Supraphysiological doses of glucocorticoids inhibit growth hormone (GH) secretion in man and experimental animals. We investigated whether glucocorticoids inhibit GH secretion through changes in the gene expression of GH, hypothalamic somatostatin (SS) and GH-releasing hormone (GHRH), and whether such changes vary with the dose and duration of glucocorticoid excess. Male rats, 6 weeks of age, were treated with injections of either saline or different doses of dexamethasone (40, 200, 500 or 1,000 micrograms/kg/day) intraperitoneally for 3 or 8 days. Total RNA extracted from the anterior pituitary and hypothalamus was analyzed by Northern blot hybridization. SS mRNA level was also assessed in smaller hypothalamic fragments containing predominantly the periventricular and paraventricular nuclei, and by in situ hybridization. A biphasic effect on SS mRNA levels was observed such that a significant increase (p < 0.001) was demonstrated in the periventricular nucleus after 3 days of dexamethasone 1,000 micrograms/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 levels showed a reduction which appeared to increase with the dose and duration of treatment and became statistically significant after 8 days at doses > or = 200 micrograms/kg/day (p < 0.05). Pituitary GH mRNA levels were increased after 3 days at doses > or = 500 micrograms/kg/day (p < 0.05) but showed no significant change at all doses after 8 days. We conclude that glucocorticoid excess is associated with changes in the gene expression of GH, hypothalamic SS and GHRH, which vary with the dose and duration of glucocorticoid treatment. Glucocorticoids inhibit GH secretion in vivo through a reduction in hypothalamic GHRH gene expression and, in animals with shorter duration of glucocorticoid excess also through an increase in SS gene expression in the periventricular nucleus.