Journal of Pathology

J Pathol 2007; 211: 206–218

Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/path.2077

Review Article

The ageing male reproductive tract

N Sampson,1 G Untergasser,2 E Plas3 and P Berger1 *
1 Institute for Biomedical Ageing Research, Austrian Academy of Sciences, Innsbruck, Austria
2 Tumor Biology and Angiogenesis Laboratory, Division of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
3 Ludwig Boltzmann Institute for Urology and Andrology, Lainz Hospital, Vienna, Austria

*Correspondence to: Abstract

P Berger, Institute for Biomedical
Ageing Research, Austrian
Academy of Sciences,
Innsbruck, Austria.
E-mail: peter.berger@oeaw.ac.at
No conflicts of interest were
declared.
Ageing of the male reproductive system is characterized by changes in the endocrine
system, hypogonadism, erectile dysfunction and proliferative disorders of the prostate
gland. Stochastic damage accumulating within ageing leads to progressive dysregulation at
each level of the hypothalamic–pituitary–gonadal (HPG) axis and in local auto/paracrine
interactions, thereby inducing morphological changes in reproductive target organs, such
as the prostate, testis and penis. Despite age-related changes in the HPG axis, endocrine
functions are generally sufficient to maintain fertility in elderly men. Ageing of the male
reproductive system can give rise to clinically relevant manifestations, such as benign
prostatic hyperplasia (BPH), prostate cancer (PCa) and erectile dysfunction (ED). In
this review, we discuss morphological/histological changes occurring in these organs and
current views and concepts of the underlying pathology. Moreover, we emphasize the
molecular/cellular pathways leading to reduced testicular/penile function and proliferative
disorders of the prostate gland.
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
Keywords: prostate; hyperplasia; erectile dysfunction; fertility; testis; testosterone

Introduction Like other ageing processes in the human body,

Ageing is defined by biological and demographic
parameters characterized by an impairment of func-
tion, decreasing environmental responsiveness and,
reciprocally, by an increased susceptibility to age-
related diseases and mortality [1]. In contrast to the
genetically programmed development of young indi-
viduals, ageing is non-directed and non-programmed.
Thus, in the sense of a genetic programme, ‘ageing’ or
‘anti-ageing’ genes do not exist and it is unlikely that
a single gene regulates this complex process. Rather,
ageing may be considered to be an impairment of
body functions over time caused by the accumula-
tion of molecular damage in DNA, proteins and lipids.
Some of this damage may be repaired by energy-
intensive repair mechanisms. This energy expenditure
is evolutionarily selected to suit the ecological niche
in a non-protected environment. However, in an envi-
ronment artificially protected (for example, by med-
ical and technological intervention), life is extended
beyond the warranty of the soma and damage accumu-
lates [2]. The accumulating damage may be eventually
manifested in age-related health issues, such as uri-
nary tract impairment, prostate hyperplasia, erectile
dysfunction and decreased fertility, osteoporosis and
general frailty, which have a significant impact on the
independence, general well-being and morbidity of the
elderly [3,4].
ageing of the male reproductive tract is caused by
multi-factorial, stochastic changes at molecular, cel-
lular and regulatory levels. Ageing leads to an array
of symptoms similar in particular to endocrine defi-
ciencies of young men, such as sexual dysfunction,
altered body composition, including increased abdom-
inal obesity, decreased muscle mass and strength
and psychosocial alterations. These and other symp-
toms of hypogonadism in young men due to known
causes, such as pituitary disease, can be treated by
androgen replacement (reviewed in [3,5,6]). This led
to the hypothesis that decreasing androgen levels in
elderly men may be responsible for similar symp-
toms and could be treated accordingly. However, age-
ing in men is a multifactorial process and should
not simply be considered a result of declining hor-
monal serum levels, particularly of androgens such
as testosterone or dehydroepiandrosterone (DHEA).
While large, prospective and randomized trials in
elderly men are still lacking, the rather non-specific
symptoms of elderly men do not appear to be sig-
nificantly correlated with circulating androgen levels
[7–9]. Thus, prevention, retardation or reversal of
age-related molecular, cellular and regulatory changes
through androgen supplementation remain speculative.
This review describes the age-related changes
in endocrine signalling and cellular and structural

Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
www.pathsoc.org.uk
The ageing male reproductive tract
alterations with respect to the ageing male reproductive
system, with emphasis on gondal function, erectile
dysfunction and the ageing prostate. In particular, we
focus on current research into the molecular mech-
anisms that underlie the age-related morphological
changes associated with the pathogenesis of benign
prostatic hyperplasia and prostate cancer, two of
the most common proliferative diseases affecting the
elderly male.
Hypothalamus–pituitary–gonadal axis:
age-related histomorphological, functional
and regulatory impairment
Ageing male characteristics develop as a result of
morphological changes in organs that are coupled to
changes in endocrine networks and testicular function
[10]. These characteristics vary significantly between
individuals and appear to be strongly influenced by
environmental and lifestyle factors [11–16]. Clinical
relevance for the age-related changes with respect
to sex steroid hormone serum levels has not been
unequivocally demonstrated (in part due to inter-
individual variation), although statistically signifi-
cant correlations have been reported for senile bone
loss [17,18], age-related changes in body composi-
tion [19,20], reduced cognitive function [21,22] and
atherosclerosis [23,24].
Ageing of the male reproductive system is dis-
tinct from the female menopause, which is char-
acterized by the cessation of reproductive capac-
ity coupled with sudden loss of gonadal endocrine
function. Endocrine dysfunctions in young men due
to pituitary deficiency, Klinefelter’s syndrome or
anorchia are attributable to defects at distinct lev-
els, either originating from primary testicular defi-
ciency or due to secondary causes at the regu-
latory level in the hypothalamus or pituitary. In
contrast, late-onset hypogonadism (LOH) develops
slowly due to molecular and cellular ageing processes
and involves each of the different regulatory levels
(hypothalamus, pituitary, testis) [10]. LOH is charac-
terized by progressive dysregulation of the hypothala-
mic–pituitary–gonadal (HPG) axis, associated with a
decline in serum testosterone [total testosterone (tT),
longitudinally: −1.6%/year) and a counter-regulatory
rise in luteinizing hormone (LH) and follicle stimu-
lating hormone (FSH) of +0.9%/year and 3.1%/year,
respectively [25]. Serum levels for sex hormone bind-
ing globulin (SHBG) conversely increase at a rate
of 1.2%/year, resulting in a more rapid decrease of
circulating free testosterone (FT) and bioavailable T
(bioT, free plus albumin-bound T) levels than tT
(2–3%/year). This gradual decline in tT is accom-
panied by the appearance of clinical symptoms that
bear similarities to hypogonadism in young men,
including decreased bone and muscle mass, abdom-
inal obesity and decreased sexual body hair and
beard growth. In addition, hypogonadism results in a
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
207
host of non-specific symptoms, including nervousness,
irritability, psychological depression, impaired mem-
ory, fatigue, insomnia, hot flushes, periodic sweating
and loss of sexual vigour. Partial hypergonadotropic
hypogonadism characterized by lowered androgen
serum levels due to primary testicular failure [26] leads
to compensatory elevated levels of FSH and LH [5,27].
This is interwoven with central defects of the hypotha-
lamus–pituitary regulatory unit, causing mild hypog-
onadotropic hypogonadism due to secondary gonadal
failure.
The causative mechanisms of the rather mod-
est age-related decline in serum T levels may be
located at all three organ and regulatory levels of
the HPG axis and may involve testicular steroido-
genesis, particularly diminished T secretory capac-
ity, as well as changes in synchronized hormone
production and altered feed-back mechanisms in the
hypothalamic–pituitary unit (Figure 1). These age-
related changes include: (a) an age-related decrease
in the maximal hypothalamic secretion of GnRH
to gonadotropes in the pituitary; (b) decreased LH-
stimulated testosterone secretion caused by persis-
tence of basal LH pulse frequency but an age-related
decline in maximal and mean LH pulse amplitude
and area; and (c) a reduction in negative feedback
of tT, bioT and fT on GnRH-driven LH secretion
[28].
Changes in primary testicular function and histo-
morphology lead to partial primary hypogonadism
in elderly men and are associated with age-related
decreases in Leydig cell number [29,30], impaired tes-
ticular perfusion due to atherosclerosis [31], thicken-
ing, widening and hernia-like protrusions of the basal
membrane of the tubuli seminiferi, increasing deposits
of lipofuscin in Leydig cells, a functional decline
in Leydig cell mitochondrial steroidogenesis due to
reduced supply of mitochondrial steroid hormone pre-
cursors [32], and a blunted rise in T, i.e. residual
but decreased testicular T secretion capacity upon
stimulation by human chorionic gonadotropin (hCG)
[5,33] (reviewed in [10]). Moreover, an age-related
cyclooxygenase-2 (COX2)-dependent tonic inhibition
of Leydig cell steroidogenesis and the expression of
the steroidogenic acute regulatory protein (StAR) may
inhibit the rate-limiting step of testosterone biosynthe-
sis [34].
Functional testicular impairment and increasing
SHBG levels lead to decreasing levels of bioT that in
turn should evoke a full compensatory up-regulation
of the hypothalamic–pituitary unit (for review, see
[5]). Although modestly elevated LH serum levels
are observed in elderly men, these levels are lower
than expected from studies with primary hypogo-
nadal young adults and seem to be the result of a
longer metabolic half-life, rather than due to increased
secretion [35]. This indicates that with increasing age
GnRH stimulation of high-amplitude LH secretion is
insufficient, due to the failure of hypothalamic neurons
to generate synchronized pulsatile GnRH secretion
J Pathol 2007; 211: 206–218 DOI: 10.1002/path
208
Figure 1. Ageing male hypogonadism. In ageing men
stochastic damage leads to gradual impairment of the
hypothalamus–pituitary–testicular axis, which is manifested as
an age-related decrease of tT, fT and bioT (A). Primary testicular
changes, including decreased numbers of Leydig cells, increased
deposits of lipofuscin and disrupted steroidogenesis, reduce
T synthesis and T synthesis reserve capacity. Age-associated
increases in SHBG serum levels further aggravate decreases
in bioT and fT compared to tT. Although decreased,
testicular functional reserve capacity is generally sufficient
for adequate GnRH/LH feed-forward signals, which should
result in fully compensatory T secretion. However, inadequate
amplitude of GnRH and LH synchronous pulses (B and
C, respectively) due to lower numbers, and insufficient
synchronization of hypothalamic neurons with ageing lowers
testicular T output and availability. Thus, mild secondary
hypogonadism of the hypothalamic–pituitary unit in elderly
men results in the inability to compensate for mostly
mild primary testicular hypogonadism/hypoandrogenism. This
secondary hypogonadism is observed, although there may
be reduced T feedback inhibition, maintained LH secretory
capacity of gonadotropes, increased LH metabolic half-life
and increased efficacy of suboptimal effective GnRH pulses
[5,28]. Men >80 years exhibit increasing LH levels, which may
also occur in middle-aged men due to the loss of elevated
opioid tone (reviewed in [6,10]). The effects of regulatory and
histomorphological changes in endocrine organs and networks
on reproduction and fertility in elderly men remain to be
fully elucidated. Solid arrows represent age-related changes in
organ functions and hormone secretion; broken lines indicate
regulatory pathways. LC, Leydig cells; SC, Sertoli cells
bursts of appropriately high amplitudes [5,10]. This
is despite a diminished sensitivity to inhibitory T
feedback and a greater potency of suboptimal GnRH
pulses on LH secretion [28]. In contrast to previous
observations that ageing men have an increased T
feedback response [5], a recent publication convinc-
ingly showed that T feedback inhibition is reduced
[28]. The functional and histomorphological age-
related changes seem to contribute to diminished T
biosynthesis and further decrease levels of fT and
bioT.
J Pathol 2007; 211: 206–218 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
N Sampson et al
Male reproductive functions, sperm
parameters and genetic risks
The second major testicular function apart from
steroidogenesis is the production of sperm. The
increase in male mean life expectancy accompanied
