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forum distance learning programme
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Urology
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Benign prostatic hyperplasia Module 115: March 2007
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Although there is no universally accepted clinical criteria for the diagnosis of BPH, it is known that
with increasing age, all men with normal testosterone activity are susceptible
(This module was facilitated by Mr Stephen Connolly)
BENIGN PROSTATIC HYPERPLASIA (BPH) is a pathological
benign enlargement of the prostate. The term is very commonly used in modern medical parlance, but clear definition
of the entity is surprisingly difficult to obtain. The prostate
clearly enlarges in an age-related fashion, but precisely
when it becomes a clinical pathology per se is unknown, and
may vary considerably between affected individuals. No universally accepted clinical criteria for a diagnosis of BPH has
ever been identified.
Autopsy studies report BPH present in over 90% of men
aged over 90 years. Many men with BPH are not bothered
by voiding difficulties, and for these, BPH is simply part of
the normal ageing process. The prostate makes up just one
part of the complex system in men that we call the bladder
outlet (see Figure 1).
As men get older, the prostate enlarges, becomes the
dominant component of the internal urinary sphincter mechanism, and may cause bladder outlet obstruction (BOO).
Following surgical removal of the prostate (prostatectomy),
continence is dependent on the function of the external urinary sphincter.
Lower urinary symptoms (LUTS) in men are common and,
like BPH, become more common with increasing age.
Between 26%-46% of men in the community aged 40-80
years complain of moderate or severe LUTS at any one
time.1 BPH principally causes LUTS by impeding bladder
emptying. Bladder dysfunction (under- or overactivity) and
prostatitis are other benign causes of LUTS, and may occur
either independently or as a consequence of BPH. Prostate
cancer may also occur concomitantly with BPH, and is the
most common ‘invasive’ malignancy affecting men.2
Similar age-related incidence can be observed, and
autopsy studies suggest at least 50% of men by the age of
80 have histological evidence of prostate cancer, although
it is likely that many of these are not ‘clinically significant’.
Risk factors
With increasing age, all men with normal testosterone
activity are susceptible to BPH. Racial differences do exist,
with African-American men more affected than Caucasians,
who in turn are more affected than Asian men. Similar to
Figure 1
The bladder outlet
Bladder
Prostate
Internal urinary
sphincter
Verumontanum
External urinary
sphincter
mechanism
Pelvic floor
Membranous
urethra
Bulbar urethra
prostate cancer, family history may be the other strongest
risk factor. Interestingly, liver disease, obesity and smoking
have each been shown in select studies to have a protective
effect from BPH, perhaps mediated by reduced active
testosterone levels.
Clinical features and diagnosis
Obstructive lower urinary symptoms are characterised by
poor stream, hesitancy, intermittency, double voiding and
dribbling. Bladder smooth muscle hypertrophy may occur as
a result of BOO and symptoms of overactive bladder (OAB;
previously called detrusor instability) such as urgency and
urge incontinence may predominate. Frequency and nocturia are non-specific symptoms, while haematuria and
dysuria generally prompt suspicion of other pathology.
Likewise, painless haematuria can be caused by BPH, but
must always prompt cystoscopy to outrule bladder neo-
This module is supported by a grant from GlaxoSmithKline
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DISTANCE LEARNING Urology
plasm. Urinalysis should always be clear with uncomplicated BPH. Physical examination should never be omitted,
and may reveal a palpable bladder or an overt prostate
malignancy on digital rectal examination.
Objective scoring systems have been devised to help
assess the severity of LUTS (International Prostate Symptom Score). This scoring system is not specific for symptoms
of prostatism, and is considered by some principally as a
research tool. Functional studies of the lower urinary tract
are called urodynamics. These range from simple non-invasive uroflowmetry (to determine the rate of urine flow) to
more invasive pressure-flow studies (the gold-standard evaluation for BOO), and cystometrography to assess for OAB.
Non-invasive post-micturition ultrasound scan of the bladder can be combined with uroflowmetry to provide an
excellent assessment of voiding efficiency.
Simple uroflowmetry can generally be found in almost
every urology clinic nationwide.
Cystoscopy is not part of the routine investigation of BPH,
but may be prompted by atypical symptoms or abnormalities on urinalysis, necessitating exclusion of bladder cancer.
Serum prostate specific antigen (PSA) is not an essential
tool for the diagnosis of BPH, but given the common nature
of prostate cancer, it is generally sought in any man who
would be considered a candidate for active therapy if a diagnosis of prostate cancer was made.
