Menopause, Hormone Therapy, and the Brain

A deep dive into the 2024 Menopause Society Meeting

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There was a fantastic session at the 2024 Menopause Society meeting on menopause and brain health. Four speakers covered cognition, dementia, and depression. Here, I am going to review my takeaways from the lecture on cognition, dementia, and Alzheimer’s disease, which was presented by Dr. Pauline Maki, PhD, and Jacob van Doorn, MS. I took extensive notes, but I have since re-listened (twice) to a recording of the session to cross-check and I also pulled some of the references that were quoted. It really was a fantastic lecture.

I know many people have heard from some corners of social media that estrogen therapy is VITAL for brain health (in caps to help get the faux urgency of these social media posts across), but I think after reading this you will feel a lot less panic and maybe a little anger about that messaging. I know some of these meno-influencers bemoan the lack of data in women’s health, but it’s rather hypocritical to do that and then ignore or mangle the science that we do have to promote a message that is interpreted by many as “every woman must take estrogen urgently now for brain health.” There are plenty of good reasons to prescribe hormone therapy, and lots of excellent researchers working to understand more about menopause, hormone therapy, and the brain, so we should let this research unfold! Isn’t that what we want? High quality research? I spoke to some amazing scientists working to answer the questions that we all have, which filled me with a lot of hope.

This is a long post, so if you just want the takeaways, head to the “Conclusions” section at the end!  I’ve also included some of the relevant slides.

The 2022 Menopause Society Guidelines Hold: Menopause Hormone Therapy is NOT Indicated For Cognition or to Prevent Dementia

This was stated quite emphatically at the beginning and again towards the end of the talk. Dr. Maki was clear that people going against the guidelines…meaning those telling women that estrogen therapy is essential to prevent dementia…are operating in what she called a “data free zone.” In addition, she mentioned that shared decision making must be based on “rational evidence based scientific literature that is reliable and reproducible.” I bring this up, because shared decision making is health care professionals collaborating with their patients on evidence based treatment decisions, it’s not a “get out of jail free” card to offer non evidence based care. 

The one caveat to in the brain health discussion, which was addressed in the lecture, is premature menopause (before age 45) and surgical menopause before age 48. In these situations menopause hormone therapy is the standard of care when safe to reduce the risk of dementia. For these women hormones are recommended until the average age of menopause, age 51-52, and then at that point a decision can be made about continuing for the standard indications. 

What are the Cognitive Changes in the Menopause Transition/Menopause?

According to the American Psychological Association, “Cognition includes all forms of knowing and awareness, such as perceiving, conceiving, remembering, reasoning, judging, imagining, and problem solving.”

There is a lot of discussion about cognitive symptoms in the menopause transition and menopause (after the final period), but we must remember that are two variables here.  Menopause is occurring, and we are also aging at the same time. This means studies are essential to distinguish between effects that could be due to menopause, and those that could be because we are getting older (as in even my husband misplaces his phone and keys all the time and he is definitely not going through menopause). It’s also essential that we have longitudinal studies, where people are followed over time and both age and accurate stage of menopause are taken into consideration. And of course symptoms must be considered as well as medical conditions that could affect cognition. 

I know that many aspects of menopause are understudied, but there are at least six longitudinal studies that have evaluated cognitive changes, and two changes emerge as being consistently related to the menopause transition/early menopause: verbal learning and verbal memory. It’s also important to know that for most women these changes are reversible. Here is the slide that lists those studies, as well as the numbers of participants

There is a notable gap in the literature when it comes to ADHD, and there are some cross sectional studies that suggest a higher rate of ADHD like symptoms in the menopause transition and early menopause. Estrogen is involved in executive function, so there is a plausible connection here. There has been some work looking at the use of stimulant medications for ADHD for women experiencing these symptoms. However, there is a big asterisk here as a worsening or development of ADHD like symptoms and treatment with stimulants have not been evaluated over longitudinal studies.

