Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide

Abstract

Objective: Evidence has been presented that in both animals and humans the rebound secretion of growth hormone (GH) following withdrawal of an infusion of somatostatin (SS) is due to the functional activation of the hypothalamic GH-releasing hormone (GHRH) neurons of the recipient organism. Based on this premise, this study has sought to assess the existence of functional interactions between endogenous GHRH released by a SS infusion withdrawal (SSIW) and growth hormone-releasing peptides (GHRPs), a class of compounds allegedly acting via GHRH. Methods: Five young dogs (3 to 4 years old, 2 male and 3 female) were administered, on different occasions, three consecutive intravenous boli of physiological saline (0.1 ml/kg), or GHRH (2 mg/kg), or EP92632 (125 mg/kg), a GHRP compound, or GHRH plus EP92632 at the end of three cycles of 1-h SS infusions (8 mg/(kgÂh)) or during a 6-h infusion of saline. Results: Under saline infusion (SALI), plasma GH levels were unaltered, whereas each SSIW cycle was followed by similar GH secretory episodes. Administration of the ®rst GHRH bolus under SALI induced a rise in plasma GH concentrations slightly higher than that induced by the ®rst cycle of SSIW, but the GH response to the second and third GHRH boli was similar to that after SSIW. Following SSIW, the response to the ®rst bolus of GHRH was higher than that during SALI, but the second and third cycles of SSIW induced GH responses similar to those evoked by the GHRH bolus. During SALI, administration of the ®rst bolus of EP92632 induced a rise in plasma GH which was higher than that induced by the ®rst GHRH bolus, the second bolus elicited a GH peak of lesser amplitude and there was a partial restoration of the GH response to the third peptide bolus. SSIW strikingly enhanced the GH release to the ®rst EP92632 bolus, a pattern also present, although to a lesser extent, with the second and third cycles of SSIW. Under SALI, combined administration of GHRH and EP92632 had a synergistic effect on GH release, but a progressive reduction was present in the GH response to the second and third GHRH plus EP92632 boli. SSIW increased only weakly the GH response to the ®rst co-administration of the peptides over that present after administration of EP92632 alone, and did not induce a GH response higher than that present during SALI when the second bolus of the peptides was administered; after the third SSIW a GH rise higher than that present during SALI was elicited by the combined administration of the peptides. Conclusions: (i) the uniformity of the GH rebound responses to multiple cycles of SSIW may indicate that the latter activate a physiological mechanism which mimics that normally controlling GH pulse generation; (ii) EP92632 elicits, under our experimental conditions, a plasma GH rise higher than that induced by GHRH; (iii) SSIW enhances the GH response to EP92639 alone, to an extent reminiscent of that following combined administration of GHRH and EP92632. This pattern reinforces the view that SSIW elicits release of end...

Somatostatin infusion withdrawal and growth hormone release in dogs and man

“…It is dif®cult to predict the response to SS withdrawal plus GHRP in GHND children. Synthetic GHSs seem to require the presence of endogenous GHRH for their full in vivo effect on GH release so it seems plausible that a moderate response to SS withdrawal plus GHRP would be observed in GHND as suggested (4).…”

“…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.…”

“…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.…”

“…Based on their results Rigamonti et al (4) suggest that the combined application of SS withdrawal and GHRP administration might be a useful test for the diagnosis of GH de®ciency (GHD), perhaps even discriminating GHD of pituitary origin from hypothalamic impairment. The diagnosis of GHD in both children and adults is far from simple and in both instances requires the use of provocative tests of GH secretion.…”

“…This procedure alone could therefore lead to a high number of false positive results although it has been used successfully to discriminate normal control from GHD children (9). Administration of GHRP at the termination of SS infusion does appear to be a robust stimulus for GH secretion both in dogs (4) and humans (6) although it seems that this is no more effective than the combined administration of GHRH plus GHRP during saline infusion (4). This latter combination has also recently been proposed as a test for GHD (10,11) and would seem to offer advantages of reproducibility as well as simplicity and rapidity over SS withdrawal since it does not require a 1-h long infusion period before injecting the secretagogue.…”