Journal of Pathology

J Pathol 2007; 211: 173–180

Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/path.2110

Review Article

The endocrine system and ageing

HS Chahal and WM Drake*
Department of Endocrinology, St Bartholomew’s Hospital, London, UK

*Correspondence to: Abstract

WM Drake, Department of
Endocrinology, St Bartholomew’s
Hospital, West Smithfield,
London EC1A 7BE, UK.
E-mail: w.m.drake@qmul.ac.uk
No conflicts of interest were
declared.
Complex changes occur within the endocrine system of ageing individuals. This article
explores the changes that occur in the metabolism and production of various hormones
and discusses the resulting clinical consequences. As individuals age there is a decline
in the peripheral levels of oestrogen and testosterone, with an increase in luteinizing
hormone, follicle-stimulating hormone and sex hormone-binding globulin. Additionally there
is a decline in serum concentrations of growth hormone, insulin-like growth factor-I and
dehydroepiandrosterone and its sulphate-bound form. Even though there are complex
changes within the hypothalmo–pituitary–adrenal/thyroid axis, there is minimal change
in adrenal and thyroid function with ageing. The clinical significance of these deficiencies
with age are variable and include reduced protein synthesis, decrease in lean body mass and
bone mass, increased fat mass, insulin resistance, higher cardiovascular disease risk, increase
in vasomotor symptoms, fatigue, depression, anaemia, poor libido, erectile deficiency and a
decline in immune function. For each endocrine system, studies have been carried out in
an attempt to reverse the effects of ageing by altering the serum hormonal levels of older
individuals. However, the real benefits of hormonal treatment in older individuals are still
being evaluated.
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
Keywords: endocrine; ageing; follicle-stimulating hormone; luteinizing hormone; oestro-
gen; testosterone; growth hormone; thyroid; adrenal; dehydroepiandrosterone

Introduction endocrine function and the ageing process and explores

In ageing individuals, endocrine changes result in a
decline in endocrine function involving the respon-
siveness of tissues as well as reduced hormone secre-
tion from peripheral glands. This is coupled with
modifications in the central mechanisms controlling
the temporal organization of hormone release, with a
dampening of circadian hormonal and non-hormonal
rhythms. All endocrine glands are subject to the effects
of ageing and many endocrine functions are so inter-
twined that reduced function in one gland adversely
affects the remainder. With the ageing process there
are associated alterations in body composition and
a decline in functional status. Compared to younger
individuals, healthy older individuals have decreased
muscle mass, increased fat mass and decreased
strength. With healthy ageing there are changes in
endocrine systems, including oestrogen (menopause),
testosterone (andropause), growth hormone/insulin-
like growth factor-I axis (somatopause), hypothala-
mic–pituitary–thyroid axis, hypothalamic–pituitary–
cortisol axis and dehydroepiandrosterone and its sul-
phate (adrenopause).
This review article attempts to delineate some
aspects of the interplay between the regulation of
the age-related changes in hormone metabolism and
production, with their clinical consequences. In eval-
uating the changes that occur in endocrine function, it
is important to distinguish between the real effects of
ageing on endocrine mechanisms from any confound-
ing factors due to the higher prevalence of age-related
illness.
Menopause
By the mid-sixth decade of life, all women experience
the menopause. Ovulation frequency decreases by
the age of 40, and reproductive ovarian function
ceases in the vast majority of women within the
next 15 years [1]. In most women ovarian follicles
function less well during this period, with serum
oestradiol concentrations being lower and follicle-
stimulating hormone (FSH) concentrations higher than
in younger women. Luteinizing hormone (LH) is
unchanged [2]. Eventually follicular activity ceases,
oestrogen concentrations fall to postmenopausal values
and LH and FSH levels rise above premenopausal
concentrations [1]. However, smaller amounts of a
weaker oestrogen, oestrone, are still synthesized from
androstenedione in the cortex of the adrenal gland

Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
www.pathsoc.org.uk
174
and in the interstitial ovarian cells [3]. Small amounts
of this oestrone can be transformed into oestradiol.
