Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone

Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans : comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone / E. Arvat, M. Maccario, L. Di Vito, F. Broglio, A. Benso, C. Gottero, M. Papotti, G. Muccioli, C. Dieguez, F.F. Casanueva, R. Deghenghi, F. Camanni, E. Ghigo

  • Journal of Clinical Endocrinology & Metabolism 86 (2001) 3 (1 March); p. 1169–1174
  • PMID: 11238504
  • DOI: 10.1210/jcem.86.3.7314


An endogenous ligand for the GH secretagogue-receptor (GHS-receptor) has recently been isolated, from both the rat and the human stomach, and named ghrelin. It is a 28-amino-acid peptide showing a unique structure with an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. In fact, it has been demonstrated that ghrelin specifically stimulates GH secretion from both rat pituitary cells in culture and rats in vivo. The aim of the present study was to test the GH-releasing activity of ghrelin in humans and to compare it with that of GHRH and hexarelin (HEX), a nonnatural peptidyl GHS, which possesses strong GH-releasing activity but also significantly stimulates PRL, ACTH, and cortisol secretion. To clarify the mechanisms of action underlying the GH-releasing activity of ghrelin in humans, its interaction with GHRH and HEX was also studied. Seven normal young volunteers (7 men; 24-32 yr old; body mass index, 20-24 kg/m(2)) were studied. All subjects underwent the administration of ghrelin, HEX, and GHRH-29 (1.0 microg/kg i.v. at 0 min) as well as placebo (2 mL isotonic saline i.v. at 0 min). Six subjects also underwent the combined administration of ghrelin and GHRH or HEX. Blood samples were taken every 15 min from -15 up to +180 min. GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after administration of ghrelin and/or HEX. Ghrelin administration induced a prompt and marked increase in circulating GH levels (Cmax, mean +/- SEM, 92.1 +/- 16.7 microg/L; area under the curve, 1894.9 +/- 347.8 microg/L.h). The GH response to ghrelin was clearly higher (P < 0.01) than the one recorded after GHRH (26.7 +/- 8.7 microg/L; 619.6 +/- 174.4 microg/L.h) and even significantly higher (P < 0.05) than after HEX (68.4 +/- 14.7 microg/L; 1546.9 +/- 380.0 microg/L x h). Ghrelin administration also induced an increase in PRL, ACTH, and cortisol levels; these responses were higher (P < 0.05) than those elicited by HEX. A significant increase in aldosterone levels was recorded after ghrelin but not after HEX. The endocrine responses to ghrelin were not modified by the coadministration of HEX. On the other hand, the coadministration of ghrelin and GHRH had a real synergistical effect (P < 0.05) on GH secretion (133.6 +/- 22.5 microg/L; 3374.3 +/- 617.3 microg/L x h). In conclusion, ghrelin, a natural ligand of GHS-receptor, exerts a strong stimulatory effect on GH secretion in humans, releasing more GH than GHRH and even more than a nonnatural GHS such as HEX. Ghrelin, as well as HEX, also stimulates lactotroph and corticotroph secretion. Ghrelin shows no interaction with HEX, whereas it has a synergistical effect with GHRH on GH secretion. Thus, ghrelin is a new hormone playing a major role in the control of somatotroph secretion in humans, and its effects are imitated by nonnatural GHS.

Original document


Research / Study
1 March 2001
Arvat, Emanuela
Benso, Andrea
Broglio, Fabio
Camanni, Franco
Casanueva, Felipe F.
Deghenghi, Romano
Di Vito, Lidia
Dieguez, Carlos
Ghigo, Ezio
Gottero, Cristina
Maccario, Mauro
Muccioli, Giampiero
Papotti, Mauro
Other organisations
Università degli Studi di Torino (UNITO) - University of Turin
Doping classes
S2. Peptide Hormones, Growth Factors
Examorelin (hexarelin)
Growth Hormone Releasing Peptide (GHRP)
Growth Hormone Secretagogues (GHS)
Growth hormone-releasing hormone (GHRH)
Document category
Scientific article
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Pdf file
Date generated
8 December 2021
Date of last modification
24 January 2022
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