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. 2024 Nov 5;156(8):1518–1528. doi: 10.1002/ijc.35244

Total testosterone, sex hormone‐binding globulin, and free testosterone concentrations and risk of primary liver cancer: A prospective analysis of 200,000 men and 180,000 postmenopausal women

Cody Z Watling 1, Rebecca K Kelly 2,3, Eleanor L Watts 1, Barry I Graubard 1, Jessica L Petrick 4, Charles E Matthews 1, Katherine A McGlynn 1,✉
PMCID: PMC11826138  PMID: 39499225

Abstract

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 (HR2) 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 HR2: 3.42, 95% CI:2.42–4.84 and 1.29, 0.97–1.72, respectively; SHBG HR2: 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 (HR2: 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 (HR2: 3.56, 2.65–4.79 and 7.72, 6.12–9.73, respectively) and females (HR2: 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.

Keywords: biomarker, cohort, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, sex hormones

What's new?

While established risk factors for liver cancer are more prevalent in males than females, these differences alone fail to explain why males are more likely to develop liver malignancies. Here, the authors investigated testosterone and sex hormone‐binding globulin (SHBG) levels in men and women as possible factors underlying sex‐related differences in liver cancer risk. Analyses show that total testosterone and SHBG are positively associated with liver cancer risk in males and females. Free testosterone, however, was inversely associated with risk in males and had no association in females. Whether these differences are causal or due to liver dysfunction remains unclear.

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1. INTRODUCTION

In 2022, liver cancer was the sixth most common cancer diagnosed globally and the third most common cause of cancer mortality. 1 Globally, hepatocellular carcinoma (HCC) is the predominant histological type of liver cancer, constituting 75–85% of all cases, whereas intrahepatic cholangiocarcinoma (ICC) is the second most common histological type, representing 10–15% of cases. 2 In most regions of the world, the incidence and mortality rates of liver cancer are approximately 2–3 times more common in males than females. 1 However, the sex differences in liver cancer rates are primarily due to the differences in HCC, as ICC rates are only 30% higher in males than females. 2 , 3 Males are more likely to have a higher prevalence of some established risk factors for liver cancer, such as chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, excessive alcohol consumption, smoking, and type 2 diabetes. However, these risk factors do not fully explain the higher rates observed in males. 4 , 5

Sex steroid hormones have been hypothesized to explain the sex differences observed in liver cancer incidence. 6 Specifically, androgens have been postulated to increase the risk of liver cancer and have been implicated in HCC signalling. 7 In particular, it has been suggested that free testosterone, the fraction of circulating testosterone not bound to any plasma protein, may be important for cancer risk, as it is the form of testosterone readily bioavailable to stimulate androgen receptors. 6 , 8 In mouse models, castration and hormone dosing have suggested that androgens promote hepatocarcinogenesis whereas estrogens may attenuate tumor formation 7 , 9 , 10 and androgen receptor overexpression has been observed in HCC tumours. 11 However, evidence from epidemiological studies is limited, with relatively few cases of liver cancer in each individual study. Two of the largest studies to date have used data from the Liver Cancer Pooling Project. A nested case–control analysis of males found that higher concentrations of androgens, such as total testosterone and dihydrotestosterone, and sex hormone‐binding globulin (SHBG) were positively associated with liver cancer risk. 12 The analysis of postmenopausal females found that SHBG was positively associated and 4‐androstenedione was inversely associated with liver cancer risk. 13 However, both studies had somewhat limited sample sizes (~1000 participants, of whom 100–200 were cases), which may have affected their statistical power. Other small epidemiological studies have found inconclusive evidence potentially due to the limited sample size and heterogeneous study designs and populations. 14 , 15 , 16 , 17 , 18

The UK Biobank prospective cohort collected blood samples from nearly the entire cohort (500,000 individuals) at recruitment and measured serum testosterone and SHBG levels. The current study aimed to assess the associations between circulating total testosterone, SHBG, and calculated free testosterone concentrations and the risk of primary liver cancer in over 200,000 men and 180,000 postmenopausal women.

