The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:M1002-M1008 (2003)
© 2003 The Gerontological Society of America
Testosterone Supplementation for Aging-Associated Sarcopenia
Shalender Bhasin
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University, Los Angeles, California.
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Abstract
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Aging of humans is associated with a loss of muscle mass and function, and an increase in fat mass. Epidemiologic studies have demonstrated a correlation between bioavailable testosterone concentrations and fat-free mass and muscle strength. Testosterone replacement in older men with low testosterone levels increases fat-free mass and muscle strength, and decreases fat mass. However, we do not know whether testosterone replacement improves physical function and other health-related outcomes, or reduces the risk of disability, falls, or fractures in older men with low testosterone levels. The long-term risks and benefits of testosterone supplementation in older men are not known.
AS humans grow older, their muscle mass decreases and fat mass increases (1–3). Aging-associated sarcopenia is an important public health problem that contributes to impaired physical function (4–6) and increased risk of falls, fractures (1,3), dependency, and death; therefore, anabolic interventions that reverse or prevent aging-related sarcopenia are desirable. The rationale for the use of anabolic therapies, such as growth hormone, testosterone, or insulin-like growth factor (IGF)-I, is based on the premise that anabolic therapies, through alterations in intramuscular gene expression, increase muscle mass, and that increased muscle mass would translate into improved muscle performance. It is further assumed that improved muscle performance would improve measures of physical function and health-related outcomes, resulting in decreased physical dependency, improved health perceptions, decreased risk of falls and fractures, and mortality. Previous studies have demonstrated unequivocally that testosterone increases muscle mass (7–17). Testosterone-induced increases in muscle mass are associated with improvements in maximal voluntary strength and leg power (18,19), but we do not know whether these improvements in muscle mass, muscle strength, and leg power translate into improvements in physical function or health-related outcomes. The effects of testosterone supplementation on quality of life, falls, fractures, or mortality are unknown.
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AGE-RELATED CHANGES IN SERUM TESTOSTERONE LEVELS
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Until recently, considerable controversy prevailed on whether testosterone levels are significantly lower in older men who are free of illness, disability, and medications that alter reproductive endocrine function. However, a number of cross-sectional (20–35) and longitudinal (36–40) studies have now demonstrated convincingly that testosterone levels decrease with normal aging, even when taking into account the confounding influences of sampling time, chronic illness, multiple medications, and assays. In the Massachusetts Male Aging Study (22,40), which was a cross-sectional as well as longitudinal survey of middle-aged men in a New England town, at least 4% of asymptomatic men, aged 40–70 years, had severe androgen deficiency as indicated by testosterone concentrations less than 150 ng/dL in association with elevated luteinizing hormone concentrations, indicative of primary testicular dysfunction. Therefore, it is likely that the prevalence of low androgen levels, defined solely in terms of testosterone concentrations, is substantially higher. Cross-sectional and longitudinal data from Harman and colleagues (23,41) on relatively healthy men in the Baltimore Longitudinal Study of Aging demonstrated unequivocally that testosterone concentrations are not only lower in older men, but that they decline progressively with aging, beginning in the third decade of life. Because sex hormone-binding globulin (SHBG) concentrations are higher in older men (22,31,42), free testosterone concentrations decline to an even greater degree than the total testosterone concentrations. The prevalence of androgen deficiency, defined solely as serum testosterone levels below the lower limit of normal for healthy young men, increases with advancing age from 5%–20% in the sixth decade to 40%–90% of men aged over 80.
Low testosterone concentrations are associated with decreased fat-free mass (FFM) in healthy hypogonadal men compared with human adult controls (43). Mauras and colleagues (44) demonstrated that lowering serum testosterone concentrations in healthy volunteers by administration of a gonadotropin-releasing hormone (GnRH) agonist decreases FFM, muscle strength, and fractional muscle protein synthesis. In epidemiological studies (45), low bioavailable testosterone concentrations are associated with low FFM (41,46), low appendicular skeletal muscle mass (3,47,48), and decreased strength of knee extension (46).
