Dr. Pauline Maki discusses current research on brain fog

Whole Transcript

Nina Coslov:

Today we continue our series of interviews with experts. I am thrilled to have Dr. Pauline Maki with us and we’ll be discussing, clarifying what the research says about brain fog during perimenopause. And Dr. Maki, I’ll let you introduce yourself and then we’ll jump in.

Dr. Pauline Maki:

Thanks, Nina. Such a pleasure to be with you. Hi, everyone. I’m Pauline Maki. I’m a professor of psychiatry, psychology and obstetrics and gynecology at the University of Illinois at Chicago. And I’m also a past president of the North American Menopause Society, and I’m on the board of trustees of the International Menopause Society.

Nina Coslov:

Thank you so much. So, let’s start with some definitions. Let’s start with brain fog, and I will just kind of throw out there, I kind of think of brain fog in two buckets. The first being forgetfulness, and that can be names, where you put your keys, why you came into a room, a word you know, a fact. And then, the second, and the way I hear it from women is, “Not feeling as sharp as I used to.” And I think that’s related to difficulty concentrating, difficulty making decisions. Anything that you would add to either of those buckets or introduce a third?

Dr. Pauline Maki:

Nina, I think those are very good. In our International Menopause Society paper, Dr. Nicole Jaff and I developed a definition because there wasn’t really an agreed-upon one. And we took that as an opportunity to kind of review the literature and come up with one. And basically, we referred to it as the constellation of symptoms that women experience when they say that subjectively their brains are changing, that they’re not functioning the way that they used to, usually in a way that’s not as pleasant, really. They’re not saying their brains are functioning as well. And we can talk a bit about the research that backs this up, but you’re exactly right to focus in on memory and attention because those are the domains that the literature really does back up for some women, certainly not for all.

Nina Coslov (02:20):

Yeah. And then, the second thing I want to just note is the timeframe. I’m going to use the word perimenopause. Menopause and perimenopause get used interchangeably, but we’re talking today mostly about the time leading up to the final menstrual period. And I’ll just remind everyone because this is very confusing, that menopause is one day in time, it is your final menstrual period. You don’t know that until 12 months later when you’ve not had another period. So, it’s a kind of look back definition. And then, after that point you are postmenopausal. And the reason that I bring this up before Dr. Maki and I start into the questions is the physiology, which is just really a word for what is happening in our bodies with our hormones during those two times, perimenopause and menopause is different. And that’s an important distinction, I think, that a lot of people miss. So, today we’re talking about perimenopause. If we merge into menopause, we will note that.

And then, the last thing I’ll say, which I think will probably come up is, I think it’s really important as we listen to people talking about perimenopause and what’s known and not known as the research, that this is a pretty nascent field. It was only in the 1990s that there really became a focus on midlife women’s health research. So, Dr. Maki and others are working really quickly and we’re trying at Women Living Better to do a little bit of our part to fill this research gap. But there is still a lot that’s not known. And so, if you’re listening to someone and they have all the answers and they have a whole bunch of certainty around anything, I think that is a red flag. I don’t know if you agree.

Dr. Pauline Maki (03:53):

I agree with you.

Nina Coslov (03:54):

Yeah. There’s more and more certainty out there, which makes me more nervous. Anyway. Okay. So, my first question is, is brain fog during perimenopause normal? And just as a slight follow-on, how do we know how it’s related to the changing hormonal patterns? And should we be worried about it if this is has been our experience?

Dr. Pauline Maki (04:17):

Those are really important questions to women and to the field of science. So, maybe we can start with how we know what we know. So, I think this is a question women should be asking when people are making claims that there are certain normative experiences in the menopause, how do they know? And is it all women? And the fact that you’re a woman, does that mean that this is real for you? Because if people are saying that, I think it’s not true. So, how do we know? Well, if you want to know how common something is, you need a large representative sample of individuals in that particular state. So, here we’re talking about the perimenopause. The first clue that there was something about forgetfulness that seemed quite real, probably came from work by Mitchell and Woods, where they did really intensive qualitative research and some quantitative research of women who were in the transition.

