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Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women’s Health Initiative Observational Study

Shufelt, Chrisandra L. MD, MS1; Merz, C. Noel Bairey MD1; Prentice, Ross L. PhD2; Pettinger, Mary B. MS2; Rossouw, Jacques E. MD3; Aroda, Vanita R. MD4; Kaunitz, Andrew M. MD5; Lakshminarayan, Kamakshi MD, PhD6; Martin, Lisa W. MD7; Phillips, Lawrence S. MD8,9; Manson, JoAnn E. MD, DrPH10

doi: 10.1097/GME.0b013e31829a64f9
Original Articles

Objective Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality.

Methods The Women’s Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009.

Results The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women.

Conclusions In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses.

From the 1Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA; 2Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; 3National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; 4MedStar Health Research Institute, Hyattsville, MD; 5University of Florida College of Medicine–Jacksonville, Jacksonville, FL; 6Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN; 7George Washington University School of Medicine and Health Sciences, Washington, DC; 8Atlanta VA Medical Center, Decatur, GA; 9Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, GA; and 10Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Received February 27, 2013; revised and accepted May 2, 2013.

A full listing of Women’s Health Initiative investigators can be found at

Funding/support: The Women’s Health Initiative program was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This work was supported by General Clinical Research Center grant MO1-RR00425 from the National Center for Research Resources, Clinical and Translational Sciences Institute grant UL1TR000124, the Edythe L. Broad Women’s Heart Research Fellowship (Cedars-Sinai Medical Center), and the Barbra Streisand Women’s Cardiovascular Research and Education Program (Cedars-Sinai Medical Center).

Financial disclosure/conflicts of interest: A.M.K. has received research funding (to the institution) from Bayer, Noven, and Teva, and has served on the advisory boards of Bayer and Noven. C.N.B.M. has received research funding (to the institution) from Gilead and consulting money from Bristol-Myers Squibb for Data Safety Monitoring Board service, and has served on the advisory board of Abbott Vascular. L.S.P. has received research funding from Eli Lilly, Novo Nordisk, PhaseBio, Amylin, and Roche, and has served on the advisory board of Boehringer Mannheim. V.R.A. has served as consultant to Novo Nordisk and Sanofi-Aventis, and has received grants from Takeda, Novo Nordisk, Sanofi-Aventis, GI Dynamics, Amylin, GSK, Boehringer Ingelheim, and N-Gene.

Address correspondence to: Chrisandra L. Shufelt, MD, MS, Suite 740 East, 8631 West Third Street, Los Angeles, CA 90048. E-mail:

© 2014 by The North American Menopause Society.