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Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo

the Kronos Early Estrogen Prevention Study

Santoro, Nanette MD; Allshouse, Amanda MS; Neal-Perry, Genevieve MD, PhD; Pal, Lubna MD; Lobo, Rogerio A. MD; Naftolin, Frederick MD, PhD; Black, Dennis M. PhD; Brinton, Eliot A. MD; Budoff, Matthew J. MD; Cedars, Marcelle I. MD; Dowling, N. Maritza PhD; Dunn, Mary RN; Gleason, Carey E. PhD; Hodis, Howard N. MD; Isaac, Barbara RN; Magnani, Maureen RN; Manson, JoAnn E. MD, DrPH; Miller, Virginia M. PhD, MSc; Taylor, Hugh S. MD, PhD; Wharton, Whitney PhD; Wolff, Erin MD, MSc; Zepeda, Viola RN; Harman, S. Mitchell MD, PhD

doi: 10.1097/GME.0000000000000756
Original Articles

Objective: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years.

Methods: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 μg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ2 tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling.

Results: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity.

Conclusions: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

1Department of Obstetrics & Gynecology

2Department of Biostatistics, University of Colorado School of Medicine, Aurora, CO

3Department of Obstetrics, Gynecology & Women's Health and Neurosciences, Albert Einstein College of Medicine, Bronx, NY

4Department of Obstetrics & Gynecology, Yale University School of Medicine, New Haven, CT

5Department of Obstetrics & Gynecology, Columbia University College of Physicians and Surgeons, New York, NY

6Department of Obstetrics & Gynecology, New York University School of Medicine, New York, NY

7Department of Epidemiology & Biostatistics, University of California at San Francisco, San Francisco, CA

8Utah Foundation for Biomedical Research, Salt Lake City, UT

9Department of Cardiology, Los Angeles Biomedical Research Institute at Harbor UCLA, Torrance, CA

10Department of Obstetrics & Gynecology, University of California at San Francisco, San Francisco, CA

11Departments of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI

12Kronos Longevity Research Institute, Phoenix, AZ

13Department of Medicine and Public Health, University of Wisconsin, Madison, WI

14Atherosclerosis Research Unit, University of Southern California, Los Angeles, CA

15Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

16Departments of Surgery and Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN

17Department of Neurology, Emory University, Atlanta, GA

18Department of Reproductive Biology and Medicine, National Institutes of Health, Bethesda, MD

19Department of Medicine, Endocrine Division, Phoenix VA Health Care System, Phoenix, AZ.

Address correspondence to: Nanette Santoro, MD, Department of Obstetrics & Gynecology, University of Colorado School of Medicine, 12631 E. 17th Avenue, Mail Stop B-198, Aurora, CO 80045. E-mail:

Received 10 May, 2016

Revised 2 August, 2016

Accepted 2 August, 2016

Genevieve Neal-Perry, Current address: Department of Obstetrics & Gynecology, University of Washington School of Medicine, Seattle, WA.

Erin Wolff, Current address: Celmatix, Inc, New York, NY.

Funding/support: The Kronos Early Estrogen Prevention Study (KEEPS was funded by grants from the Aurora Foundation to the Kronos Longevity Research Institute; the National Institutes of Health (grant HL90639 to Dr Miller); Mayo Clinic Clinical and Translational Science Award UL1 RR024150; the Mayo Foundation; Brigham and Women's Hospital/Harvard Medical School Clinical and Translational Science Award UL1 RR024139; and the University of California, San Francisco, Clinical and Translational Science Award UL1 RR024131 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health and the National Institutes of Health Roadmap for Medical Research. Study medications were supplied in part by Bayer HealthCare and AbbVie Pharmaceuticals.

Financial disclosure/conflicts of interest: N.S. reports investigator-initiated grant support from Bayer, Inc, and stock options in MenoGeniX, outside the submitted work. D.M.B. reports grant and personal fees from Novartis, and personal fees from Merck, Amgen, and Eli Lilly, outside the submitted work. E.A.B. reports personal fees from Alexion, Amarin, Amgen, Aralez, Janssen, Kowa, Merck, Regeneron, Sanofi-Aventis, and Takeda. S.M.H. reports grants from the Aurora Foundation and Pfizer Pharmaceuticals, nonfinancial support from Abbott Laboratories, and nonfinancial support from Bayer Healthcare during the conduct of the KEEPS. L.P. reports personal fees from Merck. R.A.L. reports consultation fees from Pfizer, Amigen, and Teva and grant support from TherapeuticsMD. H.S.T. reports grant support from Pfizer through Yale University and personal fees from Pfizer. E.W. reports being an employee of Celmatix, Inc. Other coauthors report no disclosures.

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© 2017 by The North American Menopause Society.