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ANABOLIC EFFECTS OF ANDROGENS
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The idea that androgens have anabolic effects is not new. Since the early observations of Kochakian (49,50) that testosterone increases nitrogen retention in castrated males of many mammalian species, there has been controversy as to whether increasing testosterone concentrations in eugonadal men above the normal range might have anabolic effects. Many athletes believe fervently that androgenic steroids increase muscle mass, strength, and athletic performance, and that higher doses are associated with greater gains in muscle mass and strength. Some athletes and recreational body builders take huge doses of androgenic steroids and "stack" multiple steroids. Athletes also believe that androgenic and anabolic activities of androgens can be dissociated. The academic view until the 1990s was diametrically opposite to the beliefs of the athletic community. The expert opinion was that replacement doses of testosterone had anabolic effects in hypogonadal men and prepubertal boys, but that testosterone doses that raised serum testosterone concentrations above the normal range did not produce further anabolic effects (51). This concept was based in part on in vitro observations that androgen receptors in humans were fully saturated at testosterone concentrations near the lower end of the normal male range (i.e., about 300 ng/dL). It is indeed ironic that recent studies of testosterone supplementation in humans have proven many of these deeply held academic views on the anabolic effects of androgens to be incorrect (8,52).
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EFFECTS OF TESTOSTERONE REPLACEMENT IN HEALTHY YOUNG HYPOGONADAL MEN
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Administration of replacement doses of testosterone to young, hypogonadal men is associated with increases in muscle mass and reductions in fat mass (7,9–11,13). Testosterone replacement also increases maximal voluntary strength in young, hypogonadal men in proportion to the increase in muscle mass (7,11). Physiologic replacement doses of testosterone increase fractional muscle protein synthesis in hypogonadal men (9).
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EFFECTS OF A SUPRAPHYSIOLOGIC DOSE OF TESTOSTERONE ON FFM, MUSCLE SIZE, AND MUSCLE STRENGTH
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When exercise stimulus and energy and protein intake are standardized, administration of a supraphysiologic dose of testosterone (600 mg of testosterone enanthate weekly, about 6 times the replacement dose) to healthy eugonadal men with prior weight-lifting experience produces gains in FFM that are similar to those produced by resistance exercise training alone (15,52). When resistance exercise training and testosterone are combined, there is an additive effect on FFM, muscle size, and strength. In addition, testosterone administration is associated with increases in quadriceps cross-sectional area and volume. Supraphysiologic doses of testosterone given to eugonadal men also produce gains in maximal voluntary strength.
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TESTOSTERONE REPLACEMENT INCREASES FFM, BODY WEIGHT, AND MUSCLE STRENGTH IN MEN WITH CHRONIC ILLNESS AND LOW TESTOSTERONE LEVELS
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Testosterone replacement of men with HIV infection (53–55) or chronic obstructive lung disease is associated with significant gains in lean body mass, muscle size, and muscle strength. In one study, HIV-infected men with lower testosterone concentrations who had lost between 5% and 15% of their body weight in the preceding 6 months were randomized to receive a replacement dose of testosterone or placebo with or without a program of resistance exercise (54). Testosterone administration alone was associated with about a 2.3-kilogram gain in FFM, similar to that produced by resistance training exercise without testosterone. Testosterone administration and resistance exercise training were each associated with significant gains in leg press strength. However, the effects of the two interventions were not additive in this study. In men with chronic obstructive lung disease with low testosterone concentrations, a replacement dose of testosterone produced approximately a 2.5-kilogram gain in FFM and significant increases in maximal voluntary strength.
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TESTOSTERONE DOSE–RESPONSE RELATIONSHIPS IN HEALTHY YOUNG MEN
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The range of normal testosterone concentrations in healthy men is wide, extending from approximately 300 ng/dL to 1200 ng/dL. Most of the previous studies of testosterone supplementation in healthy older men have used relatively low doses of testosterone for replacement and raised testosterone concentrations only into the lower end of the normal range. We asked whether it is desirable to raise testosterone concentrations into the high end of the normal range, and whether this can be done safely. Might dose response curves differ for plasma lipids, other cardiovascular risk factors, and for anabolic effects? If so, can one achieve clinically significant gains in muscle mass without affecting cardiovascular risk factors? Finally, we wished to know whether testosterone dose–response relationships are different in older versus younger men. In particular, are older men less sensitive to the effects of androgens?
