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

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 AGTH, cortisol and GH responses to HEX (2.0 mu g/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 mu g/l, p < 0.05) and GH (72.6 +/- 23.5 vs. 3.7 +/- 1.3 mu g/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 mu g/l, p < 0.05), while it did not modify GH levels. After metyrapone pretreatment the ACTH response to HEX was clearly increased (Delta AUC: 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 mu g/l, p < 0.05), while it did nor 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 mu g/l/h) was similar to that in NS (1,519.7 +/- 483.8 mu g/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.