective agents (eg, darifenacin or
solifenacin).

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Benign Prostatic Hyperplasia   |   CHAPTER 79

SURGICAL INTERVENTION
• Prostatectomy, performed transurethrally or suprapubically, is the gold standard for
treatment of patients with moderate or severe symptoms of BPH and for all patients
with complications.
• Retrograde ejaculation complicates up to 75% of transurethral prostatectomy pro-
cedures. Other complications seen in 2% to 15% of patients are bleeding, urinary
incontinence, and erectile dysfunction.

PHYTOTHERAPY
• Although widely used in Europe for BPH, phytotherapy with products such as saw
palmetto berry (Serenoa repens), stinging nettle (Urtica dioica), and African plum
(Pygeum africanum) should be avoided. Studies are inconclusive, and the purity of
available products is questionable.

EVALUATION OF THERAPEUTIC OUTCOMES


• The primary therapeutic outcome of BPH therapy is restoring adequate urinary flow
without causing adverse effects.
• Outcome depends on the patient’s perception of effectiveness and acceptability of
therapy. The American Urological Association Symptom Score is a validated stan-
dardized instrument that can be used to assess patient quality of life.
• Objective measures of bladder emptying (eg, urinary flow rate and PVR urine vol-
ume) are useful measures in patients considering surgery.
• Monitor laboratory tests (eg, blood urea nitrogen, creatinine, and PSA) and urinalysis
regularly. An annual digital rectal examination is recommended if life expectancy is
at least 10 years.

See Chapter 67, Benign Prostatic Hyperplasia, authored by Mary Lee, for a more detailed
discussion of this topic.
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