1 Pathophysiology

The prostate consists predominantly of three distinct zones (Figure 1.1):

a central zone
a peripheral zone
a transition zone, adjacent to the urethra.

Frontal view
Bladder

Prostatic Prostate
urethra

Ejaculatory
Verumontanum duct
openings

External
urethral Peripheral zone
sphincter
Transition zone
Sagittal view Central zone

Anterior
Ejaculatory commissure
duct

Verumontanum

Urethra

Figure 1.1 The prostate consists of a central zone, a peripheral zone and a
transition zone, the last of which is the usual site of development of BPH. 9

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Fast Facts: Benign Prostatic Hyperplasia

BPH develops almost exclusively in the transition zone, whereas

prostate cancer usually develops in the peripheral zone.

Pathogenesis
The growth and development of the prostate is influenced by the male
hormone testosterone and its more active metabolite dihydrotestosterone
(DHT). The enzyme 5-reductase is responsible for the conversion
of testosterone to DHT. It has two isoforms: type 2 5-reductase
predominates in the prostate, whereas both type 1 and type 2
5-reductase are common in extraprostatic tissues. BPH requires
DHT stimulation of androgen receptors; this results in the transcription
and translation of growth factors, such as epidermal growth factor
(EGF). This in turn promotes the stromal and epithelial hyperplasia
characteristics of BPH. Other factors underlying the hyperplastic
process include a reduction in programmed cell death (apoptosis)
and inflammation, which may be involved by a variety of potential
mechanisms. Transforming growth factor (TGF) is one of the factors
involved in this process. Imbalance between molecules stimulating
proliferation and those inducing apoptosis results in progressive
hyperplastic enlargement of the transition zone of the prostate
(Figure 1.2). There is also a genetic component to BPH; the gene has
yet to be properly identified, but it is probably autosomal dominant.
Patients with the familial form generally have larger prostates and
undergo surgery at an earlier age.
Although BPH is often thought to be the result of glandular
proliferation, in fact up to 60% of hyperplastic tissue is composed of
smooth muscle cells and connective tissue. Contraction of these smooth
muscle cells is under the control of the sympathetic nervous system.
When norepinephrine (noradrenaline) is released from dense core
vesicles contained within the sympathetic nerve terminal, it diffuses
across the synaptic gap to bind to numerous 1-adrenoceptors located
on the membrane of prostatic smooth muscle cells. The resultant
influx of calcium increases prostatic smooth muscle tone. Several
1-adrenoceptor subtypes are known. The 1A-subtype is the predominant
receptor in the prostate, while the 1B-subtype seems to be mainly
10 involved in peripheral vasoconstriction, and the 1D-adrenoceptors
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 Pathophysiology

(a) DHT

EGF TGF
Figure 1.2 (a) In the
normal prostate, cell
Cell Balanced Cell formation is balanced by
proliferation death programmed cell death
(apoptosis). (b) BPH
develops when growth
Normal prostate
(b) factors such as epidermal
Increased
production growth factor (EGF)
Estrogens DHT promote excessive cell
division or when lack of
EGF TGF
Decreased transforming growth
expression factor (TGF) reduces
Cell h
nc ed deat the rate of cell death.
Imbala
Cell tion DHT, dihydrotestosterone.
ifera
prol

Prostatic hyperplasia

appear to exist mainly in the liver, spleen and bladder. As a result of

these observations, there has been considerable interest in developing
pharmacological agents that are highly 1A-selective in their activity.

Pathology
The first histological sign of BPH, which may occur even in men in their
forties, is the appearance of stromal nodules in the periurethral area of
the transition zone. The nodules vary in size from a few millimeters to a
few centimeters. Nodule formation is followed by glandular hyperplasia.
Unlike clinical (symptomatic) BPH, the incidence of pathological BPH is
very similar in all populations that have been studied.
Rather surprisingly, there is no very close correlation between the
overall size of the prostate and the degree of outflow obstruction. There
are a number of factors that may account for this:
the relative proportions of stromal and glandular tissue in the prostate
variations in sympathetic nervous stimulation of prostatic smooth
muscle 11

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Fast Facts: Benign Prostatic Hyperplasia

variable enlargement of the middle lobe of the prostate, leading

to ball-valve obstruction without much overall enlargement
of the gland
variations in the response of the bladder to obstruction and aging.
However, the larger the prostate, the greater the risk of BPH progression
and complications such as acute urinary retention (AUR) and the
need for surgery.

