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Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies

Maki, Pauline M. PhD

doi: 10.1097/GME.0b013e3182960cf8
Invited Review

Objective The critical window hypothesis of hormone therapy (HT) and cognitive function states that the effects of HT depend on timing of initiation with respect to age, the menopausal transition, or both, and that optimal effects are evident with early initiation. This article reviews clinical studies that bear on this hypothesis.

Methods Recognizing that the typical pattern of HT use is early HT initiation, this review describes findings from observational studies of ever use of HT and observational studies that looked specifically at the timing of HT on Alzheimer’s disease (AD) and cognitive test performance. Randomized trials of HT and verbal memory are discussed, and neuroimaging studies bearing on the hypothesis are reviewed.

Results Observational data suggest that HT generally reduces the risk of AD. Three of three observational studies that specifically examined the timing of initiation in relation to AD risk each provide support for the window, whereas three of five observational studies of HT timing and cognitive test performance do. Randomized clinical trials of estrogen therapy in younger women find support for the hypothesis. Conjugated equine estrogens/medroxyprogesterone acetate increases risks regardless of timing. Little is known about the cognitive effects of other combination HT formulations.

Conclusions A definitive trial to test the critical window hypothesis is not feasible. Evidence drawn from other sources provides initial support for the hypothesis. Although these findings are relevant to women who use HT to treat vasomotor symptoms, HT is currently not indicated for the treatment of cognitive complaints or for dementia prevention.

From the Departments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, IL.

Received January 21, 2013; revised and accepted April 8, 2013.

The contents of this publication are solely the responsibility of the author and do not necessarily represent the official views of the National Institutes of Health.

Funding/support: This study was supported in part by R01 MH083782-01.

Financial disclosure/conflicts of interest: P.M.M. has received consultant fees from Depomed Pharmaceuticals.

Address correspondence to: Pauline M. Maki, PhD, Departments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, IL 60612. E-mail:

© 2013 by The North American Menopause Society.