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Incidence of endometrial spotting or bleeding during continuous-combined estrogen-progestin therapy in postmenopausal women with and without hypertension

Sriprasert, Intira MD1,2; Beydoun, Hind PhD3; Barnabei, Vanessa MD, PhD4; Nassir, Rami MD, PhD5; LaCroix, Andrea Z. PhD6; Archer, David F. MD1

doi: 10.1097/GME.0000000000000436
Original Articles

Objective: Endometrial spotting or bleeding is a common adverse effect among women taking continuous-combined estrogen-progestin therapy. The renin-angiotensin-aldosterone system plays a major role in hypertension and is present in the endometrium. We hypothesized that postmenopausal women with hypertension would have a higher incidence of bleeding compared with postmenopausal women without hypertension.

Methods: A multivariate mixed-effects logistic model estimated the odds ratios for the relationship of hypertension status or use of antihypertensive drugs with endometrial bleeding using the Women's Health Initiative database.

Results: The incidence of spotting or bleeding in the first 12 months of estrogen-progestin use was 42% in women aged 50 to 79 years. Women with hypertension were more likely to experience bleeding than women without hypertension (odds ratio, 1.07; 95% CI, 1.02-1.13). Overall antihypertensive medication use increased bleeding with an odds ratio of 1.24, whereas angiotensin II receptor antagonists had a reduced odds ratio (0.53).

Conclusions: Postmenopausal women with hypertension are more likely to bleed than postmenopausal women without hypertension when taking continuous estrogen-progestin, with less bleeding in women using angiotensin II receptor antagonists. This finding is novel and supports our hypothesis that the endometrial renin-angiotensin-aldosterone system may contribute to endometrial bleeding.

1Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA

2Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

3Graduate Program in Public Health, Eastern Virginia Medical School, Norfolk, VA

4Department of Obstetrics and Gynecology, School of Medicine and Biomedical Sciences, University at Buffalo, New York, NY

5Department of Biochemistry and Molecular Medicine, University of California, Davis, CA

6Division of Epidemiology, Department of Family and Community Medicine, University of California San Diego School of Medicine, San Diego, CA.

Address correspondence to: Intira Sriprasert, MD, Apartment 105, 705 North Monterey St, Alhambra, CA 91801. E-mail:

Received 2 October, 2014

Revised 23 December, 2014

Accepted 23 December, 2014

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.

Financial disclosure/conflicts of interest: D.F.A. serves as a consultant to AbbVie, Agile Therapeutics, Ascend Therapeutics, Bayer Healthcare, CHEMO, Endoceutics, Merck, Pfizer, Shionogi, TherapeuticsMD, Warner Chillcott, and Watson Pharmaceutical. He has contracts for clinical research studies with AbbVie, Endoceutics, Merck, Pfizer, Bayer Healthcare, Warner Chilcott, and TherapeuticsMD. He has received honoraria for lecturing from Merck and Pfizer and has stocks/stock options in Agile Therapeutics. I.S., H.B., V.B., R.N., and A.Z.L. declare no conflicts of interest.

© 2015 by The North American Menopause Society.