Role of Estrogens in Ovulation: A Study Using the Estrogen-Antagonist, I.C.I. 46,474

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A possible role of estrogens in regulating ovulatory release of luteinizing hormone (LH) in the estrous cycle has been examined by using a potent estrogen antagonist— I.C.I. 46,474. When administered orally at 1700 hr or before on diestrus, butnot at 0945 hr on proestrus in 4-day cycling rats, the antiestrogen prevented ovulation from occurring on the morning of estrus. The antiestrogen was also effective in interfering with ovulation in hamsters and in immature rats and mice pretreated with PMS. The minimal effective dose for blocking ovulation in 100% of the adult rats was found to be 0.5 mg⁄kg. When ovulation was blocked by giving the antiestrogen at 1700 hr, it did not prevent vaginal cornification, mating behavior or uterine ballooning, but when inhibition was effected by administration earlier in the cycle, all these estrogen-dependent parameters were either blocked or modified. A significant drop in LH content from 23 to 12 μg /gland which was detected in association with ovulation on the day of estrus in the control animals was not found in the “blocked” rats (19 μg/gland). The inhibition of ovulation by the antiestrogen could be prevented either by an intravenous administration, just before the critical period on the day of proestrus, of LH (25 μg NIH-S-11/rat) or partially purified ovine hypothalamic extract, or by the mating stimulus. It could also be fully restored by the concurrent sc administration of estradiol benzoate (400 μ/grat). These results are interpreted to mean that the antiestrogen inhibits ovulatory surge of LH from the pituitary by interfering with the antecedent positive feedback of estrogen on the hypothalamus. It is concluded that the positive estrogen-feedback forms an integral part of the chain of events leading to the ovulatory surge of LH in the estrous cycle. (Endocrinology87: 542, 1970)