2. METHODS

2.1. Study design and participants

Eligible individuals were identified for invitation to participate in the UK Biobank (total of 9.2 million individuals) using the National Health Service (NHS) patient registers. A total of 503,317 individuals aged 37–73 years consented to enrol (5.5% response rate) from 2006 to 2010. 19 At recruitment, the participants attended an assessment center and provided informed consent and detailed information about lifestyle, sociodemographic, and reproductive factors via a touchscreen questionnaire. Anthropometric measurements were taken using standardized procedures, 20 and blood samples were provided. 21 A full description of the study assessment, protocol, and ethical approval can be found on the UK Biobank website. 22

2.2. Blood collection and sex‐hormone assays

At recruitment, blood samples were obtained from nearly the entire cohort (99.7%). Blood was collected in a serum separator tube and shipped to the central processing laboratory in temperature‐controlled boxes at 4°C, then aliquoted, and stored in a central working archive at −80°C. An attempt was made to measure the serum concentrations of circulating total testosterone, SHBG, and albumin in all participants. Total testosterone and SHBG levels were measured using chemiluminescent immunoassays (Beckman Coulter AU5800) and albumin concentrations were measured using colorimetric assay (Beckman Coulter AU5800). Some participants had missing information on these assays for various reasons (e.g., below the limit of detection, unrecoverable aliquot, not returned data). For participants whose total testosterone values were missing because their values were below the lower limit of detection, we assigned a serum concentration of 0.26 nmol/L (3/4 of the lower limit of detection; n = 45 men and 32,411 postmenopausal women). The average within‐laboratory (total) coefficients of variation for each biomarker ranged from 2.1% to 8.3%. Full details of the assay methods and quality assurance protocols are available online on the UK Biobank website. 21

2.3. Free testosterone calculation

In circulation, the majority of testosterone is bound to SHBG or albumin. Approximately 2% of total testosterone circulates unbound or “free”, 8 to estimate free testosterone concentrations, we used a formula based on the law of mass action and the measured total testosterone, SHBG, and albumin concentrations determined at recruitment. 23 Further details of the free testosterone calculation formula can be found in the Data S1.

2.4. Repeat assessment

After completion of recruitment, participants who lived within a 35 km radius of the UK Biobank Coordinating Centre in Stockport were invited via email to repeat the recruitment assessment, which included providing blood samples once again. The response rate for the repeat assessment was 21%, and it was completed by ~20,000 participants.

2.5. Exclusions

Figure S1 shows the exclusion criteria used for this analysis. We excluded participants with a prevalent cancer at baseline (except C44: non‐melanoma skin cancer; n = 28,294), women who were not postmenopausal at baseline (n = 62,569), participants who did not have blood measurement data for total testosterone or SHBG (n = 28,022), or those whose reported sex did not match their genetic sex (n = 298). This left a total of 204,571 males and 178,602 females in our final sample.

2.6. Liver cancer case ascertainment

Incident liver cancer diagnoses were determined by linkage to the national cancer registries. Specifically, data were provided by NHS England for participants from England and Wales, and the NHS Central Register for participants from Scotland (see for further details: https://biobank.ndph.ox.ac.uk/crystal/crystal/docs/CancerLinkage.pdf.). Participants contributed follow‐up time from date of recruitment until the date of first registration of cancer (excluding non‐melanoma skin cancer [International Classification of Diseases 10th edition (ICD‐10): C44]), date of death, or last day of follow‐up from the cancer registry (31 December 2020 for English participants, 30 November 2021 for Scottish participants, and 31 December 2016 for Welsh participants) whichever came first. Participants were coded as having a primary event if they had an incident diagnosis of liver cancer (ICD‐10 topography code: C22). Histological subtypes of liver cancer were determined using ICD‐O‐3 morphology codes, specifically HCC: 8170‐8175 and ICC: 8032‐8033, 8041, 8050, 8070‐8071, 8140‐8141, 8160, 8260, 8480, 8481, and 8490.

