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0021-972X/01/$03.00/0 Vol. 86, No. 6
Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
COMMENTARY
Androgen Replacement Therapy in the Aging Male—A Critical Evaluation
A. VERMEULEN
Department of Internal Medicine, Section of Endocrinology, University Hospital,
9000 Gent, Belgium
Recent years have seen an increasing interest in the study
of the aging male, with a particular interest in the problem of
whether so-called rejuvenating hormones and, more specifically, androgens can
improve quality of life, counteract
progressive skeletal muscle loss and strength, prevent falls
and fractures, prolong independent living, and reduce the
dependence on medical care.
Almost a decade has elapsed since the first studies on
androgen supplementation in elderly men were published (1,
2) and, in the view of the persisting controversies
concerning
this problem as well as the increasing public interest for rejuvenating
hormones, it may be indicated to evaluate
critically the clinical relevance of the relative androgen deficiency in elderly
males, the diagnostic criteria of androgen
deficiency, as well as the risks and benefits of androgen
supplementation in elderly men.
Male hormone replacement therapy implies, of course, that
elderly men have a significant deficit in male hormone.
Therefore, the first question to be answered is whether the
common occurrence of the age-associated decline of testosterone levels is
inherent to the aging process and occurs also in healthy men or whether the
observed decline is the consequence of intercurrent disease, obesity, stress,
relative physical inactivity or medications, etc.
After years of controversy, due to differences in the characteristics of the
population studied and variation in the
timing of blood sampling (morning or afternoon) or the
frequently small number of elderly subjects studied, authors
now agree that in healthy men also there is a clear, slow but
continuous, age-dependent decline of testosterone (T) levels,
which is more pronounced for free T (FT) than for total T, a
consequence of the age-associated increase of the levels of
sex hormone binding globulin (SHBG); at 75 yr of age mean
total T level in the morning is about two thirds of the mean
level at 20 -30 yr of age, whereas the mean FT and bioactive
T (FT plus albumin bound T) level are only 40% of the mean
levels in younger males. Moreover, the circadian rhythm of
plasma T levels, with higher levels in the morning than in the
evening, is generally lost in elderly men (3).
However, wide
interindividual variations exist due to genetic factors, body
mass index, diet, social habits (alcohol, tobacco), and stress,
and about 20% of males over 70 yr old have T levels in the
upper third of males 20-40 yr of age (4). This is
in clear
distinction to the situation in postmenopausal women who all
have clearly decreased estradiol levels. It is important to
mention that this decrease, observed in cross-sectional studies, has now been
confirmed by longitudinal studies (5-9).
However, the androgen deficiency in elderly men is generally
moderate; therefore, some authors have suggested the term
partial androgen deficiency in the aging male (PADAM).
Others, in analogy with the term menopause in women, use
the term andropause, although distinct from women in
menopause, elderly men retain their reproductive capacity.
Although the decrease in (F)T levels occurs in healthy
elderly men, it is evident that sequelae of intercurrent disease
(10), medication, environmental, psychosocial, and
socioeconomic factors accelerate this age-associated
decrease. Recently, the important role of abdominal obesity
in the age-associated decrease of T levels has been stressed
(10-12).
Clinical Significance of theAge-Associated Decline in Androgen Levels in Elderly
Men.
Androgens have many physiologic actions, but does the
age-associated decrease in (F)T levels have clinical significance, and does it
indicate hypogonadism? Evidence for the clinical significance could be provided
by the eventual similarity between signs and symptoms of aging and androgen
deficiency, respectively, in young men, the existence of a significant
correlation between symptoms and (F)T levels, and the eventual beneficial effect
of androgen supplementation in elderly men with low T levels.
Similarity of Signs an Symptoms of Aging and Androgen Deficiency, Respectively, in
Young Men.
The age-associated decrease in muscle mass and strength, energy and work
capacity, body hair, and hematopoiesis; the decrease in sexual drive and
activity, bone mass, and cognitive function; the decline of memory and of the
sense of general well being; the difficulties in concentration; and the increase
in abdominal fat mass are reminiscent of the symptomatology of androgen
deficiency. However, these symptoms are multifactorial in origin; aging is
accompanied by a decrease of almost all physiological functions and, as far as
the endocrine system is concerned, by a decrease not only of gonadal and adrenal
androgen secretion but also of GH secretion. Moreover, the age-associated
decrease in physical activity is partly responsible for the decrease in muscle
mass and bone mineral density (BMD) (13). Hence, it
is not surprising that the correlation between aging symptoms and T levels is
often rather poor.
