Is combined letrozole and clomiphene superior to either as monotherapy: a systemic review and meta-analysis based on clinical trials.

Objective: This research was conducted to assess the therapeutic advantage of combined letrozole and clomiphene citrate versus monotherapy for polycystic ovarian syndrome (PCOS) patients.

Study design: Five databases were searched using the search string: (letrozole and clomiphene) AND (clomiphene OR clomiphene citrate OR CC) AND (letrozole OR LE) AND (ovulation induc* OR fertility induc* OR fertility preserv*) AND (polycystic ovarian syndrome OR PCOS). All statistical analyses were conducted in Review Manager 5.4.1. Random effect-effect model was used to pool risk ratio (RR), mean difference (MD), and odds ratio (OR) and their corresponding 95% confidence interval (CI). Moreover, qualitative analysis was conducted to qualitatively analyze ovulation, secondary outcomes, and cycle characteristics.

Results: One clinical trial and three randomized clinical trials (RCTs) were used in the study. Two studies were used in a quantitative analysis showing that combination was superior for ovulation induction (RR = 1.86 [1.37, 2.53]; p < 0.0001; I² = 0%), but the number of follicles ≥15 mm was significantly associated with the combination (MD = 0.40[0.14, 0.66]; p = 0.002; I² = 0%). On subgroup analysis, only hot flushes were significantly associated with the combination (RR = 2.67[1.12, 6.36]; p = 0.03; I² = 0%). The meta-analysis of two studies reported a significantly higher ovulation rate and number of dominant follicles in the combination therapy group compared with the LE alone arm but no significant difference in pregnancy rate, endometrial thickness, and adverse events.

Conclusion: Our study demonstrates a significant effect of the combination on ovulation induction. The combination yielded a better chance of conception and viable pregnancy. Further studies are needed to determine the live birth rate. HighlightsCombined Letrozole and Clomiphene is superior to either of these drugs alone for ovulation induction in PCOS.Our results conclude that the combination results in better ovulation, cycle characteristics, and secondary changes.Only the incidence of hot flushes as an adverse effect is increasingly reported in combination.