Benign Prostate Hyperplasia

Benign prostatic hyperplasia (BPH), also called benign enlargement of the prostate
(BEP),

adenofibromyomatous

hyperplasia

and

benign

prostatic

hypertrophy

(technically incorrect usage), is an increase in size of the prostate.

BPH involves hyperplasia of prostatic stromal and epithelial cells, resulting in the
formation of large, fairly discrete nodules in the periurethral region of the prostate.
When sufficiently large, the nodules compress the urethral canal to cause partial, or
sometimes virtually complete, urinary tract obstruction by the urethra, which
interferes with the normal flow of urine. It leads to symptoms of urinary hesitancy,
frequent urination, increased risk of urinary tract infections, urinary retention, or
contribute to or cause insomnia. Although prostate specific antigen levels may be
elevated in these patients because of increased organ volume and inflammation due
to urinary tract infections, BPH does not lead to cancer or increase the risk of cancer.
BPH involves hyperplasia (an increase in the number of cells) rather than
hypertrophy (a growth in the size of individual cells), but the two terms are often
used interchangeably, even amongst urologists.
Adenomatous prostatic growth is believed to begin at approximately age 30 years.
An estimated 50% of men have histologic evidence of BPH by age 50 years and 75%
by age 80 years; in 4050% of these men, BPH becomes clinically significant.
ETIOLOGY
Most experts consider androgens (testosterone and related hormones) to play a
permissive role. This means that androgens have to be present for BPH to occur, but
do not necessarily directly cause the condition. This is supported by the fact that
castrated boys do not develop BPH when they age. On the other hand, administering
exogenous testosterone is not associated with a significant increase in the risk of BPH
symptoms. Dihydrotestosterone (DHT), a metabolite of testosterone, is a critical
mediator of prostatic growth. DHT is synthesized in the prostate from circulating
testosterone by the action of the enzyme 5-reductase, type 2. This enzyme is
localized principally in the stromal cells; hence, those cells are the main site for the
synthesis of DHT.
DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by
diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear
androgen receptors and signals the transcription of growth factors that are mitogenic

to the epithelial and stromal cells. DHT is 10 times more potent than testosterone
because it dissociates from the androgen receptor more slowly. The importance of
DHT in causing nodular hyperplasia is supported by clinical observations in which an
inhibitor of 5-reductase such as finasteride is given to men with this condition.
Therapy with a 5-reductase inhibitor markedly reduces the DHT content of the
prostate and, in turn, reduces prostate volume and, in many cases, BPH symptoms.
Testosterone promotes prostate cell proliferation, but relatively low levels of serum
testosterone are found in patients with BPH. One small study has shown that medical
castration lowers the serum and prostate hormone levels unevenly, having less effect
on testosterone and dihydrotestosterone levels in the prostate.
While there is some evidence that estrogen may play a role in the etiology of BPH,
this effect appears to be mediated mainly through local conversion of androgens to
estrogen in the prostate tissue rather than a direct effect of estrogen itself. In canine
in vivo studies castration, which significantly reduced androgen levels but left
estrogen levels unchanged, caused significant atrophy of the prostate. Studies
looking for a correlation between prostatic hyperplasia and serum estrogen levels in
humans have generally shown none.
In 2008, Yigal Gat et al. published evidence that BPH is caused by failure in the
spermatic venous drainage system resulting in increased hydrostatic pressure and
local testosterone levels elevated more than 100 fold above serum levels. If
confirmed, this mechanism explains why serum androgen levels do not seem to
correlate with BPH and why giving exogenous testosterone would not make much
difference. This also has implications for treatment (see Minimally invasive therapies
below).
On a microscopic level, BPH can be seen in the vast majority of men as they age, in
particular over the age of 70 years, around the world. However, rates of clinically
significant, symptomatic BPH vary dramatically depending on lifestyle. Men who lead
a western lifestyle have a much higher incidence of symptomatic BPH than men who
lead a traditional or rural lifestyle. This is supported by research [citation needed] in
China showing that men in rural areas have very low rates of clinical BPH, while men
living in cities adopting a western lifestyle have a skyrocketing incidence of this
condition, though it is still below rates seen in the West. It also seems [citation
needed] that there is some connection between microcalcifications between prostate
cancer and BPH, as is demonstrated in 50-75% of men over 50 years.

RISK FACTOR
Demographic factors:
The prevalence of BPH increases with age
The risk of acquiring BPH is 47% higher among black men

Genetic factors:
There is a three-fold increase in the risk of BPH in monozygotic twins with an
affected sibling, suggesting that family history may be a risk factor; however,
the exact role of familial transmission remains ambiguous
Other genetic factors that may be related to BPH development include:
o Vitamin D3vitamin D receptor regulates both epithelial and cell growth
proliferation
o Cytochrome P45017 mediates sex steroid hormone synthesis, which may
influence BPH risk
o Steroid-5-reductase enzyme converts testosterone to DHT, which
promotes prostate cell proliferation

Behavioral and comorbid factors:

Obesity
The risk of BPH increases by 10% for each 0.05-increase in the waist-to-hip
ratio
The increase in adipose aromatization of testosterone to estrogen and the
altered levels of testosterone and sex hormonebinding globulin in patients
with increased adipose stores promote prostatic epithelial and stromal
proliferation
Obesity is also associated with an increase in sympathetic tone, which
promotes prostatic cellular proliferation through a mechanism that is not well
understood. Although still inconclusive, various mechanisms have been
proposed

to

explain

the

relationship

between

obesity

and

increased

sympathetic tone, including:

