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

Abstract

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.

Circulating Insulin-like Growth Factor-I Concentrations and Risk of 30 Cancers: Prospective Analyses in UK Biobank

“…Associations with breast, colorectal and prostate cancer have been reported previously in UK Biobank and in separate large nested case-control studies pooling data from several cohort studies (2-4,7-9). Mendelian randomization studies further support that these associations are unlikely to be the result of reverse causality (7)(8)(9). The association between IGF-I concentration and thyroid cancer concurs with previous findings of a positive association reported in the European Prospective Investigation into Cancer and Nutrition (EPIC) (24).…”

“…Insulin-like growth factor-I (IGF-I) might be associated with cancer risk due to its role in cell proliferation, differentiation, metabolism and apoptosis, and in angiogenesis (1). In large pooled nested case-control studies and meta-analyses, pre-diagnostic circulating IGF-I concentrations have been shown to be positively associated with colorectal cancer (2), breast cancer (3) and prostate cancer (4) and not associated with lung cancer risk (5,6), and there is recent evidence from Mendelian randomization analyses suggesting that the positive associations may be causal (7)(8)(9). However, evidence for a role of IGF-I in the development of less common cancers is relatively limited, with some data for cancers of the esophagus (10), stomach (11), liver (12)(13)(14), biliary tract (15), pancreas (16), malignant melanoma (17), endometrium (18,19), kidney (20), bladder (21), brain (22,23), thyroid (24), and lymphoma (25).…”

Free testosterone and malignant melanoma risk in men: prospective analyses of testosterone and SHBG with 19 cancers in men and postmenopausal women UK Biobank

“…We have previously observed associations between free testosterone and prostate cancer risk and an inverse association with SHBG in UK Biobank, and in an international consortium of 20 cohorts (6,933 cases and 12,088 controls)(7,8). These associations are consistent with evidence from two large randomised controlled trials (which aimed to reduce intra-prostatic androgen signalling)(40,41) and a Mendelian randomization study(9).…”

“…However, aside from prostate (7)(8)(9), breast (9)(10)(11), and endometrial (9,12,13) cancers, previous population-based observational with hormone measurements have had limited power to assess associations with other cancer sites (4,5,14). Current evidence of associations with other cancers is largely based on animal models and tumor cell lines (15)(16)(17), or investigated indirectly via associations with self-reported menstrual and reproductive factors in women (18,19).…”

Decreased Sperm Motility is Associated with Increased Seminal Plasma IGF-I, IGF-II, IGFBP-2 and PSA Levels in Male Infertility

“…Previous studies have suggested that higher serum IGF-I levels is associated with a higher risk of benign prostatic hypertrophy (BPH) [21] and prostate cancer [22,23]. Paradoxically, as men age, serum IGF-I levels decline [24] whereas the incidence of prostate diseases increases [25,26].…”