The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3445-3448
Copyright © 1998 by The Endocrine Society
VIII. Conclusion—Research Design Issues in Examining the Effects of Testosterone Supplementation in Older Men
Shalender Bhasin
Charles R. Drew University of Medicine and Science and
University of California Los Angeles School of Medicine
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Introduction
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Los Angeles, California 90059
THERE IS agreement that testosterone has
anabolic effects under specific experimental paradigms. For instance,
androgens promote nitrogen accretion in castrated males of many
species, women, and boys before puberty (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). Testosterone
supplementation has been shown by a variety of methods, including
dual-energy X-ray absorptiometry, underwater weighing, magnetic
resonance imaging, deuterium water dilution method, and measurements of
creatinine excretion, to augment lean body mass in healthy, hypogonadal
men (13, 14, 15, 16). Superphysiological doses of testosterone, when
administered to eugonadal men, further increase fat-free mass, muscle
size, and strength (17, 18, 19, 20, 21). However, the important issue that remains
unanswered is whether physiologic testosterone replacement can produce
clinically meaningful improvements in muscle function without
significant adverse consequences in frail, older men (22, 23, 24, 25). Only a
handful of older men have been treated with testosterone under rigorous
experimental conditions. Also, there are some inherent difficulties and
limitations in the design and conduct of androgen studies in older men
that have confounded interpretation of data in this field (6).
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Uncertainty over efficacy criteria
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Several short-term studies have demonstrated that replacement
doses of testosterone increase fat-free mass in older men with
relatively low testosterone levels. However, the magnitude of the
increase in older men has been small. For instance, Sih et
al. (23) did not find any significant change in fat-free mass by
bioelectrical impedance. Tenover (24) reported a mean increase of 1.9
kg in fat-free mass measured by under water weighing. The reasons for
the differences between the results of these two studies are not
entirely clear, although the sample size of both studies was small,
making them susceptible to both type 1 and type 2 errors. We do not
know if this increase in fat-free mass is clinically meaningful. In
fact, there is considerable debate over what magnitude of change in
fat-free mass after testosterone treatment should be considered
evidence of efficacy. The AIDS Clinical Trial Group Expert Panel has
recommended that, in HIV-infected men, a 1.5 kg increase in fat-free
mass, especially if associated with significant improvement in muscle
function, may be considered evidence of drug efficacy.
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Methods for body composition analysis
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Different investigators have used different methods for body
composition analysis. These methods do not necessarily measure the same
body compartment. Each method uses different algorithms and assumptions
for estimation of fat-free mass (26). Methodolgical differences may
account for some of the inconsistencies in the reported changes in body
composition during testosterone replacement in older men. Many of these
methods for body composition analysis are susceptible to changes in
body water. There is concern that testosterone and other anabolic
agents might produce apparent changes in body composition because of
salt and water retention. Therefore, measurements of total body and
extracellular water, although difficult, are particularly important in
these studies.
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Assessment of muscle function
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Some studies in older hypogonadal men have demonstrated modest
increases in muscle strength (22, 23). However, most of these studies
used grip strength as a measure of muscle function (22, 23). Grip
strength is a highly effort-dependent measure of muscle strength and is
not an optimum marker of frailty in older men. Weakness of the
quadriceps and triceps surae muscle groups contributes to impairments
of gait speed, balance, stair climbing, and rising from a seated
position in the elderly. Therefore, the functional tests should require
significant contributions from muscle groups that are most affected in
age-related functional deficits (27).
Most of the androgen studies in older men have focused entirely on
muscle strength. While strength is an important aspect of muscle
function, it is not the only or the most important determinant of
muscle function. Muscle power, defined as the rate of force
development, at least in the lower extremity is strongly related to
performance of functional activities in the elderly such as rising from
chair, climbing stairs, and for speed in walking. The sarcopenia that
accompanies the aging process is due in large part to the loss of the
fast twitch, type II fibers and the coincident decrease in
explosive force production. Power in the lower extremity can be
assessed by using a leg extensor power "rig," which has been
validated and used safely in people over 90 yr of age.
Muscle fatigability, the capacity to continue exerting muscular effort
while delaying the onset of fatigue, does not deteriorate as rapidly as
strength in sarcopenia; however, higher rates of fatigability affect a
person’s ability to persist in common every day activities such as
walking and stair climbing.
It is also important to correlate changes in muscle strength and power
to functional performance (27). Procedures for several lower extremity
functions have been standardized including stair climbing, the sit to
stand transitions, and walking speed and stride length. However, there
is a pressing need for the development of more sensitive measures of
task performance.
All tests of muscle strength, power, and performance are dependent to
some degree upon subject’s motivation and are susceptible to
volitional factors. Therefore, if testosterone affects motivation, the
men receiving testosterone might perform better in these
effort-dependent tests of muscle function. We need clinically useful,
standardized methods for the assessment of effort-independent muscle
performance.
The prevailing opinion in the sports literature is that androgenic
steroids do not increase exercise endurance (28, 29, 30, 31). In most studies,
measures of aerobic performance did not improve. All involved orally
active drugs in low doses. Serum drug levels were not monitored.