Menopause Hormone Therapy and Cognition: Baseline Information

As there are some cognitive changes in the menopause transition, might they respond to menopause hormone therapy?

There are four randomized double blinded placebo controlled trials looking at MHT for cognition, and these studies have looked at different hormone regimens,

including oral and transdermal therapy, and Premarin and estradiol. The studies are COGENT, ELITE, WHIMSY, and KEEPS and there was no benefit for cognition with any of the regimens.

Someone asked at the end of the session if perhaps the duration of the studies was not long enough. They ranged from 4 months to 7 years, and Dr. Maki pointed out that when studies look at exercise and nutrition for cognition, improvement is seen as soon as two months, so these studies were certainly of long enough duration to identify cognitive changes.

There are two big caveats here. The first is that these studies were all performed on women in early menopause. If you are a purist, it’s important to acknowledge that we can’t translate this to the menopause transition in either direction, meaning this absence of data doesn’t mean hormones work or don’t work for cognition in the menopause transition. While, it might seem that the most biologically plausible extrapolation is that there is likely no difference between the late menopause transition and early menopause when it comes to hormone therapy and cognition, truthfully, we can’t be certain. The menopause transition (perimenopause) is understudied when it comes to therapies.

But the bigger caveat here is the women enrolled in these studies did not have symptoms. And while I know this might be rage inducing for some, we need to know what happens in the absence of those symptoms before we study the impact of symptoms. Research takes time, and the way the media covers medicine and the way social media posts lean into the fear of missing out creates an urgency that just can’t be matched by quality science. Many of us, myself included, bemoan that women’s health is understudied. But it’s equally important to understand that when that science does happen, even when it is moving along at what feels like a brisk pace scientifically-speaking, it still seems agonizingly slow outside of the science bubble. 

What these studies tell us is that the cognitive changes seen in early menopause that are independent of hot flashes do not respond to estrogen and so, menopause hormone therapy should not be prescribed for cognition in the absence of hot flashes. 

Cognition and Symptoms of Menopause 

What about women with hot flashes and night sweats? Intuitively, it seems like they might impact cognition. 

We know that the more hot flashes a woman has, the more likely she is to have cognitive changes, and this also matches up with what we see with brain imaging studies. With hot flashes, in the words of the neuroscientist, the hippocampus goes into “overdrive,” which can affect memory circuits. And interestingly, Dr. Maki mentioned one of her studies where women received a stellate ganglion block for hot flashes objectively measured with monitors, which is important because women under report their hot flashes, especially at night. A stellate ganglion block is nerve block, so no estrogen is involved. The nerve block reduced hot flashes by about 50%, and memory improved when hot flashes improved and the magnitude of improvement in memory correlated with the magnitude of improvement in hot flashes. 

It certainly seems based on the limited data that it’s a robust, albeit understudied hypothesis, that treating hot flashes may help with cognition/memory issues. And, based on Dr, Maki’s work, this doesn’t necessarily mean estrogen. What should we do? Well, of course we should treat women with hot flashes and night sweats, which is what we recommend anyway! While science is sorting out the biology, this finding that hot flashes may be linked to cognitive changes shouldn’t be changing anything we offer to our patients, because we already offer MHT as one potential treatment for hot flashes. And of course, if the science holds with more rigorous study that there is a cognitive benefit from treatment of the hot flashes, that may also become another reason to prescribe. 

What about the impact of sleep disturbance? This was not addressed in the lecture (look, you can only cover so much in 30 minutes), but a recent paper co-authored by Dr. Maki states the following: “Although a causal role of sleep disturbance in cognitive difficulties at menopause is yet to be established, there is robust evidence from sleep deprivation studies of a causal role of sleep disturbance in verbal learning and memory difficulties.” This comes back to the basic concept of treat people if they are suffering! And hopefully more longitudinal studies will be considering sleep.

