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

H y p e r p l a s i a : C u r re n t
Clinical Practice
Bob Djavan, MD, PhD*, Elisabeth Eckersberger, MPA,
Julia Finkelstein, BSc, Geovanni Espinosa, ND, LAc, Helen Sadri, MD,
Roland Brandner, MD, Ojas Shah, MD, Herbert Lepor, MD

KEYWORDS
 Benign Prostatic Hyperplasia  Lower Urinary Tract Symptoms
 Minimally Invasive Therapy

Published Studies
Study Level Details
ARIA 3001 (US) A Randomized, double-blind, placebo controlled
ARIA 3002 (US) A Randomized, double-blind, placebo controlled
ARIA 3003 (19 Countries) A Randomized, double-blind, placebo controlled
CombAT, 2009 A Randomized, double-blind, placebo controlled,
parallel-group
Djavan, 2004 B Meta-analysis
HYCAT, 1996 A Randomized, double-blind, placebo controlled
MTOPS, 2008 A Randomized, double-blind, placebo controlled
PLESS
TRIUMPH A Randomized, double-blind, placebo controlled

Benign prostatic hyperplasia (BPH) is the most common benign adenoma in men,
affecting nearly all of them. BPH represents a clinically significant cause of bladder
outflow obstruction in up to 40% of men. The growing frequency of diagnosis is due
to increasing life expectancy and a trend toward seeking medical advice at earlier
stages of the disease.

Author Statement: There is no conflict of interest for any of the coauthors nor a funding source
involved in the research mentioned.
Department of Urology, New York University School of Medicine, New York University Hospital,
150 East 32nd Street, New York, NY 10016, USA
* Corresponding author.
E-mail address: [email protected]

Prim Care Clin Office Pract 37 (2010) 583–597

doi:10.1016/j.pop.2010.04.004 primarycare.theclinics.com
0095-4543/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
584 Djavan et al

OVERVIEW OF DIAGNOSIS, TREATMENT, AND MANAGEMENT

Advances in understanding of the epidemiology and pathophysiology of BPH have led

to changes in treatment. Although treatment was previously based on ablative
surgery, guidelines now emphasize pharmacotherapy and minimally invasive surgery.
The advent of new medical therapies for BPH and the introduction of a range of mini-
mally invasive therapies (MITs) now provide a wider range of therapeutic options for
men with lower urinary tract symptoms (LUTS) secondary to BPH. The development
of effective therapies such as alpha-adrenergic blockers and 5-alpha-reductase
(5AR) inhibitors and the possibility of their combined use represent the most significant
advance in the treatment of BPH.
Since 1991, the WHO international consensus meetings on BPH have facilitated
continued discussion on the development of clinical research criteria for BPH.
Outcomes include benefits and harms, which can be direct (such as changes in
symptoms, magnitude of symptoms, bother, and quality of life as perceived by
patients) or indirect (such as flow rate, residual urine, prostate size, and pressure
flow parameters). The American Urological Association (AUA) is currently using
a Symptom Index (SI) score (Table 1)1 to establish the severity of clinical symptoms.
Watchful waiting is recommended for patients whose clinical symptoms do not affect
their quality of life.2
Evidence from several studies has highlighted the role of prostate enlargement
in BPH progression, with strong relationships between prostate volume, need for

Table 1
International Prostate Symptom Score (IPSS)

During the last month or so, how often have you.

Not at all (0), less than 1 time in 5 (1) less than half the time (2), about half the time (3), more
than half the time (4), almost always (5)
1. Had a sensation of not emptying your bladder completely after urinating?
0 1 2 3 4 5
2. Had to urinate again less than 2 hours after you have urinated?
0 1 2 3 4 5
3. Stopped and started several times when you urinated?
0 1 2 3 4 5
4. Found it difficult to postpone urination?
0 1 2 3 4 5
5. Had a weak urinary stream?
0 1 2 3 4 5
6. Had to push or strain to urinate?
0 1 2 3 4 5
During the last month.
7. How many times did you most typically get up to urinate from the time you went to bed at
night until the time you got up in the morning?
0 1 2 3 4 5

From Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index
for benign prostatic hyperplasia. The Measurement Committee of the American Urological Associ-
ation. J Urol 1992 Nov;148(5):1549–57; with permission.
 Benign Prostatic Hyperplasia 585

BPH-related surgery, and risk of developing acute urinary retention.3 The impor-
tance of androgens in the development of prostate enlargement is now well under-
stood based on several lines of evidence. BPH does not develop in men who have
been castrated before puberty and therefore have greatly depleted levels of circu-
lating androgens. Furthermore, in men with BPH, medical or surgical castration
has been shown to cause a reduction in prostate volume.

