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Effects of oral conjugated equine estrogens with or without medroxyprogesterone acetate on incident hypertension in the Women's Health Initiative hormone therapy trials

Swica, Yael MD, MPH, MTS1; Warren, Michelle P. MD2; Manson, JoAnn E. MD, DrPH3; Aragaki, Aaron K. MS4; Bassuk, Shari S. ScD3; Shimbo, Daichi MD5; Kaunitz, Andrew MD, FACOG, NCMP6; Rossouw, Jacques MD7; Stefanick, Marcia L. PhD8; Womack, Catherine R. MD9

doi: 10.1097/GME.0000000000001067
Original Articles

Objective: The aim of the study was to determine the effect of menopausal hormone therapy on incident hypertension in the two Women's Health Initiative hormone therapy trials and in extended postintervention follow-up.

Methods: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. This analysis includes the subsample of 18,015 women who did not report hypertension at baseline and were not taking antihypertensive medication. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 5,994) or placebo (n = 5,679). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 3,108) or placebo (n = 3,234). The intervention lasted a median of 5.6 years in the CEE plus MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. The primary outcome for these analyses was self-report of a new diagnosis of hypertension and/or high blood pressure requiring treatment with medication.

Results: During the CEE and CEE plus MPA intervention phase, the rate of incident hypertension was 18% higher for intervention than for placebo (CEE: hazard ratio [HR], 1.18; 95% CI, 1.09-1.29; CEE plus MPA: HR, 1.18; 95% CI, 1.09-1.27). This effect dissipated postintervention in both trials (CEE: HR, 1.06; 95% CI, 0.94-1.20; CEE plus MPA: HR, 1.02; 95% CI, 0.94-1.10).

Conclusions: CEE (0.625 mg/d) administered orally, with or without MPA, is associated with an increased risk of hypertension in older postmenopausal women. Whether lower doses, different estrogen formulations, or transdermal route of administration offer lower risks warrant further study.

1Department of Medicine, Division of Family and Community Medicine, New York, NY

2Department of Obstetrics and Gynecology and Medicine, New York, NY

3Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA

4Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA

5Department of Medicine, Division of Cardiology, New York, NY

6Department of Obstetrics and Gynecology, Jacksonville, FL

7Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

8Stanford Prevention Research Center, Stanford Women and Sex Differences in Medicine (WSDM) Center Stanford University School of Medicine, Stanford, CA

9Department of Preventive Medicine and Medicine, University of Tennessee Health Sciences Center, Memphis, TN.

Address correspondence to: Yael Swica, MD, MPH, MTS, Columbia University Medical Center, New York, NY. E-mail:

Received 10 September, 2017

Revised 22 December, 2017

Accepted 22 December, 2017

Funding/support: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Wyeth Ayerst donated the study drugs.

Role of the Sponsor: The Women's Health Institute (WHI) Project Office at the National Heart, Lung, and Blood Institute (NHLBI), the Sponsor, had a role in the design and conduct of the study and interpretation of the data. Decisions concerning the above, as well as data collection, management, analysis, review, or approval of the manuscript, and decision to submit the manuscript for publication resided with committees composed of WHI investigators and included NHLBI representatives. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Financial disclosure/conflicts of interest: None reported: Dr. Kaunitz receives grant funding from Pfizer, TheraputicsMD, and Bayer. He also receives royalties from UpToDate. Dr. Womack receives grant funding from Bayer.

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© 2018 by The North American Menopause Society.