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 will test 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. Publications over the last year include investigations of long-term effects of assignment to CEE-based therapies on cognitive function, associations between late-life depressive symptoms and regional brain volumes, and associations between weight change and cognitive change. CEE-based hormone therapy was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the randomized clinical trial, which largely persisted through up to 4 years after the trial. The strongest statistical evidence was for global cognitive function. For domain-specific scores, the mean decrements were slightly smaller and were less significant;these decrements tended to be larger for CEE-alone compared to CEE+MPA. CEE-based therapies, when initiated after the age of 65, produce a small broad-based decrement in cognitive function that persists after their use is stopped, but the differences in cognitive function are small and would not be detectable or have clinical significance for an individual woman. In a second investigation, WHIMS investigators showed that depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. Moreover, elevated depressive symptoms were associated with smaller volumes in certain frontal lobe subregions but not in the medial temporal lobe structures, suggesting the importance of frontal lobe brain structures in late-life depressive symptoms in women. In a third investigation of 2283 older postmenopausal WHI women, we found a lack of associations between weight and cognition in women who remained stable or gained weight. However, weight loss (p <0.05), most likely signaling incipient disease, was associated with lower cognition. Cognition was not related to changes in waist circumference.
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