ROLE OF DIHYDROTESTOSTERONE AND TESTOSTERONE

Dihydrotestosterone (DHT) is twice as potent as testosterone, and it plays the most

important role in BPH progression, mediating androgenic effects in BPH. In the pros-
tate, as opposed to blood, the level of DHT is higher than that of testosterone. Further-
more, intraprostatic DHT levels remain high in aging men despite a decline in
circulating testosterone, suggesting a central role for DHT in BPH.
Testosterone is converted to DHT, a reaction catalyzed by the 5AR isoenzymes type
1 and 2. Type 2 5AR is found predominantly in the prostate and other genital tissues.
Type 1 5AR is more ubiquitous, found throughout the body wherever 5AR is
expressed, including the skin, liver, and prostate. Tissues with a high concentration
of these enzymes, such as the prostate, are therefore the major site of conversion
of testosterone to DHT. It has long been argued that the prostatic conversion of
testosterone to DHT amplifies the effects of circulating testosterone by converting it
to the more potent androgen, DHT. Given the central role of DHT as the most potent
androgen, predictably, men with genetic type 2 5AR deficiency have small and rudi-
mentary prostates and do not develop BPH as adults, although they undergo viriliza-
tion at puberty.4
This underlying prostate growth under androgenic control may be one of the key
drivers of long-term BPH disease progression. Inhibition of testosterone conversion
to DHT by targeting the 5AR isoenzymes is therefore a rational approach for the
management of BPH. This can be done using 5AR inhibitors, which are a cornerstone
of current medical therapy, along with a-blockers.

MEDICAL THERAPY
a-Blockers
Alpha(1)-adrenoceptor antagonists, or a-blockers, have become important compo-
nents in the treatment of BPH. A better understanding of how adrenergic hormone
receptors are involved in prostate disease has led to an increased use of a-blockers
in treatment, shifting the focus from surgery to better uses of pharmacotherapy.
Currently available a-blockers have similar effects on BPH, improving symptoms by
approximately 35% and maximum urinary flow rate by 1.8 to 2.5 mL/s.5
Djavan, and Marberger6,7 concluded that all a-blockers have comparable efficacy in
improving symptoms and that those that require dose titration and are initiated at
subtherapeutic doses (eg, terazosin) have a slower onset of action than those that
can be initiated at their full therapeutic dose (eg, tamsulosin). The main difference
between the a-blockers relates to their tolerability profiles, with alfuzosin and tamsu-
losin better tolerated than doxazosin and terazosin. Patients with LUTS/BPH are more
likely to discontinue a-blocker therapy because of vasodilatory adverse events, such
as dizziness, than because of retrograde ejaculation.
Earlier placebo-controlled studies showed similar results. Lepor and colleagues8
found that groups treated with 10 mg of terazosin exhibited significantly greater
increases in peak and mean urinary flow rates than the group on the placebo.
The improvements did not reach a plateau within the dose range evaluated,
586 Djavan et al

suggesting that higher doses could possibly be even more effective. In the Hytrin
Community Assessment Trial study (HYCAT), Roehrborn and colleagues9 evalu-
ated terazosin in a community-based population under usual care conditions.
Given in a daily dose of 2 to 10 mg, terazosin was more effective than placebo
in reducing the symptoms of BPH, reducing the perception of bother, and in
raising the disease-specific quality of life in men with moderate–to-severe symp-
toms of prostatism. These effects were maintained during a 12-month follow-up.
Although a-blocker therapy rapidly relieves BPH symptoms, there is no evidence
that it reduces the long-term risks of acute urinary retention and surgery, probably
because a-blockers do not reduce prostate volume.

