S TAT E O F T H E A RT R E V I E W

Lower urinary tract symptoms in men

John M Hollingsworth,1 2 Timothy J Wilt3 4
1

Department of Urology, University

of Michigan Medical School, Ann
Arbor, MI, USA
2
Center for Healthcare Outcomes
and Policy, University of Michigan
Medical School, Ann Arbor, MI, USA
3
Minneapolis VA Center for Chronic
Diseases Outcomes Research,
Minneapolis, MN 55417, USA
4
University of Minnesota School of
Medicine, Minneapolis, MN, USA
Correspondence to: T J Wilt tim.
wilt@va.gov
Cite this as: BMJ 2014;349:g4474
doi: 10.1136/bmj.g4474

thebmj.com
Use our interactive
symptom score tool
to discuss treatment
options with patients:
http://bit.do/bmj-luts

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A B S T RAC T

Benign prostatic hyperplasia (BPH) is a highly prevalent and costly condition that affects
older men worldwide. Many affected men develop lower urinary tract symptoms, which
can have a negative impact on their quality of life. In the past, transurethral resection of
the prostate (TURP) was the mainstay of treatment. However, several efficacious drug
treatments have been developed, which have transformed BPH from an acute surgical
entity to a chronic medical condition. Specifically, multiple clinical trials have shown that
adrenoceptor antagonists can significantly ameliorate lower urinary tract symptoms.
Moreover, 5 reductase inhibitors, alone or combined with an adrenoceptor antagonist,
can reverse the natural course of BPH, reducing the risk of urinary retention and the need for
surgical intervention. Newer medical regimens including the use of antimuscarinic agents
or phosphodiesterase type 5 inhibitors, have shown promise in men with predominantly
storage symptoms and concomitant erectile dysfunction, respectively. For men who do not
adequately respond to conservative measures or pharmacotherapy, minimally invasive
surgical techniques (such as transurethral needle ablation, microwave thermotherapy, and
prostatic urethral lift) may be of benefit, although they lack the durability of TURP. A variety
of laser procedures have also been introduced, whose improved hemostatic properties
abrogate many of the complications associated with traditional surgery.

Introduction
Benign prostatic hyperplasia (BPH) is fundamentally a histologic diagnosis that refers to a non-malignant proliferative
process of the cellular elements of the prostate. By age 70
years, nearly 70% of men will have histologic BPH.1 About
half of these men will develop prostatic enlargement, with
nearly half (17% in total) having associated bladder outlet
obstruction and lower urinary tract symptoms.2 Exclusive of
pharmacy spending, in the United States the direct costs of
medical services for its management exceed $1bn (0.58bn;
0.74bn) annually and are rising.3
BPH is one of the most common and costly disorders in
older men, and the associated lower urinary tract symptoms
can affect quality of life.4 In addition, lower urinary tract
symptoms, especially nocturia, increase falls and risk of
fractures.5 For these reasons, the main aim of treatment is
to reduce bothersome lower urinary tract symptoms and
prevent disease progression (for example, the development
of acute urinary retention).
In the past, treatment was limited to surgical intervention, which was carried out only in men with severe symptoms, acute urinary retention, or other sequelae of bladder
outlet obstruction, such as renal insufficiency and recurrent
urinary tract infections. However, with the introduction of
efficacious drugs, men with less severe symptoms may benefit from identification and treatment. Therefore, lower urinary tract symptoms are now more appropriately viewed as
a chronic medical condition for which lifestyle changes and
drugs have become the mainstay of initial management.

Since this paradigm shift in treatment, primary care

physicians have taken on a much more important role in
the care of men with BPH. More than two thirds of incident cases are now seen by primary care physicians.6 This
review aims to summarize the literature on lower urinary
tract symptoms related to BPH as a way to improve care for
this patient population.

Prevalence of BPH
One challenge to studying the epidemiology of BPH is a
lack of consensus on what constitutes a case. As mentioned
above, the definition of this condition involves histologic
assessment. Several studies have used examination at
autopsy to determine the prevalence of benign prostatic
SOURCES AND SELECTION CRITERIA
We searched the English language literature for human
studies without any date limits using Medline (through
PubMed), Embase (through Ovid), and the Cochrane
Database of Systematic Reviews. We incorporated a variety
of terms and synonyms for concepts in each of three distinct
filters: a disease filter for benign prostatic hyperplasia; a
publication type filter to identify observational studies,
clinical trials, and systematic reviews; and a treatment
filter designed to capture common medical and surgical
treatments. Where possible, we used controlled vocabulary
(MeSH in PubMed, Emtree in Embase). We summarize
the most clinically relevant diagnostic and management
information from these studies.
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S TAT E O F T H E A RT R E V I E W
hyperplasia. Only 8% of men during the fourth decade of
life have this condition on autopsy, but this increases to 50%
in those aged 51-60 years.1 The prevalence of histologic BPH
is similar in the US, Europe, and Asia.7
The prevalence of BPH derived from urinary flow or prostate size has also been defined statistically according to values in population based cohorts of younger men. Although
a peak urinary flow rate of 20 mL/s or more is considered
statistically normal,8 data from the Olmsted County study
showed that 6% of men aged 40-44 years had peak flow
rates less than 10 mL/s, increasing to 35% in those over
75.9 In the same cohort, prostate size (measured with ultrasound) increased by about 1.6% each year, such that the
median prostate volume for men 50 years and older was
more than 40 mL.10
Patient self report provides a more clinically relevant
assessment of the prevalence of benign prostatic hyperplasia. In general, the greater the severity of lower urinary tract
symptoms, the more detrimental they are to a mans quality
of life (the greater the bother) and the greater the desire for
(and benefit from) treatment. With the use of a validated
urinary symptom scale, 13% of men participating in the
Olmsted County study aged 40-49 years and 28% of those
older than 70 years had moderate to severe lower urinary
tract symptoms.11 It is important to note that prevalence estimates based on symptom scores depend on the cut-off point
chosen to define a case and can therefore vary substantially
in a population.12
In addition, although lower urinary tract symptoms are
associated with urinary flow and prostate size, there is substantial evidence that men can have symptoms even in the
absence of BPH, enlarged prostate on physical examination,
or abnormal urinary flow rates. This is partly because lower
urinary tract symptoms can be caused by multiple mechanisms, including prostate and bladder smooth muscle tone
and contractility.13 Moreover, the prevalence of lower urinary tract symptoms in women is not too dissimilar to that
in men.14 Thus, although lower urinary tract symptoms in
older men are often attributed to BPH, clinicians should consider other causes in their diagnosis and evaluation (such
as neurogenic bladder dysfunction, drug induced lower
urinary tract symptoms, and heart diseases with nocturnal
polyuria).

