HT Linked to Brain Atrophy but Not Subclinical Lesions: WHIMS-MRI

Susan Jeffrey

January 16, 2009

January 16, 2009 — Results of 2 new MRI analyses from the Women's Health Initiative Memory Study (WHIMS) show that hormone therapy (HT) is associated with increased brain atrophy, but not with subclinical cerebrovascular disease.

The findings suggest that brain atrophy, not ischemic brain lesions, may underlie the increase in dementia and decrease in global cognitive functioning with HT seen in the WHIMS study.

Laura H. Coker, PhD, from Wake Forest University, in Winston-Salem, North Carolina, took the lead on the paper looking at subclinical cerebrovascular disease, which was actually the primary analysis. The results were surprising, the authors note.

"We saw very little difference in brain-lesion volumes between women who had taken the estrogen-based hormone therapy and women who had taken placebo," Dr. Coker told Medscape Neurology & Neurosurgery.

Susan M. Resnick, PhD, from the Biomedical Research Center, National Institute on Aging, in Baltimore, Maryland, was lead author on the brain-volumes study. "Overall, women who had been randomized to receive hormone therapy had slightly smaller hippocampal and frontal volumes, both structures critical in maintaining normal memory function," Dr. Resnick told Medscape Neurology & Neurosurgery. The greatest negative effects were found among women with the lowest cognitive function at baseline, prior to the start of hormone therapy.

Both papers are published in the January 13 issue of Neurology.

Brain Lesions

WHIMS was an ancillary study to the landmark Women's Health Initiative trial that showed, contrary to previous observational evidence, that conjugated equine estrogens (CEE), alone and in combination with medroxyprogesterone acetate (MPA), increased the risk for heart disease, stroke, and breast cancer in postmenopausal women.

WHIMS looked specifically at dementia and global cognitive decline in women 65 years of age and older and found increases in both of these end points with CEE treatment, again with or without MPA.

The WHIMS-MRI study was undertaken to explore these results further, looking at potential mechanisms of the adverse effects using magnetic resonance imaging (MRI). The most likely suspect was subclinical, or "silent," strokes, the authors reasoned, since clinical stroke was also increased with hormone therapy in the main WHI trial.

A subset of 1403 women underwent MRI an average of 3 years after the trial for those in the CEE-plus-MPA trial and 1.4 years for the CEE-alone trial participants. Average follow-up during the trials themselves were 4 and 5.6 years, respectively.

The primary outcome measure of the WHIMS-MRI study was total ischemic-lesion volume, reported in the paper by Dr. Coker and colleagues. Results showed mean ischemic lesion volumes were slightly larger for the CEE-plus-MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Lesion volumes for those on CEE alone were similar to those on placebo.

"This finding was consistent within each trial and in pooled analyses across trials," the authors conclude.

Lesion volumes did correlate with age, smoking, a history of cardiovascular disease, hypertension, lower posttrial global cognition scores, and increased incident cases of mild cognitive impairment or probable dementia either during or after the trial.

Brain Volumes

In the same subset of 1403 women, Dr. Resnick and colleagues looked at total brain, ventricular-, hippocampal-, and frontal-lobe volumes, after adjustment for age, clinic site, estimated intracranial volume, and dementia risk factors.

The authors found that the covariate-adjusted mean frontal-lobe volume was 2.37 cubic cm lower among women assigned to HT compared with placebo (P = .004). Mean hippocampal volume was slightly lower, they note (0.10 cubic cm, P = .05), and the difference between groups in total brain volume approached statistical significance (P = .07). The results were similar whether women received CEE plus MPA or CEE alone.

The loss in hippocampal volume was greatest in women who had the lowest Mini-Mental State Examination scores at baseline, Dr. Resnick noted, "suggesting that the therapy may have accelerated a neurodegenerative process that had already begun."

The hormone regimens selected were the most widely used at the time these trials were begun, Dr. Resnick noted. Since then, other studies have been undertaken looking at the effects of estradiol, the natural form of the hormone, as well as the effects of treatment in women who begin hormone therapy closer to menopause.

In WHIMS, all the women were 65 years of age and older when they began HT, which may have been too late. However, Dr. Resnick noted, "it didn't really make sense to look at dementia in 50-year-olds."

Women who were 50 years at baseline were included in the overall WHI study, Dr. Resnick said. "One of the things that Dr. [Sally] Shumaker and Dr. Coker and their colleagues are going to do is go back and look at those women who were treated when they were 50 to 65 — it's 10 years later — and look at their cognitive function now.

"It's really a hypothesis, but there may be a window of opportunity such that if women are treated early you may have a different outcome than you would if you're treated later," she said.

In the meantime, Dr. Coker said, "these findings provide more evidence to help women make decisions about HT." Those 65 years of age and older should not begin HT, because the risks outweigh possible benefits, she said. However, "these findings do not inform the guidelines for newly menopausal women. The current recommendations are that HT be used only if needed to treat menopausal symptoms and be taken at the lowest dose and for the shortest time possible."

The Women's Health Initiative and the WHIMS-MRI study were funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services. WHIMS was funded in part by Wyeth Pharmaceuticals. Dr. Resnick reports no disclosures; disclosure information for coauthors appears in the paper. Dr. Coker reports no disclosures.

Neurology. 2009;72:125-134 Abstract,135-142. Abstract

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