Conference Coverage

Transdermal estradiol may modulate the relationship between sleep, cognition



– Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

A sleeping woman JackF/

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.

Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

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