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Adrenocorticotropin- and Cortisol-Releasing Effect of Hexarelin, a Synthetic Growth Hormone-Releasing Peptide, in Normal Subjects and Patients with Cushing’s Syndrome¹

Division of Endocrinology, Department of Internal Medicine, University of Turin, Turin; and the Division of Endocrinology, University of Naples (A.C., G.L.), Naples, Italy; and Europeptides (R.D.), Argenteuil, France

Address all correspondence and requests for reprints to: F. Camanni, M.D., Divisione di Endocrinologia, Ospedale Molinette, C. so Dogliotti 14, 10126 Torino, Italy.

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 µg/kg, iv), a hexapeptide belonging to the GHRP family, with that of human CRH (hCRH; 2.0 µg/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 studied. In normal subjects, HEX administration significantly increased ACTH (peak vs. 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 µg/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 vs. 102.8 ± 28.1 µg/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 Cushing’s disease 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 cortisol levels [366.9 ± 189.5 vs. 189.7 ± 86.3 µg/L (P < 0.005) and 209.9 ± 125.4 vs. 167.2 ± 96.3 µg/L (P < 0.02), respectively], but the cortisol increase induced by HEX was about 4-fold greater (P < 0.05) than that induced by hCRH. In patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol levels was observed after either HEX or hCRH administration. The peak GH response to HEX in normal subjects was clearly higher (P < 0.03) than that in hypercortisolemic patients (45.8 ± 20.5 vs. 22.4 ± 21.1 µg/L). In conclusion, the ACTH- and cortisol-releasing activity of HEX is similar to that of hCRH in normal subjects, whereas it is dramatically enhanced in patients with Cushing’s disease. This evidence indicates the importance of the ACTH-releasing activity of GHRPs and suggests that it could be at least partially independent of CRH-mediated mechanisms. As the stimulatory effect of HEX on ACTH and cortisol secretion is lost in patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH, these findings suggest the usefulness of GHRPs to investigate the activity of the hypothalamo-pituitary-adrenal axis in pathophysiological conditions and possibly to differentiate pituitary from ectopic ACTH-dependent Cushing’s syndrome.

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