Methionyl-GH (met-GH) infusions inhibit the GH response to GH-releasing hormone (GHRH). Met-GH infusions induce lipolysis with a rise of plasma FFA that are known to suppress GH release, but the met-GH inhibition of the GH response to GHRH occurs also when lipolysis is pharmacologically blocked by acipimox. In addition, the inhibition of GH release might be due to an enhanced release of hypothalamic somatostatin. The aim of this study was to evaluate the effect of a met-GH infusion on the GH response to GHRH when lipolysis and hypothalamic somatostatin release are pharmacologically blocked. Twelve normal subjects, randomly allocated to two groups (A and B), received GHRH (50 micrograms, iv) at 1300 h after a 4-h saline infusion or met-GH infusion (80 ng/kg.min). To block lipolysis and hypothalamic somatostatin release, subjects in group B received acipimox, an antilipolytic agent (500 mg), and pyridostigmine, an acetylcholinesterase inhibitor (60 mg), during the 6 h before iv GHRH. GHRH induced a clear GH release during saline infusion in both groups, significantly higher in group B (43.6 +/- 4.8 micrograms/L) than in group A (20.1 +/- 6.1 micrograms/L; P less than 0.02 vs. A), and only a slight increase during met-GH infusions (10.4 +/- 4.1 micrograms/L in group A; 16.7 +/- 4.2 micrograms/L in group B; P = NS). These data indicate that the GH response to GHRH is inhibited by met-GH infusions when peripheral lipolysis and hypothalamic somatostatin release are pharmacologically blocked, suggesting the possibility of autoinhibition of GH at the pituitary level.