although it appears to be safe when used during pregnancy (142,162). Risks of metformin include gastrointestinal upset and rare lactic acidosis, so it should be avoided in settings of hepatic and renal dysfunction and prior to surgery or use of contrast radiologic dye. Reported effective doses include 500 mg three times daily, 850 mg twice daily, or 1,000 mg twice daily (142,162). The medication is best tolerated when started at the lowest dose and increased gradually. Extended release formulations are associated with less gastrointestinal upset (142). Because regular ovulation may be delayed for 3 to 6 months or may not occur with metformin alone, patients may need medications to induce withdrawal bleeding to mitigate the risk of continued anovulation and endometrial hyperplasia (141). Thiazolidinediones, which include rosiglitazone and pioglitazone, have been used for ovulation induction in PCOS patients (165–168). They have less associated gastrointestinal upset than metformin. All carry the risk of liver toxicity and, in the case of rosiglitazone, cardiovascular harm, and they are typically avoided during pregnancy (141).
Dexamethasone Adjunctive oral dexamethasone may improve ovulation rates in patients resistant to clomiphene alone (147). These improvements have been reported even in the absence of adrenal hyperandrogenemia, so the mechanism of action remains unclear (169,170). Dose regimens have included 0.5 mg for 5 days starting on the first day of clomiphene, 0.5 mg for 6 weeks prior to starting clomiphene, and 2 mg for 10 days starting on the first day of clomiphene (169–172).
Oral Contraceptive Pretreatment Administration of oral contraceptives for 2 months prior to beginning a cycle of clomiphene may improve ovulation and pregnancy rates in clomipheneresistant patients, perhaps by improving a preexisting hyperandrogenic environment (147,173).
Tamoxifen Tamoxifen is an oral antiestrogen similar in structure to clomiphene that is commonly used as an adjuvant therapy for breast cancer but has been used off-label to induce ovulation (174). Ovulation and pregnancy rates are similar with tamoxifen and clomiphene (147,174). Doses start at 20 mg per day for 5 days (similar in timing to clomiphene), and can be increased to 40 or 60 mg per day in subsequent cycles. The mechanism of action for tamoxifen in inducing ovulation appears to be similar to that of clomiphene, although tamoxifen exerts less negative endometrial effects (175).
Aromatase Inhibitors These drugs include letrozole and anastrazole. Through their inhibition of aromatase-mediated conversion of androgens to estrogens and subsequent decreases in circulating estradiol, aromatase inhibitors have been approved for treatment of breast cancer. The off-label use of letrozole for ovulation induction in clomiphene-resistant patients was first reported in 2001 (176). Typical doses are 2.5 to 5 mg of letrozole or 1 mg of anastrazole daily for 5 days. Timing of administration is similar to that of clomiphene, although longer durations of 10 days have been reported (177,178). Letrozole appears to have less negative effects on endometrial development when compared to clomiphene (176). Although concerns have been raised regarding possible associations between fetal congenital anomalies and the use of aromatase inhibitors, no such increase was observed when letrozole was compared to clomiphene (179). Patients should be counseled regarding the absence of prospective, sufficiently powered studies to assess safety of off-label use of aromatase inhibitors for ovulation induction (141).