The changes in these serum concentrations result in
a series of further changes, including an increased
risk of cardiovascular events, rapid loss of skeletal
mass, vasomotor instability, psychological symptoms
and atrophy of oestrogen responsive tissue.
The risk of cardiovascular disease in premenopausal
women is lower than in men, but during the post-
menopausal period the risk increases and is equal
to males of equivalent age and risk factor profile.
Prior to this increase in risk, serum concentrations of
atherogenic lipids deteriorate. Low-density lipoprotein
and total cholesterol increase, whereas high-density
lipoprotein decreases. This decrease in cardioprotec-
tive HDL is thought to be one of the causes of
increased coronary heart disease, myocardial infarction
and stroke in postmenopausal women [4]. Hormone
replacement alters biochemical markers favourably,
but does not improve cardiovascular disease outcome
[5,6].
At the time of the menopause there is rapid loss
of bone, due to oestrogen withdrawal. This takes
place within the background of age-related bone loss
that begins in the fourth decade of life. In the
perimenopausal period, women lose 5–15% of their
bone mass, with 80% of this loss being trabecular
bone, which is more metabolically active than cortical
bone [7]. There is a modest rise in serum ionized
calcium without any change in parathyroid hormone
(PTH), indicating a possible change in PTH set-
point which is reversed by hormone action. There
is also a fall in the oestrogen-dependent components
of intestinal calcium absorption and renal tubular
reabsorption of calcium. The associated high bone
resorption with normal PTH also suggests an increased
sensitivity of bone to PTH. There is no change in
serum 1,25-vitamin D [8].
During the immediate menopausal period, when the
rate of bone loss is greatest, oestrogen replacement
maintains bone mass and reduces fracture risk [9].
Drugs that have been demonstrated to maintain bone
mass in postmenopausal women include bisphospho-
nates, which act by inhibiting bone resorption more
than formation [10], and raloxifene, which is a selec-
tive oestrogen receptor modulator acting selectively on
bone and lipid profiles [11].
Vasomotor symptoms originate in the hypothalamus,
with a resetting and narrowing of the thermoregula-
tory system [1]. The hot flush is preceded by an LH
surge, although there is no associated change in serum
oestradiol [4]. Decreased oestrogen levels may reduce
serotonin levels and thus cause an up-regulation of
the 5-HT2A receptor in the hypothalamus. Additional
serotonin is released, which causes activation of the
5-HT2A receptor, thus changing the set point tem-
perature and resulting in hot flushes [12]. However,
the full mechanism is not completely understood. Hor-
mone replacement reduces but does not eliminate such
episodes [13]. Cognitive disturbances are reported at
J Pathol 2007; 211: 173–180 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
HS Chahal et al
the menopause and certain aspects of cognition appear
to be related to changes in oestrogen. Observational
studies and clinical trials have examined the influence
of oestrogen on cognitive function, particularly mem-
ory, in postmenopausal women, but the results are far
from consistent [14]. The vaginal mucosa atrophies in
postmenopausal women, which may lead to bleeding,
as the tissue is easily injured. In addition, oestrogen
deprivation may lead to dysuria, urinary frequency
and incontinence. These symptoms may respond to
systemic or local oestrogen replacement therapy [15].
Causes of a loss in libido in postmenopausal women
may be due to a fall in both oestrogen and testosterone
levels as ovarian function stops [16].
There has been considerable debate about the
risk : benefit ratio of hormone replacement therapy,
most notably with the recent publication of the results
from the Women’s Health Initiative (WHI) study.
