HRT in Early Menopause May Preserve Brain Volume

Damian McNamara

March 21, 2018

In addition to easing symptoms of menopause, estrogen replacement therapy (ERT) may also benefit the brain.

One common formulation of ERT — the transdermal patch — was associated with long-term preservation of the volume of the dorsolateral prefrontal cortex, the region primarily responsible for working memory and executive functions, researchers report.

However, working memory did not significantly differ among those taking oral hormone replacement, a transdermal patch, a placebo pill, or patch. 

"We would not expect to see the working memory problems early on because studies in Alzheimer's disease and other dementias have shown us that the imaging findings precede any cognitive changes by decades," Kejal Kantarci, MD, from the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. "So anything we see right now in these younger women is of interest."

The study was published online March 21 in Neurology.

Hidden Benefits of Transdermal Patch?

The Women's Health Initiative Memory Study (WHIMS-MRI) study (Neurology. 2009;72:135-142) and other menopausal hormone studies have shown an association between estrogen and adverse effects on the brain, particularly in terms of risk for cognitive impairment and dementia later in life, she said.

"However, other studies have shown us there may be beneficial effects if the estrogen is given at the menopausal transition. These are two contradictory findings."

Unlike the WHIMS-MRI study, which enrolled women age 65 years and older, Kantarci and colleagues assessed women earlier, during the menopausal transition.

"This is a critical period where women are losing their hormones and where supplementation could have beneficial effects on the brain," they note.

They reassessed 75 women participating in the multicenter Kronos Early Estrogen Prevention Study (KEEPS) at the Mayo Clinic site at 7 years.

KEEPS was a multicenter, double-blinded, placebo-controlled trial evaluating 727 recently menopausal women in good cardiovascular health. Participants were randomly assigned to a pill, patch, or placebo for 4 years.

A total of 20 women took 0.45 mg/d oral conjugated equine estrogen, 22 participants took 50 μg/d transdermal 17β-estradiol, and 33 others took placebo pills and placebo patches.

Participants were aged 42 to 59 years at enrollment. Women randomly assigned to ERT also took progesterone pills for the first 12 days each month to protect the endometrium.

Although KEEPS assessed any cardiovascular benefits of menopausal hormone therapy, the current study was designed to detect any structural brain changes or cognitive differences 3 years after cessation of treatment in the original trial.

Tests of working memory and MRI were performed at baseline, 18 months, 3 years, 4 years and the 7-year follow-up point. A subset of 68 participants also had β-amyloid Pittsburgh compound B–positron emission tomography (PET) to detect brain plaques related to memory loss and Alzheimer's disease.

Dorsolateral prefrontal cortex volumes were preserved in the transdermal patch group compared with the placebo group at 7 years, but not in the oral hormonal therapy group.

"That was something that surprised us," Kantarci said. "One would think that estrogens, whether they are given through one route or another, would have similar effects. So there may be a hidden benefit with the transdermal treatment."

No Implications for HRT Prescribing

Greater volume preservation in the transdermal group also was associated with lower global cortical β-amyloid deposition on PET scans. This suggests that estradiol therapy, particularly when delivered via a patch, could have long-lasting effects on the brain, the researchers note.

"We hypothesized that this estrogen effect is through estrogen receptors and the variability in amyloid load. That is something that needs to be further tested in animal models," Kantarci said. "They might both be receptor-mediated mechanisms."

However, change in whole brain volumes did not differ between the transdermal and oral hormone therapy groups at follow-up.

Interestingly, oral hormone therapy was associated with a greater rate of decline in whole brain volume each year during active treatment compared with placebo. After therapy cessation, the researchers discovered a reversal, where the rate of decline in whole brain volume was no longer significantly greater in the oral therapy group than in the placebo group.

The researchers also measured ventricular volume. In a similar fashion, the oral hormone therapy group saw greater increases in ventricular volume compared with placebo during active treatment. Again, the rate slowed after cessation of oral treatment and was not significantly different from the rate in the placebo group at 7 years.

In contrast, observed increases in white matter lesions or hyperintensities in the oral therapy group compared with the placebo group during active treatment persisted during the 3 years off therapy. Compared with the placebo group at 7 years, the increase in white matter hyperintensities was significantly different in the oral therapy (P = .03) but not the transdermal (P = .17) group.

Results showed no significant differences in global cognitive z-score change among the three groups at 7 years.

In addition, age-adjusted analysis revealed no significant associations between the change in global cognitive z-scores in the study and changes in ventricular volumes (P  = .94), whole brain volumes (P = .77), and white matter hyperintensity volumes (P = .92).

"I don't think this study should influence the treatment of postmenopausal women by physicians," said Kantarci. "Does hormone therapy have long-term effects [on the brain]? The answer is yes from what we see in this study, but the study doesn't address whether hormone therapy should be prescribed to women or not. Hormone therapy is prescribed based on women's symptoms, not to prevent cognitive changes or brain aging."

"We can't be conclusive based on the findings of this study, but it gives us encouragement. This study gives us interest in following these women even longer and looking at this in a larger cohort," she added.

Kantarci and colleagues have secured National Institutes of Health funding to conduct the next study among women who participated at all sites in KEEPS.

"We will look at their brains with imaging to see if we see the same effects in the larger cohort, and whether the effects last longer — until the women are in their mid-60s and early 70s."

"We will also see if these brain changes have any effect on working memory or executive function. Because at the end that is what matters — if the changes we see in the brain have an influence on the functioning of the women."

Commenting on the findings for Medscape Medical News, Joanne Ryan, PhD, from Murdoch's Children's in Victoria, Australia, who was not involved in the research described the study as "interesting" and noted that it supports "many of the hypotheses related to the effects of estrogen on brain health, namely that treatment should be started at menopause and transdermal therapy is more likely to be beneficial than oral treatment."

Ryan and team published a study that showed estrogen receptor genetic polymorphisms could modify risk for dementia or Alzheimer's disease (Alzheimers Dement. 2014;10:27-35).

The Kronos Longevity Research Institute and the National Institutes of Health funded the study. Dr Kantarci serves on the data safety monitoring board for Takeda Global Research & Development Center Inc, receives National Institutes of Health funding and gets research support from Avid/Eli Lilly Company.  Ryan has disclosed no relevant financial relationships.

Neurology. Published online March 21, 2018. Abstract

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