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

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.