Mode of action of RU 486

Abstract

RU 486 is a 19-norsteroid which has a specific high affinity binding to the progesterone and glucocorticoid receptor. It is generally accepted that RU 486 acts as a pure progesterone antagonist almost without agonistic activity. RU 486 acts mainly directly on the target organ, such as the endometrium, but also to some extent indirectly through an effect on the pituitary gonadotrophin secretion. The effect of RU 486 during the menstrual cycle is dependent on time of treatment. Treatment before ovulation will result in a prolongation of the proliferative phase of the menstrual cycle, while treatment during the mid- and late luteal phase will invariably induce bleeding, often followed by a second bleeding episode at the expected time of menstruation. The only treatment period which does not influence the menstrual cycle is treatment immediately following ovulation. Treatment during the proliferative phase has no effect on endometrial morphology but inhibits follicular development and delays oestrogen and LH surge. Treatment on the first days following ovulation has no effect on ovarian steroid concentration, but will significantly delay endometrial development, cause a change in the concentration of oestrogen and progesterone receptor concentration enzyme activity and production of substances thought to be progesterone dependent. The change in endometrial development is sufficient to prevent implantation. In mid- and late luteal phase, treatment with RU 486 will result in endometrial shedding in spite of normal progesterone levels. Post-ovulatory treatment with RU 486 will also significantly change uterine contractility. In early pregnancy, withdrawal of progesterone inhibition will result in uterine contractility and a significant increase in the sensitivity of the myometrium to prostaglandin.(ABSTRACT TRUNCATED AT 250 WORDS)

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.