2.7. Statistical analysis

All statistical analyses were conducted separately for males and females. Baseline characteristics were compared between liver cancer cases and non‐cases separated by sex. Participants were categorized into sex‐specific quartiles of total testosterone, SHBG, and free testosterone concentrations (the lowest quartile was used as the reference group) and by doubling in concentration (log2 transformed; therefore, a one‐unit increase represents a doubling of circulating concentrations) to compare to previous studies. 12 , 13 , 14 Cox proportional hazards regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total testosterone, SHBG, and free testosterone concentrations and liver cancer. Penalized smoothing splines were also used to assess the associations between total testosterone, SHBG, and free testosterone concentrations among males and females. 24 , 25 Minimally adjusted Cox regression models were adjusted by region of recruitment (North‐West England, North‐Eastern England, Yorkshire & the Humber, West Midlands, East Midlands, South‐East England, South‐West England, London, Wales, and Scotland), and baseline hazard was stratified by age at recruitment (<45, 45–49, 50–54, 55–59, 60–64, ≥65 years). Multivariable Cox regression models were further adjusted for body mass index (BMI; <20, 20–22.49, 22.5–24.9, 25–27.49, 27.5–29.9, 30–32.49, 32.5–34.9, ≥35 kg/m2), height (sex‐specific categories increasing by 5 cm), physical activity (low; 0–9.99, medium; 10–49.99, high; ≥ 50 metabolic equivalent of task [MET]‐hours/week, or unknown), Townsend deprivation index (quintiles from most deprived to least deprived), smoking status (never, former, light smoker: <15 cigarettes/day, medium smoker: 15–29 cigarettes/day, heavy smoker: ≥30 cigarettes/day), alcohol consumption (non‐drinkers, <1, 1–9.99, 10–19.99, ≥20 g/day), coffee intake (non‐drinkers, 1 cup/day, 2 cups/day, 3–4 cups/day, 5+ cups/day, or unknown), ethnicity (White, mixed race, Indian/Pakistani/Bangladeshi, Chinese/Asian, Black/Black British), diabetes status (yes, no), and menopausal hormone therapy (MHT) use (never, former, current) for females only. For covariates with relatively low proportions of missingness (0.5%–1% of participants with missing data), participants were randomly assigned to categories, or the mean/median was used to replace the missing value, and participants were assigned accordingly into the category, where applicable. For covariates with ≥5% missingness (physical activity and coffee intake) a missing category was utilized. Further information on the categorization and classification of covariates can be found in the Data S1. The proportional hazards assumption was evaluated by running an interaction between the time metric and sex hormone concentrations, and no violation was observed (p > 0.05).

Random measurement error and within‐person variability are limitations when using a single measurement of an exposure, which can underestimate the exposure‐disease association, known as regression dilution bias. 26 To correct for this, estimates for trend (i.e., HRs per doubling in concentration [HR2]) were corrected for regression dilution bias using the McMahon‐Peto method. 27 Briefly, using the repeat blood measurement collected from participants collected at the follow‐up assessment (median ~4.3 years after recruitment), a ratio between the difference in the mean of the upper quartile minus the lowest quartile at follow‐up and the difference in the mean of the upper quartile minus the lowest quartile measured at recruitment was used to correct measurement error and within‐person variability. We then divided this ratio by the log HR and 95% CI and exponentiated the results to obtain the corrected HR and 95% CI. We also tested for departure from linearity by comparing models where total testosterone, SHBG, or free testosterone concentrations were modelled using splines versus modelled as a linear predictor and compared models using likelihood ratio tests.

2.8. Subgroup and sensitivity analyses

We assessed whether the associations differed by liver cancer histologic types, namely HCC and ICC. We also divided follow‐up time by the median time (~6 years) to liver cancer diagnosis and compared associations for individuals diagnosed in the first 6 years after recruitment to individuals diagnosed after 6 years of follow‐up using a competing risk approach. 28 , 29 We also examined to see if there was heterogeneity at age of diagnosis (<70 years, ≥70 years) using a competing risk approach. For non‐case defined characteristics such as age at blood collection (<60 years, ≥60 years), alcohol intake (<20 g/day, ≥20 g/day), and BMI (~median < 27 kg/m2, ≥27 kg/m2), we assessed evidence of heterogeneity using a likelihood ratio test for adding an interaction term between total testosterone, SHBG, or free testosterone (modelled per doubling in concentration) and the subgroup of interest into the model to see if this improved model fit. In sensitivity analyses, we removed participants who had evidence of chronic hepatitis B virus or chronic hepatitis C virus at recruitment (based on hospital records), adjusted for measured alanine transaminase (ALT) and aspartate transaminase (AST) levels measured at recruitment, and removed postmenopausal females who reported taking MHT at recruitment. We also assessed how adjustment for c‐reactive protein, insulin‐like growth factor‐I, and hemoglobulin A1c concentrations, measured at baseline, changed associations and no differences were observed (data not shown).

Statistical analyses were conducted using Stata version 18.0 (Stata Corporation, College Station, TX), and R version 4.1.1. All tests of significance were two‐sided, and p values <0.05 were considered statistically significant.