by a trend towards higher paternal age and develop-
ments in assisted reproduction have raised interest in
age-related aspects of male fertility. To what extent
ageing affects semen parameters and sperm function
in men is still debated, as no prospective longitudi-
nal studies are available. Age-related changes of the
testis influence sperm parameters, notably semen vol-
ume, sperm count, motility, morphology and fecun-
dity, and are reflected by a longitudinal increases
in serum FSH and LH (see above) [27,36]. Consid-
ering the multifactorial stochastic nature of ageing
processes, high intra-individual variations of sperm
parameters are not surprising. Several studies describe
age-related declines in semen volume, sperm count
and motility [36–38], indicating decreases in semen
volume of 3–22%, sperm motility of 3–37% and
morphological spermatozoal abnormalities in 4–18%
of men aged >50 years compared with younger men
(<30 years). However, these results are influenced by
increased latency time between ejaculations, due to
reduced sexual activity. Whether ageing has a nega-
tive correlation with sperm count is not yet clear. Even
when adjusted for sexual abstinence, conflicting stud-
ies report increased, decreased or unchanged sperm
counts with ageing [39–42].
Ageing is associated with testicular histomorpholog-
ical changes that develop gradually. In addition to the
above-mentioned changes, a reduction in the number
of type A dark spermatogonia, an increasing number
of multinucleated spermatogonia and development of
megalospermatocytes, giant spermatids and multilay-
ered spermatogonia has been described (for review,
see [10,37,38]). A decrease in Sertoli cell number and
function with ageing may correlate with a decreasing
sperm count.
Whilst ageing clearly has a negative effect on fecun-
dity in females, there are few studies on sperm function
related to ageing. Despite the use of different assay
techniques, (including the hamster oocyte penetration
assay, acrosome reaction and spermatozoal chromatin
condensation) no significant change in sperm function
has been determined [43,44]. However, it seems that
men contribute to the reduced fertility of couples at
the end of the fourth decade of life and to diminished
fecundity a few years later [37]. Recent investigations
suggest a reduced fecundity in terms of time to preg-
nancy (TTP) not only with rising maternal but also
paternal age [45], although further studies are required
to clearly demonstrate a correlation [37].
Male ageing seems to be coupled to genetic muta-
tions and risks that include numerical and structural
chromosomal aberrations (increased incidence of tri-
somy 21, Down’s syndrome), diseases of complex
aetiology (schizophrenia) and inherited autosomal
The ageing male reproductive tract
dominant diseases (Apert’s syndrome and achondro-
plasia; reviewed in [37,38]). However, it should be
kept in mind that the statistical power is low due to
the extremely low incidence of these genetic disor-
ders, especially when combined with the relatively rare
event of fathers of advanced age.
Erectile dysfunction: the ageing penis
Erectile dysfunction (ED), the inability to achieve
or maintain an erection of sufficient rigidity for
completion of the sexual act, affects millions of men
worldwide. ED is strongly associated with ageing and
is particularly common in men older than 50 years
[46,47]. ED is frequently associated with age-related
disorders, such as atherosclerosis, hypertension [48],
diabetes [49] and after radical prostatectomy for the
treatment of age-related prostatic disease [50].
Penile erection is a complex neurovascular function
that is predominantly mediated by nitric oxide–cGMP
(NO–cGMP) signalling in smooth muscle cells (SMC)
of helicine arteries and in the trabeculae [51]. The
messenger NO is synthesized in cavernosal nerves and
endothelial cells, which produce neuronal (nNOS) and
endothelial (eNOS) nitric oxide synthase, respectively.
Soluble NO activates guanylyl cyclases in SMC that in
turn produce cGMP, which activates protein kinase G
(PKG) to induce smooth muscle relation in the corpora
cavernosa and blood flow into cavernosal cisternae.
cGMP levels are degraded by phosphodiesterase-5
(PDE-5) to terminate smooth muscle relaxation [52].
Male ageing is characterized by slight but detectable
decreases in bioT and tissue remodelling of the corpora
cavernosa [53]. Corpora cavernosa development, SMC
homeostasis, eNOS and PDE-5 expression are strongly
dependent on the presence of androgens as shown in
hypogonadal patients. However, although T is essen-
tial for normal erection, the efficiency of T monother-
apy is limited to a small number of ED patients with
severe hypogonadism, due to the multifactorial nature
of ED [54]. SMC percentage and elastic fibres of their
ECM meshwork in the corpora cavernosa decrease
with ageing and provoke mechanical and size alter-
ations of the penis that reduce penile extensibility and
elasticity of the tunica albuginea [53]. A recent study
confirmed these findings by demonstrating that in older
healthy men mean flaccid penis size is greater and the
mean erected penis size is smaller [55]. In addition
to tissue remodelling of the corpora cavernosa, ED
is commonly caused by atherosclerotic disease of the
penile arteries, which leads to decreased oxygen ten-
sion and ischaemia-induced fibrosis. Additionally, ED
may arise due to reduced NO production as a con-
sequence of diabetes or ageing, due to lower penile
nNOS or eNOS activity via neuronal degradation or
endothelial damage, respectively [56].
Compounds, such as Sildenafil, Tadalafil and
Vardenafil have been developed that potentiate the
NO–cGMP cell-signalling system in the corpus
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
209
cavernosum, thereby amplifying smooth muscle
relaxation and vasodilation. These agents demonstrate
improvement in ED and are well tolerated [52].
The ageing prostate
Structural and cellular organization of the prostate
The prostate is a walnut-sized sex accessory gland sur-
rounding the urethra at the base of the bladder and
produces secretions that comprise a major fraction
(∼30%) of seminal plasma in human ejaculate. The
human prostate can be divided into four anatomically
distinct zones; peripheral, transition and central zones
and the anterior fibromuscular stroma. At least five
cell types [stem cells, transit-amplifying cells, basal,
secretory and neuroendocrine (NE) cells] comprise
the stratified epithelial cell layer, which is thought to
exist in a continuum of differentiation [57–59]. Sup-
porting the overlying epithelium, the prostatic stroma
consists of smooth muscle cells (SMCs), fibroblasts,
myofibroblasts, endothelial cells and components of
the extracellular matrix (ECM). Growth of the prostate
is regulated by systemic and locally-produced steroid
hormones and growth factors. Differentiated secretory
epithelial cells express androgen receptor (AR) and
oestrogen receptor beta (ERβ), which promote the
expression of sex steroid hormone-responsive genes.
Epithelially-derived growth factors, such as insulin-
like growth factor (IGF), transforming growth factor
(TGF) and epidermal growth factor (EGF), act in a
paracrine manner on the underlying stroma. Stromal
fibroblasts are responsive to sex steroid hormones via
expression of AR and ERα, which promote cellular
proliferation and stimulate the production of stromal-
derived factors that act in an autocrine and paracrine
fashion. In addition, stromal cells express aromatase
and 5-α-reductase enzymes, which catalyse the local
synthesis of bioactive steroid hormones.
Proliferative diseases of the ageing prostate
Benign prostatic hyperplasia (BPH) is a classical age-
related disease present in 20% of men at age 40 years,
with progression to 70% at age 60 [60,61]. Of the
many species with prostate glands, only man, chim-
panzee and dog are known to develop BPH [62,63].
BPH occurs in the transition zone of the prostate and
is characterized by progressive histological changes
that arise initially in the stromal compartment, which
becomes enlarged and altered in its cellular com-
position [64] (Figure 2). Focal proliferation of SMC
leads to a characteristic nodular arrangement caused
by budding and branching of epithelial glandular tis-
sue and is later accompanied by basal cell hyperplasia
of the epithelium [65]. BPH is a multifactorial disease
involving environmental, endocrine and genetic fac-
tors. Whilst no specific genetic mutations appear to
be associated with BPH, DNA methylation is globally
reduced [66]. Consistently, expression of a significant
J Pathol 2007; 211: 206–218 DOI: 10.1002/path
210 N Sampson et al

