Effects of a Progesterone Antagonist, Lilopristone (ZK 98.734), on Induction of Menstruation, Inhibition of Nidation, and Termination of Pregnancy in Bonnet Monkeys

Abstract

The effects of a progesterone antagonist, lilopristone (ZK 98.734), on induction of menstruation, inhibition of implantation or pregnancy, and termination of early and mid-pregnancy were studied in bonnet monkeys. In the regularly menstruating animals, administration of lilopristone (25 mg/day, s.c.) during the mid-luteal phase (Days 20-22 of the menstrual cycle) induced menstruation within 2-4 days after the initiation of treatment. A premature drop in circulating progesterone levels was also observed. The luteolytic effect of lilopristone was prevented by exogenous treatment with hCG; however, the animals showed premature menstruation, in spite of high progesterone levels (above 4 ng/ml). Treatment around the time of implantation (between Days 8 and 12 after the mid-cycle peak in estradiol levels) in mated animals provided 100% pregnancy protection. Treatment of pregnant animals on Days 30-32 of the menstrual cycle, i.e. about Day 20 after the estradiol peak, induced abortion in 8 of 10 animals. A significant (p less than 0.05) decrease in serum progesterone levels was observed on Day 3 after the initiation of treatment. However, the decrease was slower (slope: -0.36, r: 0.96) compared to that observed in nonpregnant animals (slope: -0.72, r: 0.95). In the other two animals, pregnancy was not affected. However, when the treatment was delayed until about Day 50 after the estradiol peak, all four animals aborted. This study suggests that lilopristone is a progesterone antagonist with a potential to induce menstruation, inhibit nidation, and terminate pregnancy. The antifertility effects are mediated through blocking progesterone action at the endometrium as well as decreasing progesterone bioavailability, which appears to be due to its effects on gonadotropin release.

Expression Profiles of Endometrial Leukemia Inhibitory Factor, Transforming Growth Factor β2 (TGFβ2), and TGFβ2 Receptor in Infertile Bonnet Monkeys1

“…The crucial role of progesterone in endowing the endometrium with receptivity has been substantiated in several reports demonstrating retardation in endometrial development and subsequent implantation failure when progesterone actions were neutralized using antiprogestins such as RU 486 (mifepristone) [8,9], ZK 98.299 (onapristone) [10][11][12], or ZK 98.734 (lilopristone) [13] in primates. These antiprogestins compete with progesterone for its binding site on PR and, once bound, make the receptor nonfunctional by inducing conformational changes.…”

Attenuation of antepartum relaxin surge and induction of parturition by antiprogesterone RU 486 in sheep

“…(11 ß-[4-dimethyl-amino phenyl]l7ß-hydroxy-l7fX- [l-propynyl] estra-4,9-dien-3-one) is a 19-norsteroid with potent antiprogesterone and antiglucocorticoid activities (Baulieu, 1989), and it reduces maternal progesterone concentrations in several species including pigs, cattle, monkeys (Rhesus and Macaca fascicularis), and humans (Nieman et al, 1987; Baulieu, 1989;Puri et receptors and such binding either blocks the interaction between progesterone receptors and DNA or impairs gene transactivation.…”

Role of progesterone in structural and biochemical remodeling of endometrium Gracy Rosario Geetanjali Sachdeva William C Okulicz Christopher I Ace

“…Our previous studies demonstrated an early decline in the progesterone concentration and premature menstruation following treatment with ZK 98.299 or ZK 98.734 in bonnet monkeys (36,37). Treatment with these antiprogestins induced early menstruation during HCG induced pseudopregnancy in bonnet monkeys (37). Treatment of bonnet monkeys with high doses of onapristone for 7 consecutive cycles led to decreased LH secretion, impaired folliculogenesis, anovulation and endometrial retardation (38).…”