Closer look at WHI and RCT research pinpoints cognitively neutral HT
In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.1 CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.4
Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.5 Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,6 CEE plus progesterone,6 and oral estradiol plus vaginal progesterone gel.7 The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).
What about women with VMS?
A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,8 small ischemic lesions on structural brain scans,9 and altered brain function.10 In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.11 The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.
Memory complaints common among midlife women
About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.14 Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.
Continue to: What causes cognitive difficulties during midlife?