Clomiphene citrate is the pharmacologic agent of choice for ovulation induction in most anovulatory patients and is the first-line therapy for many ovulatory women with infertility. It was approved for clinical use in the United States in 1967, and has since been the most commonly prescribed treatment for infertility. Clomiphene is metabolized by the liver and eliminated in the stool. It is safer, cheaper, and easier to use than gonadotropins for ovulation induction.

Clomiphene is a selective estrogen receptor modulator: it is both an antiestrogen and a weak estrogen. It acts by competing with endogenous estradiol for estrogen-binding sites in the hypothalamus and displaces estradiol from these binding sites. Therefore, it blocks the static negative feedback of estradiol upon the hypothalamus, permitting an increased release of gonadotropin-releasing hormone (GnRH) which stimulates the pituitary to increase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and release. This release of gonadotropins causes oocyte recruitment and maturation with an increasing production of estradiol. The estradiol initially produces a negative feedback upon the hypothalamus and pituitary to reduce gonadotropin secretion, limiting the number of growing oocytes. Then, as the endogenous estradiol level increases exponentially, it provides a positive feedback to initiate the LH surge.

Prior to treatment, the cause of anovulation should be evaluated and treated appropriately. Anovulatory patients should also be screened for ovarian failure, as well as associated endocrinopathies, including a pituitary tumor, thyroid or adrenal disorders.

Women with either primary or secondary amenorrhea who do not have uterine bleeding after progesterone are likely to be estrogen deficient. These patients should undergo measurement of their serum estradiol (E2) and FSH levels. If the FSH concentration is elevated, a diagnosis of ovarian failure is likely and should be explored. If premature ovarian failure (POF) is confirmed, treatment with ovulatory medications is not effective (see Chapter 95).

The estrogen-deficient amenorrheic woman who has normal or low serum levels of FSH should have an MRI of the central nervous system to rule out a hypothalamic or pituitary tumor. If the MRI is negative and the patient is believed to have hypothalamic amenorrhea, treatment is directed towards gonadotropin therapy, given that clomiphene will rarely work to cause ovulation when a low estrogen environment already exists.

Pretreatment studies should include a pelvic ultrasound to rule out pre-existing uterine abnormalities or adnexal masses. Semen analysis should be performed to verify that the male partner does not have severe oligospermia, azoospermia or another gross abnormality. The uterine and tubal factors should be investigated by obtaining a hysterosalpingogram (or hysteroscopy and laparoscopy with chromopertubation).

These pretreatment procedures should insure that multiple causes of infertility are not present. Although multifactorial infertility is not a contraindication to therapy, the chance of a full-term gestation is reduced in such patients and the couple should be afforded a realistic prognosis before undertaking therapy.

Clomiphene is administered, beginning between day 3 and day 5, following a spontaneous or induced menstrual period for 5 days. Ovulation, conception and pregnancy rates are equivalent when treatment is started in this time frame.

Treatment begins with a daily dose of 50 mg for anovulatory patients, while many physicians opt for a higher daily dose of 100 mg for those undergoing “superovulation.” During treatment, the patient can be allowed to ovulate spontaneously or monitored by ultrasound for follicle growth with planned ovulation using human chorionic gonadotropin (hCG) injection to mimic the LH surge. Urinary ovulation predictor tests, which detect the preovulatory LH surge, are a reliable method to assist the timing of intercourse and laboratory tests that assess the ovulatory response to clomiphene. If ovulation is going to occur, it will usually do so within 5–10 days, with a mean of 7 days, following the last clomiphene tablet. The ideal day for hCG administration should be based on follicle maturity, best determined by transvaginal ultrasound. The dominant follicle should be at least 18 mm in mean diameter and the endometrial stripe should be at least 7 mm in thickness before hCG is administered.

If the patient is not being monitored and intercourse is planned, ovulation should be documented in each cycle of treatment. Ovulation may be presumed if the serum progesterone level is in excess of 3 ng/mL 2 weeks after the last clomiphene tablet. If the level of progesterone is determined at the time of peak production, it is usually higher than 15 ng/mL. If menstrual bleeding does not occur within 4 weeks after the last clomiphene tablet, it can be assumed that either the patient did not ovulate or that the patient is pregnant. Appropriate evaluation should ensue.

While ovulatory patients will respond to Clomid treatment, not all anovulatory patients will. If the cycle was ovulatory and the patient did not conceive, she may be treated again with the same dose of clomiphene beginning on the same start day used previously. Monthly examinations should be performed, preceding each successive course of therapy. These examinations serve to exclude the presence of pregnancy and functional ovarian cysts that can interfere with the clomiphene treatment. Increasing the dose above 100 mg in the setting of superovulation is not believed to lead to additional follicular growth.