Hexarelin, a Synthetic Growth-Hormone Releasing Peptide, Shows No Interaction with Corticotropin-Releasing Hormone and Vasopressin on Adrenocorticotropin and Cortisol Secretion in Humans

Abstract

Hexarelin (HEX) is a synthetic growth-hormone-releasing peptide (GHRP) which acts via specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in man. Like other GHRPs, HEX possesses also significant prolactin-and adrenocorticotropin (ACTH) cortisol-releasing activity, but the mechanisms underlying these effects are even less clear. To clarify the mechanisms by which HEX stimulates the pituitary-adrenal axis in man, in 7 healthy young volunteers we studied the effects of HEX (2.0 µg/kg i.v.) and/or human corticotropin-releasing hormone (hCRH; 2.0 µg/kg i.v.) and /or arginine vasopressin (AVP; 0.17 U/kg i.m.) on ACTH and cortisol secretion. The GH responses to HEX alone and combined with hCRH and/or AVP were also studied. HEX increased ACTH and cortisol secretion (peak, mean ± SEM:26.3 ± 5.1 vs. 15.8 ± 3.1 pg/ml and 145.0 ± 11.4 vs. 131.7 ± 11.7 µg/1, p < 0.01, respectively) to levels overlapping with those induced by AVP (27.9 ± 6.1 vs. 13.1 ± 3.5 pg/ml and 167.6 ± 16.2 vs. 113.3 ± 9.4 µg/lp < 0.01, respectively) and similar to those elicited by hCRH (28.1 ± 4.6 vs. 17.4 ± 3.1 pg/ml and 182.7 ± 22.8 vs. 114.8 ± 12.3 µg/lp < 0.02, respectively). The ACTH but not the cortisol response to hCRH was higher (p < 0.02) than those to HEX when evaluated as area under the curve. The co-administration of HEX and AVP had no significant interaction on ACTH and cortisol peak levels (40.7 ± 5.3 pg/ml and 168.8 ± 13.5 µg/1, respectively). On the other hand, the co-administration of HEX and hCRH had a less than additive effect on ACTH and cortisol secretion (53.3 ± 11.2 pg/ml and 204.0 ± 13.7 µg/1, respectively). CRH and AVP had a true synergistic effect on ACTH (104.9 ± 14.2 pg/ml, p < 0.01) and an additive effect on cortisol secretion (281.3 ± 10.8 µg/1, p < 0.02). HEX did not modify the effect of CRH + AVP on both ACTH (135.5 ± 22.0 pg/ml) and cortisol secretion (261.1 ± 13.2 µg/1). The GH response to HEX (55.7 ± 19.8 vs. 2.7 ± 1.9 µg/1, p < 0.005) was unaffected by the administration of CRH alone (53.5 ± 21.0 µg/1) and/or AVP co-administration (60.2 ± 21.2 and 45.9 ± 10.6 µg/1, respectively). In conclusion, the results of this study demonstrate that GHRPs, beside their well-known GH-releasing activity, possess a remarkable ACTH-releasing activity, overlapping with that of AVP and similar to that of hCRH, two neurohormones which are known to play the major role in the control of the pituitary-adrenal axis. It is noteworthy that HEX shows no synergistic effect with either AVP or hCRH which, on the other hand, truly synergize. This evidence suggests the hypothesis that the ACTH-releasing activity of GHRPs could be, at least partially, independent of both CRH- and AVP-mediated actions in humans.

The GH, prolactin, ACTH and cortisol responses to Hexarelin, a synthetic hexapeptide, undergo different age-related variations

“…Moreover, GHRPs do not stimulate ACTH release from rat pituitary (14). Some studies in animals and in humans led to the hypothesis that GHRPs act via a CRH-mediated action (7, 21) but our recent results favor the hypothesis that, in man, the stimulatory effect of GHRPs on the HPA axis is, at least partially, independent of both CRH and arginine vasopressin (AVP) (44). Our present findings showing that the ACTH-releasing activity of HEX increases at puberty, goes down in adulthood and then shows again a trend toward increase in aging, strengthen the hypothesis that a CRH-mediated mechanism does not mediate the ACTH-releasing activity of HEX.…”

“…Interestingly, the ACTH and cortisol responses to HEX are similar to those to hCRH and AVP and the HEXinduced ACTH and cortisol rises are exaggerated and strikingly higher than those after hCRH in patients with Cushing's disease, in spite of their hypercortisolism (44,46).…”

Concordant and discordant adrenocorticotropin (ACTH) responses induced by growth hormone-releasing peptide-2 (GHRP-2), corticotropin-releasing hormone (CRH) and insulin-induced hypoglycemia in patients with hypothalamopituitary disorders: evidence for direct ACTH releasing activity of GHRP-2

“…The mechanism underlying GHRP-2's stimulation of ACTH release remains controversial. Previous studies in humans suggested that GHRP's ACTH-releasing activity may be mediated via CRH and/or AVP [3,5,7,11], or independent on both peptides [12]. Very recently, Kamoi et al [13] showed that GHRP-2 does not stimulate AVP secretion.…”

Six-week treatment with hexarelin in young dogs: evaluation of the GH responsiveness to acute hexarelin or GHRH administration, and of the orexigenic effect of hexarelin

“…GHRPs exert other neuroendocrine and behavioural actions: though with different potency, they slightly activate the hypothalamic-pituitary-adrenal axis (10)(11)(12) and also affect food intake (13)(14)(15) and sleep (16,17). The intra-or extrahypothalamic mechanisms, or both, that underlie these central effects remain elusive.…”