Sarcopenia, the loss of muscle mass, has emerged as a major public health problem in older men. Because testosterone levels are lower in older men, and its replacement increases fat-free mass in other hypogonadal states, it is being explored as a promising strategy to reverse age-associated loss of muscle mass and function. The proposed studies will address several key questions that will not be answered by the ongoing trials of testosterone replacement and are relevant to the optimization of androgen replacement regimens in older men. First, they will establish a testosterone dose-response curve with fat-free mass, fractional muscle protein synthesis, muscle size and performance, sexual function, insulin sensitivity and plasma lipids as outcome variables. Second they will compare testosterone dose-response curves for each outcome variable in healthy older men to younger men to examine if older men are relatively insensitive to the anabolic effects of testosterone. Third, they will test the hypothesis that testosterone increases fat-free mass primarily by stimulating fractional muscle protein synthesis. Young (19-35 years of age) and relatively healthy older (60-75 years of age) men will randomly receive a long acting GnRH agonist to suppress endogenous testosterone secretion and one of 4 testosterone doses: 25, 50, 25, and 300 mg testosterone enanthate/week; these doses are expected to produce mean nadir testosterone levels of 125, 300, 650, and 1300 ng/dl. Key assessments measured before and at the end of the 20 week treatment period include: 1) fat-free mass by DEXA scan, deuterium water and NaBr dilution; 2) fractional synthesis rates of mixed muscle protein and myosin heavy chain; 3) muscle size and visceral fat by CT scan; 4) muscle strength by the 1-repetition maximum method, power and functional performance in several task-specific tests; 5) sexual function by daily logs of sexual activity and EEG-coupled NPT recording; and 6) insulin sensitivity by the Minimal Model. Blood counts, chemistries, plasma lipids, PSA levels, and periodic rectal examinations will be monitored by a designated Safety Panel. Serum total and free testosterone, and dihydrostestosterone levels will serve as markers of androgen bioavailability. Standardization of energy and protein intake, strict control of the ongoing exercise level, state-of-the-art methods, randomization and careful consideration of power and effect size will help minimize the impact of the potential confounding factors.
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