Relationship between three reproductive factors and lung cancer: a two-sample Mendelian randomization study

Background: There is increasing evidence that sex hormones are involved in the development of lung cancer, but the correlation between reproductive behavior that changes sex hormone levels and lung cancer is not clear. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to explore the potential relationship between age at first sexual intercourse (AFS), menarche, menopause and lung cancer. Methods: We performed MR analysis of the data from genome-wide association study (GWAS) of European ancestry to evaluate the independent effects of three reproductive behaviors on lung cancer over all (LUCA), lung adenocarcinoma (LUAD), squamous cell lung cancer (LUSC) and small cell lung cancer (SCLC). We mainly used inverse variance weighting (IVW) method for MR analysis. Sensitivity was determined by MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis, weighted median analysis, MR-Egger analysis, and Leave-one-out analysis. Results: We found that older AFS had a causal relationship with LUCA [odds ratio (OR) = 0.6283, 95% confidence interval (CI) = 0.4959 ~ 0.7961, P = 0.0001], LUAD (OR = 0.7042, 95% CI = 0.4967 ~ 0.9984, P = 0.049) and LUSC (OR = 0.6231, 95% CI = 0.4386 ~ 0.8853, P = 0.0083) by MR analysis. Conclusion: Our results observed a causal relationship between older AFS and lower lung cancer risk. It emphasizes the importance of providing sex education since early sexual intercourse may have undesirable effects. In addition, early psychological treatment is also essential.