Treatment duration was 6 weeks or less in all but two studies. The
sample size was small, leaving open the possibility that these studies
did not have sufficient power. The outcome measures were maximal tests,
and in most cases the exercise modalities were highly motivation- and
strategy-dependent (e.g. step tests, swimming time). This issue needs
further examination using an improved experimental design and
effort—independent measures of aerobic performance.
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Other outcomes
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The health-related quality-of-life instruments are being
increasingly used in clinical trials to assess the impact of
interventions. However, the existing instruments are relatively
insensitive and are able to detect only large changes. There is a
paucity of reliable, precise, and sensitive instruments that can
measure mood, energy, sense of well being, and the impact of
interventions on the utilization of health care resources.
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Subject selection
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The published and ongoing studies of androgen replacement have
preferentially recruited healthy, older men with low testosterone
levels (22, 23, 24, 25). The subset of older men that needs these anabolic
interventions the most, namely the frail elderly, and the
"oldest-old," have not been studied. We do not know whether the
conclusions drawn from studies in healthy, older men will be uniformly
applicable to frail, chronically ill patients. Most of the published
studies have included older men of a relatively narrow age-range. There
is also a need for longitudinal and intervention studies in older men
of a variety of ages (27), with and without significant functional
impairments.
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The dose issues
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All the ongoing clinical trials have used a fixed dose of
testosterone. If these ongoing trials demonstrate an augmentation of
lean body mass by replacement doses of testosterone, the question of
what is an optimum replacement dose of testosterone will still not be
answered. On the other hand, if these studies fail to demonstrate
significant increases in lean body mass, it would remain unclear if the
failure to demonstrate significant effects resulted from inadequate
dose of testosterone or from the inclusion of men with low normal
testosterone levels. It could be argued that older men with lower
testosterone levels in the hypogondal range might have benefited.
Studies to determine the testosterone dose-dependency of various
androgen-dependent physiological processes are highly desirable
(32, 33).
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Study duration
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Most of the studies of androgen replacement in older men have been
of short duration (22, 24, 25). The longest study administered
testosterone for 1 yr (23). Several long-term studies are currently in
progress; however, at present we do not know whether testosterone’s
anabolic effects in older men can be sustained over long periods
without side effects. It is also not clear whether the anabolic effects
persist after discontinuation of testosterone administration.
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Mechanisms of testosterone-induced muscle hypertrophy
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The biochemical processes that mediate testosterone’s anabolic
effects on the muscle are not well understood. Although the prevailing
dogma is that androgens produce muscle hypertrophy, the possibility
that testosterone- induced increase in muscle size might be due in
part to muscle hyperplasia, has not been fully excluded. There is
agreement that testosterone selectively stimulates fractional muscle
protein synthesis rates (13:20). However, most of the studies of
protein dynamics have been performed under fasting conditions; it
is possible that the magnitude of the observed changes might be
different under fed state. Urban et al. (20) have proposed
that the increase in muscle protein synthesis is brought about by
stimulation of the muscle IGF-1 and a downregulation of its binding
protein IGFBP-4. Androgen receptors in the muscle are similar to those
in other tissues; however, it is not clear whether the anabolic effects
of supraphysiologic doses of androgenic-steroids are mediated through
an androgen-receptor pathway. The speculation that pharmacologic doses
of androgens may act through an androgen receptor-independent
mechanism, perhaps through an anti-glucocorticoid effect, remains to be
tested. The receptor binding studies predict that maximal effects of
testosterone should be manifest at levels that correspond to the lower
end of the normal male range (34, 35, 36). Therefore, it is possible that
the anabolic effects of supraphysiologic doses might be mediated
through androgen-receptor independent mechanisms; the possibility that
at high doses testosterone might act through nonclassical receptors has
not been excluded. The precise molecular mechanisms that mediate
age-related sarcopenia or androgen-induced muscle hypertrophy are not
known. Testosterone-induced muscle genes that mediate muscle
hypertrophy might have therapeutic applications in sarcopenic
states.
Data from experimental animals (37, 38) suggest that testosterone may
modulate neuromuscular transmission; this issue has not been examined
in humans.
We do not know if the anabolic effects of testosterone require its
conversion to dihydrotestosterone by 5-alpha-reductase. Although there
is a small amount of 5-alpha-reducatase activity within the muscle,
5-alpha reduction does not appear to be obligatory for mediating
androgen effects on the muscle. For instance, patients with benign
prostatic hypertrophy who have been treated with the 5-
alpha-reductase inhibitor finasteride do not experience muscle
wasting. Similarly, patients with congenital deficiency of 5-alpha
reductase enzyme have normal muscle mass. There has been some recent
interest in exploring the anabolic effects of dihydrotestosterone in
older men. Because this androgen cannot be aromatized, there is concern
that administration of exogenous dihydrotestosterone may produce
osteopenia because of suppression of endogenous testosterone, the
precursor for estrogen in men.
Testosterone’s effects on the muscle may be modulated by genetic
factors, GH secretory status, nutritional intake, exercise, and
myostatin levels (39). The interactions of these muscle growth
regulators have not been studied.
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Introduction
Uncertainty over efficacy...