Role of prostate-specific antigen

Prostate-specific antigen (PSA) is a glycoprotein protease secreted by
prostatic epithelial cells that liquefies semen after ejaculation. Its
secretion is often increased in patients with BPH (Figure 1.3). On
average, serum PSA levels have been reported to increase by 0.3 ng/mL
per gram of BPH tissue; however, much larger increases are usually seen
in patients with clinical prostate cancer. Elevated serum PSA levels occur
in 25% or more of men with BPH, and in most patients with prostate
cancer of significant volume. Therefore, PSA is not a diagnostic test for

Prostate gland
lumen
PSA

Prostatic
epithelial
cells
Basal cell layer

Basement
membrane PSA
Blood vessel

Figure 1.3 Prostate-specific antigen (PSA) is secreted from epithelial cells

of the prostate and constitutes an important component of prostatic
secretions. Normally only a small proportion is absorbed into the
bloodstream. Conditions that disrupt the basal cell layer, such as prostate
cancer, result in increased absorption and elevated serum PSA values. BPH
can also cause a moderate elevation of PSA. In the absence of cancer, the
12 serum PSA value can provide a useful surrogate estimate of prostate volume.

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 Pathophysiology

Predicted prostate volume (mL) 80 75+ years

70

60

50
40+ years
40

30

20

0
0.1 1.1 2.1 3.1 4.1 5.1 6.1 7.1 8.1 9.1 10.1

Prostate-specific antigen (ng/mL)

Figure 1.4 Estimated prostate volume as a function of serum PSA value at

5-year intervals, from 40+ years (the lowest curve) to 75+ years (highest).
Reproduced from Mochtar et al. 2003, with permission from the European
Association of Urology.

prostate cancer, but does afford an estimate of the probability of the

presence of prostate cancer (this, and the use of free:total PSA ratio, is
discussed on pages 279). In addition, it provides a useful surrogate
estimate for prostate volume, since in BPH the larger the gland, in
general, the higher the PSA level (specifically, a higher PSA value
predicts a greater number of actively secreting epithelial cells,
Figure 1.4). This is of clinical value, since men with larger prostates
are at significantly greater risk of disease progression than those
with smaller glands.
PSA is also valuable when selecting treatment options. In general,
5-reductase inhibitors are more effective in men with higher PSA
results (> 1.6 ng/mL).

Natural history of BPH

BPH is usually a slowly progressive condition; longitudinal population-
based studies have shown an average decline in peak urine flow rate of
about 0.2 mL/second/year and an average increase in prostate volume of
12 cm3/year. Recently it has been reported that there is some variability
between individuals in the rate of prostate growth; in general, those with 13

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Fast Facts: Benign Prostatic Hyperplasia

Nocturia
Hesitancy
Straining
Urgency
Dribbling
Intermittency
Incomplete emptying
Weak stream
Frequency
Dysuria
Irritability
Wet clothes

30 20 10 0 10 20 30 40
Better All men (%) Worse

Symptom better/worse Bothersomeness better/worse

Figure 1.5 The symptoms of BPH may remain unchanged, improve or

deteriorate slowly. Reproduced from Lee et al. 1996, with permission from
S Karger AG, Basel.

larger glands tend to suffer faster prostate growth rates. This is not,
however, always accompanied by progressive worsening of symptoms,
which may be explained partly by the fact that BPH symptoms
sometimes fluctuate considerably. Symptoms may remain stable or even
improve with time in some individuals (Figure 1.5), and patients often
make lifestyle adjustments for the disorder by, for example, restricting
their fluid intake in the evenings. Nevertheless, BPH often negatively
affects quality of life and may be associated with sexual dysfunction.

Early disease. As BPH progresses, the gland enlarges and normal

prostatic tissue becomes increasingly compressed by hyperplastic tissue.
This impinges upon the prostatic urethra (Figure 1.6), which, in turn,
becomes less distensible, causing progressive obstruction of urine
flow. Patients complain of hesitancy, a reduced stream and incomplete
bladder emptying. The detrusor muscle responds to this obstruction by
smooth muscle hypertrophy and connective tissue infiltration, resulting
14 in increased voiding pressures, decreased bladder compliance and an
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 Pathophysiology

Bladder

Detrusor
muscle

Prostatic Developing
urethra benign
hyperplastic
tissue

External
urethral
sphincter

Further
enlargement
of transition
zone by BPH

Altered bladder
function
Obstructed
prostatic
urethra
Considerable
BPH tissue
present
Peripheral zone
Transition zone
Central zone

Figure 1.6 As BPH progresses, hyperplastic tissue progressively encroaches

on the prostatic urethra, resulting in gradual obstruction of urinary flow
and secondary changes in bladder function caused by smooth muscle
hypertrophy, changes in the extracellular matrix and neuronal alterations. 15

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Fast Facts: Benign Prostatic Hyperplasia

overactive bladder in up to 70% of patients. An overactive bladder may

occur as a result of obstruction-induced changes to the nervous system,
and this might explain the irritative lower urinary tract symptoms
(LUTS) of BPH, such as frequency, urgency and nocturia. However,
LUTS may also be a result of unrelated conditions such as nocturnal
polyuria (Table 1.1), urinary tract infection, tuberculosis, carcinoma in
situ, bladder stones or neurogenic bladder dysfunction. These
differential diagnoses need to be borne in mind when a treatment
option is selected.

