Does menopausal hormone therapy affect long-term cognitive function?

Menopausal hormone therapy (HT) contains estrogen (often combined with progesterone) and is used for the treatment of menopausal symptoms such as hot flushes and night sweats. We discussed previously the history and research on HT and their conflicting findings on how HT relates to brain health and dementia risk. Despite the alarming findings from the Women’s Health Initiative Memory Study a few decades ago that found menopausal HT increased risk of cognitive impairment and dementia [1], subsequent carefully designed clinical trials have found that HT initiated close to the onset of menopause presented no cognitive risk [2; 3]. However, little is known about the long-term effects of HT on cognitive function. A follow-up study of a randomized clinical trial addressed this question and reported that there were no long-term cognitive effects of HT when HT was started in early menopause [4].

Findings come from the Kronos Early Estrogen Prevention Study (KEEPS) Continuation Study [4], which was a 14-year follow-up of the original KEEPS [2]. The original KEEPS was a randomized placebo-controlled clinical trial that enrolled 727 women who were within three years of menopause and had good cardiovascular heath (average age of 52.6 years at the start of the study). Participants were randomized to either oral synthetic estrogen (conjugated equine estrogens), transdermal bioidentical estrogen (17β-estradiol), or placebo, combined with progesterone (Prometrium, capsule taken orally daily for 12 days at the beginning of each month). The intervention lasted for four years. At the end of the intervention, cognitive functions were not different in women who received either form of HT compared to those who received placebo.

In the KEEPS Continuation Study, 299 participants from the original KEEPS were re-evaluated approximately ten years after the end of the HT/placebo intervention. Cognitive assessments from the original KEEPS were repeated for the KEEPS Continuation Study, including a battery of eleven cognitive tests that measured verbal learning and memory, auditory attention, working memory, visual attention, executive function, speeded language, and mental flexibility. Ten years after the end of the intervention, women who received either form of HT did not experience better or worse cognitive outcomes compared to those who received placebo [4]. These findings offer reassurance to women who are struggling with menopausal symptoms and are considering HT. The data suggest no negative long-term effects of HT on cognition in women with good cardiovascular health who initiate HT close to the onset of menopause. 

Data from the KEEPS studies are consistent with a large meta-analysis of over 30 randomized controlled trials that reported that menopausal HT had no overall effects on cognitive scores except some improvement observed in women who had undergone surgical menopause (i.e., removal of ovaries before natural menopause) [5]. Data from observational studies are mixed and conflicting, with some studies suggesting HT use is associated with higher risk of dementia and others showing an association with lower risk of dementia [6; 7; 8]. It is important to note that observational studies are designed to evaluate associations, not causation.

The decision on whether or not to take HT should be made carefully with your healthcare provider to maximize benefits (relief from menopausal symptoms) while minimizing risks. HT does come with risks, such as small increased risks of venous thromboembolism, stroke, coronary heart disease, and breast cancer [9]. There is a greater benefit-to-risk ratio of HT for women younger than 60 years old who are within ten years of menopause onset who have no contraindications (e.g., liver disease, prior estrogen-sensitive cancer, prior coronary heart disease, stroke, myocardial infarction, or venous thromboembolism). Risks of HT side effects depend on the type, dose, formulation, route, timing of initiation, and duration of treatment. Once you start using HT, continued discussions with your healthcare provider are recommended so you can periodically reevaluate the benefits and risks of continuing or discontinuing HT.

1. Shumaker SA, Legault C, Rapp SR et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA  289, 2651-2662.
2. Gleason CE, Dowling NM, Wharton W et al. (2015) Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med  12, e1001833; discussion e1001833.
3. Henderson VW, St John JA, Hodis HN et al. (2016) Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology  87, 699-708.
4. Gleason CE, Dowling NM, Kara F et al. (2024) Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLoS Med  21, e1004435.
5. Andy C, Nerattini M, Jett S et al. (2024) Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition. Frontiers in endocrinology  15, 1350318.
6. Imtiaz B, Tuppurainen M, Rikkonen T et al. (2017) Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology.
7. Pourhadi N, Morch LS, Holm EA et al. (2023) Menopausal hormone therapy and dementia: nationwide, nested case-control study. BMJ  381, e072770.
8. Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F et al. (2019) Use of postmenopausal hormone therapy and risk of Alzheimer's disease in Finland: nationwide case-control study. BMJ  364, l665.
9. The Hormone Therapy Position Statement of The North American Menopause Society" Advisory P (2022) The 2022 hormone therapy position statement of The North American Menopause Society. Menopause  29, 767-794.

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