. 2018 Nov;74(5):585-594.

doi: 10.1016/j.eururo.2018.07.024. Epub 2018 Aug 1.

Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies

Eleanor L Watts¹, Paul N Appleby², Aurora Perez-Cornago², H Bas Bueno-de-Mesquita³, June M Chan⁴, Chu Chen⁵, Barbara A Cohn⁶, Michael B Cook⁷, Leon Flicker⁸, Neal D Freedman⁷, Graham G Giles⁹, Edward Giovannucci¹⁰, Randi E Gislefoss¹¹, Graeme J Hankey¹², Rudolf Kaaks¹³, Paul Knekt¹⁴, Laurence N Kolonel¹⁵, Tatsuhiko Kubo¹⁶, Loïc Le Marchand¹⁵, Robert N Luben¹⁷, Tapio Luostarinen¹⁸, Satu Männistö¹⁹, E Jeffrey Metter²⁰, Kazuya Mikami²¹, Roger L Milne⁹, Kotaro Ozasa²², Elizabeth A Platz²³, J Ramón Quirós²⁴, Harri Rissanen¹⁴, Norie Sawada²⁵, Meir Stampfer²⁶, Frank Z Stanczyk²⁷, Pär Stattin²⁸, Akiko Tamakoshi²⁹, Catherine M Tangen³⁰, Ian M Thompson³¹, Konstantinos K Tsilidis³², Shoichiro Tsugane²⁵, Giske Ursin³³, Lars Vatten³⁴, Noel S Weiss³⁵, Bu B Yeap³⁶, Naomi E Allen³⁷, Timothy J Key², Ruth C Travis²

Affiliations

¹ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address: ellie.watts@ndph.ox.ac.uk.
² Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³ Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Social & Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁴ Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA; Department of Urology, University of California-San Francisco, San Francisco, CA, USA.
⁵ Public Health Sciences Division, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶ Child Health and Development Studies, Public Health Institute, Berkeley, CA, USA.
⁷ Division of Cancer Epidemiology and Genetics, U.S. National Cancer Institute, Bethesda, MD, USA.
⁸ School of Medicine, University of Western Australia, Perth, Western Australia, Australia; Western Australian Centre for Health and Ageing, Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia.
⁹ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
¹⁰ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; The Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Cancer Registry of Norway, Institute for Epidemiological Cancer Research, Oslo, Norway.
¹² School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
¹³ Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
¹⁴ National Institute for Health and Welfare, Helsinki, Finland.
¹⁵ University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁶ Department of Preventive Medicine and Community Health, University of Occupational and Environmental Health, Kitakyushu, Japan.
¹⁷ Strangeways Research Laboratory, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁸ Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
¹⁹ Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
²⁰ Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
²¹ Department of Urology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
²² Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan.
²³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
²⁴ Public Health Directorate, Asturias, Spain.
²⁵ Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
²⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; The Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Division of Reproductive Endocrinology and Infertility, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
²⁸ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
²⁹ Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
³⁰ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³¹ Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, TX, USA.
³² Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
³³ Cancer Registry of Norway, Institute for Epidemiological Cancer Research, Oslo, Norway; Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
³⁴ Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
³⁵ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
³⁶ School of Medicine, University of Western Australia, Perth, Western Australia, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia.
³⁷ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

PMID: 30077399
PMCID: PMC6195673
DOI: 10.1016/j.eururo.2018.07.024

Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies

Eleanor L Watts et al. Eur Urol. 2018 Nov.

. 2018 Nov;74(5):585-594.

doi: 10.1016/j.eururo.2018.07.024. Epub 2018 Aug 1.

Authors

Affiliations

¹ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address: ellie.watts@ndph.ox.ac.uk.
² Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³ Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Social & Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁴ Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA; Department of Urology, University of California-San Francisco, San Francisco, CA, USA.
⁵ Public Health Sciences Division, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶ Child Health and Development Studies, Public Health Institute, Berkeley, CA, USA.
⁷ Division of Cancer Epidemiology and Genetics, U.S. National Cancer Institute, Bethesda, MD, USA.
⁸ School of Medicine, University of Western Australia, Perth, Western Australia, Australia; Western Australian Centre for Health and Ageing, Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia.
⁹ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
¹⁰ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; The Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Cancer Registry of Norway, Institute for Epidemiological Cancer Research, Oslo, Norway.
¹² School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
¹³ Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
¹⁴ National Institute for Health and Welfare, Helsinki, Finland.
¹⁵ University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁶ Department of Preventive Medicine and Community Health, University of Occupational and Environmental Health, Kitakyushu, Japan.
¹⁷ Strangeways Research Laboratory, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁸ Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
¹⁹ Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
²⁰ Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
²¹ Department of Urology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
²² Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan.
²³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
²⁴ Public Health Directorate, Asturias, Spain.
²⁵ Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
²⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; The Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Division of Reproductive Endocrinology and Infertility, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
²⁸ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
²⁹ Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
³⁰ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³¹ Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, TX, USA.
³² Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
³³ Cancer Registry of Norway, Institute for Epidemiological Cancer Research, Oslo, Norway; Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
³⁴ Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
³⁵ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
³⁶ School of Medicine, University of Western Australia, Perth, Western Australia, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia.
³⁷ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

PMID: 30077399
PMCID: PMC6195673
DOI: 10.1016/j.eururo.2018.07.024

Abstract

Background: Experimental and clinical evidence implicates testosterone in the aetiology of prostate cancer. Variation across the normal range of circulating free testosterone concentrations may not lead to changes in prostate biology, unless circulating concentrations are low. This may also apply to prostate cancer risk, but this has not been investigated in an epidemiological setting.

