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Author Notes:

Correspondence: ceg@medicine.wisc.edu

Conceived and designed the experiments: CEG SA SMH FN.

Performed the experiments: EAB MIC RAL JEM GRM VMM GNP NFS HST MJB HNH.

Analyzed the data: NMD DMB.

Contributed reagents/materials/analysis tools: CSA MJB HNH.

Wrote the first draft of the manuscript: CEG.

Contributed to the writing of the manuscript: CEG NMD CSA WW SA MH.


Agree with manuscript results and conclusions: CEG NMD WW CSA EAB MIC RAL JEM GRM VMM GNP NFS HST DMB MJB HNH FN SMH SA.

The authors wish to acknowledge the passing of a dear friend and colleague, Dr. George R. Merriam, principal KEEPS investigator at the Veterans Affairs Puget Sound Health Care System and University of Washington study site. Dr. Merriam’s contributions as a researcher and clinician are a true legacy; still, he is deeply missed. We dedicate this publication to Dr. Merriam.

For a full list of acknowledgements, please see the full article.

All authors have read, and confirm that they meet, ICMJE requirements for authorship.

The manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official view of NCATS or NIH.

Information on NCATS is available at http://www.ncats.nih.gov.

Bayer HealthCare Pharmaceuticals, Inc. supplied the CLIMARA estradiol and placebo patches and Abbott Laboratories (formerly Solvay Pharmaceuticals) provided the micronized progesterone (PROMETRIUM) and placebo capsules.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

I have read the journal's policy and the authors of this manuscript have the following competing interests:

MIC declared: I have research funding from Nora Therapeutics and Ferring pharmaceuticals. I am a member of ASRM Executive Board.

NFS declared: 1. Menogenix: stock options (this is a company that has patented a novel non hormonal treatment for menopausal hot flashes and to date I have not exercised my stock options but would rather report this than give the appearance of not disclosing sufficient information). 2. Bayer, Inc: grant support (this is an investigator initiated grant that is supported by funds given to my institution. I receive no personal funds for this work).

SA declared: 1) NIH Grants to support my research—NIA P50 Center Grant to support the Wisconsin Alzheimer's Disease Research Center (ADRC). 2) NIA T32 Training Grant in the Biology of Aging and Age-Related Diseases. 3) NIA RO1 that supported the KEEPS Cognitive and Affective Study. 4) Following Pharma Industry-supported research grants to serve as a site PI to conduct treatment trials in patients with Alzheimer's disease and Mild Cognitive Impairment (MCI): Merck Sharp and Dohme; H. Lundbeck A-S; Toyama Chemical Company. 5) Rockpointe Corporation—I am on the Speaker's Bureau of this science-based education corporation that sponsors CME-accredited education programs. My presentations are on Alzheimer's disease and not related to the focus of the manuscript under review.

HST declared: I have served as a consultant to Bayer, Abbvie, Pfizer and Theraputics MD. My University has received grant support toward my work from Pfizer. I have authored papers with employees of Pfizer and Shionogi.


Research Funding:

The KEEPS-Cog project was supported by grants from the National Institutes of Health (NIH) R01 AG029624, P50AG033514, R01AG031790, grant 1UL1RR025011 from the Clinical and Translational Science Award (CTSA) program of the NIH National Center for Research Resources and the Wisconsin National Primate Research Center base grant, NIH NCRR000167.

The Parent KEEPS trial was funded by grants from the Aurora Foundation to the Kronos Longevity Research Institute, National Institutes of Health (NIH) HL90639 to VMM, Einstein College of Medicine, CTSA UL1 RR025750, KL2 RR025749 and TL1 RR025748, Mayo CTSA 1 UL1 RR024150, the Mayo Foundation, Brigham and Women’s Hospital/Harvard Medical School CTSA, CTSA UL1 RR024139 and UCSF CTSA UL1 RR024131 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research.

Additional support provided by resources and facilities of the Madison VA, and the VA Puget Sound Health Care System.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, General & Internal
  • General & Internal Medicine
  • Estrogens
  • Menopause
  • Women's health
  • Estradiol
  • Hormonal therapy
  • Progesterone
  • Depression
  • Memory

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study

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Journal Title:

PLoS Medicine


Volume 12, Number 6


, Pages e1001833-e1001833

Type of Work:

Article | Final Publisher PDF


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. 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<sup>−2</sup>(95% CI, −8.27 × 10<sup>−2</sup>to −2.44 × 10<sup>−2;</sup>ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10<sup>−2</sup>(95% CI, −5.09 × 10<sup>−2</sup>to −9.34 × 10<sup>−3</sup>; 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. 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.

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