Causal effects between different sub-phenotypes of endometriosis and female infertility: a bidirectional Mendelian randomization study

Objective‍ ‍To investigate the bidirectional causal relationship between different subtypes of endometriosis and female infertility using Mendelian randomization (MR). Methods‍ ‍A two-sample MR analysis was performed on the data sourced from publicly available genome-wide association study (GWAS) of endometriosis and infertility. For each subtype of endometriosis, instrumental variables (IVs) satisfying MR assumptions were selected, with inverse variance weighting (IVW) as primary method. Sensitivity analyses, including Cochran’s Q test, MR-Egger regression, and leave-one-out analysis, were conducted to verify the robustness of the results. Statistical significance was set at P<0.01 (Bonferroni correction), and P<0.05 was considered as suggestive significance. Results‍ ‍Among different locations of endometriosis, ovary (IVW: OR=1.26, 95%CI: 1.17~1.35, P<0.001), pelvic peritoneum (IVW: OR=1.26, 95%CI: 1.20~1.33, P<0.001), rectovaginal septum (IVW: OR=1.11, 95%CI: 1.06~1.16, P<0.001), adenomyosis (IVW: OR=1.16, 95%CI: 1.07~1.25, P<0.001), and other types of endometriosis (IVW: OR=1.10, 95%CI: 1.03~1.17, P=0.004) were significantly associated with infertility. But no such association was observed in fallopian tube and intestinal endometriosis with infertility (P>0.05). Reverse causality analysis indicated that infertility might lead to fallopian tube endometriosis (IVW: OR=1.46, 95%CI: 1.11~1.93, P=0.007), and was associated with ovarian (IVW: OR=1.56, 95%CI: 1.27~1.93, P<0.001), pelvic peritoneal (IVW: OR=1.34, 95%CI: 1.11~1.62, P=0.003), rectovaginal (IVW: OR=1.46, 95%CI: 1.11~1.93, P=0.007), and other types of endometriosis (IVW: OR=1.61, 95%CI: 1.21~2.13, P=0.001). Suggestive significance was observed statistically in infertility promoting adenomyosis (IVW: OR=1.16, 95%CI: 1.07~1.25, P0.05). Sensitivity analyses confirmed the robustness of the results. Conclusion‍ ‍Bidirectional causal relationships exist between different subtypes of endometriosis and infertility. Our findings based on MR analysis validate the clinical observation that endometriosis can lead to infertility, and we exploratively propose an important conclusion that infertility itself may also induce endometriosis. However, due to limited data, the causal relationships between intestinal/tubal endometriosis and infertility require further investigation.