Insulin levels increasing in proportion to the amount of adipose stores
increase sympathetic neural activity
Leptin, a protein hormone secreted by adipocytes, increases sympathetic
neural activity
Activation of

the

renin-aldosterone-angiotensin

system

enhances

sympathetic tone
Moderate to vigorous exercise reduces the risk of BPH by 25%
Dietary factors
High intake of polyunsaturated fats increases the risk of BPH (relative risk [RR],
1.17)
A diet high in beef products increases the risk of BPH by 25%
A fatty acidrich diet increases the substrate for the synthesis of cholesterol,
which increases the substrate for androgen synthesis
Alcohol consumption appears to have a protective effect on BPH development.
The risk decreases by 50% in men who consume three drinks of alcohol per
day. The association is thought to be related to alcohol's cardiovascular effects
and modulation of steroid hormone metabolism
Other factors:
Systemic hypertension increases the risk of severe lower urinary tract
symptoms by 76%
Elevated fasting plasma glucose increases the risk of BPH. Glucose regulation is
hypothesized to influence prostate growth. Elevated insulin levels are
associated with increased prostate volume
Cirrhosis of the liver is protective against BPH development, potentially
because of the high level of estrogen relative to androgen present
There is no clear association between smoking and BPH
EPIDEMIOLOGY
BPH is a common problem that affects the quality of life in approximately one third of
men older than 50 years. BPH is histologically evident in up to 90% of men by age 85
years. As many as 14 million men in the United States have symptoms of BPH.
Worldwide, approximately 30 million men have symptoms related to BPH.
The prevalence of BPH in white and African-American men is similar. However, BPH
tends to be more severe and progressive in African-American men, possibly because
of the higher testosterone levels, 5-alpha-reductase activity, androgen receptor
expression, and growth factor activity in this population. The increased activity leads
to an increased rate of prostatic hyperplasia and subsequent enlargement and its
sequelae.
Globally, benign prostatic hyperplasia affects about 210 million males as of 2010 (6%
of the population). The prostate gets larger in most men as they get older. For a
symptom-free man of 46 years, the risk of developing BPH over the next 30 years is

45%. Incidence rates increase from 3 cases per 1000 man-years at age 4549 years,
to 38 cases per 1000 man-years by the age of 7579 years. While the prevalence
rate is 2.7% for men aged 4549, it increases to 24% by the age of 80 years.

Disability-adjusted life year for benign prostatic hyperplasia per 100,000 inhabitants
in 2004.

PATHOPHYSIOLOGY AND PATHOGENESIS

The pathophysiology of bladder outlet obstruction in men with BPH has been
attributed to both static and dynamic factors.7 The static obstruction is due to the
bulk enlargement of the prostate encroaching upon the prostatic urethra and bladder
outlet, whereas the dynamic obstruction is related to the tension of prostate smooth
muscle. The medical therapies widely used today for treatment of BPH are targeted
to diminishing bladder outlet obstruction in order to reduce prostate volume and
relax prostate smooth muscle tension.6 Clinical data demonstrate that androgen
suppression and -blockade relieve and increase urinary flow rates in men with BPH;

these data have been used to support the hypothesis that the pathophysiology of
prostatism is due to bladder outlet obstruction.
Historically, it has often been assumed that the pathophysiology of LUTS in men is
the result of bladder outlet obstruction associated with prostatic enlargement.8 The
observation that prostatic enlargement, bladder outlet obstruction, and LUTS are all
age-dependent was interpreted to indicate that these phenomena were causally
related,9 but there is insufficient evidence for this. The relationships between
prostate volume, bladder outlet obstruction, and LUTS are optimally defined by
measuring these parameters in a group of men selected at random from the
community. Girman and colleagues5 measured prostate volume using transrectal
ultrasonography, peak flow rate, and the AUA symptom score in 464 men between
the ages of 40 and 80 years, selected at random from the residents of Olmsted
County, MN. The P and r2 values for the pairwise relationships between prostate
volume and peak flow rate, prostate volume and symptom score, and peak flow rate
and symptom score are shown in Table 2. These observations demonstrate that the
size of the prostate is a very weak determinant of symptom severity and bladder
outlet obstruction, and that bladder outlet obstruction is only a minor determinant of
symptom severity.
One explanation for the poor correlation between bladder outlet obstruction and
symptom severity is that peak flow rate is not a reliable proxy for bladder outlet
obstruction. Only a weak correlation exists between peak flow rate and synchronous
pressure

flow

studies.

Because

pressure

flow

studies

are

invasive,

these

measurements have not been performed in a community population. Investigators

have failed to show a clinically or statistically significant correlation between the
severity of bladder outlet obstruction, based upon detrusor pressures at peak flow
rate, and severity of LUTS.11
Studies comparing LUTS, bladder outlet obstruction, and prostate size among
different races provide additional evidence that prostate size is not an important
factor leading to the development of LUTS and lowered peak flow rate. The AUA
symptom score, peak flow rate, and prostate volume were measured in communitybased surveys of men in the United States (Olmsted County, MN) and Japan
(Shimomaki-nura) (Table 3).12 The Japanese men had smaller prostates, higher peak
flow rates, and more severe symptoms. The discordance between symptom scores
and prostate volumes, and symptom scores and peak flow rates, in these two
population studies, provides further evidence that the severity of LUTS is not

explained by bladder outlet obstruction or prostate volume.