3. RESULTS

After a median of 11.8 years of follow‐up, 531 cases of primary liver cancer were observed; 366 cases occurred in males (240 cases of HCC and 118 of ICC) whereas 165 cases occurred in females (46 cases of HCC, and 112 cases of ICC). Table 1 presents the baseline characteristics of liver cancer cases and those who did not develop liver cancer, separated by sex. Males and females who developed liver cancer had a higher BMI and were more likely to live with diabetes. Males who developed liver cancer reported consuming more alcohol than male non‐cases, whereas females' intake of alcohol was similar between liver cancer cases and non‐cases. At recruitment, males who developed liver cancer had higher concentrations of total testosterone and SHBG and lower concentrations of free testosterone than males who did not develop liver cancer. Female liver cancer cases at recruitment had higher SHBG and free testosterone concentrations and slightly higher total testosterone concentrations than females who did not develop liver cancer (Table 1).

TABLE 1.

Baseline characteristics of males and postmenopausal females who developed liver cancer and participants who did not develop liver cancer.

Baseline characteristics Males Postmenopausal females
Non‐cases Cases Non‐cases Cases
Number of participants 204,205 366 178,437 165
Age, years—mean (SD) 56.5 (8.2) 61.1 (6.2) 59.5 (6.0) 61.7 (5.2)
Body mass index, kg/m2—mean (SD) 27.8 (4.2) 29.9 (5.0) 27.3 (5.1) 28.3 (6.3)
Height, cm—mean (SD) 175.6 (6.8) 174.3 (7.1) 161.9 (6.2) 162.3 (6.9)
Ethnicity—White 191,990 (94.0%) 345 (94.3%) 169,641 (95.1%) 162 (98.2%)
Residence in most deprived quintile 41,404 (20.3%) 99 (27.0%) 32,862 (18.4%) 29 (17.6%)
Current smoker 25,354 (12.4%) 62 (16.9%) 15,068 (8.4%) 19 (11.5%)
Low physical activity 97,453 (47.7%) 146 (39.9%) 84,744 (47.5%) 72 (43.6%)
Diabetes 25,296 (12.4%) 129 (35.2%) 17,321 (9.7%) 25 (15.2%)
Current MHT use – – 13,808 (7.7%) 15 (9.1%)
Coffee intake—non‐drinkers 38,384 (18.8%) 74 (20.2%) 33,844 (19.0%) 165 (18.2%)
Alcohol intake, g/day—mean (SD) 24.4 (23.5) 36.2 (31.84) 10.8 (11.0) 10.6 (11.8)
Hormone concentrations
Total testosterone, nmol/L—mean (SD) 12.0 (3.7) 12.9 (5.0) 1.1 (0.7) 1.4 (1.0)
Sex‐hormone binding globulin, nmol/L—mean (SD) 39.5 (16.6) 58.0 (30.9) 60.1 (30.0) 67.1 (37.5)
Free testosterone, pmol/L—mean (SD) 219.8 (65.1) 184.1 (59.3) 14.9 (11.4) 17.1 (15.7)
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Note: Values are N (%) unless otherwise specified.

Abbreviation: MHT, menopausal hormone therapy.

Figure 1 presents the penalized smoothing spline multivariable‐adjusted Cox regression model for total testosterone, SHBG, and free testosterone and liver cancer risk among males while Figure 2 presents these results amongst females. The associations splitting participants into quartiles of concentrations are presented in Table S1 (minimally adjusted associations) and Table S2 and Figure S2 (multivariable adjusted associations). Among males, total testosterone and SHBG concentrations were positively associated with liver cancer risk (HR per doubling: 3.42, 95% CI: 2.42–4.84 and 5.44, 4.42–6.68, respectively; Figure 1). Positive associations between total testosterone and SHBG concentrations were also observed among females (HR per doubling: 1.29, 0.97–1.72 and 1.52, 1.09–2.12, respectively; Figure 2), although associations for total testosterone concentrations were not statistically significant per doubling in concentration. For free testosterone concentrations, however, an inverse association was observed with liver cancer risk in males (HR per doubling: 0.42, 0.32–0.55), and there was no evidence of an association among females (HR per doubling: 1.02, 0.79–1.31; Figures 1 and 2). When assessing departures from linearity, total testosterone and SHBG concentrations were found to be non‐linearly associated with liver cancer risk in males (p < 0.001) and total testosterone concentrations were found to be nonlinearly associated with liver cancer risk in females (p < 0.001; Figures 1 and 2).

FIGURE 1.

