The hypothalamic-pituitary-adrenal axis is inhibited via negative feedback, which in rats is mediated via type I and II steroid receptors. Although these receptors are present in neural tissue in man, their respective roles have not been systematically examined. Fast-feedback is the first component of negative feedback, occurs within two hours, and is sensitive to the rate of rising cortisol levels. This study examines the role of type I & II steroid receptors in mediating fast-feedback. A within subjects design was used. Subjects were pre-treated with placebo, spironolactone 200mg or RU486 (mifepristone)-type I & II antagonists respectively. This was followed by infusion of either placebo or hydrocortisone. 8 healthy male volunteers were studied on four separate occasions. Plasma cortisol and ACTH were measured by RIA. Significant elevations of morning basal ACTH and Cortisol following RU 486 relative to placebo or spironolactone were observed. ACTH responses to hydrocortisone (i.e. feedback) were not altered by prior administration of spironolactone. In contrast, RU 486 pre-treatment resulted in a significant attenuation of fast-feedback. These results indicate that type II receptors mediate the fast-feedback phase of negative feedback in man.