Clomiphene

Clomiphene citrate was first synthesized in 1956, introduced for clinical trial in 1960, and approved for clinical use in the United States in 1967. Clomiphene citrate is an orally active nonsteroidal agent distantly related to diethylstilbestrol.

The similarity of clomiphene's structure to an estrogenic substance is the clue to its mechanism of action. Clomiphene exerts only a very weak biologic estrogenic effect.

When exposed to clomiphene, the hypothalamic-pituitary axis is blind to the endogenous estrogen level in the circulation. Because receptor capacity is reduced and the true estrogen signal falsely lowered, negative feedback is diminished and the neuroendocrine mechanism for GnRH secretion is activated. When clomiphene is administered to normally cycling women, FSH and luteinizing hormone (LH) pulse frequency (but not amplitude) is increased, suggesting an increase in GnRH pulse frequency. Anovulatory women, however, respond in a different fashion. Clomiphene stimulates an increase in gonadotropin pulse amplitude, presumably because GnRH pulses are already operating at maximal frequency in anovulatory women with polycystic ovaries. Nevertheless, the experimental data indicate that the primary site of action is the hypothalamus.

During clomiphene administration, circulating levels of FSH and LH rise. The subsequent ovulation that occurs after clomiphene therapy is a manifestation of the hormone and morphologic changes produced by the growing follicles. Clomiphene therapy does not directly stimulate ovulation, but it retrieves and magnifies the sequence of events that are the physiologic features of a normal cycle. The effectiveness of the drug, however, may not be restricted to its ability to cause an appropriate GnRH discharge. (Source: Clinical Gynecologic Endocrinology and Infertility. Speroff, Glass, and Kase. Lippincott Williams & Wilkins. 1999)

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