MECHANISMS UNDERLYING THE NEGATIVE GROWTH-HORMONE (GH) AUTOFEEDBACK ON THE GH-RELEASING EFFECT OF HEXARELIN IN MAN

The growth hormone (GH) response to GH-releasing hormone (GHRH) is str ongly inhibited by previous administration of recombinant human GH (rh GH), likely as a consequence of a somatostatin-mediated GH negative au tofeedback. Hexarelin (HEX), a synthetic hexapeptide belonging to the GH-releasing peptide (GHRP) family, possesses a GH-releasing activity greater than that of GHRH both in animals and in man. The mechanism of action of GHRPs is yet to be completely clarified, although concomita nt actions at the pituitary and hypothalamic level have been hypothesi zed. To further clarify the mechanisms of action underlying the GH-rel easing activity of HEX, in six normal young volunteers we studied the effects of rhGH (2 U intravenously [IV]) on the GH response either to GHRH (2 mu g/kg IV) or to HEX (2 mu g/kg IV) alone or combined with GH RH and/or pyridostigmine ([PD], 120 mg orally). The GH-releasing effec t of HEX was higher than that of GHRH (area under the curve [AUC], 2,2 00.8 +/- 256.9 v 792.2 +/- 117.6 mu g/L/h, P < .001), whereas combined administration of the two substances induced a true synergistic effec t, with GH release after HEX plus GHRH (4.259.2 +/- 308.0 mu g/L/h) be ing higher (P < .02) than the arithmetic sum of the GH increases induc ed by each compound separately administered. After rhGH administration , the GH-releasing effect of HEX was blunted (1,468.9 +/- 193.7 mu g/L /h, P < .04; inhibition of 32.196), whereas that of GHRH was nearly ab olished (102.0 +/- 7.8 mu g/L/h, P < .02; inhibition of 86.1%). The GH response to combined administration of HEX and GHRH was also blunted by the previous rhGH bolus (3,070.6 +/- 481.8 mu g/L/h. P < .02; inhib ition of 26.7%). PD did not modify the GH-releasing effect of HEX eith er alone (2,456.8 +/- 317.5 mu g/L/h) or combined with GHRH (4,009.1 /- 360.8 mu g/L/h). rhGH was again able to blunt the GH response to HE X combined with PD (1,619.3 +/- 237.9 mu g/L/h, P < .02), but failed t o modify the GH response to HEX combined with GHRH and PD (4.548.4 +/- 698.0 mu g/L/h). In conclusion, these results demonstrate that rhGH a dministration only blunts the GH-releasing activity of HEX, but abolis hes that of GHRH. The blunting effect of rhGH on the GH response to HE X is probably mediated by a concomitant reduction in the activity of G HRH-secreting neurons and an increase of somatostatinergic tone. Copyr ight (C) 1997 by W.B. Saunders Company