Healthy young men, aged 18–35 years, were randomized to 1 of 5 treatment groups (8), all receiving GnRH agonist to suppress their endogenous testosterone production, and 1 of 5 different doses of testosterone enanthate ranging from a subphysiologic (25 mg weekly) up to a clearly supraphysiologic dose (600 mg weekly); treatment duration was 20 weeks. Exercise stimulus and energy and protein intake were clamped. Administration of graded doses of testosterone enanthate in GnRH agonist-treated men was associated with a dose-dependent change in serum total and free testosterone concentrations (Figure 1). The 25 mg dose was associated with serum T concentrations of about 250 ng/dl, which was a lower testosterone concentration than observed at baseline, 50 mg doses gave low normal testosterone concentrations, and higher doses produced dose-dependent increments in serum testosterone concentrations. These results were in conformity with our predicted model (8).
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Figure 1. Nadir serum testosterone concentrations in healthy young men treated with a long-acting gonadotropin-releasing hormone (GnRH) agonist and graded doses of testosterone enanthate (TE) (from Ref. 8). Serum testosterone concentrations were measured during week 16, 7 days after the previous testosterone injection
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We measured FFM by underwater weighing, dual X-ray absorptiometry, bioelectrical impedance, anthropometry, and deuterium water dilution. By underwater weighing, the 25 mg dose was associated with approximately a 1 kg loss of FFM. The 50 mg dose maintained FFM at baseline levels, and higher doses were associated with dose-dependent increments in FFM (Figure 2). There was a high degree of correlation between testosterone dose, total and free testosterone concentrations, and the gains in FFM. Similarly there were high correlations between testosterone dose or steady-state testosterone concentrations and gains in leg press strength and leg power (19). Interestingly, testosterone dose was inversely correlated with change in fat mass, with the lower doses that decreased testosterone concentrations associated with gains in fat mass and higher doses with loss of fat mass. The loss of fat mass was equally distributed between the trunk and the appendices. Also, in the appendices, as in the abdomen, the loss was proportionate between the superficial compartment and the deep compartment. Intramuscular fat as measured by magnetic resonance imaging decreased to about the same extent as did the subcutaneous fat and superficial and soft tissue fat. The visceral fat volume also decreased at high doses of testosterone (8). Plasma high-density lipoprotein (HDL) cholesterol concentrations were inversely related to testosterone dose and concentration, but significant decreases in HDL were seen only at the highest testosterone dose. Apolipoprotein (apo)-A1 decreased, apo-B and apo-CIII did not change. Insulin sensitivity, an important determinant of cardiovascular risk, measured by the insulin sensitivity index or glucose disposal index in frequently sampled intravenous glucose tolerance tests using the Bergman minimal model, did not change at any of the doses tested (56). Prostate-specific antigen (PSA) levels also did not change significantly in any group, nor did PSA levels differ significantly among groups. The absolute changes in PSA levels were very small. Measures of sexual function also did not change at any of the doses, consistent with our previous data in animals and in humans, that sexual function is maintained at serum testosterone concentrations that are at the lower end of the normal male range. Leg power, hemoglobin, red cell count, and serum IGF-I concentrations were all correlated directly with testosterone dose and concentrations, whereas SHBG level was inversely related. Scores on Young's manic scale, Beck's depression scale, and C-reactive protein did not change significantly at any dose (8).
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Figure 2. Change in fat-free mass (FFM), measured by underwater weighing during treatment with a long-acting gonadotropin-releasing hormone (GnRH) agonist and graded doses of testosterone enanthate (TE) (from Ref. 8)
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Using a multivariate analytic model, we evaluated the baseline characteristics that predict variation in response to testosterone administration (58). Testosterone dose, testosterone concentration, and age together accounted for over 78% of the variance in response. Testosterone dose alone explained 70% of the variance. Surprisingly, polyglutamine and polyglycine track lengths in exon 1 of the androgen receptor gene were not significant predictors in this model; we therefore conclude that their impact in determining the response to androgen administration is relatively small (58).