Objective: To examine whether men with low concentrations of circulating free testosterone have a reduced risk of prostate cancer.

Design, setting, and participants: Analysis of individual participant data from 20 prospective studies including 6933 prostate cancer cases, diagnosed on average 6.8 yr after blood collection, and 12 088 controls in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group.

Outcome measurements and statistical analysis: Odds ratios (ORs) of incident overall prostate cancer and subtypes by stage and grade, using conditional logistic regression, based on study-specific tenths of calculated free testosterone concentration.

Results and limitations: Men in the lowest tenth of free testosterone concentration had a lower risk of overall prostate cancer (OR=0.77, 95% confidence interval [CI] 0.69-0.86; p<0.001) compared with men with higher concentrations (2nd-10th tenths of the distribution). Heterogeneity was present by tumour grade (p_het=0.01), with a lower risk of low-grade disease (OR=0.76, 95% CI 0.67-0.88) and a nonsignificantly higher risk of high-grade disease (OR=1.56, 95% CI 0.95-2.57). There was no evidence of heterogeneity by tumour stage. The observational design is a limitation.

Conclusions: Men with low circulating free testosterone may have a lower risk of overall prostate cancer; this may be due to a direct biological effect, or detection bias. Further research is needed to explore the apparent differential association by tumour grade.

Patient summary: In this study, we looked at circulating testosterone levels and risk of developing prostate cancer, finding that men with low testosterone had a lower risk of prostate cancer.

Keywords: Androgens; Epidemiology; Pooled analysis; Prospective studies; Prostate cancer; Sex hormones; Testosterone.

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Figures

**Fig. 1**
Associations between risk of overall prostate cancer and study-specific tenths of hormone concentrations. Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, and education status. The position of each square indicates the magnitude of the relative risk, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the relative risk). The length of the horizontal line through the square indicates the 95% floated confidence interval. BMI = body mass index; FCI = floated confidence interval; OR = odds ratio; SHBG = sex hormone–binding globulin.

**Fig. 2**
Odds ratio (95% FCIs) for overall prostate cancer associated with study-specific tenths of concentrations of free testosterone. Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, and education status. BMI = body mass index; FCI = floated confidence interval; OR = odds ratio.

**Fig. 3**
Odds ratio (95% CIs) for overall prostate cancer for the 1st tenth of free testosterone concentration in comparison to the 2nd–10th tenths by study. Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, and education status. ATBC = Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; BMI = body mass index; BLSA = Baltimore Longitudinal Study of Aging; CARET = Carotene and Retinol Efficacy Trial; CHDS = Child Health and Development Studies; CI = confidence interval; EPIC = European Prospective Investigation into Cancer and Nutrition; FMC = Finnish Mobile Clinic Health Examination Survey; HHS = Helsinki Heart Study; HIMS = Health In Men Study; HPFS = Health Professionals Follow-up Study; JACC = Japan Collaborative Cohort Study; JPHC = Japan Public Health Center-based Prospective Study; MCCS = Melbourne Collaborative Cohort Study; MEC = Multiethnic Cohort Study of Diet and Cancer; MMAS = Massachusetts Male Aging Study; NBSBWG = Nordic Biological Specimen Biobank Working Group; NSHDC = Northern Sweden Health and Disease Cohort; OR = odds ratio; PCPT = Prostate Cancer Prevention Trial; PHS = Physicians’ Health Study; PLCO = Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Test of significance (studies without organised screening): p < 0.001. Test of heterogeneity between studies without organised screening = χ²₁₇ = 15.88; p = 0.53. Test of significance (studies with organised screening): p = 0.16. Test of heterogeneity between studies with organised screening = χ²₁ = 1.29; p = 0.26. Test of heterogeneity between studies with and without organised screening = χ²₁ = 0.73; p = 0.39. Test of significance (overall): p < 0.001. Test of heterogeneity overall = χ²₁₉ = 18.0; p = 0.53. ^a 1st study-specific tenth of free testosterone. ^b 2nd–10th study-specific tenths of free testosterone.

**Fig. 4**
ORs (95% CIs) for prostate cancer associated with free testosterone in the study-specific 1st tenth compared with the 2nd–10th tenths, according to characteristics of cases and controls. Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, and education status. BMI = body mass index; CI = confidence interval; IGF = insulin-like growth factor; OR = odds ratio; PSA = prostate-specific antigen. Tests for heterogeneity for case-defined factors were obtained by fitting separate models for each subgroup and assuming independence of the ORs using a method analogous to a meta-analysis. Tests for heterogeneity for non–case-defined factors were assessed with a χ² test of interaction between subgroup and the binary variable. ^a 1st study-specific tenth of free testosterone. ^b 2nd–10th study-specific tenths of free testosterone.

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Comment in

Low Testosterone and Prostate Cancer: Is the Protection Real?
Wallis CJD, Krakowsky Y, Finelli A. Wallis CJD, et al. Eur Urol. 2018 Nov;74(5):595-596. doi: 10.1016/j.eururo.2018.08.024. Epub 2018 Sep 5. Eur Urol. 2018. PMID: 30195834 No abstract available.

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Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies

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Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies

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