And they asked them, “What are you experiencing?” And 60% of those women said that they were experiencing a change in their ability to remember, that was unpleasant. So, 60%. So, 40% of women were not saying this. Then the Study of Women’s Health Across the Nation did a very large cross-sectional look, meaning that they just took women between the ages of 40 and 55 and said, “How many of you are saying that you’re forgetful? And does the frequency with which women say they’re forgetful depend on whether they’re in the perimenopause or the postmenopause?” And they even broke it down further to say that, “Does it matter if your cycles are just changing now to become less regular, versus whether they’re being skipped?” And that study found that about 40% of women were saying that they were in fact forgetful, and that the frequency with which they were complaining of this did depend on where they were in the transition.

So, that was cross-sectional, right? So, that provides some initial insight into maybe there’s something real here. Women and men are surprisingly not all that good at telling you whether or not their memory is as good as they think it is, generally. However, turns out that women in the menopause transition are in fact quite good at telling you, when they say, “My memory’s not particularly good,” when you give them neuropsychological tests where we can measure how well they’re performing relative to other people, because the tests have been normed on large samples of people, midlife women are good at telling you how good or bad their memory is. They have very good insights into what’s happening in their bodies, actually compared to other groups of individuals, which I think women should be given credit for, they’re not hypochondriacal complaining little women, they have a pretty good idea of what’s happening.

That being said, if our mood is low, we can overestimate the magnitude of our cognitive problems. So, we need to be aware of that too. So, the Study of Women’s Health Across the Nation gave a very simple memory test to large numbers of women who varied in terms of where they were in the pre, peri, or postmenopause. And they found evidence that something was changing in the perimenopause, and importantly, they found that in the postmenopause, it seemed to resolve. Okay, now let’s think about that for a second. We’re hearing from other corners that something happens in the perimenopause, and then women are on this trajectory of change, which is negative. So, the largest study of women suggests that that’s not the case. But they had a pretty simple memory measure. My current take on it based on six prospective studies, where they followed women longitudinally from the time those women were premenopausal up to the postmenopause, is that indeed there is a reliable change in women’s cognitive function when you give them tests where they need to learn and remember verbal material.

So, that’s what we’re doing right now, right? I’m giving you information verbally, if you’re at all interested in it, you should be interested in what Nina’s asking, you want to learn and remember this. So, learning this material means that you have to pay attention to what we’re discussing right now. And then, when you’re having a glass of wine or a cup of coffee with your girlfriends or friends later on, you want to remember it because you want to make sure that you get it right when you talk about this stuff. So, it’s a very important everyday functioning. It’s actually a cognitive ability, Nina, that we, because we’re born female, perform better on lifelong than our friends who are born male. So, there’s a sex difference here.

And that sex difference is known to be driven in part by circulating levels of estradiol in particular, because if you remove the ovaries, getting to your question about, is this an estrogen effect, performance on that cognitive ability decreases, and the causal role of estrogen is supported by the fact that if women are randomized to receive estrogen immediately after their ovaries are removed, they maintain their verbal memory performance, which is different from women who are not given estrogen. This is premenopausal. That suggests a causal role.

The second causal role is shown when you pharmacologically, meaning you give somebody a drug and it suppresses their estrogen, if you randomize them back to estrogen, they do not experience that decline in verbal memory, but they do if they’re not given estrogen back when they’re premenopausal. So, that suggests a causal role for estrogen in this cognitive ability where there is a sex difference.

So, then the question is, and this is where all the misinformation is, the question then is, oh, okay. So, their estrogen levels are declining in menopause and they’re never going to get their memory back. And that’s not true. The brain is plastic, the brain compensates, the brain adapts, and it adapts in the postmenopause. There are some data to suggest that we know the biology of this, which is the brain normally says, okay, this stuff in our left hemisphere that helps us to learn and remember, you have to call on your right hemisphere now, and you need your right hippocampus to do the same thing.

But if you do that, your brain will do well. And that’s this kind of compensatory hypothesis. We know this must be true because if menopause caused dementia in women, wouldn’t all women dement? Wouldn’t they all dement, and 20% of women will go on to develop dementia, and more women will develop dementia than men, in large part because they live longer, and also due to other factors. But it’s not the majority of women who develop dementia.

Nina Coslov (11:57):

So, a great follow-on to that, which it is around, it’s tempting to hear what you’re saying about women who have their ovaries removed early and the cognitive decline kind of sets in, and that are given estrogen rebound, that the question then is, should all women think about estrogen if they’re experiencing brain fog?