Figure 2. Tissue remodelling in benign prostatic hyperplasia. Global reduction in chromatin methylation may lead to altered gene
expression, in particular over-expression of genes regulating cell proliferation and down-regulation of genes encoding apoptosis
mediators. Age-related changes in systemic sex steroid hormones, together with altered activity of hormone-metabolizing
enzymes lead to an increased intra-prostatic oestrogen : androgen ratio, which may subsequently alter the expression of
steroid hormone responsive genes. In addition, increased expression of androgen receptor (AR) is observed. Remodelling of
the stromal compartment occurs with proliferation of fibroblasts, which secrete growth factors that act on the overlying
epithelial compartment, inducing cell proliferation. Increased oxygen consumption of growing tissue may result in local hypoxia
with subsequent up-regulation of hypoxia-inducible factor 1 (HIF-1) and hypoxia response genes, including FGF-2 and FGF-7.
Hypertrophic basal cells actively secrete TGF-β, which induces transdifferentiation of stromal fibroblasts into SMCs and
myofibroblasts, which further produce mitogenic growth factors. Increased TGF-β also induces remodelling of the ECM, in
particular increased expression of matrix metalloproteinases (MMPs). Altered secretions of luminal cells lead to calcification,
clogged ducts and inflammation. Infiltrating lymphocytes produce inflammatory cytokines, which further promote cell proliferation
and differentiation. IFN-γ secreted by invading lymphocytes may induce NE cell differentiation from basal cells and may lead to
increased secretion of growth-inducing neuropeptides (NEPs)

