Clomiphene Citrate

Clomiphene citrate, an indirect stimulator of FSH secretion, has been the traditional approach to ovulation induction in infertile patients with PCOS. It is typically given at a dose of 50 mg per day for 5 days starting from day 2 to day 5 of spontaneous or induced menses. The dose of clomiphene can be increased in increments of 50 mg per day each cycle if ovulation is not achieved up to a maximum dose of 250 mg, although doses in excess of 150 mg are not typically prescribed (6). Ovulation occurs in 60-85% of patients given clomiphene, 30-40% of whom become pregnant (9, 30, 31). Approximately 75% of those who conceive on clomiphene become pregnant during the first three cycles of treatment (32-34). There is an increased risk of ovarian and uterine cancer in patients continuing prolonged ovulation induction with clomiphene (35-37). Therefore, treatment is usually attempted for 3-6 cycles but no more than 12 cycles (9).

While clomiphene increases the number of follicles attaining ovulation, it also has antiestrogenic effects on the endometrium and cervical mucous, which may inhibit sperm penetration and implantation of the embryo (38); these effects may account for the discrepancy between the ovulation and conception rates (39). In addition, some studies have found a diminished effect of clomiphene on ovulation rates over time (32, 40). However, the hyperinsulinemic state of PCOS may reduce endometrial expression of the binding proteins, glycodelin and insulin-like growth factor (IGF) binding-pro-tein-1, which may also impair conception and/or increase early miscarriage rates (41). Clomiphene has also been associated with the development of ovarian cysts, risk of ovarian hyperstimulation syndrome (OHSS), and an increase in the multiple gestation rate (4-10%) (9). The risks of OHSS and multiple gestations underscore the need for careful monitoring, usually with ultrasound, of patients undergoing their first treatment cycle with clomiphene (9).

Several studies have shown that increased BMI is predictive of poor response to ovulation induction and that overweight patients require higher doses of clomiphene to ovulate (9, 42, 43). In addition to obesity, Imani et al. found that anovulatory patients with amenorrhea, increased ovarian volume, and increased androgen levels are less likely to respond to ovulation induction with clomiphene (31, 44). Finally, age is also known to be a predictor of response to clomiphene, with younger patients having higher success rates with treatment (32, 44-46). LH concentrations have not been predictive of ovarian response to treatment (9, 31).

Approximately 20-25% of anovulatory women with PCOS will not ovulate despite treatment with increasing doses of clomiphene citrate (6, 31). A few studies suggest that the addition of dexametha-sone to suppress adrenal androgen production and decrease LH levels may improve follicular development and conception rates (47-50). Daly et al. reported that this may be most helpful in women with raised dehydroepiandrosterone sulfate (DHEAS) levels but subsequent studies have shown benefit in PCOS women with normal DHEAS levels (50). Contrary to the statement of a recent consensus workshop that dexamethasone added to clomiphene had no beneficial effect (51), the cited study (47) did, in fact, show benefit as have subsequent studies (48-50). In a small, prospective, placebo-controlled study, Elnashar et al. found improved ovulation (75% vs. 15%, p < 0.001) and pregnancy rates (40% vs. 5%, p < 0.05) in clomiphene-resistant women with PCOS who were given dexamethasone on days 3-12 in addition to clomiphene compared with placebo plus clomiphene (48). While dexa-methasone may be beneficial for the short term, the long-term use of corticosteroids can cause weight gain, so, this adjunctive treatment may be less desirable in the PCOS population and further studies are needed to further examine the efficacy (6).

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