Mode of action of RU 486.

ABSTRACT

PIP: The 19-nonsteroid, RU-486, has the ability to bind strongly to the progesterone and glucocorticoid receptor and, less strongly, to the androgen receptor. It functions as a pure progesterone antagonist with almost no agonistic activity. RU-486 acts directly on the endometrium and the myometrium and indirectly on the hypothalamic pituitary axis, resulting in a decrease in pituitary gonadotropin secretion. It has different effects based on time of treatment during the menstrual cycle. RU-486 administration before ovulation prolongs the proliferative phase. Treatment during the proliferative phase suppresses follicular development and postpones the estrogen and luteinizing hormone surge, but does not alter endometrial morphology. RU-486 administration during the mid- and late-luteal phase brings on bleeding despite normal progesterone levels, sometimes followed by another episode of bleeding at the usual time of menstruation. It does not affect the menstrual cycle if administered after ovulation, but considerably slows down endometrial development and changes the level of estrogen and progesterone receptor concentration, enzyme activity, and production of likely to be progesterone-dependent substances. The effect on endometrial development of postovulation RU-486 administration impedes implantation. In addition, postovulation treatment with RU-486 significantly increases uterine contractility. RU-486 administration during early pregnancy influences uterine contractility and greatly increases the myometrium's sensitivity to prostaglandins. RU-486's effect on myometrial sensitivity to prostaglandins may persist even during the 2nd trimester of pregnancy. These effects support the combined treatment of RU-486 and a prostaglandin to terminate an early pregnancy. RU-486 treatment during pregnancy also ripens the cervix, apparently through inhibition of prostaglandin metabolism rather increased endogenous prostaglandin production.