Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank

Br J Cancer. 2020 Jul;123(2):316-324. doi: 10.1038/s41416-020-0835-5. Epub 2020 May 7.


Background: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.

Methods: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).

Results: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.

Conclusions: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Bile Ducts
  • Bile Ducts, Intrahepatic
  • Biological Specimen Banks
  • Cholangiocarcinoma / chemically induced
  • Cholangiocarcinoma / epidemiology*
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology
  • Cohort Studies
  • Contraceptives, Oral, Hormonal / adverse effects*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor beta / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hormones / adverse effects*
  • Hormones / therapeutic use
  • Humans
  • Hysterectomy / adverse effects
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / epidemiology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Menopause / drug effects
  • Middle Aged
  • Proportional Hazards Models
  • Risk Factors
  • United Kingdom / epidemiology


  • Contraceptives, Oral, Hormonal
  • ESR1 protein, human
  • ESR2 protein, human
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Hormones