Endogenous and Exogenous Estrogen, Cognitive Function, and Dementia in Postmenopausal Women: Evidence from Epidemiologic Studies and Clinical Trials

Elizabeth Barrett-Connor, M.D.; Gail A. Laughlin, Ph.D.

Disclosures

Semin Reprod Med. 2009;27(3):275-282. 

In This Article

Clinical Trials

Published randomized controlled clinical trials tend to be either small and short or large and long; obviously, only the latter have dementia outcomes.

Results from many small, short trials in younger women are inconsistent; because the results are not clearly relevant to cognitive function loss or risk of dementia in older women, they are reviewed only briefly here. These studies have been reviewed recently by Sherwin and Henry, who performed most of the original controlled clinical trials on recently oophorectomized women. Sherwin and Henry concluded that most estrogen trials showed cognitive benefit.[38] Because most of the controlled clinical trials in younger women were conducted in women who had a surgical menopause or severe menopause symptoms, it is unclear whether the observed benefit is relevant to mechanisms for protection of older women against memory loss or dementia.

Results from small clinical trials in older women are contradictory. For example, three trials in older women without dementia variously showed worse performance on 2 of 10 tests (70 women, 3-month trial of transdermal estrogen), no significant effect on 5 tests (46 women, 3-week trial of oral estrogen), or better performance on memory and visuospatial tests (37 women, 3-week trial of transdermal estrogen).[39,40,41] The reasons for these differences are not obvious.

Results from larger, longer trials generally suggest harm. The Ultra Low Dose Transdermal Estrogen Assessment (ULTRA) trial randomly assigned 417 postmenopausal women aged 60 to 80 years to transdermal very-low-dose estradiol (0.014 mg/d dose once weekly) or placebo.[42] After 2 years, there was no significant difference in performance on any of seven cognitive function tests. Women in the lowest tertile of endogenous estrogen at baseline, who might have been expected to benefit most, performed significantly more poorly on the MMSE if they were treated with estrogen.

The Heart and Estrogen/Progestin Replacement Study (HERS) clinical trail included 1063 older women who had known heart disease; women were randomly assigned to 0.625 mg daily conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate. Cognitive function tests were not obtained at baseline but were performed (after 4.2 years) at the end of the trial. Only one of the five test results differed by treatment assignment: verbal fluency performance was significantly worse in the estrogen-treated women (p = 0.02).[43]

The Women's Health Initiative Memory Study (WHIMS) is the largest postmenopausal estrogen trial of dementia ever likely to be conducted, including a subset of 2947 women aged 65 years or older who were participants in one of the two Women's Health Initiative (WHI) trials. This study was planned to combine the data from the estrogen-alone or estrogen plus medroxyprogesterone acetate arms. All women completed the 3MSE (modified Mini-Mental Status Exam) cognitive function test. During a mean follow-up of 5.4 years, women assigned to active therapy performed more poorly than did women assigned to placebo on this test of global cognitive function. They were also more likely to develop categorically defined mild cognitive impairment or dementia. The adverse effect on cognition was greater in women who had poorer global cognitive function at baseline.[44]

Three years after WHI enrollment began, a subset of 1416 (of 2089 invited) women in the estrogen plus medroxyprogesterone acetate (participants from 14 of the 39 WHIMS sites) began a more extensive study of 16 cognitive function tests, which were to have been repeated annually. After an average of only 1.3 years when the WHI trial was concluded prematurely, hormone users had poorer performance on verbal memory (p < 0.01) and better performance on figural memory (p = 0.012) compared with that of the placebo group. Results for the other 14 tests did not differ by treatment assignment.[45]

In 2008, The Cochrane Collaboration reported a detailed meta-analysis of postmenopausal hormone treatment trials and cognitive function.[46] They reviewed all published randomized, double-blind, controlled clinical trials of estrogen alone or with a progestin and cognitive function that had a treatment period of at least 2 weeks; 16 of 24 trials with usable data published up to the end of 2007 were included. The total number of women in these trials was 10,114. The average duration of the trials was between 4 and 5 years. In the unopposed estrogen and the estrogen plus progestin trials, the cognitive function test results were poorer in the hormone treatment group, but the differences were not statistically significant. The odds (OR) of cognitive impairment with unopposed estrogen was 1.34 (95% CI 0.95 to 1.90), and with estrogen plus progestogen therapy was 1.05 (95% CI 0.72 to 1.54).

The Cochrane report included separate analyses related to differences in hormone regimens and differences in populations. The authors concluded that there was insufficient evidence to show whether benefit or risk differed by specific types of treatment (e.g., transdermal versus oral delivery, standard versus other doses, or estrogen alone versus estrogen with a progestogen). They also concluded that there was insufficient evidence to show whether risk differed by the type of participants (e.g., age 60 years versus older, within 10 years of menopause versus not, surgical versus natural menopause, and presence versus absence of postmenopausal symptoms).

Hormone trials in patients who have dementia are few. The largest trial was conducted in 120 women with mild to moderate senile dementia of Alzheimer's type. Women were randomized for 1 year to conjugated equine estrogen either 0.625 or 1.25 mg/day or placebo for 1 year. The primary outcome, global assessment of change with a 7-point scale, showed absolutely no change by treatment assignment, but the clinical dementia rating scale, a secondary outcome, showed a significant difference (0.5 vs. 0.2, p = 0.01) favoring placebo.

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