Phenotype-specific efficacy of letrozole versus clomiphene citrate in polycystic ovary syndrome: a prospective cohort study

To compare the efficacy of letrozole (LT) versus clomiphene citrate (CC) for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS), with emphasis on phenotypic variation and hyperandrogenism severity. In this prospective cohort study, 207 infertile women with PCOS diagnosed by modified Rotterdam criteria were treated with escalating doses of LT (n = 103) or CC (n = 104). Patients were classified according to PCOS phenotype (A–D) and hyperandrogenism markers: modified Ferriman-Gallwey (mFG) score, total testosterone (tT), and free androgen index (FAI). The primary outcome was ovulation; secondary outcomes included clinical pregnancy and live birth rates. LT achieved significantly higher ovulation rates compared with CC (93.2% vs. 77.9%, P = 0.002). The superiority of LT was most evident in patients with mFG > 8 (94.4% vs. 78.9%, P = 0.005), FAI ≥ 7 (100% vs. 50%, P = 0.006), and tT ≥ 48 ng/dL, where LT also resulted in higher clinical pregnancy and live birth rates. Phenotype C patients showed the clearest benefit with LT (100% vs. 82.6%, P = 0.013), while no significant differences were observed in non-hyperandrogenic (Phenotype D) patients. Multivariate analysis identified age and FAI as independent predictors of clinical pregnancy. In multivariate analysis adjusted for age, BMI, and hirsutism scores, Letrozole remained a significant independent predictor of ovulation (aOR: 7.74, p = 0.008). In this prospective observational study, Letrozole was associated with higher ovulation and pregnancy rates compared to clomiphene citrate in hyperandrogenic PCOS patients, particularly those with elevated FAI, tT, or hirsutism. Both agents demonstrated comparable efficacy in non-hyperandrogenic (Phenotype D) patients. These associative findings suggest that androgen markers may help guide individualized treatment selection, though further randomized controlled trials are needed to confirm these exploratory subgroup observations.