The Role of Sex Hormones and Sex Hormone-binding Globulin in Functional Gatrointestinal Disorders: A Bidirectional Two-sample Mendelian Randomization Study.

Background And Aims: Sex hormones and sex hormone-binding globulin (SHBG) have been confirmed to involve in the pathophysiology of functional gastrointestinal disorders (FGIDs), including irritable bowel syndrome (IBS) and functional dyspepsia (FD). However, causal associations have not yet been investigated. Utilizing data from Genome-wide association studies, we conducted bidirectional two-sample mendelian randomization (MR) analyses to assess the causal relationships between sex hormones, SHBG and FGIDs.

Methods: Data for sex hormones including testosterone and estradiol, and SHBG were collected from the UK Biobank and FinnGen study. Relevant single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). Inverse variance weighted (IVW) analysis were performed to assess the causal relationships., supplemented with MR-Egger, weighted median, and weighted mode approaches. Additionally, we used Cochran's Q test to evaluate the heterogeneity of genetic variants and implemented leave-one-out analysis to assess the impact of individual SNPs on the causal estimates. Several sensitivity analyses were conducted to assess the robustness of the results.

Results: Significant negative causal relationship was found between genetically predicted testosterone and the risk of IBS (OR=0.90, 95%CI: 0.83-0.97; p=0.007). SHBG demonstrated an inverse correlation with the risk of IBS (OR=0.82, 95%CI: 0.68-0.98; p=0.035) and FD (OR=0.83, 95%CI: 0.69-0.99; p=0.048). However, no statistically significant association was found between testosterone and FD, while estradiol also showed no causal association with FGIDs.

Conclusions: Our study revealed a negative causal relationship between testosterone and IBS risk, and SHBG appears to be inversely associated with FD. This provided new ideas for the prevention and control of IBS, and future research is warranted to elucidate the underlying mechanisms driving these associations and their potential clinical implications.