5AR Inhibitors
The main circulating androgen, testosterone, is converted to DHT by the enzyme 5AR.
Although DHT is necessary for normal growth and function, it is also involved in the
development of BPH and, most likely, the initiation and maintenance of prostate
cancer. Two 5AR inhibitors, finasteride and dutasteride, have been studied extensively
in clinical trials of patients with BPH. Finasteride is a type 2 5AR inhibitor, whereas
dutasteride is a dual 5AR inhibitor that inhibits both isoenzymes. Both compounds
have been shown to inhibit serum DHT, although dutasteride is more effective.10 In
large-scale clinical trials in men with symptomatic BPH, 5AR inhibitors reduce prostate
volume, improve symptoms, reduce the risk of acute urinary retention, and decrease
the likelihood of BPH-related surgery.11,12 These medications reduce serum prostate-
specific antigen (PSA) by approximately 50% at 6 months and reduce total prostate
volume by 25% in 2 years.13 The 5AR inhibitors also have the potential to reduce
the risk of prostate cancer as a secondary benefit in men receiving treatment for
symptomatic BPH.14
The first placebo-controlled study on dutasteride was published in 2002, pooling
patients from 3 randomized trials: ARIA 3001 and ARIA 3002 in the United States,
and ARIA 3003 in 19 countries in which 2167 men received 0.5mg/d and 2158 received
placebos.12 At 24 months, serum PSA had increased by 15.8% in the placebo group,
compared with a decrease of 52.4% in the dutasteride group. Assessing the BPH
Impact Index (BII) in the same cohort, O’Leary and colleagues15 showed that dutaster-
ide resulted in clinically and statistically significant improvements from 6 months. BII
scores improved by 2.41 in men with a high baseline BII (R5 [greatest symptomatic
burden]), whereas in patients treated with the placebo, they only improved by 1.64.

Combination Therapy
Combination therapy for BPH is the combination of drugs that have proved useful as
monotherapy and are able to give the patient even great relief when combined. In the
case of BPH, a-blockers and 5AR inhibitors have been shown to be effective individ-
ually9,16,17 and are now being investigated in combination, especially in those patients
reluctant to undergo surgery and getting no relief from monotherapy. A 2008 analysis
of the Medical Therapy of Prostatic Symptoms (MTOPS) assessed the long-term treat-
ment with doxazosin, an a-blocker, and finasteride, a 5AR inhibitor.18 Three thousand
forty-seven patients were randomized to placebo, doxazosin (4 to 8 mg), finasteride
(5mg), or a combination of doxazosin and finasteride. Treatment with finasteride led
to a reduction of approximately 25% in prostate volume in those with relatively small,
moderate–sized, and enlarged prostates at baseline. The reductions in risk of acute
urinary retention and surgery with finasteride were statistically significant (P 5 .009
and P<.001, respectively). The rates of acute urinary retention and surgery in the
a-blocker arm were 0.4 and 1.3 per 100 person-years, respectively, which were not
 Benign Prostatic Hyperplasia 587

significantly different from placebo. The results lead to the conclusion that combina-
tion therapy is most functional when the patient’s PSA level is more than 1.5ng/mL,
his prostate volume greater than 30cc, and his LUTS significant.16
Because MTOPS was designed with drugs that are less used today, such as tera-
zosin and doxazosin, the Combination of Avodart and Tamsulosin (CombAT) study
published first results on the effect of combined therapy with dutasteride and tamsu-
losin as opposed to each as monotherapy, and results were assessed using the BII 17
(Table 2) and International Prostate Symptom Score (IPSS; see Table 1).19 Results
show that at 24 months, BII scores were best reduced (symptoms improved) from
baseline in the combination and second best in the dutasteride and tamsulosin
groups, and the improvement in BII was statistically (P<.001) greater with the
combined therapy than with either monotherapy. The results on the IPSS show that,
at 24 months, change in baseline IPSS was greatest with the combination, and again,
the reduction in score was significantly greater with the combination than with each
monotherapy (P<.001). The BII continued to improve with the combination and with
dutasteride alone over the 2-year study period but seemed to decline with tamsulosin
after 15 months. Additionally, the improvement in BII from the baseline was greater
than previously reported for dutasteride in the Phase III trials, probably due to the
lack of a placebo arm and a higher mean baseline BII in CombAT. It can be concluded
from these trails that combination therapy has significant benefits for patients in terms
of reduction in symptoms and prostate volume.

