Hexarelin (HEX) is a synthetic growth hormone-releasing peptide (GHRP) which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in an age-dependent manner. Like other GHRPs, HEX possesses also prolactin (PRL) and ACTH/cortisol-releasing activity. similar to that of human corticotropin-releasing hormone (hCRH). The mechanisms underlying the stimulatory effect of GHRPs on lactotrope and corticotrope secretion are even less clear and the influence of age on these endocrine activities of GHRPs is unknown. To clarify this point we studied the GH, PRL, ACTH and cortisol responses to the maximal effective dose of HEX (2.0 micrograms/kg i.v.) in: 12 prepubertal children (Pre-C, 8 male, 4 female, age 5.8-12.1 years); 12 pubertal normal short children (Pub-C, 5 male, 7 female, age 9.7-15.5 years, pubertal stage II-IV); 20 normal young adults (Young, 6 males, 14 females, age 23-32 years); and in 16 normal elderly people (Elderly, 5 male, 11 female, age 66-81 years). The GH response to HEX was clear in Pre-C (0-120 min area under curve, mean +/- S.E.M. 769.5 +/- 122.2 microgramsmin/l) but strikingly increased (P < 0.001) in Pub-C (1960.2 +/- 283.5 microgramsmin/l). The HEX-induced GH rise in Young (1829.7 +/- 243.1 microgramsmin/l) persisted similar to that in Pub-C, but decreased in Elderly (951.1 +/- 232.9 microgramsmin/I, P < 0.005); the latter was, in turn, similar to that in Pre-C. HEX induced a significant PRL increase which, however, showed no age-related variations, being similar in Pre-C (512.1 +/- 88.0 microgramsmin/l), Pub-C (584.0 +/- 106.0 microgramsmin/l), Young (554.9 +/- 56.0 microgramsmin/l) and Elderly (523.9 +/- 59.6 microgramsmin/l). The ACTH-releasing activity of HEX was present in Pre-C (1356.6 +/- 204.9 pgmin/ml) and was clearly enhanced (P < 0.02) in Pub-C (2253.5 +/- 242.8 pgmin/ml). The ACTH rise after HEX in Young (1258.1 +/- 141.2pgmin/ml) was lower (P < 0.02) than that in Pub-C and similar to that in Pre-C, while the ACTH response to HEX in Elderly (1786.5 +/- 340.1 pgmin/ml) showed a further trend toward increase, being similar to that in Pub-C. On the other hand, the cortisol response to HEX showed no significant age-related variations, being not different in Pre-C (7747.2 +/- 1031.6 microgramsmin/l), Pub-C (6106.0 +/- 862.9 microgramsmin/l), Young (6827.5 +/- 509.6 microgramsmin/I) and Elderly (7950.6 +/- 658.3 microgramsmin/l). In conclusion, our present data demonstrate that in humans the GH- and ACTH-releasing activities of HEX undergo different age-related variations, while its PRL-releasing activity is not dependent on age. These finding suggest that actions at different levels and/or on different receptor subtypes mediate the different age-related hormonal effects of GHRPs.