Diagnosis and evaluation

At presentation the diagnosis of BPH is typically based on
clinical features: an enlarged prostate, bothersome lower
urinary tract symptoms, and no other identified causes for
the urinary problems. Most primary care physicians arrive at
this diagnosis on the basis of patient reported voiding (feelings of incomplete emptying, intermittency, weak stream,
and hesitancy) or storage symptoms (frequency, urgency, and
nocturia) and possibly the finding of prostate enlargement
on digital rectal examination. In particular, nocturia is an
important factor associated with urinary symptom bother
and request for evaluation and treatment. Urine analysis can
help identify treatable conditions (such as urinary tract infection) that may contribute to these symptoms.
Prostate specific antigen (PSA) testing to screen for prostate cancer in men with suspected BPH is controversial.
Although patients and clinicians may worry that lower uriFor personal use only

nary tract symptoms are caused by prostate cancer, BPH is

not a risk factor for prostate cancer.15 Thus, use of PSA testing in most men presenting with typical lower urinary tract
symptoms in the primary care setting should be considered
to be screening, rather than part of the diagnostic evaluation. Furthermore, prostate enlargement can increase PSA
levels, reducing test specificity.16 These limitations should
be factored into testing decisions. No organization or guideline group recommends PSA screening in those over 70
years or in younger men with limited life expectancy.
The clinical value of determining post-void residual urine
in men with lower urinary tract symptoms is not well established. Similar to urinary flow rates, definitions of chronic
urinary retention as determined by the post-void residual
urine vary greatly. In addition, there are few data on the
importance of using post-void residual urine in management decisions. Therefore, for most men, post-void residual
urine evaluation, like uroflowmetry, is not necessary, and
management strategies should be based on symptoms.

Risk factors
Increasing age is the primary risk factor for BPH, and there
is no known association with family history. Other patient
factors have been implicated in its development and progression, including metabolic disorders. Specifically, data from
the Health Professionals Follow-Up study highlight an association between obesity and lower urinary tract symptoms.17
These findings were corroborated by two population based
studies of Chinese and Norwegian men.18 19 Furthermore,
data from the Baltimore Longitudinal Study of Aging showed
higher odds of prostate enlargement among obese men.20
Type 2 diabetes also seems to be a risk factor for BPH.
In addition to urinary frequency as a result of glycosuria,
insulin can bind to the insulin-like growth factor receptor
in prostate cells, leading to activation of the receptor and
the induction of prostate cell growth and proliferation.21 A
study on community dwelling men in Massachusetts found
that men with type 2 diabetes were 50% more likely to have
clinical BPH (diagnosed by a physician or treated with surgery), even after accounting for weight.22 Moreover, a cohort
study of Swedish men found that men with diabetes had the
highest median prostate growth.23
Unlike obesity and diabetes, exercise may protect against
BPH. Moderate long term exercise reduces sympathetic
nervous system activity at rest and decreases firing of sympathetic adrenergic neurons.24 This may dampen prostatic
smooth muscle tone. Results from the Health Professionals Follow-Up study show that increasing levels of physical
activity were associated with a lower risk of lower urinary
tract symptoms independent of weight control.17 Data from
the Massachusetts Male Aging study found a similar inverse
association between a mans exercise habits and his odds of
clinical BPH.22
Initial assessment and management
Initial assessment and management are dictated by a mans
symptom severity and urinary bother. Validated symptom
and bother scales are often used in urology practices and
research settings. The most popular are the American Urological Association symptom index (AUASI) and the international prostate symptom score (IPSS) (fig 1)).25 Both include
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Fig 1|International prostate
symptom score (IPSS)

a seven item questionnaire that measures the presence and

severity of voiding and storage symptoms. Scores range from
0 to 35, with moderate and severe symptoms exceeding 7
and 19 points, respectively. A clinically meaningful difference involves at least a 3 point change.26
Although use of these symptom scales is recommended,
it may not always be practical in the primary care setting.
At the very least, a brief assessment of a mans degree of
bother (none, mild, moderate, a lot) is important because
it correlates fairly well with symptom severity and decisions about treatment. Men who experience a moderate
amount to a lot of bother with urinary symptoms are likely
to benefit from drugs or surgical interventions. For men
with less bother, counseling and lifestyle changes may be
a preferable first step. This includes reassuring a man that
his symptoms do not put him at increased risk of cancer.
In addition, timed voiding, avoidance of caffeine and alcohol, adjustment of diuretic dosing, and reduction in fluid
(particularly at night) are effective management strategies
for many.2729 A randomized controlled trial showed that
treatment failures (such as initiation of medical treatment)
in men with uncomplicated lower urinary tract symptoms
enrolled in self management training were 48% lower at 12
months than in those on watchful waiting alone.29