Oesterling and colleagues3 reported the distribution of prostate size in a cohort of
randomly selected men living in Olmsted County, MN. Interestingly, the mean
prostate volume and the distribution of prostate volumes were almost identical to
subjects with both LUTS (AUA symptom score 8) and bladder outlet obstruction
(peak urinary flow rates from 4 to 15 mL/sec) who were enrolled in the Veterans
Affairs Cooperative Studies Benign Prostatic Hyperplasia Study (VA-COOP) (Figure
1).13 The fact that a random population of men has the same mean prostate volume
and distribution of prostate volume as a group of age-matched men with clinical BPH,
provides further evidence that prostate size is relatively unimportant in the
development of LUTS and bladder outlet obstruction.
Estimated median prostate volume as a function of age for the finasteride North
American Study, VA Study, and Olmsted County Community Study. Reproduced from
Boyle et al,13 with permission from the publisher, Elsever Science.Additional
evidence questioning the influence of prostatic enlargement on the pathophysiology
of LUTS in the aging male comes from studies comparing the incidences of symptoms
in men and women. Lepor and Machi14 administered the AUA symptom score to a
group of 101 males and 99 females between the ages of 55 and 79 years. Subjects
were attending a general health symposium with no emphasis on genitourinary
diseases. Mean AUA symptom scores were equivalent in men (6.9) and women (7.7).
The AUA score was subgrouped into obstructive and irritative scores. The obstructive
symptom scores in men (2.7) and women (2.9) were not significantly different.
Similarly, the irritative scores in the men (4.2) and women (4.8) were not significantly
different. The development of LUTS characteristic of BPH is a non-gender- specific
event associated with aging. It is conceivable that the pathophysiology of LUTS in
men and women is different. Nevertheless, the observation that the prevalence of
LUTS characteristic of clinical BPH is equivalent in men and women suggests that
important nonprostatic mechanisms likely exist for the development of symptoms.
One of the life-threatening consequences of BPH is the development of urinary
retention. Although prostate volume does not appear to be an important predictor of
LUTS severity, there is increasing evidence that the risk of developing urinary
retention is related to prostate size.15 Finasteride has been shown to reduce the risk
of developing urinary retention but the effect of finasteride on reducing the risk of
urinary retention is prostate-sizedependent.16 Reducing prostate volume with 5reductase inhibitors only represents a reasonable strategy for decreasing the risk of

urinary retention in men with large prostates.

In summary, there is no clinically significant relationship between prostatic
enlargement and LUTS in men with clinical BPH. There is only a weak relationship
between LUTS and bladder outlet obstruction. Therefore, factors other than prostatic
enlargement and bladder outlet obstruction must contribute to the development and
severity of LUTS.

CLINICAL MANIFESTATIONS
The diagnosis of benign prostatic hyperplasia (BPH) can often be suggested on the
basis of the history alone. Special attention to the following features is essential to
making the correct diagnosis:

Onset and duration of symptoms

General health issues (including sexual history)
Fitness for any possible surgical interventions
Severity of symptoms and how they are affecting quality of life
Medications
Previously attempted treatments

Symptoms often attributed to BPH can be caused by other disease processes, and a
history and physical examination are essential in ruling out other etiologies of (lower
urinary tract symptoms (LUTS) (see Diagnostic Considerations).
When the prostate enlarges, it may act like a "clamp on a hose," constricting the flow
of urine. Nerves within the prostate and bladder may also play a role in causing the
following common symptoms:
Urinary frequency - The need to urinate frequently during the day or night
(nocturia), usually voiding only small amounts of urine with each episode
Urinary urgency - The sudden, urgent need to urinate, owing to the sensation
of imminent loss of urine without control
Hesitancy - Difficulty initiating the urinary stream; interrupted, weak stream
Incomplete bladder emptying - The feeling of persistent residual urine,
regardless of the frequency of urination
Straining - The need strain or push (Valsalva maneuver) to initiate and maintain
urination in order to more fully evacuate the bladder
Decreased force of stream - The subjective loss of force of the urinary stream
over time

 Dribbling - The loss of small amounts of urine due to a poor urinary stream
A sexual history is important, as epidemiologic studies have identified LUTS as
an independent risk factor for erectile dysfunction and ejaculatory dysfunction

DIAGNOSIS

TREATMENT AND MEDICATIONS

Patients with mild symptoms (IPSS/AUA-SI score < 7) or moderate-to-severe

symptoms (IPSS/AUA-SI score 8) of benign prostatic hyperplasia (BPH) who are not
bothered by their symptoms and are not experiencing complications of BPH should
be managed with a strategy of watchful waiting. In these situations, medical therapy
is not likely to improve their symptoms and/or quality of life (QOL). In addition, the
risks of treatment may outweigh any benefits. Patients managed expectantly with
watchful waiting are usually re-examined annually.
Transurethral resection of the prostate (TURP) has long been accepted as the
criterion standard for relieving bladder outlet obstruction (BOO) secondary to BPH. In
current clinical practice, most patients with BPH do not present with obvious surgical
indications; instead, they often have milder lower urinary tract symptoms (LUTS) and,
therefore, are initially treated with medical therapy.
The era of medical therapy for BPH dawned in the mid 1970s with the use of
nonselective alpha-blockers such as phenoxybenzamine. The medical therapeutic
options for BPH have evolved significantly over the last 3 decades, giving rise to the
receptor-specific alpha-blockers that comprise the first line of therapy.
Alpha-1Receptor Blockade in Benign Prostatic Hyperplasia
A significant component of LUTS secondary to BPH is believed to be related to the
smooth-muscle tension in the prostate stroma, urethra, and bladder neck. The
smooth-muscle tension is mediated by the alpha-1-adrenergic receptors; therefore,
alpha-adrenergic receptorblocking agents should theoretically decrease resistance
along the bladder neck, prostate, and urethra by relaxing the smooth muscle and
allowing passage of urine.
BPH is predominantly a stromal proliferative process, and a significant component of
prostatic enlargement results from smooth-muscle proliferation. The stromal-toepithelial ratio is significantly greater in men with symptomatic BPH than in those
with asymptomatic BPH.
The 3 subtypes of the alpha-1 receptor include 1a, 1b, and 1c. Of these, the alpha-1a
receptor is most specifically concentrated in the bladder neck and prostate. Provided
that the alpha-1a subtype is predominant in the prostate, bladder neck, and urethra,
but not in other tissues, drugs that are selective for this receptor (ie, tamsulosin) may
have a potential therapeutic advantage.
Tamsulosin

is

considered

the

most

pharmacologically

uroselective

of

the

commercially available agents because of its highest relative affinity for the alpha-1a

