Circulating free testosterone and risk of aggressive prostate cancer: prospective and Mendelian randomization analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14,944 cases and 36,752 controls, including 1,870 aggressive prostate cancers). In Mendelian randomization (MR) analyses, using instruments identified using UK Biobank (up to 194,453 men) and outcome data from PRACTICAL (up to 79,148 cases and 61,106 controls, including 15,167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD=1.23, 95% CI=1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI=1.02-1.28; Phet =0.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR:1.20,1.08-1.34; blood-based:1.03,1.01-1.05) and early-onset prostate cancer (MR:1.37,1.09-1.73; blood-based:1.08,0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

International journal of cancer. 2022 May 17 [Epub ahead of print]

Eleanor L Watts, Aurora Perez-Cornago, Georgina K Fensom, Karl Smith-Byrne, Urwah Noor, Colm D Andrews, Marc J Gunter, Michael V Holmes, Richard M Martin, Konstantinos K Tsilidis, Demetrius Albanes, Aurelio Barricarte, H Bas Bueno-de-Mesquita, Chu Chen, Barbara A Cohn, Niki L Dimou, Luigi Ferrucci, Leon Flicker, Neal D Freedman, Graham G Giles, Edward L Giovannucci, Gary E Goodman, Christopher A Haiman, Graeme J Hankey, Jiaqi Huang, Wen-Yi Huang, Lauren M Hurwitz, Rudolf Kaaks, Paul Knekt, Tatsuhiko Kubo, Hilde Langseth, Gail Laughlin, Loic Le Marchand, Tapio Luostarinen, Robert J MacInnis, Hanna O Mäenpää, Satu Männistö, E Jeffrey Metter, Kazuya Mikami, Lorelei A Mucci, Anja W Olsen, Kotaro Ozasa, Domenico Palli, Kathryn L Penney, Elizabeth A Platz, Harri Rissanen, Norie Sawada, Jeannette M Schenk, Pär Stattin, Akiko Tamakoshi, Elin Thysell, Chiaojung Jillian Tsai, Shoichiro Tsugane, Lars Vatten, Elisabete Weiderpass, Stephanie J Weinstein, Lynne R Wilkens, Bu B Yeap, PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS , Naomi E Allen, Timothy J Key, Ruth C Travis

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK., Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France., Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France., Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK., Department of Population Health Sciences, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Navarra Public Health Institute, Pamplona, Spain., Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), The Netherlands., Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Child Health and Development Studies, Public Health Institute, Berkeley, CA, USA., National Institute on Aging, 251 Bayview Boulevard, Suite, Baltimore, MD, USA., Medical School, University of Western Australia, Perth, Western Australia., Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA., Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Department of Public Health and Welfare, National Institute for Health and Welfare, Helsinki, Finland., Department of Public Health and Health Policy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, San Diego, CA., University of Hawaii Cancer Center, Honolulu, HI, USA., Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland., Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland., Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., The University of Tennessee Health Science Center, College of Medicine, Department of Neurology, 847 Monroe Avenue, Suite, Memphis, TN, USA., Departmemt of Urology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan., Department of Public Health, Aarhus University, Aarhus, Denmark., Departmemt of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan., Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy., Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan., Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Surgical Sciences, Uppsala University, Uppsala, Sweden., Hokkaido University Faculty of Medicine, Sapporo, Japan., Department of Medical Biosciences, Umeå University, Umeå, Sweden., Memorial Sloan Kettering Cancer Center, Department of Radiation Oncology, New York, NY, USA., Department of Public Health and Nursing, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway., Director Office, International Agency for Research on Cancer, World Health Organization, Lyon, France.

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