The effect of acute and chronic administration of GH on plasma GH responses to GHRH were studied in patients with idiopathic GH deficiency (GHD). Nine untreated GHD patients, 1 untreated patient with postoperative craniopharyngioma, and 7 normal short children were given synthetic human GHRH-44 (100 micrograms, iv) injection before and 2 days after being given a single dose of 4 IU biosynthetic methionyl human GH (mGH), im. Twelve GHD patients, who had been treated with 0.31-0.48 IU/kg.week pituitary-derived hGH (pdGH), im, for 8-79 months, were given GHRH 2 and 14 days after a final injection of 4 IU pdGH. Three other GHD patients were given GHRH before and after 2 yr of pdGH therapy (0.35-0.39 IU/kg.week). The GHRH-induced GH response (max delta GH) was significantly inhibited after mGH administration in the 9 untreated GHD patients [2.7 +/- 0.3 (+/- SE) vs. 4.7 +/- 0.6 micrograms/L; P less than 0.01]. The patient with secondary GH deficiency also had a marked reduction in her peak plasma GH value after mGH administration (from 32.0 to 11.7 micrograms/L). Similarly, the mean max delta GH response in the 7 normal short children was significantly inhibited by prior mGH injection (max delta GH, 12.7 +/- 2.0 vs. 28.8 +/- 4.8 micrograms/L; P less than 0.01). In the 12 treated GHD patients the GHRH-induced GH response on the 2nd day after discontinuation of pdGH therapy was significantly lower than that on the 14th day (max delta GH, 3.4 +/- 1.2 vs. 6.9 +/- 1.6 micrograms/L; P less than 0.02). In the 3 GHD patients who were studied before and after 2 yrs of pdGH therapy, the plasma GH responses were similar. In each group, plasma somatomedin-C levels on the second day after GH administration were slightly but not significantly higher than those before or 14 days after the administration. The GH responses to GHRH given on 2 occasions at 7- to 14-day intervals in individuals not receiving GH were similar in both 9 normal children and 10 GHD patients. These results indicate that acute GH administration inhibits somatotroph function in GHD patients, but chronic GH therapy does not cause irreversible damage to the somatotrophs. The acute inhibition of GHRH-induced GH release after GH administration is more likely due to direct and indirect pituitary inhibition by somatomedin-C and/or somatostatin than decreased GHRH secretion.