Pharmacotherapy (table)
adrenoceptor antagonists
For men with moderate to a lot of bother from their lower
urinary tract symptoms, adrenoceptor antagonists can
For personal use only

improve symptoms and bother. By binding to 1 adrenoceptors located in the prostatic smooth muscle, they inhibit contraction of prostate tissue.34 There are three 1 adrenoceptor
subtypes (1a, 1b, and 1d), but only the 1a variety has been
shown to mediate prostatic smooth muscle tonicity.35 Given
that 1 adrenoceptors and 2 adrenoceptors are also present
in the smooth muscle of the bladder base and proximal urethra,36 37 adrenoceptor antagonists may decrease outlet
resistance caused by urethral smooth muscle too.
About 60% of men treated with an adrenoceptor
antagonist experience a meaningful reduction in urinary
symptoms within a month of starting treatment.38 39 This
relatively rapid onset of action, which occurs in a high proportion of men, is one reason why adrenoceptor antagonists are the most commonly prescribed class of drugs for
men with lower urinary tract symptoms. Another reason
for their popularity is that their effects are independent of
prostate size.40 In men who respond to an adrenoceptor antagonist, the drug often continues to work and be
well tolerated for years. However, long term clinical trials
show that these drugs do not prevent the need for surgical intervention or the risk of developing acute urinary
obstruction.41

Phenoxybenzamine
Phenoxybenzamine, a non-selective long acting antagonist,
was the first adrenoceptor antagonist shown to be efficacious for the treatment of BPH related lower urinary tract
symptoms.42 Use was limited by its side effects.
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Pharmacotherapies for lower urinary tract symptoms secondary to benign prostatic hyperplasia*
Drug

Usual dose

Reassessment

Efficacy

Side effects

At 2-4 weeks

Mean improvement in AUASI score with

Dizziness, orthostatic hypotension,
these drugs is 38% v with 17% for placebo; fatigue, nasal congestion, abnormal
peak urinary flow rates also improve more ejaculation, impotence
with adrenoceptor antagonists (22%)
than placebo (11%)30

At 3-6 months

When compared with placebo, 5ARI

Decreased libido, decreased ejaculate
monotherapy is associated with a 55%
volume, gynecomastia
reduction (95% CI 41% to 65%) in the
need for BPH surgery and a 57% reduction
(40% to 69%) in the risk of urinary
retention31

At 6-12 weeks

When combined with an adrenoceptor

antagonist, antimuscarinic drugs result
in a greater reduction of IPSS storage
subscores (WMD 0.73 points, 1.09
to 0.37; P<0.01) than adrenoceptor
antagonist monotherapy; patients treated
with combination therapy also reported
fewer voids per 24 h compared with
those on adrenoceptor antagonist
monotherapy (WMD 0.69 voids 0.97 to
0.41; P<0.01)32

Dry mouth, constipation, somnolence,

blurred vision, dyspepsia, and urinary
retention

At 4-8 weeks

PDE5 inhibitor use is associated with a

significant improvement in IPSS (2.8
points, 3.6 to 2.1; P<0.0001) and IIEF
scores (5.5 points, 4.1 to 6.9; P<0.0001)33

Headache, dizziness, flushing,

dyspepsia, and nasal congestion or
rhinitis

adrenoceptor antagonists

Non-selective:
Alfuzosin
Doxazosin
Terazosin
Selective for 1a receptor:
Silodosin
Tamsulosin

10 mg of SR daily
1 mg daily and titrate
(maximum 8 mg)
1 mg daily and titrate
(maximum 20 mg)
8 mg daily
0.4-0.8 mg daily

5 reductase inhibitors

Dutasteride
Finasteride

0.5 mg daily
5 mg daily

Antimuscarinic drugs

Non-selective:
Fesoterodine
Oxybutynin
Tolterodine
Trospium
Selective for M3 receptor:
Darifenacin
Solifenacin

4-8 mg daily
5-10 mg of ER daily
(maximum 30 mg)
2-4 mg of ER daily
20 mg twice daily
7.5-15 mg of ER daily
5-10 mg daily

Phosphodiesterase type 5 inhibitors

Tadalafil

2.5-5 mg daily

*5ARI=5 reductase inihibitor; AUASI=American Urological Association symptom index; CI=confidence interval; ER=extended release; IIEF=international index of erectile
function; IPSS= international prostate symptom score; PDE5=phosphodiesterase type 5; SR=slow release; WMD=weighted mean difference.

