E118: The Intellectual Domain of Perimenopause

Kirtly: Pregnancy brain. Menopause brain. What does that really mean? I'll admit that I never wanted to use those terms about my brain or see my colleagues using those terms because it sort of felt like airing your personal hormonal cognitive library. But I have used the phrase jet-lagged and post-call, meaning that I'd been up for 36 hours, which I was every third or fourth day for my four years of training, and of course every new mom is. It meant that my brain wasn't working as fast as my smartphone, or it meant something.

I'm Dr. Kirtly Jones from Obstetrics and Gynecology at University of Utah Health, and we're working on the 7 Domains of Perimenopause. This episode is on the intellectual domain. I trained and practiced as a reproductive endocrinologist, and have been bathed in reproductive hormones myself once upon a time.

With me is my curious and wise co-host, Dr. Katie Ward. She has a doctorate in nursing practice with a specialty in women's health and a midlife women's health practice, as well as a PhD in anthropology.

She's going to keep me on the straight and narrow in terms of what we know about how much we know about the hormone shifts of the perimenopause and how they affect cognitive function.

In the emotional domain of perimenopause, and you can check that one out on our website, we talked about the emotional issues of midlife and perimenopause. And they're not exactly the same. Midlife and perimenopause are a little different. But today is the intellectual domain. Katie, keep me straight and narrow.

Katie: Straight and narrow. Yeah. Now, I'm feeling bad for women right now because, as you mentioned, there's menopause brain or brain fog, and still, women are worried about are they getting dementia? Are they losing their memory? What's happening to them the first time they can't remember why they walked into a room or the name of the person standing next to them? But yet they know where the condiments are in the refrigerator.

Men can stand there with the door open and the ketchup is on the third shelf right where it's always been.

Kirtly: And has been for a year or two.

Katie: Yes. And he's still going, "Honey, where's the ketchup?" And she knows. So I think we need to name condiment blindness in men and start thinking about how to treat that.

Kirtly: So how would you devise a research study to see how estrogen withdrawal affects the brain? Now, remember, every woman who has a baby and breastfeeds exclusively for a year has no estrogen around at least for the first six months. So trying to see if baby brain is estrogen withdrawal is too hard because of the whole baby thing.

So how about our lab friends, the mice? You could take out their ovaries and make them run mazes and compare them to mice with ovaries. Or you could take out their ovaries and make them run mazes but give some of them estrogen back and see if they run mazes.

But mice aren't humans, and they don't have brains like humans, and mice don't complain of brain fog.

Katie: Poor mice.

Kirtly: But you can give young women a medication that stops the brain from talking to the ovaries, and estrogen and progesterone and testosterone fall. We do that for some women with estrogen-dependent diseases like endometriosis or fibroid tumors of the uterus.

Then you can give some women estrogen back in small amounts, and some don't get estrogen back, or you can let women be their own controls. You can treat them when their bodies are making no estrogen and give them a little, or you could give them placebo, and ask them to remember words or paragraph.

That study was done in a very small number of women, and there was a lower rate of word and paragraph recall when their estrogen was low compared to when they got a little bit back. And this tiny older study can show that acute estrogen withdrawal can decrease word finding and paragraph recall.

Now, everybody every month who has a normal menstrual cycle has a week where their estrogens are very low. So I'm not sure what this exactly means to us. And the perimenopause isn't complete estrogen withdrawal. It's about some fluctuations.

Well, in an effort to find out if taking estrogen in the perimenopausal period . . . in this case, six months to three years from the last period, so definitely late perimenopause. To see if it helped the heart and the brain, a study called the Kronos Early Estrogen Prevention Study was undertaken. And I was an investigator in the study.

Women who were at least six months from their last period were given estrogen and progesterone, and these are bioidentical, or a placebo. Some got estrogen patches, some got conjugated estrogen pills, and some got placebo.

Now, this study went on for several years. Lots of cognitive tests were done, and there was no difference between women who received estrogen and those who didn't. And that doesn't mean that women in this age don't have some brain fog. It just meant that estrogens didn't fix it.

There are a bunch of other studies, but the sum is there isn't a clear positive effect on cognitive function by taking estrogen.

Of course, if you have a lot of hot flushes or other symptoms that keep you from sleeping, estrogen can help the post-menopause. And if you're in the rock and roll years of the perimenopause, turning off the ovaries with low-dose birth control can help.

But are we measuring the right things? And are we asking the right questions? What happens when women just don't feel right?

Katie: Well, that is the thing. Women definitely don't feel right. And one, Kirtly, you are a rockstar for working on the KEEPS trial.

Kirtly: Thank you.

