GENE-EXPRESSION OF HYPOTHALAMIC SOMATOSTATIN AND GROWTH HORMONE-RELEASING HORMONE IN DEXAMETHASONE-TREATED RATS

Supraphysiological doses of glucocorticoids inhibit growth hormone (GH ) secretion in man and experimental animals. We investigated whether g lucocorticoids inhibit GH secretion Growth hormone through changes in the gene expression of GH, hypothalamic somatostatin (SS) and GH-relea sing hormone (GHRH), and whether such changes vary with the dose and d uration of glucocorticoid excess. Males rats, 6 weeks of age, were tre ated with injections of either saline or different doses of dexamethas one (40, 200, 500 or 1,000 mu g/kg/day) intraperitoneally for 3 or 8 d ays. Total RNA extracted from the anterior pituitary and hypothalamus was analyzed by Northern blot hybridization. SS mRNA level was also as sessed in smaller hypothalamic fragments containing predominantly the periventricular and paraventricular nuclei, and by in situ hybridizati on. A biphasic effect on SS mRNA levels was observed such that a signi ficant increase (p < 0.001) was demonstrated in the periventricular nu cleus after 3 days of dexamethasone 1,000 mu g/kg/day, but a reduction in hypothalamic SS mRNA was seen after 8 days for all doses employed (p < 0.05 or p < 0.01). On the other hand, hypothalamic GHRH mRNA leve ls showed a reduction which appeared to increase with the dose and dur ation of treatment and became statistically significant after 8 days a t doses greater than or equal to 200 mu g/kg/day (p < 0.05). Pituitary GH mRNA levels were increased after 3 days at doses greater than or e qual to 500 mu g/kg/day (p < 0.05) but showed no significant change at all doses after 8 days. We conclude that glucocorticoid excess is ass ociated with changes in the gene expression of GH, hypothalamic SS and GHRH, which vary with the dose and duration of glucocorticoid treatme nt. Glucocorticoids inhibit GH secretion in vivo through a reduction i n hypothalamic GHRH gene expression and, in animals with shorter durat ion of glucocorticoid excess, also through an increase in SS gene expr ession in the periventricular nucleus.