Terazosin and doxazosin

Terazosin and doxazosin were the first long acting 1 adrenoceptor antagonists studied for the treatment of lower urinary
tract symptoms. Multicenter trials showed a clinically significant improvement in self reported symptoms in men
receiving these drugs compared with placebo.30 43 However,
standard preparations of terazosin and doxazosin require
slow increases in dose to avoid the sudden, and sometimes
severe, fall in blood pressure that can occur when changing
from a lying to a standing position after their initial administration. Other common adverse effects include abnormal
ejaculation, asthenia, and dizziness.
Tamsulosin
Tamsulosin was the first highly selective 1 adrenoceptor
antagonist. Similar to the controlled release gastrointestinal
therapeutic system formulation of doxazosin, it does not
require titration. Large phase III trials showed that tamsulosin significantly improved urinary symptoms and peak flow
rates compared with placebo, and that it was generally well
tolerated.44 45 In trials comparing tamsulosin with other
adrenoceptor antagonists, tamsulosin increased peak flow
rates and achieved comparable improvements in symptom
score to those seen with terazosin.46 However, men taking
tamsulosin were significantly less likely to discontinue treatment for all causes than those taking terazosin.
For personal use only

Alfuzosin
Alfuzosin is another second generation selective 1 adrenoceptor antagonist. Similar to tamsulosin and the gastrointestinal therapeutic system formulations of doxazosin, it
does not require dose titration. Pooled analysis of three randomized controlled trials showed that alfuzosin significantly
reduced symptom scores (mean score changes for alfuzosin
and placebo were 6.0 and 4.2, respectively; P<0.001 for
the difference) and increased urinary flow rates.40 Alfuzosin
seems to be comparable to tamsulosin in terms of efficacy
and adverse event profile.
Silodosin
Silodosin is the newest selective 1a adrenoceptor antagonist. It provides lasting symptom relief comparable to that of
tamulosin.47 One potential advantage of silodosin over alfuzosin relates to its cardiac tolerability. Data show that it does
not routinely prolong the QT interval, which may decrease
cardiac arrhythmias in selected populations.48 However, it
is associated with a higher risk of retrograde ejaculation,49 50
and it requires dosage adjustment in patients with renal
insufficiency.
Adverse effects
One side effect of adrenoceptor antagonists relates to their
impact on pupil dilatation. More than 40% of tamsulosin
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users undergoing cataract surgery show a flaccid and billowing iris, iris prolapse through the surgical incisions, and
progressive intraoperative pupil constriction.51 Although
most commonly associated with tamsulosin, the so called
intraoperative floppy iris syndrome is also seen with terazosin, doxazosin, and alfuzosin use.52 53 Because this syndrome
can result in surgical complications (iris trauma is reported
in nearly half54), ophthalmologists should be prepared for
possible modifications to their surgical technique in patients
taking an adrenoceptor antagonist, which may increase the
complexity and cost of cataract surgery.

5 reductase inhibitors
5 reductase inhibitors are the second most commonly prescribed class of drugs after adrenoceptor antagonists for
the treatment of BPH related lower urinary tract symptoms.
Unlike adrenoceptor antagonists, these drugs do not alter
smooth muscle tone. Rather, they shrink the prostate and
decrease associated bladder outlet obstruction by blocking the conversion of testosterone to dihydrotestosterone.
The rationale behind their use is based on the observation
that the development of BPH is an androgen dependent
process.55 56 More specifically, surgical castration and the
use of gonadotrophin releasing hormone analogues reduce
prostate volume.57 58
Finasteride and dutasteride
Finasteride inhibits 5 reductase type 2 and was the first
drug in this class to be used for the treatment of BPH. In a
trial of 3040 men randomized to receive 5 mg finasteride or
placebo for one year, finasteride reduced the risk of acute
urinary retention by 57% (95% confidence interval 40% to
69%) and the need for BPH surgery by 55% (41% to 65%).31
However, a one year randomized trial comparing blockade with terazosin to finasteride and placebo showed that
although finasteride reduced prostate volume by 20%, it was
not as efficacious as terazosin and no more efficacious than
placebo in improving urinary symptoms and flow rates.59
Dutasteride is the newest 5 reductase inhibitor and it
inhibits both 5 reductase type 1 and type 2. Similar to
finasteride, dutasteride reduces the risk of acute urinary
retention and BPH directed surgery compared with placebo
(relative risk reduction 57% and 48%, respectively, at two
years) in men with moderate to severe lower urinary tract
symptoms.60
There are few comparative studies on finasteride and
dutasteride. Observational data suggest that the use of
dutasteride is associated with greater reductions in urinary
symptom scores and faster clinical improvement (within
three months) after initiation of therapy compared with finasteride, possibly because of its dual inhibitory effects.61
However, a multicenter randomized double blind trial of
once daily dutasteride versus finasteride showed that both
drugs, when given for 12 months, had similar efficacy in
improving urinary symptoms associated with BPH in men
with an enlarged prostate.62
Adverse effects and other effects
Although generally well tolerated, decreased libido and
ejaculate volume, as well as gynecomastia, are associated
with the use of 5 reductase inhibitors.
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In addition to their effects on lower urinary tract symptoms, data from two large placebo controlled randomized
studies show that finasteride and dutasteride reduce the
risk of prostate cancer by 23-25%.63 64 However, 5 reductase inhibitors also increased the risk of high grade prostate cancer. Although this association may be attributed
to histologic artifact as a result of prostate gland shrinkage,65 the US Food and Drug Administration issued a safety
announcement in 2011 regarding 5 reductase inhibitors
and high risk prostate cancer. These drugs are therefore
not indicated for chemoprevention of prostate cancer. Clinicians should discuss this information with men placed on
5 reductase inhibitors even if the treatment is not intended
for chemoprevention of prostate cancer.

