BLOCKED GROWTH HORMONE-RELEASING PEPTIDE (GHRP-6)-INDUCED GH SECRETION AND ABSENCE OF THE SYNERGIC ACTION OF GHRP-6 PLUS GH-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMOPITUITARY DISCONNECTION - EVIDENCE THATGHRP-6 MAIN ACTION IS EXERTED AT THE HYPOTHALAMIC LEVEL

GH-releasing peptide (GHRP-6; His-D Trp-Ala-Trp-D Phe-Lys-NH2) is a sy nthetic compound that releases GH in a specific and dose-related manne r through mechanisms and a point of action that are mostly unknown but different from those of GHRH. In man, GHRP-6 is more efficacious than GHRH, and a striking synergistic action on GH release is observed whe n GHRP-6 and GHRH are administered simultaneously. Based on such a syn ergistic action, it has been hypothesized that GHRP-6 acts through a d ouble mechanism by actions exerted both at the pituitary and hypothala mic levels. The aim of the present study was a-fold: 1) to further cha racterize the mechanism of action and synergistic effects of GHRP-6; a nd 2) to study its action in patients with hypothalamopituitary discon nection. Twelve patients with different neuroendocrine pathologies lea ding to a state of hypothalamopituitary disconnection (functional stal k section) and 11 age- and sex-matched normal controls were studied. E ach subject underwent 3 tests on separate occasions, being challenged with GHRH (100 mu g, iv), GHRP-6 (90 mu g, iv), or GHRH plus GHRP-6. G H was analyzed as the area under the curve (mean +/- SE, micrograms pe r L/120 min). In normal subjects GH secretion was 483.7 +/- 99.2 after GHRH, 1434.8 +/- 393.0 after GHRP-6, and 3771.5 +/- 399.6 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0.05) higher than after the arithmetic sum of GH levels after both compounds administered separately. In the group o f patients with hypothalamopituitary disconnection, the level of GH se creted after GHRH was similar to that in controls (423.4 +/- 62.8); ho wever, a complete blockade was observed after GHRP-6 (97.3 +/- 7.9), s ignificantly (P < 0.05) lower than after GHRH as well as lower than th e GHRP-6-induced GPI release in control subjects (P < 0.01). After GHR H plus GHRP-6, the patients with hypothalamopituitary disconnection sh owed severely reduced secretion (745.3 +/- 67.6; P < 0.01 vs, controls ), a value that was not significantly different from the arithmetic ad dition of levels produced by both compounds administered separately. R egarding the regulation of GH secretion, these results indicate that: 1) GHRP-6 acts at the pituitary, but its potency is minimal and lower than GHRH; 2) the main action of GHRP-6 is exerted through hypothalami c structures; 3) the synergistic action that GHRP-6 exerts over GHRH a ction is exerted at the hypothalamic level; and 4) the divergent GH se cretion after GHRH and GHRP-6 may be a useful clinical test in states of hypothalamopituitary disconnection In conclusion, the main action o f GHRP-6 for inducing GH secretion in man is exerted through hypothala mic structures, although the intimate mechanism of action is still und etermined.