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

Eleanor L Watts; Paul N Appleby; Aurora Perez-Cornago; H Bas Bueno-de-Mesquita; June M Chan; Chu Chen; Barbara A Cohn; Michael B Cook; Leon Flicker; Neal D Freedman; Graham G Giles; Edward Giovannucci; Randi E Gislefoss; Graeme J Hankey; Rudolf Kaaks; Paul Knekt; Laurence N Kolonel; Tatsuhiko Kubo; Loïc Le Marchand; Robert N Luben; Tapio Luostarinen; Satu Männistö; E Jeffrey Metter; Kazuya Mikami; Roger L Milne; Kotaro Ozasa; Elizabeth A Platz; J Ramón Quirós; Harri Rissanen; Norie Sawada; Meir Stampfer; Frank Z Stanczyk; Pär Stattin; Akiko Tamakoshi; Catherine M Tangen; Ian M Thompson; Konstantinos K Tsilidis; Shoichiro Tsugane; Giske Ursin; Lars Vatten; Noel S Weiss; Bu B Yeap; Naomi E Allen; Timothy J Key; Ruth C Travis

doi:10.1016/j.eururo.2018.07.024

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

Eur Urol. 2018 Nov;74(5):585-594. doi: 10.1016/j.eururo.2018.07.024. Epub 2018 Aug 1.

Authors

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: [email protected].
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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Adult
Aged
Biomarkers / blood
Case-Control Studies
Down-Regulation
Humans
Male
Middle Aged
Neoplasm Grading
Prospective Studies
Prostatic Neoplasms / blood*
Prostatic Neoplasms / epidemiology
Prostatic Neoplasms / pathology
Prostatic Neoplasms / prevention & control
Protective Factors
Risk Assessment
Risk Factors
Testosterone / blood
Testosterone / deficiency*
Time Factors

Substances

Biomarkers
Testosterone

Abstract

Publication types

MeSH terms

Substances

Grants and funding