Combination of an adrenoceptor antagonist and 5

reductase inhibitor
The Veterans Affairs Cooperative study tested whether combining an adrenoceptor antagonist with a 5 reductase
inhibitor produced any benefit.59 This multicenter study randomized 1229 veterans to receive placebo, terazosin, finasteride, or combination therapy. At 52 weeks of follow-up, the
absolute mean change in symptom scores for men on combination therapy (decrease of 6.2 points) was significantly
greater than that for men who received finasteride (3.2) or
placebo (2.6). However, combination therapy offered no
advantage over terazosin alone with respect to symptom
score improvement (6.1). The Prospective European Doxazosin and Combination Therapy trial had similar findings.66
Whereas the preceding studies assessed the relatively
short term impact of combination therapy on lower urinary
tract symptoms, the Medical Therapy of Prostatic Symptoms (MTOPs) trial was designed to examine the long term
effect of combination medical therapy on the risk of clinical
progression. This was defined by an increase of four points
or more in the AUASI score, need for surgical intervention,
or development of acute urinary retention.41 This six year
multicenter study randomized 3047 men aged 50 years or
more with moderate to severe lower urinary tract symptoms
(mean AUASI 16.9) to receive placebo, doxazosin, finasteride, or combination therapy.
Over a mean follow-up of 4.5 years, use of combination
therapy significantly reduced the risk of overall progression
by 66% (54% to 76%) compared with placebo (fig 2). Most
of the benefit was in lower rates of symptom progression
(risk reduction 64%, 48% to 75%), although combination therapy did reduce the need for surgical intervention
(67%, 40% to 82%) and acute urinary retention (81%, 44%
to 93%) (fig 3). This risk reduction was also significantly
greater than that associated with doxazosin or finasteride
alone. A reanalysis of the MTOPs trial suggested that prostate size (as measured by volume >25 mL) predicted benefit
from combination therapy.67
To further assess the importance of prostate size in
response to treatment, the Combination of Avodart and
Tamsulosin trial was conceived.68 This study randomized
4844 men with prostate volumes of 30 mL or greater
to receive dutasteride, tamsulosin, or combination
therapy. At four years of follow-up, the mean reduction
in patients storage symptom subscores was significantly
greater for the combination of dutasteride and tamsulo5 of 11

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episodes of urgency a day.71 Eighty per cent of patients randomized to receive extended release tolterodine and tamsulosin reported treatment benefit at 12 weeks compared with
only 62% of those who received placebo (P<0.001), 71%
who received tamsulosin monotherapy (P=0.06 v placebo),
and 65% who received tolterodine monotherapy (P=0.48
v placebo).
One of the concerns about the use of antimuscarinic
agents in men with lower urinary tract symptoms is that it
could exacerbate voiding symptoms. A recent systematic
review and meta-analysis assessed these safety concerns.32
Pooled data from seven placebo controlled trials, in which
3629 patient were randomized, showed a slight reduction in maximal urinary flow rate (weighted mean difference 0.59 mL/s, 1.04 to 0.14) and post-void residual
urine volumes (11.60 mL, 8.50 to 14.70) with combination therapy compared with adrenoceptor antagonist
monotherapy. However, the increased risk of acute urinary
retention was very small (number needed to harm 101).
As such, the addition of an antimuscarinic is an option for
men who have persistent storage symptoms even though
they are taking an adrenoceptor antagonist, although it is
recommended that post-void residual urine is monitored.69
Fig 2| Cumulative incidence of progression of benign prostatic hyperplasia in men with moderate
to severe symptoms at baseline. Progression was defined by an increase of at least four
points in the American Urological Association symptom index score, acute urinary retention,
incontinence, renal insufficiency, or recurrent urinary tract infections.

sin than for dutasteride (adjusted mean difference 0.43)

and tamsulosin (0.96) monotherapy (P<0.001). The
mean reduction in the voiding subscore was also significantly greater in the combination therapy group than in
the dutasteride (0.51) and tamsulosin (1.60) monotherapy groups (P<0.001). A recent systematic review
evaluated randomized controlled trials that assessed
combination drug therapy ( adrenoceptor antagonist
and 5 reductase inhibitor) in men with non-neurogenic
lower urinary tract symptoms.69 On the basis of findings
from five studies, the authors concluded that this combination is beneficial in patients with a prostate volume of
30-40 mL when medical treatment is intended for more
than one year.