receptor subtype. In 2008, the US Food and Drug Administration (FDA) approved a
new alpha-1a receptor selective blocker, silodosin (Rapaflo). It is indicated for
treatment of the signs and symptoms of BPH.
The efficacy of the titratable alpha-blockers doxazosin and terazosin (Hytrin) is dosedependent. Maximum tolerable doses have not been defined for any alpha-blocker;
however, the higher the dose, the more likely the adverse events (orthostatic
hypotension, dizziness, fatigue, ejaculatory disorder, nasal congestion). Despite the
requirement for dose titration and blood pressure monitoring, these older, often less
costly, alpha-blockers appear to be equally effective to tamsulosin and alfuzosin, and
the 2010 AUA guidelines state that they remain reasonable choices for patients with
moderate-to-severe LUTS due to BPH.[1]
An approximately 4- to 6-point improvement is expected in IPSS/AUA-SI scores when
alpha-blockers are used. Interestingly, alpha-blocker therapy has not been shown to
reduce the overall long-term risk for acute urinary retention (AUR) or BPH-related
surgery.[7]
Hellstrom and Sikka reported in 2006 that the acute administration of tamsulosin
effects ejaculatory function and ejaculate volume. Nearly 90% of study subjects
experienced decreased ejaculate volume, and approximately 35% experienced
anejaculation. In their study, subjects treated with alfuzosin or placebo did not
experience anejaculation.[8]
Alpha-adrenergic receptor blockers
The alpha-blocking agents administered in BPH studies can be subgrouped according
to receptor subtype selectivity and the duration of serum elimination half-lives, as
follows:
Nonselective alpha-blockers - phenoxybenzamine
Selective short-acting alpha-1 blockers - prazosin, alfuzosin, indoramin
Selective long-acting alpha-1 blockers - terazosin, doxazosin, slow-release (SR)
alfuzosin.
Partially subtype (alpha-1a)selective agents tamsulosin, silodosin
Nonselective alpha-blockers
Phenoxybenzamine was the first alpha-blocker studied for BPH. It is nonselective,
antagonizing both the alpha 1- and alpha 2-adrenergic receptors, which results in a
higher incidence of adverse effects. Because of the availability of more alpha-1-

receptorspecific agents, phenoxybenzamine is currently not often used for the

treatment of BPH. The 2010 update to the AUA guideline for BPH retains the
statement that insufficient data exist for a recommendation of phenoxybenzamine or
of prazosin for treatment of LUTS secondary to BPH. This statement was originally
published in the 2003 AUA BPH guidelines.[1]
Phosphodiesterase-5 enzyme inhibitors
Statistically significant symptomatic improvements have been reported for patients
with BPH receiving tadalafil. It has also been approved for the treatment of
simultaneous

BPH

and

erectile

dysfunction

(ED).

Phosphdiesterase-5

(PDE5)

inhibitors are known to mediate smooth muscle relaxation in the lower urinary tract.
Intraoperative floppy iris syndrome
Intraoperative floppy iris syndrome (IFIS) is characterized by miosis, iris billowing,
and prolapse in patients undergoing cataract surgery who have taken or currently
take alpha-1-blockers. It is particularly prevalent among patients taking tamsulosin.
The 2010 AUA guideline recommends that clinicians ask patients about planned
cataract surgery when offering alpha-blocker therapy for LUTS due to BPH. Alphablockers should not be initiated until cataract surgery is completed.[1] Patients
currently on alpha-blocker therapy must disclose this to their ophthalmologist prior to
cataract surgery so that the appropriate preoperative and intraoperative precautions
can be taken. Experienced ophthalmologists can thereby reduce the risk of
complications from IFIS.[9, 1]
In a review by Bell et al, exposure to tamsulosin within 14 days of cataract surgery
was significantly associated with serious postoperative ophthalmic adverse events,
specifically IFIS and its complications (ie, retinal detachment, lost lens or fragments,
endophthalmitis). No significant associations were noted with exposure to other
alpha-blocker medications or to previous exposure to tamsulosin or other alphablockers.[10]
5-Alpha-Reductase Inhibitors in Benign Prostatic Hyperplasia
Hormonal medical management emerged from the discovery of a congenital form of
pseudohermaphroditism secondary to DHT deficiency (due to a lack of 5-alphareductase activity). This deficiency produced a hypoplastic prostate. The two types of
5-alpha-reductase include type 1 (predominantly located in extraprostatic tissues,
such as skin and liver) and type 2 (predominant prostatic reductase).

Inhibition of 5-alpha-reductase type 2 blocks the conversion of testosterone to DHT,

resulting in lower intraprostatic levels of DHT. This leads to inhibition of prostatic
growth, apoptosis, and involution. The exact role of 5-alpha-reductase type 1 in
normal and abnormal prostatic development is undefined. 5-Alpha-reductase
inhibitors improve LUTS by decreasing prostate volumes; thus, patients with larger
prostates may achieve a greater benefit. Further, maximal reduction in prostate
volume requires 6 months of therapy.
5-Alpha reductase inhibitors
Finasteride (Proscar), a 4-aza-steroid, has demonstrated 5-alpha type IIblocking
activity, resulting in the inhibition of DHT-receptor complex formation. This effect
causes a profound decrease in the concentration of DHT intraprostatically, resulting
in a consistent decrease in prostate size. One third of men treated with this agent
exhibit improvements in urine flow and symptoms.
Dutasteride (Avodart) has an affinity for both type 1 and type 2 5-alpha-reductase
receptors. The significance of blockage of type 1 receptors is currently unknown.
Both finasteride and dutasteride actively reduce DHT levels by more than 80%,
improve symptoms, reduce the incidence of urinary retention, and decrease the
likelihood of surgery for BPH. Adverse effects are primarily sexual in nature
(decreased libido, erectile dysfunction, ejaculation disorder).
Both finasteride and dutasteride may reduce serum prostate-specific antigen (PSA)
values by as much as 50%. The decrease in PSA is typically maximally achieved
when the maximal decrease in prostatic volume is noted (6 months). Thus, one must
take this into account when using PSA to screen for prostate cancer.
One

prospective,

randomized,

double-blind

study

by

the

Enlarged

Prostate

International Comparator Study (EPICS) was conducted to compare the efficacy of

dutasteride to that of finasteride in men with symptomatic BPH. While this study was
conducted over the course of only one year, the data suggest that both of these
drugs were similarly effective in reducing prostate volume, improving Qmax, and
LUTS for this population. The long-term outcomes are yet to be investigated.[11]
Because these drugs interfere with the metabolism of testosterone, they are
contraindicated in children and pregnant females. In addition, pregnant females or
those who are considering conception should not handle crushed or broken tablets
because of the potential for absorption and subsequent potential risk to a male fetus.

