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Higher ovulation rate with letrozole as compared with clomiphene citrate in infertile women with polycystic ovary syndrome: a systematic review and meta-analysis

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Abstract

Background

Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. According to the latest guidelines, letrozole should be considered as the first-line pharmacological treatment for women with WHO Group II anovulation or PCOS. However, the use of letrozole as an ovulation induction agent is not FDA or EMA approved, and its use is “off-label.” The main concern with respect to letrozole regards its potential teratogenic effect on the fetus.

Purpose

To determine whether the probability of ovulation is higher with letrozole as compared to clomiphene citrate (CC) in anovulatory women with PCOS.

Methods

Randomized controlled trials (RCTs) comparing letrozole versus CC used for ovulation induction in infertile women with PCOS followed by timed intercourse (TI) or intrauterine insemination (IUI) were included in this meta-analysis. Primary outcome was ovulation. Secondary outcomes were live birth, clinical pregnancy, miscarriage, multiple pregnancy, and congenital anomalies. Subgroup analysis included patients who received letrozole or CC as first-line treatment, and patients with PCOS diagnosed according to the Rotterdam criteria.

Results

Twenty-six RCTs published between 2006 and 2019, involving 4168 patients who underwent 8310 cycles of ovulation induction, were included. The probability of ovulation was significantly higher in letrozole as compared to CC cycles (RR: 1.148, 95% CI: 1.077 to 1.223, 3017 women, 19 trials, I2: 47.7%, low-quality evidence).

Conclusion

A higher probability of ovulation is expected in infertile patients with PCOS treated with letrozole as compared to CC. The higher ovulation rate might have contributed to the higher clinical pregnancy and live birth rate. This finding is also true for patients who were administered letrozole as first-line treatment.

Trial registration

CRD42019125166

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Data availability

All data included in this study are available upon request by contacting the corresponding author.

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Authors and Affiliations

  1. National and Kapodistrian University of Athens, Irakleitou 1, 50132, Kozani, Greece

    Alexandra P. Tsiami

  2. Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, 54629, Thessaloniki, Greece

    Dimitrios G. Goulis

  3. 2nd Department of Obstetrics and Gynecology, Faculty of Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642, Thessaloniki, Greece

    Alexandros I. Sotiriadis

  4. Unit of Human Reproduction, 1st Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki Papageorgiou General Hospital, 54629, Thessaloniki, Greece

    Efstratios M. Kolibianakis

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A.T. conceived and designed the review, searched the literature, conducted the data analysis, and wrote the manuscript. S.K. designed the review, reviewed the manuscript, and provided critical scientific input regarding the field of human reproduction. A.S. was involved in data analysis and interpretation, reviewed the manuscript, and provided critical scientific input regarding the field of statistical methods and quality assessment. D.G. reviewed the manuscript and provided critical scientific input regarding the field of human reproduction. All authors approved the final version of the manuscript.

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Tsiami, A.P., Goulis, D.G., Sotiriadis, A.I. et al. Higher ovulation rate with letrozole as compared with clomiphene citrate in infertile women with polycystic ovary syndrome: a systematic review and meta-analysis. Hormones 20, 449–461 (2021). https://doi.org/10.1007/s42000-021-00289-z

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