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Chapter 28 / Endocrinology of Aging
419
28 Endocrinology of Aging
Steven W. J. Lamberts, MD, PhD
CONTENTS
INTRODUCTION
CHANGES IN HORMONE ACTIVITY DURING AGING
MENOPAUSE
ANDROPAUSE
ADRENOPAUSE
SOMATOPAUSE
1. INTRODUCTION
Throughout adult life, all physiologic functions
gradually decline. There is a diminished capacity for
cellular protein synthesis, a decline in immune function,
an increase in fat mass, a loss of muscle mass and
strength, and a decrease in bone mineral density (BMD).
Most elderly individuals die from the complications of
atherosclerosis, cancer, or dementia. However, in an
increasing number of the healthy elderly, loss of muscle
strength is the limiting factor that determines their
chances of living an independent life until death. Muscle
weakness can be caused by aging of muscle fibers and
their innervation, pain related to osteoarthritis, and
chronic debilitating diseases. In addition, a sedentary
lifestyle and decreased physical activity and disuse
seem, to be very important determinants in this decline
in muscle strength, because exercise training even at a
very old age has been demonstrated to reverse significantly the decline in physical capacity. In other words,
“use it or lose it;” activity is an extremely important
treatment for aging.
As the average length of life in Western societies
increases further, so does the interest in understanding
the considerable variations that have been observed in
the course and speed of the aging process within groups
From: Endocrinology: Basic and Clinical Principles, Second Edition
(S. Melmed and P. M. Conn, eds.) © Humana Press Inc., Totowa, NJ
of otherwise healthy individuals, with some people
exhibiting extensive decline in physiologic functions
with age and others little or none. Genetic factors,
lifestyle, and societal investments in a safe and healthy
environment are considered to be important determinants of successful aging. As life expectancy increases
further in the coming years, it becomes more and more
important to find interventions that might compress
morbidity during the last part of life, with the goal to
increase the number of years of healthy life with a full
range of functional and mental capacity, without necessarily prolonging life.
Traditionally, the endocrine system in humans has
been implicated as a driving part of the aging process.
The availability of hormone replacement of all known
hormones that might play a role in the aging process has
supported this idea. Many signs and symptoms observed
in young individuals with selected hormone deficiencies are similar to changes observed during the aging
process, and hormone replacement in young individuals
reverses virtually all these problems. Apart from these
considerations concerning the role of hormones in the
physiology of the aging process, the two clinically most
prevalent and important changes in endocrine activity
during aging that represent pathology (i.e., diseases) are
in glucose tolerance and thyroid function.
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Part IV / Hypothalamic–Pituitary
complications at an accelerated rate. Pancreatic insulin
receptor and postreceptor changes associated with aging are critical components of the endocrinology of
aging; apart from relative decreased insulin secretion by
β-cells, peripheral insulin resistance related to poor diet,
physical inactivity, increased abdominal fat mass, and
decreased lean body mass contribute to the deterioration
of glucose metabolism. Dietary management, exercise,
oral hypoglycemic agents, and insulin are the four components of treatment of these patients, whose medical
care is costly and intensive.
1.2. Changes in Thyroid Function
Fig. 1. During aging, declines in the activities of a number of
hormonal systems occur. Prolactin (PRL), TSH (thyrotropin),
and T4 (thyroxin) levels in general remain unchanged. (Left) A
decrease in growth hormone (GH) release by the pituitary gland
causes a decrease in the production of insulin-like growth factor-1 (IGF-1) by the liver and other organs (somatopause).
(Middle) A decrease in the release of luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) and decreased secretion at the gonadal level (from the ovaries, decreased E2 causes
menopause, and from the testicles, decreased testosterone [T]
causes andropause, respectively). Immediately after the initiation of menopause, serum LH and FSH levels sharply increase.
(Right) The adrenocortical cells responsible for the production
of dehydroepiandrosterone (DHEA) decrease in activity
(adrenopause), without clinically evident changes in adrenocorticotropic hormone and cortisol secretion. A central pacemaker in the hypothalamus or higher brain centers (or both) is
hypothesized, which together with changes in the peripheral
organs (the ovaries, testicles, and adrenal cortex) regulates the
aging process of these endocrine axes. (Reproduced with permission from Lamberts et al., 1997.)
