Letrozole and clomiphene versus letrozole alone for ovulation induction in women with PCOS: a systematic review and meta-analysis

We aimed to compare the efficacy and safety of letrozole and clomiphene versus letrozole alone for ovulation induction in patients with Polycystic Ovary Syndrome (PCOS). We systematically searched EMBASE, PubMed, and Cochrane databases on October 31, 2024. We included studies of women with PCOS treated with a combination of clomiphene and letrozole or letrozole alone to induce ovulation that reported any of the outcomes of interest, namely rate of mature follicles and ovulation, ovulation, pregnancy, miscarriages, endometrial thickness, and number of mature follicles. We pooled odds ratios (OR) and mean difference (MD) with 95% confidence intervals (CI) using a random effects model using R statistical software, version 4.2.1. Heterogeneity was assessed with I2 statistics, and a random effects model was used. Four RCTs and two observational studies comprising 592 patients were included. Combined therapy was associated with a higher rate of a mature follicle (OR 2.74; 95% CI 1.72-4.37; p< 0.001; I2=0%) and ovulation (OR 2.55; 95% CI 1.57-4.12; p< 0.001; I2=35.9%). The number of mature follicles, number of pregnancies, thickness of endometrial lining, and the incidence of adverse events, including headache, abdominal bloating, fatigue, back pain, breast discomfort, and night sweats, were similar between groups. In women with anovulatory infertility secondary to PCOS, letrozole and clomiphene citrate combined therapy was associated with improved mature follicle and ovulation rates, with a similar safety profile compared to letrozole alone. However, no significant impact was observed on pregnancy rates.