B e n i g n P ro s t a t i c

Hyperplasia
a,b,
Robert C. Langan, MD *

KEYWORDS
 Benign prostatic hyperplasia  Lower urinary tract symptoms
 Alpha-adrenergic blockers  5-alpha reductase inhibitors
 Transurethral resection of the prostate

KEY POINTS
 Lower urinary tract symptoms (LUTS), which may be obstructive, irritative, or both, are
most commonly the result of benign prostatic hyperplasia (BPH) in aging men.
 The American Urologic Association Symptom Index is a validated scoring system that al-
lows physicians to assess the severity of LUTS, suggest initial treatment, and monitor the
response to treatment.
 Watchful waiting is a reasonable approach to men with mild LUTS due to BPH.
 Effective pharmacotherapy for BPH includes both alpha-adrenergic blockers and 5-alpha
reductase inhibitors.
 Surgical procedures, including less invasive modalities, are generally indicated for failure
of medical therapy, refractory urinary retention, recurrent urinary tract infection, persistent
hematuria, bladder stones, or renal insufficiency.

OVERVIEW

Benign prostatic hyperplasia (BPH) is the most common benign neoplasm of aging
men and is present in approximately 8% of men in the fourth decade of life but up
to 90% of men in the ninth decade.1 BPH refers to the change in the size of the pros-
tate and not the potential symptoms that it may cause, which are usually referred to as
lower urinary tract symptoms (LUTS). LUTS may be primarily irritative, obstructive, or
mixed. Men with BPH may be asymptomatic, respond to lifestyle changes, or require
medical or surgical therapy; symptoms are more common as men age. Once primarily
treated by urologists, guidelines now emphasize a primary care approach.2,3

Disclosure Statement: The author has nothing to disclose.

a
St. Luke’s Family Medicine Residency, Sacred Heart Campus, 450 Chew Street, Suite 101,
Allentown, PA 18102, USA; b Department of Family and Community Medicine, Temple Uni-
versity School of Medicine, Philadelphia, PA, USA
* 450 Chew Street, Suite 101, Allentown, PA 18102.
E-mail address: Robert.Langan@sluhn.org

Prim Care Clin Office Pract - (2019) -–-

https://doi.org/10.1016/j.pop.2019.02.003 primarycare.theclinics.com
0095-4543/19/ª 2019 Elsevier Inc. All rights reserved.
2 Langan

The prostate is an almond-shaped gland located at the junction of the urinary

bladder and the urethra in men. Its name derives from the Greek expression for
“one who stands before,” referring to its anatomic location. It secretes a milky, alkaline
fluid that constitutes approximately 30% of the volume of semen. It is covered by a
capsule of connective tissue that contains smooth muscle fibers and elastic tissue.
Within the capsule, 3 zones are identified: (1) the transition zone, located closest to
the urethra; (2) the central zone, where the common duct from the prostate and sem-
inal vesicles is found; and (3) the large peripheral zone. The normal volume of the pros-
tate gland is approximately 20 to 30 g.

PATHOPHYSIOLOGY AND RISK FACTORS

The pathophysiology of BPH is incompletely understood.4 Histologically, hyperplasia

of glandular elements in the periurethral zone and stromal elements in the transition
zone are responsible for the symptoms reported by men and are dependent on the
bioavailability of both testosterone and dihydrotestosterone (DHT).5 There is no clear
correlation between prostate size on physical examination and symptom severity.6
So-called static symptoms are due to simple anatomic obstruction, whereas dynamic
symptoms are mediated through a number of receptors (alpha-adrenergic,7 musca-
rinic,8 and phosphodiesterase-5 [PDE-5]).9 These receptors are the target for
pharmacotherapy.
In addition to increasing age, risk factors for the development of BPH include African
American race,10 obesity,11 type 2 diabetes mellitus,12 high levels of alcohol consump-
tion,13 and physical inactivity.14

