Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis

S. Harlid received grants from the Cancer foundation in Northern Sweden (grant nos. AMP 17-856, AMP 18-915, and AMP 19-967), the Lions Cancer Research Fund in Northern Sweden (grant no. LP 20-2227), and internal funds from the Department of Radiation Sciences, Umea~ University. The coordination of EPIC is financially supported by IARC and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, MutuelleG~en~erale de l'Education Nationale, Institut National de la Sant~e et de la RechercheM~edicale (INSERM; France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF; Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (the Netherlands); Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology -ICO (Spain); Swedish Cancer Society, Swedish Research Council and Regions of Ska~ ne and V_asterbotten (Sweden); Cancer Research UK (14136 to EPICNorfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford). We would like to thank the participants and staff of the EPIC and NSHDS cohorts for their valuable contribution to this research. We thank the Biobank Research Unit at Umea~ University, VIP, the Northern Sweden MONICA study, and the County Council of V_asterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Special thanks also to Emmanouil Bouras for assistance on the meta-analysis. Furthermore, we acknowledge the use of data and biological samples from the following cohorts: EPIC-Florence [principal investigator (PI) Dr Domenico Palli], EPIC-Asturias (PI Dr J. Ram~on Quir~os) and EPIC-Cambridge (PI Professor Nick Wareham). Finally, on behalf of the EPIC-Norfolk study, we are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge (Cambridge, United Kingdom) who have enabled this research.Background: Endogenous sex hormonesmay contribute to higher colorectal cancer incidence rates in men compared with women, but despite an increased number of studies, clear evidence is lacking. Methods: We conducted a comprehensive nested case–control study of circulating concentrations of sex hormones, sex hormone precursors, and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid LC/MS-MS in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) andtheNorthern SwedenHealth and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men. Results: Circulating levels of testosterone (OR, 0.68; 95% CI, 0.51–0.89) and SHBG (OR, 0.77; 95% CI, 0.62–0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR, 0.83; 95% CI, 0.58–1.18). In a dose–response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone [relative risks (RR) per 100 ng/dL ¼ 0.98; 95% CI, 0.96–1.00; I2 ¼ 22%] and free testosterone (RR per 1 ng/dL ¼ 0.98; 95% CI, 0.95–1.00; I2 ¼ 0%). Conclusions: Our results provide suggestive evidence for the association between testosterone, SHBG, and male colon cancer development. Impact: Additional support for the involvement of sex hormones in male colon cancer.Cancer foundation in Northern Sweden AMP 17-856 AMP 18-915 AMP 19-967Lions Cancer Research Fund in Northern Sweden LP 20-2227Department of Radiation Sciences, Umea UniversityNIHR Imperial Biomedical Research Centre (BRC)Danish Cancer SocietyLigue nationale contre le cancerIARCDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonInstitut Gustave Roussy, MutuelleGenerale de l'Education NationaleInstitut National de la Sante et de la Recherche Medicale (Inserm)Deutsche KrebshilfeHelmholtz AssociationGerman Institute of Human Nutrition Potsdam-Rehbruecke (DIfE)Federal Ministry of Education & Research (BMBF)Fondazione AIRC per la ricerca sul cancroCompagnia di San PaoloConsiglio Nazionale delle Ricerche (CNR)Netherlands Government Netherlands GovernmentWorld Cancer Research Fund International (WCRF)Netherlands GovernmentHealth Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII) (Spain)Junta de AndaluciaPrincipality of AsturiasRegional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain) Catalan Institute of Oncology -ICO (Spain)Swedish Cancer Society Swedish Research Council Region of Skane (Sweden) Region of Vasterbotten (Sweden)Cancer Research UK 14136 C8221/A29017 UK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission 1000143 MR/M012190/1Swedish Research CouncilEuropean Commission VR 2017-0065