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Clomifene acts by inhibiting the action of estrogen on the hypothalamus. Zuclomifene, the more active isomer (see below), binds to estrogen receptors and stays bound for long periods of time. This prevents normal receptor recycling and causes an effective reduction in hypothalamic estrogen receptor number. Since estrogen can no longer effectively feedback on the hypothalamus, GnRH secretion becomes more pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release. Increased gonadotropin levels cause growth of the ovarian follicle, followed by follicular rupture, otherwise known as ovulation.

Clomifene can lead to multiple ovulation, and hence increasing the chance of twins (3-5% of births instead of normal ~1%). In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low. There may be an increased risk of ovarian cancer and weight gain.