Transdermal estradiol-2 (E2) hormone therapy was associated with significantly better episodic memory in postmenopausal women than no hormone therapy, while oral ET was associated with significantly better prospective memory performance, a new study suggested.

Neither delivery method of E2 — the most potent estrogen — was linked to differences in executive function performance.

Investigators also found that earlier age at menopause onset was linked to worse memory and executive function performance.

“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,” study author Liisa A.M. Galea, PhD, of the Centre for Addiction and Mental Health in Toronto, Ontario, Canada, said in a news release.

The study was published online on August 27 in Neurology.

Delivery Method Matters

Researchers analyzed data on 7251 cognitively healthy participants (mean age at baseline, 60.5 years) enrolled in the Canadian Longitudinal Study of Aging. The average age at menopause onset was 51 years. Overall, 4% used transdermal E2 therapy, 2% took the pill form, and the remaining 94% never took hormone therapy.

Women taking only E2 or E2 and progesterone/progestin were included in the E2 group. Transdermal delivery included gels and vaginal MHT. Investigators controlled for age, years of education, and vascular risk to account for significant differences among the groups.

Earlier onset of menopause was significantly associated with reduced episodic memory, reduced prospective memory, and reduced executive function (P < .001 for all). The association with reduced executive function was significantly stronger in carriers of the APOE e4 allele than in noncarriers (P = .011) and individuals with four or more children (P < .001).

Higher scores for episodic memory, such as recalling past events, were observed among women taking transdermal E2 than among those who never used MHT (P = .007).

The researchers speculated that this formulation, unlike oral E2, bypasses first-pass hepatic metabolism and leads to higher, more stable concentrations of E2.

Higher scores for prospective memory, such as remembering an appointment or to take a medication, were observed among women taking oral E2 than among those who never took MHT (P = .015). The authors hypothesized that a lower dose of E2 could be necessary to improve prospective memory.

“While we cannot say hormone therapy causes these effects, it adds to the conversation about how best to support brain health after menopause,” Galea said.

The cohort primarily had White individuals with higher incomes, and the findings may not be generalizable to other populations. In addition, the study data did not allow analysis of how hormone therapy dosage, duration, or timing might influence cognition.

Some Caveats

The question about the potential cognitive benefit of menopausal hormone therapy (MHT) is the subject of long-standing debate, Eva Hogervorst, PhD, professor of psychology, School of Sports Exercise and Health Sciences, Loughborough University, Loughborough, England, noted in an accompanying editorial.

While the study’s findings about the type of E2 administration are important, “The small numbers of MHT users should perhaps caution overinterpretation of these differential results,” Hogervorst wrote.

These findings stand in contrast to longer-term randomized controlled trials like the Kronos Early Estrogen Prevention Study and the Early vs Late Intervention Trial, Hogervorst pointed out. In these trials, no significant effect of MHT on cognition was observed up to 4 or 5 years later.

In addition, the current study included only healthy women. How the therapy might influence cognition for women in poor health, women who underwent early or premature (surgical) menopause, or women of different ethnicities, remains unclear, Hogervorst wrote.

The study was independently supported. The authors of the study and the editorial reported having no relevant financial relationships.