1.1. Glucose Tolerance
and Diabetes Mellitus
Approximately 40% of individuals 65–74 yr old and
>50% of individuals over 80 have impaired glucose
tolerance or diabetes mellitus, and nearly half of these
elderly diabetics are undiagnosed. These persons are at
risk of developing secondary, mainly macrovascular
Age-related thyroid dysfunction is common in the
elderly. Lowered concentrations of plasma levorotators
thyroxine (T4) and increased thyrotropin-stimulating
hormone (TSH) occur in 5–10% of elderly women.
These abnormalities seem to be mainly caused by autoimmunity and may therefore be an expression of ageassociated disease, rather than a consequence of the
aging process.
It is well recognized that the general symptoms of
aging can be easily confused with hypothyroidism, and
in the past, decreased thyroid function was believed to
be one of the hallmarks of the aging process. During
aging a complex number of changes occur in thyroid
hormone concentrations. Reduced outer-ring
deiodination mediated by type I deiodinase results in a
decline in T4 degradation, with a reduced generation of
triiodothyronine (T3) and a decreased clearance of reverse T3. In addition, TSH secretion appears to be
slightly decreased in healthy elderly humans when subjects with subclinical hypothyroidism are carefully excluded. The reason for such age-dependent reduction of
TSH is uncertain. However, in spite of these complex
changes in biochemical parameters, recent studies suggest that normal aging is associated with essentially
normal thyroid function. The slight decrease in plasma
T3 concentration occurs largely within the broad normal
range of the healthy elderly population, and this decrease has not been convincingly causally related to
functional changes during the aging process. Evaluation of thyroid function in the elderly is necessary on a
regular basis because of the increased prevalence of
autoimmune subclinical hypothyroidism and
nonthyroidal illness.
2. CHANGES IN HORMONE
ACTIVITY DURING AGING
During aging three other hormonal systems show
decreasing circulating hormone concentrations (Figs. 1
and 2), and these decreases have been considered mainly
physiologic. In recent years, hormone replacement strat-
Chapter 28 / Endocrinology of Aging
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Fig. 2. Changes in hormone levels of healthy women (left) and men (right) during aging process. (A,B) Estrogen secretion throughout
an individual healthy woman’s life (expressed as urinary estrogen excretion) (A) and mean free testosterone index (ratio of serum
total testosterone to sex hormone–binding globulin levels) during the life of healthy men (B). (C,D) Serum DHEAS and E and F serum
IGF-1 levels in healthy women and men during aging process. Note the difference in the distribution of ages in different panels.
(Reproduced with permission from Lamberts et al., 1997.)
egies have been developed in each case, but many of
their aspects remain controversial, and increasing hormone blood levels to those found in 30- to 50-yr-old
individuals has not been universally proven to be safe
and of benefit.
3. MENOPAUSE
The most dramatic and rapidly occurring change in
women around the age of 50 is menopause. Cycling
estradiol (E2) production from the ovarian follicles is
suddenly exhausted, reproduction stops, and (very) low,
constant E2 levels remain, mainly produced by aromatization of adrenal androgens in nonendocrine tissues,
such as adipose tissue.
This acute drop in circulating estrogen levels and the
permanent cessation of menstruation around age 50 yr
is often accompanied by vasomotor reactions, sleep disturbances, changes in skin and body composition, and a
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depressed mood. The use of hormone replacement
therapy ([HRT], estrogens or estrogen plus progestogen) rapidly alleviates these symptoms of menopause.
In women with these symptoms, HRT also improves
verbal memory, vigilance, reasoning, and motor speed,
but there is no enhancement of other cognitive functions. Generally, no benefits of HRT are observed in
asymptomatic women.
