ADRENOCORTICOTROPIN-RELEASING AND CORTISOL-RELEASING EFFECT OF HEXARELIN, A SYNTHETIC GROWTH HORMONE-RELEASING PEPTIDE, IN NORMAL SUBJECTS AND PATIENTS WITH CUSHINGS-SYNDROME

GH-releasing peptides (GHRPs) are synthetic, nonnatural molecules that strongly stimulate GH secretion, but also slightly increase PRL, ACTH , and cortisol levels in man. To investigate the mechanism underlying the ACTH- and cortisol-releasing activity of GHRPs in man, we compared the ACTH- and cortisol-releasing activity of Hexarelin (HEX; 2.0 mu g /kg, iv), a hexapeptide belonging to the GHRP family, with that of hum an GRH (hCRH; 2.0 mu g/kg, iv) in normal subjects (6 men and 6 women. 24-68 yr old) and patients with Cushing's syndrome (2 men and 15 women , 16-68 yr old). The GH response to HEX administration was also studie d. In normal subjects, HEX administration significantly increased ACTH (peak us. baseline, mean +/- SD, 32.4 +/- 17.7 vs. 16.3 +/- 7.2 pg/mL ; P < 0.005) and cortisol levels (135.9 +/- 51.0 vs. 110.0 +/- 31.6 mu g/L (P < 0.01). The ACTH and cortisol responses to hCRH [35.7 +/- 13. 2 vs. 17.1 +/- 7.7 pg/mL (P < 0.01) and 162.8 +/- 50.1 us. 102.8 +/- 2 8.1 mu g/L (P < 0.01), respectively] were similar to the responses to HEX. The stimulatory effect of HEX, but not that of hCRH, on both ACTH and cortisol secretion in Cushing's disease was clearly higher (P < 0 .01) than that observed in normal subjects. In fact, in Gushing's dise ase both HEX and hCRH elicited a clear increase in ACTH levels [381.1 +/- 350.0 vs. 52.4 +/- 25.0 (P < 0.005) and 100.0 +/- 86.2 vs. 53.3 +/ - 29.7 pg/mL (P < 0.01), respectively], but the ACTH increase induced by HEX was about 7-fold greater (P < 0.02) than that induced by hCRH. Similarly, both HEX and hCRH elicited a significant increase in cortis ol levels [366.9 +/- 189.5 vs. 189.7 +/- 86.3 mu g/L (P < 0.005) and 2 09.9 +/- 125.4 vs. 167.2 +/- 96.3 mu g/L (P < 0.02), respectively], bu t the cortisol increase induced by HEX was about 4-fold greater (P < 0 .05) than that induced by hCRH. In patients with Gushing's syndrome du e to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol l evels was observed after either HEX or hCRH administration. The peak G H response to HEX in normal subjects was clearly higher (P < 0.03) tha n that in hypercortisolemic patients (45.8 +/- 20.5 vs. 22.4 +/- 21.1 mu g/L). In conclusion, the ACTH- and cortisol-releasing activity of H EX is similar to that of hCRH in normal subjects, whereas it is dramat ically enhanced in patients with Gushing's disease. This evidence indi cates the importance of the ACTH-releasing activity of GHRPs and sugge sts that it could be at least partially independent of CRH-mediated me chanisms. As the stimulatory effect of HEX on ACTH and cortisol secret ion is lost in patients with Gushing's syndrome due to adrenal adenoma or ectopic ACTH, these findings suggest the usefulness of GHRPs to in vestigate the activity of the hypothalamo-pituitary-adrenal axis in pa thophysiological conditions and possibly to differentiate pituitary fr om ectopic ACTH-dependent Gushing's syndrome.