In order to determine the mechanism by which glucocorticosteroids decrease the serum concentration of thyrotropin (TSH), we studied eight normal subjects before and after they received 16 mg of dexamethasone daily for 2 1/2 days. Serum levels of TSH and prolactin (PRL) were measured in the basal state and in response to the intravenous administration of 200 mug thyrotropin-releasing hormone (TRH); T4, free T4 (fT4), T3, and free T3 (fT3) were measured before TRH injection. Metabolic clearance rates of TSH corrected for body surface area (MCR-TSH/m2) were determined by the method of constant infusion to equilibrium; the production rates of TSH (PR-TSH/m2) were calculated. Dexamethasone produced a decrease in basal TSH from 2.2 to 0.8 muU/ml (P less than 0.02), a statistically insignificant elevation in MCR-TSH/m2 from 25.8 to 34.1 ml/min/m2, and a decrease in PR-TSH/m2 from 79 to 30 mU/day/m2 (P less than 0.01). Peak TSH response to TRH decreased from 16.4 to 5.8 muU/ml (P less than 0.005), as did TSH reserve from 1.58 to 0.54 mU - min/ml (P less than 0.005). Repetitive TRH testing alone did not account for these changes. Basal PRL, peak PRL after TRH, and PRL reserve did not change significantly after dexamethasone administration. Although Basal T4 and fT4 did not change significantly, dexamethasone did decrease T3 from 106 to 61 ng/dl (P less than 0.001) and fT3 from 174 to 76 pg/dl (P less than 0.05). Dexamethasone produced similar changes in patients with various thyroid disorders. In addition, when plasma cortisol was lowered by metyrapone administration in 25 euthyroid patients, the serum TSH concentration rose from 1.6 to 3.1 muU/ml (P less than 0.001). These data indicate that dexamethasone a) suppresses TSH secretion without increasing fT3 and fT4 and b) blunts the TSH, but not the PRL response, to TRH. Hence, one effect of the administration of dexamethasone in high dose is a direct suppression of pituitary TSH secretion. Furthermore, physiologic levesl of circulating cortisol also have a suppressive effect on serum TSH.