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Associations between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Post-Menopausal Women

Petrick JL1,2Florio AA1Zhang X3Zeleniuch-Jacquotte A4,5Wactawski-Wende J6Van Den Eeden SK7Stanczyk FZ8Simon TG9Sinha R1Sesso HD10,11Schairer C1Rosenberg L2Rohan TE12Purdue MP1Palmer JR2Linet MS1Liao LM1Lee IM10,11Koshiol J1Kitahara CM1Kirsh VA13Hofmann JN1Guillemette C14Graubard BI1Giovannucci E9Gaziano JM11,15Gapster SM16Freedman ND1Engel LS17Chong DQ18Chen Y4,19Chan AT3,9,20Caron P14Buring JE10,11Bradwin G21Beane Freeman LE1Campbell PT16McGlynn KA1.

Hepatology. 2019 Dec 5. doi: 10.1002/hep.31057. [Epub ahead of print]




In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer 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 liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts.


Seven sex steroid hormones and SHBG were quantitated using gas chromatography-tandem mass spectrometry (GC-MS/MS) and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 post-menopausal female liver cancer 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 liver cancer were calculated using multivariable-adjusted conditional logistic regression.


A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while 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).


This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.