Unraveling the link between early sexual initiation and endometriosis: evidence from population-based analyses and genetic causal inference

This study investigates whether the timing of first sexual intercourse is associated with the risk of developing endometriosis and adenomyosis, aiming to shed light on early-life reproductive factors that may influence women's long-term gynecological health. We analyzed data from two large population-based cohorts, the National Health and Nutrition Examination Survey (NHANES) and UK Biobank using multivariable logistic regression. In addition, we performed a two-sample Mendelian randomization analysis based on GWAS summary statistics for age at first sexual intercourse (AFS) from Mills et al. and for endometriosis-related outcomes from the FinnGen consortium, to evaluate the relationship between AFS and endometriosis. Further, genetic instruments were applied to assess the potential relationship between AFS and endometriosis, including specific subtypes such as ovarian endometriosis and peritoneal endometriosis, and adenomyosis. The primary analysis method employed was the inverse-variance-weighted (IVW) approach. To ensure robustness, the study accounted for potential horizontal pleiotropy and conducted heterogeneity tests. The multivariable logistic regression analysis revealed that in the NHANES cohort, women who had their first sexual intercourse at late adolescence had a significantly higher risk of endometriosis (adjusted model, odds ratio [OR] = 1.31, 95% confidence interval [CI]: 1.01–1.70, P = 0.04) compared to those who initiated sexual activity in adulthood. In the UK Biobank cohort, the association was stronger: late adolescent AFS was associated with a 51% higher risk (adjusted model, OR = 1.51, 95% CI: 1.41–1.61, P < 0.001), and early adolescent AFS with a 73% higher risk (adjusted model, OR = 1.73, 95% CI: 1.48–2.02, P < 0.001). The IVW Mendelian randomization analysis demonstrated that delayed AFS was significantly associated with an about 30% lower risk of endometriosis (OR = 0.70, 95% CI: 0.57–0.86, P = 6.08 × 10–4) and with an about 48% lower risk of adenomyosis (OR = 0.52, 95% CI: 0.37–0.73, P = 1.37 × 10–4). Our study yielded no evidence of horizontal pleiotropy or heterogeneity. Early sexual initiation markedly increases the risks of developing endometriosis and adenomyosis, while delayed initiation may offer protective benefits. These findings highlight the potential long-term reproductive health implications of adolescent sexual behavior and support the value of preventive strategies and early education.