Cyproteroneacetate, an antiandrogenic and gonadotropin-inhibiting steroid, has a marked ACTH suppressive effect. In rats, adrenal atrophy and severe impairment of ACTH and corticosterone responses to stress are induced by a 10-day treatment with 3-0.75 mg/100 g BW cyproteroneacetate/day. Two weeks after cessation of treatment, the ACTH adrenal system has not yet recovered. The ACTH suppression is evident 6 h after a single dose. In 25 human volunteers, a single dose of 200 mg cyproteroneacetate impaired their ACTH and 11-deoxycorticosteroid response to 1 g metyrapone. A similar impairment was seen in 12 women on sequential treatment with cyproteroneacetate and ethinyl estradiol. In 4 out of 11 children treated for precocious puberty, random plasma ACTH and cortisol measurements, cortisol responses to ACTH, and ACTH and cortisol responses to insulin-induced hypoglycemia revealed severely impaired ACTH adrenal function. Questionable impairment was found in 2 out of 11 and normal function in 5 out of 11 children. In 10 patients with endogenous elevated plasma ACTH, 10 days of treatment with cyproteroneacetate, in addition to the steroid substitution, diminished the morning plasma ACTH levels. It is concluded that cyproteroneactate has a pronounced ACTH-suppressive effect. The individual susceptibility of treated patients varies and the effect is dose dependent. A cortisol-like effect must be assumed, because cyproteroneacetate-treated animals and patients under therapy can withstand stress situations without signs of adrenal insufficiency. ACTH adrenal function must, however, be closely watched in treated patients and steroid cover must be considered in conditions of stress. Great care has to be taken when the drug, with its own "stress-protective" effect, is withdrawn. The recovery of ACTH adrenal function may take several months.