We studied the effect of GH alone (1U/Kg/week s.c.; 20 pts) and in combination with ethynyl estradiol (EE; 50 ng/kg/die per os; 6 pts} on IGF-I and II plasma concentrations in age-matched (M±ES: CA 11.29±0.38 and 11.95±0.94, BA 9.97±0.55 and 9.95±0.93) pts presenting with TS and on the IGF-I generation by fibroblasts in culture from 3 TS pts and 1 control. IGF-II plasma concentration was normal and unresponsive to the treatment. IGF-I plasma basal concentration was normal and increased significantly in both groups after 12 months of treatment. No difference was found between the two treatment regimens. Furthermore, we verified the ability of the fibroblasts from TS pts to synthetize in vitro the IGF-I in basal and GH, EE or GH + EE stimulated conditions. The results indicate that TS fibroblasts produce less IGF-I than fibroblasts from control; this finding can account for a reduced paracrine/autocrine action of IGF-I in these pts, in spite of a normal IGF-I plasma concentration. Addition of increasing concentrations of GH (0-100 ng/ml of medium) induced a dose-dependent increase of IGF-I in the conditioned medium with a maximum at 50 ng/ml of GH. Addition of EE (at 0-500 pg/ml of medium) also resulted in an increased production of IGF-I with a maximum already at 25 pg/ml of EE. The combination of increasing doses of GH with 50 pg/ml of EE was additive only in the fibroblasts from one pt.