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For Polycystic Ovary Syndrome: Letrozole or Clomiphene + Letrozole?

In the most recent edition of Fertility and Sterility is an intriguing pilot study on the treatment of polycystic ovary syndrome (PCOS) by the excellent reproductive medicine specialists at the University of Iowa (https://doi.org/10.1016/j.fertnstert.2018.11.030). It is a randomized and controlled trial to evaluate whether a combination of letrozole and clomiphene results in higher ovulation rates than Letrozole alone in women with PCOS. The most common cause of lack of ovulation, PCOS is also the single most common endocrine disturbance of reproductive age women. Both letrozole (an aromatase enzyme inhibitor) and clomiphene citrate (a selective estrogen receptor modulator – SERM) are used frequently throughout the world as oral ovulation induction medications. Letrozole has emerged as the first line treatment of ovulation dysfunction in PCOS following another randomized trial that demonstrated higher ovulation rates and better live birth with lower twin rates. However, there is a frustrating lack of responsiveness by some patients following letrozole administration.

Dr. Rachel Mejia and her colleagues proposed adding the old drug, clomiphene (FDA approved in 1967), with the newer medication, letrozole (used in PCOS since the late 1990s). The Iowa-based research team studied whether combination of both agents would provide a synergy that would be better than letrozole alone. Seventy participants were randomized; 35 received letrozole 2.5 mg plus clomiphene 50 mg cycle days 3-7 and 35 received letrozole 2.5 mg cycle days 3-7 for one treatment cycle. Women who received the combination therapy had statistically higher ovulation rates than women who took letrozole alone [27 of 35 (77%) versus 15 of 35 (43%)]. There were no serious adverse events or multiple gestations in either group and side-effects were similar in both groups.

This relatively small study suggests that two-agent therapy is better than letrozole alone among PCOS patients and provides an inexpensive and safer alternative to injectable (gonadotropin) therapy in this patient population. This investigation did not look at live birth rates and until such a larger, randomized study is available, this dual therapy approach should be employed with some restraint. If live birth rates were to be shown higher for the letrozole-clomiphene combo, then dual therapy may supplant letrozole as the first line approach to PCOS ovulation problems.

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