EXPERIMENTAL STUDY Endocrine activities of alexamorelin (Ala-His-D-2-methyl-Trp- Ala-Trp-D-Phe-Lys-NH 2 ), a synthetic GH secretagogue, in humans Fabio Broglio, Andrea Benso, Cristina Gottero, Giampiero Muccioli 1 , Romano Deghenghi 2 , Ezio Ghigo and Emanuela Arvat Division of Endocrinology, Department of Internal Medicine, 1 Department of Pharmacology and Forensic Medicine, University of Turin, Italy and 2 Europeptides, Argenteuil, France (Correspondence should be addressed to E Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C. so Dogliotti 14, 10126 Torino, Italy; Email: ezio.ghigo@unito.it) Abstract Objective: Peptidyl and non-peptidyl synthetic GH secretagogues (GHS) possess signi®cant GH-, prolactin (PRL)- and ACTH/cortisol-releasing activity after i.v. and even p.o. administration, acting via speci®c hypothalamo±pituitary receptors in both animals and humans. The hexapeptide hexarelin (HEX) is a paradigmatic GHS whose activities have been widely studied in humans. The heptapeptide Ala-His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH 2 (alexamorelin, ALEX) is a new synthetic molecule which inhibits GHS binding in vitro, but its endocrine activity has never been studied in humans. Design: In six young adults we studied the effects of 1.0 and 2.0 mg/kg i.v. ALEX or HEX on GH, PRL, ACTH, cortisol and aldosterone levels and those of 20 mg p.o. (<300 mg/kg) on GH levels. Results: Basal GH, PRL, ACTH, cortisol and aldosterone levels in all testing sessions were similar. ALEX and HEX (1.0 and 2.0 mg/kg i.v.) induced the same dose-dependent increase of GH and PRL levels. Both ALEX and HEX induced a dose-dependent increase of ACTH and cortisol levels. The ACTH and cortisol responses to the highest ALEX dose were signi®cantly higher than those after HEX. Aldosterone levels signi®cantly increased after both i.v. ALEX doses, but not after HEX. The GH response to 20mg p.o. ALEX was higher, though not signi®cantly, than that to the same HEX dose. Conclusion: ALEX, a new GHS, shows the same GH-releasing activity as HEX. On the other hand, ALEX seems endowed with an ACTH-releasing activity more marked than that of HEX; this evidence could explain the signi®cant increase of aldosterone levels after its i.v. administration. European Journal of Endocrinology 143 419±425 Introduction Growth hormone secretagogues (GHS) are synthetic, non-natural, peptidyl and non-peptidyl molecules which possess a potent stimulatory effect on somato- troph secretion after i.v., s.c., intranasal and even p.o. administration in both animals and humans (1±4). The activity of GHS is not fully speci®c; in fact they possess also slight stimulatory effects on prolactin (PRL), adrenocorticotrophin (ACTH) and cortisol secretion (2, 3, 5). Though synthetic and non-natural, GHS act via speci®c receptors distributed at the pituitary level as well as within the CNS, particularly at the hypothalamic level (3, 6±8). A human GHS receptor has recently been cloned and shows no signi®cant homology with any other G-protein coupled receptor known so far (3, 6, 9, 10); however, the existence of GHS receptor subtypes has also been reported (8±11). This evidence pointed towards the existence of an endogenous GHS-like ligand which could be represented by a recently discovered gastric peptide named ghrelin (12). The mechanisms underlying the endocrine activities of GHS involve actions at the pituitary and, mainly, at the hypothalamic level (1±4). In fact, the endocrine activities of GHS are almost abolished by pituitary stalk lesions in animals as well as in patients with hypo- thalamo±pituitary disconnection (13, 14). GH-releasing peptide (GHRP)-6, a hexapeptide, was the ®rst GHS studied in humans (1, 2, 4); more recently, the endocrine activities of other hexapeptides, e.g. GHRP-2 and hexarelin (HEX), two GHRP-6 super- analogues, have also been extensively investigated in humans as well as in animals (1, 4, 15±17). Other penta-, hexa-, hepta- and octapeptides have been synthesized and reported active in humans (1±3, 18, European Journal of Endocrinology (2000) 143 419±425 ISSN 0804-4643 q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org