These data demonstrate that testosterone increases FFM, in a dose-dependent and concentration-dependent manner, and that different androgen-dependent processes, such as sexual function and anabolic effect on the muscle, have different dose–response relationships. We also predict that there will be a family of dose–response curves around a genetically determined set point that are modulated by the ambient status of other muscle growth regulators such as growth hormone, nutritional factors, mediators of inflammatory response, glucocorticoid status, as well as the status of physical activity and exercise. The Leydig cell clamp model used in our dose–response study provides an ideal experimental system to test the effects of these growth modulators. We are also intrigued by our data, in that there was considerable variability within each dose group between different individuals in terms of their anabolic response.
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MECHANISMS OF ANDROGEN ACTION ON THE MUSCLE
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The mechanisms by which testosterone increases muscle mass are not well understood. The prevalent hypothesis for which there is substantial support is that testosterone stimulates muscle protein synthesis. Testosterone supplementation has been shown to increase muscle protein synthesis in young hypogonadal men (9) and older men (59,60). This is consistent with Kochakian's observations 50 years ago that testosterone increases nitrogen retention (50). Indeed, muscle hypertrophy could not occur without an increase in muscle protein synthesis. However, several recent observations suggest that changes in muscle protein synthesis may not be the primary event in mediating androgen-induced muscle hypertrophy.
To determine whether testosterone-induced increase in muscle mass is a result of muscle fiber hypertrophy or hyperplasia, we obtained muscle biopsies from vastus lateralis muscle before and after 20 weeks of treatment in the men participating in our dose–response study. We found that testosterone increases cross-sectional areas of both type I and type II muscle fibers (Figure 3), and that the increments in fiber cross-sectional areas are correlated with testosterone dose and concentration (57). There was no change in either the absolute number or the relative proportion of type I and type II fibers. There was a dose- and concentration-dependent increase in the myonuclear number (57). The increase in myonuclear number was proportional to the increment in muscle fiber cross-sectional area. A large body of evidence suggests that myonuclei are contributed by fusion of satellite cells with existing fibers. Therefore, we hypothesized that there would be an increase in satellite cell number. Indeed, when we counted satellite cells using electron microscopy, we found that there was a dose–dependent increase in satellite cell number. These findings support the hypothesis that testosterone increases satellite cell number, which in turn mediates muscle fiber hypertrophy and changes in myonuclear number.
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Figure 3. Change in cross-sectional areas of type I and type II muscle fibers in men treated with a long-acting gonadotropin-releasing hormone (GnRH) agonist and graded doses of testosterone enanthate (TE) (from Ref. 56)
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The molecular mechanisms by which androgen administration produces an increase in satellite cell number are not well understood. Possibilities include inhibition of satellite cell apoptosis, increase in satellite cell replication, or an increased rate of differentiation of progenitor cells into satellite cells. Initial studies suggest that testosterone promotes the differentiation of mesenchymal pluripotent cells into the myogenic lineage and inhibits the differentiation of these cells into the adipogenic lineage (61). This hypothesis provides a unifying explanation for testosterone's reciprocal effects on muscle and fat mass.
A number of studies have investigated the effects of testosterone replacement in older men with low or low normal testosterone concentrations (12,14,59,60,62–64). It is important to recognize that, in all of these studies, the men that were recruited were relatively healthy and had testosterone concentrations that were either low normal or just below the lower limit of the normal male range. It is also notable that the doses of testosterone used in these studies, especially in studies that used the patch, were relatively low and produced modest increments in testosterone concentrations. Therefore, it is not surprising that the gains in FFM were also modest. These studies in older men are in general agreement that testosterone supplementation increases lean body mass and decreases fat mass. Some of the studies have shown that testosterone supplementation increases grip strength. However, these studies have not shown an increase in quadriceps strength, which is a major determinant of fall propensity. Most of the prior studies did not measure physical function, and the investigators who did examine this issue found that the perception of physical function, assessed by questionnaire, did not differ between the testosterone-treated and placebo-treated men (12). However, the men who had the lowest testosterone concentrations at baseline (being therefore clearly hypogonadal) and who presumably had the greatest increments in testosterone concentrations appeared to have significant increases in their perception of physical function (12). The issue of physical function is really at the heart of the question of efficacy of androgen supplementation in older men. These previous studies were not designed to examine objective measures of physical function or any other health-related outcome. However, a recent pilot study evaluated the effects of testosterone supplementation on rehabilitation outcomes in a geriatric evaluation and management unit (65). In these men, admitted to a Veterans Affairs rehabilitation unit and randomized to receive placebo or a replacement dose of testosterone for 12 weeks, testosterone supplementation produced greater improvements in functional independence measures and grip strength than placebo.