FIGURE 1

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Associations between circulating (A) total testosterone, (B) sex‐hormone binding globulin, and (C) calculated free testosterone concentrations and risk of liver cancer among males. Total testosterone, sex hormone‐binding globulin, and free testosterone were modelled using penalized smoothing splines. The models used age as the underlying time variable and were stratified by age group at recruitment and further adjusted for region at recruitment, body mass index, physical activity, Townsend deprivation index, smoking status, alcohol consumption, coffee intake, ethnicity, and diabetes status.

FIGURE 2.

FIGURE 2

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Associations between circulating (A) total testosterone, (B) sex‐hormone binding globulin, and (C) calculated free testosterone concentrations and risk of liver cancer among females. Total testosterone, sex hormone‐binding globulin, and free testosterone were modelled using penalized smoothing splines. The models used age as the underlying time variable and were stratified by age group at recruitment and further adjusted for region at recruitment, body mass index, physical activity, Townsend deprivation index, smoking status, alcohol consumption, coffee intake, ethnicity, diabetes status, and menopausal hormone therapy use. HR, hazard ratio.

3.1. Subgroup analyses

When cases of liver cancer were separated into HCC and ICC, there was evidence of heterogeneity for total testosterone and SHBG concentrations among both males and females. Figure 3 presents the doubling in concentration results for males and females for HCC and ICC, and Figure S3 and S4 present these results using penalized smoothing splines. Amongst males, total testosterone and SHBG were positively associated with HCC (HR per doubling: 3.56, 2.65–4.79, and 7.72, 6.12–9.73, respectively) whereas the associations with ICC were less clear as there was no evidence of an association with total testosterone (0.78, 0.53–1.14) (chi‐squared = 38.5, p < 0.001) and only a modestly positive association with SHBG (1.48, 1.04–2.11; chi‐squared = 58.1, p < 0.001). Similar associations were observed for females, total testosterone and SHBG were positively associated with HCC (HR per doubling: 1.65, 1.20–2.27 and 6.74, 3.93–11.5, respectively), but not with ICC (HR per doubling: 1.06, 0.87–1.29 for total testosterone; chi‐squared = 5.43, p = 0.02; and HR per doubling: 0.77, 0.57–1.04 for SHBG; chi‐squared = 47.8, p < 0.001; Figure 3). No evidence of heterogeneity between HCC and ICC was observed for free testosterone concentrations among males or females (Figure 3).

FIGURE 3.

FIGURE 3

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Multivariable adjusted hazard ratios for total testosterone, sex‐hormone binding globulin, and free testosterone per doubling in concentration and risk of hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) for (A) Males and (B) Females. All hormone concentrations are modelled as a doubling in concentration. The models included age as the underlying time variable and were stratified by age group at recruitment and further adjusted for region at recruitment, body mass index, physical activity, Townsend deprivation index, smoking status, alcohol consumption, coffee intake, ethnicity, diabetes status, and menopausal hormone therapy use (females only). χ2 and p values for heterogeneity represent Wald's test for heterogeneity between liver cancer subgroups and total testosterone, SHBG, or free testosterone concentrations modelled per doubling of concentrations. CI, confidence interval; HR, hazard ratio; SHBG, sex hormone‐binding globulin.

When analyses compared liver cancer cases diagnosed within the first 6 years of follow‐up and cases diagnosed after 6 years of follow‐up, associations remained largely the same, although associations for SHBG were more strongly associated with cases diagnosed within the first 6 years (Figure 4). Among males, evidence of heterogeneity was observed by age at diagnosis and time of blood draw with stronger associations between total testosterone and SHBG and liver cancer risk among males <70 years of age at the time of diagnosis (HR doubling of testosterone: 3.37, 2.44–4.67; HR doubling of SHBG: 5.98, 4.67–7.6) and <60 years of age at time of blood draw, than among males ≥70 years of age at time of diagnosis and ≥60 years at time of blood draw (Figure 4). No heterogeneity by age at diagnosis or age at blood draw was observed among females. For females, there was some heterogeneity by alcohol subgroups, where a positive association between total testosterone concentrations and liver cancer risk was observed only for females consuming 20+ g/day of alcohol per day (HR: 1.54, 1.17–2.03; Figure 4). No other evidence of heterogeneity was observed between associations by alcohol intake or BMI among either males or females (Figure 4).

FIGURE 4.

