Cognitively healthy post- menopausal women who used estradiol-based hormone therapy scored higher on memory tests than women who had never received the treatment, according to a large Canadian study.
The cross-sectional analysis, published in Neurology, assessed 7,251 women from the Canadian Longitudinal Study of Aging (mean age 61; mean menopause age 51). Researchers evaluated three domains of cognition: episodic memory, prospective memory and executive function.
Compared with women who never used menopausal hormone therapy, those prescribed transdermal estradiol showed higher episodic memory scores, while women who took oral estradiol performed better on prospective memory tasks. ‘Estradiol-based menopausal hormone therapy efficacy depends on the route of administration and cognitive domain, underscoring the importance of considering menopausal hormone therapy type,’ wrote lead author Liisa Galea, PhD, of the Centre for Addiction and Mental Health in Toronto, and colleagues.
Earlier age at menopause was linked with lower performance across all three domains. Notably, neither oral nor transdermal estradiol use was associated with improved executive function. ‘However, poor episodic memory can be a predictor for later-life Alzheimer’s disease, the most common form of dementia,’ Galea cautioned. ‘Alzheimer’s disease risk is higher in older women and could be related to menopausal loss of neuroprotective sex steroids, including estradiol, the most potent estrogen.’
The findings revive long-running debates about menopausal hormone therapy’s role in brain health. ‘Around 60 percent of women going through menopausal transition complain of memory issues, but only about a quarter is thought to have objective memory impairment,’ observed Eef Hogervorst, PhD, of Loughborough University.
In the 1990s, many clinicians prescribed hormone therapy in the belief it could protect against dementia and cardiovascular disease. However, the Women’s Health Initiative Memory Study (WHIMS) later linked combined oral therapy in women over 65 to a higher dementia risk. This led to a sharp decline in use – from nearly 27 percent of US women in 1999 to under 5 percent in 2020.
Hogervorst noted that the ‘healthy cell-bias’ theory may explain these conflicting outcomes, with estrogen supporting healthy neurons in younger women but potentially accelerating damage in older women already at risk.
While causality cannot yet be confirmed, Galea and colleagues said their results provide ‘clarity to inconsistencies in the literature’ and may help guide precision medicine approaches for cognitive ageing.
