Siwen Wang1,2, Yi-Xin Wang1, Helena Sandoval-Insausti1, Leslie V Farland3, Jan L Shifren4, Dan Zhang2, JoAnn E Manson5,6,7, Brenda M Birmann7, Walter C Willett1,5,7, Edward L Giovannucci1,5,7, Stacey A Missmer8, Jorge E Chavarro1,5,7. 1. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 2. Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. 3. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman University of Arizona College of Public Health, University of Arizona, Tucson, AZ, USA. 4. Department of Obstetrics and Gynecology, Midlife Women's Health Center, Massachusetts General Hospital, Boston, MA, USA. 5. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 6. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 7. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 8. Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, East Lansing, MI, USA.
Abstract
STUDY QUESTION: Are menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk? SUMMARY ANSWER: Irregular and long menstrual cycles throughout the reproductive lifespan were associated with increased risk of total invasive cancer, especially obesity-related cancers. WHAT IS KNOWN ALREADY: Long and irregular menstrual cycles have been associated with lower risk of pre-menopausal breast cancer and higher risk of endometrial cancer, but associations with other malignancies are less clear. STUDY DESIGN, SIZE, DURATION: Prospective cohort study. Prospective follow-up of 78 943 women participating in the Nurses' Health Study II between 1989 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We followed 78 943 pre-menopausal women without cancer history who reported the usual length and regularity of their menstrual cycles at different ages (14-17, 18-22 and 29-46 years). Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity-related. We fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association between menstrual cycle characteristics and cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: We documented 5794 incident cancer cases during 1 646 789 person-years of follow-up. After adjusting for BMI and other potential confounders, women reporting irregular cycles at age 29-46 years had an 11% (95% CI: 2-21%) higher risk of total invasive cancer than women reporting very regular cycles at the same age. This association was limited to obesity-related cancers, with a 23% (95% CI: 9-39%) higher risk and was strongest for endometrial cancer (HR = 1.39; 95% CI: 1.09-1.77). Findings were comparable for cycle characteristics earlier in life and for menstrual cycle length. Very irregular cycles at age 14-17 years were associated with significant increase in risk of colorectal cancer (HR = 1.36; 95% CI: 1.02-1.81). LIMITATIONS, REASONS FOR CAUTION: Our study might be subject to recall bias for findings pertaining to cycle characteristics in adolescence and early adulthood, as these were retrospectively reported. Generalizability to non-White women may be limited, as 96% of participants were White. WIDER IMPLICATIONS OF THE FINDINGS: Women with irregular or long menstrual cycles in mid-adulthood had a statistically significantly higher risk of developing cancer, especially obesity-related cancers. This association was not limited to gynecological cancers. Obesity-related cancers may need to be added to the spectrum of long-term health consequences of long or irregular cycles, possibly warranting targeted screening among women who experience long or irregular cycles in mid-adulthood. STUDY FUNDING/COMPETING INTEREST: This work was supported by grants U01 CA176726, U01 HL145386 and R01 HD096033 from the National Institutes of Health. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
STUDY QUESTION: Are menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk? SUMMARY ANSWER: Irregular and long menstrual cycles throughout the reproductive lifespan were associated with increased risk of total invasive cancer, especially obesity-related cancers. WHAT IS KNOWN ALREADY: Long and irregular menstrual cycles have been associated with lower risk of pre-menopausal breast cancer and higher risk of endometrial cancer, but associations with other malignancies are less clear. STUDY DESIGN, SIZE, DURATION: Prospective cohort study. Prospective follow-up of 78 943 women participating in the Nurses' Health Study II between 1989 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We followed 78 943 pre-menopausal women without cancer history who reported the usual length and regularity of their menstrual cycles at different ages (14-17, 18-22 and 29-46 years). Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity-related. We fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association between menstrual cycle characteristics and cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: We documented 5794 incident cancer cases during 1 646 789 person-years of follow-up. After adjusting for BMI and other potential confounders, women reporting irregular cycles at age 29-46 years had an 11% (95% CI: 2-21%) higher risk of total invasive cancer than women reporting very regular cycles at the same age. This association was limited to obesity-related cancers, with a 23% (95% CI: 9-39%) higher risk and was strongest for endometrial cancer (HR = 1.39; 95% CI: 1.09-1.77). Findings were comparable for cycle characteristics earlier in life and for menstrual cycle length. Very irregular cycles at age 14-17 years were associated with significant increase in risk of colorectal cancer (HR = 1.36; 95% CI: 1.02-1.81). LIMITATIONS, REASONS FOR CAUTION: Our study might be subject to recall bias for findings pertaining to cycle characteristics in adolescence and early adulthood, as these were retrospectively reported. Generalizability to non-White women may be limited, as 96% of participants were White. WIDER IMPLICATIONS OF THE FINDINGS: Women with irregular or long menstrual cycles in mid-adulthood had a statistically significantly higher risk of developing cancer, especially obesity-related cancers. This association was not limited to gynecological cancers. Obesity-related cancers may need to be added to the spectrum of long-term health consequences of long or irregular cycles, possibly warranting targeted screening among women who experience long or irregular cycles in mid-adulthood. STUDY FUNDING/COMPETING INTEREST: This work was supported by grants U01 CA176726, U01 HL145386 and R01 HD096033 from the National Institutes of Health. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Authors: Changzheng Yuan; Donna Spiegelman; Eric B Rimm; Bernard A Rosner; Meir J Stampfer; Junaidah B Barnett; Jorge E Chavarro; Amy F Subar; Laura K Sampson; Walter C Willett Journal: Am J Epidemiol Date: 2017-04-01 Impact factor: 4.897
Authors: Caren G Solomon; Frank B Hu; Andrea Dunaif; Janet E Rich-Edwards; Meir J Stampfer; Walter C Willett; Frank E Speizer; Joann E Manson Journal: J Clin Endocrinol Metab Date: 2002-05 Impact factor: 5.958
Authors: Jonathan R Bull; Simon P Rowland; Elina Berglund Scherwitzl; Raoul Scherwitzl; Kristina Gemzell Danielsson; Joyce Harper Journal: NPJ Digit Med Date: 2019-08-27
Authors: Yi-Xin Wang; Mariel Arvizu; Janet W Rich-Edwards; Jennifer J Stuart; JoAnn E Manson; Stacey A Missmer; An Pan; Jorge E Chavarro Journal: BMJ Date: 2020-09-30