M. Hermann et al.

/ Experimental Gerontology 35 (2000) 12671279

1267

Experimental Gerontology 35 (2000) 12671279

www.elsevier.nl/locate/expgero

Aging of the male reproductive system

M. Hermann, G. Untergasser, H. Rumpold, P. Berger*
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria
Received 4 June 2000; received in revised form 15 June 2000; accepted 15 June 2000

Abstract
Reproductive and sexual physiology, changes in body composition and mental performance in the
aging male cannot simply be reduced to presumptive hypogonadism dened by low androgen serum
levels or by decreasing levels of growth hormone (GH) and melatonin. Morphological changes in
organs at different regulatory levels of hormonal networks governing, for example reproduction,
such as diminished hypothalamic pulse generator mass, focal degeneration and loss of Leydig cells
in testicular tissue, lead to diminished reserve capacities in production and to loss of coordinated
pulsatile release of hypothalamic neuropeptides (e.g. gonadotropin releasing hormone, GnRH) and
consequently diminished release of pituitary protein and glycoprotein hormones and testicular
steroid hormones. Owing to presumptive alterations in feedback sensitivity, decreased testosterone
levels do not necessarily upregulate pituitary LH secretion. Alternatively, increased serum levels of
LH and FSH can be observed in old men either because of primary hypogonadism or to decreased
hypothalamic opioid tone. In general, endocrine functions are sufcient to maintain fertility in elderly
men because, except for sperm motility, quantitative and qualitative functional semen parameters are
apparently not affected by age. Nevertheless, reduced endocrine and organic functions might become
critical at different levels, with high inter-individual variability, of the hypothalamo/pituitary/gonadal-axis. One of the most intriguing organic manifestations of male aging is benign prostatic hyperplasia (BPH), the pathologic prevalence of which closely matches age. Age-associated changes in the
endocrine system and in local networks of epithelial, stromal and luminal factors may play important
roles in BPH development. q 2000 Elsevier Science Inc. All rights reserved.
Keywords: Aging; Male; Fertility; Testosterone; Growth hormone; Prostate; Testis; Reproduction

1. Introduction
Progress in preventive and therapeutic medicine, such as vaccination or the advent of
antibiotics, has dramatically increased the average life expectancy of both genders in most
industrialized countries. This progress, however, is unfortunately paralleled by age-associated
* Corresponding author. Tel.: 143-51258391924; fax: 143-512-5839198.
E-mail address: peter.berger@oeaw.ac.at (P. Berger).
0531-5565/00/$ - see front matter q 2000 Elsevier Science Inc. All rights reserved.
PII: S 0531-556 5(00)00159-5

1268

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

morbid and premorbid changes in function, such as prostate hyperplasia (BPH), osteoporosis or general frailty, that limit free and independent life for elderly men (reviewed by
Bakshi and Miller, 1999). As a consequence, a major task of modern society is not merely
to extend life, but to also ensure the independence and health of this aging population,
thereby increasing the quality of life and, as a byproduct, lowering the costs of care for the
elderly.
Aquired hypogonadism of the aging male is not well dened because of the lack of ageadjusted reference values and its unclear pathophysiological consequences. Lower androgen serum levels of elderly men are not linked to a cessation of reproductive capacity
(reviewed by Gooren, 1996; Plas et al., 2000), which distinguishes male aging from female
menopause, where unequivocal cessation of reproductive capacity coupled to loss of
gonadal endocrine function is observed. Primary testicular age-related dysfunction with
regard to diminished androgen production or spermiogenesis might be reected by a rise in
gonadotropin serum levels, similar to female menopause. The proportion of such cases
seems to increase with age and to contribute to the statistically signicant overall increase
in serum FSH and LH of elderly men (Gray et al., 1991; Madersbacher et al., 1993). On the
other hand, a secondary drop of sex steroid serum levels, despite sufcient testicular and
pituitary reserves of production capacities and loss of circadian rhythmicity (Bremner et
al., 1983), are because of decreased masses of releasing hormones (GnRH) at each
hypothalamic pulse and an age-associated loss of neurohormone synchrony of the
hypothalamic pulse generator followed by lower amounts of released pituitary gonadotropins (reviewed by Gooren, 1996; Veldhuis et al., 2000).
Aging male characteristics develop in a triangle of morphological changes in organs,
partially coupled to endocrine networks and fertility. These highly variable individual
characteristics seem to be strongly inuenced by lifestyle and environmental factors.
Despite the above-mentioned variability, the majority of elderly men suffer from BPH.
Herein we present an overview of age-associated changes in the male reproductive
system, hormonal networks and their most important consequence: The age-associated
growth of the prostate leading to BPH in elderly men. A major focus will be on the three
regulatory levels of prostatic growth and differentiation, involving luminal factors necessary for optimal fertility, but acting for decades in a retrograde fashion.

2. Age-related changes in the hypothalamic, pituitary, gonadal axis

Testosterone (T) and, to a greater extent, free T and bioavailable or weakly bound T
(albumin-bound T) decline with age in men (reviewed in Morley and Perry, 1999;
Hermann and Berger, 1999), as shown by a decrease of ^35% of total and of 50% of
free T levels between the ages of 20 and 80. Plasma levels of bioavailable T below the
lower normal limit (,70 ng/dl) occur in 7% of elderly men in the age group 4060, 20%
are affected in the age group 6080 and 35% in the age group over 80 years old (reviewed
by Vermeulen and Kaufman, 1995).
There is no clear consensus about the causative mechanism of this rather
modest age-associated decline, which may originate from all three levels of the

Hormone
T
Free T
DHT
Estradiol
SHBG
DHEA
DHEAS
FSH
LH
Free GPHalpha
GH
Prolactin

+
+

*
+
+
*
*
*
+

Serum levels in young men

Serum levels in old men

Age (years/o)

References

11.51 nmol/l
0.23 nmol/l
0.85 nmol/l
96 pmol/l
26.2 nmol/l
22 nmol/l
12 mmol/l
619 ng/l;
3.67 IU/l
142 ng/l
20 ng/ml
6.8 mg/l

10.27 nmol/l
0.16 nmol/l

37.9 nmol/l
5 nmol/l
3 mmol/l
1948 ng/l
6.65 IU/l
279 ng/l
3.2 ng/ml
6.06 mg/l

40/70
40/70
40/70
40/70
40/70
2030/7080
2030/7080
27 ^ 4/72 ^ 3
40/70
27 ^ 4/72 ^ 3
2029/6079
40/70

Gray et al., 1991

Gray et al., 1991
Gray et al., 1991
Gray et al., 1991
Gray et al., 1991
Labrie et al., 1997
Labrie et al., 1997
Madersbacher et al., 1993
Gray et al., 1991
Madersbacher et al., 1993
Rudman et al., 1981
Gray et al., 1991

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

Table 1
Age related reproductive hormonal changes in men

1269

1270

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

hypothalamo-pituitarytesticular axis (reviewed in Gooren, 1996; Hermann and Berger,

1999; Morley and Perry, 1999).
Decreased numbers of Leydig cells (Neaves et al., 1984), impaired testicular perfusion
(Suoranta, 1971) and reduced release of T upon stimulation by hCG (Harman and
Tsitouras, 1980) support a primarily testicular cause of lower serum T levels, i.e. primary
hypogonadism. In addition, it has been shown that the LH levels are elevated in response
to the decline of T levels with aging (Deslypere and Vermeulen, 1984), although these
levels are lower than those observed in younger men with similarly decreased T levels
(Korenman et al., 1990). Rarely do the LH serum levels of elderly men rise outside of the
normal, suggesting that the changes are predominantly because of an alterations in functions of the hypothalamicpituitary unit, i.e. secondary hypogonadism. Interestingly, in
men very old men (.80), elevated LH levels are not unusual, perhaps due to a decrease in
their opioid tone, since endogenous opioids suppress the release of GnRH and therefore
LH (reviewed by Morley and Perry, 1999).
Hypothalamic impairment of stimulating LH and subsequent androgen secretion is inferred
from the loss of circadian rhythm of LH and T levels (Bremner et al., 1983; Pincus et al., 1996).
The nycthemeral variations in plasma T levels are signicantly decreased in elderly men
(Deslypere and Vermeulen, 1984). The reduced number of spontaneous high amplitude LH
pulses in elderly men does not seem to be a consequence of a decreased sensitivity of the
gonadotrophs to LHRH, but rather may be the consequence of the release of smaller amounts
of LHRH at each pulse (Kaufman et al., 1991).
In addition to aging per se, other hereditary, environmental (obesity, stress), psychosocial (depression, smoking, drugs) or socio-economical (diet, hygiene) factors may inuence serum T levels in elderly men, resulting in even lower circulating T levels
(Vermeulen and Kaufman, 1995). Age related hormonal changes in men are summarized
in Table 1.
3. Fertility
An important issue in the process of male aging is the maintenance of fertility (reviewed by
Plas et al., 2000): while female fertility ends at the entrance into menopause around the age of
50, men do not show such an unavoidable and clear-cut cessation of reproductive capacity.
Nonetheless, increasing life expectancy, in conjunction with a trend towards higher maternal
and paternal ages and improvements in assisted reproduction, especially intracytoplasmic
sperm injection (ICSI), have renewed interest in the issue of male fertility with advancing age.
In this context, it is important to discriminate between healthy aging males without
concomitant diseases and those with chronic illnesses that signicantly inuence male
gonadal function (Turner and Wass, 1997).
There are several age-associated histomorphological alterations of the testis, such as
accumulation of the aging pigment lipofuscin in Leydig cells (Sasano and Ichijo, 1969),
thickening and hernia-like protrusions of the basal membrane causing a dilation of the
tubuli seminiferi and brotic thickening of the tunica albuginea of the testis by approximately 30% (Johnson et al., 1984), reduced testicular perfusion (Sasano and Ichijo, 1969;
Suoranta, 1971) and reduced number of Leydig cells, which produce T (Neaves et al.,
1984) (Table 2).