The study consisted of two parallel randomized,
double-blind, placebo-controlled clinical trials of hor-
mone therapy to determine whether conjugated equine
oestrogen alone (for women with prior hysterectomy)
or in combination with progestin would reduce car-
diovascular events in mostly healthy postmenopausal
women. The combined oestrogen and progestin com-
ponent of the WHI was stopped early, as women taking
hormonal therapy were determined to have an exces-
sive risk of breast cancer [5]. At the time the trial was
stopped, risks of coronary heart disease, stroke and
pulmonary embolism were significantly increased in
the oestrogen + progestin group. Risks of colorectal
cancer and of hip fracture were decreased and mortal-
ity risk was not significantly different. The unopposed
oestrogen arm was continued and the results were
similar to the combined conjugated equine oestrogen
arm in terms of heart disease, stroke and thromboem-
bolic events. A striking but not statistically signifi-
cant decrease in the incidence of breast cancer was
observed [17]. Further analysis from the WHI study
showed that oestrogen therapy alone or in combina-
tion with progestin treatment increased the risk of both
dementia and mild cognitive impairment [18]. Another
multicentre, prospective, controlled trial of oestrogen
+ progestin in postmenopausal women with estab-
lished coronary disease failed to support the use of
hormone replacement therapy for the secondary pre-
vention of heart disease [6]. Patients need to under-
stand that recent studies have shown that hormone
replacement therapy can carry an increased risk of
ischaemic stroke, coronary events, venous thrombo-
sis and possibly breast cancer. In order to minimize
these hazards, hormone replacement therapy should be
considered only for severe menopausal symptoms and
for the shortest possible time in women who are fully
informed of these risks [19].
Andropause
Ageing is associated with changes in gonadal steroid
production in men as well as women. As the
The endocrine system and ageing
population is living to an older age, there has been
much interest in the study of the ageing male with
reference to so called ‘rejuvenating hormones’, in par-
ticular androgens. For many years there was much
debate as to whether serum total testosterone levels
were truly lower in healthy older men, or whether this
decline was attributable to the ageing process, with the
observed decline occurring as a result of confound-
ing effects due to chronic illness and medications.
However, from cross-sectional and longitudinal stud-
ies there is now agreement that in healthy men there
is a gradual but progressive age-dependent decline
in testosterone levels, termed the andropause [20,21].
This is more marked for free testosterone than for total
testosterone, due to an age-associated increase of sex
hormone-binding globulin levels [22]. The age-related
decline in testosterone level does not start at any spe-
cific point in older subjects and it varies from modest
to severe (with unclear clinical consequences), which
is different from the sharp reduction of oestrogen pro-
duction in females at the menopause [23].
The decline in serum testosterone concentrations
is mainly due to decreased production rates in older
men [24] and this is a result of abnormalities at
all levels of the hypothalamic–pituitary–testicular
axis [25]. In longitudinal studies, serum LH and
FSH levels show an age-related increase. However,
serum LH concentrations often do not reciprocate the
decline in testosterone with age [26] — most likely
a result of impaired gonadotrophin-releasing hormone
secretion and alterations in gonadal steroid feedback
mechanisms [27]. The testosterone response to LH and
human chorionic gonadotrophin decreases with ageing
[28] and the circadian rhythm of plasma testosterone
secretion, with higher levels in the morning than in
the evening, is generally lost in older men [29].
The clinical features associated with reduced testos-
terone levels in ageing men include increased fat mass,
loss of muscle and bone mass, fatigue, depression,
anaemia, poor libido, erectile deficiency [20], insulin
resistance [30] and higher cardiovascular risk [31].
These are similar to changes associated with testos-
terone deficiency in young men, so the syndrome of
androgen deficiency of the ageing male (ADAM) has
been proposed. However, each of these clinical fea-
tures may also occur in older men with normal andro-
gen levels and so the ADAM syndrome has not been
universally accepted [32].
As there is a certain proportion of middle-aged and
older men with serum total testosterone levels below
the reference range for young adult males, there is
a suggestion that supplementing testosterone in older
men with low testosterone levels into a range that is
mid-normal for healthy, young men may prevent or
reverse the effects of ageing [33]. Over the last decade,
several clinical studies have been undertaken to deter-
mine whether testosterone supplementation in ageing
is beneficial. Despite several trials examining vari-
ous parameters, including body composition, muscle
strength, bone density, metabolism and lipid profile,
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
175
there is still no consensus as to whether androgen
treatment is beneficial to men over 50. Much of the
uncertainty is due to the brief duration of many of the
protocols, such that the effects of prolonged testos-
terone replacement are not clear.
