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Background Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using newly available data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we aimed to investigate the associations of circulating concentrations of IGF-I, sex hormone-binding globulin (SHBG), total and calculated free testosterone with prostate cancer risk. Patients and methods For prospective analyses of prostate cancer incidence and mortality, we studied 199,698 male UK Biobank participants using Cox proportional hazards models. Multivariable-adjusted hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample of up to 7,776 men. A 2-sample Mendelian randomization (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from 79,148 cases and 61,106 controls from the PRACTICAL consortium. We used cis - and all ( cis and trans ) SNP MR approaches. Results After a mean follow-up of 6.9 years, 5,402 men were diagnosed with and 295 died from prostate cancer. Higher circulating IGF-I was associated with an elevated risk (HR per 5 nmol/L increment=1.09, 95% CI 1.05-1.12) and prostate cancer mortality (HR per 5 nmol/L increment=1.15,1.02-1.29) in observational analyses. Cis - and all SNPs MR analyses also supported the role of IGF-I in prostate cancer diagnosis ( cis -MR odds ratio per 5 nmol/L increment=1.34,1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05-1.15), and higher SHBG was associated with a lower risk of prostate cancer (HR per 10 nmol/L increment=0.95,0.94-0.97), but neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. Conclusion(s) These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression. Key message Prostate cancer is the second most common cancer in men, but modifiable risk factors have not been identified. Using large-scale prospective observational and genetic data we investigated the associations of circulating IGF-I, SHBG and testosterone with prostate cancer diagnosis and mortality. Our results implicate IGF-I and the sex hormones in prostate cancer development. Highlights Prostate cancer is the second most common cancer in men, but no modifiable risk factors are established. We examined the associations of circulating IGF-I, SHBG, total and free testosterone with prostate cancer risk in UK Biobank. Men with higher IGF-I had a higher risk of diagnosis and mortality. Mendelian randomization also supported a causal role. Men with higher free testosterone had a higher prostate cancer risk, and men with higher SHBG had a lower risk. The results implicate IGF-I and the sex hormones in prostate cancer development.

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