Dr. Pauline Maki (12:23):

Only women who go through menopause early should think reflexively about whether they should go on estrogen, and here’s why. Nina, I in my youth, because I’ve been in this field since I was 26. So, I have been studying estrogen, menopause and cognition for a very, very long time. I used to be a believer, I used to think, oh, women should go on hormone therapy to prevent Alzheimer’s disease, like all women should. And I’ve completely changed my mind about that. I do think there’s a certain group of women who benefit, and I think it’s women who have persistent hot flashes.

And that’s because me and my good colleague Rebecca Thurston, have shown that there’s this association. We don’t know if it’s causal between hot flashes and white matter hyperintensities. And then, prior to my work with Dr. Thurston, I did a study with my colleagues at Northwestern showing that if you treat moderate to severe hot flashes with a non-hormonal intervention, so suggesting it doesn’t have to be estrogen, but if you treat the hot flashes, memory bounces back. And it was a proof of concept, randomized trial, was something called stellate ganglion blockade. But the point of the study was that hot flashes were associated with memory problems, and if you treated the hot flashes, memory improved in relation to the magnitude of improvement in the hot flashes. So, this suggests a personalized approach for who might benefit from treatment. Doesn’t necessarily have to be estrogen, though estrogen is really good at taking away hot flashes.

It could be any one of the non-hormonal intervention with a significant effect size. And this might be very relevant, especially for black women and brown women whose hot flashes go untreated and who experience hot flashes well into their 60s on average. And that’s the point at which we really need to make sure that we’re optimizing our brain health, we need to sleep better, and we can’t sleep well if we’re being woken up with hot flashes. So, our work suggests that there’s this nexus of vasomotor symptoms in sleep that needs to be addressed in a certain subset of women.

Nina Coslov (14:51):

So, just to clarify, estrogen, there have been many studies on the use of menopause hormone therapy, also called hormone therapy, and what we’re talking about is estrogen and then progestin or progestogen, if you have a uterus, is indicated or approved by the FDA for vasomotor symptoms.

Dr. Pauline Maki (15:10):

That’s right.

Nina Coslov (15:10):

And there have been many studies on that. So, if you have vasomotor symptoms, there is also a benefit to cognition. But the absence of vasomotor symptoms, unless you enter menopause or you stop ovulating for a surgical reason or otherwise, before the age of 40, it is not indicated for a general cognitive boost.

Dr. Pauline Maki (15:32):

Right, So, Nina, what we need to talk about is, why would we think that it’s not beneficial in women without hot flashes? So, how do we know what we know? So, if hormone therapy generally is good for memory, then we should be able to give it to women without hot flashes and see a boost to memory. Right? We should. That should be your test. So, I did the first large scale clinical trial of this many years ago in 2007, and found no benefit to memory after four months in 183 women who were randomized to receive either hormone therapy or placebo. That was the first hint that in the natural postmenopause, it’s not doing much to the brain. Maybe surprise, surprise. The Women’s Health Initiative cognitive aging study found no signal for hormone therapy improving memory. Then people were like, “Well, maybe it’s because it’s older women.” So, then Mark Espeland published a study called WHIMSY, looking at women aged 50 to 54 in the WHI found no signal for a benefit to memory. Oh, so maybe it’s just because it was conjugated equine estrogen and medroxyprogesterone acetate.

(16:59):

Well, so then the KEEPS study came on and they had a head-to-head comparison of conjugated equine estrogen and hydroxyprogesterone… or conjugated equine estrogen versus estradiol, they used micronized progesterone. There was no hint for either estradiol or conjugated equine estrogen. And then, the ELITE study came on and they used estradiol and they found no benefit, regardless of whether you were older or younger. So, every one of these hypotheses that we didn’t see it because so far has failed. That being said, the one, “it failed because…” that I promote, which is “it failed because…” they didn’t screen-in women with moderate to severe hot flashes. That study hasn’t been done. I think we’re going to be doing it in the fall.

Nina Coslov (17:48):

Fantastic.

Dr. Pauline Maki (17:49):

That study hasn’t been done.

Nina Coslov (17:51):

And this was all postmenopausal women, right?

Dr. Pauline Maki (17:53):

This is all postmenopausal women.

Nina Coslov (17:57):

But just to our point about research gaps, there has not been a study in premenopausal women, just again, to kind of highlight what’s known and not known.