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

1271

Table 2
Age related changes in the testis
Testosterone production
Lipofuscin
Fibrotic thickening
Testicular perfusion
Leydig cell numbers
Abnormal spermatozoa
Semen volume
Sperm count
Sperm motility

+
*
*
+
+
*

(Vermeulen and Kaufman, 1995)

(Sasano and Ichijo, 1969)
(Johnson et al., 1984)
(Suoranta, 1971)
(Neaves et al., 1984)
(Murray and Meacham, 1993)
(Nieschlag et al., 1982)
(Nieschlag et al., 1982)
(Nieschlag et al., 1982; Haidl et al., 1996)

Consequences on spermiogenesis of the above-mentioned morphological alterations are

not easily delineated due to the lack of data and the high intra-individual variations of
spermiograms. Although in autopsy studies, a reduction of spermiogenesis was reported to
be more evident in men over 40 as compared to younger men (Sasano and Ichijo, 1969),
classical parameters of spermiograms, i.e. semen volume, sperm count, total number of
spermatozoa, do not change signicantly with age, as shown in fertile young fathers (24
37 year) and elderly fertile men (6088 year) (Nieschlag et al., 1982). The only semenparameter that seems to decline with age is sperm motility (Nieschlag et al., 1982; Haidl et
al., 1996), which could also be due to increasing latency periods, since aging is related to
decreased frequencies of intercourse.
Functional parameters, like the fertilizing potential or the acrosome reaction and chromatin condensation, do not differ between young and elderly men (Nieschlag et al. 1982;
Haidl et al., 1996).
Although there is no correlation in numerical aberrations, the frequency of structural
chromosomal abnormalities in spermatozoa positively correlates with increasing paternal
age. The percentage of spermatozoa showing structural abnormalities is 2.8% in men aged
2024 year, and increases 4-fold to 13.6% in men over 45. The increased frequency of
structural abnormalities may be secondary to prolonged exposure of germ cells to mutagens (Murray and Meacham, 1993). Paternal ages of more than 40 years were associated
with a 20% greater chance of birth defects, as in 20-year old fathers, which increased by
another 10% in paternal ages of 50 years (Friedman, 1981). The American Fertility
Society has expanded its guidelines on the use of donor semen for intrauterine insemination by recommending an age limit of 50 years or less for semen donors to reduce the risk
of potential structural or autosomal dominant genetic abnormalities (Bordson and
Leonardo, 1991).
4. Regulation of growth in the aging prostate
4.1. General and developmental aspects
The prostate as the target organ of the hypothalamic-pituitarytesticular axis is closely
connected to the endocrine network and to reproduction. Growth of the prostate in elderly

1272

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

Fig. 1. Growth regulation of the human prostate. The human prostate consists of two compartments, stroma and
epithelium, both containing distinctively differentiated cell types. Short-living secretory epithelial cells, steadily
renewed by dividing pluripotent basal cells, and neuroendocrine Apud cells form a pseudostratied columnar
epithelium. In contrast to the epithelium, the stroma consists of long living smooth muscle cells and broblasts
that surround the secretory epithelium and are involved in contraction of the prostate gland during ejaculation.
Epithelial renewal and secretory function is dependent on sex-steroid-hormones, in particular on dihydrotestosterone (DHT), generated locally through conversion of testosterone by 5-a reductase. Besides steroid hormones,
epithelial cells are susceptible to pituitary-derived protein hormones, such as growth hormone (GH) and prolactin
(PRL). Apart from endocrine factors, locally produced auto/paracrine factors provide a variety of stromal/
epithelial interactions important in the physiological regulation of prostatic growth. Epithelial-derived epidermal
(EGF) and transforming growth factors (TGFs) as well as stromal broblast growth factors (FGFs) inuence
homeostasis of cell growth and death between the distinct compartments. Further, luminal factors, such as zinc,
prostaglandins, prostasomes and kallikreins (hk2, PSA) are benecal for optimal fertilization, but at the same time
might inuence epithelial renewal and secretory function (for a more detailed description see the corresponding
chapters).

men leads to the most common and costly age-related disease, i.e. benign prostatic hyperplasia (BPH). In autopsy studies, this can be detected in almost 80% of the male population
by the age of 80. Twenty-ve percent of elderly men suffering from BPH will require
medical treatment to alleviate urinary obstruction (National Kidney and Urological
Disease Advisory Board, 1990). In addition to expensive surgical treatment, therapeutic
interventions interfering with sex steroid hormone metabolism with 5a-reductase inhibitors have been developed, but the benets are limited. Aromatase inhibitors did not show
signicant effects on BPH in clinical trials (Marcelli and Cunningham, 1999).
Age-related increase in prostate volume is caused by cellular hyperplasia of basal cells
of the acinus and of stromal cells, i.e. smooth muscle cells and broblasts. Quantitative
morphometric analysis of symptomatic BPH patients compared to healthy controls

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

1273

revealed a 33% increase in stromal volume (Shapiro and Steiner, 1996). Moreover, apoptosis of stromal cells is reduced, and lifespan of BPH stromal cells exceeds 30 years.
Although mean proliferation indices of epithelium and stroma are quite similar, and
epithelial cells regularly undergo programmed cell death, no apoptotic cells can be
detected in the stroma (Claus et al., 1997), providing evidence that changes in the epithelium/stroma ratio occur during the development of BPH.
Embryonic, pubertal and age-related prostatic growth is mainly governed by hormonal
networks at different levels: Three regulatory levels affecting prostatic growth and function can be discerned, comprising endocrine factors (sex steroid hormones and pituitaryderived protein hormones), local factors acting in auto/paracrine manners between epithelial and stromal cells (broblast growth factors, FGFs, insulin-like growth factors, IGFs,
epidermal growth factor, EGF) (Shapiro and Steiner, 1996), and nally luminal factors
(zinc, kallikreins, prostaglandins and others) originally needed for optimal fertility but at
the same time acting in a retrograde manner on the prostate of aging males. Changes of
those factors in their absolute and relative concentrations are considered to favor proliferative disorders of the prostate by altering the balance of cell growth and death. The
following will give a brief overview on molecular growth regulatory networks of the
prostate (Fig. 1).
4.2. Endocrine factors and prostatic growth
4.2.1. Sex steroids
Several hypothesis have been put forward to explain the development of BPH based on
alterations of local sex steroid metabolism (reviewed by Marcelli and Cunningham, 1999).
Growth and development of the prostate in puberty is primarily dependent on androgens,
predominantly T and its most bioactive metabolite, dihydrotestosterone (DHT), which is
generated locally by the 5a-reductase II. Androgens are considered to have a role in the
pathogenesis of proliferative disorders, since they do not occur in men castrated prior to
puberty who do not receive subsequent androgen therapy. Estrogens seem to potentiate the
effect of androgens; simultaneous administration of T and estrogens in dogs causes
prostatic overgrowth, apparently by upregulation of the epithelial androgen receptor
(AR) (Marcelli and Cunningham, 1999).
The estrogen hypothesis is based on the observation that the stroma of BPH patients
compared to normal prostates contains higher concentrations of estrogens, presumably as a
consequence of elevated aromatase activity (Krieg et al., 1993). Further, it is conceivable
that aromatase activity might be upregulated by FSH expressed by prostatic cells (Dirnhofer et al., 1998). The mRNA of aromatase was detected in prostatic tissue by reverse
transcriptasepolymerase chain reaction (RT-PCR) and its level of expression did not
change in BPH and PCa, as shown by Northern Blot analysis (Hiramatsu et al., 1997).
Interestingly, decreased prostatic estrogen-receptor (ER) mRNA levels were observed
with age (Bonnet et al., 1993), which might explain the poor efcacy of aromatase inhibitor therapies (Atamestane w) in the treatment of symptomatic BPH (Marcelli and
Cunningham, 1999), although estradiol serum levels seem to correlate with BPH (Schatzl
et al., 2000). Thus, it can be assumed that sex steroid hormones are important for

1274

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

embryonic and pubertal prostate development, for epithelial cell renewal and secretory
function, and also play a permissive role for prostatic growth after puberty.
4.2.2. Growth hormone/insulin-like growth factor I
Growth hormone (GH, somatotropin) is secreted by the pituitary subsequent to stimulus
from the growth hormone releasing hormone (GHRH). GH stimulates the production of
IGF-I that in turn, is responsible for growth of the target organs. The prostate, expressing
the corresponding receptors, is responsive to both IGF-I and GH (Cohen et al., 1994;
Untergasser et al., 1999). Systemic administration of GH to hypophysectomized immature
rats increases prostatic weight, presumably, because of the upregulation of androgen
receptor, IGF-I and IGF-I-R; whether the effect is primarily due to GH or to IGF-I
(reviewed in Reiter et al., 1999) remains to be determined. A potential direct role of
GH on prostatic growth was shown on an androgen-dependent prostate tumor cell line
(LnCAP) and on prostatic smooth muscle cells, the proliferation of which is increased
upon GH exposure (Untergasser et al., 1999) and blocked by GH antagonists (Reiter et al.,
1999), consistent with the nding of enlarged prostatic sizes in acromegalic men (Colao et
al., 1999).
4.2.3. Prolactin
PRL, the cognate molecule of GH, stimulates proliferation and differentiation of
prostatic epithelial cells (Nevalainen et al., 1997; Reiter et al., 1999). Transgenic mice
overexpressing Prolactin (PRL) show a 20-fold increase of prostatic weight (Wennbo et
al., 1997), which can partially be explained by the stimulating effect of PRL on testicular
steroidogenesis (Reiter et al., 1999).
Immunohistochemically, PRL receptors were found only in the secretory epithelium,
basal epithelial cells were negative. In organ cultures, exogenous administration of hPRL
increased DNA synthesis of epithelial cells. Additional effects of PRL on prostatic cells
are stimulation of the mitochondrial aspartate amino-transferase and of the zinc uptake
mechanism (Costello et al., 1999). Interestingly, androgen-dependent expression of PRL
has been observed in rat prostatic epithelium in vivo and in organ culture, suggesting a role
as an auto/paracrine factor (Nevalainen et al., 1997).
4.3. Local factors
4.3.1. Insulin-like growth factor system
The human prostate contains all elements of the IGF network (IGF-I and -II, IGFBP-2,
-3 and -4, IGF-R). IGF-I is predominantly found in prostatic epithelial cells, which also
produce IGFBP-2, -3 and -4, whereas IGF-II is mainly expressed in stromal cells; the latter
also produce IGFBP-2, -3 and -4 (Cohen et al., 1994). IGF-I receptors are present on
epithelial cells (Cohen et al., 1994). Studies investigating the direct role of IGFs on
prostatic cell growth showed proliferative effects that are negatively regulated by IGFbinding proteins (Sutkowski et al., 1999). An IGF-independent effect was shown for
IGFBP-3 that was able to induce apoptosis and mediate the effect of TGFb 1 (Rajah et
al., 1997). Prostatic mRNA levels of IGF-I, IGF-II and IGF-I receptor have been studied in
BPH patients compared to healthy control groups and young men. In contrast to normal

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

1275

prostatic tissue of young men, IGF-I, IGF-II and IGF-I-R were signicantly elevated in
BPH tissue (Bonnet et al., 1993). Moreover, increases of PSA and kallikrein 2 (hK2)
serum-levels have been reported in BPH and PCa patients (Recker et al., 2000).
Kallikreins are known to activate EGF and NGF from their precursor molecules in epithelial cells, and to proteolitically cleave IGFBP-3, a proapoptotic gene product in prostate
stromal cells (Sutkowski et al., 1999). Disturbances of the local balance of proliferative
IGFs and antiproliferative IGFBPs may be involved in abnormal stromal growth of the
prostate.
4.3.2. Epidermal growth factor/transforming growth factor a
Transcripts and proteins of these mitogenic factors and their common receptor are
present only in epithelial cells of the prostate, suggesting auto-/paracrine functions (De
Bellis et al., 1996). Notably, cells of prostate cancer in a progressive state switch from
production of EGF to TGFa, contributing to growth and unrestrained proliferation (Seth et
al., 1999).
4.3.3. Fibroblast growth factors
The source of FGFs in the prostate are stromal cells. All members of the FGF-family act
in a paracrine fashion on epithelial cells and are autocrine mitogens for stromal cells. The
predominant FGF transcript is FGF 7 (KGF), followed by FGF 2 and traces of FGF 1
(Ittman and Mansukhani, 1997). All FGFs are potent mitogens, especially for epithelial
cells expressing FGFR I and II in higher amounts than stromal cells (Ittman and Mansukhani, 1997). Recently, FGF 9 and FGF 10 were expressed in prostatic stromal cells.
Notably, BPH tissue has an increased transcription rate of FGF I receptors compared to
normal prostatic tissue (Hamaguchi et al., 1995).
4.3.4. Transforming growth factor b
TGFb 1 concentrations in seminal plasma are higher that in any other physiological
biological uid (Chu et al., 1996). In the prostate, it is predominantly produced in the basal
cells of the acinus the corresponding receptors being expressed in epithelial cells, TGFb
RI in the basal and TGFb RII in the secretory cells. In stromal cells, the staining-intensity
for TGF and its receptors is much less (Royuela et al., 1998). From a functional point of
view, TGFb is a pleiotropic factor playing an important role in the regulation of growth
and differentiation of prostatic cells (Lee et al., 1999) by inhibiting proliferation and
inducing apoptosis. In prostatic stroma, it is responsible for smooth muscle cell differentiation, and thus, might be involved in the development of smooth muscle cell-containing nodules, characteristic of BPH (Lee et al., 1999).
Changes of prostatic TGFb occuring in benign and malignant diseases are noteworthy;
during malignant transformation, a loss of functional TGF R expression occurs accompanied by an increased TGFb production. This loss of functioning receptors provides an
advantage for growth to these cells. The increased local TGFb concentration found in
prostatic cancer tissue correlates to elevated production of extracellular matrix, increased
angiogenesis and inhibition of host immune function (Lee et al., 1999).

1276

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

4.4. Luminal/epithelial interactions

4.4.1. PSA, prostaglandins and zinc
Secretion of luminal proteins and low molecular weight factors could also be affected by
age and contribute to the imbalance of cell growth and death in prostatic tissue. Factors
originally needed for optimal fertility might, at the same time, inuence prostate epithelial
cell renewal and secretory function.
PSA is produced in prostatic epithelial cells after androgen stimulus. In addition to its
clinical use as a screening marker for prostate carcinoma, this member of the kallikrein
family plays a signicant biological role in the liquefaction of seminal uid by cleaving
seminal-vesicle-derived semenogelins I and II. Moreover, PSA, as a serine protease, has
been shown to cleave IGFBP-3, thereby interfering with the growth regulatory actions of
the IGF axis (Plymate et al., 1996). This ability of PSA presumably accounts for the
presence of IGFBP-3 fragments, in contrast to intact IGFBP-2 and -4 in human seminal
plasma. Growth regulatory functions of PSA due to IGFBP-3 cleavage have been shown
on prostatic cells (Sutkowski et al., 1999).
Moreover, age-related changes in concentrations of low molecular weight factors, such
as of zinc and prostaglandins present in micromolar range in seminal uid and their effects
on epithelial cell growth and secretory function, remain to be analyzed.
The prostate contains the highest concentration of zinc of any organ in the human body.
Zinc levels were shown to decrease in prostatitis (Fair et al., 1976) and in prostate
carcinoma (Zaichick et al., 1997). Zinc uptake is inuenced by androgens and PRL
(Costello et al., 1999). From a functional point of view, zinc plays an important role in
regulating citrate metabolism via inhibition of m-aconitase (Costello et al., 1999). Additionally, zinc inhibits cell growth of prostatic cancer cell lines, although whether this effect
is mediated via necrosis (Iguchi et al., 1998) or apoptosis (Liang et al., 1999) is still under
investigation, in our, and other, laboratories.
4.4.2. PSP 94 and GPH-a
Recently, it has been shown that the prostate-specic protein 94 (PSP 94), one of the
predominant proteins found in the seminal plasma, can induce apoptosis in the PC 3
prostate cancer cell line (Garde et al., 1999). Further, the alpha subunit of glycoprotein
hormones, which shares a common structural motif, the so-called cystine knot, with
other protein growth factors, is present in vast amounts in seminal plasma, exceeding
serum levels of 10 000-fold. It is secreted in an androgen-dependent manner by prostatic
epithelial cells, and our own data suggest a growth inhibitory effect on prostatic smooth
muscle cells, on the androgen independent (PC3) and the androgen independent (LnCAP)
prostatic cancer cell lines (Rumpold et al., unpublished data). The biological signicance
of both molecules remains to be claried.
In summary, the male reproductive system can be viewed as an interactive homeostatic
network in which changes at different levels may occur during the course of aging.
Depending on their origin, i.e. the hypothalamic GnRH pulse generator, the anterior
pituitary gonadotropes or the steroidogenic cells in the testis, these changes may result
in a loss of circadian rhythmicity as well as altered serum levels of hormones. Although
these changes are far less drastic than those conferred by menopause in women, men show

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

1277

highly age-related clinical symptoms, such as BPH, which may be a result of the abovementioned changes in the homeostatic networks. Although these changes do not seem to
be of clinical importance for the persistent fertility of aging men, they might be signicant
in the development of BPH, the etiology of which is largely unknown. Although proliferation and secretion of epithelial cells is under control of sex-steroid hormones, their
serum levels cannot be correlated with the development of BPH. Thus, research has been
focused on elucidating local prostatic networks of growth-stimulatory and inhibitory
factors and their changes with age. Stromal-epithelial and epithelial-luminal interactions
as a consequence of lifelong prostatic reproductive function might inuence cell regulatory mechanisms leading to abnormal growth of stromal cells.
Acknowledgements
This work was supported by the Austrian Science Funds (P 13652-GEN). We would like
to thank Drs Plas, Madersbacher and Dirnhofer for continuous collaboration and intensive
discussions.
References
Bakshi, S., Miller, D.K., 1999. Assessment of the aging man. Med. Clin. North. Am. 83, 11311149.
Bonnet, P., Reiter, E., Bruyninx, M., Sente, B., Dombrowicz, D., de Leval, J., Closset, J., Hennen, G., 1993.
Benign prostatic hyperplasia and normal prostate aging: differences in types I and II 5 alpha-reductase and
steroid hormone receptor messenger ribonucleic acid (mRNA) levels, but not in insulin-like growth factor
mRNA levels. J. Clin. Endocrinol. Metab. 77, 12031208.
Bordson, B.L., Leonardo, V.S., 1991. The appropriate upper age limit for several semen donors: a review of the
genetic effects of paternal age. Fertil. Steril. 56, 397401.
Bremner, W.J., Vitiello, M.V., Prinz, P.N., 1983. Loss of circadian rhythmicity in blood testosterone levels with
aging in normal men. J. Clin. Endocrinol. Metab. 56, 12781281.
Chu, T.M., Nocera, M.A., Flanders, K.C., Kawinski, E., 1996. Localization of seminal plasma transforming
growth factor-beta1 on human spermatozoa: an immunocytochemical study. Fertil. Steril. 66, 327330.
Claus, S., Berges, R., Senge, T., Schulze, H., 1997. Cell kinetic in epithelium and stroma of benign prostatic
hyperplasia [see comments]. J. Urol. 158, 217221.
Cohen, P., Peehl, D.M., Baker, B., Liu, F., Hintz, R.L., Rosenfeld, R.G., 1994. Insulin-like growth factor axis
abnormalities in prostatic stromal cells from patients with benign prostatic hyperplasia. J. Clin. Endocrinol.
Metab. 79, 14101415.
Colao, A., Marzullo, P., Spiezia, S., Ferone, D., Giaccio, A., Cerbone, G., Pivonello, R., Di Somma, C.,
Lombardi, G., 1999. Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases:
an ultrasonographic and endocrine study in acromegaly, GH deciency, and healthy subjects. J. Clin. Endocrinol. Metab. 84, 19861991.
Costello, L.C., Liu, Y., Zou, J., Franklin, R.B., 1999. Evidence for a zinc uptake transporter in human prostate
cancer cells which is regulated by prolactin and testosterone. J. Biol. Chem. 274, 1749917504.
De Bellis, A., Ghiandi, P., Comerci, A., Fiorelli, G., Grappone, C., Milani, S., Salerno, R., Marra, F., Serio, M., 1996.
Epidermal growth factor, epidermal growth factor receptor, and transforming growth factor-alpha in human
hyperplastic prostate tissue: expression and cellular localization. J. Clin. Endocrinol. Metabol. 81, 41484154.
Deslypere, J.P., Vermeulen, A., 1984. Leydig cell function in normal men: effect of age, life-style, residence, diet,
and activity. J. Clin. Endocrinol. Metab. 59, 955962.
Dirnhofer, S., Berger, C., Hermann, M., Steiner, G., Madersbacher, S., Berger, P., 1998. Coexpression of
gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. Prostate
35, 212220.