Antimuscarinic drugs
Storage symptoms can be caused directly by associated bladder outlet obstruction from prostatic enlargement or from
secondary effects of the obstruction on the bladder itself.70
In this second situation, treatments that target the prostate
exclusively may not relieve urinary urgency and increased
daytime frequency. This is the rationale behind using an antimuscarinic agent (alone or combined with an adrenoceptor
antagonist) for men with storage symptoms.
Antimuscarinic drugs work by blocking the muscarinic
receptors on the detrusor muscle and urothelium, which are
stimulated by acetylcholine during detrusor contraction.
Several studies have examined the efficacy of antimuscarinic drugs, alone and in combination with an adrenoceptor antagonist, in men with storage symptoms.69 The
most definitive data come from a study of 879 men aged
40 years or more who had BPH related lower urinary tract
symptoms, with eight or more voids a day and three or more
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Phosphodiesterase type 5 inhibitors

Tadalafil is the latest drug to be approved for the treatment
of BPH related lower urinary tract symptoms. Commonly
used as an erectile aid, it targets the phosphodiesterase type
5 (PDE5) enzyme, and 55-70% of men with mild to severe
lower urinary tract symptoms report erectile dysfunction.72 73
Although the mechanisms underlying the association are not
clear, lower urinary tract symptoms and erectile dysfunction
have common links (for example, the nitric oxide-cGMP pathway) that are potential targets for PDE5 inhibitors.74 Moreover, the PDE5 enzyme is highly expressed in the bladder
neck, prostatic urethra, and prostate tissue.75
Seven trials have been reported in which 3214 men with
concomitant moderate to severe lower urinary tract symptoms and erectile dysfunction were randomized to receive
a PDE5 inhibitor versus placebo. Findings from these trials were summarized in a recent meta-analysis.33 Over a
median follow-up of 12 weeks, PDE5 inhibitors reduced the
severity of lower urinary tract symptoms compared with
placebo (mean symptom score change 2.8 points, 3.6 to
2.1; P<0.001), with no differences in urinary flow rates.
However, data on long term efficacy are lacking. Not surprisingly, regular use of a PDE5 inhibitor improved patient
reported sexual function. Side effects occurred in 16% of
men using PDE5 inhibitors and included flushing, headache, and sinusitis. Preliminary data only are available on
the combination of a PDE5 inhibitor and an adrenoceptor
antagonist.69
Phytotherapy
A third of men who choose non-surgical management of their
lower urinary tract symptoms initially report taking herbal
preparations, either alone or combined with prescription
drugs.76 Although nearly 30 different phytotherapeutic compounds are marketed for the treatment of symptomatic BPH,
extracts from the fruit of the American saw palmetto Serenoa
repens are the most commonly used.77
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A 1998 systematic review and meta-analysis of generally low quality trials suggested that S repens extracts provided mild improvement in symptoms.78 Rates of adverse
effects (such as diarrhea, decreased libido, and ejaculatory
disorders) were comparable between the intervention and
placebo groups. However, there have been rare reports of
hepatic and pancreatic toxicity associated with extract
use.79 80
In the interim, more rigorous studies have been conducted. The Saw Palmetto Treatment for Enlarged Prostates
trial randomized 225 men aged over 50 years with moderate to severe lower urinary tract symptoms to receive saw
palmetto fruit extract (160 mg twice daily) or placebo.81
Over one year of follow-up there was no significant difference in symptom scores or secondary endpoints between
the two groups.
More recently, results from another large study showed
that increasing doses of saw palmetto fruit extract did not
reduce lower urinary tract symptoms or other outcomes
related to BPH more than placebo.82 An updated systematic
review, which included data from both of these trials,81 82
concluded that S repens does not improve lower urinary
tract symptoms or urinary flow rates compared with placebo in men with BPH, even at double and triple the usual
dose.83

Surgical options
For men with moderate to severe lower urinary tract symptoms in whom pharmacotherapy has not provided adequate
symptom relief, specialist referral for consideration of surgical intervention is appropriate. Urology consultation is also
recommended for patients who develop recurrent urinary
tract infections, gross hematuria, bladder calculi, or renal
insufficiency secondary to BPH, as well as for those who
wish to pursue surgery as the primary treatment. Because
failure rates after BPH surgery are higher in patients without evidence of associated bladder outlet obstruction, many
urologists perform additional testing before surgical intervention.84
Pressure flow studies are regarded as the gold standard
for the objective assessment of associated bladder outlet
obstruction, defined as a maximum flow rate less than 12
mL/s with detrusor pressure at maximum flow greater than
20 cm H2O.85 However, questions have been raised about
the acceptability of these tests owing to their associated
morbidity and costs.86 Thus, attempts have been made
to diagnose associated bladder outlet obstruction noninvasively. Neither ultrasound measurements of post-void
residual urine nor prostate volume show good sensitivity
for diagnosing this condition.87 However, measurements
of bladder wall thickness and bladder weight show some
promise.87 In cases where maximum urinary flow rates are
less than 10 mL/s and an adequate volume of urine was
voided, uroflowmetry alone is sufficient.38

Fig 3|Cumulative incidence of acute urinary retention (A) and invasive treatment (B) for benign
prostatic hyperplasia
For personal use only

Transurethral resection of the prostate

If the patient chooses surgery, and there is enough evidence
of associated bladder outlet obstruction, the urologist should
discuss the risks and benefits of the various interventions.
Transurethral resection of the prostate (TURP) has been the
standard method of surgical management of BPH for more
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than half a century. This entails endoscopic removal of the
adenoma using a monopolar electrocautery loop. Although
highly effective and durable at relieving lower urinary tract
symptoms (average improvement in symptom score at 16
months is 10-18 points from baseline), it carries measurable risks.88 Specifically, men undergoing TURP are at risk
of dilutional hyponatraemia, which occurs when irrigant
solution is absorbed into the bloodstream during surgery. The
incidence of this so called TURP syndrome in contemporary
case series is between 0.8% and 1.4%.89 Other complications
that have been reported in more than 5% of patients include
erectile dysfunction, contracture of the bladder neck, need
for blood transfusion, urinary tract infection, and hematuria.90 Although bipolar resection abrogates many of these
complications,91 newer procedures have been developed
(discussed below), some of which do not require a general
anesthetic and can be carried out in an outpatient setting
with few adverse events.

Minimally invasive surgical therapy

Transurethral needle ablation
During this procedure, low level radiofrequency energy
is directly applied to prostate tissue to produce selective
necrosis.92 A recent systematic review identified nine studies that compared transurethral needle ablation (TUNA) with
TURP.93 Although TUNA significantly improved symptom
scores (12.6 points at one year follow-up, 14.0 to 11.4;
P<0.001) and quality of life scores (2.6 points at one year
follow-up, 3.0 to 2.2; P<0.001) over baseline, it was not
as effective as TURP with regard to these subjective measures. The difference in means at one year follow-up was 3.7
points (2.1 to 5.3) for studies reporting symptom scores and
0.6 points (0.1 to 1.2) for studies reporting quality of life
scores, with both favouring TURP. TURP was also associated
with greater improvements in peak urinary flow rates and
post-void residual urine. The difference in means at one year
follow-up was 5.9 mL/s (7.7 to 4.1) for studies reporting
peak urinary flow rates and 25.0 mL (20.9 to 29.1) for studies
reporting post-void residual urine, with both favouring TURP.
Furthermore, the efficacy of TUNA declines in the long term,
as shown by a significantly higher retreatment rate than for
TURP (10% v 1%).
Transurethral microwave thermotherapy
Transurethral microwave thermotherapy (TUMT) heats
prostate tissue to 45-60C.94 A systematic review identified
15 studies that included comparisons of this technique and
TURP, sham procedures, and adrenoceptor antagonist
monotherapy.95 Pooled analyses showed that TUMT was
an effective alternative to treatment with an adrenoceptor
antagonist for BPH in men with no history of retention or
prostate surgery. At six month follow-up, men treated with
TUMT had significantly greater symptom relief, as measured
by IPSS, than those on terazosin (weighted mean difference
4.20 points, 5.25 to 3.15). However, TURP provided
greater improvements in symptom score and flow rate, as
well as a reduced need for retreatment compared with TUMT.
The weighted mean difference for four studies reporting IPSS
at follow-up was 1.00 points (2.03 to 0.03) and 5.08 mL/s
(3.88 to 6.28) for peak urinary flow rate, with both favouring TURP.
For personal use only

Prostatic urethral lift

Several other minimally invasive, parenchymal sparing
approaches have been developed.96 97 Prostatic urethral lift is
one such approach that has shown promising results. Under
cystoscopic guidance, prostatic urethral lift consists of transurethral placement of suture based implants that mechanically hold the lateral prostatic lobes apart.98 A recent review
conducted by the UK National Institute for Health and Care
Excellence suggests that this approach is safe and efficacious
for the treatment of lower urinary tract symptoms.99 However, patient selection is important, and prostatic urethral lift
should not be regarded as a substitute for surgery.
Laser prostatectomy
To lessen surgical morbidity, a variety of laser procedures
have also been developed. The first was visual laser ablation
of the prostate.100 101 Because patients who underwent this
procedure often developed long term dysuria and retention,
it quickly fell out of favor.
The holmium laser was introduced next.102 103 Its wavelength penetrates less than 500 m into tissue and is highly
absorbed by water. Although the holmium laser can vaporize
tissue, it is more commonly used to enucleate the prostate
adenoma.
Photoselective vaporization of the prostate has also been
described.104 This approach is based on potassium titanyl
phosphate laser energy, the wavelength of which is in the
visible green spectrum. The newest surgical laser is the thulium laser. With tunable wavelength between 1.75 m and
2.22 m, the thulium laser allows for tissue vaporization or
cutting.105
The holmium, potassium titanyl phosphate, and thulium
laser procedures provide similar improvement in symptoms
and quality of life to TURP.106108 These laser procedures
are also associated with less blood loss than traditional
TURP.106108 This allows for earlier hospital discharge after
surgery, shortening the average length of stay by about
one day. Their improved hemostatic properties might offer
particular advantages for men who are taking anticoagulants and those with cardiac or renal disease, given that the
requirement for bladder irrigation during and after surgery
is reduced and hemoglobin levels maintained.
A recent analysis of national Medicare data highlights the
growing popularity of these newer procedures.109 Between
1999 and 2005, the total number of BPH directed procedures
rose by 44%. Minimally invasive surgical therapies (TUNA
and TUMT) and laser procedures increased by 529% during
the same period. Collectively, they account for 57% of all BPH
surgical procedures, whereas traditional TURP accounts for
only 39%. Almost all TUMT and 86% of TUNA procedures
are performed in the physicians office. More than three quarters of laser procedures are carried out on an outpatient basis.
Looking ahead
Botulinum neurotoxin type A
Until recently, botulinum neurotoxin type A was considered
a possible alternative to surgical intervention for men with
medical refractory lower urinary tract symptoms secondary to BPH. This toxin has multiple urological indications,
including treatment of neurogenic and idiopathic detrusor
overactivity.110 111 When administered intraprostatically, it
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is thought to induce prostate apoptosis, leading to prostate
atrophy and size reduction; inhibit sensory neurons in the
prostate and reduce afferent signals to the central nervous
system; and relax prostate smooth muscle cells.112 113
Most studies on botulinum neurotoxin type A injection
therapy have been non-experimental.114 One small randomized double blind placebo controlled trial suggested
that the toxin was superior to saline injection with respect
to symptom and urinary flow rate improvement, as well as
post-void residual urine and prostate volume reduction.115
Buoyed by these findings, a larger trial was launched by the
drug company Allergan.116 However, it found that the toxin
was no more efficacious than sham injection. The development of botulinum neurotoxin type A injection therapy for
refractory lower urinary tract symptoms has therefore been
discontinued.

