Ep. 342 Understanding Menopause: Hormonal Shifts in Women’s Brains with Dr. Lisa Mosconi

I am delighted and honored today to interview Dr. Lisa Mosconi. She is an Associate Professor of Neuroscience in neurology and radiology at Cornell Medicine and Director of the Women’s BRAIN Initiative and the Alzheimer’s Prevention Clinic at Weill Cornell Medicine, New York Presbyterian Hospital. She is also a globally acclaimed neuroscientist with a Ph.D. in neuroscience and nuclear medicine and the author of the New York Times bestseller The XX Brain and, more recently, The Menopause Brain.

In our conversation, we discuss how women’s brains change during perimenopause and menopause, looking at the significance of puberty, pregnancy, and perimenopause, as well as the lack of medical research on women and medical gaslighting. We explore the concept of bikini medicine and its misconceptions regarding women’s health and hormones alongside the crucial roles of hormones like estradiol, progesterone, and testosterone in our neuroendocrine system. Dr. Mosconi also provides insights into evolving menopausal treatments, including lifestyle interventions. 

Dr. Mosconi is an esteemed figure in neuroscience and a prominent voice in women’s health. I am confident you will gain valuable insights and perspectives from my discussion with her today.

“Estrogen is an umbrella term that includes many different types of hormones, and estradiol is the one that we all want.”

– Dr. Lisa Mosconi

IN THIS EPISODE YOU WILL LEARN

• How women’s brains change during perimenopause and menopause
• How the lack of information for young girls can lead to medical gaslighting and confusion during perimenopause
• Dr. Mosconi explains how a simple sugar is used as a tracer to track glucose metabolism in the brain during perimenopause
• Why brain changes during menopause may lead to mental fatigue and brain fog
• How the lack of training and research on menopause in medical residency programs leads to a poor understanding among clinicians
• Why women need to consider their brain and metabolic health during perimenopause
• Why estrogen is essential after menopause
• The benefits of HRT for menopausal women
• How stress impacts hormone production

Connect with Cynthia Thurlow

• Follow on Twitter
• Instagram
• LinkedIn
• Check out Cynthia’s website.
• Submit your questions to support@cynthiathurlow.com

Connect with Dr. Lisa Mosconi

• On her website
• On Instagram

The Menopause Brain will come out on March 12th, 2024.

Transcript

Cynthia Thurlow: [00:00:02] Welcome to Everyday Wellness podcast. I’m your host, Nurse Practitioner, Cynthia Thurlow. This podcast is designed to educate, empower, and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives.

[00:00:29] Today, I had the distinct honor of interviewing Dr. Lisa Mosconi. She is an Associate Professor of Neuroscience in Neurology and Radiology at Cornell Medicine and the Director of the Women’s Brain Initiative and the Alzheimer’s Prevention Clinic at Weill Cornell Medicine, NewYork-Presbyterian Hospital. She’s also a world-renowned neuroscientist with a PhD in neuroscience and nuclear medicine. She’s also the author of the New York Times bestselling book The XX Brain, which I talk about incessantly, and the author of The Menopause Brain, which is her newest book.

[00:01:05] Today, we spoke at great length about the changes that she sees in women’s brains during perimenopause and menopause, the significance of the three P’s, Puberty, Pregnancy and Perimenopause. The impact on the lack of medical research for women and medical gaslighting. What is bikini medicine and why it provides a great misunderstanding of the connection of women’s health and hormones, the role of estradiol and why it is the most bioactive hormone, but also the significance of progesterone and testosterone, our neuroendocrine system, the evolution of menopausal treatment, including lifestyle. I know you will love this conversation as much as I did recording it. 

[00:01:56] Dr. Mosconi, I cannot tell you how excited I’ve been to have a podcast interview with you. Your book, The XX Brain and now The Menopause Brain are books that I know have impacted so many thousands and thousands of women, certainly clinicians like myself. Thank you for the work that you do and thank you for carving out time out of your busy schedule to have this discussion. 

Dr. Lisa Mosconi: [00:02:16] Thank you so much for having me and for the discussion. I think it is so important to take the research and the information out of academia and really making it accessible to all women who need it and who could really benefit from it. So, this is totally my honor and my privilege to be here. 