Advanced disease. Progressive impairment of bladder emptying

may culminate in AUR, a distressing condition requiring urgent
catheterization and often hospitalization. If gradual overdistension
occurs, painless retention may result in enuresis, in addition to the
usual LUTS (see Table 2.2, page 23). In severe cases, the degree of
bladder overdistension may preclude full recovery of bladder function.
Risk factors for AUR have recently been defined (Table 1.2). Men with
enlarged prostates are more likely than those with small prostates to
develop acute retention or need prostate surgery.
Although uncommon, prolonged outflow obstruction can also cause:
bladder stone formation (Figure 1.7)
formation of bladder diverticula (Figure 1.8)
recurrent urinary tract infections
chronic urinary retention
deterioration of renal function (rare)
hematuria, sometimes with clot retention
sexual dysfunction.

TABLE 1.1
Causes of nocturnal polyuria

Congestive cardiac failure

Antidiuretic hormone disturbance
Sleep disturbance
Excessive evening fluid intake
16

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 Pathophysiology

TABLE 1.2
Risk factors for acute urinary retention

Age of patient (risk increases with age)

Large hyperplastic prostate
High PSA values
Increased post-void residual urine
Reduced urinary flow rate (Qmax < 10 mL/s)
Previous history of acute urinary retention
Severe lower urinary tract symptoms

(a) (b)

Figure 1.7 (a) A plain abdominal radiograph showing multiple bladder

stones in situ. (b) Outflow obstruction may result in the formation of a
bladder stone.

Figure 1.8 A large diverticulum

caused by prolonged bladder
outflow obstruction.

17

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Fast Facts: Benign Prostatic Hyperplasia

Factors influencing the development of BPH

The only clearly defined risk factors for BPH are age and the presence of
androgens secreted by functioning testes. Other factors, however, may
influence the prevalence of clinical disease.

Race and environment. Clinical BPH has been reported to be more

common in Western societies. Asian races appear to have a lower
incidence than white races, and there is some evidence that Asians who
migrate to Western countries increase their risk of developing BPH,
suggesting that environmental factors are also involved. As westernized
diets are increasingly adopted in countries such as Japan and China,
and their populations age, so the incidence of BPH appears to be rising.

Diet. BPH has been reported to be less common in men who eat large
amounts of vegetables. It has been suggested that certain vegetables
protect against BPH because they contain phytoestrogens, such as
genistein, which have antiandrogenic effects on the prostate. This
may account for reported differences in incidence of BPH between
East and West, but strong evidence supporting this theory has yet
to be produced.

Genetics. Clinical BPH seems to run in families. If one or more first-

degree relatives have been affected, then the individual is at greater
risk of being afflicted by the disorder and is more likely to undergo
surgery for the condition.

Changing terminology in BPH

It is now appreciated that BPH is in fact a pathological rather than a
clinical diagnosis. LUTS may or may not be due to BPH; similarly,
bladder outflow obstruction (BOO) may or may not be present. The
three interrelated components of the disease are illustrated in Figure 1.9.
When all three are present then the patient is at greatest risk of disease
progression. A recent epidemiological study of the prevalence of LUTS
(EpiLUTS study) has concluded that almost three-quarters of men over
the age of 40 are troubled at times by urinary symptoms such as
18 frequency and urgency.
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 Pathophysiology

LUTS BPE

BPH

BOO

Figure 1.9 The three components of BPH benign prostatic enlargement

(BPE), lower urinary tract symptoms (LUTS) and bladder outflow obstruction
(BOO) may occur independently or, commonly, together.

Key points pathophysiology

BPH is a gradually progressive condition.

Prostate enlargement often results in symptoms and bladder
outflow obstruction.
Men with larger prostates (and higher PSA values) are at greater
risk of complications such as AUR and the need for surgery.
BPH can negatively affect quality of life and may be associated
with sexual dysfunction.

Key references
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Fozard J. Symptoms and signs of The natural history of untreated
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25361.

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Fast Facts: Benign Prostatic Hyperplasia

Berry SJ, Coffey DS, Walsh PC, Girman CJ, Epstein RS, Jacobsen SJ
Ewing LL. The development of et al. Natural history of prostatism:
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Mochtar CA, Kiemeney LALM, Roehrborn CG, Malice M, Cook TJ,

van Riemsdijk MM et al. Prostate- Girman CJ. Clinical predictors of
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Fast Facts

Fast Facts:
Benign Prostatic
Hyperplasia
Seventh edition

Roger S Kirby MA MD FRCS

Professor of Urology
The Prostate Centre
London, UK

Peter J Gilling FRACS

Head of School
Bay of Plenty Clinical School, Tauranga
Associate Professor of Surgery
University of Auckland
New Zealand

Declaration of Independence
This book is as balanced and as practical as we can make it.
Ideas for improvement are always welcome: [email protected]

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Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.