HRT and cognitive changes in perimenopause: what the research does and doesn't show

By The Krevie Team  |  Last reviewed: May 2026

The relationship between hormone therapy and cognitive function in perimenopausal and menopausal women has been studied for three decades — and the results are genuinely mixed. The original WHIMS trials found adverse cognitive effects in older postmenopausal women taking older hormone formulations. The KEEPS-Cog trial, using more recently postmenopausal women and different formulations, found neither benefit nor harm. More recent follow-up data from the KEEPS Continuation study, published in late 2024, confirmed no long-term cognitive difference between women who had taken hormone therapy and those who had not. Understanding why these studies reached different conclusions requires looking at the details: who was enrolled, what formulation was used, and when treatment began.

What hormone therapy is

Hormone therapy (HT) — sometimes referred to as HRT — is a medical treatment prescribed to address hormone changes that occur during the menopausal transition. In women, this primarily means supplementing oestrogen, and in those with an intact uterus, a progestogen is typically added to protect the uterine lining.

Oestrogen receptors are present throughout the body, including in brain tissue. This is the basis for the hypothesis that oestrogen levels influence cognitive function: the brain's oestrogen receptors are involved in neuroprotective mechanisms, and some animal models have shown oestrogen to support hippocampal function and neuronal resilience. The theory that HT might therefore protect cognition in menopausal women shaped research priorities from the 1990s onwards.

HT is a prescription-only medical treatment in the UK. Formulations, routes of administration (oral, transdermal, gel, patch), progestogen types, and doses have changed considerably since the large trials of the late 1990s and early 2000s. This is relevant when reading older trial data, since formulations tested in early studies are not identical to those most commonly prescribed today.

It is important to be clear at the outset: Krevie products are food supplements. Food supplements are not medicines, do not act on hormone receptors, and are not a substitute for medical treatment. The purpose of this article is to describe what the research says about hormone therapy and cognition — not to guide decisions about HT, which should be made with a GP.

What the research shows

WHIMS — the Women's Health Initiative Memory Study

WHIMS was the largest randomised controlled trial designed to assess the effect of hormone therapy on dementia and cognitive function. Conducted within the broader Women's Health Initiative, it enrolled women aged 65 and older and tested two regimens: conjugated equine estrogens plus medroxyprogesterone acetate (CEE+MPA), and conjugated equine estrogens alone (CEE). The combined treatment arm results were reported by Shumaker et al. (2003) in JAMA: 4,532 participants, mean follow-up approximately four years. The trial found that CEE+MPA increased the risk for probable dementia (HR 2.05, 95% CI 1.21–3.48; 45 vs 22 per 10,000 person-years; p=0.01). Alzheimer's disease was the most common dementia classification in both groups. Oestrogen-alone results, published the following year, found a hazard ratio of 1.49 (95% CI 0.83–2.66) for probable dementia — elevated but not statistically significant on its own; pooled across both trials, the overall HR was 1.76 (95% CI 1.19–2.60, p=0.005).

A comprehensive review of WHIMS findings by Coker et al. (2010) also reported that CEE+MPA was associated with lower mean brain volumes in the hippocampus (p=0.05) and frontal lobe (p=0.004) compared with placebo. These findings were widely reported and led to substantial caution around HT use for cognitive purposes in older women.

What is critical to note: WHIMS enrolled women who were, on average, at least a decade past menopause. The formulations used — particularly synthetic progestogens — are not those most commonly prescribed in current clinical practice. These design features matter greatly for interpreting the findings.

KEEPS-Cog — the Kronos Early Estrogen Prevention Study Cognitive sub-study

KEEPS-Cog was designed to address a key limitation of WHIMS: it studied women who were recently postmenopausal (within three years of their final menstrual period), not women who were already a decade past menopause. Gleason et al. (2015) published results from 693 women (mean age 52.6 years) randomised to either oral conjugated equine estrogens (o-CEE, 0.45 mg/day), transdermal estradiol (t-E2, 50 mcg/day), or placebo, for up to four years. The primary finding: hormone therapy — in either form — did not significantly alter cognitive performance on any measured domain, including verbal learning, auditory attention, working memory, or speeded language. One noteworthy secondary finding was that o-CEE produced improvements on the Profile of Mood States assessment — specifically the negative affect subscales — whereas t-E2 did not produce this effect on mood measures. No significant cognitive benefit or harm was observed in either HT group.

KEEPS Continuation — long-term follow-up, 2024

To understand whether the cognitive neutrality observed during KEEPS persisted over time, the KEEPS Continuation study re-evaluated participants approximately ten years after the original trial. Gleason et al. (2024), published in PLOS Medicine, analysed data from 275 participants. The finding remained consistent: women previously randomised to hormone therapy performed similarly on all cognitive measures to those previously randomised to placebo, approximately a decade after treatment ended. The strongest predictor of later cognitive performance was baseline cognition and cognitive trajectory during the original KEEPS trial — not HT assignment.