Cynthia Thurlow: [00:02:34] Oh, thank you so much. I would love to start the conversation talking about the research that you do and what are some of the changes that you see in women’s brains as they’re navigating their 30s, into their 40s, into late perimenopause and menopause? What are some of the things that are happening in our brains. And I think for everyone that’s listening, most of my audience are 35 and older, many of whom are in perimenopause and transitioning into menopause. And I jokingly say to my children, who are teenagers, “One of the reasons why I take cognition and brain health so seriously is I never want to be a burden.” And I think that so many of the changes that are ongoing, I think if we better understood what was happening in our brains, we probably would be more conscientious working with our healthcare team and researchers to ensure that we mitigate what’s happening as we are getting older.

Dr. Lisa Mosconi: [00:03:29] Yes, and I completely agree with you. My research has been so important for me personally and for my family as well. And we were talking about your mom and your family, because I have a family history of Alzheimer’s disease that really affects the women in my family. And my grandmother had Alzheimer’s. Her two sisters had Alzheimer’s. Well, it was very shocking and very heartbreaking, but also really eye opening in a way, because as a society, we’re just not aware that there are things that everyone can do to protect their brains and really support brain health. From the moment we’re born until very last minute on this earth, there are so many things that everyone can do on a daily basis that can really support and nourish your brain health or not, and have the opposite effect. 

[00:04:22] So I have changed my lifestyle in a very brain healthy oriented way, and so have my parents. And I really love that. My parents are, like, the epitome of brain health at this point. They do everything they can from the right diet, they exercise. My mom does headstands, like, twice a week, [laughs] it’s amazing.

Cynthia Thurlow: [00:04:46]: Amazing.

Dr. Lisa Mosconi: [00:04:47]: Yes. So, I think it’s really important to share the research so that everyone can feel more empowered to take control of their health and to really also take control of their brain health up to a certain point. There are things that we can do that we need to understand so that they can become part of our healthcare plan and what we have learned– So, I’ve been doing brain imaging pretty much my entire life. I started fairly young. I was very fortunate because my parents are nuclear physicists, both of them. Yes. And so, their students would come over– I’m Italian. I’m from Florence. It’s like one big family, [chuckles] pretty much. So, their students would come over to get better and ask questions, and they would sit down in the kitchen with my dad going over differential equations and all the different things they do. And some of the other students would babysit me, and they would talk to me about brain scanners and positron decay and this isotope and these other things. 

[00:05:44] So, I basically grew up into science, especially nuclear medicine and nuclear physics. So, I started really young, and I have been focused on women’s brains ever since I was allowed to, really, which is in college. For my thesis, I was looking at panic attacks and anxiety disorders and doing EEGs and EKGs and event-related potentials to look at differences between boys and girls back then, or young men in terms of activation patterns. And then I took it further, and I started looking at Alzheimer’s disease and dementia and how we can prevent these disorders by keeping sex and gender in mind, which is something that was very, very new when I started. So, I’m finally getting back to your question, [chuckles] which is, what can we see? We can see changes in the brain that are usually subtle but significant, at least in a statistical point of view. And what we have learned is that aging in the brain is actually not linear for women. 

[00:06:49] There’s this paradigm or this conception that aging is just linear, that at some point, you hit a threshold and then you start losing neurons a little bit at a time. But this is actually not what happens, especially not for women, where the aging process looks more like you’re going down the stairs, and there’s very, very specific steps, which I call the three P’s, Puberty, Pregnancy, and Perimenopause. And things are fine pretty much until you hit one of these milestones. And those are very turbulent times in a woman’s life. Puberty is just as turbulent for a boy’s brain, but for a girl, there’s something more on top of just puberty, because that’s when we start having a menstrual cycle. And I think that the connection between the brain and the ovaries have been really overlooked in health and in medicine, especially in my field of neurology and neuroscience, we hardly ever consider that. And my work is showing that we really should. 

Cynthia Thurlow: [00:07:51] Yeah. It’s interesting to me how little information, certainly with my generation, there was about the changes we would experience in puberty, other than, you’re going to start having a menstrual cycle, you’ll start bleeding every month, and then pregnancy. It’s very focused on the fetus as it should be. But when I was reading your book, understanding these changes that are occurring, we used to call it momnesia, where you felt like you just couldn’t think. We used to call it placental steal. We would laugh about it. So many of us were pregnant at the same time on this nurse practitioner service I worked on, and we’re like, “Oh, it’s placental steal.” There’s more blood flow going to the baby than our brains and laughing about it, not realizing there’s actually things going on physiologically. 

