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

Abstract

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.

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project

“…These findings are in line with observations from three studies conducted in Asian countries [17,19,41], that found older age at menarche was associated with BTC risk. Conversely, no association between age at menarche and BTC was found in studies conducted in Western Europe or the United States (Supplemental Table 9) [15,16,40,42]. Asian women have a lower BMI than women of other ethnicities which may delay puberty onset [31][32][33].…”

Lipid alterations in chronic liver disease and liver cancer

“…Lastly, steroid hormones play an important role in hepatocarcinogenesis. 157 , 158 Oestrogen shows a significantly protective effect against HCC, 159 while elevated serum oestrogen and high expression levels of oestrogen-related proteins are associated with CCA 160 , 161 and poor clinical outcomes. 161 Thus, tamoxifen may potentially aid CCA therapy.…”

“… 161 Thus, tamoxifen may potentially aid CCA therapy. 162 As such, the use of oral contraception is associated with an increased risk of CCA, 158 but not HCC development. 163 …”

Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations

“…47 Interestingly, recent reports from the United Kingdom described an association between long-term oral contraceptive use and baseline levels of 4-androstenedione with an increased iCCA risk. 48,49 Taken together, estrogen likely plays an important role in CCA development, and further investigation on the effect of the relationship between the obesity-related estrogens and obesity-related CCA growth axes is warranted.…”