Growth hormone–insulin-like growth
factor-I axis
Growth hormone (GH) is both anabolic and lipolytic
and the action of growth hormone on peripheral tissues
is mediated, in part, by circulating (hepatic-generated)
or paracrine insulin-like growth factor-I (IGF-I) [34].
The secretion of GH undergoes dramatic changes
during life. GH output is relatively low before puberty,
but with sexual maturation and adolescence there is
a period of high GH output and accelerated somatic
growth [35]. With ageing, numerous studies have
shown that GH secretion and serum GH concentrations
fall, both basally and in response to stimuli, and this is
paralleled by a decline in IGF-I [34]. GH production
and IGF-I concentrations decline by more than 50% in
healthy older adults [36]. The progressive decline in
GH secretion has been termed the ‘somatopause’. In
older subjects the decrease in GH secretion is known
to cause a reduction of protein synthesis, a decrease
in lean body mass and bone mass and a decline in
immune function [34].
The neuroendocrine mechanisms of the somatopause
are uncertain. Early studies suggesting senescent
changes in the pituitary [37,38] have not been sup-
ported by the observations that there is no decrease
in the number of pituitary somatotroph cells [39] or
that exogenous growth hormone-releasing hormone
(GHRH) [40,41] or GH-releasing peptide analogues
[42] are able to rejuvenate GH output and plasma IGF-
I levels in older individuals. Consequently, attention
has shifted to potential alterations of the hypothalamic
regulation of GH secretion, with data suggesting an
age-dependent decrease in endogenous hypothalamic
GHRH output, contributing to the age-associated GH
decline [43]. Low physical fitness and higher adiposity
in older individuals also contributes to the decreased
GH secretion [44], although the mechanisms underly-
ing these observations are not clear. Low IGF-I levels
reflect decreased GH secretion rather than a loss of
hepatic responsiveness to the hormone, as circulating
IGF-I levels increase similarly in young and old men
after exogenous administration of either GH or GHRH
[34].
In younger GH-deficient adults there are alterations
in body composition, including physical performance,
psychological well-being and substrate metabolism,
which resemble the ageing phenotype. These features
are improved by long-term hormone replacement with
recombinant human GH [45]. This had led to the
suggestion that the elderly have genuine GH deficiency
and, by implication, would benefit from GH treatment.
There are many unanswered questions about the use
J Pathol 2007; 211: 173–180 DOI: 10.1002/path
176
of GH in older individuals. A study published in 1990
showed that 6 months treatment of recombinant GH
in 12 healthy 61–81 year-old men who had serum
IGF-I concentrations below those of healthy younger
men resulted in an increase in lean body mass by 9%
and a decrease in adipose tissue mass by 15% [46].
However, the weekly dose of GH was approximately
twice as high as the dose used in non-elderly GH-
deficient adults, the study was not double-blinded
and there was no assessment of muscle strength,
exercise endurance or quality of life [47]. A double-
blind placebo-controlled study showed that GH with
or without sex steroids in healthy women (n = 57)
and men (n = 74) aged 65–88 years increased lean
body mass and decreased fat mass [48]. However,
there was no change in muscle strength or maximal
oxygen uptake during exercise. These findings were
similar to a previous randomized, controlled, double-
blind trial in 1996, in which 52 healthy men aged
>69 years with well-preserved functional ability but
low baseline IGF-1 levels were given 6 months of
physiological doses of GH [49]. Body composition
improved but functional ability did not. A further study
recruited 18 healthy older men (aged 65–82 years)
who initially underwent progressive weight training
for 14 weeks to invoke a trained state, then were
randomized to receive GH or placebo while continuing
a further 10 weeks of strength training [50]. The
results suggested that supplementation with GH does
not augment the response to strength training in
older men.
