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Menopause. 2018 Jan;25(1):11-20. doi: 10.1097/GME.0000000000000956.

Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study.

Author information

Department of Medicine, University of California at Los Angeles, Los Angeles, CA.
Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, New York, NY.
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI.
Department of Medical Oncology and Therapeutics, City of Hope National Medical Center, Duarte, CA.
Departments of Medicine and Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA.
Department of Family, Population and Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, New York, NY.
Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, D.C.
Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, FL.
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.



To determine the association between use of vaginal estrogen and risk of a global index event (GIE), defined as time to first occurrence of coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause.


For this prospective observational cohort study, we used data from participants of the Women's Health Initiative Observational Study, who were recruited at 40 US clinical centers, aged 50 to 79 years at baseline and did not use systemic estrogen therapy during follow-up (n = 45,663, median follow-up 7.2 years). We collected data regarding incident CHD, invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, death, and self-reported use of vaginal estrogen (cream, tablet). We used Cox proportional-hazards regression models to adjust for covariates.


Among women with an intact uterus, the risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, and pulmonary embolism/deep vein thrombosis were not significantly different between vaginal estrogen users and nonusers, whereas the risks of CHD, fracture, all-cause mortality, and GIE were lower in users than in nonusers (GIE adjusted hazard ratio 0.68, 95% confidence interval 0.55-0.86). Among hysterectomized women, the risks of each of the individual GIE components and of the overall GIE were not significantly different in users versus nonusers of vaginal estrogen (GIE adjusted hazard ratio 0.94, 95% confidence interval 0.70-1.26).


The risks of cardiovascular disease and cancer were not elevated among postmenopausal women using vaginal estrogens, providing reassurance about the safety of treatment.

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