To investigate the mechanism of adrenal suppression by high-dose MPA, we performed direct and indirect stimulation tests in postmenopausal women with disseminated breast cancer who were receiving MPA and in a postmenopausal breast cancer control group. A partial adrenal insufficiency was found during Synacthen stimulation, confirmed by a slight increase of 11-desoxycortisol after metyrapone, despite a sufficient rise in ACTH levels. Peak levels of androstenedione and 17-OH progesterone after Synacthen correlated with those after metyrapone. Peak cortisol levels after Synacthen also correlated with the sum of cortisol and 11-desoxycortisol values after metyrapone, indicating the presence of a maximum adrenal response and a sufficient rise of endogenous ACTH after metyrapone. As the peak levels of cortisol and androstenedione were highly correlated with baseline values, a short Synacthen stimulation test may give a good indication as to whether adrenal suppression by MPA is adequate. The adrenal androgen androstenedione is the precursor of the main postmenopausal oestrogen, oestrone. In this way, adrenal suppression may constitute an important therapeutic effect of high-dose MPA.