Growth hormone (GH) exerts a negative feedback on its own secretion through direct and indirect mechanisms. Normal children, unlike adults, display consecutive GH responses after repeated GH-releasing hormone (GHRH) administration. In this study, we investigated the effects of long-term GH administration on this peculiar secretory pattern. Eight children with severe short stature and impaired GH responses to suprapituitary provocative stimuli associated with normal GH responsiveness to GHRH, underwent, while on chronic treatment with biosynthetic GH and on the 10th day following drug withdrawal, a double bolus GHRH test (two GHRH injections of 1 microg/kg b.w. given as i.v. boluses two hours apart). During GH therapy the GH response to the first GHRH bolus appeared to be reduced, though not significantly so, compared to that observed at diagnosis; after treatment withdrawal, this response returned quite similar to pretreatment. Both during and after treatment, the GH response to the second GHRH bolus was comparable for magnitude to that evoked by the first application. In conclusion, even prolonged treatments with rhGH do not induce persisting alterations of the physiological mechanisms subserving GH regulation.