Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review

Kaltsas, Aris; Efthimiou, Anna; Roidos, Christos; Tzikoulis, Vasileios; Georgiou, Ioannis; Sotiriadis, Alexandros; Zachariou, Athanasios; Chrisofos, Michael; Sofikitis, Nikolaos; Dimitriadis, Fotios

doi:10.3390/biomedicines13092051

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Open AccessReview

Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review

by

Aris Kaltsas

^1,†

,

Anna Efthimiou

^2,†,

Christos Roidos

³

,

Vasileios Tzikoulis

³

,

Ioannis Georgiou

⁴

,

Alexandros Sotiriadis

⁵

,

Athanasios Zachariou

⁶

,

Michael Chrisofos

¹,

Nikolaos Sofikitis

⁶ and

Fotios Dimitriadis

^3,*

¹

Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece

²

Department of Obstetrics, Gynecology and Assisted Reproduction, Maternity—Health, 15232 Chalandri, Athens, Greece

³

Department of Urology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece

⁴

Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece

⁵

First Department of Obstetrics and Gynecology, Papageorgiou General Hospital of Thessaloniki, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece

⁶

Laboratory of Spermatology, Department of Urology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Biomedicines 2025, 13(9), 2051; https://doi.org/10.3390/biomedicines13092051

Submission received: 6 August 2025 / Revised: 19 August 2025 / Accepted: 21 August 2025 / Published: 22 August 2025

(This article belongs to the Special Issue Maternal-Fetal and Neonatal Medicine)

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Abstract

Letrozole, a third-generation aromatase inhibitor initially developed for breast cancer, has become the preferred first-line agent for ovulation induction (OI), particularly in women with polycystic ovary syndrome (PCOS). This narrative review critically evaluates the efficacy, safety, and clinical applications of letrozole across diverse infertility contexts. Compared to clomiphene citrate, letrozole is associated with higher ovulation and live birth rates, a lower risk of multiple gestation, and a more favorable endometrial environment. Its pharmacokinetics—marked by transient estrogen suppression and a short half-life—limit embryonic exposure, supporting its favorable safety profile. Emerging data from large, randomized trials and meta-analyses demonstrate no increase in congenital anomalies, miscarriage, or adverse perinatal outcomes in letrozole-conceived pregnancies. Moreover, maternal side effects are generally mild, and the risk of ovarian hyperstimulation syndrome is low. Letrozole has also shown utility in mild stimulation protocols, fertility preservation for estrogen-sensitive malignancies, and clomiphene-resistant PCOS. Key clinical strategies—such as early-cycle initiation, lowest effective dosing, and individualized monitoring—optimize therapeutic outcomes while minimizing potential risks. While long-term offspring data remain limited and mechanistic concerns persist, current evidence robustly supports letrozole as a safe and effective option for OI, balancing reproductive success with maternal–fetal safety across a range of infertility indications.

Keywords: letrozole; ovulation induction; polycystic ovary syndrome; clomiphene resistance; infertility management; ovarian hyperstimulation; estrogen-sensitive cancers

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MDPI and ACS Style

Kaltsas, A.; Efthimiou, A.; Roidos, C.; Tzikoulis, V.; Georgiou, I.; Sotiriadis, A.; Zachariou, A.; Chrisofos, M.; Sofikitis, N.; Dimitriadis, F. Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review. Biomedicines 2025, 13, 2051. https://doi.org/10.3390/biomedicines13092051

AMA Style

Kaltsas A, Efthimiou A, Roidos C, Tzikoulis V, Georgiou I, Sotiriadis A, Zachariou A, Chrisofos M, Sofikitis N, Dimitriadis F. Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review. Biomedicines. 2025; 13(9):2051. https://doi.org/10.3390/biomedicines13092051

Chicago/Turabian Style

Kaltsas, Aris, Anna Efthimiou, Christos Roidos, Vasileios Tzikoulis, Ioannis Georgiou, Alexandros Sotiriadis, Athanasios Zachariou, Michael Chrisofos, Nikolaos Sofikitis, and Fotios Dimitriadis. 2025. "Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review" Biomedicines 13, no. 9: 2051. https://doi.org/10.3390/biomedicines13092051

APA Style

Kaltsas, A., Efthimiou, A., Roidos, C., Tzikoulis, V., Georgiou, I., Sotiriadis, A., Zachariou, A., Chrisofos, M., Sofikitis, N., & Dimitriadis, F. (2025). Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review. Biomedicines, 13(9), 2051. https://doi.org/10.3390/biomedicines13092051

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Letrozole at the Crossroads of Efficacy and Fetal Safety in Ovulation Induction: A Narrative Review

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