Drugs that inhibit fibrosis

Fibrosis may be another therapeutic target for the management of lower urinary tract symptoms. Fibrogenesis is
recognized as a major cause of morbidity in chronic inflammatory diseases.117 118 Chronic inflammation has been noted
in several histological studies of the prostate, and some data
suggest that chronic prostatic inflammation may contribute
to the development of lower urinary tract symptoms. Specifically, raised collagen content, higher levels of inflammation
and fibrocytes, increased tissue stiffness, and reduced levels
of elastin and glandularity characterize periurethral prostate
tissue in men with moderate to severe lower urinary tract
symptoms.119
Thus, for men who do not respond to, are intolerant of,
or become refractory to current drug treatments, drugs that
inhibit fibrosis may prove useful. Transforming growth factor
1 is a multifunctional cytokine with many regulatory activities, including cell proliferation and migration, inflammation, and fibrosis. Given its central role in fibrosis, antagonists
of transforming growth factor 1 are potential candidates.
Several large and small molecule drugs that inhibit this
growth factor are currently being tested in trials for patients
with fibrotic diseases and, perhaps, lower urinary tract symptoms in the future.120
Guidelines
The AUA and the European Association of Urology (EAU)
have released BPH guidelines.38 39 In patients who present
with complicated lower urinary tract symptoms (suspicious
digital rectal examination, hematuria, abnormal PSA, painful
urination, recurrent urinary tract infection, palpable bladder,
or neurological disease), guidelines recommend consulting a
urologist, who will have access to evaluations beyond those
recommended as a part of basic management.
For men with uncomplicated lower urinary tract symptoms
and little or no bother, education about the condition, reassurance that cancer is not a cause of the symptoms, and periodic
monitoring are all that are needed.
In men with bothersome uncomplicated lower urinary tract
symptoms, the AUA recommends screening for polyuria (3 L
urine/24 h) with a frequency volume chart. If polyuria is present, then fluid intake should be reduced (goal 1 L urine/24
h). Predominant nocturnal polyuria (>33% of the 24 hour
urine output occurs at night) also warrants fluid restriction
For personal use only

FUTURE RESEARCH QUESTIONS

What is the optimal management approach in men with
asymptomatic chronic urinary retention as a result of
benign prostatic hyperplasia?
What is the role and impact of the placebo response,
especially in men taking herbal treatments with little
adverse effect?
Is the combination of a phosphodiesterase type 5 inhibitor
and an adrenoceptor antagonist efficacious in men with
lower urinary tract symptoms?
Are fibrosis inhibitors useful in the treatment of lower
urinary tract symptoms?
Does treatment for lower urinary tract symptoms affect
falls, fracture, and other outcomes in elderly men?

and consideration of causes other than BPH (such as obstructive sleep apnea). Drugs for treating BPH (table) and other
treatments, such as desmopressin, can also be prescribed.
In men who have bothersome uncomplicated lower urinary tract symptoms without polyuria, clinicians should
initially consider modifiable factors, including concomitant
drug use (such as diuretics) and behaviors such as physical
inactivity, excess alcohol intake, and consumption of irritative foods). Men should be advised to void before sleep or
long trips or meetings. If pharmacotherapy is needed, the
AUA and EAU recommend monitoring the patient to assess
treatment success and adverse effects. The time to treatment
assessment depends on the drug prescribed (table). For successfully treated patients, annual follow-up is recommended.
Treatment failure and symptom progression warrant referral.

Conclusion
Lower urinary tract symptoms are common in older men.
They are often bothersome and can greatly reduce quality of
life. Most men can be evaluated and successfully treated by
targeted symptom control, with the primary goal of reassurance and improvement in symptoms.
In men with mild to moderate symptoms, lifestyle
approaches may be sufficient. For those in whom conservative measures are unsuccessful, an adrenoceptor
antagonist, possibly combined with a 5 reductase inhibitor (especially for men with large prostates) or an antimuscarinic drug, can improve symptoms within one to three
months. Furthermore, pharmacotherapy can slow down
the long term progression of disease (when an adrenoceptor antagonist and 5 reductase inhibitor are combined),
including acute urinary retention. Additional surgical and
minimally invasive procedures provide a larger and often
durable response. They are mainly indicated for men with
more severe symptoms or those who do not adequately
respond to pharmacotherapy. There is no clear evidence
that raised post-void residual urine alters the effectiveness of treatment. The use of additional testing, including
detailed physical and neurologic examination, PSA, and
urodynamic testing, is rarely indicated in primary care. The
use of these strategies can provide high value patient care.
Contributors: Both authors conceived the idea; contributed intellectual
content; acquired and analyzed evidence; and wrote, reviewed, and edited
the manuscript.
Competing interests: Funding from the Agency for Healthcare Research and
Quality (1K08HS020927-01A1 to JMH).
Provenance and peer review: Commissioned; externally peer reviewed.
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