Causal Effects of Circulating Sex Hormone Levels on the Risk of Endometriosis: A Two-Sample Mendelian Randomization Study

Abstract

Background:Endometriosis is a chronic, estrogen-dependent, immune-modulated disorder with unclear causal contributions from circulating sex hormones. Understanding whether hormone levels directly influence risk may guide prevention and targeted therapies. To evaluate the causal effects of circulating sex hormones—estradiol (E2), total testosterone (TT), free testosterone (FT), estrone (E1), and sex hormone–binding globulin (SHBG)—on the risk of endometriosis using a two-sample Mendelian randomization (MR) framework, with clinical contextualization from a tertiary-care cohort.Methods:A two-sample MR study was performed using large, sex-stratified, European-ancestry genome-wide association studies (GWAS) summary statistics for hormones and endometriosis harmonized via MR-Base/OpenGWAS. Independent genome-wide significant Single Nucleotide Polymorphisms (SNPs) served as instruments, with multiple sensitivity and pleiotropy-robust estimators (MR-Egger, weighted median/mode, MR-PRESSO, radial MR). Multivariable MR accounted for SHBG and body mass index (BMI). A local cohort of 50 reproductive-age women with surgically or histologically confirmed endometriosis was analyzed descriptively (IBM SPSS Statistics 26.0) for phenotype benchmarking.Results:In primary analyses, higher genetically proxied estradiol (E2) increased endometriosis risk (IVW OR 1.18), while total testosterone (TT) and free/bioavailable testosterone (FT) were protective. SHBG showed a modest association that attenuated in multivariable models. Estrone (E1), evaluated as an exploratory exposure, was not statistically significant. E1 was not significant (OR 1.10, p = 0.100). Sensitivity analyses showed no major directional pleiotropy; >98% of SNPs satisfied Steiger directionality. Reverse MR found no evidence for endometriosis affecting hormone levels. The tertiary-care cohort reflected the typical clinical spectrum, reinforcing generalizability.Conclusions:This MR analysis supports a causal role for higher estradiol in increasing, and higher testosterone in reducing, endometriosis risk, with SHBG acting indirectly via steroid modulation. Findings were robust across sensitivity checks and integrated with clinical and mechanistic evidence, suggesting endocrine-targeted strategies may have preventive or risk-stratification potential.