Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility. Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity. Cancer risk
Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer. This may only be the case in those who have never been and do not become pregnant. Subsequent studies have failed to support those findings.Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer. Thyroid cancer risk was not associated with the number of pregnancies carried to viability. Pharmacology
Pharmacodynamics
Selective estrogen receptor modulator activity
Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM). It consists of a racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties. It is a mixed agonist and antagonist of the estrogen receptor (ER). Clomifene activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels. Conversely, it is an antagonist of the ERβ. Clomifene has antiestrogenic effects in the uterus. There is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts. Positive effects of clomifene on bone have been observed.
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 a lack of human chorionic gonadotropin (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 3 and continuing for 5 days. By that time, FSH levels are rising steadily, causing the development of a few follicles. Follicles, in turn, produce the estrogen, which circulates in serum. In the presence of clomifene, 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 rapidly pulsatile, which results in increased pituitary gonadotropin release. (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene.