Brain effects of menopausal HT differ for pill, patch delivery
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Early menopausal women experienced different changes in cognitive health imaging biomarkers based on route of delivery of hormone therapy vs. placebo in the Kronos Early Estrogen Prevention Study, according to a speaker.
“Effects of early menopausal HT on imaging biomarkers of cognitive health differ by the formulations and administration routes,” Kejal Kantarci, MD, MS, professor of radiology and director at Mayo Clinic Women’s Health Research Center and associate director at Mayo Clinic Alzheimer’s Disease Research Center, told Healio. “We are at the beginning of our investigation. More research is needed to determine the biological reasons behind brain changes during menopausal HT.”
Kantarci presented findings at the North American Menopause Society virtual meeting.
The Kronos Early Estrogen Prevention Study (KEEPS) enrolled 727 women aged 42 to 58 years who were within 36 months of their last menses and had no prior CVD events. The participants were enrolled from 2005 to 2009 at nine U.S. academic sites and were randomly assigned to treatment with 0.45 mg oral conjugated equine estrogen pills (Premarin, Pfizer) daily or a 50 ug transdermal 17-beta-estradiol patch (Climara, Bayer) or to placebo pills or patch. Oral micronized progesterone was given to active treatment groups 12 days each month.
Within the trial, 118 participants at the Mayo Clinic site also participated in a neuroimaging study to assess the effects of HT on imaging biomarkers of cognitive health. The women underwent MRI and cognitive testing at baseline, 18, 36 and 48 months within the KEEPS trial period. Participants also underwent MRI and cognitive test 84 months after baseline, or 3 years after the trial concluded.
HT effects on brain volume, white matter hyperintensities
Scans at 48 months showed no difference in the decline in brain volume for HT users vs. the placebo groups, whereas women who received oral HT had a greater increase in ventricular expansion vs. placebo (P = .03). However, 3 years after the trial ended, there was no difference in the rate of increase of ventricular expansion, suggesting the rate of change disappears after HT ends, Kantarci said. No change in cognitive function was found between the groups.
Researchers also analyzed aortic hemodynamics preceding hypertension in KEEPS participants who were normotensive (n = 53; mean age, 60 years). Greater increases in white matter hyperintensities were seen in the oral HT group vs. placebo (P = .03) at 84 months. Women with a greater amount of thrombogenic microvesicles in the blood had larger increases in white matter hyperintensities.
“The thrombogenic properties of estrogens, particularly the oral conjugated equine estrogen formulation, may be responsible for the accelerated increases in the white matter hyperintensities in women who were on menopausal HT,” Kantarci said during the presentation.
Prefrontal cortex, amyloid-beta deposition analysis
Analysis of the prefrontal cortex showed more volume was preserved in the group assigned patch HT vs. placebo. There was no significant difference between oral HT and placebo.
Researchers also conducted a cross-sectional study at 84 months using PET imaging to measure beta-amyloid loads in the brain. Overall, women in the transdermal estradiol group had the lowest level of amyloid-beta deposition. When beta-amyloid results were compared with prefrontal cortex volume measurements, an association was found linking lower beta-amyloid levels to greater preservation of the prefrontal cortex for the transdermal estradiol group (P < .01). There was no association found in either the placebo or oral estrogen groups.
“It is interesting that participants who took estradiol via skin patches maintained brain volume in the dorsolateral prefrontal cortex, an area of the brain that assists with memory, thinking, planning and reasoning, over the 7 years of the study,” Kantarci said. “Women who maintained volume in this area of the brain were also more likely to have a lower amount of the amyloid plaque deposits that are related to Alzheimer’s disease. This suggests that estradiol therapy may have long-term effects on the brain.”
More research is being conducted at eight KEEPS sites to further explore the risks and benefits of menopausal HT as it relates to preventing Alzheimer’s disease (n = 688, mean age, 65 years). The study is scheduled to run through 2023.
Perspective
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Pauline M. Maki, PhD
It may be that estradiol has certain advantages over conjugated equine estrogen for brain health, but this is still an open question due to the limited number of head-to-head studies. Broadly, it is difficult to reconcile the possibility of deleterious effects of conjugated equine estrogen on brain health in early postmenopausal women in light of the broader literature.
While there is strong evidence from the WHI randomized hormone therapy trial that conjugated equine estrogen combined with medroxyprogesterone aceteate increases dementia risk when initiated after age 65 years, WHI findings on younger women show no harm, and the effect of conjugated equine estrogen alone on dementia risk in older women was neutral in WHI. It is also important to recognize that the observational studies that gave rise to the hypothesis that estrogens could protect against cognitive decline and dementia were comprised almost entirely of women who used conjugated equine estrogen. Indeed, meta-analyses of those conjugated equine estrogen studies showed a reduction in Alzheimer’s disease of 29%. Notably, that effect is similar to the 26% reduced risk for death from Alzheimer’s disease reported in in 2017 among women randomized to conjugated equine estrogen in the WHI (Manson JE, et al. JAMA. 2017;doi:10.1001/jama.2017.11217). That reduction was seen after 18 years of follow-up of WHI participants. Lastly, the dosage of conjugated equine estrogen in KEEPS was 0.425 mg, which may be too low to see benefits, as the dose more commonly used in the literature was 0.625 mg.
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Kantarci K. How to KEEP sharp: The KEEPS cognition follow-up. Presented at: North American Menopause Society Annual Meeting; Sept. 28-Oct. 3, 2020 (virtual meeting).
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