1278

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

Fair, W.R., Couch, J., Wehner, N., 1976. Prostatic antibacterial factor. Identity and signicance. Urology 7, 169
177.
Friedman, J.M., 1981. Genetic disease in the offspring of older fathers. Obstet. Gynecol. 57, 745749.
Garde, S.V., Basrur, V.S., Li, L., Finkelman, M.A., Krishan, A., Wellham, L., Ben-Josef, E., Haddad, M., Taylor,
J.D., Porter, A.T., Tang, D.G., 1999. Prostate secretory protein (PSP94) suppresses the growth of androgenindependent prostate cancer cell line (PC3) and xenografts by inducing apoptosis. Prostate 38, 118125.
Gooren, L.J.G., 1996. The age-related decline of androgen levels in men: Clinically signicant? Br. J. Urol. 78,
763768.
Gray, A., Feldmann, A., McKinlay, J.B., Longcope, C., 1991. Age, disease and changing sex hormone levels in
middle-aged men: results of the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 73, 1016
1625.
Haidl, G., Jung, A., Schill, W.B., 1996. Ageing and sperm function. Hum. Reprod. 11, 558560.
Hamaguchi, A., Tooyama, I., Yoshiki, T., Kimura, H., 1995. Demonstration of broblast growth factor receptor-I
in human prostate by polymerase chain reaction and immunohistochemistry. Prostate 27, 141147.
Harman, S.M., Tsitouras, P.D., 1980. Reproductive hormones in aging men. I. Measurement of sex steroids, basal
luteinizing hormone, and Leydig cell response to human chorionic gonadotropin. J. Clin. Endocrinol. Metab.
51, 3540.
Hermann, M., Berger, P., 1999. Ageing of the male endocrine system. Rev. Physiol. Biochem. Pharm. 139, 90
122.
Hiramatsu, M., Maehara, I., Ozaki, M., Harada, N., Orikasa, S., Sasano, H., 1997. Aromatase in hyperplasia and
carcinoma of the human prostate. Prostate 31, 118124.
Iguchi, K., Hamatake, M., Ishida, R., Usami, Y., Adachi, T., Yamamoto, H., Koshida, K., Uchibayashi, T.,
Hirano, K., 1998. Induction of necrosis by zinc in prostate carcinoma cells and identication of proteins
increased in association with this induction. Eur. J. Biochem. 253, 766770.
Ittman, M., Mansukhani, A., 1997. Expression of broblast growth factors (FGFs) and FGF receptors in human
prostate. J. Urol. 157, 351356.
Johnson, L., Petty, C.S., Neaves, W.B., 1984. Inuences of age on sperm production and testicular weights in
men. J. Reprod. Fertil. 70, 211218.
Kaufman, J.M., Giri, M., Deslypere, J.M., Thomas, G., Vermeulen, A., 1991. Inuence of age on the responsiveness of the gonadotrophs to luteinizing hormone-releasing hormone in males. J. Clin. Enodcrinol. Metab.
71, 12551260.
Korenman, S.G., Morley, J.E., Mooradian, A.D., Davis, S.S., Kaiser, F.E., Silver, A.J., Viosca, S.P., Garza, D.,
1990. Secondary hypogonadism in older men: Its relation to impotence. J. Clin. Endocrinol. Metab. 71, 963
969.
Krieg, M., Nass, R., Tunn, S., 1993. Effect of aging on endogenous level of 5 alpha-dihydrotestosterone,
testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J.
Clin. Endocrinol. Metab. 77, 375381.
Labrie, F., Belanger, A., Cusan, L., Gomez, J.L., Candas, B., 1997. Marked decline in serum concentrations of
adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J. Clin. Endocrinol.
Metab. 82, 23962402.
Madersbacher, S., Stulnig, T., Huber, L.A., Schonitzer, D., Dirnhofer, S., Wick, G., Berger, P., 1993. Serum
glycoprotein hormones and their free alpha-subunit in a healthy elderly population selected according to the
SENIEUR protocol. Analyses with ultrasensitive time resolved uoroimmunoassays. Mech. Aging. Dev. 71,
223233.
Lee, C., Sintich, S.M., Mathews, E.P., Shah, A.H., Kundu, S.D., Perry, K.T., Cho, J.S., Ilio, K.Y., Cronauer,
M.V., Janulis, L., Sensibar, J.A., 1999. Transforming growth factor-beta in benign and malignant prostate.
Prostate 39, 285290.
Liang, J.Y., Liu, Y.Y., Zou, J., Franklin, R.B., Costello, L.C., Feng, P., 1999. Inhibitory effect of zinc on human
prostatic carcinoma cell growth. Prostate 40, 200207.
Marcelli, M., Cunningham, G.R., 1999. Hormonal signaling in prostatic hyperplasia and neoplasia. J. Clin.
Endocrinol. Metab. 84, 34633468.
Morley, J.E., Perry III, H.M., 1999. Androgen deciency in aging men. Med. Clin. North. Am. 83, 12791289.
Murray, M.J., Meacham, R.B., 1993. The effect of age on male reproductive function. World J. Urol. 11, 137140.

