The GH-releasing effect of ghrelin, a natural GH secretagogue, is only blunted by the infusion of exogenous somatostatin in humans

OBJECTIVE: Ghrelin, a 28-amino-acid peptide purified from the stomach and showing a unique structure with an n-octanoyl ester at the serine 3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R). Ghrelin strongly stimulates GH secretion in both animals and humans, showing a synergistic effect with GH-releasing hormone (GHRH) but no interaction with synthetic GHS. However, the activity of ghrelin as well as that of non-natural GHS is not fully specific for GH; ghrelin also induces a stimulatory effect on lactotroph and corticotroph secretion, at least in humans. DESIGN: To further clarify the mechanisms underlying the GH-releasing activity of this natural GHS, we studied the effects of somatostatin (SS, 2.0 μg/kg/h from -30 to +90 min) on the endocrine responses to ghrelin (1.0 μg/kg i.v. at 0 min) in seven normal young male volunteers [age (mean ± SEM) 28.6 ± 2.9 years; body mass index (BMI) 22.1 ± 0.8 kg/m²]. In the same subjects, the effect of SS on the GH response to GHRH (1.0 μg/kg i.v. at 0 min) was also studied. MEASUREMENTS: Blood samples were taken every 15 min from -30 up to +120 min. GH levels were assayed at each time point in all sessions; PRL, ACTH and cortisol levels were assayed after ghrelin administration alone and during SS infusion. RESULTS: The GH response to ghrelin (hAUC0^{0′→120′} 2695.0 ± 492.6 μg min/l) was higher (P < 0.01) than that after GHRH (757.1 ± 44.1 μg min/l). SS infusion almost abolished the GH response to GHRH (177.0 ± 37.7 μg min/l, P < 0.01); the GH response to ghrelin was inhibited by SS (993.8 ± 248.5 μg min/l, P < 0.01) but GH levels remained higher (P < 0.05) than with GHRH. Ghrelin induced significant increases in PRL, ACTH and cortisol levels and these responses were not modified by SS. CONCLUSIONS: Ghrelin, a natural GHS-R ligand, exerts a strong stimulatory effect on GH secretion in humans and this effect is only blunted by an exogenous somatostatin dose which almost abolishes the GH response to GHRH. The stimulatory effect of ghrelin on lactotroph and corticotroph secretion is refractory to exogenous somatostatin, indicating that these effects occur through pathways independent of somatostatinergic influence.