Potentiation of GnRH response by clomiphene citrate

The method whereby clomiphene citrate (CC) induces ovulation in anovulatory women is not known. It probably binds to cytoplasmic estrogen receptors throughout the reproductive axis, with a central hypothalamic site postulated as a major center of action. Three patients who had severe hypothalamic amenorrhea and were clinically and biochemically unresponsive to CC alone had ovulation induced with the intermittent intravenous administration of gonadotropin-releasing hormone (GnRH). When CC was added to the GnRH, an enhanced secretory response of estradiol was demonstrated in all the patients. One patient demonstrated hyperstimulation, with large increments of estradiol and the development of multiple follicles, similar to what occurred with a larger dosage of GnRH alone. This finding suggests that CC may potentiate the response to GnRH, indicating that the action of CC is, at least in part, extrahypothalamic.