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

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. LubenTapio 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

Bloomberg School of Public Health

Research output: Contribution to journal › Article

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. We found that men with low circulating free testosterone had a 23% reduced risk of overall prostate cancer, but there was some evidence that these men had an increased risk of developing high-grade disease.

Original language	English (US)
Pages (from-to)	585-594
Number of pages	10
Journal	European Urology
Volume	74
Issue number	5
DOIs	https://doi.org/10.1016/j.eururo.2018.07.024
State	Published - Nov 2018

Keywords

Androgens
Epidemiology
Pooled analysis
Prospective studies
Prostate cancer
Sex hormones
Testosterone

ASJC Scopus subject areas

Urology

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Watts, E. L., Appleby, P. N., Perez-Cornago, A., Bueno-de-Mesquita, H. B., Chan, J. M., Chen, C., Cohn, B. A., Cook, M. B., Flicker, L., Freedman, N. D., Giles, G. G., Giovannucci, E., Gislefoss, R. E., Hankey, G. J., Kaaks, R., Knekt, P., Kolonel, L. N., Kubo, T., Le Marchand, L., ... Travis, R. C. (2018). Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies. European Urology, 74(5), 585-594. https://doi.org/10.1016/j.eururo.2018.07.024

Low Free Testosterone and Prostate Cancer Risk : A Collaborative Analysis of 20 Prospective Studies. / Watts, Eleanor L.; Appleby, Paul N.; Perez-Cornago, Aurora; Bueno-de-Mesquita, H. Bas; Chan, June M.; Chen, Chu; Cohn, Barbara A.; Cook, Michael B.; Flicker, Leon; Freedman, Neal D.; Giles, Graham G.; Giovannucci, Edward; Gislefoss, Randi E.; Hankey, Graeme J.; Kaaks, Rudolf; Knekt, Paul; Kolonel, Laurence N.; Kubo, Tatsuhiko; Le Marchand, Loïc; Luben, Robert N.; Luostarinen, Tapio; Männistö, Satu; Metter, E. Jeffrey; Mikami, Kazuya; Milne, Roger L.; Ozasa, Kotaro; Platz, Elizabeth A.; Quirós, J. Ramón; Rissanen, Harri; Sawada, Norie; Stampfer, Meir; Stanczyk, Frank Z.; Stattin, Pär; Tamakoshi, Akiko; Tangen, Catherine M.; Thompson, Ian M.; Tsilidis, Konstantinos K.; Tsugane, Shoichiro; Ursin, Giske; Vatten, Lars; Weiss, Noel S.; Yeap, Bu B.; Allen, Naomi E.; Key, Timothy J.; Travis, Ruth C.

In: European Urology, Vol. 74, No. 5, 11.2018, p. 585-594.

Research output: Contribution to journal › Article

Watts, EL, Appleby, PN, Perez-Cornago, A, Bueno-de-Mesquita, HB, Chan, JM, Chen, C, Cohn, BA, Cook, MB, Flicker, L, Freedman, ND, Giles, GG, Giovannucci, E, Gislefoss, RE, Hankey, GJ, Kaaks, R, Knekt, P, Kolonel, LN, Kubo, T, Le Marchand, L, Luben, RN, Luostarinen, T, Männistö, S, Metter, EJ, Mikami, K, Milne, RL, Ozasa, K, Platz, EA, Quirós, JR, Rissanen, H, Sawada, N, Stampfer, M, Stanczyk, FZ, Stattin, P, Tamakoshi, A, Tangen, CM, Thompson, IM, Tsilidis, KK, Tsugane, S, Ursin, G, Vatten, L, Weiss, NS, Yeap, BB, Allen, NE, Key, TJ & Travis, RC 2018, 'Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies', European Urology, vol. 74, no. 5, pp. 585-594. https://doi.org/10.1016/j.eururo.2018.07.024

Watts, Eleanor L. ; Appleby, Paul N. ; Perez-Cornago, Aurora ; Bueno-de-Mesquita, H. Bas ; Chan, June M. ; Chen, Chu ; Cohn, Barbara A. ; Cook, Michael B. ; Flicker, Leon ; Freedman, Neal D. ; Giles, Graham G. ; Giovannucci, Edward ; Gislefoss, Randi E. ; Hankey, Graeme J. ; Kaaks, Rudolf ; Knekt, Paul ; Kolonel, Laurence N. ; Kubo, Tatsuhiko ; Le Marchand, Loïc ; Luben, Robert N. ; Luostarinen, Tapio ; Männistö, Satu ; Metter, E. Jeffrey ; Mikami, Kazuya ; Milne, Roger L. ; Ozasa, Kotaro ; Platz, Elizabeth A. ; Quirós, J. Ramón ; Rissanen, Harri ; Sawada, Norie ; Stampfer, Meir ; Stanczyk, Frank Z. ; Stattin, Pär ; Tamakoshi, Akiko ; Tangen, Catherine M. ; Thompson, Ian M. ; Tsilidis, Konstantinos K. ; Tsugane, Shoichiro ; Ursin, Giske ; Vatten, Lars ; Weiss, Noel S. ; Yeap, Bu B. ; Allen, Naomi E. ; Key, Timothy J. ; Travis, Ruth C. / Low Free Testosterone and Prostate Cancer Risk : A Collaborative Analysis of 20 Prospective Studies. In: European Urology. 2018 ; Vol. 74, No. 5. pp. 585-594.

