Studies on brain health fall into two categories: 1.) cognition and 2.) dementia and Alzheimer’s disease.
When it comes to brain health, Pauline Maki, PhD, is an internationally recognized expert.
Menopausal hormone therapy and cognition
The impact of age and therapy type (estrogen alone or estrogen + a progestogen) on cognition in randomized controlled trials
Dr. Maki allowed us to use her slide to show the effect of menopausal hormone therapy across the age range and when estrogen is used alone and when it’s used with a progestogen.
- [TOP LEFT] The only benefit (green smiley face) is for estrogen alone in women who experience an early menopause (before age 45). Estrogen improves their cognition.
- [TOP RIGHT] In women over 65 estrogen alone does not have benefit on cognition
- [BOTTOM LEFT] In women who experience a natural menopause, estrogen and a progestogen does not have benefit.
- [BOTTOM RIGHT, left side] In women over 65, oral estradiol + vaginal progesterone showed no benefit
- [BOTTOM RIGHT, right side] In women over 65, CEE + MPA used in the Women’s Health Initiative caused harm
- This is where the black box warning for menopausal hormone therapy comes from.
“Twenty-five years ago, I thought estrogen benefited cognition and prevented Alzheimer’s disease and should be used for prevention and then I did a randomized controlled trial (COGENT) and proved myself wrong.”
_______
“And then three other groups tested estrogen on cognition (WHIMSY, KEEPS, ELITE) and came to the same conclusion. Those trials also show that estrogen has no benefit on cognition.”
— Pauline Maki, PhD
The four randomized controlled trials in younger women of menopausal hormone therapy and cognition (as noted above)
Note these are studies in women who do not have hot flashes. This answers the question: does estrogen have neuroprotective effects? The answer is no.
|
Study |
Cognitive Complaints in Early Menopause Trial |
WHI Memory |
Kronos Early Estrogen Prevention Study |
Early Versus Late Intervention Trial with Estradiol |
|
Year |
2007 | 2014 | 2015 |
2016 |
|
Citation |
Maki, 2007 |
Espeland, 2014 JAMA Intern Med |
Gleason, 2015 Plos Med. |
Henderson, 2016 |
|
Study drug(s) |
CEE/MPA |
CEE (.625 mg) or CEE/MPA (.625 mg/2.5 mg) |
E2 patch (50 mg/wk) or
CEE (0.45 mg) + |
Oral E2 |
|
# of women |
180 |
1326 | 693 |
234 |
|
Age range |
45 to 55 y |
50 to 54 y | 42 to 58 y < 36 m of FMP |
< 6 y since FMP |
|
Followed for |
4 months |
7.2 years | 4 years |
4 years |
|
Effect of estrogen |
NO |
NO
|
NO
|
NO
|
Menopausal hormone therapy and Dementia
Note that because it is so difficult to do a primary prevention study on Alzheimer’s Disease (i.e., it requires thousands of women followed for more than a decade), we do clinical trials where we study Alzheimer’s Disease-related outcomes like memory, to gain insights into MHT and risk for dementia.
A follow up to the Women’s Health Initiative 18 years later found a 26% reduced risk of dying from Alzheimer’s Disease in 29,000 women who used menopausal hormone therapy.
Dr. Maki points out,
“While this seems like a positive benefit, you’d have to treat 2004 women to save 1 woman from getting Alzheimer’s Disease — 2003 would not benefit and be taking on the associated risks.”
Observational data
In this post, about being a smart reader of research, we explained the differences between double-blind randomized controlled trials (RCTs) and observational studies. As a reminder, double-blind RCTs produce the strongest evidence, they test hypotheses and can established cause and effect. Observational studies come from real world settings and can generate hypotheses but cannot establish cause and effect.
With that said, large observational population studies of menopausal hormone therapy and dementia representing 365,000 women (in the UK, Taiwan, Finland, Denmark) have also not shown a benefit of menopausal hormone therapy. In fact, these large country studies have shown some harm in 1 in 2000 women. A small effect size but statistically significant.
Video: Dr. Maki explains the scientific research on MHT and brain health (on LinkedIn)
Click on image to play video
Dr. Maki’s work has linked vasomotor symptoms (hot flashes and night sweats) to memory decline, Alzheimer’s Disease biomarkers, tiny stroke-like lesions in the brain, and overactivity in memory circuits in the brain.
So using MHT for its primary indication (for vasomotor symptoms) may very well be beneficial.
We still do not know if…menopausal hormone therapy improves cognition in women with bothersome hot flashes and night sweats.
→ Studies have only been done in women without hot flashes and in those women menopausal hormone therapy does not help cognition.
_______
We still do not know if…menopausal hormone therapy improves cognition in perimenopause — where the intial decline in verbal memory is noticed.
→ Studies have only been done in postmenopausal women and in those women menopausal hormone therapy does not help cognition.
Learn more about brain health in my previous video discussion with Dr. Maki where we covered:
- How we know brain fog during perimenopause is real and whether we should be worried about our long-term cognitive health if this is our experience.
- The link between estrogen and cognition.
- The data that support the idea that hormone therapy is not helpful in women without hot flashes.
- What lifestyle things we can do to support our cognitive health as we age.
- The relationship between sleep and Alzheimer’s.
- The latest on what we’re learning from brain imaging studies about changes to our brains during perimenopause.
You can find the full transcript for this conversation here.
Cited studies
Randomized Controlled Studies
Maki PM, Gast MJ, Vieweg AJ, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology. 2007 Sep 25;69(13):1322-30.
Gleason CE, Dowling NM, Kara F, James TT, Salazar H, Ferrer Simo CA, Harman SM, Manson JE, Hammers DB, Naftolin FN, Pal L, Miller VM, Cedars MI, Lobo RA, Malek-Ahmadi M, Kantarci K. Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLoS Med. 2024 Nov 21;21(11):e1004435.
Henderson VW, St. John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016; 87(7):699–708.
Espeland MA, Shumaker SA, Leng I, Manson JE, Brown CM, LeBlanc ES, Vaughan L, Robinson J, Rapp SR, Goveas JS, Wactawski-Wende J, Stefanick ML, Li W, Resnick SM; WHIMSY Study Group. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med. 2013 Aug 12;173(15):1429-36. doi: 10.1001/jamainternmed.2013.7727. PMID: 23797469; PMCID: PMC3844547.
Observational Studies
Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F, Vattulainen P, Gissler M, Ylikorkala O, Mikkola TS. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019 Mar 6;364:l665.
Vinogradova Y, Dening T, Hippisley-Cox J, Taylor L, Moore M, Coupland C. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021 Sep 29;374:n2182.
Pourhadi N, Mørch LS, Holm EA, Torp-Pedersen C, Meaidi A. Menopausal hormone therapy and dementia: causal link remains uncertain rather than unlikely. BMJ. 2023 Aug 2;382:1776.
Sung YF, Tsai CT, Kuo CY, Lee JT, Chou CH, Chen YC, Chou YC, Sun CA. Use of Hormone Replacement Therapy and Risk of Dementia: A Nationwide Cohort Study. Neurology. 2022 Oct 24;99(17):e1835-e1842.
