In GH-deficient adults, rhGH has pronounced effects on total body water, fat free mass, and fat mass. Recently, we observed a gender difference in IGF-I responsivity to rhGH that was sex steroid dependent. The aim of the present study was to assess the effect of rhGH therapy on body composition parameters with due attention to the gender differences in biological responsiveness to rhGH. Forty-four women [36.9 +/- 11.9 yr (mean +/- SD)] and 33 men (37.2 +/- 13.8 yr) with GH deficiency were studied every 6 months during 2 yr. The treatment goal was to achieve IGF-I levels within the age-adjusted normal range. Total body water, fat free mass, and fat mass were measured by bioimpedantiometry. To reach the treatment goal, the daily rhGH dose (IU/kg/d) had to be significantly higher in women than in men at all time intervals. During rhGH therapy, total body water and fat free mass increased significantly in both men and women (P < or = 0.01 by ANOVA), but changes were more pronounced in men. Fat mass decreased during rhGH treatment and reached its nadir at 6 months, which was more pronounced in men than in women (P = 0.02 by ANOVA). After the initial decrease, fat mass increased again and reached baseline values after 2 yr of treatment. In both men and women, the total body water and fat free mass increases were closely related to the IGF-I increments (P < 0.001 by Pearson's correlation test). The decrease in fat mass correlated significantly with the increase in IGF-I in men (r = -0.89, P < 0.001), not in women. Confirming our earlier data, IGF-I responsivity to rhGH was significantly higher in men than in women at all time intervals (P < 0.01 by ANOVA). Total body water and fat free mass responsivities were also higher in men than in women (P < 0.01 by ANOVA). In conclusion, gender differences in IGF-I responsivities to rhGH are accompanied by gender differences in the extent of body composition changes to rhGH. Probably because of these gender differences in IGF-I responsivity, the increases of total body water and fat free mass to rhGH replacement were greater in men than in women. Remarkably, however, in men, only total body water and fat free mass responses relative to changes in IGF-I increased during the 2 yr of rhGH therapy (P = 0.02 and 0.01, respectively, by ANOVA). In our opinion, this phenomenon might be explained by the increasing target organ sensitivity to IGF-I over time.