Phytotherapy
Medical therapy with a-blockers and 5AR inhibitors has been extended with the
growing interest in phytotherapy; around one in 5 men are currently using complemen-
tary and alternative methods.20,21 The most commonly used phytotherapies for BPH
are extracts of Serenoa repens (saw palmetto), thought to have antiandrogenic, anti-
proliferative, and antiinflammatory effects, and extracts of the African plum tree’s
bark.22,23 Because BPH is not a life-threatening condition, using drugs composed
of natural ingredients with low side-effects is attractive to many patients. The

Table 2
BPH Impact Index

Q1. Over the past month, how much physical discomfort did any urinary problems cause you?
None (0), only a little (1), some (2), a lot (3)
Q2. Over the past month, how much did you worry about your health because of any urinary
problems?
None (0), only a little (1), some (2), a lot (3)
Q3. Overall, how bothersome has any trouble with urination been during the past month?
Not at all bothersome (0), bothers me a little (1), bothers me some (2) bothers me a lot (3)
Q4. Over the past month, how much of the time has any urinary problem kept you from doing
the kinds of things you would normally do?
None of the time (0), a little of the time (1), some of the time (2), most of the time (3), all of the
time (4)

From AUA Guideline on the management of benign prostatic hyperplasia (BPH) 2003. Updated
2006, with permission. Available at: http://www.auanet.org/content/guidelines-and-quality-care/
clinical-guidelines.cfm?sub5bph. Accessed April 2010.
588 Djavan et al

effectiveness of phytotherapies compared with placebos is still debated, and studies

are proving difficult to execute. A randomized, double-blind, placebo-controlled study
did not show any benefit of Serenoa repens over the placebo arm in respect to
symptom relief at 1 year.24 As a result of this trial, the Complementary and Alternative
Medicine for Urological Symptoms (CAMUS) trial with 3300 participants testing
Serenoa repens, African plum tree extract, an alpha-adrenergic blocker, and a placebo
shifted its endpoint from a measure of long-term efficacy to determining any short-
term (6–8 months) symptom relief.25 The results are anticipated in 2011.

Role of Anticholinergic Therapy

In patients with overactive bladder symptoms, anticholinergic drugs can be consid-
ered. As an alternative to bladder retraining, anticholinergics block the parasympa-
thetic pathway, thereby abolishing or reducing the severity of detrusor muscle
contractions. Unfortunately no current anticholinergics target the bladder muscles
specifically, and they often cause side effects, such as dry mouth or dry eyes, because
of their effect on muscarinic receptors in other body parts. In a review of 32 placebo
controlled trials of anticholinergics, Herbison and colleagues26 found small but statis-
tically significant differences in symptoms. Anticholinergic drugs improved symptoms
of overactive bladder, such as number of leakages, episodes per day, number of voids
per day, and urodynamic measures. It is still unclear which anticholinergic drugs work
best, what is the most effective route of administration and which population groups
would benefit most.
Additionally, studies have shown that Botulinum toxin can be effective in cases of
detrusor overactivity and overactive bladder syndrome not effectively treated by anti-
cholinergenics.27 This treatment is not yet approved by the US Food and Drug Admin-
istration but warrants further study.

PATIENT ASSESSMENT AND TREATMENT ALLOCATION

The last decade has witnessed significant changes in the therapeutic approach to BPH.
Before the early 1990s, choice of therapy was limited; watchful waiting was advised if
the symptoms and their impact on quality of life did not warrant surgical intervention
or if surgery was impractical because of comorbidity or patient preference. Transure-
thral resection of the prostate (TURP) had become the surgical treatment of choice
over open resection. Phytotherapy was available, although over-the-counter use of
such preparations was not well characterized until later. The advent of medical therapy
with alpha(1)-antagonists and 5AR inhibitors resulted in a significant change in practice.
There was a steady decline in the use of TURP accompanied by a dramatic increase in
the use of medical therapy and, to a lesser extent, MIT.28,29

USE OF SYMPTOM QUESTIONNAIRE

The most commonly used symptom index for BPH is the SI score questionnaire devel-
oped by the AUA. The index comprises 7 questions on frequency, nocturia, weak
urinary stream, hesitancy, intermittence, incomplete emptying, and urgency. Patients
are asked to score all 7 categories on a range from 0 (not at all) to 5 (almost always).
Scores are added, and classification of symptoms is either mild (0–7), moderate (8–
19), or severe (20–35). This evaluation of symptoms is superior to unstructured inter-
views. The index has been shown to be internally consistent and sensitive to change
with treatment, showing practicality and reliability for use in practice.1
 Benign Prostatic Hyperplasia 589