number of genes is altered in BPH [67], in partic- Table 1. Distribution and frequency of cancer in different
ular those encoding epithelial/stromal-derived growth anatomical zones of the prostate [184]
factors (Figure 2). Percentage of total Frequency of
Prostate cancer (PCa) is the most common non- Zone glandular tissue (%) PCa (%)
cutaneous malignancy in men in Western countries
Transition 5–10 20
[68,69] and is strongly age-dependent. Pre-malignant Central 25 1–5
dysplastic lesions (prostatic intraepithelial neoplasia, Peripheral 70 70
PIN) are characterized by enlarged nuclei, attenuation
of basal epithelial layer, proliferation of secretory cells
and aberrant differentiation. PINs are regarded as the widely accepted [72–74]. Growing evidence supports
most likely pre-invasive stage of prostatic adenocarci- a PCa stem cell model in which genetic and/or epi-
noma [70,71]. PCa is a multifocal, non-clonal and het- genetic changes accumulate in ageing prostate stem
erogeneous tumour that is most commonly associated cells, associated factors or stem cell niches that pro-
with the peripheral zone (Table 1). Treatment using mote aberrant growth, cell survival and differentia-
androgen ablation strategies is initially successful in tion leading to tumourigenesis (Figure 3) [75–77].
most cases; however, highly aggressive and androgen- In support of this model, a potential PCa stem cell
independent (aiPCa) tumours may recur, for which population that forms tumours in vivo was recently
treatment is mainly palliative. The existence of pro- identified [78]. The most frequent tumour-associated
static stem cells located in the basal epithelium is now genetic event identified to date is fusion of the 5

