The type I glucocorticoid receptor antagonist spironolactone was administered to healthy volunteers to determine the effect of type I receptor blockade on adrenocorticotropic hormone (ACTH) and cortisol secretion in humans. On separate days and in a double-blind, randomized fashion, placebo and each of four increasing doses of spironolactone were administered orally to subjects. Doses were selected to be within the clinically used range and, following drug administration, baseline and ovine-corticotropin releasing hormone (oCRH)-stimulated ACTH and cortisol plasma levels were measured. In contrast to the clear effects of type II glucocorticoid receptor blockade on human pituitary adrenal function, no relationship between spironolactone dose or plasma levels and either basal or oCRH-stimulated pituitary-adrenal function was noted at doses comparable to those which induce type I receptor blockade and cardiovascular therapeutic effects in the kidney. These data suggest that, at physiologically relevant doses, type I glucocorticoid receptor blockade does not affect HPA axis function.