Mild elevation of PSA can occur with either BPH or early
prostate cancer, and prostate biopsies are often required to
exclude cancer. PSA has recently been shown to provide a
surrogate marker for gland size in men with BPH. This can
have implications for choice of pharmacological therapy.
Natural history
Difficulty clarifying the natural history of BPH is fuelled
by the mismatch that occurs between the symptoms, signs
and histopathology, as well as the lack of any universallyaccepted clinical definition.
Most clinical definitions of BPH employ a combination of
age, symptoms scores, measures of prostate size, urinary
flow rates (ml/s), and post-micturition residual urine volumes. However, differing thresholds for each parameter
within the different studies make comparison for the purpose of meta-analysis unsatisfactory.
The most respected longitudinal study on BPH is based
on a population of 2,115 Caucasian men aged 40-80 years
from Olmstead County, Minnesota in the US.1 These men
were observed over a period approaching one decade, and
this study provides the best evidence of the progressive and
clear age-related nature of this disease process.
The prostate gland increased in size and symptoms deteriorated with time. Acute urinary retention was observed to
occur in 2.8% of men over a four-year period, with 3% of
men undergoing surgery for BPH during six years of observation. Alternative information can be derived from
placebo-controlled arms of randomised trials.
The well-publicised Medical Therapy for Prostate Symptoms study (MTOPS) supported the Olmstead County study
and suggested AUR to be uncommon, with a cumulative
FORUM March 2007
incidence of 2% in 750 men over a four-year period.3 Other
studies such as the Proscar Long-term Efficacy and Safety
(PLES) study suggest this incidence to be higher, with AUR
in 7%.4 Both leading studies report that the most common
progression event for men with BPH is symptomatic deterioration.
The most precise definition of BPH may be obtained from
urodynamic parameters proving bladder outlet obstruction in
symptomatic men. A recent report allowed observation of
conservative management (no treatment) in 170 urodynamically-defined symptomatic men with BOO over a period of at
least 10 years.5 The results showed that most patients did
not deteriorate to a significant degree, and 83% remained
untreated following this prolonged period of conservative
management, with AUR only being encountered in 4%.
Aetiology and therapeutic targets
The prostate gland is composed of epithelial glandular
tissue and mesenchymal stromal tissue, each presenting a
different potential therapeutic target.
While the glandular component is under strong testosterone influence, the mesenchymal component is essentially
resistant to androgens. Constituting up to 40% of the gland
volume, the mesenchymal component contains smooth
muscle cells with a high adrenoceptor concentration.
Adrenoceptor blockade causes relaxation of these muscle
cells and reduces the tonic contractility of the smooth
muscle within the bladder outlet. The adrenoceptor is found
throughout the vascular system, and blocker therapy was
originally devised as therapy for hypertension. A sub-classification of adrenoceptors into four subtypes has been
described, with the 1A subtype being most dominant in the
prostate.6 Clinical efficacy is not, however, completely
dependent on selectivity for this receptor.
Testosterone is produced by the testes under influence of
the hypothalamic-pituitary axis. Within the glandular cells
of the prostate, the cytoplasmic enzyme 5 α-reductase converts testosterone to the much more active metabolite
hydrotestosterone which binds to the nucleus-located androgen receptor and induces genomic transcriptional changes
within the cells to promote growth.
Drugs which inhibit 5 α-reductase block the most active
form of androgenic stimulus to the prostate, but avoid the
significant side-effects that are caused by the androgen
deprivation strategies such as might be used for prostate
cancer (LHRH analogues and anti-androgen medications).
Pharmacological therapy
More prompt onset of action and a better side-effect profile
make adrenoceptor blockade (AAB) the first choice for most
urologists in preference to 5 α-reductase inhibition (5ARI).
AAB achieves effective symptomatic relief for some men
and also objectively improves urodynamic parameters (such
as flow rate). There are many different AAB preparations, all
with seemingly comparable efficacy. Terazosin (Hytrin) and
indoramin (Doralese) are examples of agents selective for
the α-1 receptor but with no further sub-selectivity.
Tamsulosin (Omnexel) remains the only α-1A selective
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adrenoceptor antagonist currently available. Alfuzosin
(Xatral) has perhaps benefited most from involvement in
well-publicised important recent studies. Men with acute
urinary retention (AUR) undergoing trial without catheter
were shown to have improved success with a reduction in
need for BPH surgery when taking the alfuzosin over a sustained period.7 No other AAB agent has yet demonstrated
proven efficacy with AUR.
