Gallbladder cancer (GBC) has a female predominance, although other biliary tract cancers (BTCs) such as extrahepatic and intrahepatic bile duct (EHBDC and IHBDC) and ampulla of Vater (AVC) have a male predominance. The role of female reproductive factors in BTC etiology remains unclear.
We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.
During 21,681,798 person-years of follow-up, 875 GBC, 379 IHBDC, 450 EHBDC, and 261 AVC cases occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births: 1.72, 95% CI: 1.25, 2.38). Age at menarche (HR per year increase: 1.15, 95% CI: 1.06, 1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years: 1.13, 95% CI: 1.04, 1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR: 1.19, 95% CI: 1.09, 1.31) and EHBDC HR: 1.11, 95% CI: 1.01, 1.22) in Asian women only.
We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest sex hormones may have distinct effects on cancers across the biliary tract and vary by geography.

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