FIGURE 4

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Multivariable adjusted hazard ratios for total testosterone, sex‐hormone binding globulin, and free testosterone per doubling in concentration and risk of liver cancer by subgroups for (A) Males and (B) Females. All hormone concentrations were modelled as doubling in concentration (log2). The overall analysis hazard ratios and confidence intervals were obtained from the multivariable adjusted model, uncorrected for regression dilution/measurement error. The models included age as the underlying time variable and were stratified by age group at recruitment and further adjusted for region at recruitment, body mass index, physical activity, Townsend deprivation index, smoking status, alcohol consumption, coffee intake, ethnicity, diabetes status, and menopausal hormone therapy use (females only). χ2 and p value for heterogeneity represent Wald's test for heterogeneity of time to diagnosis and age at diagnosis between the liver cancer subgroup and testosterone, SHBG, or free testosterone concentrations modelled per doubling of concentrations. For age at blood collection, alcohol intake, and body mass index, χ2 and p values for heterogeneity were determined via likelihood ratio tests to include an interaction term between total testosterone, SHBG, or free testosterone concentrations and the subgroup of interest. CI, confidence interval; HR, hazard ratio; SHBG, sex hormone‐binding globulin.

3.2. Sensitivity analyses

In sensitivity analyses that removed participants with chronic hepatitis at baseline or further adjusted for ALT or AST in multivariable adjusted models, associations for males and females remained the same (Table S3).

4. DISCUSSION

In this prospective analysis that included over 200,000 males and nearly 180,000 postmenopausal females, total testosterone and SHBG concentrations were found to be positively associated with primary liver cancer risk in both males and females. However, free testosterone concentrations were inversely associated with primary liver cancer risk in males but were not significantly associated with liver cancer risk in females. In analyses separated by HCC and ICC, associations for total testosterone and SHBG were stronger for HCC in males and females, and modest or no associations were observed between SHBG and ICC in either males or females. The associations for free testosterone did not differ by HCC or ICC among either males or females. Total testosterone and SHBG levels were also more strongly associated among males diagnosed with liver cancer before 70 years of age and for those who had provided their blood sample before 60 years of age.

Males have been shown to nearly have 2–3 times greater rates of HCC than females in many regions of the world, 1 which has led to the hypothesis that testosterone, and other androgens such as dihydrotestosterone may promote hepatocarcinogenesis. 7 , 30 This contrasts with ICC, as males have only ~30% greater rates of ICC than females around the world, 1 and in the current study, females had a higher rate of ICC than males. Evidence from cell and animal models has also suggested that testosterone and other androgens can promote hepatocarcinogenesis, 31 , 32 although some studies have suggested that testosterone may inhibit cellular proliferation of hepatocytes. 33 In our analyses, total testosterone concentrations were positively associated with liver cancer risk, although this association was only observed for HCC. This result is in line with previous studies among males, including a nested case–control analysis among American cohorts 12 as well as smaller studies from Asia. 17 , 34 Similar earlier analyses conducted in the UK Biobank using approximately 100 male liver cancer cases also reported a positive association between total testosterone concentrations and liver cancer risk. 35 However, in two prospective studies conducted among participants from Europe, there was no association between total testosterone concentrations and HCC among males with cirrhosis 18 or among a generally healthy sample. 14 In a study that examined genetically predicted circulating total testosterone concentrations and liver cancer risk using Mendelian randomization (MR), there was a non‐significant positive association for males. 36 However, the genome‐wide association study (GWAS) of liver cancer on which it was based included only 304 cases of liver cancer from a Finnish population, which may have limited the power of the analysis.

For females, total testosterone concentrations were not as strongly associated with liver cancer risk, although associations appeared to be non‐linearly higher among women who had total testosterone levels >2 nmol/L. Associations were also stronger for HCC, whereas there was no evidence of an association for ICC. ICC was more common among females in this sample, which is in line with national estimates of primary liver cancer in the UK. 37 This could potentially explain why total testosterone concentrations were not strongly associated with overall liver cancer risk among females. In comparison to previous studies, a non‐significant positive association was observed among females between total testosterone concentrations and HCC in a nested case–control study including American cohorts 13 ; however, evidence from MR studies has suggested no evidence of an association. 38