COMPARING MEDICAL TREATMENT APPROACHES: TRIUMPH STUDY

A large-scale international study, the Trans European Research into the use of
Management Policies for BPH in Primary Health Care (TRIUMPH) study, has sought
to characterize assessment and treatment practices for BPH across Europe. This
prospective, cross-sectional, observational study was conducted in 6 European coun-
tries, enrolling newly and previously diagnosed patients with LUTS suggestive of
BPH.30 One-year follow-up data were available for 5057 patients.
The study demonstrated that initial assessment varied significantly between coun-
tries; for example, the use of PSA testing in the total study population was 73%, but for
individual countries, it ranged from 41% in Germany to 88% in Spain.31 The use of
serum creatinine measurements, digital rectal examinations (DRE), and uroflow
measurements also varied considerably between countries. When initial assessment
of 4979 newly presenting patients in the TRIUMPH study was examined, the use of
different tests was found to vary between general practitioners and office-based urol-
ogists, with urologists performing more tests than general practitioners on average.32
Serum creatinine measurements, DRE, and uroflow measurements are all recommen-
ded for routine use in the current European Association of Urology (EAU) guidelines for
management of BPH,33 whereas PSA testing is recommended for men with a greater
than 10-year life expectancy where knowledge of prostate cancer status would
change patient management.

WATCHFUL WAITING

Watchful waiting is usually decided on through a combination of the patient’s prefer-

ence and the physician’s assessment of the disease and its progression, without strict
criteria existing and with individual feeling paramount to the decision. Overall, it seems
that patients with mild symptom and bother scores, those with low PSA scores and
prostate volume, and those with stable postvoid residual volumes (PVRs) are deemed
the best candidates for watchful waiting.34
One study on watchful waiting, the Olmstead County Study of Urinary Symptoms
and Health Status enrolled 2115 men aged 40 to 79 years over a course of 6 years.35
The study found that age was a significant factor in seeking treatment; the incidence of
treatment in men aged 40 to 49 years was 3.3 per 1000 person-years, which rose to 30
per 1000 person-years in men older than 70 years. This suggests that as a progressive
disease, watchful waiting is more likely to be an option in younger patients with BPH. A
study following patients in 6 European countries found that the number of patients
treated with watchful waiting was 30% of the study population, with figures ranging
from 20% in Italy to 69% in the United Kingdom.32
However, some men eventually require surgical intervention. In a Veterans Affairs’
study, 556 men with moderate BPH symptoms were randomized to receive TURP
or watchful waiting. The findings demonstrated high rates of crossover (conversion)
from watchful waiting to surgery in men with high or low degrees of bother during 5
years of follow-up.36 Higher bother at baseline was associated with a higher crossover
rate than lower bother. These findings have been confirmed in a longitudinal study of
397 men with mild LUTS (IPSS < 8) due to BPH who were followed over a 4-year period
of watchful waiting.37 At the end of follow-up, 31% of patients had clinical progression,
defined as a worsening of symptoms with migration to the moderate (IPSS 8–18) or
severe (IPSS 19–35) symptom group and an increase of at least 3 points on the
IPSS. At 4 years, 84% of patients had a worse IPSS than at baseline. When baseline
characteristics for patients with and without clinical progression were compared, PSA
(P<.001), obstructive symptom score (P 5 .04), and transitional zone volume (P<.001)
590 Djavan et al