It is important to ask why studies in elderly men to date have failed to demonstrate improvements in muscle strength and physical function. Very few studies have looked at these issues, and the ones that did had methodological problems. Most of these studies included men whose testosterone concentrations were low normal. Low doses of testosterone used produced relatively small increments in testosterone concentrations. Most of the studies failed to control for the compounding influence of the learning effect. These studies used measures of physical function that are susceptible to floor and ceiling effects. For example, a commonly used measure in studies of anabolic therapies has been the sit-to-stand transition. However, sitting up from a chair requires less than 25%–30% of maximal voluntary strength, whereas most healthy older men or relatively stable HIV-infected young men have baseline quadriceps strength that is well above this threshold. Thus, one would not expect these individuals to show either impairment in this measure of physical function at baseline or to demonstrate improvements after testosterone or other anabolic interventions. Therefore, it is critical for future studies of older men to develop measures of physical function that are independent of floor and ceiling effects, and to show them to be androgen responsive in hypogonadal men.
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ROLE OF 5-ALPHA-REDUCTASE IN MEDIATING ANDROGEN EFFECTS ON MUSCLE
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Another important issue from the perspective of developing selective androgen receptor modulators as anabolic agents relates to whether 5-alpha reduction of testosterone to dihydrotestosterone (DHT) is obligatory for mediating its anabolic effects. One of the concerns about giving testosterone to older men has been whether it would increase the risk of prostate disease. Testosterone effects on the prostate require its conversion to DHT. If 5-alpha reduction of testosterone were not obligatory for mediating its anabolic effects, it would be highly desirable to develop congeners of androgens that are not 5-alpha reduced or give androgens in conjunction with a 5-alpha reductase inhibitor. There are two lines of evidence that suggest that 5-alpha reduction of testosterone to DHT is not required for mediating its anabolic effects on the muscle. First, males in families with a genetic 5-alpha reductase deficiency develop normal muscle mass at puberty. Second, men taking finasteride for benign prostatic hypertrophy or androgenic alopecia do not undergo muscle wasting. These models are not conclusive because all the kindreds that have been described to date have had mutations of only the type 2 5-alpha reductase isoform. Similarly, finasteride is a weak inhibitor of type 2 5-alpha reductase. Thus, it still remains unclear whether reduction of testosterone to 5-alpha DHT is necessary for mediating anabolic effects.
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POTENTIAL RISKS OF TESTOSTERONE SUPPLEMENTATION IN OLDER MEN
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Replacement doses of testosterone given over short time periods of months to young hypogonadal men are known to be safe. However, in older individuals, there is concern about testosterone effects on the risk of prostate and cardiovascular diseases (66–68). Testosterone can induce and exacerbate sleep apnea probably by direct effects on neuromusculature of the upper airway. Testosterone increases red cell mass, which may lead to erythrocytosis, can cause transient fluid retention, and may produce gynecomastia. However, from the public health perspective, the two major issues are whether testosterone supplementation increases the risks of prostate and cardiovascular disease.
There is general agreement that testosterone does not directly cause either benign prostatic hypertrophy or prostate cancer. However, many older men dying of other causes have microscopic foci of prostate cancer. How many of these foci will spontaneously become clinically overt is largely unknown. Because prostate cancer is an androgen-responsive neoplasm, there is concern that these microscopic foci of cancer might be exacerbated by androgen administration in older men (68). Serum PSA levels are lower in androgen-deficient men and increase in response to androgen administration. Testosterone supplementation will lead to more intensive monitoring with many more PSA levels being done. This, in turn, will lead to more biopsies and hence diagnosis of many more subclinical cancers. Large prospective studies of testosterone replacement in older men are needed to determine its long-term risks. To detect a 30% increment in prostate cancer incidence rates, 6000 to 8000 individuals will need to be randomized and treated with either placebo or testosterone for 5 to 7 years (68).
