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Clomiphene citrate has long been the first-line fertility treatment for anovulatory women (including those with polycystic ovary syndrome [PCOS]). This selective estrogen-receptor modulator antagonizes estrogen's negative feedback on the hypothalamus, resulting in increased secretion of gonadotropin-releasing hormone and, ultimately, stimulation of follicular development. However, clomiphene has drawbacks (e.g., high rates of failure and multiple pregnancies) and adverse effects (e.g., hot flashes, mood changes, visual disturbances). Aromatase inhibitors affect hypothalamic-pituitary-ovarian function by blocking estrogen synthesis and might be more effective for achieving pregnancy. NIH-supported investigators conducted a double-blind, multicenter, randomized trial involving 750 women with PCOS and ovulatory dysfunction. Participants received clomiphene citrate (50 mg daily) or the aromatase inhibitor letrozole (2.5 mg daily) for up to 5 cycles. Doses were escalated (up to 150-mg clomiphene and 7.5-mg letrozole) if ovulatory response was poor or absent.
Women who received letrozole had higher cumulative rates of ovulation (62% vs. 48%; P<0.001) and live birth (28% vs. 19%; P=0.007) than those who received clomiphene. Likelihood of pregnancy loss (32% vs. 29%) or twin pregnancy (3% vs. 7%) did not differ significantly between groups. Overall risk for congenital anomalies also did not differ significantly, although 4 of 102 neonates in the letrozole group and 1 of 66 in the clomiphene group had major congenital anomalies (P=0.65). Letrozole was associated with higher incidence of fatigue and dizziness, and clomiphene with more hot flashes.
Legro RS et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014 Jul 10; 371:119. (http://dx.doi.org/10.1056/NEJMoa1313517)
Comment
In showing letrozole's strengths as a first-line treatment for infertile women with PCOS, these data should transform the treatment of such women (although letrozole is not FDA approved for this indication and is not yet likely to be covered by insurance for such use). The study did not address anovulation from other causes, so it remains unknown whether this aromatase inhibitor has broader superiority over clomiphene for inducing ovulation. In addition, the trial was insufficiently powered to determine if letrozole raises risk for congenital anomalies (which will require further study involving thousands of women). Letrozole is unlikely to increase this risk more than clomiphene because its half-life is much shorter than clomiphene's; moreover, the anomaly rates in both treatment groups were similar to those in the general population (5.8% of spontaneously conceived pregnancies; N Engl J Med 2012; 366:1803).