The Womens Health Initiative (WHI) randomized, placebo-controlled clinical trials of hormone therapy (HT) were designed to test the hypothesis that conjugated equine estrogens alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA) protected postmenopausal women against the development of heart disease. The WHI Memory Study (WHIMS) was an ancillary study to the WHI trials, which consisted of parallel placebo-controlled randomized clinical trials of 0.625 mg/day CEE therapy with and without 2.5 mg/day MPA in women with a uterus or post-hysterectomy, respectively. WHIMS investigated the effect of CEE-Alone and CEE+MPA on risk for probable dementia and mild cognitive impairment in women age 65 and older, as well as the effects of these treatments on global cognitive function. The WHI Study of Cognitive Aging (WHISCA), an ancillary study to WHIMS, was developed to investigate the effects of HT on domain-specific cognitive function in women without dementia. WHISCA enrolled 2305 women at 14 of the WHIMS sites, distributed across the two parallel trials. WHISCA was initiated on average 3 years after WHI randomization and the primary outcome was the effect of HT on rates of cognitive change, adjusted for time since randomization. The WHIMS CEE+MPA trial terminated earlier than planned (July, 2002) due to an adverse risk-to-benefit profile in the main WHI trial. Subsequently, the WHI CEE-Alone Trial also was terminated early (February, 2004). Results from the WHIMS trials showed that CEE-Alone or CEE+MPA increase the risk of dementia and have adverse effects on global cognition in women aged 65 years or older. HT also has been shown to increase the risk of clinical stroke in women 65 years and older. The initial report of WHISCA findings showed that CEE + MPA had a negative impact on verbal memory (p <0.01) and a trend to a positive impact on figural memory (p = 0.012) over time compared with placebo with no effect on other cognitive domains. In addition, these effects were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. These findings suggest that HT may have different effects across different cognitive domains. The findings from the CEE-Alone Trial in women with prior hysterectomy who were randomized to CEE or placebo show that CEE alone did not affect domain-specific cognitive function over time. Participants in the WHISCA and WHIMS studies continue to be followed through telephone cognitive assessments as they pass through the risk period for cognitive decline. Over the 2011-2015 period the NIA is assuming the primary funding role for the WHIMS Suite of Studies through a Research and Development Contract. This contract also includes continued cognitive follow-up of women in the WHIMS-Younger (WHIMS-Y) study, who were randomized to hormone therapy through the WHI when aged 50-54 years. The WHIMS-Y study tests the hypothesis that hormone therapy around the time of the menopause may benefit cognitive function later in life. The WHIMS Suite of Studies is conducted by Wake Forest University, which is also the site for the Southeast Regional Center for WHI and leads the Aging, Cognition and Functional Status interest group for the WHI. Over the last year, we have continued to perform cognitive follow-up evaluations through telephone assessments in the original WHIMS cohort (WHIMS extension study) and in the more recently established WHIMS-Y study of women randomized to HT versus placebo when aged 50-55. We performed and published a validation study of selected cognitive measures to validate and determine the 6-month reliability of our procedures for telephone assessment. One hundred ten women, aged 65 to 90, without dementia were randomly assigned to receive two administrations of the same cognitive test battery 6 months apart in one of four combinations (Time 1 administration/Time 2 administration): telephone/telephone, telephone/face to face, face to face/telephone, face to face/face to face. The battery included tests of attention;verbal learning and memory;verbal fluency;executive function;working memory;global cognitive functioning;and self-reported measures of perceived memory problems, depressive symptoms, sleep disturbance, and health-related quality of life. Test-retest reliability, concurrent validity, relative bias associated with telephone administration, and change scores were evaluated. Time 1 scores were not statistically different across groups. There was no significant bias for tests or questionnaires administered by telephone (P's >.01), nor was there a difference in mean change scores between administration modes except for Category Fluency (P = .01) and California Verbal Learning Test long-delay free recall (P = .004). Mean test-retest coefficients for the battery were not significantly different between groups, although individual test-retest correlation coefficients were generally higher within modes than between modes. This study shows that telephone administration of cognitive tests and questionnaires to older women can be performed in a reliable and valid manner. Use of telephone batteries, along with established methods of certification and monitoring of testing procedures, can substantially reduce the cost and burden of cognitive assessments and increase enrollment, retention, and data completeness, thereby improving study validity. We also published an initial paper on the WHIMS-Y sample, detailing the rationale, design, and baseline characteristics of WHIMS-Y. WHIMS-Y enrolled enrolled 1361 women who were aged 50-55 years and postmenopausal at WHI enrollment. It examines whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. Initial results from the WHIMS-Y study were based on 1326 postmenopausal women studied with the telephone cognitive assessment battery an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years. A second administration of the cognitive battery was repeated 1 year later. Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean (95% CI) intervention effect of 0.02 (-0.08 to 0.12) standard deviation units. Similarly, no overall differences were found for any individual cognitive domain (all p greater than 0.15). Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy;however, this may be a chance finding. Our findings show that CEE-based therapies produced no overall sustained benefit or risk years later to cognitive function when administered to postmenopausal women aged 50 to 55 years. However, our study does not address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.

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National Institute on Aging (NIA)
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