The method by which estradiol-based hormone therapy is delivered, either via patches or by pills, during and after menopause may be associated with differences in memory performance according researchers at the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada. Their findings, published in Neurology, the medical journal of the American Academy of Neurology, found that transdermal estradiol (E2) given with either patches or gels, was associated with better memory of words or events, known as episodic memory, while oral administration of estradiol was linked with improved prospective memory, or remembering to do things in the future.
“Hormone therapy is often considered to help manage symptoms of menopause but deciding whether to use it—and which type to use—can be a complex and personal decision,” said senior study author Liisa A. M. Galea, PhD, senior scientist at CAMH. “This study highlights that the type of estradiol therapy used may influence cognitive performance differently across various types of memory. Understanding these links could help inform more tailored approaches to maintaining brain health after menopause.”
The study data was derived from cross-sectional data contained in the Canadian Longitudinal Study of Aging, which includes 7,251 cognitively healthy postmenopausal individuals, with a mean age of 61 and average menopause onset at age 51. Cognitive performance in this study was assessed through standardized tests targeting episodic memory, prospective memory, and executive function. Participants self-reported their use of estradiol-based hormone therapy (MHT) showing that four percent used transdermal forms and two percent used oral forms.
Linear regression models controlled for age, education, and vascular risk factors. “We separately examined the associations of age at menopause and E2-based MHT with performance in three cognitive domains,” the researchers wrote. “Earlier age at menopause was significantly associated with lower scores across all cognitive domains tested.”
Examining estradiol specifically, the research team found that “transdermal E2 was associated with higher episodic memory scores…whereas oral E2 was associated with higher prospective memory scores, compared with individuals who had never taken MHT.” The effects were consistent regardless of the presence of the Alzheimer’s disease genetic risk variant APOE ε4, or the number of children the woman had conceived.
These new memory associations add to earlier work such as the Kronos Early Estrogen Prevention Study (KEEPS), which found that transdermal E2 showed no benefit on executive function or verbal memory, while suggesting it may have fewer negative structural brain effects compared with other hormone therapies. Animal studies, which often administer estradiol subcutaneously, have consistently showed positive effects on tasks managed by the hippocampus region of the brain such as episodic memory.
While the differences in memory performance based on the form of estradiol used for MHT is striking, the researchers noted that it may not be surprising. They noted that estradiol interacts differently with brain areas such as the hippocampus and frontal cortex depending on route of administration. Transdermal estradiol avoids first-pass hepatic metabolism, allowing for higher bioavailability and more stable hormone levels, which may enhance its cognitive effects.
Perhaps the most important finding from this study was that neither form of E2 therapy was associated with worse cognitive performance in any domain. “This finding is consistent with previous work showing that E2-based MHT has either positive effects or neutral effects on cognition, brain health, and disease risk,” the researchers wrote.
Clinical implications of the findings include the potential for more targeted MHT prescriptions based on individual needs and risk factors. For example, transdermal estradiol might be more appropriate for those looking to maintain their episodic memory, while oral dosing could be better suited for protecting prospective memory.
A limitation of this research is that the population of women included were mostly white and relatively affluent, which may reduce generalizability. Further, the cognitive tests were administered only in English, and thus excluded some participants.
“Because our study is cross-sectional and observational, this could lead to selection bias in MHT use and residual confounding,” the researchers wrote. “As such, we cannot establish causality between menopause age, MHT use, and cognitive outcomes, and further longitudinal and interventional studies are needed to confirm our findings and to elucidate any underlying mechanisms.”
Because of this, the researchers now plan to more precisely study the effects of hormone therapy over time, combinations of hormone therapies and to widen the diversity within the participant pool.
