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Emory University, School of Medicine Atlanta, Georgia 30329
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Introduction |
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Age-associated alterations in body composition can have effects on metabolism, but the impact of these changes on overall health and function in older men is not clear. For example, aging is associated with a decline in glucose tolerance, but the contribution of increasing abdominal fat stores to glucose intolerance in this age group is unknown. Similarly, the exact relationship between muscle mass and muscle strength in older adults is not straightforward. Like muscle mass, muscle strength declines with aging in both sedentary and endurance trained individuals. Muscle strength, especially maximal strength, correlates with muscle mass at any age (correlation coefficient of 0.79 in one study of subjects older than 65 yr; 2), but decreases more profoundly with advanced age than does muscle mass.
Significant declines with age in muscle mass and strength are strong predictors of functional problems. The clinical correlates of sarcopenia, the age-related loss in skeletal muscle, include falls, fractures, loss of mobility, and development of dependence in basic activities of daily living. Not just muscle strength, but also endurance, power, and task-specific performance are important in maintaining function. Age-related sarcopenia not only affects muscle strength but may also have metabolic consequences. Although yet unproved, these may include a lower basal metabolic rate, abnormal thermoregulation, impaired glucose metabolism, and worsening of osteopenia.
The nitrogen retaining effects of androgens were first described in 1935 in experiments in castrated dogs. Since that time, androgen therapy has been shown repeatedly to increase muscle mass in castrated males from a number of animal species. In humans, testosterone given in replacement doses to hypogonadal young adult men has been shown to increase lean body mass, increase the synthesis of skeletal muscle, increase muscle size, and improve muscle strength. Some studies also have reported a decline in fat mass with testosterone therapy in these young men. Additionally, supraphysiological replacement of testosterone in healthy eugonadal young men has been shown to increase lean body mass, muscle size, and strength, even in the absence of exercise.
For the older man, the questions in regard to testosterone replacement therapy and body composition are multiple. First, with physiological replacement therapy, can clinically meaningful increases in muscle mass and strength be achieved? Second, do older men have the same anabolic and compositional responses to testosterone as do younger men, or are they some how more insensitive to testosterone’s anabolic properties? Third, are there changes in body fat mass that occur with physiological testosterone replacement in older men and, if so, are these of such magnitude that metabolic consequences result (such as decreased insulin resistance).
In regard to the first question as to whether clinically meaningful changes in muscle mass and strength occur with testosterone therapy, the goal is NOT to produce an older version of "Mr. Universe" or an olympic athlete, but rather to have the older man maintain or improve strength so that his functional capacity can be maximized. These are not easy endpoints to demonstrate, and an increase in muscle mass with therapy may not necessarily lead to a meaningful increase in muscle strength, and an increase in muscle strength may not directly translate into a significant improvement in functional status.
To date, there have been no studies on the effects of testosterone replacement therapy in chronically diseased or frail older men, and studies involving physiological replacement dosing of testosterone in healthy older (>50 yr) men are limited; the total number of older men treated in all published studies combined is somewhat less than 75, and the length of therapy has varied from 1 to 18 months. The results from these testosterone replacement studies in older men, however, have been consistent; reported are treatment-related declines in body fat mass ranging from 6.4% to 14%, and increases in lean mass ranging from 3.2% to 5.0% (3). One additional study, involving testosterone therapy in older, abdominally obese men, noted a mean 9.1% decline in visceral fat mass with a concomitant decline in fasting blood glucose concentrations (4). There are several completed but as yet unpublished studies involving 3 years of testosterone replacement in older men. Preliminary data from one of these studies suggests that lean body mass may increase as much as 8%, while body fat decreases 17%, in men on testosterone therapy (Tenover JL, unpublished results). When comparing the scope of body compositional effects of testosterone therapy in the older men with those noted in replacement therapy in hypogonadal young men, the magnitude of the fat mass changes appear similar, while the lean body mass changes are less dramatic in the older men. This issue, however, has not been fully explored, and more data, especially as regards the dose-response of muscle to the anabolic actions of androgens with age, are needed.
In terms of strength changes, six out of seven studies that have evaluated strength in older men on testosterone replacement have demonstrated a statistically significant increase in strength with therapy (3, 5). Most of these studies have been blinded and placebo-controlled, but most also have used grip strength as the primary strength measure; only two studies, involving fewer than 15 men in all, have evaluated lower extremity strength. No published studies have yet evaluated functional performance in response to testosterone therapy.
Overall, although the data on the body compositional changes, strength improvements, and metabolic consequences of testosterone replacement therapy in older men are limited, testosterone therapy appears to hold some promise for beneficial effects for this age group. More study needs to be done to address the many unknowns in this arena.
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