were found to be significantly higher in men with progression compared with those
without progression.
The evidence from these and other studies suggests that watchful waiting may not
always be the optimal approach for men with mild symptomatic BPH.32,33,38 It may
therefore be more appropriate to identify those men at risk of progression so that
they can be managed more effectively, reducing the risk of progression, symptom
deterioration, and acute urinary retention and surgery. The combination of several
risk factors into nomograms may have clinical utility in helping physicians identify
at-risk men. One such example was constructed to predict the risk of BPH progres-
sion using data from the dutasteride phase III program, and it showed a predictive
accuracy of approximately 71%.39 However, given that prostate volume is strongly
related, in an age-dependent manner, to serum PSA in men with BPH but with no
evidence of prostate cancer,40 serum PSA alone may be sufficient for risk
stratification.41
Treatment costs per patient were also examined in the TRIUMPH study.42 Medica-
tion was the most important cost driver, accounting for 72% of total treatment costs.
Treatment of patients with worse voiding and filling/storage symptoms was associ-
ated with greater costs (P<.001). Linear regression showed that certain medication
choices, acute urinary retention, urinary tract infections (UTIs), renal dysfunction,
and surgery were associated with higher treatment costs.
The TRIUMPH study serves to highlight the differences in current clinical practice
that exist across Europe, with considerable disparity between the choices of watchful
waiting and medical therapy and in the types of medical therapy selected (classes of
drugs and monotherapy vs combination therapy).28 An examination of patient charac-
teristics from the study found that patient heterogeneity did not account for the vari-
ations in patient management between countries.29 The authors concluded that
choice of therapy seems to be influenced by local clinical practice preferences, differ-
ences in national health care systems, and possibly, drug availability and pricing rather
than by evidence-based clinical guidelines.29,31 Another potential driver of therapeutic
choice, patient preference, was not examined in this study. It is important that patient
expectations of therapy and adverse events are included in treatment decisions to
ensure that therapy is tailored to individual patient needs and that health-related
quality of life is addressed.42

RISK OF PROGRESSION AS A DRIVER FOR TREATMENT ALLOCATION

BPH is a progressive disease in some men.43 BPH progression has been studied using
various measures, including increased symptom severity or bother, decreased urinary
flow, prostate enlargement, development of acute urinary retention, obstructive
nephropathy, occurrence of UTI or incontinence, and need for surgical intervention.
Longitudinal community-based studies provide key insights into the natural history of
the disease. In the Olmsted County Study, a cohort of 631 randomly selected men
aged 40 to 79 years was followed for 5 years. Their average baseline prostate volume
significantly increased with increasing age, with a mean annual increase of 1.6%
reported across all age groups.44 Data for urinary symptoms were reported for the entire
baseline study population of 2115 men, with a mean increase in AUA-SI score of 0.18
points per year observed during 42 months of follow-up.45 The mean increase in score
ranged from 0.05 points for men in their forties to 0.44 points for men in their sixties. A
median decrease in peak urinary flow rate of 2.1% per year was also reported.46 Again,
this was found to be age-related, with men aged 70 years and more showing a faster
decline (6.2% per year) than men in their forties (1.1% per year).
 Benign Prostatic Hyperplasia 591

Randomized controlled trials also provide evidence of the progressive nature of

BPH. For example, in the MTOPS study,42 a composite measure of any of the following
was used to define progression: 4-point increase in AUA-SI score, acute urinary reten-
tion, incontinence, UTI/urosepsis, or renal insufficiency. This study enrolled 3047 men
aged at least 50 years, with an AUA-SI score of 8 to 35, a peak urinary flow rate
between 4 and 15 mL/s, and a voided volume of at least 125 mL. The MTOPS study
demonstrated that over a 4-year period, of the 737 men who received placebo, 17%
had a BPH progression event, 14% had a 4-point increase in AUA-SI score, 2% had
acute urinary retention, and 5% had surgery. Prostate volume also increased by
a median of 24% after a mean follow-up of 4.5 years.47
A subsequent analysis of data from the placebo arm in the MTOPS study was used
to determine the risk factors for BPH progression.48 In this study population, prostate
volume of 31 mL or more, PSA level of 1.6 ng/mL or more, maximum flow rate less than
10.6 mL/s, PVR of 39 mL or more, or age 62 years or older were found to significantly
increase the risk of overall BPH progression. These findings are in agreement with
those from previous community-based studies and randomized clinical trials in which
PSA level and total prostate volume are well-defined risk factors for BPH progres-
sion.49 Knowing the clinical characteristics that may predict the progression of BPH
allows physicians to identify symptomatic men at risk of progression at an early stage
and treat them appropriately.

