Age at Menopause, Reproductive Life Span, and Type 2 Diabetes Risk: Results from the EPIC-InterAct study

JUDITH S. BRAND 0 MSC 0 10 YVONNE T. VAN DER SCHOUW 0 PHD 0 10 N. CHARLOTTE ONLAND-MORET 0 PHD 0 10 STEPHEN J. SHARP 0 MSC 0 8 KEN K. ONG 0 PHD 0 8 KAY-TEE KHAW 0 PHD 0 7 EVA ARDANAZ 0 PHD 0 13 14 PILAR AMIANO 0 PHD 0 11 12 13 HEINER BOEING 0 PHD 0 16 MARIA-DOLORES CHIRLAQUE 0 13 15 FRANOISE CLAVEL-CHAPELON 0 PHD 0 9 FRANCESCA L. CROWE 0 PHD 0 5 BLANDINE DE LAUZON-GUILLAIN 0 PHD 0 6 9 ERIC J. DUELL 0 PHD 0 3 GUY FAGHERAZZI 0 PHD 0 6 9 PAUL W. FRANKS 0 PHD 0 1 4 SARA GRIONI 0 MSC 0 2 LEIF C. GROOP 0 PHD 0 RUDOLF KAAKS 0 PHD 0 TIMOTHY J. KEY 0 PHD 0 5 PETER M. NILSSON 0 PHD 0 KIM OVERVAD 0 PHD 0 DOMENICO PALLI 0 SALVATORE PANICO 0 J. RAMN QUIRS 0 OLOV ROLANDSSON 0 PHD 0 CARLOTTA SACERDOTE 0 PHD 0 MARIA-JOS SANCHEZ 0 PHD 0 13 NADIA SLIMANI 0 PHD 0 BIRGIT TEUCHER 0 PHD 0 ANNE TJONNELAND 0 PHD 0 ROSARIO TUMINO 0 DAPHNE L. VAN DER A 0 PHD 0 EDITH J.M. FESKENS 0 PHD 0 CLAUDIA LANGENBERG 0 PHD 0 8 NITA G. FOROUHI 0 PHD 0 8 ELIO RIBOLI 0 PHD 0 NICHOLAS J. WAREHAM 0 PHD 0 8 THE INTERACT CONSORTIUM 0 0 Publica) , Madrid , Spain; the 1 Department of Public Health and Clinical Medicine, Umea University , Umea , Sweden; the 2 Fondazione IRCCS Istituto Nazionale 3 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, L'Hospi- talet de Lolgbregat , Barcelona , Spain; the 4 Depart- ment of Clinical Sciences, Clinical Research Center, Malmo General Hospital, Lund University , Malmo , Sweden; the 5 Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford , Oxford , U.K.; the 6 University Paris Sud 11 , UMRS 1018, Villejuif , France; the 7 Department of Public Health and Primary Care, University of Cam- bridge, Addenbrooke's Hospital , Cambridge , U.K.; the 8 Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital , Cambridge , U.K.; the 9 INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018: Nutrition, Hormones and Women's Health, Institut Gustave Roussy (IGR) , Villejuif 10 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht , Utrecht , the Netherlands; the 11 Instituto BIO-Donostia, Basque Government , San Sebastian , Spain; the 12 Public Health Di- vision of Gipuzkoa, Basque Government , San Sebastian , Spain; the 13 Consortium for Biomed- ical Research in Epidemiology and Pub- lic Health (CIBER Epidemiologa y Salud 14 Navarre Public Health Institute , Pamplona , Spain; the 15 Department of Epide- miology, Murcia Regional Health Council , Murcia , Spain 16 Department of Epidemiology, German Insti- tute of Human Nutrition Potsdam-Rehbruecke , Nuthetal , Germany; the C a r d i o v a s c u l a r OBJECTIVEdAge at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk. RESEARCH DESIGN AND METHODSdData were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied. RESULTSdMean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04-1.69), 1.09 (0.90-1.31), 0.97 (0.861.10), and 0.85 (0.70-1.03) for women with menopause at ages ,40, 40-44, 45-49, and $55 years, respectively, relative to those with menopause at age 50-54 years. The HR per SD younger age at menopause was 1.08 (1.02-1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [1.01-1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all . 0.05). CONCLUSIONSdEarly menopause is associated with a greater risk of type 2 diabetes. - M tion in womens reproductive life, enopause is an important transias it signals the end of fertility. Timing of menopause is also an important determinant of future disease risk. For example, an early age at menopause is associated with an increased risk of cardiovascular disease (CVD) (1) and bone fractures (2,3). Conversely, an early menopause protects against breast (4,5), endometrial (6), and ovarian cancer (7). Changes associated with the menopause transition, in particular loss of ovarian function and subsequent decline in endogenous estrogens, have been postulated as mediators of these differences in risk (8,9). While the relationship between menopausal age and CVD risk is well established, its association with type (...truncated)