To determine whether differences in the neuroendocrine control of GH are present between children and adult subjects, the GH response to GHRH (1 μg/kg) (group 1), insulin-induced hypoglycemia (0.1 U/kg iv) (group 2), clonidine (150 μg/m2 po) (group 3) and iv arginine (0.5 g/kg in 30 min) (group 4) after GHRH pretreatment (1 μg/kg) was studied in 26 short-stature normal children (mean age 10.2 years). The results were compared with historical data in adults. No differences were present among mean peak GH levels after the first and second stimuli in groups 1, 2 and 3, while in group 4 the GH response to arginine administration was lower than that obtained after the initial GHRH (0.43±0.04 vs 0.9±0.13 nmol/l). Moreover, comparing the GH peak values following the second stimulus, it appears that the greatest GH responses were elicited by GHRH (1.31±0.23 nmol/l) and clonidine (1.11±0.22 nmol/l), while the lowest was elicited by arginine (0.43±0.04 nmol/l). In adults, sequential GHRH administration leads to inhibition of the response of the somatotropes, probably mediated by an increase in hypothalamic somatostatin. Our results confirm that after GHRH prestimulation GHRH elicits a significant GH response suggesting that activation of the somatostatinergic tone is less effective in children. This hypothesis also explains the low GH response to arginine which acts selectively through somatostatin inhibition.