Currently, the long-term use (5–10 yr or more) of
HRT after menopause is surrounded by controversy;
many studies in the past indicated advantages regarding prevention of the three chronic disorders most
common in elderly women: cardiovascular diseases,
osteoporosis, and dementia. However, these beneficial
effects are a double-edged sword because long-term
HRT is accompanied by a significant increase in the
incidence of breast cancer, thrombosis, and stroke. The
controversy has arisen partly because of differences in
the selection of participating menopausal women in
the large prospective trials with HRT. For example, the
inclusion of nurses, who are probably more aware of
the advantages of healthy lifestyle than the “normal”
population of menopausal women, might have introduced a “healthy user bias” in several of the best prospective clinical trials, which were, however, mostly
observational and not randomized controlled.
In 2002, the interim results of the Women’s Health
Initiative Trial were published. This is a randomized
controlled trial to assess the risks and benefits of intervention strategies in the postmenopausal population in
t he United States. The trial has in fact shown that HRT
increases the risk of developing cardiovascular disease,
including coronary heart disease (the primary outcome)
and stroke, although it showed benefits for preventing
hip fractures and bowel cancer. The relative risks of
developing invasive breast cancer, coronary heart disease, and stroke were increased, although the absolute
risks remained very small. One treatment arm of the
trial included more than 16,000 postmenopausal women
who were taking continuous combined estrogenprogestagen HRT, using conjugated equine estrogens
(0.625 mg) plus medroxyprogesterone acetate (2.5 mg
daily), tested against placebo. This primary prevention
study was due to run for 8.5 yr, but was halted at just
over 5 yr because the number of cases of breast cancer
had reached a prespecified safety limit. For 10,000
women taking HRT each year, compared with those not
taking it, there would be an additional eight cases of
invasive breast cancers, seven heart attacks, eight
strokes, and eight pulmonary embolisms. However,
there would also be six fewer bowel cancers and five
fewer hip fractures. Overall mortality was not increased
with therapy.
Part IV / Hypothalamic–Pituitary
The decision to stop the trial and to change US recommendations for the use of postmenopausal HRT for
primary prevention of chronic conditions might not be
automatically applicable. First, one should realize that
the weight and BMI of the US female population were,
in general, high, and these factors alone make the participants more prone to breast cancer, stroke, thrombosis, and cardiovascular disease while in their excess
adipose tissue enough estrogens might have been produced by aromatization of adrenal androgens, making
the intake of additional HRT a pharmacologic rather
than a replacement therapy. Second, more and more
evidence is provided that genetic testing, such as for
estrogen receptor (ER) polymorphisms and factor V
Leiden, will not only better predict a positive outcome
of HRT on cardiovascular disease, but the chances of
developing thrombosis as well. Third, HRT’s potential
impact on the incidence of dementia needs to be considered.
Women seem to be at higher risk of developing
Alzheimer disease, and this is in part owing to their
increased longevity. It has been suggested that the abrupt
decline of estrogen production at menopause may be
associated with a vulnerability of the female brain. Elderly men have an intrinsic supply of estrogen because
they aromatize testosterone into estradiol within the
brain. There is strong experimental evidence that in
the intact brain estradiol might play a key neuroprotective role by delaying the initiation phase of onset of
neurodegenerative disease. It was demonstrated that in
mice lacking the ERα, estrogen protects the brain from
injury by accelerating and amplifying the activity of this
receptor. As a consequence, genes that help the brain
cells survive are activated, or genes that harm the brain
cells are suppressed.
Postmenopausal HRT was considered to prevent or
delay cognitive decline and dementia in postmenopausal
women. In a systematic review and metaanalysis of all
observational studies conducted thus far, it was concluded that HRT started at age 50, at the start of menopause, is associated with a decreased risk of dementia
(summary odds ratio: 0.66; 95% confidence interval:
0.53–0.82). However, many of these studies also have
important methodologic limitations, with the healthy
user bias mentioned earlier an important one. In the
Women’s Health Initiative Trial, a randomized controlled trial, in which HRT was started at age 65, no
improvement of cognitive function was observed.
