Action of an Estrogen Antagonist on Reproductive Mechanisms in the Rat1

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Abstract
A nonsteroidal compound (CN-55, 945-27) was found to inhibit uterine responsiveness to 17[beta]-estradiol and to stimulate LH secretion when administered orally (25 [mu]g/kg) to adult intact rats. Since the compound was not observed to prevent the blastocyst per se from implanting and developing normally, these effects may account for its ability to prevent pregnancy when given daily (25 [mu]g/kg) or as a single dose (500 [mu]g/kg) post coitus. That is, the compound may inhibit implantation mechanisms, which in the rat require estrogen and a functional corpus luteum, by antagonizing the action of estrogen and/or stimulating the release of LH (luteolytic action in the rat). The fact that CN-55,945-27 inhibited the decidual response in adult intact rats is consistent with the conclusion that the compound exerts its antifertility activity by blocking implantation. The compound showed no direct action on the ovary in terms of affecting growth, steroidogenesis or ovulation. It did exhibit, under various experimental conditions, several endocrine activities which were not observed in normal adult animals. For example, the compound was shown in ovariectomized immature rats to be mildly estrogenic as well as antagonistic to the action of 17[beta]-estradiol on the uterus. In adult intact rats, however, the uterine weight and nucleic acid (RNA, DNA) content in addition to the vaginal smear data indicated that CN-55,945-27 acts only as an estrogen antagonist. Similarly, the compound (25 [mu]g/kg) increased pituitary FSH and decreased plasma FSH in rats ovariectomized 30 days earlier, but not in intact animals. No effect was seen in either pituitary or plasma FSH levels in ovariectomized animals given 1 mg/kg. The compound did not affect pituitary or plasma LH levels when given for 135 days, as opposed to the marked increase in plasma LH (simultaneous decrease in pituitary LH) observed in adult intact rats treated for 14 days. These observations indicate that the biological activity of CN-55,945-27 depends on the duration of treatment as well as the dosage and the endocrine state of the animal.