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

• Type of Material: Article
• Authors: Nanette Santoro, University of Colorado; Amanda Allshouse, University of Colorado; Genevieve Neal-Perry, Albert Einstein College of Medicine; Lubna Pal, Yale University; Rogerio A. Lobo, Columbia University; Frederick Naftolin, New York University; Dennis M. Black, University of California San Francisco; Eliot A. Brinton, Utah Foundation for Biomedical Research; Matthew J. Budoff, University of California Los Angeles; Marcelle I. Cedars, University of California at San Francisco; N. Maritza Dowling, University of Wisconsin; Mary Dunn, Kronos Longevity Research Institute; Carey E. Gleason, University of Wisconsin; Howard N. Hodis, University of Southern California; Barbara Isaac, Albert Einstein College of Medicine; Maureen Magnani, Albert Einstein College of Medicine; JoAnn E. Manson, Harvard University; Virginia M. Miller, Mayo Clinic; Hugh S. Taylor, Yale University; Whitney Wharton, Emory University; Erin Wolff, National Institutes of Health; Viola Zepeda, Kronos Longevity Research Institute; S. Mitchell Harman, Kronos Longevity Research Institute
• Language: English
• Date: 2017-03-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 The North American Menopause Society.
• Final Published Version (URL): http://dx.doi.org/10.1097/GME.0000000000000756
• Title of Journal or Parent Work: Menopause
• ISSN: 1072-3714
• Volume: 24
• Issue: 3
• Start Page: 238
• End Page: 246
• Grant/Funding Information: Study medications were supplied in part by Bayer HealthCare and AbbVie Pharmaceuticals.; 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.
• Keywords: Insomnia; Hormone therapy; Hot flashes; Obstetrics & Gynecology; REPLACEMENT; Night sweats; METAANALYSIS; Irritability; HEALTH; Science & Technology; POSTMENOPAUSAL WOMEN; SLEEP; Menopause; VASOMOTOR SYMPTOMS; Life Sciences & Biomedicine; CONTROLLED-TRIAL; HOT FLASHES; EXPERIENCE; HORMONE-THERAPY
• Research Categories: Biology, Biostatistics; Health Sciences, Obstetrics and Gynecology

Abstract

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-E 2 ) 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 x 2 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-E 2 , and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E 2 , 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-E 2 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.