Interaction of the growth hormone releasing peptide hexarelin with somatostatin

Growth hormone releasing peptides (GHRPs) are potent growth hormone (GH) secretagogues. Their interaction with growth hormone releasing hormone (GHRH) has been studied extensively. Data on their interaction with somatostatin (SS) are limited. The aim of this study was to determine the effect of changing SS tone and the effects of SS withdrawal on the somatotroph response to hexarelin and GHRH, alone or in combination. In addition, we studied the effect of SS on the prolactin (PRL) and cortisol response to hexarelin.

Boluses of saline, hexarelin (1 microgram/kg), GHRH-(1-29)-NH2 (1 microgram/kg) or hexarelin plus GHRH-(1-29)-NH2 were administered intravenously 1 hour after the start of a 3-hour constant intravenous infusion of saline, SS(1-14) (20 micrograms/m2/h) (SS20) or SS(1-14) (50 micrograms/m2/h) (SS50). In a second group of studies, the same boluses as above were administered intravenously at the time of withdrawal of a 3-hour constant intravenous infusion of saline or SS20. In a subset of the second group of studies, saline, hexarelin (0.5 microgram/kg) or GHRH-(1-29)-NH2 (0.5 microgram/kg) was administered intravenously two hours before the withdrawal of the SS(1-14) infusion, which was administered at a higher dose of 50 micrograms/m2/h. Studies were performed in a random order.

Twelve healthy adult males (20.3-34.6 years) were studied.

Serum GH and PRL concentrations were measured by immunoradiometric assays. Serum cortisol concentrations were measured by radioimmunoassay.

Infusion of SS20 resulted in a significant reduction in the peak GH response to hexarelin, GHRH-(1-29)-NH2 or hexarelin plus GHRH-(1-29)-NH2 (P < 0.05). The peak serum GH concentrations following the intravenous administration of the two secretagogues, separately or in combination, were reduced further by the higher dose of SS50, but these were not significantly different from their respective peak serum GH concentrations obtained during the infusion of SS20. The peak serum GH concentration following the intravenous administration of hexarelin plus GHRH-(1-29)-NH2 remained large (52.6 +/- 7.2 mU/l; mean +/- SEM) despite the high dose of SS(1-14) (50 micrograms/m2/h). SS(1-14) did not affect the PRL and cortisol response to hexarelin. Withdrawal of SS20 infusion at the time of intravenous bolus administration of hexarelin, but not GHRH-(1-29)-NH2 or hexarelin plus GHRH-(1-29)-NH2, resulted in a significant increase in peak serum GH concentration (P = 0.03). The intravenous administration of hexarelin (0.5 microgram/kg) or GHRH-(1-29)-NH2 (0.5 microgram/kg) during an intravenous infusion of SS50 resulted in a small GH response (peak concentrations 6.8 +/- 3.6 mU/l and 2.4 +/- 0.5 mU/l, respectively) but the later withdrawal of the infusion was not followed by a rise in serum GH concentrations.

This study shows that SS and hexarelin counteract their respective inhibitory and stimulatory action on GH secretion and provides further evidence for their interaction in vivo. The stimulatory effect of hexarelin on the lactotroph and the hypothalamo-pituitary-adrenal axis is unaltered by SS. Hexarelin plus GHRH are synergistic and have potent GH-releasing activity despite a high dose SS infusion. Withdrawal of SS enhances the GH response to hexarelin, which may reflect simultaneous endogenous GHRH release synergizing with hexarelin. A single cycle of pretreatment with hexarelin during SS infusion is insufficient to allow synthesis and storage of sufficient GH to influence its release following SS withdrawal. These findings add further to the data already gathered about GHRPs and their complex interaction with the main regulators of GH secretions.