MHT Use Can Affect Cognitive Health Depending on Administration Method

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Menopausal hormone therapy (MHT) may have different effects on postmenopausal women depending on the route of administration and the cognitive domain tested, report investigators at The Menopause Society’s 2025 Annual Meeting. The investigators emphasized that these study results help clarify mixed literature on MHT, serving as a source to inform emerging therapeutic approaches for cognitive aging among women post-menopause.¹

Further, estradiol (E2), the most potent estrogen, has the greatest binding affinity for estrogen receptors (ER), whereas estrone (E1) has significantly lower binding affinity. Oral E2 is largely converted to E1 through first-pass metabolism, and conversely, transdermal E2 largely avoids this conversion, resulting in higher circulating E2. Because they rely on different brain regions, the cognitive domains of executive functions and episodic memory may be differentially sensitive to MHT.¹

Previous research, such as a 2013 trial (NCT01124773) published in JAMA Internal Medicine, found that conjugated equine estrogen (CEE)-based hormone therapies administered to postmenopausal women aged 50 to 55 years had no overall sustained benefit or risk to cognitive function. Specifically, the global cognitive function scores from those receiving CEE-based therapies were similar to those receiving placebo (P = .66), with no notable differences for any individual cognitive domain, such as verbal memory, attention, executive function, verbal fluency, and working memory (P > .15). These authors observed that CEE-based therapies may have adversely influenced verbal fluency in women who had a prior hysterectomy or hormone therapy use; however, the finding may have been unrelated.^2,3

Because menopause represents a key transition point in the aging trajectory and there are mixed reports on MHT’s influence on aging, these study investigators conducted their investigation to explain and clarify the associations of MHT and cognitive health in postmenopausal women. The objective was to examine how E2- and E1-based MHT and certain administration routes affect certain cognitive domains. Baseline data in 4776 mostly healthy postmenopausal women from the Canadian Longitudinal Study of Aging were enrolled to understand the influence of E2- and E1-based MHT on performance in 3 cognitive domains: episodic memory, prospective memory, and executive functions.¹

The data show that transdermally administered E2 was associated with higher episodic memory scores (p = .0077, Cohen d = .193), whereas orally administered E2 and transdermal E1 were associated with higher prospective memory scores (E2: p = .0413, Cohen d = 0.212; E1: p = .0413, Cohen d = .306) compared with those who did not receive MHT. Additionally, it was found that neither MHT formulation nor route of administration impacted the executive functions composite. Using a combination of multiple estrogens—such as oral E2 with vaginal E1—or progestogens alone was not associated with cognitive benefits compared to those who never used MHT.¹

These findings emphasize the different effects that E2- and E1-based MHT may have on postmenopausal women depending on the route of administration and cognitive domain tested. Notably, the investigators wrote that their findings may reflect dose-dependent effects of estrogens, with episodic memory potentially benefiting from greater ER activation than prospective memory.¹

REFERENCES

1. Gravelsins L, Puri TA, Alexander MW, et al. S-11 – One Size Does Not Fit All: Menopause Hormone Therapy Type and Route of Administration Influences Cognitive Health. Presented at: The Menopause Society Annual Meeting; Orlando, Florida. October 21–25, 2025.

2. Espeland MA, Shumaker SA, Leng I, et al. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med. 2013;173(15):1429-1436. doi:10.1001/jamainternmed.2013.7727

3. Memory Study of Youngest Women Enrolled in the Women's Health Initiative Hormone Therapy (HT) Arm (WHIMS-Y). ClinicalTrials.gov identifier: NCT01124773. Updated November 6, 2017. Accessed October 20, 20