Correlation Between Aging Symptoms and (F)T Levels.
Whereas the age-associated decrease of BMD with an exponential increase in
bone fracture rate with age (14,
15) is well established, the role of the partial androgen deficiency in
aging males in this decrease remains to be established (16).
Indeed, available data are equivocal, some studies showing a significant, albeit
weak, association between FT levels and BMD at some but not all bone sites (13,17,18),
whereas others did not find any correlation (19-21).
Recently, several large-scale studies, involving several hundreds of elderly men
(22-24), found bio-T
to be significantly associated with bone density at radius, spine and hip;
however, the correlation with
bioavailable estradiol, the levels of which decline in elderly
males, was even stronger, suggesting that part of the
androgen effects on bone are at least partially indirect,
mediated via their aromatization (25). Nevertheless
bio-T
also was correlated with all regions of proximal femur BMD
and total body BMD after adjustment for age (24).
Barrett-
Connor et al. (26) observed a significant negative
graded
association between levels of total and bioavailable estradiol
but not bio-T and fracture prevalence in males (median age
67 yr, range 56-87 yr) independently of age, body mass
index, or exercise.
On the basis of these recent large-scale studies it seems
reasonable to accept a role of the decreased T levels in the
age-associated osteopenia.
Aging is also accompanied by a increase in abdominal fat
mass and a decrease of muscle mass. We (27) as well
as
Seidell et al. (28) and Tchernof et al. (29)
observed
abdominal fat mass to be inversely correlated with FT,
independently of age. Visceral fat accumulation is highly
significantly associated with increased risk of cardiovascular
disease, impaired glucose tolerance, and non-insulindependent diabetes mellitus
(syndrome X) (30, 31).
Whether the abdominal obesity is the consequence of the low T levels or vice
versa is not clear. Indeed, obesity induces a decrease of T levels via a
decrease in SHBG levels, and morbid obesity (BMI >35) also induces a decrease of
FT (11).
The age-associated decline in muscle mass (12 kg between
20 and 70 yr of age), which is most pronounced for the fast
twitch type II fibers (32), is a major contributor
to the ageassociated decline in muscle strength and early onset of fatigue (33)
and a strong predictor of falls, fractures, and loss
of independent living. In fact, maximal muscle strength correlates with muscle
mass independently of age (34).
Whereas van den Beld et al. (24) observed that in
men 73-
97 yr of age, serum T levels were, independently of age,
positively related to isometric grip strength and leg extension
strength, and Abassi et al. (35) observed a
correlation
between T levels and severity of loss of muscle function in
institutionalized men who have lower T concentrations than
healthy elderly men, Baumgartner et al. (36)
observed in
elderly men (65-97 yr old) a significant correlation between
FT and muscle mass, but not grip strength. Verhaar et al.
(37), similarly, did not find any association
between T levels and muscle strength.
It should be stressed that although a correlation exists
between the lower T concentration and reduced muscle function in older men, T is
not the only factor responsible for the age-associated muscle loss.
The prevalence of atherosclerosis in men increases spectacularly with aging. In
the view of the higher prevalence
in men than in women, the decrease of high density lipoprotein cholesterol
(HDL-C) levels at puberty in boys
(38), the atherogenic lipid profile in hirsute
women, and the
sporadic reports of premature cardiovascular disease in
athletes abusing anabolic/ androgenic steroids, this difference
is generally considered to be related to the higher androgen
levels in men. Nevertheless, the vast majority of crosssectional studies show a
positive correlation between FT levels and HDL-C (39-41)
and a negative correlation with
fibrinogen, plasminogen activator inhibitor-1 (42),
and
insulin levels as well as with coronary heart disease (43,
44),
but not with cardiovascular mortality (45-47).
However, the
correlation between T levels and HDL-C and insulin
sensitivity is only observed within the physiologic male concentration range of
T (48, 49). Androgen
blockade by GnRH leads to an increase of HDL-C and, to a lesser extent, of total
cholesterol, the effect of which is neutralized when T
enanthate was injected in parallel, to maintain physiological
T concentrations (48), whereas supraphysiological T
levels
induce an increase in low density lipoprotein cholesterol
(LDL-C) and a decrease of HDL-C (40) Moreover, it
should
be realized that, beside the effects on lipids, T has direct
effects on several vasoactive factors such as endothelin (50),
prostacyclin, and thromboxane A2 (51).
