Associations of testosterone, sex hormone-binding globulin, and related hormones with risks of cancer death, incident cancer, and incident prostate cancer in men: individual participant data meta-analyses

Background Whether differences in sex hormones influence cancer risk in men remains uncertain. We aimed to clarify the association of circulating testosterone, sex hormone-binding globulin (SHBG), and related hormones with risks of cancer death, incident cancer, and incident prostate cancer by means of individual participant data (IPD) meta-analyses. Methods A systematic review of the literature using MEDLINE, Embase, OpenGrey, and Mednar was conducted from date of database inception till July 22, 2019, with bridge searches using MEDLINE till Jan 21, 2026. Prospective cohort studies comprising 1000 or more community-dwelling men with testosterone concentrations measured using mass spectrometry and a follow-up of 5 years or more were included. Two-stage random-effects meta-analyses were performed, controlling for baseline age, previous cancer, BMI, marital status, alcohol consumption, smoking status, physical activity, hypertension status, and diabetes status. Risk of bias was assessed using the Newcastle–Ottawa method. This study was prospectively registered with PROSPERO (CRD42019139668). Findings Ten studies provided IPD (24 510 men; 276 931 participant-years; 2847 cancer deaths), and one provided aggregate data (1535 men; 184 cancer deaths). Five studies provided IPD for incident prostate cancer (12 280 men; 151 373 participant-years; 918 events). Lower total testosterone concentrations were associated with higher risk of cancer death (median of first vs median of fifth quintile Q1:Q5 hazard ratio HR 1·18, 95% CI 1·04–1·34), as were lower dihydrotestosterone concentrations (Q1:Q5 1·21, 1·06–1·38), the risk increasing with testosterone concentrations less than 8.6 nmol/L. SHBG and luteinising hormone concentrations were non-linearly associated with risk of cancer death (lowest risk: SHBG Q3:Q5 HR 0·81, 95% CI 0·68−0·97; luteinising hormone Q2:Q5 0·73, 0·59–0·90). Men with very low baseline testosterone concentrations had a higher risk of incident cancer, the risk increasing with concentrations less than 7.3 nmol/L. Lower SHBG or lower luteinising hormone concentrations were associated with higher risk of incident prostate cancer (Q1:Q5 HR 1·28, 95% CI 1·07−1·54; Q1:Q5 1·45, 1·13−1·86); testosterone was not associated with this outcome. Estimates of I 2 indicated negligible to moderate heterogeneity across most analyses. Interpretation Lower total testosterone or dihydrotestosterone concentrations in men were associated with a higher risk of cancer death, and mid-range SHBG or luteinising hormone concentrations were associated with a lower risk. Men with lower SHBG or luteinising hormone concentrations had an associated higher risk of incident prostate cancer. Sex hormones could serve as biomarkers for cancer risk, warranting further investigation of these observed associations. Funding Medical Research Future Fund; Government of Western Australia; Lawley Pharmaceuticals.