HRT administered for 1 yr in women with mild to
moderate Alzheimer disease did not slow disease progression, nor did it improve global, cognitive, or functional outcome. However, the use of high-dose
estrogens to improve cognition in women with demen-
Chapter 28 / Endocrinology of Aging
tia was reported in a small study. In a prospective study
of incident dementia among 1357 men (mean age: 73.2
yr) and 1889 women (mean age: 74.5 yr) residing in a
single county in Utah, it was again demonstrated that
prior HRT use is very closely associated with reduced
risk of dementia. There was a highly statistical HRT
duration-dependent decrease in incident dementia in
women after the age of 80, with a decrease in incident
dementia in women who had used HRT more than 10 yr
in the past compared with that found in men. There was
no apparent benefit of current HRT in the older group
of women.
These considerations on the advantages and risks of
HRT in healthy postmenopausal women are very sobering. There is no doubt that early HRT, taken immediately at menopause, alleviates most symptomatology
and is, in principle, safe in the shortterm. In women in
whomcardiovascular disease is symptomatic, other (preventive) medications including β-blockers, ACE-inhibitors, aspirin, and/or statins have been proven to be
effective. In addition, in symptomatic osteoporosis,
bisphosphonates have preventive efficacy similar to or
even better than HRT.
Recent studies demonstrated that a higher than usual
dietary intake of phytoestrogens (isoflavones and
lignans) is associated with a lower aortic stiffness in
postmenopausal women, suggesting that phytoestrogens have a protective effect on the risk of atherosclerosis and arterial degeneration through an effect on arterial walls, especially among older women. Interestingly,
alcohol consumption was also inversely associated with
aortic stiffness, supporting the concept that moderate
alcohol consumption decreases the risk of cardiovascular disease in postmenopausal women.
In summary, the verdict on the use of HRT in healthconscious women is, in general, negative at present.
With the further development of genetic testing to identify those women who might benefit most, and/or are
most at risk for thrombotic events and/or breast cancer,
the decision to prescribe HRT early after menopause in
order to obtain the early beneficial effects on subjective
well-being, as well as possible late delaying effects on
dementia, might remain an option.
3.1. Selective ER Modulators
A new development in the preventive treatment of
the consequences of long-term estrogen deficiency in
menopause is the availability of targeted estrogen
replacement therapy using selective estrogen receptor
modulators (SERMs). Early studies using tamoxifen in
the treatment of breast cancer indicated variable
estrogenic and antiestrogenic actions of the compound
in different organs. Tamoxifen suppresses the growth
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of ER-positive breast cancer cells; in addition, longterm tamoxifen treatment of patients surviving breast
cancer indicated a partial protection against age-related
decrease in BMD. These observations were explained
by the fact that tamoxifen, and other compounds such
as raloxifene, have antiestrogenic actions on normal
and cancerous breast tissue, but agonistic actions on
bone, lipids, and blood vessel walls. The differential
effects of these SERMs in different organs may be
explained by the activation of different forms of ER, in
which the form is the “classic” estrogen, whereas the β
form mediates the vascular and bone effects of estrogens. Raloxifene, in contrast to tamoxifen and estradiol, does not stimulate endometrial thickness and
vaginal bleeding. It has protective effects for vertebral
fractures in menopausal women with osteoporosis. A
very promising effect of raloxifene is its reported
chemoprotective action on breast cancer.
4. ANDROPAUSE
Age-associated hypogonadism develops not as
clearly in men as in women. The key difference from
menopause is the gradual, often subtle change in androgen levels in men compared with the precipitate fall of
estrogen production in women (Fig. 2). There is general
agreement that as men age, there is a decline in the concentration of serum total testosterone that begins after
age 40. In cross-sectional studies, the annual decline in
total and “free” testosterone is 0.4 and 1.2%, respectively. The higher decline in free testosterone levels is
related to the increase in levels of SHBG with aging.
“Andropause” is characterized by a decrease in testicular Leydig cell numbers and in their secretory capacity,
as well as by an age-related decrease in episode and
stimulated gonadotropin secretion.
It remains unclear whether the well-known biologic
changes during aging in men, such as reduction in sexual
activity, in muscle mass and strength, and in skeletal
mineralization, are causally related to these changes in
testosterone bioactivity (“andropause”).