Circulating SHBG concentrations were shown among both males and females to be strongly associated with liver cancer risk, particularly for HCC, where the risk was ~6–8 times greater per doubling of concentrations. In previous studies, SHBG concentrations have been consistently positively associated with liver cancer risk. 12 , 13 , 14 , 35 SHBG is a glycoprotein primarily produced in the liver and has a clear associations with liver dysfunction; higher concentrations of SHBG are associated with liver cirrhosis and are high among individuals with late‐stage chronic liver disease. 39 In subgroup analyses, associations with SHBG were stronger for liver cancer cases diagnosed within the first 6 years of follow‐up in both males and females. Therefore, SHBG may be an early marker of liver dysfunction and liver cancer. This hypothesis is supported by the results of a MR study using GWAS data from the UK Biobank, which suggested that SHBG may not be causally associated with liver cancer risk in males or females but, instead, be a consequence of liver injury. 40 However, that study did not separate histologic types of liver cancer and GWAS data were only available for 168 liver cancer cases, limiting statistical power. In our analyses, among males <70 years of age at the time of diagnosis, or who provided blood samples before the age of 60 years, stronger associations between total testosterone and SHBG concentrations and liver cancer risk were observed. This finding may reflect differences in concentrations with ageing, as testosterone decreases with age among males whereas SHBG increases. 41

Previous cross‐sectional evidence has suggested that total testosterone and SHBG concentrations may be inversely associated with metabolic dysfunction associated steatotic liver disease (MASLD), higher liver proton density fat fraction, and obesity. 42 , 43 , 44 This has been hypothesized to be due to increased aromatization of androgens, insulin, and cytokines downregulating SHBG production common in individuals with greater adiposity. 42 , 45 However, the relationship between these mechanisms and the development of liver cancer remains unclear. Higher SHBG concentrations may reflect a greater degree of liver cirrhosis and, therefore, a greater risk of developing liver cancer; however further research elucidating this mechanism and the transition of MASLD resulting in low SHBG concentrations to liver cirrhosis with high SHBG is needed.

In males, greater adiposity is associated with reduced total testosterone concentrations through pituitary feedback on luteinizing hormone as there is higher free testosterone concentrations due to a decrease in SHBG. 46 However, in females, obesity is associated with higher testosterone concentrations, despite lower SHBG levels and higher free testosterone levels. 47 In females, there is minimal negative feedback by circulating free testosterone on the hypothalamic–pituitary‐gonadal axis, which is primarily regulated by estrogens and progesterone, therefore SHBG and total testosterone are not co‐regulated like in males. 8 In males with hepatic disease, there is an increase in SHBG concentrations, therefore reducing negative feedback of free testosterone, resulting in higher total testosterone levels. However, in females, the reduction in negative feedback of free testosterone is less than in males therefore having minimal impact on testosterone levels. As such, this could be one potential explanation for the difference in association for total testosterone between males and females and liver cancer risk.

Free testosterone concentrations were inversely associated with liver cancer risk among males while no association was observed among females. A similar inverse association between free testosterone and HCC among males was observed in a nested case–control analysis conducted in the Liver Cancer Pooling Project, which included 78 HCC cases and 211 controls. 12 However, a positive association between dihydrotestosterone, the most potent androgen, and free testosterone and total liver cancer (274 cases and 764 controls) was observed in this study. For postmenopausal females, similar null findings between free testosterone and HCC have been observed in a nested case–control study of 83 cases and 180 controls. 13 Free testosterone was estimated using measured concentrations of total testosterone, SHBG, and albumin; therefore, the strong positive association from SHBG, as a consequence of liver dysfunction, may contribute to the observed inverse association among males, as individuals with high SHBG levels would have low levels of calculated free testosterone. In males with cirrhosis, feminization can occur due to increases in estradiol and SHBG, and a decrease in free testosterone. 39 SHBG prevents testosterone from diffusing out of the blood stream and binding to androgen receptors. 48 Therefore, it has been hypothesized that higher SHBG concentrations, as a result of liver cirrhosis, may lead to upregulation of the hypothalamus‐pituitary‐gonadal axis to produce more testosterone to maintain homeostasis and greater bioavailable testosterone concentrations. 8 , 49 , 50 , 51 The strong positive association observed between SHBG and liver cancer risk may therefore contribute to the inverse association observed for calculated free testosterone as well as the positive association observed for total testosterone concentrations. The free testosterone hypothesis suggests that only unbound testosterone is biologically active. However, the role of albumin and other binding proteins, such as corticosteroid‐binding globulin, in regulating testosterone bioavailability and its effect on the liver is less clear as testosterone can disassociate from albumin and become biologically active, with evidence suggesting this may occur in capillaries of organs that have long transit times, such as the liver. 8 , 52 Calculated free testosterone concentrations may therefore not represent the biologically active concentrations in the liver. Therefore, whether free testosterone contributes to hepatocarcinogenesis, is a byproduct of liver dysfunction due to increased SHBG, or has a true inverse association, remains to be elucidated. The results from the present study suggest that total testosterone concentrations may be positively associated with HCC risk in both males and females, although the results are not in line with the free testosterone hypothesis as inverse or null associations were observed for males and postmenopausal females, respectively, and further research is needed.

