Somatostatin infusion withdrawal and growth hormone release in dogs and man.

Abstract

The hypothalamic neuropeptides growth hormonereleasing hormone (GHRH) and somatostatin (SS), respectively, stimulate and inhibit the release of growth hormone (GH) from the anterior pituitary gland in both man and other animals. Even before the discovery of GHRH (in 1982) a series of small peptides, derived from met-enkephalin, had been developed and shown to specifically release GH in vitro (1). These GH-releasing peptides (GHRPs) along with a number of non-peptide analogues (collectively termed GH secretagogues; GHS) are now known to act on a specific GH secretagogue receptor (GHS-R), present in the hypothalamus and pituitary (2). Recently, a peptide isolated from rat stomach (and called ghrelin) was identified as an endogenous ligand for the GHS-R and suggests another pathway in the regulation of GH secretion (3). In this issue of the European Journal of Endocrinology, Rigamonti et al. (4) investigate functional interactions between GHRH and a GHRP on the GH response that occurs at the end of a peripheral infusion of SS. The rebound GH response to SS withdrawal is well documented in both humans and other animals and appears to be mediated by increased hypothalamic GHRH release. The mechanism of action of synthetic GHSs is complex. Although in vitro studies have shown a direct pituitary action of GHSs, the GH response is attenuated in humans and other animals with hypothalamic‐pituitary disconnection or following blockade of endogenous GHRH, suggesting that activation of hypothalamic GHRH neurones is an important mechanism of action of these compounds in vivo (5). Numerous studies have reported the effects of SS withdrawal, GHRH administration and GHS administration on GH release in both man and other animals. Here, Rigamonti et al. (4) have tried to probe the interaction between endogenously released GHRH following SS withdrawal and exogenously administered GHRP in dogs since they are a good model for GH regulation in humans. Whereas administration of GHRH at the end of SS infusion had a slight additive effect on GH secretion compared with the response seen during saline infusion, a marked enhancement of the GH response was seen following administration of GHRP at the termination of SS infusion compared with saline infusion. This is in agreement with the findings of a similar study performed in man using SS, GHRH and the synthetic GHS, hexarelin (6). It is possible that this reflects a synergistic interaction between endogenous GHRH (following SS withdrawal) with the administered GHRP. However, this hypothesis has not been tested directly and it is important to note that while the acute GH response to SS withdrawal can be blocked by GHRH antiserum in rats, a GHRH antagonist failed to prevent the GH rise to SS withdrawal in humans (7), highlighting potential species differences in the generation of GH pulses. This is an important point, since it reminds us that we must remain cautious in the extrapolation of animal data to human physiology. Furthermore, if the GH response to SS withdrawal is not due to increased GHRH then what other mechanisms could be responsible (ghrelin perhaps)? The answer to this question may give us more insight into interactions between SS, GHRH and GHSs involved in the regulation of GH secretion.