Data have also suggested that the age-related decline
in testosterone seen in men may contribute to the
reduction in GH secretion; thus, testosterone may act
synergistically with GH in reversing this GH secretion
decline. Non-pharmacological doses of combined GH
and testosterone in older men have been shown to
improve selected aspects of physical performance
and increased muscle IGF-I gene expression without
measurably changing body composition or muscle
strength [51]. In a more recent study, co-administration
of low-dose GH with testosterone resulted in beneficial
changes in mid-thigh muscle and aerobic capacity [52].
The initial enthusiasm for the potential benefits of
GH replacement in aged individuals has been severely
dampened by its known adverse side-effects, including
arthralgia, carpal tunnel syndrome, oedema and hyper-
glycaemia. There are also particular concerns over the
links between the GH–IGF–I axis and the develop-
ment of cancer in the normal population [47,48]. Stud-
ies to date have been for a maximum of 12 months,
so long-term safety data are not available. Currently
there is no ‘magic pill’ that reverses the process of
ageing, and GH therapy for ‘anti-ageing’ has currently
not been proved to be effective [47]. Long-term stud-
ies are required to determine the efficacy and safety of
GH treatment in older adults who are not GH-deficient.
It remains to be seen whether GH secreatagogues are
beneficial in the elderly.
J Pathol 2007; 211: 173–180 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
HS Chahal et al
Hypothalmo–pituitary–thyroid axis
The hypothalmo–pituitary–thyroid axis undergoes a
significant number of complex physiological alter-
ations associated with ageing. However, direct age-
related changes need to be distinguished from indirect
alterations caused by simultaneous thyroid or non-
thyroidal illness, or other physiological or pathophys-
iological states whose incidence increases with age.
Several changes formerly believed to be a direct result
of the ageing process have subsequently been shown to
be due to the increased prevalence of subclinical thy-
roid disease and/or the result of non-thyroidal illness.
This makes interpretation of thyroid function tests dif-
ficult in the elderly [53]. Thyroid hormone clearance
decreases with age, but thyroid hormone secretion
is also reduced, leading to unchanged total and free
serum thyroxine (T4) concentrations [54]. In contrast
to thyroxine, serum total and free triiodothyronine (T3)
concentrations decrease with ageing. This reduction is
believed to be mostly due to reduced peripheral con-
version of T4 to T3, due either to the direct effect of
non-thyroidal illness or to ageing itself [53].
In older, apparently euthyroid patients, serum
thyroid-stimulating hormone (TSH) concentrations
may be reduced [55,56], but this is usually a patholog-
ical finding indicating either exogenous or endogenous
thyrotoxicosis [57]. However, in elderly patients with-
out clinical or subclinical hyperthyroidism, slightly
decreased serum TSH is seen [56,58]. An age-
dependent reduction of daily TSH secretion rate has
been reported [59]. The reason for such age-dependent
reduction of TSH secretion is uncertain. It may be
due to supersensitivity of thyrotrophs to the neg-
ative feedback from T4, but other theories, such
as reduced hypothalamic thyroid-releasing hormone
secretion, have not been excluded [53]. The ampli-
tude of the nocturnal pulses of TSH secretion, which
results in the majority of 24 h TSH secretion, is lower
in older subjects [60]. This decrease probably results
in decreased T4 secretion in response to the decrease
in T4 clearance in older individuals [54].
The prevalence of thyroid disease increases with
age and all forms of thyroid disease are encountered.
However, the clinical manifestations are different from
those encountered in younger patients. In the elderly,
autoimmune hypothyroidism is particularly prevalent.
Hyperthyroidism is mainly characterized by cardiovas-
cular symptoms and is frequently due to toxic nodular
goitres. Thyroid carcinoma is also more aggressive
[61]. Ageing is also associated with the appearance of
thyroid autoantibodies, but the biological and clinical
significance of this is still unknown. Some data have
shown that these thyroid autoantibodies are rare in
healthy centenarians and in other highly selected aged
populations, whereas they are frequently observed in
unselected or hospitalized elderly patients, thus sug-
gesting that these autoantibodies are not the conse-
quence of the ageing process itself, but rather are
related to age-associated disease [62].