Katie: That was honestly one of our major important studies. But I think what it showed, we keep getting that same result. So, since then, we've done another trial, the ELITE trial, and it was trying to see, "Is there a timing hypothesis here?" If you get your estrogen late versus early, does that make a difference? And still, no cognitive benefit for estrogen either way.

So when we do these kinds of really randomized, controlled, scientifically designed studies, we just can't see that estrogen is making a big difference.

We went back to the KEEP study later, I'm sure you know this, and looked at those people 10 years down the road and still no difference. And there wasn't a difference between the people that got the bioidentical and the older estrogens. And so we really do have a lot of good scientific, evidence-based data that says estrogen is not the thing that's making a difference in cognitive decline in women.

And just this year, in fact just last month, the International Menopause Society came out with a very strong statement to that effect, saying that hormones are not for preventing cognitive decline.

The one exception for that is women who lose their ovaries early. So people who have premature ovarian insufficiency or have a surgical menopause early for some other important reason. And for those people, we do know that replacing their estrogen until the age that they would've gone through menopause naturally is really important.

But I think what you were saying about the estrogen is not . . . by itself, it's not changing the brain. It's changing how we sleep, whether or not we're being woken up all night with night sweats. Maybe it's helping with joint pain, and so you can exercise more and move more.

But the other thing that you mentioned, and I just want to stick a pin in this, is that perimenopause is not necessarily marked by clearly declining levels of estrogen. It's the fluctuations. It's these wide fluctuations.

And I think the measurement that you mentioned is really important, because what's causing the brain fog might not be the estrogen and progesterone that we can measure. Those just happen to be the big molecules that we know how to measure. But maybe it's the other neurotransmitters that are telling our ovaries to make that, or maybe it's some other ingredient that gets made along with estrogen and progesterone.

So I think you're right. I don't know that we know the answer to this yet about what's causing the brain fog, that you can't remember what your partner's name is or what you went into the room for. But I think we do have really good evidence that estrogen is not going to be the thing that saves you from cognitive decline later.

Kirtly: Right. So are sensitive brain scans helpful? Probably not. And maybe our measurements are a pretty dull tool for measuring our amazing brain. It's good for when people have serious decline in function, but not just a little bit of brain fog. And so we need help with this.

Kirtly: In our virtual Scope studio is Dr. Christine Cliatt Brown. She's a behavioral neurologist at the Cognitive Disorders Clinic at the University of Utah.

Christine, I know you're busy. I'm really grateful that you joined us. Christine, what's brain fog?

Dr. Cliatt Brown: Brain fog is a word that I think all neurologists are familiar with. We've heard it a lot. A lot of us dread it a little bit because it's just so common, and it's often associated with a ton of other conditions.

Brain fog is often described as things like slowed thinking, poor focus, mental fatigue, forgetfulness, losing your train of thought. And we often associate it with post-COVID. We know COVID causes a lot of brain fog. We associate it with perimenopause, sleep disorders, fibromyalgia, migraine, and a variety of autoimmune conditions.

I generally think of brain fog as the impact on brain function of non-brain factors, because the reality is that our brains rely on our entire body to work.

Sleep is a good example of this. If we're not getting good sleep, if we're not getting enough sleep, we're getting interrupted sleep, whatever the cause of our sleep problems, if our sleep is disrupted, our brains are not going to function properly.

It doesn't mean there's a brain disorder, but our brains need that sleep in order to properly clear out waste, to solidify memories, and to get the rest that they need to be firing on all cylinders. So if you're not getting good sleep, that often causes things like slowed thinking, poor focus or inattention, and a lot of mental fatigue.

I'm sure you've all heard that drowsy driving is as bad as drunk driving, and that's really true. We see that when our brains don't get enough rest, they're not going to function appropriately, and can cause a huge impact.

When we think about just one night of poor sleep, that's one thing. But a lot of people, including people with perimenopause, have chronic poor sleep, just this baseline disrupted, poor-quality sleep piling up day by day. And that can cause a huge impact.

And then things like hormone shifts can impact our brain function. When we're having all these symptoms of perimenopause present for a long period of time, those symptoms often can get a bit worse over time, become really noticeable, and just invade your day-to-day life, and it can be very distressing.

Kirtly: And then it builds on its own. Then you have sleep performance anxiety, meaning you know you don't sleep and then you get anxious about not sleeping, and then you get anxious about not remembering. You know who that guy is, you know he's your partner, but you forget his name. Probably not, but you mix him up. But I know you always remember where the ketchup is, right?

Katie: Right. Always.

Kirtly: Always remember where the ketchup is. Yeah.

Katie: So, Christine, if you see a woman . . . and I know you probably don't. You're a referral clinic, right? But if you were to see a woman like I do in her 40s and 50s and she's concerned that something is wrong with her memory, what advice would you give me? What things should I be listening for?

One of my barometers is if the patient tells me that her kids or her husband are concerned, then I'm a little bit more concerned than if she just says, "I can't function at work."

Dr. Cliatt Brown: I mean, finding out what family thinks is definitely helpful. It's true that I'm going to be a little more concerned if the family is more concerned. But if the patient's worried but the family's not worried and everyone else thinks that it sounds like just normal aging or something like that, then that makes me, of course, less concerned.

But there are some times that someone who has actual dementia might really notice their symptoms and be very distressed by the changes in themselves. In those people, the family is usually also worried. So family is a good barometer. Co-workers can be a good barometer as well.

In general, when we're thinking of the types of brain fog symptoms that we see in perimenopause, the things that aren't concerning to me are going to be things like misplacing items, my glasses, my phone, the remote. Forgetting why you walked into a room, not concerning to me at all. Slowed thinking, difficulty focusing, to me, none of those are very concerning.

In perimenopausal women, the cognitive changes are often those typical brain fog symptoms. But we do add in a bit of decline in things like verbal memory and word retrieval that I don't see so much in other brain fog sort of settings.

Because they're so common, the things that make me kind of separate out what are the concerning word-finding difficulties, what are the concerning verbal memory problems versus what's not so concerning, is if there's a loss of skills associated with it. That, for me, is very concerning.

Not just, "Oh, it takes me longer to do this task," or, "I have to make sure I don't have distractions to do this task," but really, "I try to do it, and I can't even figure out how to do it. I'm not capable of it anymore." That is more concerning and warrants more evaluation.

Taking a little while to find a word and then it kind of coming to you later is not super concerning, but if you're not knowing what words mean and they're typical words that you really should know, that would be more concerning. Frequently not recalling the names of very familiar people, like close family or close friends, is concerning.

And we're all going to do that thing every once in a while where . . . especially, let's say, if you have kids or grandkids. You call someone the wrong name and then self-correct it or maybe don't even realize you accidentally said it. That's fine.

But if you are looking at your own child and genuinely do not know their name, that would be very concerning. It's more than just a simple mistake. So those are the sorts of things that would make me want to get extra testing.

Katie: That's super helpful.

Kirtly: If you have someone and they reach that kind of a bar . . . and I guess, to me, who has always counted on my cognitive ability being as fast as my phone, to actually not be able to remember my son's name seems like a very low bar. But if that happens, how do you test them? What do you do?

Dr. Cliatt Brown: So it really depends on the person. Often, we'll start with just a basic cognitive screening test in the primary care setting. So you see your primary care provider and they might do a short cognitive screening test lasting maybe 10 to 15 minutes.

If that ends up being super normal, then we're definitely less concerned. If it's abnormal, then sometimes we'll proceed with some other testing.

Maybe if the symptoms are really concerning or if that initial testing isn't quite what we expected, sometimes we'll do longer cognitive testing that we call neuropsychological testing. That's going to be three, four hours of very detailed cognitive testing where we compare you to peers of a similar age and similar level of education.

That's something that primary care is able to refer someone to if they have some concerns, especially if someone is maybe in the borderline sort of range. They're not quite sure, "Is this normal or is this not normal?" That's a really good role for neuropsychological testing.

For a lot of people in perimenopause, the main thing we're going to do is watch things over time in the primary care setting. Repeat over time tests like the MoCA or other shorter cognitive tests.

People with perimenopause usually have relatively mild cognitive symptoms when we measure it using tests like that, and they really shouldn't have clear progressive decline over time.

If there's significant worsening over time, especially if it's not with some clear trigger, like "I haven't slept more than two hours this whole week," then that would be reason to get further testing. In those cases, we might proceed with something like a brain MRI or that neuropsychological testing.

Sometimes, though, on cognitive screening tests or on neuropsychological testing, a patient's results might be completely normal. And for a doctor, that's so reassuring. We feel really good about that. But for a patient, that can often feel invalidating. It feels like your doctor's saying, "Nothing is wrong with you. Your cognition is perfectly normal," when in day-to-day, you're seeing that your cognition is not normal.

But the truth is that our tests don't capture everything. And our tests are made not to see what a brain is doing day-to-day in your home environment, but rather to see what your brain can do while you're sitting in a quiet room with a person sitting directly in front of you, keeping you on task the whole time.