There are no data that show that testosterone given in replacement doses to older men with low testosterone concentrations increases risk of cardiovascular disease, although this is an issue of enormous public health importance. In young hypogonadal men, testosterone can lower HDL by approximately 5%–10%. Alexandersen and colleagues, in a meta-analysis of about 30 published studies, concluded that testosterone levels are lower in men with coronary artery disease than in men without coronary artery disease (69). Most studies are also in agreement, that testosterone in replacement doses in older men has little or only a modest effect on plasma HDL cholesterol. Some recent studies have shown that testosterone improves coronary blood flow through a direct effect on the vessel wall. Testosterone has been reported to reduce visceral fat and improve insulin sensitivity. In mice that are null for low-density lipoprotein receptor and that have been widely used as an animal model of atherosclerosis, castration accelerates atherogenesis and testosterone supplementation retards atherosclerosis progression. Testosterone effects in retarding atherosclerosis in this animal model are mediated through its conversion to estrogen because these beneficial effects are abrogated when testosterone is given in conjunction with an aromatase inhibitor. Thus, the available data do not support the presumption that testosterone supplementation will increase cardiovascular risk. It seems more likely that testosterone will have neutral or even slightly beneficial effects on atherosclerosis progression. This issue is of enormous public health importance and should be evaluated in prospective clinical studies.
It is remarkable that most models of life span extension are characterized by lower levels of growth factors, growth hormone, and reproductive hormones. Therefore, it would be important to keep an open mind as to what effect administration of testosterone or other hormones might have on life span.
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SYNOPSIS
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Testosterone supplementation, in a variety of clinical and experimental paradigms, increases FFM and maximal voluntary strength and leg power and decreases fat mass. The testosterone effects on the muscle are dose- and concentration-dependent. Testosterone induces muscle fiber hypertrophy by promoting myogenesis, probably via an increase in satellite cell number, and inhibiting adipogenesis. Different androgen-dependent processes appear to have different dose–response relationships, so that it may be possible to achieve clinically meaningful increments in muscle mass without adversely affecting prostate or cardiovascular risk. We do not know whether testosterone supplementation of older men will improve physical function or whether it will reduce risk of disability, falls, fractures, and other health outcomes. Because studies to date have been in healthy older men, it is unknown whether testosterone has similar anabolic effects in older men with physical impairments or chronic illness or in frail elderly men. The molecular mechanisms by which testosterone stimulates myogenesis are largely unknown and are of potential importance for drug discovery.
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Acknowledgments
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Address correspondence to Shalender Bhasin, MD, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University, 1731 East 120th Street, Los Angeles, CA 90059. E-mail: sbhasin{at}ucla.edu
Received May 8, 2003
Accepted June 16, 2003
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References
|
|---|
- Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol.. 1998;147:755-763.[Abstract/Free Full Text]
- Novak LP. Aging, total body potassium, fat-free mass, and cell mass in males and females between ages 18 and 85 years. J Gerontol A Biol Med Sci.. 1972;27:438-443.
- Melton LJ3, Khosla S, Riggs BL. Epidemiology of sarcopenia. Mayo Clinic Proc.. 2000;75:S10-S13.
- Bassey EJ, Fiatarone MA, O'Neill EF, Kelly M, Evans WJ, Lipsitz LA. Leg extensor power and functional performance in very old men and women. Clin Sci.. 1992;82:321-327.[Medline]
- Whipple RH, Wolfson LI, Amerman PM. The relationship of knee and ankle weakness to falls in nursing home residents: an isokinetic study. J Am Geriatr Soc.. 1987;35:13-20.[Medline]
- Wolfson L, Judge J, Whipple R, King M. Strength is a major factor in balance, gait, and the occurrence of falls. J Gerontol A Biol Med Sci.. 1995;50:64-70.