Furthermore, alfuzosin has recently been shown to reduce
the need for surgery and thus have beneficial impact on the
natural history and clinical progression of the condition,
something which was thought not to be the case based on
studies involving other α-blockers.8
Prior to this study it had been thought that addition of
finasteride (5ARI) was required to do anything other than
improve symptoms.3 Ancillary effects of adrenoceptor blockade most likely include favourable effects on hypertension.
In fact, doxazosin (Cardura) is marketed as an anti-hypertensive agent and it may also have positive effects on lipid
profiles and erectile function.
The enzyme 5 α-reductase has two subtypes, with type 2
being found almost exclusively in prostate tissue. Finasteride (Proscar), a selective type-2 inhibitor, was the first
agent from this class and has been on the market for almost
two decades now. Dutasteride (Avodart) is a much newer
agent and the combined types 1 and 2 inhibition of this
agent has fuelled claims of much greater suppression of the
active form of testosterone within prostate cancer cells.
The next 12 months should see much progress in our
knowledge of dutasteride. In general, 5ARI works more
slowly than AAB, and clinical benefit should not be expected
within three months of commencing therapy. 5ARI agents
will reduce serum PSA levels, so each patient should be
evaluated for prostate cancer prior to commencing this therapy.
The optimum benefit from 5ARI seems to occur in men
with large prostate glands.3 Ancillary effects of 5ARI such
as the beneficial effect on BPH-related haematuria have
been demonstrated.9 The impact on prostate cancer development remains unknown. Initial hopes that it may prevent
prostate cancer now appear unfounded. Counter-fears that
it may in fact increase high-grade prostate cancers still need
to be demonstrated with any conclusion.10
The role of anticholinergic therapy deserves special mention because an overactive bladder in older men is
commonly caused by bladder outlet obstruction due to BPH.
Contrary to the perception of some, anticholinergic therapy, when given in combination with an α-blocker, is
unlikely to significantly interfere the voiding phase of bladder function, and the likelihood of acute urinary retention is
low.11
It is certainly reasonable to try anticholinergic therapy as
part of a combination therapy for men with prominent symptoms of urgency suggesting overactive bladder.
Phytotherapeutics (herbal remedies)
Remedies derived from plants and vegetations currently
drive large markets for symptomatic BPH, particularly in
FORUM March 2007
mainland Europe (greater than 50% market share in some
parts of Italy and Germany) and North America.
Saw palmetto (Serenoa repens) is perhaps the most popular example.
The active extract is obtained from the partially-dried ripe
fruit of the American dwarf palm tree, and aside from mild
gastrointestinal upset, little in the way of side-effects or drug
interactions have been reported.
Reasonable clinical efficacy (surpassing the expected
placebo effect) have been reported in some prospective clinical trials; however, satisfactory size ‘gold-standard’
randomised controlled trials remain elusive.
Historically administered with pumpkin seeds or nettle
root extracts, many different preparations of this herbal
remedy exist.
The clinical effect may be related to an anti-inflammatory
or hormonal-mediated mechanism, but given the large
number of differing preparations, it remains unclear which
components are most active.12
Most conventional medical practitioners, upon the advice
of expert panels of critics, still await satisfactory conclusive
studies.
Surgical treatment
Historically, in previous centuries, BPH and bladder outlet
obstruction was not an uncommon cause of renal failure and
death, a situation which only really changed with the advent
of open surgery for BPH.
Now almost never a life-threatening disease, the role of
Irish surgeons in the early descriptions of open prostate
surgery can be reflected upon. In 1901, Sir Peter Freyer,
originally from Galway, described the open transvesical
prostatectomy, followed in 1945 by Peter Millin, native of
Co Down, who described the open retropubic prostatectomy.
Both procedures in their era gained massive widespread
acceptance and each retains a select place in the armamentarium of the modern urologic surgeon even today.
Both therapies for large benign obstructing prostates, the
Millin’s prostatectomy further provided anatomical insight
for the radical retropubic prostatectomy now performed regularly today for organ-confined prostate cancer across the
world.
Prostatectomy for benign disease should never be confused with radical prostatectomy for organ-confined prostate
cancer. In the mid-decades of the 20th century,
transurethral resection of prostate (TURP) gained popularity initially in the US and later widespread acceptance based
on the perceived reduced morbidity of the operation in comparison to the open alternative.
