GROWTH-HORMONE (GH) SECRETION IN ACTIVE ACROMEGALY AFTER THE COMBINEDADMINISTRATION OF GH-RELEASING HORMONE AND GH-RELEASING PEPTIDE-6

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (called GHRP-6) is a synthetic compoun d that releases GH in a dose-related, specific, and nonspecies-specifi c manner, through mechanisms different from those of GHRH. Being, norm ally, more potent than GHRH, GHRP-6 shows a striking synergistic actio n when administered simultaneously with GHRH, although the mechanisms and point of action of such a potentiating effect are unknown. The aim of the present study was 2-fold: 1) to further characterize the actio ns and mechanisms of GHRP-6 as well as its synergistic effects, and 2) to study its actions in acromegalic patients. Eleven acromegalic pati ents and 12 normal subjects, age and sex matched as controls, underwen t 3 tests each on separate occasions, being challenged with GHRH (100 mu g, iv), GHRP-6 (90 mu g, iv), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE; micrograms per L/120 min). I n normal subjects, GH secretion was 686 +/- 227 after GHRH, 1787 +/- 5 10 after GHRP-6, and 4111 +/- 671 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0 .05) higher than the arithmetic sum of GH levels after both compounds administered separately. In acromegalic patients, the level of GH secr eted after GHRH was 1468 +/- 499, that after GHRP-6 was 2595 +/- 762, and that after GHRH plus GHRP-6 was 4949 +/- 1043; this last value was not significantly different from the arithmetical addition of levels produced by both compounds administered separately. These results indi cate that GH-secreting pituitary adenomas respond surprisingly well to either GHRH or GHRP-6 despite being deprived for long periods (even y ears) of the physiological regulation exerted by the hypothalamus. In addition, the synergistic action of GHRH plus GHRP-6 was observed in n ormal subjects, but not in acromegalic patients. These results suggest that GHRP-6 does not need to operate through hypothalamic factors to exert its GH-releasing action, even for eliciting a greater response t han GHRH. On the other hand, the synergistic effect of GHRH plus GHRP- 6 appears to need the cooperation of the hypothalamus, but how this oc curs is still undetermined.