The inverse correlation between T levels and the severity
of coronary artery disease as reported by Phillips et al. (43),
may be related to the fact that low androgen levels are accompanied by an
accumulation of abdominal visceral fat (28,
29), which is known to be associated with increased
cardiovascular risk factors (52), and Tchernof et
al. (29) observed that upon multivariate analysis,
adjusting for visceral obesity, the correlation between androgen levels and
lipid parameters lost its significance.
As to the role of the age-associated decline in T levels in
the highly negative correlation between sexual desire,
arousal, activity, and age, Schiavi (53) reported
that men
desiring intercourse with a greater frequency than once a
week, had higher T levels than men with lower frequency.
Moreover they observed (54) that men with the
primary
diagnosis of hypoactive sexual desire had significantly lower
T levels than controls. Similarly, Pfeilschifter et al. (55)
reported that men with greater sexual activity had higher bio-T
levels than men with a lower frequency and they conclude
that androgen deficiency may contribute to the age-related
decline in male sexuality. Nilsson et al. (56)
finally, in an
epidemiological study of 500 51-yr-old men, observed that
low levels of bio T were associated with low sexual activity.
However, other authors (57,
58) did not observe any correlation between plasma T levels within the
normal range
and sexual activity. Moreover, it is known that healthy males
have much higher T levels than required to maintain sexual
function, although Schiavi (53) as well as Bancroft
(59) suggested that circulating androgen levels in
elderly men might be insufficient to sustain nocturnal penile tumescence
and adequate sexual function.
As to erectile dysfunction, which increases dramatically
with age, whereas androgens, acting both centrally and peripherally (60)
are essential for normal penile erection and T-stimulating nitric oxide
synthesis in the corpora cavernosa
(60, 61), androgen
deficiency is rarely the major cause of
impotence in elderly males, although it may play a subsidiary
role. There is good evidence that, whereas nocturnal penile
tumescence is androgen dependent, erection in response to
visual erotic stimuli is androgen independent (62).
Davidson
et al. (63) suggested that the effects of T may be
mediated
via changes in genital sensitivity.
Finally there is good evidence for a strong correlation
between T levels and cognitive performance such as spatial
abilities or mathematical reasoning (64,
65), findings which
were confirmed in Western and non-Western groups of
healthy males (64). Studies addressing correlations
between
T levels and cognitive functions specifically in elderly man
are not available.
As to the role of T in the depressed mood frequently
observed in elderly men, whereas data in the literature are
rather divergent [for review see Christiansen (66)],
a recent
large study by Barrett-Connor et al. (67) involving
856 men
age 50-89 yr showed a significant inverse correlation between
bioavailable T and a depression score, independent of
age and weight.
In summary, many aging symptoms in men are suggestive
of androgen deficiency and, in fact, there frequently exists a
weak correlation of these signs with plasma T levels; many,
but not all, studies show the persistence of these correlations
after correction for age.
Nevertheless, it should be kept in mind that most of the
aging symptoms are multifactorial in origin and that the age-associated decrease
in GH levels might play an important
role in the symptomatology (68), because symptoms
of GH
deficiency in young men and the symptoms of aging again
show a striking similarity; decrease in muscle mass, increase
in abdominal fat, thinning of the skin, asthenia, and
adynamia.
Aging and Adrenal Androgens
Aside from a decrease in the secretion and plasma levels of
T, aging is accompanied by a decrease of the plasma levels
of the major adrenal androgen, dehydroepiandrosterone sulfate (DHEAS). The
age-associated decrease is the most important decrease of all hormones; at 75 yr
of age, mean
DHEAS levels are only 20% of levels in young adults and,
whereas rather important interindividual variations exist, all
men and women show an important age-dependent decrease
(69-71).
Does this decrease have clinical significance? Although it
has been reported that in animals that do not secrete DHEAS,
administration of DHEAS generally in pharmacological
doses, has antiatherogenic, immunostimulatory, and anticarcinogenic effects, the
effects of DHEAS in man remain
questionable. Functional parameters of daily living in the
oldest males were reported to be lowest in men with the
lowest DHEAS levels (72), whereas data of Abassi et
al. (73)
show that men with higher DHEAS levels appear to be more
fit and leaner than men with lower DHEAS levels. This, of
course, does not indicate a causal role of DHEAS in physical
fitness or general well-being. Moreover, it has been reported
that men with low DHEAS levels would be at higher risk of
cardiovascular mortality within the next 2 yr (74,75),
but this
has not been confirmed (76,77).
Finally, the increase in physical well-being after DHEAS administration reported
by
some authors (78) was not confirmed by others (79),
but
there is some evidence that DHEAS administration to men
with Addison's disease improves general well-being (80,
81).
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