RU 486: a steroid with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day.

Abstract

RU 486 is a synthetic steroid hormone antagonist which acts at the receptor level. It has intrinsic antiprogesterone and antiglucocorticosteroid properties in animals. The antiglucocorticosteroid activity in humans was investigated by evaluating the pituitary-adrenal response to RU 486 in men and in pregnant and nonpregnant women. In nonpregnant women, RU 486 (.apprxeq. 1 mg/kg of body wt/day) produced an interruption of the luteal phase without affecting the pituitary-adrenal axis, indicating a more potent antiprogesterone than antiglucorticosteroid effect. In the course of pregnancy interruption by RU 486 (.apprxeq. 4 mg/kg/day), there was a significant increase in plasma corticotropin, .beta.-lipotropin and cortisol concentrations. In normal men, RU 486 administration led to a dose-dependent stimulation of plasma corticotropin, .beta.-endorphin and cortisol. This disinhibition of the pituitary-adrenal axis was only observed during the morning hours of the circadian rhythm. When administered concomitantly with 1 mg of dexamethasone at midnight, 6 mg of RU 486/kg completely suppressed the dexamethasone inhibitory effect on the pituitary-adrenal axis. RU 486 is an antiglucocorticosteroid that disrupts the negative pituitary feedback of the morning cortisol rise and administered dexamethasone. The results demonstrate the possibility of optimizing the antiprogestational effect of the compound and its potential use for human fertility control by modifying the dose and the time of administration of the drug and minimizing the antiglucocorticosteroid effect.