Endogenous sex steroid hormones and risk of liver cancer among US men: Results from the Liver Cancer Pooling Project
Zeni Wu,
Jessica L. Petrick,
Andrea A. Florio,
Chantal Guillemette,
Laura E. Beane Freeman,
Julie E. Buring,
Gary Bradwin,
Patrick Caron,
Yu Chen,
A. Heather Eliassen,
Lawrence S. Engel,
Neal D. Freedman,
J. Michael Gaziano,
Edward L. Giovannuci,
Jonathan N. Hofmann,
Wen-Yi Huang,
Victoria A. Kirsh,
Cari M. Kitahara,
Jill Koshiol,
I-Min Lee,
Linda M. Liao,
Christina C. Newton,
Julie R. Palmer,
Mark P. Purdue,
Thomas E. Rohan,
Lynn Rosenberg,
Howard D. Sesso,
Rashmi Sinha,
Meir J. Stampfer,
Caroline Y. Um,
Stephen K. Van Den Eeden,
Kala Visvanathan,
Jean Wactawski-Wende,
Anne Zeleniuch-Jacquotte,
Xuehong Zhang,
Barry I. Graubard,
Peter T. Campbell,
Katherine A. McGlynn
Affiliations
Zeni Wu
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Jessica L. Petrick
Slone Epidemiology Center, Boston University, Boston, MA, USA
Andrea A. Florio
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Chantal Guillemette
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec-(CHU de Québec) Research Center–Université Laval, Québec, QC, Canada; Faculty of Pharmacy and Cancer Research Center, Laval University, Québec, QC, Canada
Laura E. Beane Freeman
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Julie E. Buring
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
Gary Bradwin
Clinical and Epidemiologic Research Laboratory, Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA, USA
Patrick Caron
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec-(CHU de Québec) Research Center–Université Laval, Québec, QC, Canada
Yu Chen
Department of Population Health, New York University School of Medicine, New York, NY, USA
A. Heather Eliassen
Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Lawrence S. Engel
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
Neal D. Freedman
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
J. Michael Gaziano
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Edward L. Giovannuci
Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
Jonathan N. Hofmann
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Wen-Yi Huang
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Victoria A. Kirsh
Ontario Institute for Cancer Research, Toronto, ON, Canada; Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Cari M. Kitahara
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Jill Koshiol
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
I-Min Lee
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
Linda M. Liao
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Christina C. Newton
Department of Population Science, American Cancer Society, Atlanta, GA, USA
Julie R. Palmer
Slone Epidemiology Center, Boston University, Boston, MA, USA
Mark P. Purdue
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Thomas E. Rohan
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, NY, USA
Lynn Rosenberg
Slone Epidemiology Center, Boston University, Boston, MA, USA
Howard D. Sesso
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
Rashmi Sinha
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Meir J. Stampfer
Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Caroline Y. Um
Department of Population Science, American Cancer Society, Atlanta, GA, USA
Stephen K. Van Den Eeden
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Kala Visvanathan
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
Jean Wactawski-Wende
Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA
Anne Zeleniuch-Jacquotte
Department of Population Health, New York University School of Medicine, New York, NY, USA
Xuehong Zhang
Department of Nutrition, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Barry I. Graubard
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
Peter T. Campbell
Albert Einstein College of Medicine, New York, NY, USA
Katherine A. McGlynn
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA; Corresponding author. Address: National Cancer Institute, 9609 Medical Center Drive, 6E-446, Bethesda, MD 20892, USA. Tel.: +1 240 276 7297..
Background & Aims: Incidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts. Methods: Concentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography–mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men. Results: Higher concentrations of total testosterone (OR per one-unit increase in log2 = 1.77, 95% CI = 1.38–2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21–2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22–20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27–2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33–0.68). Conclusions: Higher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk. Impact and implications: This study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men.
