The prostate is a target organ of the GH and IGF-I axis because prostate hypertrophy is found in acromegaly, reduced prostate size is found in GH deficiency (GHD) patients, and additionally, IGF-I is reported to be a positive predictor factor of prostate cancer. To investigate whether GH replacement therapy in adult patients with GHD has adverse effects on the prostate, we studied the effect of 12-month GH or GH plus testosterone replacement on prostate pathophysiology in 24 adult patients with GHD (11 euandrogenemic and 13 hypoandrogenemic), compared with 24 age-matched healthy controls. At study entry, GHD patients had lower prostate volume than controls (19.4 +/- 1.7 vs. 24.9 +/- 1.7 ml; P = 0.03). After 12 months of treatment, all hypoandrogenemic patients achieved normal testosterone levels, and prostate volume increased in the patients to the same level as controls (25.0 +/- 1.9 ml). The percentage increase in prostate volume was greater in hypoandrogenemic patients receiving both GH and testosterone replacement (51 +/- 11%) than in those receiving GH replacement alone (15 +/- 3%; P < 0.0009). At baseline, prostate volume was similar in GHD patients below or above 60 yr of age (16.8 +/- 1.3 vs. 23 +/- 3.6 ml; P = 0.08), whereas after treatment it was higher in the latter patients (21.8 +/- 1.2 vs. 29.5 +/- 3.9 ml; P = 0.04). Prostate-specific antigen (PSA) and free PSA did not change, whereas PSA density was significantly reduced after treatment in hypoandrogenemic patients; there was also no change in calcifications, cysts, or nodules. In conclusion, GH replacement restores prostate size to normal in both young and elderly patients, with no increase in prostate abnormalities. Because the simultaneous treatment with GH and testosterone induces an increase of prostate size by 50% of baseline on average, care is suggested in elderly patients with prostate hyperplasia to avoid any risk of prostate symptoms. In these cases, GH replacement might be performed sequentially to reduce the hypertrophic effect of combining GH and testosterone.