PRESENTATION AND ASSESSMENT

Men with symptomatic BPH may present with obstructive symptoms, irritative symp-
toms, or a combination of both (Table 1). The American Urologic Association Symp-
tom Index (AUASI)15 is a validated, self-administered, quantitative measure of the
severity of LUTS due to BPH (Box 1). The AUASI score ranges from 0 (no symptoms)
to 35 (severe symptoms). In addition to diagnosis of BPH, the AUASI can aid in
selecting initial therapy (see Pharmacologic and Surgical Treatment sections) and
monitoring the response to therapy; a 3-point change on the AUASI scale is consid-
ered significant.16 In addition to the 7 symptom questions, an eighth question is often
added to assess quality of life due to BPH: If you were to spend the rest of your life with
your urinary condition just the way it is now, how would you feel about this? Scores for
this question range from 0 (delighted) to 6 (terrible).17 This 8-question symptom index
is called the International Prostate Symptom Score.
A number of medications may cause LUTS.18 Excessive alcohol, caffeine, or diuretic
use may result in diuresis. Anticholinergic medications, such as dicyclomine, impair

Table 1
Lower urinary tract symptoms of benign prostatic hyperplasia

Obstructive Symptoms Irritative Symptoms

1. Sensation of incomplete bladder emptying 1. Dysuria
2. Straining to void 2. Nocturia
3. Urinary hesitancy 3. Urinary frequency
4. Weak urinary stream 4. Urinary urgency

Data from Sarma AV, Wei JT. Benign prostatic hyperplasia and lower urinary tract symptoms. N Engl
J Med 2012;367(3):248–57.
 Benign Prostatic Hyperplasia 3

Box 1
American Urologic Association symptom index

In the past month, how often have you experienced the following symptoms?a
1. Sensation of not completely emptying your bladder
2. Need to urinate less than 2 hours after urinating
3. Stopped and started again while urinating
4. Found it difficult to postpone urination
5. Had a weak urinary stream
6. Had to push or strain to begin urinating
7. How many times do you get up at night to urinate?b
a
Scoring for questions 1 to 6: 0: Not at all; 1: Less than 20% of the time; 2: Less than 50% of
the time; 3: 50% of the time; 4: More than 50% of the time; 5: All of the time.
b
Scoring for question 7: Each time is worth 1 point (maximum of 5 points)
Total score is the sum of the scores for questions 1 to 7 (minimum 0, maximum 35)
Adapted from Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association
symptom index for benign prostatic hyperplasia. J Urol 1992;148:1555; with permission.

contractility of the smooth muscle of the urinary tract and may cause obstructive
symptoms. First-generation antihistamines, including diphenhydramine, increase
outlet obstruction. Other medications that may produce LUTS are alpha-agonists,
beta-blockers, and calcium channel blockers. If feasible, potentially offending medica-
tions should be stopped to see if symptoms improve.
On physical examination, a digital rectal examination (DRE) should be done to
assess sphincter tone, prostate size, and the presence of prostate nodules or
masses. If a nodule or mass is noted, urology consultation for potential biopsy is rec-
ommended. DRE tends to underestimate the prostate volume.19 A focused neuro-
logic examination should be done to assess for neurologic diseases that might
produce LUTS.
A limited laboratory assessment should be done in men with suspected BPH.
A urinalysis is recommended to exclude infection, which can produce LUTS,
and hematuria, which is not typically seen in BPH and should prompt further eval-
uation.20 If infection is detected, it should be treated before initiating therapy spe-
cific for BPH. Prostate-specific antigen (PSA) testing can be considered for men
who are have at least a 10-year life expectancy and desire screening, after an
appropriate discussion of its risks and limited benefits.20 PSA may be used to es-
timate the size of the prostate.21 Of note, PSA is not useful for differentiating BPH
from prostate cancer. If urinary obstruction is suspected, renal function should be
assessed with a serum blood urea nitrogen and creatinine, and ultrasound of the
bladder to measure residual volume should be done.22 Otherwise, imaging tests
and urodynamics are generally not indicated for men with suspected BPH.

