Original article
Pancreas, biliary tract, and liver
Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma

https://doi.org/10.1016/j.cgh.2017.05.036Get rights and content

Background & Aims

Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC.

Methods

We performed a case–control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC.

Results

The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32–0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 ± 0.9 years) vs nonusers (mean 59.2 ± 1.1 years; P = .001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20–0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67–11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88–79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40–0.77; P = .01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7–41.3 months) and 24.1 months for nonusers (95% CI, 19.02–29.30 months; P = .008).

Conclusion

In a case–control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

Section snippets

Methods

The current investigation is part of an ongoing hospital-based case–control study, which was approved by the Institutional Review Board at the University of Texas MD Anderson Cancer Center. Written informed consent for participation was obtained from each participant.

Cases were new patients with pathological or radiological evidence of HCC who were treated at MD Anderson. The control subjects were healthy and genetically unrelated family members (ie, spouses) of patients at MD Anderson who had

Results

Table 1 shows that cigarette smoking was not associated with HCC risk in women. Consistent with our previous reports race, hepatitis C virus (HCV), hepatitis B virus (HBV), alcohol use, diabetes, hypothyroidism, early adulthood obesity, and positive family history of cancer were significant risk factors for HCC in U.S. women.5, 6, 17

Table 2 shows female characteristics in cases and control subjects. A significant impact was observed only among estrogen users yielding a 50% reduction in HCC risk

Discussion

This study demonstrates 50% reduction in HCC risk development among women who used MHT. The observed reduced risk of HCC among estrogen users in this study was supported by 3 additional findings: (1) The positive correlation between age at HCC onset and duration of estrogen use. The adjusted linear regression analysis revealed significant coefficients indicating that in women with long-term use of estrogen, HCC tended to be diagnosed at an older age. (2) Attenuation of the magnitude of

References (43)

  • Q. Wei et al.

    Estrogen suppresses hepatocellular carcinoma cells through ERbeta-mediated upregulation of the NLRP3 inflammasome

    Lab Invest

    (2015)
  • R.G. Simonetti et al.

    Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials

    Ann Oncol

    (1997)
  • J.M. Llovet et al.

    Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

    Hepatology

    (2003)
  • M. Serper et al.

    Association of provider specialty and multi-disciplinary care with hepatocellular carcinoma treatment and mortality

    Gastroenterology

    (2017)
  • J.M. Llovet et al.

    Hepatocellular carcinoma

    Lancet

    (2003)
  • E.B. Gold

    The timing of the age at which natural menopause occurs

    Obstet Gynecol Clin North Am

    (2011)
  • C. Fitzmaurice et al.

    The Global Burden of Cancer 2013

    JAMA Oncol

    (2015)
  • D.L. White et al.

    Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012

    Gastroenterology

    (2017)
  • M.M. Hassan et al.

    Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study

    Int J Cancer

    (2008)
  • M.M. Hassan et al.

    Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States

    Hepatology

    (2009)
  • I. Shimizu

    Impact of oestrogens on the progression of liver disease

    Liver Int

    (2003)

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by National Institutes of Health R03 grant nos. ES11481 (to MMH), CA-106458 (to MMH), ONYX-33839 (to MMH) and the Sheikh Ahmed Center for Pancreatic Cancer Research (to RAW) at the University of Texas MD Anderson Cancer Center.

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    © 2017 by the AGA Institute