In a group of more than 400 independently living
elderly men ages 73–94 (mean age: 78 yr), a positive
association was observed between serum total and free
testosterone concentrations and muscle strength as
well as an inverse relationship with fat mass. In addition, low bioavailable testosterone was associated with
a depressed mood in a population-based study in 856
men (age: 50–89).
Many persuasive reports in the literature demonstrate
that treatment of men of all ages (young, adult, and old)
with clear clinical and biochemical hypogonadism with
testosterone replacement instantly reverses vasomotor
activity (flushes and sweats): improves libido, sexual
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activity, and mood; increases muscle mass, strength,
and bone mineralization; prevents fractures; decreases
fat mass; and decreases fatigue and poor concentration.
Additionally, the treatment of adult healthy men with
supraphysiologic doses of testosterone, especially when
combined with resistance exercise training, increases
fat-free mass and muscle size and strength.
A search for studies reporting the results of androgen
therapy in older men demonstrates that most studies
were small, short-term, noncontrolled, and without uniform endpoints.
Numerous studies of large populations of healthy
men have shown a marked rise in the incidence of
impotence to >50% in men ages 60–70. Although this
increase in impotence occurs in the same age group
that shows a clear decline in serum (free) testosterone
levels, no causal relationships have been demonstrated.
Testosterone replacement therapy in elderly men is in
most instances not effective for the treatment of loss of
libido or impotence in individuals with serum testosterone concentrations within the normal age-matched
range; other factors such as atherosclerosis, alcohol
consumption, smoking, and the quality of personal
relationships seem to be more important denominators. Only in the case of clear hypogonadism are the
decrease in libido and potency restored by testosterone
therapy. This suggests that there is a theshold level
of testosterone in the low normal range, below which
libido and sexual function are impaired and above
which there is no further enhancement of response.
Summarizing the literature available on the preventive treatment of healthy elderly men with testosterone
at a dose that increases serum testosterone concentrations to those observed in 20-to 30-yr-olds demonstrates
limited anabolic effects on body composition (a slight
decrease in fat mass, and a slight increase in muscle
mass). In addition, minor beneficial effects on muscle
strength or physical performance have been observed in
a minority of studies.
Detailed analysis of a number of studies in which
elderly men selected on the basis of the presence of
“low” pretreatment serum testosterone concentrations
suggests a beneficial effect of testosterone replacement
therapy on muscle strength, BMD, mood, as well as
(subjective) aspects of the quality of life.
In conclusion, testosterone at supraphysiologic
doses when administered to eugonadal men increases
muscle mass and strength. “Replacement” therapy
directed at restoring serum testosterone therapy in
healthy elderly males to levels observed between the
age of 30 and 50 lowers fat mass and increases lean
mass to a limited extent without a clear beneficial effect
on muscle strength and physical performance. At
Part IV / Hypothalamic–Pituitary
present, it remains uncertain whether testosterone
replacement produces clinically meaningful improvements in muscle function without significant adverse
effects in frail older men or in elderly men with serum
testosterone concentrations between 7.0 and 11.4
nmol/L.
If one decides to start testosterone replacement the
major goal of therapy is to replace testosterone levels
to as close to “physiologic” age-matched levels as possible. The dose should thus be titrated according to
serum levels. At present, the duration of administration
of testosterone is uncertain. Control of prostate size,
prostate-specific antigen levels, and hematocrit levels
is mandatory. The identification of elderly men who
might benefit most from testosterone treatment remains
uncertain, and the risks to the prostate and possible
effects on the process of atherosclerosis remain subjects for study. The concept of developing androgenic
compounds with variable biologic action in different
organs (selective androgen receptor modulation) is
currently being pursued.
5. ANDRENOPAUSE
5.1. Dehydroepiandrosterone
Humans are unique among primates and rodents
because the human adrenal cortex secretes large
amounts of the steroid precursors DHEA and its sulfate
derivative DHEAS. Serum DHEAS concentrations in
adult men and women are more than 100 times higher
than those of testosterone and more than 1000 times
higher than those of estradiol. In healthy subjects, serum
concentrations of DHEAS and its sulfate are highest in
the third decade of life, after which the concentrations of
both gradually decrease, so that by the age of 70–80 yr,
the values are about 20% of peak values in men and 30%
of peak values in women (Fig. 2).
