A paradoxical effect of an antiestrogen, CI-628, on implantation in the mouse

Some triphenylethylene compounds (TPE), commonly known as antiestrogens, have been reported to interfere with pregnancy. This effect of these TPE compounds was attributed to their antagonistic effects to estrogen in the uterus and/or the embryo. Paradoxically, recent evidence suggests that several TPE compounds act as estrogen agonists in inducing embryo implantation in the uterus of ovariectomized, progesterone-treated, delayed-implanting mice. The present study was undertaken to determine the effect of CI-628, a TPE compound, on normal pregnancy and its site of action. Mice were given a single injection of CI-628 (1.5, 5, or 15 micrograms/mouse, ip) on Day 3, Day 4, or both days and killed on Day 8 for examination of implantation sites or unimplanted embryos. CI-628 at 5 and 15 micrograms reduced the implantation rate when injected on Day 3 or Days 3 and 4, but not when administered only on Day 4. The lower dose of the compound (1.5 micrograms) was ineffective in altering implantation. The implantation failure was overcome to various degrees by simultaneous injection of progesterone (2 mg/mouse, sc), but not by estradiol-17 beta (20 ng/mouse, sc). These results suggest that Day 3 is critical for CI-628 to exert its inhibitory effect and that this compound appears to affect ovarian progesterone synthesis and/or secretion. This suggestion is consistent with our findings that animals that showed implantation following injection of 5 or 15 micrograms of CI-628 had higher serum progesterone levels than those without implantation. Serum progesterone levels of animals bearing implantation sites following 5 micrograms of CI-628 on Day 3 or Day 4 were comparable to those of vehicle-treated controls, whereas the level of this steroid in animals treated with 15 micrograms of CI-628 and having implantation sites was relatively lower. However, a small number of animals that had implantation following treatment with 5 micrograms of CI-628 on Days 3 and 4 showed lower progesterone levels compared to those of the controls, but not different from those of some of the treated animals without implantation. Treatment with estrogen could not restore progesterone levels or implantation. In summary, the results suggest that CI-628 acts as an estrogen antagonist in interfering with implantation at the ovarian level in intact, pregnant mice.