We measured the cortisol and corticosterone responses to insulin-induced hypoglycemia in 13 growth hormone (GH)-deficient children and 30 short children without GH deficiency. Although there was no difference between the two groups in 1) degree of hypoglycemia attained, 2) baseline cortisol, 3) baseline coricosterone, or 4) cortisol 40 min after insulin injection, GH-deficient children had a significantly greater corticosterone response to this stress (3.6 ± 0.4versus1.9 ± 0.2μg/dl). (All data are presented as mean ± SEM.) In order to explore the effect of GH on corticosterone secretion, we measured cortisol and corticosterone responses to synthetic (1-24) ACTH before and after 3 days of exogenous GH (0.2 unit/ kg/day). In 13 GH-deficient children, GH treatment caused a significant decrease in the corticosterone response to ACTH (2.2 ± 0.2μg/dl before GH to 1.6 ± 0.2μg/dl;t=5.22,p<0.001; pairedttest) despite the fact that there was no significant change in the cortisol response to ACTH (18 ± 2μg/dl before and 16 ± 2μg/dl after). When seven short children who were not GH deficient underwent a similar 3-day course of GH, the decrease in their corticosterone response was much less although still statistically significant (2.0 ± 0.5 to 1.8 ± 0.5μg/dl; pairedttest,p<0.05). Again, the stimulated levels of cortisol were not affected by GH treatment (19 ± 4versus18 ± 3μg/dl) These results indicate that GH modulates the adrenal response to ACTH by suppressing corticosterone secretion without affecting cortisol secretion. In summary, this study presents two new findings. First, corticosterone levels are elevated during insulin tolerance testing in children with GH deficiency and, second, a 3-day course of GH replacement therapy causes a reduction in corticosterone serum levels after ACTH administration to more normal levels without altering the corresponding cortisol concentrations. As corticosterone is a less potent glucocorticoid, it might function as a cortisol antagonist when present in increased amounts and play a role in the poor recovery from hypoglycemia frequently observed in individuals with GH deficiency.