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Evidence Library · The decision

Ovulation induction in polycystic ovary syndrome

Letrozole beats clomiphene here. The same drug comes last in unexplained infertility.

If you have polycystic ovary syndrome and are not ovulating, this is one of the clearer answers in fertility medicine.

750 women with PCOS were randomly assigned, double-blind, to letrozole or clomiphene for up to five cycles:

OutcomeLetrozoleClomipheneEffect
Cumulative live birth103 of 374 (27.5%)72 of 376 (19.1%)Rate ratio 1.44 (95% CI 1.10 to 1.87)
Ovulation per cycle61.7%48.3%P<0.001
Twin pregnancy3.4%7.4%No significant difference
Pregnancy loss31.8%29.1%No significant difference

An absolute difference of 8.4 percentage points, or roughly twelve women treated with letrozole instead of clomiphene for one additional live birth.

For completeness rather than alarm: there were four major congenital anomalies in the letrozole group and one in the clomiphene group. That difference was not statistically significant (P = 0.65) and the trial was not designed to answer that question. The numbers are reported here because leaving them out of a consent document would be the wrong call.

Do not carry this result across to a different diagnosisIn 900 couples with unexplained infertility, the same three-way comparison gave live birth rates of 32.2% with gonadotropin, 23.3% with clomiphene, and 18.7% with letrozole. Letrozole was the worst of the three.

Same drug, opposite conclusion, different diagnosis. If letrozole is offered to you, the question is what it is being offered for.
Where this comes from:
36. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119-129.
37. Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al. Letrozole, gonadotropin, or clomiphene for unexplained infertility. N Engl J Med. 2015;373(13):1230-1240.

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