Dementia and Brain Imaging and Hot Flashes

There was a review of some of the cross sectional brain imaging studies, which look at the impact of menopause on human brain structure, connectivity, energy metabolism, and amyloid beta deposition. These include some of the studies that have been amplified in the media and on social media that have frightened many women. Some meno-influencers have claimed these studies are proof that women’s brains will shrink and crumble without hormone therapy. It is clear from the data presented that we should not be making those conclusions. 

Much of this brain imaging data is from the studies listed on the slide below.

What you may not hear online is the limitations of these studies. This doesn’t mean the studies aren’t important, they are very important, but knowing the limitations puts them into perspective. These studies are almost all cross sectional, meaning they are a snapshot in time and so the true meaning of the findings cannot be determined. In addition, the few that are longitudinal are within stage, meaning the studies don’t follow women from pre to peri to post menopause. They just aren’t long enough to cover the entire menopause experience. Several of the studies emphasize hormonal changes and not symptoms and most have a low sample size, apparently even for neuroimaging studies. And finally, many of them are over represented with people who have the APOE4 variation, which is the biggest genetic risk for Alzheimer’s disease. We heard that these cross sectional studies could misinterpret a sex difference (meaning, for example, this is just how women’s brains are at age 47) versus a true menopause effect. The take home message: we must wait for the longitudinal data. 

Here is a slide showing some of the hypotheses which have been generated, but have yet to be validated. 

I want to focus on this point, because I have spoken at several events, and heard comments from several women who were angry that I said we shouldn’t be prescribing menopause hormone therapy for the sole purpose of prevention of dementia because according to them, “Studies shows the brain shrinks” or that, “Studies show the brain is starving for estrogen.” At this lecture we were advised that while this neuroimaging research is important, these studies are only at the stage where they have generated hypotheses that still need to be tested, and should not be used to guide clinical decisions. It’s a tragedy that the press and/or meno-influencers are twisting this important work for attention, page clicks, or who knows what. 

We did hear about ongoing work in brain imaging in menopause from the Adult Aging Brain Connectome (AABC), which seems to be designed to answer some of the questions raised by other brain imaging studies (you can read more about the study here). It was exciting to hear about a large, multi-site study that will be evaluating both women and men, and for the women there will be long term follow up from premenopause onwards. This is an exciting space, and we need to let the data unfold.

Dr. Maki discussed the ongoing MenoBrain study, which has also received a lot of press. In this study, more hot flashes were associated with more white matter hyperintensities in the brain, which some people call stroke-like lesions. There was a BIG EMPHASIS here: WE DON’T KNOW IF THIS IS CAUSAL. Meaning, are these white matter hyperintensities the direct result of hot flashes or are people with vulnerable vasculature (blood vessels) more likely to develop hot flashes? 

Women with more hot flashes are the sub group who are more likely to get dementia, and more white matter intensities are also associated with a greater risk of dementia. In addition, more hot flashes are associated with more Alzheimer’s biomarkers. Dr. Maki said that “perhaps” we are getting closer to precision medicine, and perhaps we are “getting to a hypothesis of who might benefit from menopause hormone therapy.” 

And who might that be? To quote Dr. Maki, “The very women we should be treating,” which means the women with hot flashes and night sweats.

So while science is trying to sort this out, we should continue to treat the hot flashes and night sweats! And there is no data yet to support that treating with estrogen would necessarily be superior to any other method for treating hot flashes. The only major advantage is that it is the most studied and, based on what we know, the most effective, although admittedly the other therapies are not as well studied.  

What Does the Evidence Tell Us About Dementia and Menopause Hormone Therapy? 

We must first start with randomized controlled trials, and the only one with the long term data is the Women’s Health Initiative (WHI). The initial five year data from the WHI showed that while taking Premarin alone had a neutral effect on dementia, taking Premarin plus medroxyprogesterone acetate doubled the risk of dementia for women over age 65. But after 18 years follow up, looking at the risk of dying from Alzheimer’s Disease for those who had started hormones over age 65, the effect of Premarin and medroxyprogesterone acetate was neutral and with oral Premarin along there was a 26% decreased risk of death from Alzheimer’s. What gives? This seems contradictory? 

