Clomifene: Mode of action

On day 21 of the menstrual cycle, high levels of estrogen and progesterone cause negative feedback inhibition at the hypothalamus and anterior pituitary. As a result, decreased LH levels leads to atrophy of the corpus luteum, subsequently leading to decreased production of estrogen and progesterone. This will release the feedback inhibition of the hypothalamus and anterior pituitary, causing the FSH level to rise again at day 22.

Clomiphene is given at day 2 menses. By that time, FSH level is rising steadily, causing development of a few follicles. Follicles in turn produce the estrogen, which circulates in serum. Clomiphene 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. As a result, the body perceives a low level of estrogen, similar to day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release. Increased FSH level causes growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation.