Clomiphene citrate is the usual first choice for ovulation induction in most patients because of its relative safety, efficacy, route of administration (oral), and relatively low cost (142). Clomiphene citrate is indicated primarily in patients with adequate levels of estrogen and normal levels of FSH and prolactin. It is generally ineffective in hypogonadotropic patients who already have a poor estrogen supply (143). Patients with inappropriate gonadotropin release (an increased LH-to-FSH ratio), such as that which occurs in PCOS, are candidates for therapy with clomiphene citrate. As many as 80% of certain patients can be expected to ovulate after clomiphene citrate therapy. Contraindications to the use of clomiphene citrate include pregnancy, liver disease, and preexisting ovarian cysts. Side effects include hot ﬂashes and poorly understood visual symptoms, which generally were viewed as an indication to discontinue subsequent clomiphene citrate use. The risk of multiple pregnancy is increased with clomiphene citrate compared with an overall of risk of approximately 8% (142). The majority of multiple gestations are twins; triplets and higher order multiple gestations are rare.
The most commonly recommended treatment regimen for clomiphene citrate is 50 mg daily for 5 days, beginning on the third to fifth day of menstrual or withdrawal bleeding. Cycles may be monitored by measuring midluteal progesterone levels to assess ovulation. Ovulation may be confirmed by an appropriate rise of basal body temperature and menses occurring at the expected time after the temperature rise. Ultrasonographic monitoring to assess folliculogenesis may be helpful, especially when hCG is used to induce ovulation. Endometrial thinning caused by the antiestrogenic effects of clomiphene citrate may be detected with midcycle ultrasound. With these data, it is possible to immediately adjust the dose in the subsequent cycle if a given regimen is ineffective. Dosage increases of 50 mg per day are usually used, and more than 70% of conceptions occur at doses no higher than 100 mg per day for 5 days (144). Dosages higher than 150 mg per day for 5 days are usually ineffective, and patients who remain anovulatory with this dosage should undergo further evaluation accompanied by changes in the therapeutic plan. Longer courses of clomiphene citrate therapy, and adjunctive therapy with glucocorticoids, are suggested if a patient does not ovulate with standard therapy (145).
Although a large randomized trial demonstrated that clomiphene alone is superior to metformin alone in achieving live birth in women with PCOS, a meta-analysis suggests that for some patients with PCOS, metformin and clomiphene combined may increase the likelihood of ovulation compared with clomiphene alone (146,147). Thinning of the endometrium at midcycle in the face of adequate midcycle estradiol and lack of success with repeated cycles of clomiphene are generally indications to consider injectable gonadotropins. Aromatase inhibitors, such as letrozole, were suggested as an option for ovulation induction (148).