Dr. Pauline Maki (18:05):

There’s been no study. So, there’s been small randomized trials in women with acute onset of menopause in the premenopause, right? So, surgical removal of the ovaries, those studies do suggest that estrogen’s probably important, at least until the typical age of menopause. But we recommend that for women anyway, for their bones, but only in that setting. So, medical societies do suggest that. But now it’s like I’m 30 again and everybody’s saying, “Oh, every woman should go on estrogen again.” But if it worked, then those trials in the postmenopause should have found benefit to memory. And those were big studies funded by the National Institutes of Health. They showed no signals. So, it’s not just that. We have to ask ourselves, is there harm?

We have some pretty big studies out of the United Kingdom, out of Finland and out of Taiwan recently that show us small, probably not relevant at an individual level because it’s so small, 1.1, 1.2 hazard ratio, increased risk of dementia, but they’re not showing a lowered risk of dementia.

Nina Coslov (19:29):

Right, right.

Dr. Pauline Maki (19:30):

And there’s one study that did show a lowered risk of dementia with all formulations, for all women. And we know that’s not true because the Women’s Health Initiative showed that conjugated equine estrogen and hydroxyprogesterone acetate increased the risk. So, is there a group of women for whom hormone therapy might be indicated? Again, I think it’s the women who have hot flashes, and that’s the women who have the indication. And there, I think there could very well be a benefit to the brain, mediated in part because women with hot flashes are chronically sleep-deprived and sleep deprivation is a very, very bad thing for the brain. And don’t we already know that sleep deprivation makes us foggy?

Nina Coslov (20:18):

Yes. Can’t think straight.

Dr. Pauline Maki (20:21):

Can’t think straight.

Nina Coslov (20:23):

Right. So, that’s a great segue into, I wanted to tackle this, the pharmacological or the hormone therapy thing first because I feel like it’s so loud out there right now. But what I always am more hopeful about is, what does the research say about the things that we can do to non-pharmacologically, lifestyle and otherwise, to support our cognitive health as we age?

Dr. Pauline Maki (20:49):

And here we have signals in the randomized trial data. So, we do know what benefits memory. If we’re sedentary, we can’t keep that up. Do we need to run marathons? Do we need to go to the gym in cute little outfits, do that stereotypical thing? No, we just need to

Nina Coslov (21:09):

Good. I don’t have any.

Dr. Pauline Maki (21:09):

… do brisk walking. I used to, I’m too old now. Now they’re all kind of old and ratty, but I still put them on. So, we need to walk briskly, often. We need to get our heart rate up, preferably, we do this outside. The data actually shows that. And preferably, we do this with friends.

Nina Coslov (21:28):

And when you say often.

Dr. Pauline Maki (21:37):

150 minutes.

Nina Coslov (21:38):

Yeah, okay. 150, brisk.

Dr. Pauline Maki (21:41):

It appears that we can break it up during the day. We don’t want to give women another thing to do. So, go up the stairs, park far away in the parking lot, do that kind of thing. What about diet? Well, here we have good randomized trial data to show that the Mediterranean diet actually seems to prevent the preclinical stage of dementia. So, that to me is pretty convincing. And so, what does that mean? Do you need to just be hard on yourself again, because you’re eating a little red meat? No, you just need to eat more of the Mediterranean diet. So, train yourself to grab the hummus instead of the chips, have carrot sticks around so that some of the time you eat those instead, just eat more of it. Substitute the olive oil. But there’s really good data for that. But one of the most important things we can do, Nina, is to control our blood pressure, control our lipids.

Blood pressure in particular seems to be important because it leads to these, what are called white matter hyperintensities in the brain, these small ischemic vascular lesions in the brain. And our data actually show a link between hot flashes and those as well. So, particularly if you’re a woman who’s got a little bit of hypertension and you’re still flashing, we really need to think about ways that you can control your exposure to these small vascular lesions. And you can, just control the hypertension, control the hot flashes. The interesting thing about our work, Nina, which is hypothesis generating, but I think it’s important is, my work with Rebecca Thurman suggests that it doesn’t matter if you perceive the hot flashes.

Nina Coslov (23:35):

Interesting.

Dr. Pauline Maki (23:36):

That the association with brain difficulties, with memory problems is irrespective of whether you detect them.