This study has numerous strengths, including the large sample size, long follow‐up time, and detailed covariate adjustment, with standardized measurements taken by trained professionals for anthropometric metrics. Total testosterone and SHBG levels were both measured using validated assays, and a subsample of participants had two measurements, therefore making it possible to correct for measurement error and regression dilution bias. Participants were also followed via the cancer registry, which contained histological information, thereby minimizing loss to follow‐up and allowing us to explore associations by liver cancer histological subtypes.

This study also had some limitations. The UK Biobank did not measure all sex hormones, such as dihydrotestosterone (a more potent androgen), and progesterone. While estradiol was measured, only 17,000 men and 16,000 postmenopausal women in our sample had a measured value because the majority were being below the limit of detection and therefore could not be reliably analyzed due to limited numbers. Free testosterone was calculated rather than measured; therefore, the true values may differ. However, previous evidence has suggested that estimation via the law of mass action is a valid approach to estimate concentrations. 53 In postmenopausal women, only 165 cases of liver cancer were observed, which may make the analyses underpowered to detect some associations, particularly for histologic group analyses. The serology of chronic HCV and HBV infections was not determined at recruitment or during follow‐up. However, in the sensitivity analyses, we removed participants with chronic hepatitis as indicated from medical records, and the results largely remained the same. Although we conducted analyses looking at participants diagnosed <6 years after recruitment and those diagnosed 6+ years after recruitment and the results were the similar, this may not be enough time to account for pre‐existing liver disease and may subject results to reverse causality. We also imputed testosterone concentrations for postmenopausal females below the limit of detection, which could result in measurement error and attenuate associations. Total testosterone is known to exhibit diurnal variation, with levels being highest in the morning. As not all participants provided blood samples in the morning, measurement error cannot be conclusively ruled out. Finally, the UK Biobank is a generally healthy population, and the results may not be generalizable to other populations.

5. CONCLUSION

Total testosterone and SHBG were both positively associated with HCC in males and females; however, free testosterone was inversely associated with risk in males but not associated with risk in females. Further research exploring the mechanisms of how sex hormones may influence liver cancer risk is needed to understand sex differences in liver cancer among males and females as well as to determine if the hormones are causally associated with liver cancer or consequences of liver dysfunction.

AUTHOR CONTRIBUTIONS

Cody Z. Watling: Investigation; writing – original draft; writing – review and editing; validation; visualization; formal analysis; methodology; conceptualization. Rebecca K. Kelly: Investigation; writing – review and editing. Eleanor L. Watts: Investigation; writing – review and editing. Barry I. Graubard: Investigation; writing – review and editing. Jessica L. Petrick: Investigation; writing – review and editing. Charles E. Mathews: Investigation; writing – review and editing; resources. Katherine A. McGlynn: Supervision; conceptualization; investigation; writing – review and editing.

FUNDING INFORMATION

Cody Z. Watling is supported by the Canadian Institutes of Health Research Fellowship (#187861). Cody Z. Watling, Eleanor L. Watts, Charles E. Mathews, and Katherine A. McGlynn are supported by the National Institutes of Health Intramural Program.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interests to declare.

ETHICS STATEMENT

Ethical approval was obtained from the Northwest Multi‐Centre Research Ethics Committee (reference number: 21/NW/0157).

Supporting information

DATA S1. Supporting Information.

IJC-156-1518-s001.pdf (1.3MB, pdf)

ACKNOWLEDGEMENTS

The authors would like to thank the participants of the UK Biobank and those involved in building the resource.

Watling CZ, Kelly RK, Watts EL, et al. Total testosterone, sex hormone‐binding globulin, and free testosterone concentrations and risk of primary liver cancer: A prospective analysis of 200,000 men and 180,000 postmenopausal women. Int J Cancer. 2025;156(8):1518‐1528. doi: 10.1002/ijc.35244

DATA AVAILABILITY STATEMENT

This study has been conducted using the UK Biobank Resource under Application Number 43456. The UK Biobank is an open access resource and bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/. Further information is available from the corresponding author upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

DATA S1. Supporting Information.

IJC-156-1518-s001.pdf (1.3MB, pdf)

Data Availability Statement

This study has been conducted using the UK Biobank Resource under Application Number 43456. The UK Biobank is an open access resource and bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/. Further information is available from the corresponding author upon request.

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