It has been shown that hexarelin stimulates ACTH and cortisol secretion in patients with Cushing's disease. The ACTH release induced by this peptide is 7-fold greater than that obtained by hCRH. The mechanism of action of hexarelin on the hypothalamic-pituitary-adrenal axis has not been fully elucidated. Although controversial, there is evidence that it might be mediated by arginine vasopressin (AVP). The aim of this study was to evaluate the ACTH and cortisol releasing effects of GHRP-6 in patients with Cushing's disease and to compare them with those obtained with DDAVP administration. We studied 10 patients with Cushing's disease (8 female, 2 male; age: 36.7 +/- 4.2 yr), 9 with microadenomas, who were submitted to both GHRP-6 (2 microg/kg iv) and DDAVP (10 micro g i.v.) in bolus administration on 2 separate occasions. ACTH was measured by immunochemiluminometric assay and cortisol by radioimmunoassay. The sensitivities of the assays are 0.2 pmol/l for ACTH, and 11 nmol/l for cortisol. GHRP-6 was able to increase significantly both ACTH (pmol/l, mean +/- SE; basal: 15.5 +/- 1.7 vs peak: 45.1 +/- 9.3) and cortisol values (nmol/l, basal: 583.0 +/- 90.8 vs peak: 1013.4 +/- 194.6). ACTH AUC (pmol/l min(-1)) and cortisol AUC (nmol/l min(-1)) values were 1235.4 and 20577.2, respectively. After DDAVP administration there was a significant increase in ACTH (basal: 13.0 +/- 1.4 vs peak: 50.5 +/- 16.2) and cortisol levels (basal: 572.5 +/- 112.7 vs peak: 860.5 +/- 102.8. AUC values for ACTH and cortisol were 1627.6 +/- 639.8 and 18364.7 +/- 5661.4, respectively. ACTH and cortisol responses to GHRP-6 and DDAVP did not differ significantly (peak: 45.1 +/- 9.3 vs 50.5 +/- 16.2; AUC: 1235.4 +/- 424.8 vs 1627.6 +/- 639.8). There was a significant positive correlation between peak cortisol values after GHRP-6 and DDAVP administration (r = 0.87, p = 0.001). Our results show that GHRP-6 is able to stimulate ACTH and cortisol release in patients with Cushing's disease. These responses are similar to those obtained after DDAVP injection. These findings could suggest the hypothesis that both peptides act by similar mechanisms, either at hypothalamic or pituitary level.