Watling Cody Z, Kelly Rebecca K, Watts Eleanor L, Graubard Barry I, Petrick Jessica L, Matthews Charles E, McGlynn Katherine A
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
Int J Cancer. 2025 Apr 15;156(8):1518-1528. doi: 10.1002/ijc.35244. Epub 2024 Nov 5.
In most countries, males have ~2-3 times higher incidence of primary liver cancer than females. Sex hormones have been hypothesized to contribute to these differences, but the evidence remains unclear. Using data from the UK Biobank, which included ~200,000 males and ~180,000 postmenopausal females who provided blood samples at recruitment, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for a doubling in hormone concentration from multivariable adjusted Cox regression for circulating total testosterone, sex-hormone binding globulin (SHBG), and free testosterone concentrations and risk of primary liver cancer. After a median of 11.8 years of follow-up, 531 cases of primary liver cancer were observed, of which 366 occurred in males and 165 occurred in females. Total testosterone and SHBG were shown to be positively associated with liver cancer risk in both males and females (Total testosterone HR: 3.42, 95% CI:2.42-4.84 and 1.29, 0.97-1.72, respectively; SHBG HR: 5.44, 4.42-6.68 and 1.52, 1.09-2.12, respectively). However, free testosterone was inversely associated with primary liver cancer in males (HR: 0.42, 0.32-0.55) and no association was observed in females. When analyses compared two main liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), there was evidence of heterogeneity; associations for total testosterone and SHBG concentrations were only positively associated with HCC in both males (HR: 3.56, 2.65-4.79 and 7.72, 6.12-9.73, respectively) and females (HR: 1.65, 1.20-2.27 and 6.74, 3.93-11.5, respectively) but not with ICC. Further research understanding the mechanisms of how sex-steroids may influence liver cancer risk is needed.
在大多数国家，男性原发性肝癌的发病率比女性高约2至3倍。有假说认为性激素是导致这些差异的原因，但证据仍不明确。利用英国生物银行的数据，该数据包括约20万名男性和约18万名绝经后女性，这些人在招募时提供了血样，我们通过多变量调整的Cox回归估计了循环总睾酮、性激素结合球蛋白（SHBG）和游离睾酮浓度翻倍时的风险比（HR）和95%置信区间（CI）以及原发性肝癌的风险。经过中位数为11.8年的随访，观察到531例原发性肝癌病例，其中366例发生在男性中，165例发生在女性中。总睾酮和SHBG在男性和女性中均显示与肝癌风险呈正相关（总睾酮HR分别为：3.42，95%CI：2.42 - 4.84和1.29，0.97 - 1.72；SHBG HR分别为：5.44，4.42 - 6.68和1.52，1.09 - 2.12）。然而，游离睾酮在男性中与原发性肝癌呈负相关（HR：0.42，0.32 - 0.55），在女性中未观察到相关性。当分析比较两种主要的肝癌亚型，即肝细胞癌（HCC）和肝内胆管癌（ICC）时，有证据表明存在异质性；总睾酮和SHBG浓度的相关性仅在男性（HR分别为：3.56，2.65 - 4.79和7.72，6.12 - 9.73）和女性（HR分别为：1.65，1.20 - 2.27和6.74，3.93 - 11.5）中与HCC呈正相关，而与ICC无关。需要进一步研究以了解性类固醇可能影响肝癌风险的机制。
