Supplementary Materials

Recently, human blood metabolites have been identified as crucial in uncovering the fundamental biological mechanisms underlying female reproductive disorders. Consequently, our study aimed to assess the causal link between human blood metabolites and female reproductive diseases.We used summary data from genome-wide association studies on serum metabolites and reproductive diseases. The Canadian Longitudinal Study on Aging(CLSA) provided data on 1,091 blood metabolites and 309 metabolite ratios (N=8299). The FinnGen consortium supplied data on polycystic ovary syndrome (PCOS), ectopic pregnancy, and female infertility. Additional data on miscarriages were obtained from research by Triin Laisk et al. We conducted a two-sample Mendelian randomization (MR) study using various statistical methods (IVW, MR-Egger, WM) and sensitivity analyses. Multivariate Mendelian randomization (MVMR) was performed to account for metabolite interactions. Our study identified 38 associations among 309 metabolite ratios, 1,091 metabolites and five female reproductive diseases, encompassing 28 metabolites, three metabolite ratios and five unknown metabolites. MVMR revealed that 5alpha-androstan- 3alpha,17alpha-diol monosulfate has direct influences on ectopic pregnancy independently of other metabolites. Similarly, 1-Stearoyl-GPE(18:0) directly affects female infertility. Cortolone glucuronide (1) and X-12849 have independent effects on PCOS. The effect of 5alpha-androstan- 3alpha,17alpha-diol monosulfate on PCOS became non-significant after adjusting for ectopic pregnancy.