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Original Investigation |

Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years

Mark A. Espeland, PhD1; Sally A. Shumaker, PhD2; Iris Leng, PhD, MD1; JoAnn E. Manson, MD, DrPH3; Candice M. Brown, PhD4; Erin S. LeBlanc, MD, PhD5; Leslie Vaughan, PhD2; Jennifer Robinson, MD, MPH6; Stephen R. Rapp, PhD7; Joseph S. Goveas, MD8; Dorothy Lane, MD, MPH9; Jean Wactawski-Wende, PhD10; Marcia L. Stefanick, PhD11; Wenjun Li, PhD12; Susan M. Resnick, PhD13; WHIMSY Study Group
[+] Author Affiliations
1Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
2Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, North Carolina
3Division of Preventive Medicine, Department of Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
4Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
5Center for Health Research, Kaiser-Permanente Northwest, Portland, Oregon
6Division of Cardiology, Departments of Epidemiology and Medicine, University of Iowa, Iowa City
7Department of Psychiatry and Behavioral Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
8Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee
9Department of Preventive Medicine, Stony Brook University, State University of New York, Stony Brook
10Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo
11Department of Medicine, Prevention Research Center, Stanford University, Palo Alto, California
12Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester
13Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
JAMA Intern Med. 2013;173(15):1429-1436. doi:10.1001/jamainternmed.2013.7727.
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Importance  Postmenopausal hormone therapy with conjugated equine estrogens (CEEs) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women.

Objective  To test whether prescribing CEE-based hormone therapy to postmenopausal women aged 50 to 55 years has longer-term effects on cognitive function.

Design  Trained, masked staff assessed participants with an annual telephone-administered cognitive battery that included measures of global and domain-specific cognitive functions. Cognitive testing was conducted an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years, and repeated 1 year later. Enrollment occurred from 1996 through 1999.

Setting  Forty academic research centers.

Participants  The study population comprised 1326 postmenopausal women, who had begun treatment in 2 randomized placebo-controlled clinical trials of hormone therapy when aged 50 to 55 years.

Intervention  The clinical trials in which the women had participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years.

Main Outcomes and Measures  The primary outcome was global cognitive function. Secondary outcomes were verbal memory, attention, executive function, verbal fluency, and working memory.

Results  Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean (95% CI) intervention effect of 0.02 (−0.08 to 0.12) standard deviation units (P = .66). Similarly, no overall differences were found for any individual cognitive domain (all P > .15). Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 (−0.33 to −0.02) and −0.25 (−0.42 to −0.08), respectively; however, this may be a chance finding.

Conclusions and Relevance  CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years. We are not able to address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.

Trial Registration  clinicaltrials.gov Identifier: NCT01124773

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Consolidated Standards of Reporting Trials Diagram Describing Women’s Health Initiative Memory Study of Younger Women Enrollment and Retention
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