Age-Associated Sarcopenia—Issues in the Use of Testosterone as an Anabolic Agent in Older Men

Shalender Bhasin and Joyce S. Tenover

Charles R. Drew University of Medicine and Science Los Angeles, California Wesley Woods Geriatric Hospital Emory University Atlanta, Georgia

Address correspondence and requests for reprints to: Shalender Bhasin, M.D., Professor of Medicine, and Chief, Charles R. Drew University of Medicine and Science, 1621 E. 120th Street, Los Angeles, California 90059.


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 Introduction
 References
 
Sarcopenia in old age has been targeted as a major area of research by the National Institute of Aging in recognition of its importance as a significant public health problem (1, 2). The hypothesis that older men are hypogonadal and that testosterone replacement might reverse or prevent age-related sarcopenia is being investigated in several ongoing clinical trials. Because of the lack of good biological markers of androgen action, the issue of androgen deficiency and replacement in elderly men remains mired in debate (3, 4). The proponents of testosterone substitution posit that many physiological changes that attend the aging process such as decreased sexual function, osteoporosis, and muscle wasting are substantially attributable to androgen deficiency (3, 4, 5, 6, 7). Further support for this viewpoint is provided by data demonstrating that replacement doses of testosterone increase fat-free mass, muscle size, and strength in healthy, young, hypogonadal men (8), and can augment fat mass and trabecular bone density in middle-aged hypogonadal men (9). The opponents argue that the majority of ambulatory older men have serum testosterone levels within the normal range, even though serum testosterone levels, particularly free or bioavailable testosterone levels, are on average lower in older men than younger men (10). Further adding to the confusion is the uncertainty concerning whether relative insensitivity to testosterone contributes to the physiological changes that attend the aging process. Because a significant proportion of older men have serum testosterone levels that are in the low normal, but not clearly in the hypogonadal range, an age-related relative androgen insensitivity could render them androgen deficient. Indeed, androgen receptor number and affinity are decreased in a number of organs of the aging rat. There has never been a study, however, that directly assessed the sensitivity of older men to the anabolic effects of testosterone. Limited data that do exist suggest that older men have increased rather than decreased sensitivity to gonadotropin suppressing activity of testosterone (11). Thus, although the androgen insensitivity hypothesis might explain some of the age-related changes in body composition and muscle mass, the data supporting a generalized or even a tissue-specific androgen resistance in older men are lacking.

In the absence of clinically useful and practical markers of androgen action, the strategy used by many investigators in the field has been to examine if androgen substitution in older men with low normal or low testosterone levels will improve the physiological derangements that have been attributed to androgen deficiency. In this respect, initial short-term trials (12, 13, 14, 15) provided evidence that replacement doses of testosterone can be administered safely for 4–16 weeks to carefully selected older men with "relative" androgen deficiency. These studies also demonstrated that testosterone replacement produces modest gains in fat-free mass and strength and improves sense of well being in relatively healthy older men with low normal testosterone levels. Improvements in biochemical markers of bone formation and resorption have also been reported. The lack of systemic toxicity in these short term trials encouraged investigators to launch longer-term studies to examine the physiological consequences of testosterone substitution.

The paper by Sih et al. (16) in this issue of JCEM (see page 1661) is important in that this is the first published study on the effects of longer-term testosterone treatment in older men. Similar trials are currently underway in several other centers. These authors examined the effects of testosterone administration in men who were 50 yr of age or older and had bioavailable testosterone levels less than 60 ng/dL with the major goal of assessing upper extremity strength and side effects. The men received either placebo or 200 mg testosterone cypionate by intramuscular injections every 14–17 days. The men given testosterone had greater increases in grip strength and hemoglobin levels and a significant decrease in leptin levels. The treatment regimen produced no significant changes in memory or body composition. Sexual function was not examined. There were no significant changes in serum prostate specific antigen (PSA) levels or digital rectal examination of the prostate.