- Bhasin S, Storer TW, Berman N, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab.. 1997;82:407-413.[Abstract/Free Full Text]
- Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab.. 2001;281:E1172-E1181.[Abstract/Free Full Text]
- Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab.. 1996;81:3469-3475.[Abstract]
- Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypergonadism. J Clin Endocrinol Metab.. 1996;81:4358-4365.[Abstract]
- Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab.. 2000;85:2839-2853.[Abstract/Free Full Text]
- Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab.. 1999;84:2647-2653.[Abstract/Free Full Text]
- Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab.. 2000;85:2670-2677.[Abstract/Free Full Text]
- Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab.. 1992;75:1092-1098.[Abstract]
- Young NR, Baker HW, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab.. 1993;77:1028-1032.[Abstract]
- Strawford A, Barbieri T, Neese R, et al. Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss. J AIDS.. 1999;20:137-146.
- Strawford A, Barbieri T, Van Loan M, et al. Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial. JAMA.. 1999;281:1282-1290.[Abstract/Free Full Text]
- Bhasin S, Woodhouse L, Storer TW. Proof of the effect of testosterone on skeletal muscle. J Endocrinol.. 2001;170:27-38.[Abstract]
- Storer TW, Magliano L, Woodhouse L, Casaburi R, Bhasin S. Testosterone dose-dependently increases muscle strength and leg power, but not specific tension in healthy, young men. J Clin Endocrinol Metab. In press.
- Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab.. 1983;56:1278-1281.[Abstract]
- Davidson JM, Chen JJ, Crapo L, Gray GD, Greenleaf WJ, Catania JA. Hormonal changes and sexual function in aging men. J Clin Endocrinol Metab.. 1983;57:71-77.[Abstract]
- Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab.. 1991;73:1016-1025.[Abstract]
- Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab.. 2001;86:724-731.[Abstract/Free Full Text]
- Harman SM, Tsitouras PD, Costa PT, Blackman MR. Reproductive hormones in aging men. II. Basal pituitary gonadotropins and gonadotropin responses to luteinizing hormone-releasing hormone. J Clin Endocrinol Metab.. 1982;54:547-551.[Abstract]
- Harman SM, Tsitouras PD. Reproductive hormones in aging men. I. Measurement of sex steroids, basal luteinizing hormone, and Leydig cell response to human chorionic gonadotropin. J Clin Endocrinol Metab.. 1980;51:35-40.[Abstract]
- Morley JE, Kaiser F, Raum WJ, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. PNAS.. 1997;94:7537-7542.[Abstract/Free Full Text]
- Murono EP, Nankin HR, Lin T, Osterman J. The aging Leydig cell: VI. Response of testosterone precursors to gonadotrophin in men. Acta Endocrinologica (Copenhagen).. 1982;100:455-461.
- Nankin HR, Calkins JH. Decreased bioavailable testosterone in aging normal and impotent men. J Clin Endocrinol Metab.. 1986;63:1418-1420.[Abstract]
- Nieschlag E, Lammers U, Freischem CW, Langer K, Wickings EJ. Reproductive functions in young fathers and grandfathers. J Clin Endocrinol Metab.. 1982;55:676-681.[Abstract]
- Swerdloff RS, Wang C. Androgen deficiency and aging in men. West J Med.. 1993;159:579-585.[Medline]
- Simon D, Preziosi P, Barrett-Connor E, et al. The influence of aging on plasma sex hormones in men: the Telecom Study. Am J Epidemiol.. 1992;135:783-791.[Abstract/Free Full Text]
- Tenover JS, Matsumoto AM, Plymate SR, Bremner WJ. The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate. J Clin Endocrinol Metab.. 1987;65:1118-1126.[Abstract]
- Vermeulen A. Clinical review 24: androgens in the aging male. J Clin Endocrinol Metab.. 1991;73:221-224.[Medline]
- Vermeulen A, Kaufman JM. Diagnosis of hypogonadism in the aging male. Aging Male.. 2002;5:170-176.[Medline]
- Zumoff B, Strain GW, Kream J, et al. Age variation of the 24-hour mean plasma concentrations of androgens, estrogens, and gonadotropins in normal adult men. J Clin Endocrinol Metab.. 1982;54:534-538.[Abstract]
- Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal Assessment of Serum Free Testosterone Concentration Predicts Memory Performance and Cognitive Status in Elderly Men. J Clin Endocrinol Metab.. 2002;87:5001-5007.[Abstract/Free Full Text]
- Morley JE, Kaiser FE, Perry HMI, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism.. 1997;46:410-413.[Medline]
- Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. Am J Epidemiol.. 1997;146:609-617.[Abstract/Free Full Text]
- Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab.. 1999;84:3681-3685.[Abstract/Free Full Text]
- Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab.. 2002;87:589-598.[Abstract/Free Full Text]
- Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, Metter EJ. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab.. 2002;283:E284-E294.[Abstract/Free Full Text]
- Pirke KM, Doerr P. Age related changes and interrelationships between plasma testosterone, oestradiol and testosterone-binding globulin in normal adult males. Acta Endocrinologica (Copenhagen).. 1973;74:792-800.