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Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The ageing male reproductive tract 211

Figure 3. Schematic representation of differentiation processes in the development and progression of PCa. Androgen-independent
(AI) prostatic stem cells in the basal epithelial layer accumulate mutations in mediators of terminal growth arrest/differentiation
during ageing (red/green), leading to inappropriate proliferation and differentiation of transit-amplifying daughter cells (blue) into
intermediate luminal cells (white; bold black line). Transit-amplifying daughter cells may also differentiate into NE cells (grey;
thin black line). Changes in epithelial secreted proteins (e.g. tumour cells actively secrete TGF-β1) that act on the surrounding
stroma induce the formation of reactive stroma. Reactive stroma is associated with transdifferentiation of fibroblasts (yellow) into
SMC and myofibroblasts (pink), which in turn secrete growth factors that further stimulate stromal and epithelial proliferation
(broken line). Remodelling of the ECM by increased production of matrix metalloproteinases and structural components is
also apparent. Infiltrating lymphocytes (green stars) stimulate the production of inflammatory cytokines (such as IL-6 and
IL-8), which promote proliferation, angiogenesis and metastasis. Androgen ablation/acquirement of androgen independence
results in apoptosis of androgen-dependent (AD) secretory epithelial cells, leaving the ai stem and basal cells intact. Loss of
TGF-β-secreting AD differentiated cells releases stem/basal cells from the inhibitory effects of TGF-β, promoting further altered
proliferation/differentiation (red arrows), leading to the generation of an androgen-independent tumour [57,183] comprising
predominantly cells of an intermediate basal phenotype but also NE cells, which secrete neuropeptides (NEPs) that may contribute
to disease progression. The increased differentiation of clusters of NE cells is perhaps mediated by IFN-γ secreted by lymphocytes.
Increased levels of Her-2/neu enable basal cells to resume cell proliferation. Differentiation markers that classify each of the
different epithelial cell types are indicated. Prostate cancer stem cells have not been unequivocally isolated to date, thus this list of
markers (italicized) derives from studies of potential PCa stem cells [78], other cancer stem cells and non-tumourigenic prostatic
stem cells. Tumourigenic transit-amplifying cells lose expression of β1 integrin and differentiate into luminal cancer cells, which are
the predominant tumour cell type. The increased numbers of NE cells and their origin in tumours is unclear but may differentiate
from tumour luminal cells or from more differentiated AI intermediate basal cells

