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Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased hematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes.<\/jats:p>","DOI":"10.7554\/elife.58914","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T08:00:40Z","timestamp":1602835240000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.58914","source":"Crossref","is-referenced-by-count":49,"title":["Effects of lifelong testosterone exposure on health and disease using Mendelian randomization"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6740-7858","authenticated-orcid":true,"given":"Pedrum","family":"Mohammadi-Shemirani","sequence":"first","affiliation":[{"name":"Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Department of Medical Sciences, McMaster University, Hamilton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Chong","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Pigeyre","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Department of Medicine, McMaster University, Hamilton Health Sciences, Hamilton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0099-4167","authenticated-orcid":true,"given":"Robert W","family":"Morton","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, McMaster University, Hamilton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hertzel C","family":"Gerstein","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Department of Medicine, McMaster University, Hamilton Health Sciences, Hamilton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-4760","authenticated-orcid":true,"given":"Guillaume","family":"Par\u00e9","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada"},{"name":"Department of Pathology and Molecular Medicine, McMaster University, Michael G. 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