J S Brand1, N C Onland-Moret2, M J C Eijkemans1, A Tjønneland3, N Roswall3, K Overvad4, G Fagherazzi5, F Clavel-Chapelon5, L Dossus5, A Lukanova6, V Grote7, M M Bergmann8, H Boeing8, A Trichopoulou9, M Tzivoglou10, D Trichopoulos11, S Grioni12, A Mattiello13, G Masala14, R Tumino15, P Vineis16, H B Bueno-de-Mesquita17, E Weiderpass18, M L Redondo19, M J Sánchez20, J M Huerta Castaño21, L Arriola22, E Ardanaz23, E J Duell24, O Rolandsson25, P W Franks26, S Butt27, P Nilsson28, K T Khaw29, N Wareham30, R Travis31, I Romieu32, M J Gunter33, E Riboli33, Y T van der Schouw1. 1. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 2. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands n.c.onland@umcutrecht.nl. 3. Danish Cancer Society Research Center, Copenhagen, Denmark. 4. Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark. 5. Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805 Villejuif, France. 6. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany Department of Medical Biosciences, University of Umeå, Umeå, Sweden. 7. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. 8. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany. 9. WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, 75 M. Asias Street, Goudi GR-115 27, Athens, Greece Hellenic Health Foundation, 13 Kaisareias Street, Athens GR-115 27, Greece. 10. Hellenic Health Foundation, 13 Kaisareias Street, Athens GR-115 27, Greece. 11. Hellenic Health Foundation, 13 Kaisareias Street, Athens GR-115 27, Greece Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA Bureau of Epidemiologic Research, Academy of Athens, 28 Panepistimiou Street, Athens GR-106 79, Greece. 12. Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 13. Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. 14. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy. 15. Cancer Registry and Histopathology Unit, 'Civic - M.P. Arezzo' Hospital, ASP Ragusa, Italy. 16. School of Public Health, Imperial College, London, UK HuGeF Foundation, Torino, Italy. 17. Dt. for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Dt. of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands Dt. of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom Dt. of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. 18. Department of Community Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway Cancer Registry of Norway, Oslo, Norway Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Samfundet Folkhälsan, Helsinki, Finland. 19. Public Health Directorate, Asturias, Spain. 20. Andalusian School of Public Health, Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. 21. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. 22. Public Health Department of Gipuzkoa, Instituto BIO-Donostia, Basque Government, CIBERESP, San Sebastian, Spain. 23. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain Navarre Public Health Institute, Pamplona, Spain. 24. Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain. 25. Department of Public Health and Clinical Medicine, Family Medicine Umeå University, 901 87 Umeå, Sweden. 26. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Clinical Research Center, Skåne University Hospital, Lund University, Malmö, Sweden Department of Medicine, Umeå University, Umeå, Sweden. 27. Department of Surgery, Institute of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden. 28. Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmo, Sweden. 29. University of Cambridge, Cambridge, UK. 30. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. 31. Cancer Epidemiology Unit, University of Oxford, Oxford, UK. 32. International Agency for Research on Cancer (IARC-WHO), Lyon, France. 33. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Abstract
STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) 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); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.
STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) 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); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.
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