Nina Coslov:

Interesting. So, the sleep waking is one part, but there’s a subconscious one that might be happening that is also leading to… Interesting, really.

Dr. Pauline Maki:

Right, right. So, women are, as I mentioned, in a unique position to know if their memory is good or not. They’re pretty tuned into their bodies, which not all individuals are. College students, for example, are terrible at it. The thing is, you might want to experiment on your own brain. So, if you’re like, “Oh, I don’t know if I want to commit to hormone therapy for my hot flashes.” Well, why don’t you take charge of that decision with your provider? Try it and see if you feel better. And if you don’t feel your brain is any better, then I think you’re a pretty good judge of that. If you feel your brain is better, then maybe you’re one of those individuals whose brains will respond to it. There are some new data to suggest that there may be less amyloid, so less of this marker of Alzheimer’s disease in women who initiate hormone therapy.

I don’t want to poo-poo that, maybe that’s real and maybe that there’s a signal that we need to pay attention to. But the point is that that hasn’t been shown in a randomized trial yet. It has been shown to be lower in women who choose to go on hormone therapy in one study. So, we need to know if that’s a reliable finding and we need to replicate it in a randomized trial. If that proves to be true, then we’ll need to maybe have another discussion. But right now, it’s not proven yet, and we don’t know if it will. And all the other studies that are out there showing that hormones are linked to lower Alzheimer’s-like profiles are all observational, and they suffer from the same issue that we’ve had leading up to the studies that showed no benefit of hormones on cognition. So, healthier women have this option sometimes more often than other women, and that may be accounting for some of these differences.

Nina Coslov (26:00):

So, following on from that, studies and new studies, and new studies need to be replicated, there are increasingly lots of studies out there and online and in our inboxes and in our feeds. And to get clicks, they need to have exciting headlines and sometimes scary headlines. And so, there are three kind of particular studies I just want to drill down and just get your take on what they tell us and what they don’t tell us. The first we’ve talked about already, which are the studies that show that women who reach menopause early do benefit cognitively from taking estrogen. And we’ve already said that does not mean that all women should take estrogen, only those with hot flashes.

Dr. Pauline Maki (27:12):

Right.

Nina Coslov (27:13):

So, I think we covered that one. The second one, and I want to read the actual title, the study, recent title, it was Menopause Hormone Therapy Significantly Alters the Pathophysiological Biomarkers of Alzheimer’s Disease. Is there applicability for that to women at large or do you know the study that I’m-

Dr. Pauline Maki:

Is that Depypere, Yeah, that’s the Depypere one. Yeah, that’s the one I just talked about. I do think this was a well-conducted study, in that they measured these Alzheimer’s biomarkers before women initiated hormone therapy and after, so they did look at within-person change, and then they compared it to women who didn’t have hormone therapy. It wasn’t randomized who got it, so the women elected in the clinic to go on it. But I do think that’s hypothesis generating. So, there may be something there. When I spoke to the lead author of the manuscript, I wanted to know, are those women with hot flashes?

Nina Coslov:

Yes.

Dr. Pauline Maki:

Because our work probably suggests that in fact, it would be reasonable-

Nina Coslov:

Right.

Dr. Pauline Maki:

… in part, mediated by sleep. So, we know that one night’s sleep deprivation increases the markers of Alzheimer’s disease in the cerebral spinal fluid.

Nina Coslov:

Wow.

Dr. Pauline Maki:

So, the role of sleep in Alzheimer’s disease is getting appropriately, a lot of attention. And this is cool, Nina. I don’t know if you know this work. So, our brains build up these Alzheimer’s proteins during the day. At night, there is a wave, almost like an ocean wave, that mechanically clears these proteins from our brain.

Nina Coslov:

Wow.

Dr. Pauline Maki (29:34):

It was a fabulous study published by a postdoc. I’d love to be that postdoc. It was a beautiful study, high-impact study that showed that one of the rules of sleep, and one of the reasons that when we’re well-rested, we function better cognitively, is because there’s this mechanical clearing of those proteins. So, women are waking up multiple times during the evening because they’re having these hot flashes. So, it wouldn’t surprise me at all if you gave a woman with persistent hot flashes hormone therapy, and her hot flashes are decreasing and she’s sleeping better. That’s exactly what I would predict.

