The inhibitory action of physiological to pathophysiological serum cortisol levels on TSH secretion were investigated in 12 patients with Addison's disease on 3 occasions. 1) In continuation of the conventional hydrocortisone (HC) substitution, a medium dose of HC (0.5 mg/kg) was infused over 23 h. 2) After 24-h withdrawal of HC, the patients had placebo infusion over 23 h. 3) After 5 days of dexamethasone (1.5 mg/day), a high dose of HC (2.0 mg/kg) was infused over 23 h. Blood sampling was performed every 10 min during the last 10 h of the study period, followed by a TRH test (10 micrograms, iv), To mimic the normal diurnal rhythm for serum cortisol, HC was infused in graduated doses, and during medium dose infusion, the serum cortisol level and the TSH pulsatility pattern were similar to those seen in normal controls. The TSH mean level was 1.0 +/- 0.5 mU/L during medium doses of HC, increasing significantly (P < 0.05) to 2.0 +/- 1.6 mU/L during the low cortisol state and was significantly (P < 0.05) suppressed to 0.4 +/- 0.2 mU/L during high doses of glucocorticoids, when the pulse frequency was also significantly reduced (P < 0.01). Together with a dose-dependent inhibitory action of glucocorticoids on the TSH response to TRH, our data indicate that even physiological serum levels of cortisol have an influence on endogenous TSH secretion, probably caused by regulation of the pituitary sensitivity to TRH.