GROWTH HORMONE-RELEASING PEPTIDES - CLINICAL AND BASIC ASPECTS

Growth hormone (GH)-releasing peptides (GHRPs), a family of synthetic oligopeptides which stimulate GH release, were identified more than a decade ago. The effects of these peptides on GH release have been desc ribed in vivo and in vitro, in both animals and humans, using various doses and administration routes. It is generally accepted that GHRPs s timulate the release of GH by acting at the level of the pituitary thr ough a receptor different to that for the endogenous GH-releasing horm one (GHRH). In addition, it has been reported that there are specific binding sites for these peptides in the hypothalamus and that systemic administration of GHRPs increases the expression of the immediate ear ly gene c-fos in a subpopulation of hypothalamic neurons. However, the identity of these hypothalamic neurons and the mechanism of action of GHRPs at both the hypothalamic and pituitary levels remain unknown. O ne interesting aspect of GHRPs is that they are orally active and this phenomenon has been demonstrated in both animals and humans. Furtherm ore, these drugs stimulate GH secretion in humans dose-dependently wit h the magnitude and duration of this response being comparable to that seen with an intravenous peptide bolus. We have studied the oral acti vity of GHRP-2 on GH release in normal children. In addition, we have analyzed the response to GHRP-2 of obese adolescents, as well as the e ffects of an intravenous bolus of GHRH alone and GHRH plus GHRP-2. Ora lly administered GHRP-2 stimulates GH secretion in normal children and , although it seems that this drug is more potent in girls, there were no statistical differences between the groups. Characteristically, GH levels started to increase by 15 min, peaked at 60 min and returned t o basal concentrations by 180 min. The effect of GHRP-2 was synergisti c with GHRH 1-29 NH2. In addition, obese subjects appeared to have a g reater response to this peptide than did normal controls. To study the effects of GHRPs on hypothalamic GHRH and somatostatin neurons, femal e dwarf rats (dw/dw) were treated continuously with GHRP-6 (1 mg/kg pe r 24 h) for 14 days. In situ hybridization for GHRH and SS was perform ed. We found that GHRP-6 stimulated GHRH mRNA levels in the posterior arcuate nucleus (ARC), with no significant effect in the anterior ARC or ventromedial hypothalamic neurons. SS mRNA levels in the posterior periventricular nucleus (PeN) were decreased after GHRP-6 treatment, w hile no effect was seen in the anterior PeN, ARC, or lateral paraventr icular nucleus. These results suggest that GHRP-6 treatment modulates hypothalamic neurons controlling GH secretion; however, whether this e ffect is direct or mediated through another factor remains to be eluci dated.