Nina Coslov:

Yeah. Interesting.

These women were not all, they didn’t all have a pre-genetic disposition to Alzheimer’s?

Dr. Pauline Maki:

No, they didn’t. And in fact, they found that for the women who have that genetic predisposition, some of the time it was enhanced. But I will say, that could be a statistical artifact to the fact that the levels of these Alzheimer’s disease biomarkers in women who don’t carry that gene, they’re harder to detect because you really only detect them more. But it may very well be that for women who carry the APOE e4  4 allele which is the genetic risk factor for Alzheimer’s disease, sleep deprivation for those women could be particularly harmful.

Nina Coslov (30:58):

Yes.

Dr. Pauline Maki (30:58):

And that estrogen is really good at enhancing sleep, in part because it takes away the hot flashes. I see this as a very, very realistic. I would even make that prediction based on my own data. So, there may be some legitimacy to this. So, then the question is, is that true for all women? And there we don’t know.

Nina Coslov (31:22):

Data gap to be filled, hopefully.

Dr. Pauline Maki (31:24):

It’s a data gap. But here’s where I’m going to balance that out. So, in the Women’s Health Initiative memory study, conjugated equine estrogen and medroxyprogesterone acetate increased the risk-

Nina Coslov (31:42):

Of dementia.

Dr. Pauline Maki (31:43):

… of dementia. And a lot of women want to say, “Okay, that study was invalid because it used conjugated equine estrogen. And I would say that that could be true. However, the very hypothesis that hormone therapy might lower the risk of Alzheimer’s disease was based on studies in the 1990s when that was the formulation we used in the United States. And if the Women’s Health Initiative is correct, that the number of women that you’d need to treat with hormone therapy to increase the risk of Alzheimer’s disease is 436. In other words, you’d need to treat 436 women with that formulation to cause one case of dementia.

Nina Coslov (32:42):

So, you’re saying it shouldn’t be a reason that someone who’s having persistent hot flashes doesn’t use the therapy, but it is not a reason to use it just for cognition.

Dr. Pauline Maki (32:51):

Just for cognition, yeah. Exactly. And there is this harm that we are not seeing, with one exception of one study that I told you about, where even the formulation that caused dementia in a randomized trial was shown to lower the risk by more than 30%. Those data don’t make sense, even what we know. With the exception of that study, the other recent studies that our population level, Finland is population level data shows some harm.

So, what are we going to believe, the Alzheimer’s disease biomarker data from a study or the entire population of women in Finland between a certain age? And I think that’s where the marketing of this comes in. That’s where we need to think, okay, why should a woman consider using hormone therapy? Because it’s very good at taking away hot flashes. And hot flashes, we know are not these benign things, right? They seem to be associated with poor sleep and poor work-related quality of life, et cetera. So, maybe in those women, those are the ones who are going to derive the cognitive benefit. Maybe that’s why historically we have seen lower rates of Alzheimer’s disease in women who used hormone therapy because they were using it for hot flashes. And that’s a very old idea.

Nina Coslov (34:16):

So, the last kind of study, or it might not just be one study, but there’s been a lot more imaging of brains lately, perimenopausal brains. And those studies show structural changes in women’s brains, you alluded to before. I think they also show whether it’s a compensatory hypothesis, that they kind of reconnect in different ways or they morph in some ways. Can you just kind of comment on what you take from the increased scanning of perimenopausal brains?

Dr. Pauline Maki (34:51):

There is no large-scale longitudinal study to compare a woman’s brain when she’s premenopausal to peri to post. We’re doing the largest one right now. The NIH just funded me to do that a couple of years ago with Susan Bilkimer. So, we’re doing that hard study that takes seven years to do. What we’re seeing right now is primarily cross-sectional data. Some postmenopausal women followed longitudinally. There’s not a reliable signal from those studies. They come out from one lab. I think they’re hypothesis-generating, but they haven’t been shown in a prospective longitudinal study with large numbers of women. There are some technical details that make interpreting that study kind of difficult, some issues of confounding of risk factors of Alzheimer’s disease with menopause stage, low numbers of women followed longitudinally, and some other aspects.

Nina Coslov (36:02):

Early days.

