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. 2020 Aug;72(2):535-547.
doi: 10.1002/hep.31057.

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Postmenopausal Women

Jessica L Petrick  1   2 , Andrea A Florio  1 , Xuehong Zhang  3 , Anne Zeleniuch-Jacquotte  4   5 , Jean Wactawski-Wende  6 , Stephen K Van Den Eeden  7 , Frank Z Stanczyk  8   9 , Tracey G Simon  10 , Rashmi Sinha  1 , Howard D Sesso  11   12 , Catherine Schairer  1 , Lynn Rosenberg  2 , Thomas E Rohan  13 , Mark P Purdue  1 , Julie R Palmer  2 , Martha S Linet  1 , Linda M Liao  1 , I-Min Lee  11   12 , Jill Koshiol  1 , Cari M Kitahara  1 , Victoria A Kirsh  14 , Jonathan N Hofmann  1 , Chantal Guillemette  15   16 , Barry I Graubard  1 , Edward Giovannucci  10 , J Michael Gaziano  12   17 , Susan M Gapster  18 , Neal D Freedman  1 , Lawrence S Engel  19 , Dawn Q Chong  20 , Yu Chen  4   21 , Andrew T Chan  3   10   22 , Patrick Caron  15 , Julie E Buring  11   12 , Gary Bradwin  23 , Laura E Beane Freeman  1 , Peter T Campbell  18 , Katherine A McGlynn  1
Affiliations

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Postmenopausal Women

Jessica L Petrick et al. Hepatology. 2020 Aug.

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed.

Figures

Figure 1.
Figure 1.
Schematic of sex steroid hormone metabolism. Quantitated sex steroid hormones are highlighted in red. Sex hormone binding globulin (SHBG) is not shown, as it is not part of the sex steroid metabolism pathway.
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