Both DHEA and DHEAS seem to be inactive precursors, which, via a number of enzymes, are transformed within human tissues by a complicated network
of enzymes into androgens and/or estrogens. The key
enzymes are aromatase, steroid sulfatase, 3β-hydroxysteroid-dehydrogenases, and at least seven organ-specific 17β-hydroxysteroid dehydrogenases. Labrie
introduced the name “intracrinology” to describe this
synthesis of active steroids in peripheral target tissues,
where the action is exerted in the same cells in which
synthesis takes place, without release in the extracellular space and general circulation. In postmenopausal
women, nearly 100% of sex steroids are synthesized in
peripheral tissues from precursors of adrenal origin
except for a small contribution from ovarian and/or
adrenal testosterone and androstenedione. Thus, in
postmenopausal women, virtually all active sex ste-
Chapter 28 / Endocrinology of Aging
roids are made in target tissues by an intracrine mechanism. Also in elderly males the intracrine production
of androgens is important: less than 50% of androgens
is derived from testicular production.
As already stated, the situation of a high secretion
rate of adrenal precursor sex steroids in men and women
is completely different from animal models used in the
laboratory, in which the secretion of sex steroids takes
place exclusively in the gonads. In many experiments,
it has been demonstrated that (long-term) administration of DHEA to rats and mice prevents obesity, diabetes mellitus, cancer, and heart disease, while it enhances
immune function.
These experimental animal data have been used as an
argument that administration of DHEA in adult/elderly
individuals prolongs life-span and might be an “elixir of
youth.” Supportive data in humans are few, however,
and highly controversial.
Several randomized placebo-controlled studies
demonstrated that oral administration of DHEA might
have beneficial effects on perceived physical and psychologic well-being in both sexes without an effect on
libido. A number of other, well-controlled trials with
DHEA subsequently did not demonstrate a clinically
significant effect.
A physiologic functional role of DHEA in women
has been demonstrated. However, in a careful doubleblind study in women with adrenal insufficiency, administration of DHEA (50 mg/d) normalized serum
concentrations of DHEA, DHEAS, androstenedione
and testosterone. DHEA significantly improved overall well-being, as demonstrated by scores for depression and anxiety, the frequency of sexual thoughts,
sexual interest, as well as satisfaction with both mental
and physical aspects of sexuality.
In conclusion, DHEA(S) is a universal precursor to
the peripheral local production and action of estrogens
and androgens in the elderly. The addition of DHEA
(50 mg) to the existing big pool of DHEA(S) in
unselected elderly individuals has no or only limited
clinical effects, especially in elderly women. It is
unknown whether the increase in sex steroid levels
induced by long-term administration of DHEA is safe
regarding the development of ovarian, prostate, or
other types of steroid-dependent cancers. DHEA is
currently widely used within the United States as a
“treatment against aging.” With the scientific verdict
still out, without further confirmation of DHEA’s
reported beneficial actions in humans, and without a
better understanding of its potential risks, it is premature to recommend the routine use of DHEA for delaying or preventing the physiologic consequences of
aging.
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5.2. Cortisol
Cortisol production by the adrenals seems to have a
major impact on memory and cognition. In cross-sectional as well as longitudinal studies, it was demonstrated that higher cortisol levels are associated with
poorer memory performance and a higher likelihood of
memory decline, especially in women. The detrimental
effects of cortisol seem to be directed at the hippocampus. An iv bolus of 35 mg of hydrocortisone reduces
hippocampal glucose metabolism, as measured by
positron emission tomography scan, in elderly individuals by 12–16%, and the hippocampal volume, measured
by magnetyic resonance imaging, is smaller in patients
with Cushing’s syndrome.
