Glucocorticoid regulation of growth hormone (GH) secretagogue-induced growth responses and GH secretagogue receptor expression in the rat

Synthetic GH-releasing peptides such as GHRP-6 are potent GH secretagogues (GHSs) in several species, but attempts to stimulate growth by continuous G HS exposure have had limited success. GHSs also release ACTH and adrenal st eroids, Since glucocorticoid excess is associated with poor linear growth, stimulation of the hypothalamopituitary-adrenal (HPA) axis by continuous GH S administration may compromise their growth-promoting effects. We have now examined the effects of continuous GHRP-6 infusion (100 mu g/day, s.c. for 14 days) in normal 150-day-old female rats, and in adrenalectomized (Adx) rats with or without dexamethasone (Dex) replacement. Infusion of GHRP-6 di d not significantly affect body weight gain compared with excipient-treated controls in either intact rats (controls, 9.0 +/- 1.6 vs GHRP-6, 11.8 +/- 0.9 g) or Adx rats (4.4 +/- 1.5 vs 7.9 +/- 2.7 g). However, GHRP-6 signific antly increased weight gain in Adx rats treated with Dex (controls, 3.5 +/- 1.4 vs GHRP-6, 15.4 +/- 1.6 g; P<0.01). Adrenalectomy decreased plasma tri glycerides (P<0.01), and Dex treatment increased plasma cholesterol (P<0.00 1), GHRP-6 treatment did not affect these plasma lipids. Dex treatment also reduced plasma GH-binding protein levels and hepatic GH binding (P<0.05). Pituitary GH content was decreased in Adx rats (P<0.05) but not in Dex-trea ted Adx rats. Adrenalectomy markedly decreased GHS-receptor mRNA expression in the arcuate (P<0.001) and ventromedial nuclei (P<0.01), whilst Dex trea tment normalized GHS-receptor expression. These results suggest that adrena l steroids are necessary for normal GHS-receptor expression and GHRP-6-indu ced weight gain, but long-term stimulation of the HPA axis by continuous GH S exposure may be detrimental to the growth response. (C) 2000 Harcourt Pub lishers Ltd.