Petrick JL1,2, Florio AA1, Zhang X3, Zeleniuch-Jacquotte A4,5, Wactawski-Wende J6, Van Den Eeden SK7, Stanczyk FZ8, Simon TG9, Sinha R1, Sesso HD10,11, Schairer C1, Rosenberg L2, Rohan TE12, Purdue MP1, Palmer JR2, Linet MS1, Liao LM1, Lee IM10,11, Koshiol J1, Kitahara CM1, Kirsh VA13, Hofmann JN1, Guillemette C14, Graubard BI1, Giovannucci E9, Gaziano JM11,15, Gapster SM16, Freedman ND1, Engel LS17, Chong DQ18, Chen Y4,19, Chan AT3,9,20, Caron P14, Buring JE10,11, Bradwin G21, Beane Freeman LE1, Campbell PT16, McGlynn 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.