Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations. We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed. The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced. The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00114114.).