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Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

Cintron, Dahima MS1; Lahr, Brian D. MS2; Bailey, Kent R. PhD2; Santoro, Nanette MD3; Lloyd, Robin MD4; Manson, JoAnn E. MD, DrPH5; Neal-Perry, Genevieve MD, PhD6; Pal, Lubna MBBS, MS, FRCOG7; Taylor, Hugh S. MD7; Wharton, Whitney PhD8; Naftolin, Fredrick MD9; Harman, S. Mitchell MD, PhD10; Miller, Virginia M. PhD11

doi: 10.1097/GME.0000000000000971
Original Articles

Objective: This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17β-estradiol (t-E2; 50 μg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study.

Methods: Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients.

Results: Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change −1.27 [o-CEE] and −1.32 [t-E2]) when compared with PBO (−0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (r s = 0.170, P < 0.001 for hot flashes; r s = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS.

Conclusions: Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women.

1Mayo Clinic Graduate School, Mayo Clinic Rochester, MN

2Department of Health Sciences Research Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, MN

3Department of Obstetrics and Gynecology, University of Colorado at Denver, Aurora, CO

4Department of Internal Medicine, Mayo Clinic, Rochester, MN

5Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

6Department of Obstetrics and Gynecology, University of Washington, Seattle, WA

7Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT

8Department of Neurology, Emory University, Atlanta, GA

9NYU Interdisciplinary Program in Menopause Medicine, New York University, New York, NY

10Kronos Longevity Research Institute and the Phoenix Veterans Administration Health Care System, Phoenix, AZ

11Department of Surgery and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN.

Address correspondence to: Virginia M. Miller, PhD, Professor of Surgery and Physiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail:

Received 19 April, 2017

Revised 7 July, 2017

Accepted 7 July, 2017

Funding/support: KEEPS would not have been possible without funding by grants from the Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639 to VMM, NIH P50 AG 44170 to VMM, 1 UL1 RR024150*, TL1 TR000137 to the Mayo Foundation, Brigham and Women's Hospital/Harvard Medical School CTSA, CTSA UL1 RR024139 and UCSF CTSA UL1 RR024131, the Mayo Clinic Office of Health Disparities Research, and the Mayo Foundation; Pfizer: for the limited goal of measurement of estrogens in already collected blood samples.

Financial disclosure/conflicts of interest: H.S.T. reports grant support to Yale University from Pfizer. None of the other authors declared conflicts of interest.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 by The North American Menopause Society.