• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
• Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
• Slone Epidemiology Center at Boston University, Boston, MA, USA.
• 1] Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA [2] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
• 1] Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA [2] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA [3] Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
• AARP, Washington DC, WA, USA.
• Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
• Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
• Department of Epidemiology and Biostatistics, School of Public Health and Health Services, George Washington University, Washington DC, WA, USA.
• Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women.

METHODS: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248).

RESULTS: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility.

CONCLUSIONS: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.