The endocrine system and ageing
A major, unresolved issue is whether and to what
extent the complex physiological changes seen in
the hypothalmo–pituitary–thyroid axis contributes to
the pathogenesis of age-associated diseases such as
atherosclerosis, coronary heart disease and neurologi-
cal disorders [53].
Hypothalmo–pituitary–adrenal axis
The hypothalamo–pituitary–adrenal (HPA) axis is
involved in life-sustaining homeostatic and allostatic
adjustments to internal and external stressors. This
stress-adaptive axis is a dynamic feedback network
with circadian rhythmicity and pulsatile neurohormone
secretion [63]. However, how ageing causes changes
in the axis is incompletely understood. With age there
are variable changes in the effects of cortisol on ACTH
secretion or of ACTH on cortisol secretion [64]. How-
ever, there appears to be no deficiency of adrenal
production of corticosteroids in ageing [65]. Healthy
ageing likely disrupts neuroendocrine mechanisms that
coordinate within axis pulsatile and 24 h rhythmic cor-
tisol release, and also alters the inter-axis mechanisms
that link LH and cortisol release. In older subjects,
serum cortisol secretion concentrations may vary more
within a 24 h period as compared to younger subjects
[63]. There is a 20–50% increase in 24 h mean cor-
tisol levels between 20 and 80 years of age [66]. The
evening nadir in serum cortisol concentrations may be
higher and earlier in older subjects [66,67]. Levels of
corticosteroid binding globulin have not been shown to
alter with age [68]. With dexamethasone, inhibiton of
ACTH and cortisol secretion is similar to younger indi-
viduals [64], but this inhibition may be slower in onset
[69]. In older women, serum cortisol concentrations
increase more with exogenous ACTH [64]. The rise
in serum concentrations in fasting older and younger
men are similar and serum cortisol response to stress
is prolonged in older individuals [63]. Several studies
have shown gender-specific, age-related alterations in
the HPA axis. With healthy ageing there is an increase
in the cortisol response to challenge from CRH and
diminished hypothalamic–pituitary sensitivity to glu-
cocorticoid feedback inhibition. However, this is more
profound in older women than older men [68].
Age-related changes in the HPA axis may have far-
reaching physiological significance. There is growing
evidence supporting the view that chronic cortisol
excess may lead to hippocampal atrophy and cognitive
impairment during ageing. The alterations in cortisol
circadian amplitude and phase could be involved in
the aetiology of sleep disorders in the elderly [66].
Additionally, in older females increasing levels of
HPA axis activity, as measured by urinary free cortisol
excretion, are associated with a decline in memory
performance [70]. In healthy older men, cortisol levels
are inversely related to bone mineral density and
the rate of bone loss, suggesting that bone density
and the rate of involutional bone loss in healthy
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
177
individuals might also be regulated by the HPA axis
[71]. Furthermore, in both men and women cortisol
levels are strongly associated with a risk of clinical
fractures [72]. Lastly, there is an association between
24 h cortisol production rate and increased body fat
in older men. Thus, the increase in HPA axis activity
may play a role in the alterations in body composition
and central fat distribution that are seen in ageing [73].
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA) and its sulphate-
bound form (DHEAS) are the most abundant steroid
hormones, although their physiological functions have
not been fully delineated. As well as an abdundant cir-
culating adrenal androgen, DHEA(S) is also thought
to act directly as a neurosteroid that may have car-
dioprotective, antidiabetic, anti-obesity and immuno-
enhancing properties [74]. There has been much debate
on the anti-ageing properties of DHEA and its poten-
tial as a ‘hormone of youth’ [75]. Unlike the rela-
tively unaffected cortisol biosynthesis, the major age-
related change in the human adrenal cortex is a striking
decrease in the biosynthesis of DHEA(S) [66,76,77].
The blood level of DHEA, most of which is present in
the sulphated form (DHEAS), peaks at approximately
20 years of age and declines rapidly and markedly
after the age of 25 [76]. By the age of 80, patients
have DHEA levels 10–20% of those of younger coun-
terparts [78]. Histomorphological analysis of adrenal
specimens suggests that ageing results in alterations
within the adrenal cortex, resulting in a reduction in
the size of the zona reticularis, this being responsible
for the diminished production of DHEA [79].
