VOL.16 NO.

6 JUNE 2011

Medical Bulletin

Pathology and Medical Therapy of

Benign Prostatic Hyperplasia
Dr. Steve Wai-hee CHAN
Division of Urology, Department of Surgery, Queen Elizabeth Hospital

Dr. Steve Wai-hee CHAN

This article has been selected by the Editorial Board of the Hong Kong Medical Diary for participants in the CME programme of the Medical
Council of Hong Kong (MCHK) to complete the following self-assessment questions in order to be awarded CME credit under the programme upon
returning the completed answer sheet to the Federation Secretariat on or before 30 June 2011. The CME accreditation is in application. The number
of CME credit is subject to the final decision of the organisations.

Introduction
Benign Prostatic Hyperplasia (BPH) is a progressive
condition characterised by prostate enlargement
accompanied by lower urinary tract symptoms (LUTS)1,2.
It contributes to, but is not the sole cause of LUTS. It is
well known that BPH and the resultant LUTS is very
common in elderly men3,4 and has a great impact on
the patients quality of life5. It was estimated that in the
male population, a histological prevalence at autopsy of
50% in men aged 50-60 years and of 90% over 80 years6
was seen. 75% of men > 50 years old had symptoms
arising from BPH, and 20-30% of men reaching 80 years
old required surgery 1,2. Despite the fact that BPH is
one of the commonest diseases that are managed by
urologists and it has a big impact on public health, the
aetiology and pathophysiology are still not yet clear.

Aetiology
Several mechanisms are now believed to be important
in the development and progression of BPH:

Tissue Remodelling

McNeal demonstrated that BPH first develops in the

periurethral transition zone of the prostate7 and all the
BPH nodules develop either in the transition zone or in
the periurethral region. Although early transition zone
nodules appear to occur either within or immediately
adjacent to the preprostatic sphincter, as the disease
progresses and the number of prostatic nodules
increases, they can be found in almost any portion of the
transition or periurethral zone. The nodular enlargement
is androgen-dependent and the tissue remodelling
involves both the epithelium and fibromuscular
stroma8,9. These nodules are characterised by a reduced
epithelium-to-stroma ratio, determined by an imbalance
between growth and death programmes of stromal
cells, leading to increased final stromal volume10,11,12.
The underlying mechanism may be attributable to the
involvement of enhanced expression of anti-apoptotic
cell death mechanisms in the human prostate, resulting
in a growth imbalance in favour of cell proliferation that
might ultimately support hyperplasia11,13,14.

Hormonal Alterations

Although androgens do not cause BPH, the development

of BPH requires the presence of testicular androgens

during prostate development, puberty and ageing.

Despite the fact that the serum level of testosterone
decreases with age, it is known that the intra-prostatic
levels of the active metabolite dihydrotestosterone
(DHT) as well as the androgen receptor (AR) remain
high15,16. DHT is predominantly generated by prostatic
5-alpha reductase, which is present in fibroblasts of the
stroma and in basal epithelial cells and recent androgenresponsive genes studies showed that androgen
signalling is significantly elevated in hyperplastic tissue
relative to the adjacent normal prostate17.

Inflammation

BPH has been frequently observed to be associated

with chronic prostatitis and now chronic inflammation
is believed to support the process of fibromuscular
growth in BPH18. Many studies including major studies
like the Reduction by Dutasteride of Prostate Cancer
Events (REDUCE) trial and the subgroup analysis of the
Medical Therapy of Prostate Symptoms Study (MTOPS)
found correlation between inflammation of the prostate
and BPH19,20. It was proposed that inflammation of the
prostate caused tissue injury, and cytokines produced
by the inflammatory cells might serve to drive local
growth factor production and angiogenesis in the tissue
as a wound healing process, resulting in tissue growth.

Metabolic Syndrome

BPH and the metabolic syndrome are believed to be

associated according to recent studies. The metabolic
syndrome is defined as abdominal obesity associated
with hyperinsulinaemia, insulin resistance and two
additional cardiovascular risk factors 21 . Diabetes
mellitus, hypertension, obesity and low high-density
lipoprotein cholesterol (HDL-C) levels constitute risk
factors for the development of BPH22,23,24.

