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

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.

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank

“…11 Another recent study from the Liver Cancer Pooling Project (LCPP) reported that higher levels of circulating oestradiol in women were associated with an increased ICC risk. 12 Taken together, these results suggest that factors that affect oestrogenic regulation may play a role in the aetiology of ICC.…”

“…In epidemiologic investigations of circulating sex steroid hormones and ICC risk, two studies have reported higher levels of circulating oestradiol in both men and women cholangiocarcinoma cases compared to controls. 11,12 One of these studies was based in the LCPP and reported that a doubling of circulating oestrogen levels in women was associated with a 40% increased ICC risk. 12 Neither study reported associations with circulating androgen levels.…”

“…11,12 One of these studies was based in the LCPP and reported that a doubling of circulating oestrogen levels in women was associated with a 40% increased ICC risk. 12 Neither study reported associations with circulating androgen levels.…”

Estradiol is significantly associated with prognosis in non-surgical liver cancer patients: from bench to bedside

“…It is estimated that about 42,810 individuals will be diagnosed with liver cancer in the United States in 2020, of whom 30,160 will die [ 2 ]. In virtually all countries, males exhibit incidence and mortality rates 2 to 3 times higher than women [ 1 , 3 ]. As such, addressing the high mortality and poor prognosis associated with liver cancer remains an urgent priority.…”

“…In contrast, however, some other studies have reported no significant prognostic differences between males and females [ 8 ]. Some recent studies have reported that estrogen may play a role in the prognosis of patients with liver cancer [ 10 – 12 ], while others have reported no such effect [ 3 ]. Unfortunately, most—if not all—of these studies were performed using a pool of patients in surgical and non-operative states, even though surgery is a vital factor influencing patient prognosis [ 13 ].…”