The Potential Role of Female Sex Hormones in Patients With Inflammatory Bowel Disease: A 2-Sample Mendelian Randomization Study

Abstract

INTRODUCTION: An association between female sex hormones and inflammatory bowel disease (IBD) has been reported in epidemiological studies. However, a solid causal relationship has not been established. Therefore, we performed a 2-sample Mendelian randomization (MR) study to explore the causal association between genetically predicted female sex hormone exposure, especially estrogen, and IBD. METHODS: Genetic variants for female sex hormone exposure (ovulatory function, reproductive function, oral contraceptive pills, and hormone replacement therapy) were obtained from genome-wide association studies. Summary statistics for IBD were derived from the International Inflammatory Bowel Disease Genetics Consortium. We applied inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods in this MR study. Heterogeneity, horizontal pleiotropy, and sensitivity analyses were conducted to confirm the accuracy and robustness of our results. RESULTS: Our study found that genetically predicted age at menarche was associated with an increased risk of Crohn's disease (odds ratio [OR]IVW 1.235, 95% confidence interval [CI] 1.028–1.484, P = 0.024), genetically predicted age of the last used hormone replacement therapy was associated with an increased risk of ulcerative colitis (ORWM 1.636, 95% CI 1.011–2.648, P = 0.045), and genetically predicted number of live births was related to a decreased risk of Crohn's disease (ORIVW 0.583, 95% CI 0.373–0.912, P = 0.018). DISCUSSION: This study provided evidence for a link between female sex hormone exposure, especially estrogen, and IBD. Further investigations are needed to explore the causal effect of estrogen on IBD activity and the underlying mechanism of estrogen in IBD.