Hormone Replacement Therapy and Cognitive Function

Observational studies have suggested that postmenopausal hormone replacement therapy (HRT)
may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive.
The effects of HRT on dementia and mild cognitive impairment were assessed in a subgroup of participants
in the Women’s Health Initiative Memory Study (WHIMS) (a multicenter, randomized, double-blind, placebo-
controlled clinical trial). There were two study arms, one involved 4,532 postmenopausal women who
received continuous combined estrogen (conjugated equine estrogens [CEE] plus medroxyprogesterone
acetate [MPA]) or placebo, and the other involved 2,947 hysterectomized women randomized to continuous
unopposed CEE or placebo. All participants were aged 65 years or older. CEE with or without MPA did not
protect against (but substantially increased the risk of) dementia of any cause or cognitive decline. Incidence
of probable dementia in the estrogen-alone trial was statistically similar to that in the estrogen plus progestin
trial. When data from both trials were pooled, the overall risk for probable dementia was increased by 76%
(HR, 1.76; 95% CI, 1.19 to 2.60; P = 0.005). A second report from WHIMS suggested that cognitive
decline in women aged 65 years and older was greater in those receiving hormone therapy than in those
receiving placebo (HR, 1.25; 95% CI, 0.97-1.60).
The WHIMS results clearly indicate that CEE with or without MPA should not be used to prevent dementia
or enhance cognition in women older than 65 years.