GH-releasing peptides (GHRPs), a class of small synthetic peptide and non-peptide compounds, act on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in both humans and other animals. GHRPs, like corticotropin-releasing hormone (CRH), also possess acute ACTH- and cortisol-releasing activity, although the mechanisms underlying the stimulatory effect of GHRPs on the hypothalamo-pituitary-adrenal (HPA) axis are still unclear. In recent years, studies in humans and other animals have provided evidence that the rebound GH rise which follows withdrawal of an infusion of somatostatin (SS) (SSIW) is due, at least in part, to the functional activation of GH-releasing hormone (GHRH) neurons of the recipient organism. Unexpectedly, in humans, SS infusion, at a dose inhibiting basal GH secretion, has been associated with an activation of the HPA axis, leading to the hypothesis that this response was mediated, at least in part, by a central nervous system ACTH-releasing mechanism activated by the SS-induced decrease in GH secretion. Interestingly, the rebound GH rise which follows SSIW was magnified by the administration, before SS withdrawal, of a GHRP, implying that the SSIW approach could also be exploited to investigate in vivo the functional interaction in the process of GH and/or ACTH/cortisol secretion between endogenous GHRH (and/or other ACTH-releasing mechanisms) and GHRPs. In the present study, six young beagle dogs were given, on different occasions, at the beginning and at the end of a 3-h i.v. infusion of SS or saline (SAL), a bolus of physiological SAL or a GHRP compound, EP51216. SSIW induced a GH rebound rise without affecting plasma cortisol concentrations, while the withdrawal of SAL infusion was ineffective on either hormone paradigm. Administration of EP51216 at the beginning of SAL infusion evoked release of both GH and cortisol, whereas EP51216 administration at the withdrawal of SAL infusion evoked somatotroph and cortisol responses which were reduced in amplitude and duration. SS infusion significantly reduced the secretion of GH elicited by EP51216 but did not affect the rise of plasma cortisol levels. Interestingly, SSIW resulted in a marked enhancement of the somatotroph and cortisol responses evoked by EP51216. The marked rise of plasma GH levels induced by the GHRP after SSIW recalled that occurring after acute combined administration of recombinant human GHRH and EP51216, implying that exogenously delivered GHRP had synergized with the endogenous GHRH release triggered by SSIW. In contrast, acute combined administration of GHRH and the GHRP induced a cortisol response not different from that induced by GHRP alone, indicating that endogenous GHRH release was not involved in the enhanced cortisol response following EP51216 administration after SSIW. Similarly, the direct involvement of endogenous CRH could be ruled out, since i.v. administration of ovine CRH after SSIW evoked cortisol peak levels not different from those evoked by CRH at the withdrawal of SAL infusion. In conclusion, enhancement of the GH response to EP51216 alone by SSIW, to an extent reminiscent of that following combined administration of GHRH and EP61216, reinforces the view that SSIW elicits release of endogenous GHRH. Further studies are indeed necessary for a better understanding of the mechanisms underlying the enhanced cortisol response, since from now on the involvement of endogenous GHRH or CRH can be ruled out.

Ghrelin, a novel endogenous ligand for the GH secretagogue receptor, has been reported to stimulate GH secretion and food intake in both humans and other animals. Interestingly, recent data indicate that ghrelin is up- and down-regulated in anorexia nervosa (AN) and obesity, which are also known to be accompanied by increased and reduced GH levels respectively. Ageing is associated with a gradual but progressive reduction in GH secretion, and by alterations in appetite and food intake. The role of ghrelin in the decline of somatotroph function and the anorexia of ageing is unknown. To investigate the influence of age on circulating levels of ghrelin, a total of 19 young and old normal weight subjects (Y-NW, n=12; O-NW, n=7), six patients with active AN (A-AN), and seven patients with morbid obesity (OB) were studied. In addition to fasting plasma ghrelin concentrations, baseline serum TSH, IGF-I and insulin levels were measured. Mean plasma ghrelin concentrations in A-AN or OB were higher and lower respectively than those present in Y-NW. Interestingly, mean plasma ghrelin concentrations in O-NW were significantly lower than those present in Y-NW and superimposable on those of OB. The mean fasting plasma ghrelin concentrations in all groups of subjects were negatively correlated with body mass index and serum insulin levels, but not with TSH and IGF-I levels. This study provides evidence of an age-related decline of plasma ghrelin concentrations, which might explain, at least partially, the somatotroph dysregulation and the anorexia of the elderly subject.