Pathophysiology

According to the classical model and belief, the size

of the prostate increases with BPH, thus resulting in
the obstruction of the urine flow that accounts for the
LUTS. Therefore, the logic was previously surgery like
prostatectomy or drugs that can reduce the resistance to
urine flow can resolve LUTS. However, it is now known
that the pathopysiology of BPH is much more complex:
prostatic hyperplasia increases urethral resistance,
resulting in compensatory changes in bladder function.
The obstruction-induced changes in detrusor function,
compounded by age-related changes in both bladder
and nervous system function, lead to urinary frequency,

VOL.16 NO.6 JUNE 2011

urgency and nocturia, the most bothersome LUTS. This

concept can at least be partly proven from the study by
Neal et al, which showed prostatectomy could resolve
the emptying problem of LUTS but not the storage
problem25.
Half of the stromal hyperplasia is composed of smooth
muscle elements26 and it was believed that the enlarged
prostate caused obstruction via both dynamic and static
mechanisms 27. The static component was due to the
physical presence of the prostate obstructing the urine
stream within the prostatic urethra and the dynamic
obstruction was thought to be the result of smooth
muscle hyperplasia and contraction28 and was mediated
by alpha 1 adrenoceptor subtype29.
As in most chronic diseases, BPH is progressive: it
requires a long period to evolve from earlier tissue
alterations to clinical onset with LUTS30 or if untreated,
it is often complicated with bladder dysfunction and
hypertrophy possibly leading to acute urinary retention
(AUR).

Medical Therapy
Current strategies for treating men with LUTS are
watchful waiting, pharmacologic therapies and surgery
and this article will focus on medical therapy.

Phytotherapy

The most commonly used phytotherapies for BPH

are extracts of Serenoa repens (sau palmetto), thought
to have antiandrogenic, anti-proliferative and antiinflammatory effects, and extracts of the African plum
trees bark. Many patients found phytotherapies
attractive as they have low side effects. A randomised,
double-blind, placebo-controlled study did not show
any benefit of Serenoa repens over the placebo arm in
respect to symptom relief at 1 year31.

Alpha Blockers Monotherapy

There are 3 subtypes of the alpha 1 adrenergic receptor:

the alpha 1a, alpha 1b and alpha 1d receptors. The
alpha 1a receptor subtype is the most dominant in
the prostate and contraction of the human prostate is
mediated predominantly by alpha 1a-adrenoceptors32.
Therefore selective blocking of this subtype can result in
the reduction of the symptoms due to BPH by relaxing
smooth muscle tone in the prostate and bladder neck.
Alpha 1b receptor blockade is to be avoided as it is
present in the capacity vessels and is responsible for
hypotension and undesirable cardiovascular side
effects33. Other side effects of the alpha receptor blockers
apart from orthostatic hypotension include dizziness,
asthenia and nasal congestion. A unique side effect
of this group of medications is the intraoperative
floppy iris syndrome, which is characterised by miosis,
iris billowing and prolapse in patients undergoing
cataract surgery who have taken or are currently taking
alpha receptor blockers. Therefore, it is critical for all
patients taking alpha-1 receptor blockers to alert their
ophthalmologist if they are contemplating cataract
surgery.
Alpha blockers are one of the most effective forms of
medical treatment to reduce symptoms in most men

Medical Bulletin
with LUTS suggestive of BPH. They are considered
an appropriate option by the American Urological
Association (AUA) 34 and a large number of clinical
studies have demonstrated its efficacy. Typically
significant symptom relief could be obtained within
1-2 weeks of starting therapy and reduce symptom
scores by 5-8 points on the AUA-SI scale, with no clear
differences between the agents within the class 34,35.
Another important clinical use of alpha blockers is to
treat acute urinary retention. A randomised, double
blind, placebo-controlled study showed that starting
an alpha blocker after catheterisation in acute urinary
retention increased the chance of successful trial without
catheter (TWOC)36.