In patients with LUTS and enlarged prostates, 5-alpha-reductase inhibitors are

believed to be appropriate and effective treatment.
5-Alpha reductase inhibitors and prostate cancer
On June 9, 2011, the US Food and Drug Administration (FDA) announced revisions to
the prescribing information for 5-alpha reductase inhibitors (5-ARIs). These agents
include finasteride (Proscar, Propecia) and dutasteride (Avodart, Jalyn). 5-ARIs are
indicated for benign prostatic hypertrophy and alopecia.
Data from 2 large, randomized, controlled trials observed an increased risk of being
diagnosed with a more serious form of prostate cancer (high-grade prostate cancer)
in trial participants taking 5-ARIs. The 2 trials are the Prostate Cancer Prevention Trial
(PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.
Both of these trials observed a decreased incidence of prostate cancer overall when
preventive treatment included 5-ARIs, but an increased incidence of high-grade
prostate cancer in men taking dutasteride or finasteride compared with placebo.[12,
13]
The revised prescribing information recommends that prior to initiating therapy with
5-ARIs, perform appropriate evaluations to rule out other urological conditions,
including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).

Combination Therapy
The alpha-1-receptor blockers provide rapid relief, while the 5-alpha-reductase
inhibitors target the underlying disease process.[7] The Medical Therapy of Prostatic
Symptoms (MTOPS) trial demonstrated that combination therapy reduced the risk of
progression and produced a greater improvement in IPSS than therapy with
finasteride or doxazosin alone. The risks of AUR and BPH-related surgery were
reduced with combination therapy or finasteride in comparison with doxazosin
monotherapy.[14]
The Symptom Management After Reducing Therapy (SMART-1) trial demonstrated
that after 6 months of combination therapy, discontinuation of the alpha-1-blocker is
possible in men with moderate LUTS. However, those with severe LUTS may require
longer combination therapy.[14]
Anticholinergic Agents

Historically, anticholinergics were discouraged in men with BPH because of concerns

of inducing urinary retention. Trials have demonstrated a slight increase in PVR;
however, AUR rates were low. Importantly, these trials consisted of patients with low
baseline PVR.
The 2010 AUA BPH guidelines recommend anticholinergic agents for management of
LUTS in patients who do not have an elevated PVR and whose LUTS are primarily
irritative. Baseline PVR should be obtained prior to initiation of anticholinergic
therapy, to assess for urinary retention.[15] Caution with anticholinergics is
recommended with patients whose PVR is greater than 250-300 mL.[1]
Landmark Clinical Trials
Numerous phase II and phase III trials of drugs used in the treatment of BPH have
been conducted. A few landmark studies are selected below.
The Proscar Long-Term Efficacy and Safety Study (PLESS), patients treated with
finasteride (5 mg/d) were at a significantly lower risk of developing AUR or needing
surgery.[16] This was a multicenter, 4-year, double-blind, placebo-controlled study of
3,040 men. Men with PSA levels of more than 10 ng/mL and those with prostate
cancer were excluded.
The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated that
combination therapy with doxazosin and finasteride was well tolerated, and was
superior to placebo and monotherapy with either agent. The primary endpoints of the
study were reduction in AUA-SI score, AUR, recurrent infections, renal insufficiency,
incontinence, changes in flow, and PSA level and a lower rate of invasive treatments.
MTOPS was a multicenter, 4- to 6-year, double-blind, randomized, placebo-controlled
trial of 3,047 men with symptomatic BPH.[17]
In the Alfuzosin Long-Term Efficacy and Safety Study (ALTESS), alfuzosin (10 mg/d)
decreased the risk of LUTS deterioration and significantly improved QOL and peak
urinary flow rate. ALTESS was a 2-year, double-blind, placebo-controlled study of
1,522 men. Notably, these men had greater risk factors for BPH progression (ie, older
age, higher IPSS scores, larger prostate size, lower Qmax, and higher PVR) than those
in the MTOPS trial. Alfuzosin did not reduce the risk of AUR but tended to reduce the
risk of surgery.[18]
In the international real-life practice study of alfuzosin once daily (ALF-ONE), 3 years
of alfuzosin (10 mg/d) decreased IPSS by one third, with significant improvements in

