Objective: To verify the hypothesis of an increased sensitivity to GH in obesity (OB) and Cushing's syndrome (CS). Design: We studied the effects of short-term administration of low-dose rhGH on circulating IGF-I levels in patients with simple OB or CS and in normal subjects (NS 2 ) underwent s.c. administration of 5 mg/kg per day rhGH at 2200 h for four days. Serum IGF-I, IGF-binding protein-3 (IGFBP-3), GHbinding protein (GHBP), insulin and glucose levels were determined at baseline and 12 h after the first and the last rhGH administration. Results: Basal IGF-I levels in NS 239X3^22X9 mgal were similar to those in OB 181X5^13X7 mgal and CS 229X0^29X1 mgalX Basal IGFBP-3, GHBP and glucose levels in NS, OB and CS were similar while insulin levels in NS were lower P , 0X01 than those in OB and CS. In NS, the low rhGH dose induced a sustained rise of IGF-I levels (279X0^19X5 mgalY P , 0X001Y a non-significant IGFBP-3 increase and no change in GHBP, insulin and glucose levels. In OB and CS, the IGF-I response to rhGH showed progressive increase (246X2^17X2 and 311X0^30X4 mgal respectively, P , 0X01 vs baseline). Adjusting by ANCOVA for basal values, rhGH-induced IGF-I levels in CS (299.4 mg/l) were higher than in OB (279.1 mg/l, P , 0X01), which, in turn, were higher P , 0X05 than in NS (257.7 mg/l). In OB, but not in CS, IGFBP-3 and insulin levels showed slight but significant P , 0X05 increases during rhGH treatment, which did not modify glucose levels in any group; thus, in the OB patient group a significant fall in glucose/insulin ratio was observed. Conclusions: Short-term treatment with low-dose rhGH has enhanced stimulatory effect on IGF-I levels in OB and, particularly, in hypercortisolemic patients. These findings support the hypothesis that hyperinsulinism and hypercortisolism enhance the sensitivity to GH in humans.