INTERVENTIONAL THERAPY
Surgical Intervention Options
Surgery remains an important part of treatment for BPH. Different forms of surgery,
broadly classified into TURP, open surgery, and minimally invasive procedures, are
currently used. TURP has become the most common form of contemporary surgery
and is the reference standard for the treatment of LUTS secondary to BPH. Obstruct-
ing adenomatous tissue is removed using a cutting diathermy current applied via
a loop. The distal end of the incision is the verumontanum, which represents the prox-
imal extremity of the distal sphincter mechanism. Bleeding vessels can also be easily
visualized and coagulated. An option for patients with prostate glands of 25 g or less is
to perform a transurethral incision of the prostate (TUIP). Men in their forties and fifties
who present with a lifelong history of voiding difficulty that seems to be principally
related to narrowing at the bladder neck (bladder neck dyssynergia) are seen to benefit
most for TUIP. This technique may also be effective in men with a combination of mild
prostatic enlargement and bladder neck obstruction. Open prostatectomy (retropubic
prostatectomy[ RPP]) aims to remove the central obstruction by shelling it out along
the cleavage plane between the adenoma and compressed normal prostatic tissue.
In contrast, radical prostatectomy comprises excision of the whole prostate gland
and seminal vesicles, perineally or via a suprapubic approach. This procedure is
used to treat localized prostatic adenocarcinoma. A modified form of TURP, bipolar
TURP (B-TURP), can be done in normal saline, a conductive medium, instead of the
conventional nonconductive irrigation fluid. This should help eliminate the dilutional
hyponatremia and transurethral resection syndrome caused by hypotonic/hypo-
osmolar fluid irrigation.50 A lack of homogenous trials has so far hampered the
comparisons between TURP and B-TURP. One meta-analysis of 16 trials with a total
of 1406 patients found no clinically relevant differences in short-term efficacy.51
Patients unsuitable for transurethral or open surgery due to comorbid disease and
those who wish to avoid the recognized morbidity—particularly relating to sexual
function—may choose minimally invasive surgery.
592 Djavan et al

Minimally Invasive Surgery

Compared with other procedures, minimally invasive surgery is associated with
shorter postoperative hospitalizations and decreased morbidity. Although there is
a plethora of shorter-term data on minimally invasive techniques, there are limited
long-term data, so these procedures have not yet replaced TURP as the gold standard
for the surgical management of BPH.
Minimally invasive surgery includes several promising treatments, such as
Holmium laser resection, plasma kinetic vaporization, and GreenLight laser vapor-
ization. Holmium laser resection enables complete enucleation of the prostate gland
(as does RPP) and is considered to be a serious contender for the gold standard for
large prostates (>100 g). This technique has been shown to be safe and effective,
and it is associated with decreased blood loss and complications compared with
TURP. However, it has high start-up costs, longer operative times, and a steep
learning curve. Long-term randomized prospective studies comparing laser treat-
ments with other treatments for BPH are ongoing. Another option is using Green-
Light laser to vaporize prostatic tissue. A study by Coz and Domenech52 showed
very good results in the use of GreenLight laser to treat BPH; AUA score was
reduced from a mean of 22 before treatment to a mean of 11.4 after 30 days,
and urine flow rate increased. Complications included delayed removal of the cath-
eter (11.1%), dysuria (16.6%), and late hematuria (11.1%). The few trials comparing
GreenLight laser to TURP53 show divergent results, and more trials with longer
follow-up are needed.
Cooled transurethral microwave thermotherapy (TUMT) has emerged as an alterna-
tive to medical treatment for patients unsuitable for surgery. Microwaves are used to
heat obstructive prostatic tissue under topical urethral anesthesia to a temperature of
40  C  1 C for 45 minutes to 1 hour. A single 1-hour outpatient treatment can result in
significant improvements. In a 2003 study, Osman and colleagues54 showed that
microwave therapy was well tolerated and that there was an overall subjective
success rate in 83% of patients after at least 1 year. In more than 55% of patients,
the improvements were marked and showed a successful urodynamic change to
unobstructed. It was also found that TUMT achieved better results in those with higher
grades of bladder outlet obstruction, lower age, and larger prostates. These findings
are in line with earlier studies showing that the improvement is not due to the placebo
effect,55 is not temporary, and can last for up to 5 years.56 The fast onset of action with
a-blockers and the long-term efficacy of TUMT point to combining the 2 treatment
options. This possibility was explored in a 1999 study of 41 patients who were treated
with TUMT with or without neoadjuvant and adjuvant tamsulosin administration.57 The
combination of the 2 treatment modalities resulted in significantly lower mean IPSS at
2 weeks and 6 weeks than those in the TUMT-only group. TUMT can therefore be
considered a promising treatment option alone and in combination with other estab-
lished treatments.