NONPHARMACOLOGIC TREATMENT

In men with mild LUTS symptoms from BPH (usually defined as an AUASI score of
0–7), medical or surgical treatment is not required. In the Medical Therapy of Pros-
tatic Symptoms Study,23 fewer than 5% of men with mild symptoms who did not
receive treatment had a progression of their symptoms as defined by a 4-point
or greater increase in their AUASI score. No cases of acute kidney injury due to
obstructive uropathy occurred. Men who choose nonpharmacologic treatment
(Box 2) should be reassessed annually with the AUASI.
4 Langan

Box 2
Nonpharmacologic management of lower urinary tract symptoms

1. Moderate use of alcohol

2. Moderate use of caffeine
3. Avoid medications that may produce lower urinary tract symptoms
4. Limit salt intake
5. Maintain a time voiding schedule
6. Limit fluid intake 1 to 2 hours before sleep

Data from McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the manage-
ment of benign prostatic hyperplasia. J Urol 2011;185(5):1793–803.

PHARMACOLOGIC TREATMENT

Men with moderate to severe LUTS from BPH (AUASI score of 8 or higher) or mild
LUTS that are deemed bothersome by the patient may be offered pharmacologic
treatment. The 2 major classes of medications for BPH are alpha-adrenergic blockers
and 5-alpha reductase inhibitors. The PDE-5 inhibitor tadalafil is also approved by the
Food and Drug Administration (FDA) for the treatment of BPH. Many men also are
interested in the use of alternative therapy to treat LUTS.

ALPHA-ADRENERGIC BLOCKERS

The smooth muscle of the prostate and bladder neck is under the control of alpha-
adrenergic nerves. Stimulation of these sympathetic nerve fibers is associated with
contraction of the smooth muscle and an increase in dynamic urinary obstruction.7
The alpha-adrenergic blockers (“alpha blockers”) were originally developed as antihy-
pertensive agents, but fell out of favor after the alpha-blocker doxazosin was found to
have higher rates of stroke and combined cardiovascular events when compared with
a thiazide diuretic in the ALLHAT trial.24 However, their utility at blocking the sympa-
thetic fibers in the prostate and bladder and improving LUTS has led to their wide-
spread use for this indication.
Alpha blockers are further subdivided based on their selectivity for alpha-adrenergic
receptors located in the urinary tract. There does not seem to be a significant differ-
ence in the efficacy of these agents.25,26 On average, alpha blockers will reduce an
AUASI score by 4 to 6 points.4 Symptom relief typically occurs within 1 week after
starting therapy, but may take as long as 4 weeks to achieve.
Nonselective alpha blockers carry the highest risk of orthostatic hypotension,27 and
should be started at a low dose and titrated up over the period of a few weeks. They are
also associated with an increased risk of falls and fractures.28 In general, alpha
blockers should not be combined with PDE-5 inhibitors due to the risk of hypoten-
sion.29 In 2005, there were reports of progressive intraoperative miosis, billowing
and flaccid iris, and prolapse of the iris toward the incision site in men who had recently
started alpha blockers and were undergoing cataract surgery.30 This condition was
later termed intraoperative floppy iris syndrome, and the risk appears to be highest
in men taking tamsulosin. It is recommended that men who are planning on cataract
surgery in the next few weeks to months should not be started on an alpha-blocker.31
However, it is unclear if men who have been taking alpha blockers should stop it before
surgery or how long after surgery alpha blockers may be safely started.
Alpha blockers are listed in Table 2.
 Benign Prostatic Hyperplasia 5

Table 2
Alpha-adrenergic blockers

Type Drug Dose Side Effects

Nonselective Doxazosin 1 mg daily; titrate to maximum  Rhinitis
dose of 8 mg daily  Headache
Terazosin 1 mg daily; titrate to maximum  Orthostatic hypotension
dose of 20 mg daily (avoid use of
phosphodiesterase-5
inhibitors and titrate dose
slowly)
Selective Alfuzosin 10 mg daily  Retrograde ejaculation
Silodosin 8 mg daily  Rhinitis
Tamsulosin 0.4 mg daily; titrate to  Intraoperative floppy iris
maximum of 0.8 mg daily syndrome (tamsulosin)

Data from Sarma AV, Wei JT. Benign prostatic hyperplasia and lower urinary tract symptoms. N Engl
J Med 2012;367(3):248–57.

