Circulating sex hormone-related biomarkers and risk of inflammatory bowel disease: a prospective cohort study in the UK Biobank

Abstract Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder with increasing global burden, while its risk factors remain incompletely understood. Sex hormones may influence immune and inflammatory processes, but epidemiological evidence linking circulating sex hormone-related biomarkers to incident IBD risk is limited. This study aimed to investigate these associations and explore the potential role of systemic inflammation. Methods We conducted a prospective cohort study of 306,790 participants from the UK Biobank. Baseline estradiol, testosterone, sex hormone-binding globulin (SHBG), and estradiol-to-testosterone (E/T) ratio were assessed as exposures. Incident IBD, CD, and UC were identified through linked health records. The models were adjusted for demographic characteristics, lifestyle factors, metabolic factors, comorbidities, and medication use. We applied Cox regression models, sex-stratified analyses, interaction analyses, sensitivity analyses, and exploratory mediation analyses to investigate these associations. Results During follow-up, 2,121 participants developed IBD, including 735 CD and 1,520 UC cases. In fully adjusted models, higher SHBG levels were associated with lower risks of incident IBD (Q4 vs. Q1: HR 0.78, 95% CI 0.69–0.90) and CD (HR 0.61, 95% CI 0.48–0.76). Sex-stratified analyses showed that the inverse association between SHBG and CD risk remained significant among females, although no significant interaction by sex was observed. No consistent associations were found for testosterone, estradiol, or the E/T ratio. Exploratory mediation analyses suggested that INFLA-score partially accounted for the observed associations between SHBG and CD and UC risk, with estimated mediation proportions of 15.7% and 29.8%, respectively. Conclusions Higher SHBG levels were associated with reduced risks of incident IBD and CD. Systemic inflammation may partially explain the observed associations between SHBG and IBD outcomes. Further investigations are needed to clarify the potential biological role of sex hormone-related factors in IBD development. Trial registration No trial registration was required for this observational study.