Dr. Pauline Maki (36:05):

Yeah, it’s early days. And it’s observational. So, menopause stage data are observational. So, whenever you have an observational study of brain imaging, you need large numbers of women. Now, there is some data from the British Biobank that suggests some menopause-related changes, and those may be real and we need to look into that. But some women seem to experience changes and other women don’t. Oh, surprise, surprise, right? Surprise, surprise. So, we need precision medicine here. We need to ask which women experience brain changes. And those are the women we need to help.

My hypothesis, and you don’t need a Ph.D. in neuroscience to formulate this hypothesis, is that it’s the women who continue to experience menopause symptoms that remain untreated, especially those that affect sleep. I also think women who experience a new onset of depression or recurrent depression, I would fully expect their brains to show changes, adverse changes. If their depression goes untreated, it’s a period of extreme stress for some women. They’re making changes in their life about relationships, families, jobs, and it’s compounded with a brain that’s learning to adapt to stressors in a hormonal milieu that’s not optimized to do that.

When estradiol levels are variable, we cannot regulate our stress, most of us can’t regulate our stress, or some of us can’t regulate our stress as well. And it shouldn’t surprise us that our brain is not going to be functioning as well if we can’t manage our stress well. So, I mentioned that because it suggests different solutions depending on what the cause is.

So, if it’s depression, we need to treat the depression. If it’s stress levels, if it’s associated with estradiol variability, I’m convinced that giving oral contraceptives or hormone therapy to take away that variability can be very helpful until the ovaries shut down and are no longer variable.

Nina Coslov (38:26):

Right, right.

Dr. Pauline Maki (38:27):

And this is very important news for women. We don’t want to scare them from hormone therapy for those who need it, but we don’t want to push it for all the women who don’t need it.

Nina Coslov (38:38):

Yeah. That’s a great summary. That was all that I had. Are there any other things that you thought I’d ask or…

Dr. Pauline Maki (38:49):

No, I don’t know what you find, but I find that at midlife, I’ve got a lot of friends who are at the peak of their careers. They’re rocking it, but their demands at home from their partners, from their spouses, from their parents, from their children, if they have them, and even from their friends, are more demanding. So, there are a lot of demands placed, and there’s not a lot of time to do the hard work of learning to meditate. Right?

Nina Coslov (39:26):

Absolutely.

Dr. Pauline Maki (39:26):

Getting good sleep, taking that walk. And I think sometimes, maybe more often than not, and maybe more often in certain social strata, there’s a tendency to go out and have that glass of wine or two or three with the friends, with the girls. And I think women may be reflexively, sometimes more often turning to alcohol-

Nina Coslov (39:49):

Interesting.

Dr. Pauline Maki (39:49):

… than they should. I just want to say that for women, and you don’t want to punish yourself, but two glasses. That’s it. That’s all we should be having at a given sitting, two glasses. And we don’t want to do that too often because alcohol is not good for the brain. It’s part of the Mediterranean diet, but if you go to Greece or Italy, they’re having a glass of wine with dinner, they’re not having half a bottle of wine-

… with dinner, right?

Nina Coslov

And then, it goes back to the sleep, then it sort of ruins your sleep.

Dr. Pauline Maki:

That’s exactly the point, Nina. That’s exactly the point. So, we need to think about how we cope with our stress, and we need to think about how that may be a temporary fix without a long-term fix. And we don’t know about marijuana really, because one strain of marijuana, cannabis is not another strain of cannabis. And if it calms us down, is it impacting our sleep? And what is it doing to our cognitive performance?

Dr. Pauline Maki (40:53):

That’s a complete unknown black box. But again, I think women should pay attention to when their brain’s functioning well, when it’s not functioning well. For me, I noticed because I’m a vegetarian, I was feeling a little sluggish and I was like, “Oh, I haven’t taken my vitamin B12 in a while.” Vitamin B12 is really important for brain function. And for me, after three days of doing it, I was like, “Ah, there it is.”

Nina Coslov (41:19):

Yeah, yeah. And the other thing that you mentioned that I think, it just gives credence to it. And I think one of the things that I’m trying to do through Women Living Better is just normalize a lot of this for women, that we all experience it. And you mentioned the fluctuating estradiol and our stress response. And I think that is huge and it goes unnoticed, and if you just think about that thought alone, that you have this, if you look at the… I have it on the website, the data from Nanette Santoro’s relative of 18 months, of her fluctuating hormones. If you think about that going on in our body, and then that impacts our stress response, right? Give yourselves a break.