So we're not measuring what we're seeing in day-to-day life. And normal performance on neuropsychological testing or short cognitive screening tests doesn't mean your cognitive symptoms aren't present, but it does mean that when you're in an ideal environment, your brain is capable of performing well, which reassures us strongly against neurodegenerative causes. But of course, that leaves all the non-degenerative stuff: the poor sleep, the perimenopause, the COVID brain fog, all that stuff.

Katie: I think that's where women are so frustrated because they really do see an increase in this, of walking in the room and can't remember, and other irritating sort of signs of having an irritable brain.

And then of course, there's the woman who does have a family history of some dementia or Alzheimer's in her family. I think for those people, there's really a heightened sense of anxiety the first time that starts to happen in the perimenopause.

Is there any evidence that that perimenopausal brain fog should be an early warning sign? Should people be extra concerned when that happens?

Dr. Cliatt Brown: I would say not really. Perimenopausal brain fog, to me, is not an early warning sign of Alzheimer's disease. It's rather just our brain's unfortunately normal reaction to these hormonal changes, disrupted sleep, mood changes, and all these other symptoms.

In someone who has a family history of dementia, like you mentioned, the situations where I'm worried about strong genetic causes of things like Alzheimer's disease are mostly going to be when you have multiple family members who developed that disease very early in life, like in their 30s through 50s.

Most of the time, having a family history of Alzheimer's disease in someone's 70s, 80s is not very concerning to me because it's unfortunately extremely common.

The . . . I definitely forgot what I was saying. Sorry. Ah.

Katie: I think that was really just perimenopause. It was brain fog.

Kirtly: That's okay.

Dr. Cliatt Brown: So when we're seeing these sorts of symptoms and it's fitting with it potentially being perimenopausal sort of symptoms, like you mentioned earlier, we would consider things like hormone replacement therapy for symptoms that may be indirectly impacting cognition, the sleep, the hot flashes. But we don't expect that hormone replacement therapy to actually improve cognition or make those cognitive symptoms disappear.

Of course, everyone wants a cure for these problems, but unfortunately, there just isn't one. And sometimes when our patients leave a clinic visit with reassurance and no prescription, that's another thing that can feel very invalidating. The truth is just that we know perimenopause impacts cognition, but right now, we don't have a pill to make that better.

And so the things that are in people's control is to focus on the sleep, the exercise, all the other lifestyle factors that we know have some degree of benefit. And then to consider monitoring those symptoms and watching how that impacts cognition, checking to see, "Hey, every time I have a terrible night's sleep, is that worsening my brain fog? Do I do worse the next day?"

And if you're seeing that that's the problem, then that's where you put your focus. You focus on improving your sleep. If you see that, "Hey, my cognition is worse every time I'm depressed or irritable or anxious," then maybe you focus on the management of those mood symptoms and see if that helps with your cognitive symptoms as well.

We don't often talk about these problems, and I think that is honestly part of the problem. I think that we need to talk to each other about these problems to understand what's normal and what's not normal.

We know from research actually that when women talk to other women, their cortisol levels decrease. And cortisol is a stress hormone. So when we talk to our friends, when we share our experiences, that's honestly a good therapy. It helps alleviate stress. It helps you see that you're not alone.

And I think a lot of us are embarrassed to share perimenopausal symptoms or cognitive symptoms. Maybe you're scared about it. But talking about those symptoms and seeing that you're not alone can help you realize, "Hey, you know what? This is actually part of normal life, unfortunately." And then you can focus a little more on the things you can do to potentially make it better instead of getting stuck in a cycle of worry and anxiety over the symptoms.

Kirtly: So how do women 40 to 55 protect their brain? You mentioned some things. And there's recently been a huge study from England that looked at significantly modifiable factors that people can do to decrease their chances of developing dementia, but more importantly, make themselves feel better.

Dr. Cliatt Brown: So the big ones are going to be exercise, sleep, diet, and cognitively and socially engaging activities. Those are the biggest ones.

For exercise, for me, that means 30 minutes a day, 5 days a week. Especially moderate aerobic exercise can improve the function of the memory part of the brain and reduce the risk of dementia in the future.

For sleep, that means treating any sleep problems, focusing on having a regular sleep schedule. And then if you have sleep apnea or something like that, you have to treat it, because untreated sleep apnea increases the risk of dementia.

Following a healthy diet like the Mediterranean diet or the MIND diet is very good. In general, these are diets that are going to be higher in produce like leafy greens and berries. They're going to be higher in the healthy fats like olive oil, nuts, fish twice a week, and lower in the unhealthy fats, the red meats and fried foods, higher in whole grains, and then lower in the simple carbohydrates like white bread, white rice, sweets.

And then for cognitively engaging activities, I just recommend that people engage their brain in a variety of ways. You don't have to force yourself to do crossword puzzles if you hate crossword puzzles.