The physiological consequences of a decline in
DHEA with age are not fully understood. Many have
speculated that administration of DHEA may reverse
ageing effects and there is widespread commercial
availability of DHEA outside the regular pharmaceu-
tical networks, without adequate scientific evidence
[80]. Cross-sectional studies have noted an association
between the decline in DHEAS levels and cardiovas-
cular disease, breast cancer, low bone mineral density,
depressed mood, type 2 diabetes and Alzheimer’s dis-
ease. However, this may reflect the ageing process per
se rather than there being a causal relationship [81].
This age-related decline in circulating DHEA(S)
has led to a number of randomized trials assessing
the effect of oral DHEA in otherwise healthy older
subjects. In the first randomized placebo-controlled
cross-over trial, 50 mg DHEA was administered to 13
men and 17 women aged 40–70 years for 6 months.
There was an improvement in well-being and no
change in insulin sensitivity or body composition.
Bioavailable IGF-I increased slightly, whereas HDL
cholesterol decreased in women [82]. In the largest
study to date, a double-blind randomized parallel study
of 140 men and 140 women aged 60–79 years, who
were given 50 mg DHEA or placebo daily, showed
J Pathol 2007; 211: 173–180 DOI: 10.1002/path
178
no improvement in well-being or cognition [83]. In
the study, women >70 years had increased libido, and
slight but significant gains in bone mineral density
were observed in women but not in men. Other trials
have failed to demonstrate any benefit of DHEA
on well-being, mood, cognition or activities of daily
living [84–86]. From these studies, it can be concluded
that the decline in DHEA concentrations does not
necessarily lead to impaired well-being, cognition or
sexuality per se [80].
In healthy ageing there is a marked sexual dimor-
phism in adrenal hormone regulation. In older women,
lower DHEA(S) and higher cortisol levels are seen
compared to older men, which persists into advanced
age. This is in contrast to cortisol levels in men and
women, which show a progressive, parallel increase
with ageing. The consequence of sexual dimorphism
in adrenal hormones may have implications for age-
related changes in cardiovascular disease, brain func-
tion and bone metabolism [68].
In summary, there is no clear clinical consequence
of the age-related decrease in serum concentration
of DHEA and there are no clear benefits of DHEA
replacement in older individuals [80].
Conclusion
Complex changes are seen in many endocrine sys-
tems with ageing that occur independently of factors
associated with the higher prevalence of age-related
illnesses. Endocrine deficiencies in older individuals
include a decrease in the peripheral levels of oestro-
gen and testosterone, with an increase in LH, FSH
and sex hormone-binding globulin. In addition there
is a decline in serum concentrations of GH, IGF-I and
DHEA(S). The endocrine functions that are essential
to life, such as adrenal and thyroid functions, show
a minimal overall change in basal levels with ageing,
even though there are complex changes that do occur
within the hypothalmo–pituitary–adrenal/thyroid axis.
The clinical significance of these deficiencies with
age are variable and are still being evaluated. The
menopause results in a series of changes in lipid
metabolism, bone loss, vasomotor symptoms and pos-
sible changes in cognition. Likewise, declines in
gonadal function in men are associated with increased
fat mass, loss of muscle and bone mass, fatigue,
depression, anaemia, poor libido, erectile deficiency,
insulin resistance and higher cardiovascular disease
risk. Similarly, a decline in the GH–IGF–I axis results
in reduced protein synthesis, decrease in lean body
mass and bone mass and a deterioration in immune
function. Changes in adrenal hormones have variable
clinical significance.
For each endocrine system there have been many
studies trying to reverse the effects of ageing by
restoring the serum hormonal levels of older indi-
viduals back into ‘younger ranges’. However, cur-
rently it is unclear whether treatment of many of these
J Pathol 2007; 211: 173–180 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
HS Chahal et al
aged-related changes is ultimately beneficial. So far
research has not found the ‘magic pill’ to reverse the
process of ageing and the quest for a ‘hormone of
youth’ still carries on.
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