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Reference: N Engl J Med 2014 Jul 10;371(2):119 (level 2 [mid-level] evidence)
Polycystic ovary syndrome (PCOS) affects 4%-8% of women of reproductive age and is a common cause of anovulatory subfertility (Arch Gynecol Obstet 2012 Jun;285(6):1737). Clomiphene citrate is a selective estrogen receptor modulator that induces ovarian stimulation, and has traditionally been the first-line therapy for infertility in this patient population. More recently, other treatments such as metformin and aromatase inhibitors have been evaluated, but these agents have not consistently been shown to be superior to clomiphene for fertility outcomes. A new randomized trial compared the safety and efficacy of the aromatase inhibitor letrozole to clomiphene for treatment of infertility in 750 women aged 18-40 years with PCOS.
Included women had ≥ 1 patent fallopian tube and normal uterine cavity, a male partner with a sperm concentration ≥ 14 million sperm/mL, and mutual agreement with their partner to have regular intercourse during the study period. Women received either letrozole 2.5 mg/day orally vs. clomiphene citrate 50 mg/day orally on cycle day 3 for 5 days and for up to 5 menstrual cycles. The live birth rate was 27.5% for women receiving letrozole vs. 19.1% for those receiving clomiphene (p = 0.007, NNT 12), with no significant differences between groups in the rates of congenital anomalies in live births, pregnancy loss, or twin pregnancy. Compared to clomiphene, letrozole was associated with a significantly decreased frequency of hot flushes, but significantly increased frequency of fatigue and dizziness.
Previously unpublished data from this trial are contained within a recent Cochrane review of 26 randomized trials evaluating letrozole in women with anovulatory PCOS. This review found that letrozole was associated with increased live birth and pregnancy rates compared to clomiphene citrate, with the improvement in live birth rate primarily being driven by this new trial (Cochrane Database Syst Rev 2014 Feb 24;(2):CD010287). In addition, the data from this trial have been incorporated into a new guideline by the Endocrine Society, which reviewed an earlier conference abstract of these data. Although the guideline did not include any recommendations on comparative efficacy of letrozole or clomiphene, it now includes a strong recommendation for clomiphene citrate, or comparable estrogen modulators such as letrozole, as first-line treatment of anovulatory infertility in women with PCOS (J Clin Endocrinol Metab 2013 Dec;98(12):4565). Letrozole has been approved by the U.S. Food and Drug Administration for several breast cancer indications, but is not currently indicated for infertility treatment in women with PCOS.
For more information see the Polycystic ovary syndrome and Treatment of infertility in women topics in DynaMed.