The critical window hypothesis

One framework that has emerged from this body of conflicting evidence is the "critical window" or timing hypothesis: that the cognitive effects of hormone therapy depend substantially on when treatment is initiated relative to menopause. The hypothesis, reviewed in detail by Sherwin and Henry (published in Menopause), suggests that HT initiated close to the onset of menopause operates on a neurologically responsive brain, whereas HT initiated well after menopause — as in WHIMS — encounters different tissue conditions. This may explain the discrepancy between WHIMS (older women, adverse effects) and observational studies showing cognitive associations with HT use in younger women. It also explains why KEEPS-Cog (recently postmenopausal women) found neither benefit nor harm: the window may have already largely closed by the point of randomisation, or the doses used were insufficient to detect an effect.

This framework remains debated in the literature. No randomised trial has yet definitively tested whether HT initiated at the precise onset of perimenopausal transition confers cognitive protection — the logistical challenges of such a trial are considerable.

A different pathway: cellular energy metabolism

Separate from the HT literature, there is a growing body of research on whether supporting cellular energy metabolism can influence cognitive performance in perimenopausal and menopausal women. This pathway is entirely distinct from hormonal mechanisms.

Oestrogen has a known role in supporting brain energy metabolism — it promotes glucose uptake and mitochondrial function in neural tissue. As oestrogen levels decline during the menopausal transition, some researchers have proposed that this creates a relative energy deficit in brain tissue, and that nutrients supporting cellular ATP production — particularly creatine — may be relevant.

The CONCRET-MENOPA trial (Forbes, Korovljev, Ostojic et al., 2025), published in the Journal of the American Nutrition Association, tested this directly. In a randomised, double-blind trial of 36 perimenopausal and menopausal women (mean age 50.1 ± 5.7 years), medium-dose creatine hydrochloride (1,500 mg/day) was superior to placebo in improving reaction time (6.6% vs 1.2%, p<0.01) and increasing frontal brain creatine levels (16.4% vs 0.9%, p<0.01). This mechanism — creatine replenishing phosphocreatine stores to support ATP regeneration in neural tissue — operates independently of oestrogen receptors or any hormonal pathway.

This is not a comparison between creatine supplementation and HT. They act through entirely different mechanisms and measure different outcomes. The CONCRET-MENOPA trial measured reaction time and brain creatine concentrations; HT trials measure dementia incidence and cognitive domain scores. These are different questions.

Frequently asked questions

Further reading

• Taking creatine alongside HRT: what the research says about combining them — how two different mechanisms can be used in parallel
• Creatine HCl vs creatine monohydrate: why the form matters for women over 40 — the specifics of the CONCRET-MENOPA trial and what was tested
• What nutrients does the research actually link to cognitive changes in perimenopause? — an overview of the ingredients studied for cognitive health in midlife women

Krevie and this research area

If you are considering hormone therapy or discussing your options with a GP, that conversation should happen with your healthcare provider. Krevie is a food supplement and has no role in that decision.

For those interested in food-based support for cognitive ingredients studied in the research literature, The Foundation contains citicoline (CDP-choline) (500 mg), pine bark (200 mg), and saffron extract (28 mg) — each dosed to their primary published trial. The Krevie Routine combines The Foundation with Creatine Companion, which provides creatine HCl at 1,500 mg per day — the dose used in CONCRET-MENOPA. Both are food supplements, used alongside whatever medical pathway is right for you.

References

1. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study. JAMA. 2003;289(20):2651–2662. PubMed 12771112
2. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. JAMA. 2004;291(24):2947–2958. PubMed 15213206
3. Coker LH, Espeland MA, Rapp SR, et al. Postmenopausal hormone therapy and cognitive outcomes: the Women's Health Initiative Memory Study (WHIMS). J Steroid Biochem Mol Biol. 2010;118(4–5):304–310. PubMed 19932751
4. Gleason CE, Dowling NM, Wharton W, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015;12(6):e1001833. PubMed 26035291
5. Gleason CE, Dowling NM, Wharton W, et al. Long-term cognitive effects of menopausal hormone therapy: KEEPS Continuation study. PLOS Med. 2024;21(11):e1004458. PubMed 39570992
6. Forbes SC, Korovljev D, Ostojic J, et al. The Effects of 8-Week Creatine Hydrochloride and Creatine Ethyl Ester Supplementation on Cognition, Clinical Outcomes, and Brain Creatine Levels in Perimenopausal and Menopausal Women (CONCRET-MENOPA). J Am Nutr Assoc. 2026;45(3):199–210. PubMed 40854087