Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome (Jul 2014)

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome
N Engl J Med 2014; 371:119-129July 10, 2014
Richard S. Legro, M.D., Robert G. Brzyski, M.D., Ph.D., Michael P. Diamond, M.D., Christos Coutifaris, M.D., Ph.D., William D. Schlaff, M.D., Peter Casson, M.D., Gregory M. Christman, M.D., Hao Huang, M.D., M.P.H., Qingshang Yan, Ph.D., Ruben Alvero, M.D., Daniel J. Haisenleder, Ph.D., Kurt T. Barnhart, M.D., G. Wright Bates, M.D., Rebecca Usadi, M.D., Scott Lucidi, M.D., Valerie Baker, M.D., J.C. Trussell, M.D., Stephen A. Krawetz, Ph.D., Peter Snyder, M.D., Dana Ohl, M.D., Nanette Santoro, M.D., Esther Eisenberg, M.D., M.P.H., and Heping Zhang, Ph.D


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Abstract taken from PubMed

Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.
In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period.
Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.
As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
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Comment in:
    • In the article by Legro et al. (July 10 issue),1 further clarification is needed regarding the eligibility criteria of male partners of patients with the polycystic ovary syndrome. In a separate article by the authors2 (cited as reference 8 in their article), eligibility included a sperm concentration of 14 million per milliliter in at least one ejaculate within the past year, with at least some motile sperm, yet the present article in the Journal states that the criterion was documented motility according to World Health Organization (WHO) cutoff points. The WHO criteria, which are outlined by Cooper et al.3(cited as reference 11 in the article), list the lower limit of progressive motility as 28% (2.5th percentile) in a population of men who are presumed to be fertile. Given the potential effect of different levels of sperm motility on the likelihood of conception, the methods used to control for this factor need to be presented in further detail.
      Richard Bronson, M.D.
      Stony Brook University Medical Center, Stony Brook, NY
      No potential conflict of interest relevant to this letter was reported.

    • Legro et al. report that treatment with letrozole was superior to treatment with clomiphene in terms of higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. We wonder whether serum prolactin levels were evaluated at baseline and throughout the study. The polycystic ovary syndrome and hyperprolactinemia are both common causes of infertility in women. Up to 64% of women with mild hyperprolactinemia fulfill the modified Rotterdam diagnostic criteria for the polycystic ovary syndrome.1 Therefore, we believe that it is mandatory to measure serum prolactin levels when assessing the cause of infertility, even if the patient has the polycystic ovary syndrome. Furthermore, it is important to elucidate the cause of hyperprolactinemia and to assess the need for treatment with dopamine agonists.
      In addition, there is some evidence that letrozole regulates the expression of pituitary prolactin and luteinizing hormone and affects serum prolactin levels.3 Serum prolactin positively correlates with insulin resistance, which has an important role in the pathogenesis of the polycystic ovary syndrome. Hence, the superiority of letrozole over clomiphene in the current study might be explained by the effect of letrozole on serum prolactin levels.
      Ivan Kruljac, M.D.
      Dražan Butorac, M.D.
      Milan Vrkljan, M.D., Ph.D.
      University of Zagreb, Zagreb, Croatia No potential conflict of interest relevant to this letter
      The authors reply: Bronson points out the disparity between our published descriptions of the entry criteria regarding semen analysis. In our protocol, available with the full text of the article at NEJM.org, and in the original published protocol summary,1 the correct criteria are a sperm concentration of 14 million per milliliter in at least one ejaculate within the past year, with at least some motile sperm. We apologize for this miscommunication. However, we disagree that sperm motility is an important predictive factor for pregnancy outcome. We addressed this issue in a previous study of semen qualities in fertile and infertile men (performed under a standardized semen-analysis protocol), in which we found that none of the individual semen qualities (concentration, motility, or morphologic variables) alone or in combination was a powerful discriminator of fertility.

  • There is a well-documented large within-person variation in sperm properties in both fertile and infertile men over time. One study showed that sperm motility can vary by up to a factor of 4 in an individual man over time.3 In our study, couples had regular intercourse without inseminations, so it is unlikely that the semen properties that were observed in the baseline sample were highly correlated with those present during intercourse. We have completed the analysis of a large, multicenter study involving couples with unexplained infertility in which the female patients underwent a single intrauterine insemination per cycle after ovulation triggering.4 In that study, we prospectively evaluated all key semen properties in each sample, and we believe that these data are more suited to answering Bronson's inquiry about the contribution of sperm motility to conception.
    Kruljac et al. inquire about the role of mild prolactin excess in the outcomes of our study. As noted in our article, prolactin excess was an exclusion criterion in the study. We did not follow prolactin levels during the study, so we cannot specifically address the question of the effect of letrozole on prolactin levels. However, we found that the mean prolactin levels at screening (as determined in the local study-site laboratories) were well within normal limits, with no difference between the treatment groups, regardless of the pregnancy outcomes, including ovulation, pregnancy, and live birth (Figure FIGURE 1) Screening Serum Prolactin Levels, According to Treatment Group and Outcome.) (P>0.35 for all comparisons).
    Richard S. Legro, M.D.
    Penn State College of Medicine, Hershey, PA
    Heping Zhang, Ph.D.
    Yale University School of Public Health, New Haven, CT
    for the Eunice Kennedy Shriver NICHD Reproductive Medicine Network
    Since publication of their article, the authors report no further potential conflict of interest.


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