The effect of administration of human growth hormone (HGH) (3 mg every 6 hr for 6 days) on the endogenous GH response to insulin-induced hypoglycemia at 8, 12, 24, and 48 hr posttreatment was studied in 11 healthy male adults. Free fatty acid, cortisol, and glucose responses pre- and posttreatment with HGH were evaluated concurrently. Control subjects received saline injections to evaluate relationship of GH responses to the periodicity of insulin tolerance tests. The data were compared for each subject pre- and posttreatment with HGH as well as by comparison of the results of the saline-treated group with those of the HGH-treated group. The mean maximal GH concentration in response to insulin-induced hypoglycemia for all the subjects (n = 16) was 31.1 +/-3.6 ng/ml (+/-SEM) on day 1 of the control period and 23.4 +/-3.1 (SEM) on day 2, not statistically significant.A significant decrease in the maximal peak GH response (n = 8) after insulin-induced hypoglycemia was observed at 8 and 12 hr after HGH administration was terminated with mean peak values for GH of 4.6 +/-1.3 ng/ml and 10.4 +/-1.9 ng/ml, respectively (P < 0.01). A progressive return to control values was noted between 12 and 24 hr. The GH responsiveness of the saline-treated group (n = 5) was unchanged from that observed during the control period. The fasting glucose values were unchanged in the GH-treated group from those of the control period or of the saline-treated controls. Insulin resistance was apparent at 8 hr posttreatment with HGH. No differences in FFA response after insulin-induced hypoglycemia were observed in GH-treated or saline-treated subjects. The rise in plasma cortisol after insulin-induced hypoglycemia was comparable in the GH-treated and saline-treated group. Diurnal variation in plasma cortisol was maintained during the period of GH suppression. These observations support the concept that GH can modulate its secretion by means of an auto-feedback mechanism.