Jessica L Petrick1,2, Andrea A Florio1, Xuehong Zhang3, Anne Zeleniuch-Jacquotte4,5, Jean Wactawski-Wende6, Stephen K Van Den Eeden7, Frank Z Stanczyk8,9, Tracey G Simon10, Rashmi Sinha1, Howard D Sesso11,12, Catherine Schairer1, Lynn Rosenberg2, Thomas E Rohan13, Mark P Purdue1, Julie R Palmer2, Martha S Linet1, Linda M Liao1, I-Min Lee11,12, Jill Koshiol1, Cari M Kitahara1, Victoria A Kirsh14, Jonathan N Hofmann1, Chantal Guillemette15,16, Barry I Graubard1, Edward Giovannucci10, J Michael Gaziano12,17, Susan M Gapster18, Neal D Freedman1, Lawrence S Engel19, Dawn Q Chong20, Yu Chen4,21, Andrew T Chan3,10,22, Patrick Caron15, Julie E Buring11,12, Gary Bradwin23, Laura E Beane Freeman1, Peter T Campbell18, Katherine A McGlynn1. 1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD. 2. Slone Epidemiology Center, Boston University, Boston, MA. 3. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA. 4. Department of Population Health, New York University School of Medicine, New York, NY. 5. NYU Perlmutter Cancer Center, New York University School of Medicine, New York, NY. 6. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY. 7. Division of Research, Kaiser Permanente Northern California, Oakland, CA. 8. Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles, CA. 9. Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA. 10. Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 11. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. 12. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA. 13. Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY. 14. Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. 15. Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec-(CHU de Québec) Research Center-Université Laval, Québec, QC, Canada. 16. Faculty of Pharmacy, Laval University, Québec, QC, Canada. 17. VA Boston Healthcare System, Boston, MA. 18. Epidemiology Research Program, American Cancer Society, Atlanta, GA. 19. Department of Epidemiology, University of North Carolina, Chapel Hill, NC. 20. Division of Medical Oncology, National Cancer Centre Singapore, Singapore. 21. Department of Environmental Medicine, New York University School of Medicine, New York, NY. 22. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA. 23. Clinical and Epidemiologic Research Laboratory, Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA.
Abstract
BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54). CONCLUSIONS: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.
BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54). CONCLUSIONS: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.
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