Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis, and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in exaggerated effects, and/or have been of relatively short duration or employed previously treated men, which could result in dampened effects. The goal of this study was to determine the magnitude and time course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle mass and strength, erythropoiesis, prostate volume, energy, sexual function, and lipids in previously untreated hypogonadal men. We selected 18 men who were hypogonadal (mean serum testosterone +/- SD, 78 +/- 77 ng/dL; 2.7 +/- 2.7 nmol/L) due to organic disease and had never previously been treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14 men completed 36 months. The mean serum testosterone concentration reached the normal range by 3 months of treatment and remained there for the duration of treatment. Bone mineral density of the lumbar spine (L2-L4) increased by 7.7 +/- 7.6% (P < 0.001), and that of the femoral trochanter increased by 4.0 +/- 5.4% (P = 0.02); both reached maximum values by 24 months. Fat-free mass increased 3.1 kg (P = 0.004), and fat-free mass of the arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not statistically significant. Strength of knee flexion and extension did not change. Hematocrit increased dramatically, from mildly anemic (38.0 +/- 3.0%) to midnormal (43.1 +/- 4.0%; P = 0.002) within 3 months, and remained at that level for the duration of treatment. Prostate volume also increased dramatically, from subnormal (12.0 +/- 6.0 mL) before treatment to normal (22.4 +/- 8.4 mL; P = 0.004), principally during the first 6 months. Self-reported sense of energy (49 +/- 19% to 66 +/- 24%; P = 0.01) and sexual function (24 +/- 20% to 66 +/- 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat-free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the other tissues took only 3-6 months. These results provide the basis for monitoring the magnitude and the time course of the effects of testosterone replacement in hypogonadal men.