Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study

Introduction: Reproductive endocrine disorders (RED), including polycystic ovary syndrome (PCOS), endometriosis (EMs), and female infertility (FI), significantly affect women's health globally, with varying prevalence across different regions. These conditions can be addressed through medication, surgical interventions, and lifestyle modifications. However, the limited understanding of RED's etiology and the substantial economic burden of its treatment highlight the importance of investigating its pathogenesis. Metabolites play a critical role in metabolic processes and are potentially linked to the development of RED. Despite existing studies suggesting correlations between metabolites and RED, conclusive evidence remains scarce, primarily due to the observational nature of these studies, which are prone to confounding factors.

Methods: This study utilized Mendelian Randomization (MR) to explore the causal relationship between metabolites and RED, leveraging genetic variants associated with metabolite levels as instrumental variables to minimize confounding and reverse causality. Data were obtained from the Metabolomics GWAS Server and the IEU OpenGWAS project. Instrumental variables were selected based on their association with the human gut microbiota composition, and the GWAS summary statistics for metabolites, PCOS, EMs, and FI were analyzed. The MR-Egger regression and random-effects inverse-variance weighted (IVW) methods were employed to validate the causal relationship. Cochran's Q test was employed to evaluate heterogeneity, sensitivity analysis was performed using leave-one-out analysis, and for pleiotropy analysis, the intercept term of MR-Egger's method was investigated.

Results: The MR analysis revealed significant associations between various metabolites and RED conditions. For instance, a positive association was found between 1-palmitoylglycerophosphocholine and PCOS, while a negative association was noted between phenylacetate and FI. The study identified several metabolites associated with an increased risk and others with protective effects against PCOS, EMs, and FI. These findings highlight the complex interplay between metabolites and RED, suggesting potential pathways through which these conditions could be influenced or treated.

Conclusion: This MR study provides valuable insights into the causal relationship between metabolites and female reproductive endocrine disorders, suggesting that metabolic alterations play a significant role in the pathogenesis of PCOS, EMs, and FI, and offering a foundation for future research and therapeutic development.