Polycystic ovarian syndrome (PCOS) is a leading cause of infertility due to chronic anovulation. Letrozole is the first-line treatment for ovulation induction, but combination therapy with clomiphene citrate (CC) may enhance outcomes. We conducted a systematic search of three databases until October 2024, including randomized controlled trials (RCTs). Bias was assessed using the Revised Cochrane risk of bias tool (RoB 2). Six RCTs with 619 PCOS patients were included. The combination of Letrozole and CC resulted in a higher, though non-significant, ovulation rate (53.74%) vs. Letrozole alone (40.08%) (OR 1.22, 95% CI [0.88, 1.69], P = 0.23). Lower-dose combination therapy (50 mg CC + 2.5 mg Letrozole) significantly improved ovulation (OR 4.45, 95% CI [2.19, 9.08], P < 0.001), whereas higher-dose therapy (100 mg CC + 5 mg Letrozole) had no effect. Pregnancy rates were higher with combination therapy (26.25% vs. 22.18%) but not significant (OR 1.26, 95% CI [0.84-1.88], P = 0.26). Miscarriage rates were lower (OR 0.32, 95% CI [0.12-0.88], P = 0.03). Lower-dose combination therapy also increased the proportion of follicles > 15 mm (OR 4.09, 95% CI [1.94, 8.60], P < 0.001), with no significant differences in endometrial thickness, follicular size, or progesterone levels. Side effects were similar, though hot flushes were more common with combination therapy (OR 2.99, 95% CI [1.23, 7.23], P = 0.02). Our results support lower-dose combination therapy for improved ovulation, follicle count, and pregnancy outcomes while reducing miscarriage risk.
Keywords: Clomiphene citrate; Combination; Letrozole; Ovulation; Polycystic ovarian syndrome.
© 2025. The Author(s), under exclusive licence to Society for Reproductive Investigation.