Glucocorticoid excess inhibits somatic growth in man and laboratory animals. While the mechanism involved is likely to be multifactorial, indirect evidence suggesting the role of an enhanced endogenous somatostatin (SS) tone has been reported. However, there has been no direct evidence indicating an increased synthesis or secretion of hypothalamic SS. In this study, we investigated the effects of glucocorticoids on hypothalamic SS expression by measuring the peptide and mRNA content of SS in whole hypothalamic blocks of male Sprague-Dawley rats sacrificed 4 weeks after adrenalectomy or sham operation. Adrenalectomy decreased the SS content in the rat hypothalamus (p < 0.05), an effect which was reversed by dexamethasone treatment for 10 days. On the other hand, total hypothalamic SS mRNA levels were unaffected by adrenalectomy, but became significantly decreased following dexamethasone treatment (p < 0.05). Using in situ hybridization, this reduction in SS gene expression was shown to occur consistently in the periventricular nucleus and in the parvocellular subdivision of the paraventricular nucleus. The effects of adrenalectomy and dexamethasone on SS mRNA levels were further quantitated in hypothalamic fragments containing predominantly the periventricular and paraventricular nuclei. Somatostatin mRNA levels in these tissue fragments were marginally increased by adrenalectomy (p < 0.05), but showed a 50% reduction following dexamethasone treatment (p < 0.0001). In conclusion, our findings suggest that the inhibitory effect of glucocorticoids on somatic growth is probably not mediated via an effect on hypothalamic SS gene expression.