Corticotropin-Releasing Effect of Hexarelin, a Peptidyl GH Secretagogue, in Normal Subjects Pretreated with Metyrapone or RU-486, a Glucocorticoid Receptor Antagonist, and in Patients with Addison’s Disease

Abstract

GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules which possess strong GH-releasing activity but also stimulatory effect on hypothalamo-pituitary-adrenal axis. The ACTH and cortisol responses to Hexarelin (HEX), a peptidyl GHS, are abolished by low-dose dexamethasone pretreatment in normal subjects but are exaggerated and higher than those after hCRH in patients with pituitary ACTH-dependent Cushing’s disease, in spite of their hypercortisolism. Based on the foregoing, we studied the ACTH, cortisol and GH responses to HEX (2.0 µg/kg i.v. at 0 min) alone and after metyrapone (2 g p.o. at 23:00 h the night before) or RU-486 (400 mg p.o. at 02:00 h), a glucocorticoid receptor antagonist, in 6 normal women (NS, age 26–34 years). The endocrine responses (mean ± SEM) to HEX alone were also studied in 8 patients with Addison’s disease (AD, 6 males, 2 females, age 30–77 years; last hydrocortisone administration the day before testing). In NS, HEX stimulated basal ACTH (peak, mean ± SEM: 26.0 ± 7.8 vs. 10.7 ± 2.0 pg/ml, p < 0.05), cortisol (163.2 ± 18.3 vs. 137.4 ± 15.4 µg/l, p < 0.05) and GH (72.6 ± 23.5 vs. 3.7 ± 1.3 µg/l, p < 0.01) levels. Metyrapone markedly increased basal ACTH (294.4 ± 61.6 pg/ml, p < 0.05), reduced basal cortisol (19.6 ± 7.2 µg/l, p < 0.05), while it did not modify GH levels. After metyrapone pretreatment the ACTH response to HEX was clearly increased (ΔAUC: 2,857.4 ± 901.9 vs. 367.3 ± 274.0 pg/ml/h, p < 0.05), while the GH response was not modified. HEX did not stimulate the low cortisol levels after metyrapone pretreatment. RU-486 significantly increased basal ACTH (76.6 ± 12.5 pg/ml, p < 0.05) and cortisol (312.7 ± 22.2 µg/l, p < 0.05), while it did not modify basal GH levels. RU-486 pretreatment did not modify the ACTH, cortisol and GH responses to HEX. In AD, HEX elicited a marked ACTH response (6,619.4 ± 3,365.8 pg/ml/h; p < 0.01), which was clearly higher (p < 0.01) than that in NS after HEX alone but not significantly different from that after HEX+MET. The GH response to HEX in AD (1,325.6 ± 284.1 µg/l/h) was similar to that in NS (1,519.7 ± 483.8 µg/l/h). In conclusion, our present data demonstrate that the ACTH-releasing activity of HEX is increased in primary hypoadrenalism as well as in normal subjects after metyrapone but not after RU-486 pretreatment. These findings indicate that in normal subjects as well as in hypocortisolemic patients the ACTH-releasing activity of GHS is enhanced by the lack of negative glucocorticoid feedback.