Study «Rapp SR, Espeland MA, Shumaker SA, ym. Effect of e...»1
Population: Women aged 65 years or older from 39 of 40 clinical centers participating in Women's Health Initiative (WHI). Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (92.6%) were enrolled in the estrogen plus progestin component of WHIMS.
Study design: A randomized, double-blind, placebo-controlled clinical trial. A total of 4381 participants (96.7%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002. Global cognitive function was measured annually with the Modified Mini-Mental State Examination.
Interventions: Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236).
Results: The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 4.2 years). Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (p=.03), but these differences were not clinically important. Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and non-adherence to study protocol, did not alter the findings. Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period. More women in the estrogen plus progestin group had a substantial and clinically important decline (≥2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (p=.008).
Conclusions: Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.
Study «Espeland MA, Brunner RL, Hogan PE, ym. Long-term e...»2
Population: 2,304 women aged 65-80 years and free of probable dementia at enrollment originally participating in Women's Health Initiative (WHI).
Interventions: 0.625 mg/day of conjugated equine estrogen (CEE), with or without medroxyprogesterone acetate (MPA, 10 mg/day), and matching placebos.
Study design: The Women's Health Initiative Study of Cognitive Aging (WHISCA) examined whether above mentioned therapies influenced domain-specific cognitive function at initial assessment, an average of 3.0 years after randomization to CEE-based therapies or placebos, and subsequent age-related rates of change in eight cognitive domains over the remaining average 2.6 years of on-trial follow-up. Annual administration of a battery of cognitive tests during and following the trial. The cognitive test battery included: 1) the Primary Mental Abilities Vocabulary test to assess verbal knowledge, 2) letter and semantic fluency tests to assess verbal fluency, 3) the Benton Visual Retention Test (BVRT) to assess short-term figural memory, 4) the California Verbal Learning Test (CVLT) to assess verbal memory, 5) the Digit Span Forward and Backward Test to assess attention and working memory, 6) the Card Rotations Test to measure spatial ability, 7) the Finger Tapping Test to assess fine motor speed, 8) and the Modified Mini Mental State (3MS) Exam to assess global cognitive function. Quality control was maintained through recertification of test administrators twice during the first year and annually thereafter. General linear models were used to compare on-trial and post-trial mean standardized test scores between treatment groups, with adjustment for baseline risk factors for cognitive impairment.
Results: Assignment to CEE-based therapies was associated with small mean relative decrements in global and several domain-specific cognitive functions on-trial, which largely persisted through up to 4 years post-trial. The strongest statistical evidence was for global cognitive function: 0.07 standard deviation decrements both on-trial (p=0.007) and post-trial (p=0.01). Among domain specific scores, the mean relative decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.
Conclusions: CEE-based therapies, when initiated after age 65 years, produce a small broad-based decrement in cognitive function that persists after their use is stopped. Differences in effects among cognitive domains suggest that more than one mechanism may be involved.
Study «Kang JH, Weuve J, Grodstein F. Postmenopausal horm...»3
Population: The study included 13,807 participants aged 70 to 81 years, who participated in The Nurses' Health Study (MHS). NHS is a prospective cohort begun in 1976, comprising 121,700 female nurses who report health information via biennial mailed questionnaires. The women were divided in five groups according their MHT use (own report of the use): Nonusers (n=4,258, past users (n=4,611), current users of estrogen+progestin (n=1,358), current users of estrogen only (n=3,580, current users of estrogen only – recent initiators (n=282).
Study design: Two telephone cognitive assessments, 2 years apart, between 1995 and 2003. Cognitive tests: 1) General cognition, 2) verbal memory, 3) category fluency, and 4) attention Multiple linear regression was used to estimate adjusted mean declines and logistic regression to estimate adjusted risks of substantial decline in cognition (> or =2 SD of baseline performance) across hormone groups. APOE genotype was available in a subset of 3,667 participants, and genotyping was performed with laboratory personnel blinded to participants' cognitive performance and hormone use.
Results: Overall, little difference was found in mean cognitive decline between current hormone users and never users. However, for long‐term users of estrogen alone or combined with progestin, an increased risk of substantial decline was observed on most cognitive tests (relative risk [RR] = 1.25 to 1.72). Decline was particularly high among women initiating hormones at older ages compared with never users: for example, on our test of general cognition, RR of substantial decline was 1.74 (95% CI 1.08, 2.81) and mean difference in decline was -0.43 (95% CI -0.73, -0.12). No significant interactions between hormone use and APOE epsilon4 allele were observed.
Conclusions: Postmenopausal hormone therapy provides no appreciable cognitive benefits in older women.