Since that time, TURP has remained the gold-standard
surgical therapy for an obstructing prostate and at one point
was the most common operation performed requiring hospitalisation in the US. TURP remains a common operation
performed today in Irish hospitals; however, improved knowledge of natural history and better pharmacological
alternatives reduce the numbers undergoing this surgery
each year. How this will be affected in the future with an
ageing population remains to be seen.
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Current indications for TURP include symptoms unresponsive to medical therapy, recurrent infections or urinary
retention, bladder calculi, diverticula, intractable bleeding
from the prostate or renal failure caused by BOO and BPH.
Most TURPs involve resection of less than 30g of tissue and
the expected morbidity from this surgery is very low indeed.
No surgery, however, is risk-free and morbidity increases
with age and clearly also with prostate size. Open surgery
remains a valid therapy for large prostates unsuitable for
TURP, although the choice of surgical technique remains at
the discretion of the surgeon.
Hospitalisation may now be as short as 48 hours, and
prostatectomy remains the most effective means of treating
BOO caused by BPH. Alternatives to TURP have been
sought in a quest to provide an easier, less morbid operation
for what is sometimes a frail patient. Prostatic stents,
transurethral needle ablation, and microwave therapies,
have all been examined and have been found clearly inferior to TURP.13 Early reports of laser prostatectomy are good;
however, currently only case series (level 3 evidence) exists.
No randomised control trials have been reported.14
Acute urinary retention
This painful inability to pass urine is treated acutely by
catheterisation and decompression of the bladder. The best
definitive management strategy to prevent further AUR is
debated.
The strongest risk factor for AUR is a prior history of the
same. Precipitated cases (where a clear underlying precipitant can be identified, such as alcohol, anaesthesia,
constipation, urinary infection, trauma, or an acute medical
deterioration) should be distinguished from spontaneous
episodes.15
The argument for early prostatectomy (usually TURP) can
be made much more readily for spontaneous cases in which
BPH is the sole factor.
Recent evidence has substantiated the use of alfuzosin
prior to a trial of micturition.7 The absence of a clear precipitating event, advancing age, a large prostate volume and
high post-void residual volumes following a successful trial
of micturition all predict recurrent AUR. Prostatectomy (usually TURP) remains the definitive management for cases of
recurrent AUR.
Sexual dysfunction
There is an increasing awareness that many older men
remain sexually active. While no direct causative association
between BPH and sexual dysfunction has been established,
both erectile and ejaculatory dysfunctions share a common
pattern of age-associated prevalence with BPH.16
The 5α-reductase inhibitors may cause both forms of
sexual dysfunction, with reduced libido being the most
common complaint.
Adrenoceptor blockers have no greater effect on libido than
placebo, but for an unknown reason tamsulosin has been
associated with some ejaculatory dysfunction (unrelated to
retrograde ejaculation) in a manner not observed with alfuzosin. Retrograde ejaculation is a common sequel to TURP.
FORUM March 2007
Future treatment developments
Despite the known progressive nature of BPH, knowledge
regarding natural history currently lends increasing support
to non-operative intervention for BPH in the individual.
Hence, the future will see an ongoing large input from the
pharmaceutical industry.
Pending conclusive evidence, herbal remedies will remain
‘alternative therapy’. The mode of prostatectomy may
change as we search for the ‘easier’ or less morbid option,
but rather than being a thing of the future, it seems urethral
stents, transurethral needle-ablation and transurethral
microwave therapies may already be a thing of the past.
TURP, in early 2007, remains the gold-standard intervention for the vast majority of patients needing invasive
treatment.
Laser prostatectomy is the most promising novel surgical
therapy for BPH and will likely present the greatest challenge to TURP. The current task is to prove conclusively that
laser prostatectomy is as efficacious, and in this area
progress is being made.
At present, laser prostatectomy is only available in a few
limited centres across the country and remains experimental, but this may change.