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title = "Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies",

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 (phet = 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. We found that men with low circulating free testosterone had a 23% reduced risk of overall prostate cancer, but there was some evidence that these men had an increased risk of developing high-grade disease.",

keywords = "Androgens, Epidemiology, Pooled analysis, Prospective studies, Prostate cancer, Sex hormones, Testosterone",

author = "Watts, {Eleanor L.} and Appleby, {Paul N.} and Aurora Perez-Cornago and Bueno-de-Mesquita, {H. Bas} and Chan, {June M.} and Chu Chen and Cohn, {Barbara A.} and Cook, {Michael B.} and Leon Flicker and Freedman, {Neal D.} and Giles, {Graham G.} and Edward Giovannucci and Gislefoss, {Randi E.} and Hankey, {Graeme J.} and Rudolf Kaaks and Paul Knekt and Kolonel, {Laurence N.} and Tatsuhiko Kubo and {Le Marchand}, Lo{\"i}c and Luben, {Robert N.} and Tapio Luostarinen and Satu M{\"a}nnist{\"o} and Metter, {E. Jeffrey} and Kazuya Mikami and Milne, {Roger L.} and Kotaro Ozasa and Platz, {Elizabeth A.} and Quir{\'o}s, {J. Ram{\'o}n} and Harri Rissanen and Norie Sawada and Meir Stampfer and Stanczyk, {Frank Z.} and P{\"a}r Stattin and Akiko Tamakoshi and Tangen, {Catherine M.} and Thompson, {Ian M.} and Tsilidis, {Konstantinos K.} and Shoichiro Tsugane and Giske Ursin and Lars Vatten and Weiss, {Noel S.} and Yeap, {Bu B.} and Allen, {Naomi E.} and Key, {Timothy J.} and Travis, {Ruth C.}",

year = "2018",

month = nov,

doi = "10.1016/j.eururo.2018.07.024",

language = "English (US)",

volume = "74",

pages = "585--594",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "5",

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TY - JOUR

T1 - Low Free Testosterone and Prostate Cancer Risk

T2 - A Collaborative Analysis of 20 Prospective Studies

AU - Watts, Eleanor L.

AU - Appleby, Paul N.

AU - Perez-Cornago, Aurora

AU - Bueno-de-Mesquita, H. Bas

AU - Chan, June M.

AU - Chen, Chu

AU - Cohn, Barbara A.

AU - Cook, Michael B.

AU - Flicker, Leon

AU - Freedman, Neal D.

AU - Giles, Graham G.

AU - Giovannucci, Edward

AU - Gislefoss, Randi E.

AU - Hankey, Graeme J.

AU - Kaaks, Rudolf

AU - Knekt, Paul

AU - Kolonel, Laurence N.

AU - Kubo, Tatsuhiko

AU - Le Marchand, Loïc

AU - Luben, Robert N.

AU - Luostarinen, Tapio

AU - Männistö, Satu

AU - Metter, E. Jeffrey

AU - Mikami, Kazuya

AU - Milne, Roger L.

AU - Ozasa, Kotaro

AU - Platz, Elizabeth A.

AU - Quirós, J. Ramón

AU - Rissanen, Harri

AU - Sawada, Norie

AU - Stampfer, Meir

AU - Stanczyk, Frank Z.

AU - Stattin, Pär

AU - Tamakoshi, Akiko

AU - Tangen, Catherine M.

AU - Thompson, Ian M.

AU - Tsilidis, Konstantinos K.

AU - Tsugane, Shoichiro

AU - Ursin, Giske

AU - Vatten, Lars

AU - Weiss, Noel S.

AU - Yeap, Bu B.

AU - Allen, Naomi E.

AU - Key, Timothy J.

AU - Travis, Ruth C.

PY - 2018/11

Y1 - 2018/11

N2 - 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 (phet = 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. We found that men with low circulating free testosterone had a 23% reduced risk of overall prostate cancer, but there was some evidence that these men had an increased risk of developing high-grade disease.

AB - 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 (phet = 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. We found that men with low circulating free testosterone had a 23% reduced risk of overall prostate cancer, but there was some evidence that these men had an increased risk of developing high-grade disease.

KW - Androgens

KW - Epidemiology

KW - Pooled analysis

KW - Prospective studies

KW - Prostate cancer

KW - Sex hormones

KW - Testosterone

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