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Dorsolateral prefrontal cortex volumes were preserved in early menopausal women who had used transdermal estradiol (Climara) but not oral estrogen (Premarin), according to a 7-year longitudinal study.

Women who had used a transdermal 17β-estradiol patch for 4 years as hormone-replacement therapy (HRT) in their early 50s had better preservation of dorsolateral prefrontal cortical volume compared with women on placebo 3 years later, reported Kejal Kantarci, MD, of the Mayo Clinic in Rochester, MN, and colleagues in .

"The greater preservation of the volume in that region of the brain also correlated with less amyloid deposition in the entire brain, a possible clue that menopausal HRT might have long-term beneficial effects on the brain," Kantarci told MedPage Today.

The rates of change in global brain volumes and cognitive function in recently menopausal women who used either transdermal estradiol or oral conjugated equine estrogen did not differ from placebo 3 years after HRT ended, she added.

Observational studies have indicated that estrogen may preserve neurologic function and decrease the risk of dementia if administered early in menopause. "While hormone therapies randomly administered later in women's life, after the age of 65 years, have been shown to increase risks for cognitive impairment, this is not evident when these are prescribed to younger women," said Mark Espeland, PhD, of the Wake Forest School of Medicine in Winston-Salem, NC, who was not involved in the study.

The Kronos Early Estrogen Prevention Study (KEEPS), a multicenter, randomized, double-blinded, placebo-controlled trial, showed that oral estrogen and transdermal estradiol in early menopause did not show an effect in biomarkers of cognitive function or atherosclerosis during 4 years of HRT. The ancillary MRI brain study of KEEPS participants found greater ventricular expansion in the oral estrogen group than in the placebo group and found that the trends for white matter hyperintensities increased in both treatment groups in that time.

For this study, the researchers evaluated a subset of women from the Mayo Clinic enrollment site of the ancillary study to see whether any adverse effects on brain structure continued and whether differences in cognitive function emerged 3 years after HRT stopped.

Women enrolled in the KEEPS MRI study were between 42 and 56 years old and within 5 to 36 months past their last menses. Participants had magnetic resonance imaging (MRI) examinations and cognitive testing at baseline and were randomized to receive oral conjugated equine estrogen (0.45 mg/d), transdermal 17β-estradiol patch (50 μg/d), or placebo pills or patch.

The cohort included 75 healthy women with an average age of 53. At randomization, 20 of these women had received oral estrogen, 22 had received an estradiol patch, and 33 received placebo.

During HRT, the women had MRI and cognitive tests at 18, 36, and 48 months. For this current study, MRI and the cognitive tests were repeated at 3 years after the HRT phase (7 years from randomization); 68 women also had Pittsburgh compound B (PiB) positron emission tomography scans.

At the 7-year point, the rates of change in global brain volumes and cognitive function in either treatment group did not differ from placebo. Contrary to the changes in global brain volumes, the volume of white matter hyperintensities tended to increase both during and after the end of estrogen therapy in both treatment groups. Although the magnitude of increase from baseline to month 84 was similar in the oral estrogen (mean increase 0.08cm³) and transdermal estradiol (mean increase 0.07 cm³) groups, the rate of increase in white matter hyperintensities volume was statistically significantly greater than placebo only among oral estrogen users.

Both during treatment and 3 years later, the transdermal estradiol group preserved dorsolateral prefrontal cortex volumes compared with placebo. This correlated with lower global cortical β-amyloid deposition in this group. Compared with those on placebo, women who used oral estrogen had greater ventricular volumes while being treated, but those changes stopped once treatment ended.

"The good news from this study is that the authors found no evidence that hormone therapies administered near the time of menopause had any long-term adverse effects on cognitive function," said Espeland, an investigator with the Women's Health Initiative Memory Study of Younger Women (WHIMSY), a prior trial that showed that HRT appeared to have no long-term effects on global cognitive function in early menopausal women.

While hormone therapies appear to be safe, "because of the unknown long-term consequences of the small increases in white matter disease, use of these agents should not be extended beyond the time necessary for treating menopausal symptoms," Espeland told MedPage Today.

"While our data indicates that menopausal hormonal therapy has long-term effects on the brain, the investigation of these effects is far from over," said Kantarci. More research is needed to determine the biological reasons behind brain changes during therapy and why oral estrogen and transdermal estradiol influence brain structure differently, she added: "A larger, multi-site study on KEEPS participants is on its way to answer some of these questions."

The researchers added that because KEEPS included recent menopausal women with good cardiovascular health, these results may not be generalizable to women with high cardiovascular risk or type 2 diabetes.

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