Strong early impact of letrozole on ovulation induction outperforms clomiphene citrate in polycystic ovary syndrome: a systematic review with meta-analysis

Background: Polycystic ovary syndrome is one of the most frequent endocrinological problems causing infertility in women worldwide. The main problem in these women is hyperandrogenism and/or chronic oligo/anovulation, which leads to infertility. In this systematic review and meta-analysis, we aimed to investigate the efficacy of a relatively new drug for ovulation induction, letrozole, by comparing it to the first line of treatment for ovulation induction, clomiphene citrate. Methods: A literary search was conducted in three databases and included randomized clinical trials comparing letrozole and clomiphene citrate for ovulation induction for women with polycystic ovary syndrome. The diagnosis of polycystic ovary syndrome was determined according to the Rotterdam criteria. We pooled data using a random-effects model. Results: Our search provided a total of 1,994 articles, of which we included 25 studies. In the letrozole group, endometrial thickness was significantly higher (Mean Difference=1.70, Confidence Interval: 0.55-2.86; Heterogeinity: I2=97%, p-value=0.008); odds for ovulation (Odds Ratio=1.8, Confidence Interval: 1.21-2.69; Heterogeinity: I2=51%, p-value=0.010) and pregnancy (Odds Ratio=1.96, Confidence Interval: 1.37-2.81; Heterogeinity: I2=32%, p-value=0.002) were significantly higher; the resistance index of subendometrial arteries was significantly lower (Mean Difference=-0.15, Confidence Interval: -0.27- -0.04; Heterogeneity: I2=92%, p-value=0.030). Conclusion:  Women with polycystic ovary syndrome treated with letrozole for ovulation induction had higher ovulation and pregnancy rates, their endometrium became thicker, the resistance index of subendometrial arteries was lower. The lower resistance index of the subendometrial arteries can improve intrauterine circulation, which may provide better circumstances for embryo implantation and development. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: No ethical approval was required for this systematic review with meta-analysis, as all data were already published in peer-reviewed journals. No patients were involved in the design, conduct, or interpretation of our study. The datasets used in this study can be found in the full-text articles included in the systematic review and meta-analysis. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable All relevant data are within the manuscript and its Supporting Information files.