Effects of dexamethasone and alprazolam, a benzodiazepine, on the stimulatory effect of hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans

Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamopituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26-34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 mu g/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at -90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA. or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs, baseline, mean +/- SEM: 28.0 +/- 6.7 vs. 11.7 +/- 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 +/- 15.0 vs. 137.7 +/- 12.6 mu g/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 +/- 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 +/- 2.5 mu g/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX(3.6 +/- 0.9 pg/ml, p < 0.01 and 10.7 +/-: 2.0 mu g/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 +/- 2.0 pg/ml) and cortisol levels(127.6 +/- 14.5 mu g/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 +/- 2.4 pg/ml, p < 0.05 and 111.0 +/- 6.0 mu g/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 +/- 20.5 vs. 2.2 +/- 0.7 mu g/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 +/- 5.5 mu g/l, p < 0.05) while it was not modified by DEXA pretreatment(78.7 +/- 7.6 mu g/l). In conclusion, our present data demonstrate that the ACTH-and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.