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

Watts, Eleanor L.; Appleby, Paul N.; Pérez-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 Elin; Hankey, Graeme J.; Kaaks, Rudolf; Knekt, Paul; Kolonel, Laurence N.; Kubo, Toshikazu; Marchand, Loı̈c Le; Luben, Robert; Luostarinen, Tapio; Männistö, Satu; Metter, E. Jeffrey; Mikami, Kōichi; Milne, Roger L.; Ozasa, Kotaro; Platz, Elizabeth A.; Quirós, J. Ramón; Rissanen, Harri; Sawada, Norie; Stampfer, Meir J.; Stanczyk, Frank Z.; Stattin, Pär; Tamakoshi, Akiko; Tangen, Catherine M.; Thompson, Ian M.; Tsilidis, Konstantinos K.; Tsugane, Shoichiro; Ursin, Giske; Vatten, Lars J.; Weiss, Noel S.; Yeap, Bu B.; Allen, Naomi E.; Key, Timothy J.; Travis, Ruth C.

doi:10.1016/j.eururo.2018.07.024

Cited by 93 publications

(107 citation statements)

References 41 publications

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“…9 Men with kidney disease are at higher risk of having a very low circulating testosterone concentration, 35 which in turn has been associated with a lower prostate cancer risk. 7 Findings from the present study showed that higher circulating urea and phosphate concentrations were associated with an increased prostate cancer risk, while cystatin-C and total protein circulating concentrations (both markers of kidney function) were associated with a lower risk. However, only the associations of cystatin-C and phosphate with risk were significant in the last four years of follow-up.…”

Section: Discussionmentioning

confidence: 43%

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Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

et al. 2020

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Background Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank. Methods A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure. Results After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death. Conclusion We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.

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Section: Discussionmentioning

confidence: 43%

“…6 Moreover, men with low free testosterone concentrations may have a lower risk of overall prostate cancer. 7 However, the aetiology of prostate cancer is not well understood, and there is a need to identify novel risk factors for the disease.…”

Section: Introductionmentioning

confidence: 99%

Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

et al. 2020

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“…KS, TH and hypopituitarism are conditions associated with clinically low testosterone concentrations . Low circulating testosterone concentrations may reduce prostatic androgen receptor signalling and may therefore reduce prostate cancer risk . In our analysis, there was no association with prostate cancer diagnosis in the combined hypogonadal cohort, although men diagnosed with KS had a 42% lower risk.…”

Section: Discussioncontrasting

confidence: 54%

“…Although there are large differences in global incidence rates, little is known regarding potentially modifiable risk factors. However, data from an international pooled individual‐level meta‐analysis of prospective studies have shown that high circulating insulin‐like growth factor‐I (IGF‐I) concentrations are associated with an increased risk of prostate cancer and that low free testosterone is associated with a reduced risk …”

Section: Introductionmentioning

confidence: 99%

Hormone‐related diseases and prostate cancer: An English national record linkage study

Watts

Goldacre

Key

et al. 2019

Intl Journal of Cancer

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Insulin-like growth factor-I (IGF-I) and testosterone may be related to prostate cancer risk. Acromegaly is associated with clinically high IGF-I concentrations. Klinefelter's syndrome, testicular hypofunction and hypopituitarism are associated with clinically low testosterone concentrations. We aimed to investigate whether diagnosis with these conditions was associated with subsequent prostate cancer diagnosis and mortality. We used linked English national Hospital Episode Statistics and mortality data from 1999 to 2017 to construct and follow-up cohorts of men aged ≥35 years diagnosed with (i) acromegaly (n = 2,495) and (ii) hypogonadalassociated diseases (n = 18,763): Klinefelter's syndrome (n = 1,992), testicular hypofunction (n = 8,086) and hypopituitarism (n = 10,331). We estimated adjusted hazard ratios (HRs) and confidence intervals (CIs) for prostate cancer diagnosis and death using Cox regression in comparison with an unexposed reference cohort of 4.3 million men, who were admitted to hospital for a range of minor surgeries and conditions (n observed cases = 130,000, n prostate cancer deaths = 30,000). For men diagnosed with acromegaly, HR for prostate cancer diagnosis was 1.33 (95% CI 1.09-1.63; p = 0.005; n observed cases = 96), HR for prostate cancer death was 1.44 (95% CI 0.92-2.26; p = 0.11; n deaths = 19). Diagnosis with Klinefelter's syndrome was associated with a lower prostate cancer risk (HR = 0.58, 95% CI 0.37-0.91; p = 0.02; n observed cases = 19) and hypopituitarism was associated with a reduction in prostate cancer death (HR = 0.53, 95% CI 0.35-0.79; p = 0.002; n deaths = 23). These results support the hypothesised roles of IGF-I and testosterone in prostate cancer development and/or progression. These findings are important because they provide insight into prostate cancer aetiology.Additional Supporting Information may be found in the online version of this article.

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“…Epidemiological studies have also reported an inverse association between prostate cancer risk and circulating SHBG 8 , although results from MR analyses are inconclusive 9 .…”

Section: Introductionmentioning

confidence: 99%

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Watts

Fensom

Smith-Byrne

et al. 2020

Preprint

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Background: Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using newly available data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we aimed to investigate the associations of circulating concentrations of IGF-I, sex hormone-binding globulin (SHBG), total and calculated free testosterone with prostate cancer risk. Patients and methods: For prospective analyses of prostate cancer incidence and mortality, we studied 199,698 male UK Biobank participants using Cox proportional hazards models. Multivariable-adjusted hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample of up to 7,776 men. A 2-sample Mendelian randomization (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from 79,148 cases and 61,106 controls from the PRACTICAL consortium. We used cis- and all (cis and trans) SNP MR approaches. Results: After a mean follow-up of 6.9 years, 5,402 men were diagnosed with and 295 died from prostate cancer. Higher circulating IGF-I was associated with an elevated risk (HR per 5 nmol/L increment=1.09, 95% CI 1.05-1.12) and prostate cancer mortality (HR per 5 nmol/L increment=1.15,1.02-1.29) in observational analyses. Cis- and all SNPs MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment=1.34,1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05-1.15), and higher SHBG was associated with a lower risk of prostate cancer (HR per 10 nmol/L increment=0.95,0.94-0.97), but neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. Conclusion(s): These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

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

Cited by 93 publications

References 41 publications

Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

Hormone‐related diseases and prostate cancer: An English national record linkage study

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

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