DataSheet2_Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study.xlsx

IntroductionReproductive 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.
MethodsThis 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.
ResultsThe 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.
ConclusionThis 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.

引言
生殖内分泌疾病（Reproductive endocrine disorders, RED）涵盖多囊卵巢综合征（PCOS）、子宫内膜异位症（EMs）与女性不孕症（FI），在全球范围内严重影响女性健康，且不同地区的患病率存在差异。此类疾病可通过药物治疗、外科干预及生活方式调整进行干预。然而，目前对RED的病因学认知不足，且其治疗带来的经济负担沉重，凸显了探究其发病机制的重要性。代谢物在代谢过程中发挥关键作用，且可能与RED的发生发展存在关联。尽管已有研究提示代谢物与RED之间存在相关性，但确凿证据仍较为匮乏，这主要是因为此类研究多为观察性研究，易受混杂因素影响。
方法
本研究采用孟德尔随机化（Mendelian Randomization, MR）方法探究代谢物与RED之间的因果关联，借助与代谢物水平相关的遗传变异作为工具变量，以最大限度减少混杂因素与反向因果偏倚。研究数据来源于代谢组全基因组关联分析服务器（Metabolomics GWAS Server）及IEU开放全基因组关联分析项目（IEU OpenGWAS project）。工具变量的筛选基于其与人类肠道菌群组成的关联，并对代谢物、PCOS、EMs及FI的全基因组关联分析汇总统计量进行分析。本研究采用MR-Egger回归与随机效应逆方差加权（random-effects inverse-variance weighted, IVW）方法验证因果关联。通过科克伦Q检验（Cochran’s Q test）评估异质性，采用留一法分析开展敏感性分析，并借助MR-Egger方法的截距项进行多效性分析。
结果
MR分析显示，多种代谢物与RED存在显著关联。例如，1-棕榈酰甘油磷脂胆碱与PCOS呈正相关，而苯乙酸盐与FI呈负相关。本研究鉴定出若干与PCOS、EMs及FI患病风险升高相关的代谢物，以及若干具有保护作用的代谢物。这些发现揭示了代谢物与RED之间复杂的相互作用，提示了可用于影响或治疗此类疾病的潜在通路。
结论
本项MR研究为代谢物与女性生殖内分泌疾病之间的因果关联提供了宝贵见解，表明代谢改变在PCOS、EMs及FI的发病机制中发挥重要作用，并为未来的研究与治疗开发奠定了基础。