The demonstration of a lack of significant changes in serum levels of prostate specific antigen or digital rectal examination of the prostate during a 1-yr treatment period is reassuring and has implications for subsequent trials in this field of investigation. Although there is agreement that testosterone does not induce prostate cancer, the concern is that testosterone administration may unmask subclinical microscopic foci of cancer that otherwise might have remained silent. Prostate volumes were not measured in this study, but other studies have shown that testosterone replacement in hypogonadal men, or administration of slightly supraphysiological doses to healthy young men, does not increase prostate size above the physiological range. Considering the long time course for the development of detectable prostate cancer or symptomatic benign prostatic enlargement, resolution of these concerns will require much longer-term studies and a substantially larger sample of older men.

The paper, although precedent-setting in this field, has some shortcomings. The authors used grip-strength as a measure of muscle strength. While improvements in grip strength are encouraging, it is equally important to demonstrate improvements in lower extremity muscle strength, particularly quadriceps strength, which is far more relevant to lower extremity weakness, abnormalities of gait, and falls in older men (1). Although strength is an important determinant of muscle performance, muscle fatigue, power, and task-specific performance are equally if not more important in the context of age-related frailty. Grip strength is highly effort-dependent, and therefore susceptible to potential bias in response to the motivational effects of the intervention. Also, because of the known interaction between androgens and resistance exercise (17), exercise stimulus needs to be controlled. Similarly, it is desirable to standardize the energy and protein intake during the intervention period. These goals are not easy to achieve in free-living, ambulatory individuals. From a public health perspective, it would also be important to include quantitative measures of quality of life, sense of well-being, and economic impact in androgen-intervention studies.

Even after taking into account the difficulties of conducting long-term studies in older men, the high drop out rates in this study are disconcerting. Three men receiving placebo and seven men receiving testosterone discontinued the study prematurely; three out of seven men who dropped out of the testosterone group did so because of marked increases in hemoglobin. It is widely known that testosterone increases red blood cell count and hemoglobin levels, but the magnitude of the increase obtainable in older men has not been readily appreciated. Previous studies of younger men given supraphysiologic doses of testosterone esters have reported only modest or no changes in hemoglobin levels (17), while studies involving older men have often shown more marked increases in these parameters (18, 19). The mechanisms of the age-related differences in hemoglobin response to testosterone are not known. Reassuringly, none of the participants in this current study, including those who experienced marked increases in hemoglobin levels, developed congestive heart failure or exacerbation of hypertension.

The effects of testosterone on leptin are interesting. Testosterone-treated men had lower leptin levels than those assigned to the placebo group. Previous studies (20) have demonstrated lower leptin levels in men than in women. Also, serum leptin levels decline in hypogonadal men given replacement doses of testosterone. These data therefore suggest that testosterone should be added to the list of hormones that regulate circulating leptin levels.

Unlike some previous reports, testosterone had no significant effect on body composition in this study. Because the dose of testosterone used in this study was similar to that employed in previous studies in older men, one reason for the discrepancy between studies might be the difference in the methods used to measure body composition. In the current study, the investigators used bioelectrical impedance, while other studies have used under-water weighing, dual energy x-ray absorptiometry (DEXA) scanning, or total body potassium to evaluate fat and fat-free mass. It also is not known whether higher doses of testosterone might have been able to produce significant increases in fat-free mass and muscle size or greater increases in strength. Unfortunately, the dose-dependency of testosterone’s anabolic effects is not known, and testosterone dose-response studies in older men are sorely needed to optimize the testosterone replacement regimens.

Most of the ongoing studies of testosterone replacement, including the one published in this issue of JCEM (16), have preferentially recruited relatively healthy, older men. Therefore, it still remains to be determined whether androgen replacement in older men with chronic diseases and frailty will improve muscle mass and function.

The authors deserve applause for being the first to demonstrate the feasibility and relative safety of administering replacement doses of testosterone to older men over a 1-yr period. However, several critical issues with respect to the usefulness and long-term safety of androgen-substitution for reversing or preventing sarcopenia and frailty in older men remain unresolved.

Received March 28, 1997.

Accepted April 1, 1997.


    References
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 Introduction
 References
 

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