Transdermal Estrogen Benefits Cognitive Functioning in Perimenopausal Women

While earlier observational studies suggested that hormone treatment may improve cognitive functioning in peri- and postmenopausal women, studies from the Women’s Health Initiative (WHI) demonstrated that estrogen replacement therapy started in postmenopausal women (65 years or older) did not enhance cognitive functioning, nor did it decrease the risk of dementia.

Because most of the women participating in the WHI were older, researchers hypothesized that there might be some sort of “critical window” such that hormone replacement therapy initiated near the onset of menopause may reduce future risk of developing neurodegenerative disorders and may improve cognition; however, using estrogen after this period may not have the desired effects.

Subsequent studies lent support to this study, suggesting that estrogen, while it may not enhance cognitive functioning in older, postmenopausal women, may have a protective effect on the brains of younger women. Conversely, premature estrogen deficiency – as occurs after the removal of the ovaries prior to the onset of menopause — may increase a woman’s risk of developing cognitive problems or dementia at a later age. However, studies examining the impact of estrogen on cognitive functioning have yielded mixed results.

According to data from the KEEPS study presented at the Alzheimer’s Association International Conference earlier this year, transdermal estrogen may be beneficial for sleep and cognition in younger postmenopausal women. KEEPS, the Kronos Early Estrogen Prevention Study, is a randomized, double-blind, placebo-controlled, prospective trial comparing oral conjugated equine estrogen to transdermal estradiol in women aged 42-58 years who are within 36 months of their final menstrual period.

In this study, women receiving transdermal estradiol performed better on subjective tests of memory than women receiving oral estrogen or placebo. In addition, women with transdermal estradiol experienced less cortical atrophy and were less likely to show amyloid on brain imaging. Better functioning on cognitive tests correlated with better sleep quality.

We look forward to seeing more data from the KEEPS study. Current recommendations from the US Preventive Services Task Force does not support the use of combined estrogen and progestin for the primary prevention of cognitive decline or dementia in postmenopausal women; however, the KEEPS study suggests that some women may benefit from treatment with transdermal estradiol.

Ruta Nonacs, MD PhD

HRT Started Close to Menopause Safe for Cognition (Medpage Today)

KEEPS Report (North American Menopause Study)