Selective Short-acting Alpha 1 Blockers

Prazosin was the first selective alpha 1 antagonist

investigated for BPH. It was shown to be better tolerated
than the non-selective alpha blocker phenoxybenzamine37
but still it requires multiple daily dosing, and side
effects of postural hypotension is sill problematic.
Despite the fact that the side effects are quite prominent,
Prazosin is still commonly prescribed in Hong Kong
due to its low cost.

Long Acting Selective Alpha 1 Blockers

Terazosin was the first selective long-acting alpha

1 blocker investigated for the treatment of BPH. A
multicentre, randomised, placebo-controlled trial
showed statistically significant improvements over
symptoms and peak flow rate 38. Doxazosin was the
second alpha 1 blocker approved by the FDA for
treating BPH. Two multicentre, randomised trials were
performed comparing various doses of doxazosin with
placebo39,40. Although doxazosin has a longer half-life,
the studies did not confirm any clinical advantage. Both
terazosin and doxazosin exhibited lowering of blood
pressure only in those men who were hypertensive at
baseline41,42 which was desirable. The more common side
effects of terazosin and doxazosin included dizziness
(10-15%), fatigue (8%) and hypotension (1.5-4%).
Tamsulosin was the third alpha 1 blocker to be
approved for the treatment of BPH. It was the first
subtype selective alpha 1 antagonist and was tenfold
more selective for the alpha 1a versus alpha 1b subtype43
but there was no demonstrable subtype selectivity of
tamsulosin for the alpha 1a versus alpha 1d subtypes.
Trials showed 0.4mg tamsulosin was able to achieve
significant improvements in symptom scores and peak
flow rate without the need for dose titration, in contrary
to doxazosin and terazosin44,45. However, the side effect
profile of tamsulosin is quite similar to doxazosin and
terazosin with dizziness, fatigue and hypotension, with
the additional side effect of retrograde ejaculation or
anejaculation46.
Alfuzosin 10mg daily is the fourth alpha 1 blocker
approved by FDA for the treatment of symptomatic
BPH and it has no selectivity for the alpha 1 subtype.
It has good tolerability and has significant clinical
improvement in LUTS without dose titration47,48. The
AUA Guidelines Committee concluded that alfuzosin
has comparable clinical efficacy with tamsulosin and
the other approved alpha blockers but does not cause
ejaculatory dysfunction49.

VOL.16 NO.6 JUNE 2011

Medical Bulletin
Silodosin a newer selective alpha 1a receptor blocker
and effective for both storage and voiding symptoms in
BPH patients versus placebo, especially in patients with
severe symptoms (IPSS >= 20)50. Marks et al reported a
pooled analysis of two phase 3 randomised trials which
showed rapid significant improvement within 3-4 days
of initiation of silodosin51. The efficacy of the drug was
also supported by urodynamic effect studies which
showed improvement in peak flow rate, maximal bladder
capacity and reduction of detrusor overactivity 52.

5 Alpha Reductase Inhibitors

The main circulating androgen, testosterone, is

converted to di-hydroxytestosterone (DHT) by the
enzyme 5-alpha reductase (5AR) and DHT is involved
in the development of BPH. There are 2 isoenzymes
of 5ARs: finasteride inhibits type 2 and dutasteride
inhibits both type 1 and 2 isoenzymes of 5AR. They
can reduce the intraprostatic DHT by 80-90% and lead
to atrophy of the prostate and subsequently shrinkage
in prostate volume by 25% in 2 years and reduce the
serum prostate specific antigen (PSA) by approximately
50% over 6 months 53. In the patients whose PSA are
monitored, doubling the PSA value of the patients on 5
AR inhibitors is necessary. IPSS can be reduced by IPSS
3-4 points and sustained improvement of peak flow rate
by 2ml/s and reduce the risk of acute urinary retention
as well as BPH-related surgery by greater than 5054,55.
The symptom relief from 5ARIs is most pronounced in
larger glands (>40 ml) and the AUA Guidelines do not
recommend them for men who do not have evidence of
prostate enlargement56.
5ARIs generally provide less symptomatic improvement
compared to alpha-adrenergic receptor blockers and
their onset of action is slow and occurs at 3-6 months but
they reduce the long-term risk of progression to acute
urinary retention and surgery54,55. The most notable side
effects are sexual side effects: decreased libido, erectile
dysfunction and ejaculatory disorder. Rarely, some men
note breast tenderness.