Stephen Connolly is specialist registrar in urologic surgery at
Tallaght Hospital, Dublin
References
1. Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic
hyperplasia. Urology 2001; 58 (suppl 6A): 5-16
2. Trends in Irish cancer incidence 1994-2002, with projections to 2020.
National cancer Registry 2006. www.ncr.ie/pubs/pubfiles/proj_2020.pdf
3. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of
doxazosin, finasteride and combination therapy on clinical progression of
benign prostatic hyperplasia. NEJM 2003; 349 (25): 2387-2398 [MTOPS]
4. Roehrborn CG, Boyle P, Bergner D et al. Serum prostate specific antigen
and prostate volume predict long-term changes in symptoms and flow rate:
results of a four-year, randomized trial comparing finasteride versus
placebo. PLESS Study Group. Urology 1999; 54: 662-669
5. Thomas AW, Cannon A, Bartlett E, Ellis-Jones J, Abrams P. The natural
history of lower urinary tract dysfunction in men: minimum 10-year
urodynamic follow-up of untreated bladder outlet obstruction. BJUI 2005; 96:
1301-1306
6. Andersson KE, Lepor H, Wyllie MG. Prostatic alpha-1 adrenoceptors and
uroselectivity. Prostate 1997; 30: 202-215
7. McNeill SA, Hargreave TB, Roehrborn CG; ALFAUR study group. Alfuzosin
10mg once daily in the management of acute urinary retention: results of a
double-blind placebo-controlled study. Urology 2005; 65: 83-89
8. Roehrborn CG, for the ALTESS study group. Alfuzosin 10mg once daily
prevents overall clinical progression of benign prostatic hyperplasia but not
acute urinary retention: results of a 2-year placebo-controlled study. BJU
Int 2006; 97: 734-741
9.Foley SJ, Soloman LZ, Wedderburn AW et al. A prospective study of the
natural history of hematuria associated with benign prostatic hyperplasia
and the effect of finasteride. J Urol 2000; 163 (2): 496-498
10. Andriole G, Bostwick D, Civantos F et al. The effects of 5alphaReductase inhibitors on the natural history, detection and grading of prostate
cancer: current state of knowledge. J Urol 2005; 174 (6): 2098-2104
11. Athanasopoulos A, Gyftopoulos K, Giannitsas K et al. Combination
treatment with an alpha-blocker plus an anticholinergic for bladder outlet
obstruction: a prospective, randomized, controlled study. J Urol 2003; 169
(6): 2253-2256
12. Lowe FC, Fagelman E. Phytotherapy in the treatment of benign
prostatic hyperplasia. Current Opin Urol 2002; 12: 15-8
13. Fitzpatrick JM, Mebust WK. Minimally invasive and endoscopic
management of benign prostatic hyperplasia. In: Walsh PC, Retik AB,
Vaughan ED Jr, Wein AJ [Ed.] Campbell’s Urology. 2002. 8E. 1379-422
14. Tan AH, Gilling PJ. Lasers in the treatment of benign prostatic
hyperplasia: an update. Curr Opin Urol 2005; 15: 55-8
15. Fitzpatrick JM, Kirby RS. Management of acute urinary retention. BJUI
2006; 97 (suppl 2): 16-20
16. Giuliano F. Impact of medical treatments for bening prostatic
hyperplasia on sexual function. BJUI 2006; 97 (suppl 2): 34-8
DL how to
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Urology: Benign prostatic hyperplasia Module 115: March 2007
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forum distance learning programme
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Urology
Benign prostatic hyperplasia Module 115: March 2007
1. Autopsy studies report BPH present in over 90% of men
aged:
6. LUTS in men is common, but becomes less common with
increasing age
over 70 years
True
over 80 years
False
over 90 years
2. Cystoscopy is part of the routine investigation of BPH
7. Most TURPs involve resection of less than:
20g of tissue
30g of tissue
True
5g of tissue
False
3. TURP (transurethral resection of prostate) remains a
common operation in Irish hospitals today
True
False
4. Which of the following statements is true:
The enzyme 5 α-reductase has four subtypes of
which type 4 is found almost exclusively in
prostate tissue
The enzyme 5 α-reductase has two subtypes of
8. Which of the following statements is false:
The 5 α-reductase inhibitors may cause both
erectile and ejaculatory dysfunction, with reduced
libido being the most common complaint
The 5 α-reductase inhibitors does not cause
erectile or ejaculatory dysfunction, and complaints
about reduced libido are rare
9. In previous centuries, BPH and bladder outlet obstruction
was not an uncommon cause of renal failure and death, a
situation which only really changed with the advent of open
surgery for BPH
True
which type 2 is found almost exclusively in
5. No universally accepted clinical criteria for a diagnosis of
BPH has ever been identified
False
10. The optimum benefit from 5ARI seems to occur in men
with small prostate glands
True
True
False
False
Our thanks to GlaxoSmithKline whose support made this module possible
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prostate tissue
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