Activation of the Hypothalamo-Pituitary-Adrenal Axis by the Growth Hormone (GH) Secretagogue, GH-Releasing Peptide-6, in Rats

Abstract

GH-releasing hexapeptide (GHRP-6) is a synthetic secretagogue that stimulates the release of GH by acting at both hypothalamic and pituitary sites. GHRPs also consistently elicit small, but significant, increases in plasma concentrations of ACTH and adrenal steroids. As these secretagogues do not release ACTH directly, they probably interact with the hypothalamic peptidergic systems controlling ACTH release, such as CRH and arginine vasopressin (AVP). We have now examined the activation of the hypothalamo-pituitary-adrenal axis by GHRP-6 in conscious rats. In a series of experiments, rats were injected i.v. with 10 microg GHRP-6, 2 microg CRH, 0.5 microg AVP, or saline, alone or in combination, and serial plasma samples withdrawn and assayed for ACTH, corticosterone, and GH. CRH and AVP increased plasma ACTH levels in all rats, whereas ACTH and corticosterone responses to GHRP-6 were variable and were dependent on the prevailing activity of the hypothalamo-pituitary-adrenal axis. GHRP-6 stimulated the largest ACTH responses in rats that had the lowest basal plasma ACTH and corticosterone levels before GHRP-6 administration. GHRP-6 given in combination with CRH did not increase ACTH levels beyond the response to CRH alone (change in ACTH, 1570 +/- 207 vs. 1714 +/- 245 pg/ml), whereas the combination of GHRP-6 and AVP markedly increased ACTH levels compared with the effects of AVP alone (change in ACTH, 5587 +/- 669 vs. 2338 +/- 451 pg/ml; P < 0.05). The GH responses to GHRP-6 were significantly greater in rats with low basal plasma ACTH and corticosterone levels than in rats with elevated ACTH and corticosterone levels (change in GH response, 119 +/- 27 vs. 29 +/- 7 ng/ml; P < 0.01). CRH alone significantly inhibited GH release (pre- vs. 40 min post-CRH, 11.9 +/- 3.8 vs. 1.7 +/- 0.4 ng/ml; P < 0.05), whereas AVP alone had no effect on GH levels. Neither CRH nor AVP had any effect on the GH response to GHRP-6. We suggest that GHRP-6 acts via the hypothalamus to mediate the release of ACTH, and that these effects are probably mediated at least in part via the release of endogenous CRH and are subject to regulation by circulating glucocorticoids.

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

“…Among the effects of GHS-R ligands unrelated to GH release, moderate but consistent elevation of serum adrenocorticotropin (ACTH) and glucocorticoid levels have been reported for a variety of GHSs in different species (2,5,6,8,9,23). In good agreement, it was shown recently that ghrelin is able to elicit ACTH and cortisol responses in humans (18,20), as well as ACTH and corticosterone release in rats and mice respectively (19,24).…”

“…In addition, GHSs are able to elicit a number of biological responses in different endocrine and non-endocrine systems. These include modulation of food intake (3,4), stimulation of prolactin secretion (2, 5 -7), activation of the corticotropic axis (2,5,6,8,9), as well as a variety of cardiovascular effects (10,11). Recently, an unexpected widespread pattern of GHS-binding sites in a variety of peripheral tissues has been demonstrated in humans (12), thus not only providing the basis for their currently known effects, but also strongly suggesting additional, as yet undefined, biological actions of these synthetic compounds.…”

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

“…However, Thomas et al (1997) have shown that GHRP-6 mediated the release of ACTH and cortisol in conscious rats. The mechanism by which ghrelin and synthetic GHSs stimulate the pituitary-adrenocortical axis is still unknown, but seems to be mediated via the hypothalamus as it is lost after cutting the pituitary stalk (Loche et al, 1995).…”

“…The mechanism by which ghrelin and synthetic GHSs stimulate the pituitary-adrenocortical axis is still unknown, but seems to be mediated via the hypothalamus as it is lost after cutting the pituitary stalk (Loche et al, 1995). They may interact with hypothalamic peptides (e.g., corticotrophin-releasing hormone, arginine vasopressin, and neuropeptide Y) controlling ACTH release (Broglio et al, 2003;Dickson and Luckman, 1997;Korbonits et al, 1999;Thomas et al, 1997), most probably primarily via arginine vasopressin (Korbonits et al, 1999). In swine, some recently developed selective GHSs, such as ipamorelin, induced massive GH secretion without any elevation in ACTH, cortisol, or PRL release (Raun et al, 1998), whereas GHRP-6 and GHRP-2 administration in this species caused a strong activation of the pituitary-adrenocortical axis.…”

“…In man, synthetic GHSs such as GHRP-6 also stimulates the secretion of Prolactin (PRL), adrenocorticotropic hormone (ACTH), and cortisol (Arvat et al, 2001;Casanueva and Dieguez, 1999;Lamberts, 1999;Massoud et al, 1996;Smith et al, 1997). Moreover in rats, GHRP-6 activates the pituitary-adrenocortical axis (Thomas et al, 1997).…”