Although testosterone levels and muscle mass decline with age, many older men have serum testosterone level in the normal range, leading to speculation about whether older men are less sensitive to testosterone. We determined the responsiveness of androgen-dependent outcomes to graded testosterone doses in older men and compared it to that in young men. The participants in this randomized, double-blind trial were 60 ambulatory, healthy, older men, 60-75 yr of age, who had normal serum testosterone levels. Their responses to graded doses of testosterone were compared with previous data in 61 men, 19-35 yr old. The participants received a long-acting GnRH agonist to suppress endogenous testosterone production and 25, 50, 125, 300, or 600 mg testosterone enanthate weekly for 20 wk. Fat-free mass, fat mass, muscle strength, sexual function, mood, visuospatial cognition, hormone levels, and safety measures were evaluated before, during, and after treatment. Of 60 older men who were randomized, 52 completed the study. After adjusting for testosterone dose, changes in serum total testosterone (change, -6.8, -1.9, +16.1, +49.5, and +101.9 nmol/liter at 25, 50, 125, 300, and 600 mg/wk, respectively) and hemoglobin (change, -3.6, +9.9, +20.9, +12.6, and +29.4 g/liter at 25, 50, 125, 300, and 600 mg/wk, respectively) levels were dose-related in older men and significantly greater in older men than young men (each P < 0.0001). The changes in FFM (-0.3, +1.7, +4.2, +5.6, and +7.3 kg, respectively, in five ascending dose groups) and muscle strength in older men were correlated with testosterone dose and concentrations and were not significantly different in young and older men. Changes in fat mass correlated inversely with testosterone dose (r = -0.54; P < 0.001) and were significantly different in young vs. older men (P < 0.0001); young men receiving 25- and 50-mg doses gained more fat mass than older men (P < 0.0001). Mood and visuospatial cognition did not change significantly in either group. Frequency of hematocrit greater than 54%, leg edema, and prostate events were numerically higher in older men than in young men. Older men are as responsive as young men to testosterone's anabolic effects; however, older men have lower testosterone clearance rates, higher increments in hemoglobin, and a higher frequency of adverse effects. Although substantial gains in muscle mass and strength can be realized in older men with supraphysiological testosterone doses, these high doses are associated with a high frequency of adverse effects. The best trade-off was achieved with a testosterone dose (125 mg) that was associated with high normal testosterone levels, low frequency of adverse events, and significant gains in fat-free mass and muscle strength.

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The objective of this study was to determine whether physiological testosterone replacement increases fat-free mass (FFM) and muscle strength and contributes to weight maintenance in HIV-infected women with relative androgen deficiency and weight loss. Fifty-two HIV-infected, medically stable women, 18-50 yr of age, with more than 5% weight loss over 6 months and testosterone levels below 33 ng/dl were randomized into this double-blind, placebo-controlled trial of 24-wk duration. Subjects in the testosterone group applied testosterone patches twice weekly to achieve a nominal delivery of 300 mug testosterone over 24 h. Data were evaluable for 44 women. Serum average total and peak testosterone levels increased significantly in the testosterone group, but did not change in the placebo group. However, there were no significant changes in FFM (testosterone, 0.7 +/- 0.4 kg; placebo, 0.3 +/- 0.4 kg), fat mass (testosterone, 0.3 +/- 0.7 kg; placebo, 0.6 +/- 0.7 kg), or body weight (testosterone, 1.0 +/- 0.9 kg; placebo, 0.9 +/- 0.8 kg) between the two treatment groups. There were no significant changes in leg press strength, leg power, or muscle fatigability in either group. Changes in quality of life, sexual function, cognitive function, and Karnofsky performance scores did not differ significantly between the two groups. High-density lipoprotein cholesterol levels decreased significantly in the testosterone group. The patches were well tolerated. We conclude that physiological testosterone replacement was safe and effective in raising testosterone levels into the mid to high normal range, but did not significantly increase FFM, body weight, or muscle performance in HIV-infected women with low testosterone levels and mild weight loss. Additional studies are needed to fully explore the role of androgens in the regulation of body composition in women.

Previous studies of Delta 4-androstene-3,17-dione (4-androstenedione) administration in men have not demonstrated sustained increments in testosterone levels, fat-free mass (FFM), and muscle strength, and failure to demonstrate androstenedione's androgenic/anabolic effects has stifled efforts to regulate its sales. To determine whether 4-androstenedione has androgenic/anabolic properties, we evaluated its association with androgen receptor (AR) and its effects on myogenesis in vitro. Additionally, we studied the effects of a high dose of 4-androstenedione on testosterone levels, FFM, and muscle strength in hypogonadal men. We determined the dissociation constant (K(d)) for 4-androstenedione using fluorescence anisotropy measurement of competitive displacement of fluorescent androgen from AR ligand-binding domain. AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, pluripotent C3H10T1/2 cells, in which androgens stimulate myogenesis through an AR pathway. We determined effects of a high dose of androstenedione (500 mg thrice daily) given for 12 wk on FFM, muscle strength, and hormone levels in nine healthy, hypogonadal men. 4-Androstenedione competitively displaced fluorescent androgen from AR ligand-binding domain with a lower affinity than dihydrotestosterone (K(d), 648 +/- 21 and 10 +/- 0.4 nm, respectively). In C3H10T1/2 cells, 4-androstenedione caused nuclear translocation of AR and stimulated myogenesis, as indicated by a dose-dependent increase in myosin heavy chain II+ myotube area and up-regulation of MyoD protein. Stimulatory effects of 4-androstenedione on myosin heavy chain II+ myotubes and myogenic determination factor expression were attenuated by bicalutamide, an AR antagonist. Administration of 1500 mg 4-androstenedione daily to hypogonadal men significantly increased serum androstenedione, total and free testosterone, estradiol, and estrone levels and suppressed SHBG and high-density lipoprotein cholesterol levels. 4-androstenedione administration was associated with significant gains in FFM (+1.7 +/- 0.5 kg; P = 0.012) and muscle strength in bench press (+4.3 +/- 3.1 kg; P = 0.006) and leg press exercises (+18.8 +/- 17.3 kg; P = 0.045). 4-androstenedione is an androgen that binds AR, induces AR nuclear translocation, and promotes myogenesis in vitro, with substantially lower potency than dihydrotestosterone. 4-androstenedione administration in high doses to hypogonadal men increases testosterone levels, FFM, and muscle strength, although at the dose tested, the anabolic effects in hypogonadal men are likely because of its conversion to testosterone.

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