Causal Relationships Between Pregnancy, Menstrual History, and Endometrial Cancer With Mediating Effects of Metabolism‐Related Traits
Background
Periods and pregnancy may affect the development of endometrial cancer by affecting the secretion of sex hormones, but the causal relationship is not clear, and its mediating factors need to be explored.
Methods
In this study, multivariable Mendelian randomization was used to analyze summary statistics of genome‐wide association studies of European ancestry, to evaluate the effect of 10 period‐ or pregnancy‐related factors on endometrial cancer. In addition, we performed the heterogeneity test and pleiotropy test to analyze the sensitivity. Because of the effect of sex hormones on body metabolism and the relationship between metabolism‐related traits and cancer, we explored the mediating effect of metabolism‐related traits by two‐step Mendelian randomization.
Results
This study showed that age at menarche ( p = 1.21e − 05; OR = 0.6852; 95% CI: 0.5784–0.8116), age at menopause ( p = 0.00098; OR = 1.242; 95% CI: 1.0919–1.4127), and sex hormone–binding globulin (SHBG) levels ( p = 7.4e − 07; OR = 0.5914; 95% CI: 0.4804–0.7281) have an independent causal relationship with the incidence of endometrial cancer. Moreover, several obesity‐related traits play a mediating role in the causal relationship between age at menarche and endometrial cancer. The mediators and their mediating effects are BMI (55.54%), obesity (30.37%), waist circumference preference (27.67%), body fat percentage (17.61%), and waist‐to‐hip ratio (14.82%). These results are robust to sensitivity analysis.
Conclusion
This study demonstrated the independent effect of pregnancy‐ and period‐related factors on endometrial cancer and suggested that avoiding obesity may be an effective method to prevent endometrial cancer for patients with premature menarche.