As leptin, an ob gene product, plays a pivotal role in the regulation of adiposity and energy homeostasis, the level of its expression is likely to fluctuate under various physiological, nutritional, and disease conditions. Reports regarding the effect of GH on serum leptin levels are inconsistent. We have measured serum leptin levels and correlated them with several variables in patients with acromegaly, patients with adult GH deficiency (GHD), and normal controls. In 116 normal subjects, the mean serum concentration of leptin was 5.0+/-2.8 (mean +/- SD) ng/mL in men (n = 42) and 10.7+/-7.3 ng/mL in women (n = 73), respectively. As reported previously, the leptin levels in women were significantly (P < 0.001) higher than in men, and there was a strong positive correlation between log-transformed serum leptin levels and percent body fat in simple regression analysis (in men: r = 0.606; P < 0.0001; in women: r = 0.707; P < 0.0001). In 36 acromegalic patients, the percent body fat mass was significantly lower than that in normal subjects, and the mean serum leptin level was 2.2+/-1.8 ng/mL in men (n = 18) and 3.6+/-2.5 ng/mL in women (n = 18). Analysis of covariance revealed that serum leptin levels in acromegalics were significantly lower than those in normal subjects after correcting percent body fat (P = 0.016 for men and P < 0001 for women). In male patients with GHD (n = 20), the mean percent body fat was significantly (P < 0.05) higher than that in age-matched controls, whereas the value in female GHD patients (n = 15) did not differ from that in age-matched controls. Serum leptin levels in GHD patients were 5.1+/-2.5 ng/mL in men and 11.5+/-8.1 ng/mL in women, which were not different from those in normal subjects adjusted for percent body fat mass. In multiple regression analysis models with log-transformed leptin as the dependent variable, gender, percent body fat (or body fat mass), and serum insulin-like growth factor I levels entered the equations at a statistically significant level. These data suggest that excess GH/insulin-like growth factor I reduces serum leptin levels by reducing body fat mass and/or by unknown mechanisms.