nocturia and bother score. ALF-ONE was conducted in 689 European men with a
mean age of 67.6 years. Clinical progression of worsening of IPSS (4 points) was
seen in 12.4%, AUR in 2.6%, and requirement of BPH-related surgery in 5.7%.
Alfuzosin was well tolerated, with dizziness the most common adverse effect (4.5%).
Notably, symptom worsening during treatment and high PSA levels appeared to be
the best predictors of clinical progression.[19]
Four-year results in the Combination of Avodart and Tamsulosin (CombAT) study
revealed that for men with prostate volumes of 30-58 mL, combination therapy with
dutasteride (dual 5-alpha-reductase inhibitor) and tamsulosin (alpha-1-blocker)
improved symptoms, urinary flow, and QOL better than monotherapy with either
drug, although not in men who had a prostate volume of 58 mL or more.[20] The
adverse-effect profile of combination therapy was similar to that of monotherapy,
although drug-related adverse events were more common with combination therapy.
[21] CombAT is a 4-year, multicenter, randomized, double-blind, parallel group study
of 4,844 men aged 50 years or older with moderate-to-severe BPH symptoms (IPSS
12), prostate volume of 30 mL or greater, and a PSA level of 1.5-10 ng/mL. This
study contributes to the standard of care shifting towards combined drug therapy in
appropriately selected patients, while better defining the role of the alpha-blockers.
[15]
Phytotherapeutic Agents and Dietary Supplements
Phytotherapeutic agents and dietary supplements are considered emerging therapy
by the AUA Guidelines panel and are not recommended for the treatment of BPH
because of the lack of evidence at this time.
Pharmaceuticals derived from plant extracts are widely used throughout the world for
the treatment of various medical ailments. In 1998, Americans spent a total of $3.65
billion on all herbal remedies. In France and Germany, plant extracts have a market
share of up to 50% of all drugs prescribed for symptomatic BPH. In the United States,
these agents are also popular and readily available.
The attraction to phytotherapeutic agents appears to be related to the perception of
therapeutic healing powers of natural herbs, the ready availability, and the lack of
adverse effects.
Most of the phytotherapeutic agents used in the treatment of LUTS secondary to BPH
are extracted from the roots, seeds, bark, or fruits of plants listed below. Some

suggested active components include phytosterols, fatty acids, lectins, flavonoids,

plant oils, and polysaccharides. Some preparations derive from a single plant; others
contain extracts from 2 or more sources.
Each agent has one or more proposed modes of action. The following modes of action
are suggested:
Antiandrogenic effect
Antiestrogenic effect
Inhibition of 5-alpha-reductase
Blockage of alpha receptors
Antiedematous effect
Anti-inflammatory effect
Inhibition of prostatic cell proliferation
Interference with prostaglandin metabolism
Protection and strengthening of detrusor
The origins of phytotherapeutic agents are as follows:
Saw palmetto, (American dwarf palm; Serenoa repens, Sabal serrulata) fruit
South African star grass (Hypoxis rooperi) roots
African plum tree (Pygeum africanum) bark
Stinging nettle (Urtica dioica) roots
Rye (Secale cereale) pollen
Pumpkin (Cucurbita pepo) seeds
Saw palmetto (American dwarf palm)
Extracts of saw palmetto berries are the most popular botanical products for BPH.
The active components are believed to be a mixture of fatty acids, phytosterols, and
alcohols. The proposed mechanisms of action are antiandrogenic effects, 5-alphareductase inhibition, and anti-inflammatory effects.
The recommended dosage is 160 mg orally twice daily. Studies show significant
subjective improvement in symptoms without objective improvements in urodynamic
parameters. Minimal adverse effects include occasional GI discomfort.
The 2010 AUA guidelines, based on more recent studies, do not detect a clinically
meaningful effect of saw palmetto on LUTS. Further clinical trials are underway.[1] In
fact, in a double-blind, multicenter, placebo-controlled randomized trial at 11 North
American clinical sites, saw palmetto extract was studied at up to 3 times the

standard dose on lower urinary tract symptoms attributed to BPH. Saw palmetto
extract was no more effective than placebo on the American Urological Association
Symptom Index. No clearly attributable adverse effects were identified. Similar to the
Saw Palmetto Treatment for Enlarged Prostates (STEP) study, saw palmetto was not
found to be beneficial for the treatment of LUTS in men.[22]
African plum tree (P africanum)
Suggested mechanisms of action include inhibition of fibroblast proliferation and antiinflammatory and antiestrogenic effects. This extract is not well studied.
Rye (S cereale)
This extract is made from pollen taken from rye plants growing in southern Sweden.
Suggested mechanisms of action involve alpha-blockade, prostatic zinc level
increase,

and

5-alpha-reductase

activity

inhibition.

Significant

symptomatic

improvement versus placebo has been reported.

Treatment of Concomitant Erectile Dysfunction
It is recommended to first establish the alpha-1 blocker dose before treating the
erectile dysfunction. The medication used to treat erectile dysfunction should be
titrated to the lowest effective dose. Furthermore, sildenafil doses of greater than 25
mg should not be taken within 4 hours of any alpha-blocker.[23, 24, 25]
In addition to treating erectile dysfunction, sildenafil may improve mild-to-moderate
LUTS. Nitric oxide may mediate relaxation of the prostatic urethra and/or bladder
neck. The utility of phosphodiesterase inhibitors in the treatment of LUTS has yet to
be defined.[26]
Recent trials have addressed the use of long-acting phosphodiesterase type 5
inhibitors (tadalafil) and have found them to be significantly better than placebo in
improving the symptoms of BPH/LUTS.
Transurethral Resection of the Prostate
TURP is considered the criterion standard for relieving BOO secondary to BPH. The
indications to proceed with a surgical intervention include the following:
AUR
Failed voiding trials
Recurrent gross hematuria

Urinary tract infection

Renal insufficiency secondary to obstruction
Additional indications for surgical intervention include failure of medical therapy, a
desire to terminate medical therapy, and/or financial constraints associated with
medical therapy. However, TURP carries a significant risk of morbidity (18%) and
mortality risk (0.23%).
TURP is performed with regional or general anesthesia and involves the placement of
a working sheath in the urethra through which a hand-held device with an attached
wire loop is placed. High-energy electrical cutting current is run through the loop so
that the loop can be used to shave away prostatic tissue. The entire device is usually
attached to a video camera to provide vision for the surgeon.
Although TURP is often successful, it has some drawbacks. When prostatic tissue is
cut away, significant bleeding may occur, possibly resulting in termination of the
procedure, blood transfusion, and a prolonged hospital stay. Patients are usually
monitored overnight and discharged the following morning, with or without a
catheter.
Irrigating fluid may also be absorbed in significant quantities through veins that are
cut open, with possible serious sequelae termed transurethral resection syndrome
(TUR syndrome). However, this is very rare and does not occur with saline irrigation
used in bipolar devices. A urinary catheter must be left in place until the bleeding has
mostly cleared.
The large working sheath combined with the use of electrical energy may also result
in stricturing of the urethra.
The cutting of the prostate may also result in a partial resection of the urinary
sphincteric mechanism, causing the muscle along the bladder outlet to become weak
or incompetent. As a result, when the patient ejaculates, this sphincteric mechanism
cannot keep the bladder adequately closed. The ejaculate consequently goes
backwards into the bladder (ie, retrograde ejaculation), rather than out the penis.
Additionally, if the urinary sphincter is damaged, urinary incontinence may result.
The nerves associated with erection run along the outer rim of the prostate, and the
high-energy current and/or heat generated by such may damage these nerves,
resulting in impotence.

