Association between premature menopause and the risk of biliary tract cancer: A nationwide cohort study

Abstract

Introduction: Recent studies indicate a potential link between female reproductive factors and the risk of biliary tract cancer (BTC). However, this association remains controversial due to conflicting results, highlighting the need for further investigation into hormonal influences on BTC development. Methods: We conducted a nationwide cohort study using data from the Korean National Health Insurance System, following 1059,533 menopausal women aged 40–69 years (median follow-up: 9.3 years). Cox proportional hazards regression was applied to assess the risk of cholangiocarcinoma (CCA) and gallbladder cancer (GBC) in relation to reproductive factors, particularly premature menopause (before age 40) and total reproductive period (time from menarche to menopause). The primary outcome was the incidence of BTC, specifically CCA and GBC. Results: During 9.87 million person-years of follow-up, 4198 women (0.40 %) were diagnosed with BTC. Premature menopause was associated with a significant increase in risk for both CCA (adjusted HR 1.29, 95 % CI: 1.01–1.64) and GBC (adjusted HR 1.42, 95 % CI: 1.03–1.97). A shorter total reproductive period (<30 years) was associated with a higher risk of BTC, with an adjusted HR of 1.10 (95 % CI: 0.99–1.21) for CCA and 1.15 (95 % CI: 1.01–1.33) for GBC. Other female reproductive factors assessed showed no significant associations. Conclusions: Premature menopause is associated with an increased risk of BTC, suggesting reduced lifetime exposure to female hormones as a risk factor. These results highlight the importance of considering reproductive history in identifying high-risk women and may inform targeted screening strategies for early detection. © 2025 Elsevier Ltd