EFFECTS OF TREATMENTS ON SEXUAL FUNCTION

Treatment for BPH can cause deterioration in sexual function, which can have
a significant impact on patients’ quality of life. The risks should be discussed
with each patient before beginning treatment. Libido, erectile function, and ejac-
ulatory function can all be affected in different ways by different treatment
approaches. Alpha-adrenergic blockers and 5AR inhibitors can affect sexual
and ejaculatory function.58 The MTOPS study’47 found slightly decreased libido
and erectile and ejaculatory function with finasteride and combination therapy.
 Benign Prostatic Hyperplasia 593

Box 1
Indications for intervention in clinical BPH

A. Absolute indications for intervention in clinical BPH (mostly surgery)

1. Chronic retention: patients with impaired renal function, hydronephrosis (high-pressure
chronic retention), or overflow incontinence
2. Acute retention: patients receive a trial of medical therapy before surgery is considered
3. Stone formation
4. Recurrent hematuria: patients who are unresponsive to 5AR therapy and recurrent
infection caused by residual urine
B. Relative indications for intervention in clinical BPH (mostly pharmacotherapy)
1. Patients with moderate-to-severe symptoms and abnormal flow less than 15 mL/s
2. Recurrent urinary infections associated with bladder outflow obstruction and high PVR
urine

Adapted from AUA and EAU guidelines.45,64

a-Blocker therapy rarely contributes to a decrease in libido or sexual func-

tion.59–61 Surgical treatments carry additional risks to sexual function, and as
with medical treatment, different aspects of sexual function can be affected by
different treatments. Transurethral resection involving cauterization can potentially
damage the ejaculatory ducts. Although erectile dysfunction now occurs in less
than 5% of cases,62 ejaculatory function is negatively affected in more than
half of all treatment cases.63 Patients receiving minimally invasive procedures
report disruption of sexual function less frequently, but effects vary for every
patient. Patients being treated surgically are likely to have more severe urinary
symptoms than those being treated medically. This means that for every patient,
the balance between improving poor urinary function and retaining sexual function
must be found.

AUA/EAU GUIDELINES SUMMARY

Current guidelines on the management of BPH published by the AUA and the EAU
include systematic reviews of data to support the different assessments and interven-
tions available.32,45 However, although the 2 sets of guidelines provide guidance on
absolute indications for treatment (for example renal impairment), they contain little
guidance on the identification of men at risk of progression and the choice of watchful
waiting versus active therapy. For example, the EAU guidelines state that ‘‘Watchful
waiting is recommended for patients with mild symptoms that have minimal or no
impact on their quality of life.’’45 In contrast, the AUA guidelines state that ‘‘Watchful
waiting is the preferred management strategy for patients with mild symptoms. It is
also an appropriate option for men with moderate to severe symptoms who have
not yet developed complications of BPH’’ (Box 1).64

SUMMARY

The last decade has witnessed a significant shift in emphasis in the management of
BPH, with medical therapies and, to a lesser extent, MITs becoming the predominant
active therapy choice.
594 Djavan et al

Current guidelines may lag behind available evidence in their guidance on assess-
ment and management of men with BPH. A critical review of guidelines for BPH
found considerable differences in the overall quality of the available guidelines,
particularly concerning methodology of guideline development.65 Examination of
risk factors for BPH progression has identified that baseline prostatic enlargement
is a precursor and that PSA level is a reliable surrogate for prostate volume and
therefore represents a robust measure of future progression risk. Taken together,
this evidence demonstrates that men at risk of progression can be identified through
PSA assessment.
Watchful waiting may prove inadequate for many men with mild symptomatic BPH
at risk of progression. The lack of therapeutic intervention in these men exposes them
to a greater risk of symptom deterioration, acute urinary retention, and surgical inter-
vention. Data from large-scale clinical studies have demonstrated that treatment with
5AR inhibitors significantly ameliorates symptoms of BPH and, in contrast to
a-blockers, reduces the long-term risks of acute urinary retention and BPH-related
surgery in men at risk of progression. However, despite the large body of clinical
evidence that demonstrates the benefits of 5AR inhibitors in reducing the risk of
BPH progression, it seems that they are often underprescribed in at-risk men in
everyday clinical practice, especially as a first-choice therapy to ameliorate symptoms
and reduce the risk of BPH progression. In order for men at risk of BPH progression to
be managed effectively, clinical practice should change to reflect the level 1 evidence
for 5AR inhibitors in reducing their risk of progression.

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