Combination of Alpha Blockers and

5ARs
Alpha blockers and 5ARIs

Theoretically, alpha blockers provide early relief,

whereas 5ARIs provide long-term disease management
and this concept was confirmed with the Medical
Therapy of Prostatic Symptoms MTOPS trial in
2003 57 . MTOPS enrolled 3057 men with LUTS and
clinical BPH and randomised them to treatment with
placebo, doxazosin, finasteride, or a combination of
doxazosin and finasteride over a period of 4 to 5 years.
The combination treatment resulted in significantly
better outcomes in terms of overall risk of clinical
progression (defined as an increase above baseline of
>=4 points in the AUA-SI, AUR, urinary incontinence,
renal insufficiency or recurrent urinary tract infection)
compared with either doxazosin or finasteride alone.
But this observation was significant only in patients with
a baseline prostate volume <25ml58. The Combination of
Avodart and Tamsulosin (CombAT) study investigated
the effects of combination therapy with dutasteride and
tamsulosin as opposed to each as monotherapy and that
showed combination therapy had significant benefits for

patients in terms of reduction in symptoms and prostate

volume59.
Although combination therapy has the benefits from
both alpha blockers and 5AR inhibitors, the problem
with this combination therapy is cost and the patients
may suffer from sides effects from either or both of these
drugs.

Anticholinergics

Current understanding about the pathophysiology

of BPH shows the change in bladder function in
association with BPH constitutes an important factor in
the development and progression of bothersome LUTS
in BPH. Anticholinergics block the parasympathetic
pathway, thereby abolishing or reducing the severity
of detrusor muscle contractions. It is believed that
storage symptoms are more bothersome to the patients
and in patients with prominent overactive bladder
symptoms, anticholinergic drugs can be considered60.
The Tolterodine and Tamsulosin in Men with LUTS
and Overactive Bladder study recruited nearly 900
patients into placebo versus tamsulosin 0.4mg versus
extended-release tolteridine 4mg versus a combination
of tolterodine and tamsulosin 61. The conclusion was
that the patients with voiding and storage problems did
not respond to monotherapy with either alpha blockers
or anti-muscarinic agents but had a statistically and
clinically significant treatment benefit from combination
therapy of an alpha blocker and an antimuscarinic
agent. Side effects experienced by the patients were
typical of the agents including dry eyes and mouth,
constipation and retention of urine but the incidence of
acute urinary retention was low. Similar improvement
in symptoms was observed in patients who failed
previous alpha blocker treatment62 and after treatment
with alpha blocker and 5AR inhibitor combination
therapy by the addition of anticholinergics63.

PDE-5 Inhibitors

There is growing interest in using phosphodiesterase 5

(PDE-5) inhibitors in the management of BPH but the
precise mechanism of action is not yet fully understood.
Sildenafil and Tadalafil were found to provide
improvement of IPSS by 6-7 points versus placebo but
neither sildenafil and tadalafil improved the peak flow
rate significantly64,65. The combination of alpha blocker
and PDE-5 inhibitor has also been studied and the
patients in the combination group of receiving both
alfuzosin 10mg daily and sildenafil 25mg daily had the
greatest benefits in IPSS, peak flow rate and erection
compared with either drug alone 66. However, PDE5 inhibitors have officially been licensed only for the
treatment of erectile dysfunction and pulmonary arterial
hypertension. Treatment beyond these indications is
experimental.

Conclusions
Medical therapy is indicated in patients with bothersome
lower urinary tract symptoms and alpha blockers are
usually the first option due to its rapid onset of action.
In those patients with persistent bothersome storage
symptoms, addition of an anti-muscarinic agent can
be considered after assessment with post void residual
volume measurement to rule out baseline urinary

VOL.16 NO.6 JUNE 2011

retention. The 5AR inhibitors are usually prescribed
for long term treatment, especially those with bigger
prostate volume. The patients individual condition and
wish need to be evaluated together with consideration
about the benefits, costs and side effects of the drug
to facilitate decision making in determining the best
medical treatment for the patient.

Medical Bulletin
31.
32.
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34.

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