In a small prospective study in healthy elderly individuals, an association between adrenal steroid hormones and cognitive function was confirmed. Free
cortisol levels appeared to be associated with cognitive
impairment, and a lower degree of cortisol suppression
after administration of dexamethasone was associated
with an increased risk of cognitive decline. These findings support the concept that stress and anxiety have
important consequences regarding to the degree and
speed of the decline in memory and other cognitive
abilities in the elderly. Clear clinical developments
regarding to medical intervention in this process remain
elusive, however.
6. SOMATOPAUSE
The third endocrine system that gradually declines in
activity during aging is the GH/ IGF-1 axis. Mean pulse
amplitude, duration and fraction of GH secreted, but not
pulse frequency, gradually decrease during aging. In
parallel, there is a progressive fall in circulating IGF-1
levels in both sexes. There is no evidence for a “peripheral” factor in this process of somatopause, and its triggering pacemaker seems mainly localized in the
hypothalamus, because pituitary somatotropes, even in
very old individuals, can be restored to their youthful
secretory capacity during treatment with GH-releasing
peptides.
The expectation that this decline in GH and IGF-1
secretion contributes to the decline in functional capacity in the elderly (“somatopause”) is mainly derived
from studies in which GH replacement therapy of GHdeficient adults was shown to increase muscle mass,
muscle strength, bone mass, and the quality of life. A
beneficial effect on the lipid profile and an important
decrease in fat mass were also observed in such patients.
As in hypogonadal individuals, adult GH deficiency can
thus be considered a model of normal aging, because a
number of catabolic processes that are central in the
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Fig. 3. Schematic representation of the regulation of GH/IGF-1
axis, as well as potential hormonal intervention of different compounds to activate this axis on different levels (left).
biology of aging can be reversed by administration of
GH.
In 1990, Rudman published the findings of a trial
that provoked headlines in the popular press. In this
trial, healthy older men were administered recombinant human GH, heralded as a treatment for aging. The
initial optimism prompted many investigators to start
clinical trials to investigate the possible benefits of GH
in older people. However, today it seems fair to state
that GH remains a promising treatment still looking for
a proven indication.
Rudman’s study concerned men with IGF-1 levels
that were deficient by young adult standards. In the 12
men receiving active treatment for 6 mo, fat mass fell,
lean body mass rose by 8.8% (p < 0.05), and lumbar
vertebral density (but not other bone sites) rose by 1.6%
(p < 0.05). Compared with age-related differences
observed in cross-sectional studies, these were massive effects. However, the trial should only be regarded
as a pilot study because the treatment groups were not
randomized and the subjects were not blinded. In a
subsequent similar study, only 18 of 62 subjects completed 12 mo of treatment without experiencing one or
more of the three common side effects: carpal tunnel
syndrome, gynecomastia, and hyperglycemia. Patients
who produced higher IGF-1 levels experienced more
side effects. Subsequent trials have generally confirmed the changes in fat and lean tissue but shown
inconsistent effects on bone density.
Part IV / Hypothalamic–Pituitary
Furthermore, in contrast to the findings in younger
GH-deficient adults with pituitary disease, the potentially beneficial changes in muscle and other lean body
tissue obtainable in older people have not translated into
improved functional abilities. Exercise programs have
proven ability to enhance muscle mass and strength,
even in very frail elderly people. Adding GH treatment
to an exercise intervention produced no additional benefit for healthy males. Although the exercise-related GH
responses of older people are attenuated, it has not been
shown that a youthful GH response is necessary for older
people to benefit maximally from exercise.
Other components of the GH/IGF-1 axis are effective in activating GH and IGF-1 secretion (Fig. 3).
