Hexarelin is a stronger GH-releasing peptide than GHRH in normal cycling women but not in anorexia nervosa

Anorexia nervosa (AN) is a chronic disease in which an enhanced GH response to GHRH, a paradoxic increase after TRH and LH RH, and low IGF1 levels may be present according to the patient’s clinical state. It is well known that the GH hypersecretory state commonly found in the “acute phase” of AN is restored with weight gain. The new synthetic hexapeptide, Hexarelin (HEX), which is chemically similar to GH-releasing peptide 6, has recently been shown to possess a stronger GH-releasing activity than GHRH in humans and to share a synergistic effect with GHRH when administered intra venously. Indeed, HEX shows a slight Cortisol and PRL-releasing activity. The aim of the study was to evaluate the effect of iv administration of old (GHRH) and new (HEX) GH-releasing peptides on GH, PRL and Cortisol secretion in 9 AN patients in the “recovery phase” of the disease, after partial but significant weight gain. For controls we studied 7 nomal cycling women. No significant difference in GH secretion after GHRH was found between AN and controls. GHRH was not able to release Cortisol or PRL either in AN or controls. HEX produced a significantly (p<0.05) higher GH peak in controls than in AN, while GH AUC was slightly but not significantly higher. Indeed, only in controls HEX was a stronger GH-releasing peptide than GHRH. These findings could be explained by the fact that, in AN, GH secretion is already stimulated both by reduced IGF1 leveis and by increased GHRH/somatostatin ratio. As reported in the literature, the action of HEX action is only slightly influenced by variations in somatostatin tone. It therefore appears likely that the absolute or relative GHRH increase present in AN could partially mimic the unknown hypothalamic factor necessary for HEX action on the hypophisis and that, following a structural modification of pituitary HEX receptors, GHRH would become able to bind to HEX receptors on somatotropic cells. Consequently, the pituitary cells would already be over-activated and so unable to respond maximally to HEX stimulation. Indeed, in AN, GHRH might play a role of negative modulation in the control of HEX action. Finally, in our study HEX was able to produce a persistent PRL release in controls but not in AN, thus suggesting that its action could be partially dependent on the estrogen milieu, while it stimulated Cortisol secretion only transiently in the patients studied.