5-ALPHA REDUCTASE INHIBITORS

Prostatic tissue is stimulated by both testosterone and its metabolite DHT, which is
produced through the action of the enzyme 5-alpha reductase. Blocking the action
of 5-alpha reductase has the benefit of reducing the stimulation of prostatic tissue
through reduction of levels of DHT while preserving the androgen effects of testos-
terone. The available 5-alpha reductase inhibitors, finasteride and dutasteride, reduce
prostate size by as much as 25% and reduce the AUASI score by 4 to 5 points in men
with larger prostates, although over a much longer period than is seen with alpha-
adrenergic blockers (typically 2–6 months) (Table 3).32 Unlike alpha-adrenergic
blockers, 5-alpha reductase inhibitors are associated with a reduced risk of acute uri-
nary retention (number needed to treat of 26) and surgical intervention (number needed
to treat of 18) after 4 years.33 Although dutasteride inhibits both subsets of 5-alpha
reductase and finasteride inhibits only one, their efficacy appears to be similar.34 The
5-alpha reductase inhibitors should be used only in men with large prostates as deter-
mined by DRE, ultrasound, or the use of a surrogate marker, such as PSA.
Side effects of 5-alpha reductase inhibitors include decreased libido, erectile
dysfunction, decreased ejaculation, and gynecomastia.32 Because prostate cancer
is also stimulated by DHT, trials were undertaken to assess if these medications could
be used to reduce the risk of developing neoplasms of the prostate. Use of either
agent was associated with a 6% absolute risk reduction in the development of pros-
tate cancer but also an increased risk of developing a moderate-risk to high-risk pros-
tate cancer for unknown reasons.35–37 Consequently, 5-alpha reductase inhibitors are
not recommended as chemoprophylaxis against the development of prostate cancer.
Because PSA levels decrease by approximately 50% after 6 months of therapy, any
significant increase in PSA should prompt urologic evaluation.4

COMBINATION ALPHA-ADRENERGIC BLOCKERS/5-ALPHA REDUCTASE INHIBITORS

A number of trials have explored the use of combinations of alpha-adrenergic blockers

and 5-alpha reductase inhibitors in the treatment of LUTS.23,38 Combinations
including doxazosin with finasteride and tamsulosin with dutasteride demonstrated
superior improvement in AUASI scores when compared with each component alone.
The American Urologic Association lists combination therapy as an option, stating
6 Langan

Table 3
5-alpha reductase inhibitors

Drug Enzyme Inhibited Dose Side Effects

Finasteride 5-alpha reductase, type 2 5 mg daily  Abnormal ejaculation
Dutasteride 5-alpha reductase, types 1 and 2 0.5 mg daily  Decreased prostate-specific
antigen level
 Erectile dysfunction
 Gynecomastia
 Increased risk of high-grade
prostate cancer

Data from Sarma AV, Wei JT. Benign prostatic hyperplasia and lower urinary tract symptoms. N Engl
J Med 2012;367(3):248–57.

that, “The combination of an alpha-blocker and a 5a-reductase inhibitor (combination

therapy) is an appropriate and effective treatment for patients with LUTS associated
with demonstrable prostatic enlargement based on volume measurement, PSA level
as a proxy for volume, and/or enlargement on DRE.”20 Fixed-dose combination ther-
apy is more expensive than the individual components and combination therapy is
associated with more side effects. Currently, the only fixed-dose product available
in the United States is dutasteride 0.5 mg/tamsulosin 0.4 mg.