Dr. Pauline Maki (42:00):

Be kind.

Nina Coslov (42:00):

Yes.

Dr. Pauline Maki (42:03):

Be as kind to… yourself as you would be to your friend.

Nina Coslov (42:06):

Yes.

Dr. Pauline Maki (42:06):

And it will level off.

Nina Coslov (42:08):

It does level off.

Dr. Pauline Maki (42:09):

It does, it does. But you don’t have to endure that.

Nina Coslov (42:13):

Right, so-

Dr. Pauline Maki (42:14):

So you can go on an oral contraceptive or a transdermal estrogen with IUD, like Nanette beautifully demonstrated can be useful for women. And then, women’s brains are wired differently than men with respect to how emotional circuitry is wired.

And there’s beautiful data now showing that this happens at puberty, where the brain areas that regulate the emotion become more uncoupled in women, so that their amygdala is more reactive to… and we evolved to do this. We evolved for alertness to things that could affect reproduction, ostensibly. And in boys, what happens is the opposite. They become more emotionally regulated. So, you can actually look at functional connectivity in different areas of the brain. It’s fascinating science.

Nina Coslov (43:11):

Wow.

Dr. Pauline Maki (43:12):

So, when we are emotionally heightened, we go internal, we ruminate, we have this self-dialogue. “Why did I do that? Why did I say that? I’m a terrible friend, I’m a terrible partner. Why did I do that? Oh, my child forgot their homework. I’m such a bad mother.” Instead of saying, “My child forgot their homework, they really need to remember their homework.”

Or we have this negative dialogue that we’re predisposed to because of the way that our brains are wired, and society tells us this. And so, part of being kind to ourselves, in my opinion, is unlearning that tendency to engage in this negative self-talk, the same way that you would tell your friend if she said, “I’m such a bad mother, my child forgot that.” “You’re not a bad mother.”

Nina Coslov (44:20):

What are you talking about? Right. What are you talking about?

Dr. Pauline Maki (44:21):

What are you talking about? Voice for us, for ourselves. And I’m a big proponent of cognitive behavioral therapy because it does tell us, “Okay, you’re going to learn what your negative thoughts are. I’m going to help you do that, but then I’m going to expect you to unlearn those.” And you can actually see how the brain rewires. And I think that can be extremely helpful to women as they’re transitioning through the menopause, especially since the stress circuitry gets a little wonky at this time.

Nina Coslov (44:51):

And meditation, I’ve started and stopped a million times. But just sitting even for five minutes, you see those thoughts come in, even just about your sitting, right?

Dr. Pauline Maki (44:59):

Oh, yes. Yes.

Nina Coslov (45:00):

About how badly you’re sitting. Right? And you can just, “Wait a minute, where are these generating from?” So, I think all of those points are a great place to wrap up, because there is a lot that we need to recognize about the hormonal changes that are happening and give credence to them. And then, know that there are things that we can do. And a lot of them do fall in the take care of yourself bucket.

Dr. Pauline Maki (45:23):

Take care of yourself.

Nina Coslov (45:24):

Be kind yourself, take care of yourself, make a little extra time, as you said, for the little bit longer of a walk. Connect with people. Do the things that you need. And much like when we eat something and we know that doesn’t make us feel good, I loved your analogy of think about when your brain is functioning well and when it’s not, and what’s happened in the days, hours leading up to that? If we just pay attention to these things, I think that can go a long way.

Dr. Pauline Maki (45:49):

Right, and pay attention to that thought when you forget something, that thought that says, “Oh my goodness, am I dementing like my grandmother?” Stop that thought. Stop that thought and say, “Oh, I was listening to Nina and she told me that 40 to 60% of women have this experience, and that really only if I have a lot of hot flashes, do the data suggest that I need to be a little concerned about what I’m going to do from a menopause perspective.” That’s a really important thing. Yeah. You’re forgetting, like other people.

Nina Coslov (46:20):

Yeah. It’s normal.

Dr. Pauline Maki:

It’s normal.

Nina Coslov:

It’s going to be okay. Well, thank you so, so much for your time, and I look forward to sharing this with others because this is really valuable information for all of us at this age to hear.

Dr. Pauline Maki:

Well, thank you for foraging for the truth.