Katie: Oh, thank god.

Dr. Cliatt Brown: But find some things that you enjoy and try to give yourself a little bit of variety. Maybe you have an artistic endeavor, maybe you do some reading, maybe you build stuff at home.

And then socially engaging activity is also very important. We know that if people become socially isolated, they're at a much higher risk of dementia.

And then the general other tips that I have are to limit distractions and avoid multitasking. We live in a world where there's constant entertainment, constant noise everywhere, and we're all expected to do three things at once. And we know that no one is as good at multitasking as they are at doing a single task at a time.

So if you have perimenopause-related brain fog, that's going to be so much worse. And you may find that you do better if you limit distractions. Don't listen to a podcast while trying to work, except for this one.

Kirtly:I  like cooking and podcasting at the same time.

Katie: I do too.

Dr. Cliatt Brown: And then I also don't recommend spending money on all these different supplements that claim to boost brain function. I'm not a fan of those.

Katie: Me neither.

Kirtly: I think that you really outlined really amazing epidemiologic data that's real science in terms of what keeps people healthy, and the way the healthiest of us at 90 behaved when we were 50. But anything that's good news about neurocognitive disorders that's coming down in your world?

Dr. Cliatt Brown: Yeah. So we've made a lot of really big advancements, particularly in the diagnosis and treatment of Alzheimer's disease over the past 10 years or so. We have infusion therapies that slow cognitive and functional decline in mild Alzheimer's disease by about 30%. We're, of course, still far from a cure, but this is, of course, a big step forward.

We also have blood tests for Alzheimer's disease now. These are tests that are not helpful for people who have either normal cognition or brain fog, but these are helpful tests in diagnosing those who have significant cognitive decline in a pattern concerning for Alzheimer's disease. That sort of scenario is where these blood tests perform the best.

Katie: Well, that's exciting. I mean, I think the good news for perimenopausal women is that menopausal hormone therapy is helpful with a lot of the things that you just talked about. Again, if you're sleeping better, if you're feeling better, and you can get the exercise, that is really helpful. And those things do matter in protecting your brain.

But I still . . . and I say this probably every episode, so I'm starting to sound like a broken record. But so much of the social media, and you were just talking about what's in your feed and the stress, is built to scare you. So people are getting these crazy messages.

There's one current one. I don't even want to say it because it makes me so angry. But people are really being frightened that menopause is damaging their brain, and if they don't get on hormones right away, there's going to be this destruction that can't be reversed.

Then there are other influencers that sound very credentialed, and polished, and they're recommending everybody run out and get tested. And really, what I think they're doing is actually creating the kind of stress that makes all of this worse.

And so I think that's the message I want people to hear, is we've got this exciting new testing that you were just talking about. We've got treatments that help with the perimenopause symptoms, and odds are you're going to be just fine.

The most important thing is to lead a healthy life for as long as you can. Yeah, as you said, move, eat well, sleep, stay connected. Those are the things that add more good years, not just more years.

Kirtly: Well, I've been thinking about hormones in the brain all of my career and I'm grateful to have a chance to talk to an expert about the brain. And thanks, Christine, Dr. Cliatt Brown. Thanks for joining us, and being so calm. I appreciate the calm. Thank you.

Kirtly: Well, back to brain fog. A recent study from a researcher at the University of Utah looked at 4.5 million surveys of Americans between 2013 and 2023. The rates of self-reported cognitive difficulties in people under 40 nearly doubled, up to 10% describing difficulties remembering things and concentrating or focusing.

And the increase started before COVID, so maybe we're more distracted by our phones and media, or we're more anxious about our economic and physical situations, or we're just talking about it more.

So what do we think we know about cognitive function during the perimenopause? We know that it's a common concern. We know it doesn't necessarily mean dementia is in your future. We don't think that estrogen is a cure-all, but it can help with the hot flushes and sleeplessness that can make it difficult to focus.

We also know that if you're experiencing this, you're in good company, and you should be sharing with others a laugh over coffee, or ask for a moment to collect your thoughts. You don't have to say, "I'm having brain fog." Just say, "Can you give me a moment?"

Put your phone down and try to do one thing at a time. Be in this moment. Try to eat well, get some exercise, and prioritize sleep, and talk to your clinician if you're concerned.

And as we work our way through the 7 Domains of Perimenopause, you can get all of our conversations on this important time of women's lives wherever you get your podcasts, or at womens7.com.

This is a transitional time of life, and I hope it can be full of curiosity, and joy, and laughter with friends and family. And if you're struggling, we can help. Thanks for joining us.