untranslated region of the androgen-regulated gene
TMPRSS2 to the oncogenic ETS transcription factor
family members, ERG and ETV1, that are commonly
over-expressed in PCa [79]. However, although sev-
eral genes with weak to moderate penetrance are asso-
ciated with PCa, it is thought that multiple genetic
alterations lead to tumour development [80–83].
The differences in zonal susceptibility to prostatic
disease may result from different sensitivities to sex
steroid hormones and/or differences in expression of
apoptosis-associated genes [84]. Although PCa and
BPH are distinct pathologies arising from different
cellular events, gene expression profiles of different
stages of PCa [85–88] and BPH [67] reveal some
similarities, indicating a level of homogeneity [89].
Local and systemic sex steroid hormones in
prostatic disease
Control of prostate growth and function is main-
tained by a finely tuned balance between cellular
concentrations of sex steroid hormones and locally
produced paracrine and autocrine growth factors.
Intraprostatic levels of sex steroid hormones change
upon ageing, with the stromal oestrogen/androgen
ratio increasing via enhanced aromatization of andro-
gens and decreased conversion of dihydrotestosterone
(DHT) [90–92]. Despite numerous studies, there is no
conclusive evidence of a strong correlation between
elevated oestrogen or reduced androgen and increased
incidence of BPH or PCa. However, at least permissive

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Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
212
involvement is implicated by reports showing that
men castrated before puberty develop neither PCa nor
BPH, and prolonged or untimely treatment of rodents
with oestrogens leads to pre-malignant dysplasia and,
in combination with androgens, malignancy [93–95].
Changes in androgen- and oestrogen-metabolizing
enzymes have also been reported in hyperplastic and
malignant prostates [96–100] and may contribute to
aiPCa progression [101–103].
Sex steroid hormones act via nuclear receptors that
bind specific DNA motifs in the promoters of target
genes and via poorly understood genomic and non-
genomic alternative pathways [104–106]. Oestrogen
receptors alpha and beta (ERα, ERβ) are found pre-
dominantly in the stroma and epithelium, respectively
[102], although ERα is aberrantly expressed in pro-
static epithelium in some PCa [100]. ERβ is reportedly
initially up-regulated in early PCa but strongly down-
regulated in high-grade PCa [107,108]. The androgen
receptor (AR) is expressed in both epithelial and stro-
mal cells of the adult prostate. In contrast to rodents
that do not develop BPH, AR is up-regulated in
an age-associated manner in dog and man and pro-
motes continued proliferation and differentiation of
the prostate, perhaps contributing to BPH pathogenesis
[109–111]. AR is often increased in aiPCa and upon
androgen ablation in vitro, and continued expression
of androgen-responsive genes has been shown [112].
In addition to changes in sex steroid hormone receptor
expression and function permitting aberrant activation
by weak steroid hormones, disease-associated alter-
ations in steroid hormone intracellular signalling may
also be mediated via changes in receptor co-regulators
[113–115] and/or by modulating the expression of
hormone receptor target genes [116]. Given the large
number of androgen- and oestrogen-responsive genes
[117,118], age-associated changes in sex steroid hor-
mones potentially affect numerous cellular pathways.
Altered stromal–epithelial interactions in disease
onset/progression
Prostatic stem cell homeostasis is maintained by
an androgen-controlled balance of the inhibitory
cytokine TGF-β and mitogenic cytokines, such as
EGF, FGF and SCF [119]. The TGF-β1 signalling
cascade appears to be down-regulated by AR, possi-
bly by direct interactions [120–123]. The age-related
decrease in androgen levels may thus lead to increased
TGF-β and perhaps sensitizes stem cells to stimula-
tory signals resulting in excessive cellular prolifera-
tion. Expression of the anti-apoptotic protein Bcl-2 is
often increased in BPH and PCa [124,125] and may
provide a mechanism by which cells overcome the
apoptotic effects of TGF-β in prostatic disease. Thus,
an imbalance in the rate of proliferation and apoptosis
may lead to enhanced cell survival and accumulation,
which perhaps contributes to prostate enlargement in
BPH [126–128].
Disruption of the androgen–oestrogen equilibrium
is thought to stimulate changes in stromal-derived
J Pathol 2007; 211: 206–218 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
N Sampson et al
factors that act on the prostatic epithelium, leading
to reactivation of growth, hyperplasia and neoplas-
tic transformation. This so-called ‘reactive stroma’
exhibits numerous changes, including ECM deposi-
tion and fibroblast transdifferentiation to myofibrob-
lasts, which are highly abundant in BPH and PCa,
and may be induced by oestrogens and epithelial-
derived TGF-β1 [64,92,129]. Moreover, the subse-
quent enhancement of fibroblast proliferation serves
to regenerate the fibroblast pool, which, however, also
undergoes transdifferentiation, generating a vicious
circle whose consequence is manifested as the stro-
mal expansion and prostate enlargement associated
with BPH. Significantly, the continual and irreversible
transdifferentiation into myofibroblasts becomes histo-
logically conserved and is thought to be one of the key
mechanisms driving stromal expansion and prostate
enlargement in BPH [130]. The age-dependent loss of
growth suppression was recently linked to increasing
expression of stromal-derived factor 1 (SD-1) [131].
Several studies also implicate the pro-apoptotic gene
p53 in the development of reactive stroma. Initial up-
regulation of p53 in stromal fibroblasts by tumour cells
may subsequently select for an apoptosis-resistance
subpopulation of fibroblasts lacking p53 that then
induce tumour progression in adjacent epithelial cell
populations [132,133].
The stromal insulin-like growth factor (IGF) axis,
which acts in a paracrine manner on prostatic epithe-
lial cells, is modulated by the action of andro-
gens [134–136], locally produced proliferative IGFs
and anti-proliferative IGF-binding proteins (IGFBPs),
which play key roles in numerous aspects of nor-
mal and neoplastic prostate development [137]. Co-
culture experiments demonstrate that IGF-I mediates
tumour-stromal cell interactions of PCa to accelerate
tumour growth [138]. IGFBP-3, the most abundant
IGFBP, may promote the survival of aiPCa cells in
an androgen-depleted environment [139] and is also
implicated in the development of BPH [140,141].
Cellular senescence is proposed to be an ageing-
associated process, with senescent cells accumulating
in tissues with age [142,143]. Senescent fibroblasts
secrete factors that stimulate proliferation, differen-
tiation and invasiveness of pre-malignant epithelial
cells directly or indirectly [144–146]. However, it
remains debatable whether senescence plays a role in
the prostate in vivo.
Luminal–epithelial interactions/local
neuroendocrine system
Prostatic NE cells differentiate from prostatic epithe-
lial progenitor cells [147] and secrete numerous pep-
tides, neuropeptides and hormones. Rather than exist-
ing as single isolated cells, NE cells appear to form
networks of communicating cells with long neurite-
like extensions, which may reach the lumen of the
prostatic acini [148]. Increased NE differentiation is
associated with PCa and may contribute to disease
The ageing male reproductive tract
progression via neuropeptide secretion [149–151]. In
contrast, fewer NE cells are detected in large nod-
ules of BPH although they are present in smaller
developing nodules, which may represent growing foci
[152,153]. NE differentiation can be induced in cul-
tured PCa cells under a variety of conditions, includ-
ing serum starvation and androgen depletion, sug-
gesting the involvement of multiple pathways. IFN-γ
induces NE transdifferentiation of primary prostatic
basal epithelial cells, raising the possibility that infil-
trating inflammatory T lymphocytes may contribute to
NE differentiation [154]. Recent studies also impli-
cate the male-specific protocadherin-PC and EGF in
NE differentiation [155,156]. NE phenotype increases
during androgen-deprivation therapy and may even
be directly induced by androgen-suppression treatment
regimes [157].
Chronic inflammation
Chronic intraprostatic inflammation is suspected to
play a role in the pathogenesis of BPH and PCa
[64,158–160]. Moreover, proliferative inflammatory
atrophy (PIA) shares molecular traits with PIN [70,71].
Chemoattractants, such as GM-SCF produced by PCa
cells [161] and possibly BPH cells, lead to the initial
infiltration of cells, including chronically activated T
cells and macrophages into the glandular epithelium
and stroma [162,163]. These infiltrating cells are
responsible for increased production of inflammatory
cytokines (particularly IL-15 in stromal cells, IFN-γ
in basal and stromal cells and IL-8 in epithelial cells)
and may support fibromuscular growth [162,164].
Prostatic inflammation has been linked by several
studies to sex steroid hormones [165,166], although
the mechanistic details remained unclear. An excel-
lent recent study showed that direct macrophage-PCa
cell to cell interactions mediated by VCAM-1 stim-
ulate macrophage production of cytokines, including
IL-1β, which lead to removal of sex steroid hor-
mone receptor-bound co-repressor protein complexes
containing TAB 2, resulting in the transcriptional acti-
vation of a selective set of steroid hormone receptor
downstream target genes [163]. The dismissal of the
holo-co-repressor complex appears to be mediated by
a phosphorylation-induced conformational change in
TAB 2, which weakens its association with the lig-
anded hormone receptor while enhancing its interac-
tion with other proteins in the holorepressor complex
[163]. This regulatory system may serve to integrate
genome-wide responses to specific signalling path-
ways, particularly in reversing negative gene regula-
tion by sex steroid hormones [163].
The steroid hormone vitamin D is implicated in pre-
venting PCa [167] and can suppress the high levels
of IL-6 produced by SMCs in BPH and tumour cells
via AR in a ligand-independent manner and can indi-
rectly suppress IL-8 production [168,169]. IL-8 pro-
motes stromal and epithelial cell proliferation and is
up-regulated in BPH and aiPCa. IL-8 is also implicated
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
213
in angiogenesis [170,171] and autocrine regulation of
differentiation and function of NE prostatic tumour
cells [172]. IL-8 is induced by TGF-β1 [173] and is
produced by senescent prostatic epithelial cells [174],
indicating a possible link between senescence of the
ageing prostate and tissue growth in BPH/PCa.
Clinical aspects/future directions
Progress has been made in the treatment of BPH using
combined therapy of α-adrenergic blocking agents and
5-α-reductase inhibitors [175]. However, due to treat-
ment side-effects and resistance to these therapies, sur-
gical intervention often remains the only effective but
invasive and expensive treatment. A number of new
compounds are undergoing clinical trials for PCa and
BPH [176,177]. Extensive cross-talk between numer-
ous signalling pathways and the dynamic molecular
changes during disease progression suggest that com-
bined or sequential targeting of several different sig-
nalling pathways may be beneficial. There is an urgent
need for the development of new molecular markers
for use as (a) early diagnostic tools, (b) prognostic
markers and (c) specific-therapeutic targets for BPH
and PCa. New biomarkers, such as autoantibody signa-
tures, may improve early detection of PCa and report-
edly show a greater specificity and sensitivity than
prostate-specific antigen (PSA) [178], which remains
the most common, albeit limited, means of PCa diag-
nosis and prognosis [179,180]. In addition, markers
are required that can reliably distinguish between clin-
ically indolent prostate tumours and those with a high
potential for recurrence. Large-scale gene profiling
comparisons [181,182] are the most likely means to
identify molecular components involved in PCa pro-
gression and will facilitate the development of new
prognostic tools. In addition, such studies will provide
a much needed greater understanding of the molecu-
lar mechanisms and in particular the role of steroid
hormones in disease development.
Conclusion
Age-associated changes in the hypothalamus–pitui-
tary–gonadal (HPG) axis play a pivotal role in the
ageing male reproductive tract, resulting in altered
testicular function and changes in semen output and
fecundity. These may be related to altered steroidoge-
nesis of the ageing testis, ultrastructural histomorpho-
logical changes at the testicular level and functional
and morphological compromises of the ageing sperma-
tozoa. The prostate is also sensitive to changes in the
HPG axis being regulated by a finely tuned balance of
sex steroid hormones and locally produced paracrine
and autocrine growth factors. Thus, the common anal-
ogy of male ageing with hypoandrogenism in young
adults is inappropriate, given the presumably small
contribution of hypoandrogenism to the non-specific
syndromal ensemble of widespread clinical signs of
J Pathol 2007; 211: 206–218 DOI: 10.1002/path
214
ageing in the general male population. Rather, the
complex ageing processes affecting testicular function
in combination with endocrine, cellular and structural
alterations of the prostate are determined by a com-
plex interaction of several systems affecting the male
reproductive tract.
Disruption of the androgen–oestrogen equilibrium
stimulates changes in stromal-derived factors that
act on the prostatic epithelium leading to reactiva-
tion of growth, hyperplasia and neoplastic transfor-
mation. In particular, TGF-β1 is thought to provide
the stimulus for the continual and irreversible his-
tological reorganization of the prostatic stroma that
leads to prostate enlargement and BPH. Progression
of PCa is also mediated by altered stromal–epithelial
interactions, which are intimately regulated by sex
steroid hormones. PCa is thought to arise due to
accumulating mutations in ageing stem cells that
result in inappropriate proliferation and differentiation
of transit-amplifying daughter cells. Consequently,
altered growth factor secretion by inappropriately dif-
ferentiated luminal cells contributes further to growth
dysregulation of both stromal and epithelial com-
partments, facilitating tumour progression. BPH- and
PCa-associated cells secrete chemoattractants promot-
ing infiltration of macrophages and cytokine secre-
tion, which may induce further intra- and intercellular
changes in molecular signalling. Due to their high
frequency, BPH and PCa will become increasing clin-
ical and socio-economic problems as the demographic
trend of Western populations with higher percentages
of elderly people continues. Extended efforts in iden-
tifying factors involved in the mechanisms of organ-
specific tissue remodelling are essential for the pre-
vention and treatment of these age-related proliferative
prostatic diseases.
Acknowledgements
This work was supported by the Austrian Science Fund
(FWF; NRN S9307-B05). NS is a recipient of a Lise Meitner
Scholorship (FWF; M903-B05).
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