It’s not entirely clear why the results diverge, but if we accept both to be true then a logical conclusion would be some women are more vulnerable to early negative effects from Premarin and medroxyprogesterone acetate, while for others, there may be a longer term benefit from Premarin alone. But it’s important to put these numbers in perspective, as shown in this slide below. If we look at the dementia risk for women age 65 and older, for every 436 women who are prescribed Premarin and medroxyprogesterone acetate, one will develop dementia related to the therapy. If we look at the absolute risk reduction in dying from Alzheimer’s disease from Premarin, and this 26% reduction is thrown around on social media as a reason to take estrogen (conveniently not mentioning this can only apply to one hormone regimen, oral Premarin), then 2004 women would need to take hormone therapy to prevent one death from Alzheimer’s disease. 

Also, keep in mind Premarin and medroxyprogesterone acetate is not the “go to” regimen for anyone.

But there’s more. 

There are quite a few observational studies that suggest a small risk of dementia from taking menopause hormone therapy. I’ve included the salient slide below so you can see the studies (also easier than me typing out all of the references). This was referred to as a “reliable signal in the epidemiological literature as a small risk of harm.” This is shown in data from multiple countries looking at different formulations and looking at starting the therapy early vs late in menopause. 

This does not mean women taking hormone therapy should panic that it is bad for their brains. This is observational data and the absolute risks here are low, but it does mean, we don’t know what we don’t know, and so we must be careful of what I like to call wishful extrapolation.

The final conclusion was there are far more proven effective ways to protect brain health, such as those I wrote about in this recent post. Really, there is a lot!

Conclusions

• Dr. Maki, who is on the leading edge of hormone therapy and brain health research, made a strong case showing the 2022 Menopause Hormone Therapy Guidelines from the Menopause Society still hold when it comes to cognition and dementia. Hormone therapy should not be prescribed for the purposes of cognition or prevention of dementia. She is a true expert, which is why I pay attention to what she says. 

• Menopause hormone therapy is indicated for brain health for women who go through menopause before age 45 and those who have surgical menopause before age 48. They should take hormones, if it is safe for them, until age 51-52 and then reassess their need.

• In the setting of hot flashes or night sweats, treatment may help cognition. This is an active area of research. But we already recommend treating hot flashes and night sweats, so we should continue to do this and not let women suffer while science sorts out any downstream positive effects. Treatment for hot flashes does not only mean menopause hormone therapy. 

• Hot flashes are emerging as a marker for an increased risk for dementia, but causality has yet to be determined. It is not known for sure if treatment will reduce the risk of dementia, but again, while that is being sorted out, don’t suffer! 

• While science tries to come up with precision medicine, don’t panic because we already recommend hormone therapy for treating hot flashes and night sweats. And also, don’t panic if you can’t take hormones, because it may be that treating the hot flashes is what matters, not the estrogen. 

• Try not to get worked up over brain imaging studies that are reported in the press. These are important studies, but they can’t tell us about treatment unless they are longitudinal and include treatment and placebo arms. These studies are scientifically valuable, but most of them are hypotheses generating, not treatment driving. 

• The role of estrogen therapy in dementia is far from certain, so we should let the science evolve. This is what we have wanted all along, right? Good science to guide women. Well, good science takes time. We have many fantastic people working in this space, and they are asking all the right questions.

• There are many things to do to protect brain health, so please, think beyond estrogen.

As always, the information here is not direct medical advice. If you have questions, leave them below. I try to reply to the easier ones directly in the comments (obviously, again, not individual medical advice). For those questions that are more complex, I tuck them away to incorporate them in future posts.

References

P. M. Maki & N. G. Jaff (2022) Brain fog in menopause: a health-care professional’s guide for decision-making and counseling on cognition, Climacteric, 25:6,570-578, DOI: 10.1080/13697137.2022.2122792