Open Prostatectomy
This procedure is now reserved for patients with very large prostates (>75 g),
patients with concomitant bladder stones or bladder diverticula, and patients who
cannot be positioned for transurethral surgery.
Open prostatectomy requires hospitalization and involves the use of general/regional
anesthesia and a lower abdominal incision. The inner core of the prostate (adenoma),
which represents the transition zone, is shelled out, thus leaving the peripheral zone
behind. This procedure may involve significant blood loss, resulting in transfusion.
Open prostatectomy usually has an excellent outcome in terms of improvement of
urinary flow and urinary symptoms.
More recently, laparoscopic simple prostatectomy has been performed at a number
of institutions and appears to be feasible. However, prostatectomy performed in this
fashion still appears to be associated with risk for significant blood loss. Experience
to date with this procedure is limited.
Minimally Invasive Treatment
There is considerable interest in the development of other therapies to decrease the
amount of obstructing prostate tissue while avoiding the above-mentioned adverse
effects associated with TURP. These therapies are collectively called minimally
invasive therapies.
Most minimally invasive therapies rely on heat to destroy prostatic tissue. This heat
is delivered in a limited and controlled fashion, in the hope of avoiding the
complications associated with TURP. They also allow for the use of milder forms of
anesthesia, which translates into less anesthetic risk for the patient.
Heat may be delivered in the form of laser energy, microwaves, radiofrequency
energy, high-intensity ultrasound waves, and high-voltage electrical energy. As in
TURP, delivery devices are usually passed through a working sheath placed in the
urethra, although they are usually of a smaller size than that needed for TURP.
Devices may also simply be attached or incorporated into a urinary catheter or
passed through the rectum, from which the prostate may also be accessed.
Keep in mind that many of these minimally invasive therapies are undergoing
constant improvements and refinements, resulting in increased efficacy and safety.
Ask urologists about the specifics of the minimally invasive therapies that they use

and what results they have experienced.

Transurethral Incision of the Prostate
Transurethral incision of the prostate (TUIP) has been in use for many years and, for a
long time, was the only alternative to TURP. It may be performed with local
anesthesia and sedation. TUIP is suitable for patients with small prostates and for
patients unlikely to tolerate TURP well because of other medical conditions. TUIP is
associated with less bleeding and fluid absorption than TURP. It is also associated
with a lower incidence of retrograde ejaculation and impotence than TURP.
Lasers
Lasers deliver heat to the prostate in various ways. Lasers heat prostate tissue,
causing tissue death by coagulative necrosis, with subsequent tissue contraction;
however, laser coagulation of the prostate in this specific sense has met with limited
results.
Lasers have also been used to directly evaporate, or to melt away, prostate tissue,
which is more effective than laser coagulation. Photoselective vaporization of the
prostate produces a beam that does not directly come into contact with the prostate;
rather, it delivers heat energy into the prostate, resulting in destruction/ablation of
the prostate tissue.
Potassium-titanyl-phosphate (KTP) and holmium lasers are used to cut and/or
enucleate the prostate, similar to the TURP technique. These are widely used laser
techniques.
Transurethral vaporization/ablation with the KTP or holmium laser can be performed
with general or spinal anesthesia and can be performed in an outpatient setting.
Catheter time usually lasts less than 24 hours. Studies suggest that photoselective
vaporization of the prostate can significantly improve and sustain symptomatic and
urodynamic outcomes.
This procedure has been quite useful in patients who require anticoagulation for
various medical conditions, since anticoagulation does not need to be interrupted for
this procedure, thus further decreasing patient risk.[28, 29]
Lasers may be used in a knifelike fashion to directly cut away prostate tissue (ie,
holmium laser enucleation of the prostate), similar to a TURP procedure. The
holmium laser allows for simultaneous cutting and coagulation, making it quite useful

for prostate resection. Laser enucleation of the prostate has proved to be safe and
effective for treatment of symptomatic BPH, regardless of prostate size, with low
morbidity and short hospital stay.
TUR syndrome is not seen with this technique, because iso-osmotic saline is used for
irrigation. Additionally, removed prostatic tissue is available for histologic evaluation,
whereas vaporization/ablation technique does not provide tissue for evaluation.
Holmium laser enucleation of the prostate may prove to be the new criterion
standard for surgical management of BPH.[29, 30]
Laser treatment usually results in decreased bleeding, fluid absorption, and length of
hospital stay, as well as decreased incidence of impotence and retrograde ejaculation
when compared with standard TURP. However, healing from laser treatment does not
occur until after a period when dead cells slough; thus, patients may experience
urinary urgency or irritation, resulting in frequent or uncomfortable urination for a
few weeks.
The results of laser therapy vary from one another because not all wavelengths yield
the same tissue effects. For example, interstitial lasers (eg, indigo lasers) are
designed to heat tissue within the confines of the prostate gland and spread radiant
energy at relatively low energy levels. They do not directly involve the urethral
portion; thus, irritative symptoms following the procedure are potentially reduced.
Contact lasers such as KTP or holmium, on the other hand, are designed to cut and
vaporize at extremely high temperatures They usually bring about more relief of
urinary symptoms than treatment with medicines, but not always as much as is
provided with TURP. However, KTP laser vaporization and holmium laser enucleation
yield results that rival those of TURP.
Transurethral Microwave Therapy
The use of microwave energy, termed transurethral microwave therapy (TUMT),
delivers heat to the prostate via a urethral catheter or a transrectal route. The
surface closest to the probe (the rectal or urethral surface) is cooled to prevent injury.
The heat causes cell death, with subsequent tissue contraction, thereby decreasing
prostatic volume.
TUMT can be performed in the outpatient setting with local anesthesia. Microwave
treatment appears to be associated with significant prostatic swelling; a considerable
number of patients require a urinary catheter until the swelling subsides. In terms of

