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Pharmacology: Pharmacodynamics: Clomifene citrate is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, Clomifene citrate has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy.
Clomifene citrate is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomifene citrate initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event in response to a course of clomifene citrate therapy is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis, resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.
Clomifene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function. Although there is no evidence of a "carryover effect" of Clomifene citrate, spontaneous ovulatory menses have been noted in some patients after Clomifene citrate therapy.
Mechanism of Action: Clomifene appears to inhibit estrogen in hypothalamus, thereby inhibiting negative feedback of estrogen on gonadotropin production. It may also result in direct stimulation of the hypothalamic-pituitary axis. Zuclomifene, a more active isomer, stays bound for long period of time.
In normal physiologic female hormonal cycling, at 7 days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH and LH at the hypothalamus and anterior pituitary. If fertilization does not occur in the post-ovulation period, the corpus luteum disintegrates due to lack of beta-HCG. This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.
Therapeutically, clomifene is given early in the menstrual cycle. It is typically prescribed beginning on day 1, 3 or 5 and continuing for 5 days. By the time, FSH level is rising steadily, causing development of a few follicles. Follicles in turn produce the estrogen, which circulated in serum. In the presence of clomifene, the body perceives a low level of estrogen, similar to a day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release. (It should be noted that more rapid, lower amplitude pulses of GnRH lead to increased LH/FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the production of LH/FSH). Increased FSH level causes growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation.
Pharmacokinetics: Clomifene citrate is absorbed from the gastrointestinal tract. It is metabolized in the liver and slowly excreted via the bile. Unchanged drug and metabolites are excreted in the feces. The biological half-life is reported to be 5 days although traces are found in the feces for up to 6 weeks. Enterohepatic recirculation takes place.