M. Hermann et al. / Experimental Gerontology 35 (2000) 12671279

1279

Neaves, W.B., Jonson, L., Porter, J.C., Parker Jr, C.R., Petty, C.S., 1984. Leydig cell numbers, daily sperm
production and serum gonadotropin levels in aging men. J. Clin. Endocrin. Metab. 59, 756763.
Nieschlag, E., Lammers, U., Freischem, C.W., Langer, K., Wickings, E.J., 1982. Reproductive functions in young
fathers and grandfathers. J. Clin. Endocrin. Metab. 55, 676681.
Nevalainen, M.T., Valve, E.M., Ingleton, P.M., Nurmi, M., Martikainen, P.M., Harkonen, P.L., 1997. Prolactin
and prolactin receptors are expressed and functioning in human prostate. J. Clin. Invest. 99, 618627.
Pincus, S.M., Mulligan, T., Iranmanesh, A., Gheorghiu, S., Godschalk, M., Veldhuis, J.D., 1996. Older males
secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger
males. Proc. Natl. Acad. Sci. USA 93, 1410014105.
Plas, E., Berger, P., Hermann, M., Puger, H., 2000. How is fertility affected in aging men? Exp. Gerontol. (in
press).
Plymate, S.R., Rosen, C.J., Paulsen, C.A., Ware, J.L., Chen, J., Vessella, R.E., Birnbaum, R.S., 1996. Proteolysis
of insulin-like growth factor-binding protein-3 in the male reproductive tract. J. Clin. Endocrinol. Metab. 81,
618624.
Rajah, R., Valentinis, B., Cohen, P., 1997. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis
and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and
IGF-independent mechanism. J. Biol. Chem. 272, 12 18112 188.
Recker, F., Kwiatkowski, M.K., Piironen, T., Pettersson, K., Huber, A., Lummen, G., Tscholl, R., 2000. Human
glandular kallikrein as a tool to improve discrimination of poorly differentiated and non-organ-conned
prostate cancer compared with prostate-specic antigen. Urology 55, 481485.
Reiter, E., Hemmuy, B., Bruyninx, M., Cornet, A., Klug, M., McNamara, M., Closset, J., Hennen, G., 1999.
Effects of pituitary hormones on the prostate. Prostate 38, 159165.
Royuela, M., De Miguel, M.P., Bethencourt, F.R., Sanchez-Chapado, M., Fraile, B., Paniagua, R., 1998. Transforming growth factor beta 1 and its receptor types I and II. Comparison in human normal prostate, benign
prostatic hyperplasia, and prostatic carcinoma. Growth Factors 16, 101110.
Rudman, D., Kutner, M.H., Rogers, C.M., Lubin, M.F., Fleming, G.A., Bain, R.P., 1981. Impaired growth
hormone secretion in the adult population: relation to age and adiposity. J. Clin. Invest. 67, 13611369.
Sasano, N., Ichijo, S., 1969. Vascular patterns of the human testis with special reference to its senile changes.
Tohoku J. Exp. Med. 99, 269280.
Schatzl, G., Brossner, C., Schmid, S., Kugler, W., Roehrich, M., Treu, T., Szalay, A., Djavan, B., Schmidbauer,
C.P., Soregi, S., Madersbacher, S., 2000. Endocrine status in elderly men with lower urinary tract symptoms:
correlation of age, hormonal status, and lower urinary tract function. The Prostate Study Group of the Austrian
Society of Urology. Urology. 55, 397402.
Seth, D., Shaw, K., Jazayeri, J., Leedman, P.J., 1999. Complex post-transcriptional regulation of EGF-receptor
expression by EGF and TGF-alpha in human prostate cancer cells. Br. J. Cancer 80, 657669.
Shapiro, E., Steiner, M.S., 1996. Role of growth factors in prostatic development. In: Kirby, R. (Ed.). Textbook of
Benign Prostatic Hyperplasia, ISIS Medical Media, Oxford, pp. 1719.
Suoranta, H., 1971. Changes in the small blood vessels of the adult human testis in relation to age and to some
pathological conditions. Virch. Arch. Abt. A. Path. Anat. 352, 165181.
Sutkowski, D.M., Goode, R.L., Baniel, J., Teater, C., Cohen, P., McNulty, A.M., Hsiung, H.M., Becker, G.W.,
Neubauer, B.L., 1999. Growth regulation of prostatic stromal cells by prostate-specic antigen. J. Nat.
Cancer. Inst. 91, 16631669.
Turner, H.E., Wass, J.A.H., 1997. Gonadal function in men with chronic illness. Clin. Endocrin. 47, 379403.
Untergasser, G., Rumpold, H., Hermann, M., Dirnhofer, S., Jilg, G., Berger, P., 1999. Proliferative disorders of
the aging human prostate: Involvement of protein hormones and their receptors. Exp. Gerontol. 34, 275287.
Veldhuis, J.D., Iranmanesh, M., Godschalk, M., Mulligan, T., 2000. Older men manifest multifold synchrony
disruption of reproductive neurohormone outow. J. Clin. Endocrinol. Metab. 85, 14771486.
Vermeulen, A., Kaufman, J.M., 1995. Aging of the hypothalamo-pituitary-testicular axis in men. Horm. Res. 43,
2528.
Wennbo, H., Kindblom, J., Isaksson, O.G., Tornell, J., 1997. Transgenic mice overexpressing the prolactin gene
develop dramatic enlargement of the prostate gland. Endocrinology 138, 44104415.
Zaichick, V., Sviridova, T.V., Zaichick, S.V., 1997. Zinc in the human prostate gland: Normal, hyperplastic and
cancerous. Inter. Urol. Nephrol. 29, 565574.