efficacy, TUMT places between medical therapy and TURP. The 2010 AUA guidelines
state TUMT is an effective option for partially relieving symptoms that may be
considered in patients with moderate or severe LUTS secondary to BPH.[31]
Transurethral Needle Ablation of the Prostate
Transurethral needle ablation of the prostate (TUNA) involves using high-frequency
radio waves to produce heat, resulting in a similar process of thermal injury to the
prostate as previously described. A specially designed transurethral device with
needles is used to deliver the energy.
TUNA can be performed under local anesthesia, allowing the patient to go home the
same day. Similar to microwave treatment, radiofrequency treatment is quite
popular, and a number of urologists have experience with its use. Radiofrequency
treatment appears to reliably result in significant relief of symptoms and better urine
flow, although not quite to the extent achieved with TURP. The 2010 AUA guideline
update considers TURP an appropriate and effective treatment option for moderate
or severe LUTS.[1]
High-Intensity Ultrasound Energy Therapy
High-intensity ultrasound energy therapy delivers heat to prostate tissue, with the
subsequent process of thermal injury. High-intensity ultrasound waves may be
delivered rectally or extracorporeally and can be used with the patient on
intravenous sedation. Urinary retention appears to be common with its use.
High-intensity ultrasound energy also produces moderate results in terms of
improvement of the urinary flow rate and urinary symptoms, although its use is now
relatively limited compared with the more popular TUNA and TUMT.
High-intensity ultrasound is considered investigational at this time and should not be
offered outside of clinical trials.
Mechanical Approaches
Mechanical approaches are used less commonly and are usually reserved for patients
who cannot have a formal surgical procedure. Mechanical approaches do not involve
the use of energy to treat the prostate.
Prostatic stents are flexible devices that can expand when put in place to improve
the flow of urine past the prostate. Complications associated with their use include

encrustation, pain, incontinence, and overgrowth of tissue through the stent, possibly
making their removal quite difficult.
In September 2013, the FDA authorized the marketing of the first permanent implant
to relieve low or blocked urine flow in men aged 50 years and older with an enlarged
prostate. The UroLift system (NeoTract Inc) relieves urine flow by pulling back
prostate tissue that is pressing on the urethra. Approval was based on 2 studies of
274 men with BPH implanted with 2 or more UroLift sutures.[32] The UroLift was
successfully inserted in 98% of participants, and a 30% increase in urine flow and a
steady amount of residual urine in the bladder was observed. Patients reported fewer
symptoms and improved quality of life in the 2 years following device implantation.
Diet
Data from the Prostate Cancer Prevention Trial revealed that a diet low in fat and red
meat and high in protein and vegetables may reduce the risk of symptomatic BPH.
Additionally, regular alcohol consumption was associated with a reduced risk of
symptomatic BPH, but this is to be interpreted cautiously given the untoward effects
of excessive alcohol consumption.
COMPLICATIONS
Prostate gland enlargement becomes a serious problem when it severely interferes
with your ability to empty your bladder. If this is the case, you'll probably need
surgery. Complications of enlarged prostate include:
Acute urinary retention. Acute urinary retention is a sudden, painful inability
to urinate. This may occur after you've taken an over-the-counter decongestant
medication for allergies or a cold. When you are unable to urinate at all, your
doctor may thread a tube (catheter) through your urethra into your bladder. Or,
your doctor may put in a suprapubic tube a catheter that drains your bladder
through the lower abdomen. The type of catheter you need will depend on your
particular circumstances. Some men with an enlarged prostate require surgery
or other procedures to relieve urinary retention.
Urinary tract infections (UTIs). Some men with an enlarged prostate end up
having surgery to remove part of the prostate to prevent frequent urinary tract
infections.
Bladder stones. These are mineral deposits that can cause infection, bladder
irritation, blood in the urine and obstruction of urine flow and are generally
caused by the inability to completely empty the bladder.

 Bladder damage. This occurs when the bladder hasn't emptied completely
over a long period of time. The muscular wall of the bladder stretches and
weakens and no longer contracts properly. Often, symptoms of bladder damage
improve after prostate surgery or other treatment, but not always.
Kidney damage. This is caused by high pressure in the bladder due to urinary
retention. This high pressure can directly damage the kidneys or allow bladder
infections to reach the kidneys. When an enlarged prostate causes obstruction
of the kidneys, a condition called hydronephrosis a swelling of the urinecollecting structures in one or both kidneys may result.
Most men with an enlarged prostate don't develop these complications. However,
acute urinary retention and kidney damage in particular can be serious health threats
when they do occur.
PROGNOSIS
The majority of patients with BPH can expect at least moderate improvement of their
symptoms with a decreased bother score and improved quality of life. Lower urinary
tract symptoms (LUTS), secondary to BPH, may affect sexual wellbeing including
erectile function. Medical therapy for BPH may also effect sexual function,
beneficially and harmfully, so this must be considered on an individual basis. Some
studies suggest that patients with a low risk for progression may be able to
discontinue first-line therapy with alpha-blockers after several months of therapy.
However, the majority of patients will require ongoing therapy.