PHOSPHODIESTERASE-5 INHIBITORS

As previously mentioned, PDE-5 is present throughout prostatic tissue, the bladder

detrusor muscle, and vascular smooth muscle that is associated with the urinary
tract.9 The PDE-5 inhibitors, which were initially approved by the FDA for the treatment
of erectile dysfunction, may also improve LUTS. When PDE-5 is inhibited, the resulting
increase in cyclic AMP and cyclic guanosine monophosphate relaxes smooth muscle.
Of the available PDE-5 inhibitors, only tadalafil has been approved for the treatment of
LUTS from BPH. In a 12-week trial, daily tadalafil improved the AUASI by 3.8 points.39
Side effects include headache, indigestion, back pain, flushing, and nasal congestion.
Combining tadalafil with an alpha-adrenergic blocker or nitrate can cause symptom-
atic hypotension.29

COMPLEMENTARY MEDICATIONS

A number of herbal supplements have been tried for the treatment of LUTS. Perhaps
the most extensively studied has been saw palmetto (Serenoa repens), but a 2012
Cochrane review concluded that it did not improve urinary flow or prostate size.40
There is insufficient evidence to support the use of other supplements, such as African
plum bark, purple cone flower roots, stinging nettle, South African star grass, rye pol-
len extract, or pumpkin seeds.20

SURGICAL THERAPIES

Several procedures are available for the treatment of symptomatic BPH. General indi-
cations for surgical treatment are listed in Box 3. The most commonly performed sur-
gical procedure is transurethral resection of the prostate (TURP), which is considered
the gold standard. Men should be screened for urinary tract infection as part of a pre-
operative evaluation; if present, it should be treated before surgery. Potential compli-
cations include retrograde ejaculation, erectile dysfunction, hematuria, urethral
 Benign Prostatic Hyperplasia 7

Box 3
Indications for surgical treatment of benign prostatic hypertrophy

1. Failure of medical therapy

2. Refractory urinary retention
3. Recurrent urinary tract infection
4. Persistent hematuria
5. Bladder stones
6. Renal insufficiency

Data from McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the manage-
ment of benign prostatic hyperplasia. J Urol 2011;185(5):1793–803.

stricture, and urinary tract infection. Approximately 5% to 10% of men who undergo
TURP will require a repeat procedure with 10 years.20
A number of less invasive procedures have been developed for the treatment of
BPH. In general, these procedures are associated with less morbidity than TURP
but are also associated with a higher risk of need for retreatment. Healthy men with
low surgical risk are appropriate for TURP, whereas men with higher surgical risk or
who cannot tolerate general anesthesia may require less invasive surgical treatment.
Examples of these procedures include photoselective vaporization of the prostate,
transurethral incision of the prostate, transurethral laser prostatectomy, and transure-
thral microwave prostate.
Prostatic urethral lift is a noninvasive procedure in which a permanent implant is
placed via cystoscopy that relieves the obstruction from BPH. Studies have shown
that it produces an improvement in AUASI of up to 11 points in as early as 3 months,41
and these improvements have been shown to persist after 5 years.42 Unlike TURP,
prostatic urethral lift is not associated with side effects such as erectile dysfunction
or retrograde ejaculation.43 Patients should have large (greater than 100 g) prostates
that can be compressed with a rigid cystoscope.

SUMMARY

In summary, BPH is a common condition in aging men that is frequently associated

with troublesome LUTS. The AUASI is a validated, self-administered tool that can
be used to diagnose LUTS, guide initial treatment, and assess response to treatment.
Watchful waiting is a reasonable option for men with mild symptoms. The mainstay of
pharmacologic treatment is alpha-adrenergic blockers and 5-alpha reductase inhibi-
tors. There is no evidence to support the use of herbal supplements in the treatment
of LUTS. Surgical therapy is effective and is indicated for men with complications from
BPH or who fail medical therapy.

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 Benign Prostatic Hyperplasia 9

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10 Langan

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