Human GH-releasing hormone [hGHRH-40 (GHRH)] stimulates GH release in a dose-dependent fashion when administered as single iv bolus doses or as continuous 90-min infusions. However, there has been variability in the GH responses, and it appears that there are waxing and waning effects of GHRH. To address whether these are a result of the dose of GHRH, time, or intermittent changes in sensitivity of the somatotrophs, we administered 6-h infusions of vehicle and different doses of GHRH to six normal men. In addition, an iv bolus injection of GHRH was given after 5.5 h of infusion to evaluate residual GH secretory capacity. The subjects were given infusions of either vehicle or GHRH (1, 3.3, and 10 ng/kg X min), followed by an iv bolus injection of 3.3 micrograms/kg on four separate occasions. GHRH infusions stimulated GH secretion compared to basal secretion. The changes from basal GH secretion (mean +/- SEM) were 2.0 +/- 1.6, 4.6 +/- 1.5, 12.7 +/- 5.1, and 8.2 +/- 1.8 ng/ml X h during the vehicle and GHRH (1, 3.3, and 10 ng/kg X min) infusions, respectively. The changes from basal GH secretion for 2 h after the iv bolus dose (after 5.5 h of infusion) were 33.3 +/- 8.7, 22.4 +/- 3.8, 14.0 +/- 3.6, and 10.5 +/- 2.0 ng/ml X h on the vehicle and GHRH (1, 3.3, and 10 ng/kg X min) infusion days, respectively. The magnitude of the GH response was inversely related to the GHRH infusion dose. The total amount of GH released during the 7.5-h study periods was not different among the vehicle and 3 GHRH infusion days. Thus, it appears that a finite amount of GH is released by GHRH. There was variability in the degree of responsiveness to the continuous infusions of GHRH. Surges of GH release occurred during the GHRH infusions, which may be attributed to intermittent secretion of a GH inhibitor, such a somatostatin.