- Katznelson L, Rosenthal DI, Rosol MS, et al. Using quantitative CT to assess adipose distribution in adult men with acquired hypogonadism. Am J Roentgenol.. 1998;170:423-427.[Abstract/Free Full Text]
- Mauras N, Hayes V, Welch S, et al. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab.. 1998;83:1886-1892.[Abstract/Free Full Text]
- Morley JE, Baumgartner RN, Roubenoff R, Mayer J, Nair KS. Sarcopenia. J Lab Clin Med.. 2001;137:231-243.[Medline]
- Perry HM, III, Miller DK, Patrick P, Morley JE. Testosterone and leptin in older African-American men: relationship to age, strength, function, and season. Metabolism.. 2000;49:1085-1091.[Medline]
- Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev.. 1999;107:123-136.[Medline]
- Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol Med Sci.. 2002;57A:M772-M777.[Abstract/Free Full Text]
- Kochakian CD. History, chemistry and pharmacodynamics of anabolic-androgenic steroids. Wien Med Wochenschr.. 1993;143:359-363.[Medline]
- Kochakian CD. Comparison of protein anabolic proerties of various androgens in the castrated rat. Am J Physiol.. 1950;60:553-558.
- Wilson JD. Androgen abuse by athletes. Endocrine Rev.. 1988;9:181-199.[Medline]
- Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med.. 1996;335:1-7.[Abstract/Free Full Text]
- Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metabol.. 1998;83:3155-3162.[Abstract/Free Full Text]
- Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA.. 2000;283:763-770.[Abstract/Free Full Text]
- Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med.. 1998;129:18-26.[Abstract/Free Full Text]
- Singh AB, Hsia S, Alaupovic P, et al. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin Endocrinol Metab.. 2002;87:136-43.[Abstract/Free Full Text]
- Sinha-Hikim I, Artaza J, Woodhouse L, et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab.. 2002;283:E154-E164.[Abstract/Free Full Text]
- Woodhouse LJ, Reisz-Porszasz S, Javanbakht M, et al. Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab.. 2003;284:E1009-E1017.[Abstract/Free Full Text]
- Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab.. 2002;282:E601-E607.[Abstract/Free Full Text]
- Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol.. 1995;269:E820-E826.
- Taylor WE, Bhasin S, Singh R, Artaza J, Gonzalez-Cadavid NF. Testosterone promotes myogenesis in pluripotent mesenchymal cells. Endocrine Society National Abstracts, 84th Annual Meeting. 2002:432.
- Morley JE, Perry HM, III, Kaiser FE, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc.. 1993;41:149-152.[Medline]
- Sih R, Morley JE, Kaiser FE, Perry HMI, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab.. 1997;82:1661-1667.[Abstract/Free Full Text]
- Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol Med Sci.. 2001;56A:M266-M272.[Abstract/Free Full Text]
- Bakhshi V, Elliott M, Gentili A, Godschalk M, Mulligan T. Testosterone improves rehabilitation outcomes in ill older men. J Am Geriatr Soc.. 2000;48:550-553.[Medline]
- Bhasin S, Buckwalter JG. Testosterone supplementation in older men: a rational idea whose time has not yet come. J Androl.. 2001;22:718-731.[Medline]
- Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol Med Sci.. 2002;57A:M76-M99.[Free Full Text]
- Bhasin S, Mac P, Singh AB, Carter HB, Lee MI, Cunningham GR. Managing the risk of prostate disease during testosterone administration in older men. J Androl.. 2003;24:299-311.[Free Full Text]
- Alexandersen P, Haarbo J, Chrisiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis.. 1996;125:1-13.[Medline]
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Abstract
Age-Related Changes in Serum...
