title: Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study.
abstract: BACKGROUND
  Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.
  
  
  RESULTS
  KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y.
  
  
  CONCLUSIONS
  The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00154180 and NCT00623311.
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America; Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, United States of America.
authors.forename: Carey E
authors.initials: CE
authors.lastname: Gleason
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, United States of America; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: N Maritza
authors.initials: NM
authors.lastname: Dowling
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Emory Alzheimer's Disease Research Center, Atlanta, Georgia, United States of America.
authors.forename: Whitney
authors.initials: W
authors.lastname: Wharton
authors.affiliation: Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: Departments of Surgery and Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Miller
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America; Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, United States of America.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Atwood
authors.affiliation: Utah Foundation for Biomedical Research, Salt Lake City, Utah, United States of America.
authors.forename: Eliot A
authors.initials: EA
authors.lastname: Brinton
authors.affiliation: Obstetrics & Gynecology, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Marcelle I
authors.initials: MI
authors.lastname: Cedars
authors.affiliation: Obstetrics & Gynecology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Rogerio A
authors.initials: RA
authors.lastname: Lobo
authors.affiliation: VA Puget Sound Health Care System, Tacoma, Washington, United States of America; Division of Metabolism, Endocrinology and Nutrition, University of Washington, Tacoma, Washington, United States of America.
authors.forename: George R
authors.initials: GR
authors.lastname: Merriam
authors.affiliation: Neuroscience and Obstetrics & Gynecology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Neal-Perry
authors.affiliation: Obstetrics & Gynecology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Nanette F
authors.initials: NF
authors.lastname: Santoro
authors.affiliation: Obstetrics & Gynecology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
authors.affiliation: Epidemiology & Biostatistics, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Black
authors.affiliation: Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Budoff
authors.affiliation: Atherosclerosis Research Unit, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Howard N
authors.initials: HN
authors.lastname: Hodis
authors.affiliation: Obstetrics & Gynecology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Frederick
authors.initials: F
authors.lastname: Naftolin
authors.affiliation: Kronos Longevity Research Institute, Phoenix, Arizona, United States of America; Division of Endocrinology, Phoenix VA Medical Center, Phoenix, Arizona, United States of America.
authors.forename: S Mitchell
authors.initials: SM
authors.lastname: Harman
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America; Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
mesh_terms: D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D004958:Estradiol / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D019964:Mood Disorders / Q000188:drug therapy*; D017698:Postmenopause; D011374:Progesterone / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D012307:Risk Factors; D014481:United States
chemical_list: D004966:Estrogens, Conjugated (USP); D011374:Progesterone; D004958:Estradiol