Long-acting derivatives of the hypothalamic peptide
GH-releasing hormone (GHRH) given twice daily subcutaneously for 14 d to healthy men 70 yr old increased
GH and IGF-1 levels to those encountered in 35-yrolds. This finding supports the concept that somatopause is primarily hypothalamically driven, and that
pituitary somatotropes retain their capacity to synthesize and secrete high levels of GH. GH-releasing peptides (GHRPs) are oligopeptides with even more
powerful GH-releasing effects. Originally developed
by design, it has recently been demonstrated that
GHRPs mediate their GH-secretory effects through
endogenous specific receptors. Nonpeptide analogs
such as MK-677 and L692,429 have powerful GHreleasing effects, restoring IGF-1 secretion in the elderly to levels encountered in young adults. Long-term
oral administration of MK-677 to healthy elderly individuals increased lean body mass, but not muscle
strength. If proven to be GH specific, these orally active
GHRP derivatives might be important alternatives
to subcutanously administered GH for studies in the
reversal of somatopause, in the prevention of frailty,
and in the reversal of acute catabolism.
Recombinant IGF-1 produces less fluid retention and
lower blood glucose than GH. Four weeks of treatment
of healthy older women (mean age: 71 yr) with either
GH or recombinant human IGF-1 (rhIGF-1) produced
potentially beneficial and adverse effects similar to
those seen in men, although rhIGF-1 was better tolerated. In combination with a reducing diet and a program
of exercise, these treatments produced weight loss in
healthy but obese older women without compromising
lean body mass or gains in muscle strength, but side
effects were a problem, causing 5 of 33 subjects to drop
out.
In a 26-wk randomized, double-blind, placebo-controlled parallel-group trial in healthy elderly men and
women, the effects of GH and/or sex steroids (testosterone in men, estrogens and progesterone in
Chapter 28 / Endocrinology of Aging
women) on body composition, strength, and endurance, as well as adverse effects were studied. GH with
or without sex steroids induced in these healthy aged
women and men the well-known increase in lean body
mass and decrease in fat mass. The combination of GH
and testosterone caused a marginal increase in muscle
strength and maximum oxygen uptake in men, but
women had no significant change in strength or cardiovascular endurance. Formation of edema, carpal tunnel syndrome, arthralgias, and deterioration of glucose
tolerance or even development of diabetes frequently
occurred, limiting the use of GH in aging.
Another still unsolved issue is the safety of long-term
administration of GH. Epidemiologic studies, together
with many experimental data, suggest that the IGF-1
system is involved in tumor development and progression. It remains uncertain at present whether long-term
GH treatment in the elderly thereby might contribute to
the risk of prostate, breast, and/or colon cancer.
In conclusion, the use of GH and/or other compounds
that activate IGF-1 bioactivity in the treatment of the
elderly, either as a preventive intervention delaying the
aging process or as a treatment to counteract frailty and/
or catabolism, has not been proven to be safe and successful. At present, the use of GH therefore cannot be
advised in elderly individuals.
427
REFERENCE
Lamberts SW, van den Beld AW, van der Lely AJ. The endocrinology of aging. Science 1997;278:419–424.
SUGGESTED READINGS
Blackman MR, Sorkin JD, Münzer T, et al. Growth hormone and
sex steroid administration in healthy aged women and men.
JAMA 2002;288:2282–2292.
Grady D. Postmenopausal hormones: therapy for symptoms only.
N Engl J Med 2003;348:1835–1854.
Labrie F, Luu-The V, Lin SX. Intracrinology: role of the family of
17 beta-hydroxysteroid dehydrogenases in human physiology
and disease. J Mol Endocrinol 2000;25:1–6.
Lamberts SW. The endocrinology of aging and the brain. Arch
Neurol 2002;59:1709–1711.
Li CI, Malone KE, Porter PL, Weiss NS, Tang MC, CushingHaugen KL, Daling JR. Relationship between long durations
and different regimens of hormone therapy and risk of breast
cancer. JAMA 2003;289:3254–3263.
Riggs BL, Hartmann LC. Selective estrogen-receptor modulators:
mechanisms of action and application to clinical practice. N Engl
J Med 2003;348:618–629.
Rowe JW, Kahn RL. Human aging: usual and successful. Science
1987;237:143-149.
Rudman D, Feller AG, Nagraj HS. Effect of human growth hormone in men over 60 years old. N Engl J Med 1990;323:1–6.
Vermeulen A. Androgen replacement therapy in the aging male:
a critical evaluation. J Clin Endocrinol Metab 2001;86:2380–
2390.