[00:08:33] And then certainly by the time you get to perimenopause, I think most women, maybe they weren’t cognizant of it in the two previous P’s, but suddenly they’re aware that something is changing quite significantly. And in our traditional allopathic environment, a lot of women gaslit when they’re experiencing symptoms. And so, I definitely want touch on that and say this in the most loving way possible. As a licensed healthcare provider myself, I wasn’t prepared for what perimenopause would be like. But one of the things I found interesting that you discuss in the book is talking about the lack of medical research on women in the 1960s and up until the 1990s, and how the FDA kind of became involved in controlling what subjects were being utilized in research. And do you think that has had an impact on our evolution in terms of understanding what women experience throughout their lifetime? 

Dr. Lisa Mosconi: [00:09:30] Oh, for sure. I think that’s been a medical disaster for women. So, the female ban in medicine goes back to the 1960s, like you said, where women were excluded from experimental clinical trial, and this kind of male predominant inclusion criteria are still found in some fields of medicine, although, of course, now women are encouraged to apply for clinical trials. There’s really no system in place to ensure that a woman has the time to be part of a clinical trial, which I find problematic very often. Yes, they have some sort of reimbursement fees for travel expenses and whatnot. But what if you need a babysitter? Who pays for that? How many days can you skip at work? How much of your time can you really dedicate to something that is not your family or something else that’s important to you? So, in the end, not that many women are part of clinical trials still today. And when we look at basic science in preclinical work, this is so important to determine which kind of drugs will then move on to human testing. 

[00:10:35] Most cell lines are male cells, so we don’t have enough women in research, and even in human research and even preclinical research is strongly focused on male’s health and male’s physiology, which we know really doesn’t have that much to do with female physiology or female metabolic activity on the way that we metabolize drugs or the way that we metabolize anything for what matters. And that is especially problematic when it comes to our brains, because there’s something that is quite pervasive in medicine, which is called bikini medicine, where historically, physicians, but also scientists truly believed that women were essentially smaller men with different reproductive organs, which is like saying that, from a medical perspective, what makes a woman are those body parts that fit under a bikini, and that’s it. So that’s a problem in neurology, because your brain will never fit under a bikini. For centuries, there’s been this misunderstanding that hormones in reproductive life do not matter one bit for brain health. Sex differences do not matter, are not real. 

[00:11:49] If you even just mention them, you get labeled as a neurosexist, which is very dangerous, because what we are saying, in my field, at least, is that there are biological or physiological differences between the sexes that are important for health, not for behavior, not for intelligence, not for whether you want to wear pink or blue, that’s psychology. And I [unintelligible 00:12:14] to somebody else. But for us, there are real differences in the brain of women and of men that are especially important because they dictate the way that their brain ages. And there’s hardly any research done on it because the research has been done on men. Men have a different reproductive system. For instance, men don’t go through menopause. So, in the end, we have very little information about menopause in general and about the menopause brain in particular.

[00:12:43] And I find that to be extremely problematic because women are half of the population. All women, God willing, will go through menopause at some point in their lives. All women have brains and over 85% of women experience neurological symptoms, brain symptoms during menopause, they just don’t know that those symptoms are coming from the brain. But those are brain symptoms and we’re talking about very common textbook symptoms of menopause, like hot flashes. I can’t even tell you how many of my friends who are a little bit older, maybe, but they will say to me, “I’m having the hot flashes. There’s got to be something wrong with my skin.” Like, “No, honey, [laughs] it’s certainly not your skin. That’s your brain that’s sending mixed signals that make you feel sweaty or overheated or flushed, but your skin is totally fine. That’s actually a sign of your brain changing because your hormones are changing.” And there they would be like, “What if it happens at night?” That’s the same thing as the night sweats. We call them two different things for whatever reason, but it’s actually vasomotor symptoms is the category. And they can be very disruptive. They can disrupt your sleep as well. And so, then we have the sleep disturbances of menopause, which also can be unrelated to hot flashes and not sweats.

[00:14:00] Sleep is disturbed during menopause for over 60% of all women who just can’t sleep well. And then we know about the mood swings, right from pop culture. Hate that term, mood swings, just so disrespectful in so many ways. But there are changes in mood and affect that are very important and need addressing. And then there’s brain fog and forgetfulness and memory lapses. And these are all signs that your brain is changing along with your ovaries and reproductive health or reproductive life. So, I think this is very important information to have because so many women just really worry that they’re either getting dementia or that they’re going crazy. So, a lot of my research has been focused on really understanding what happens to your brain as woman go through menopause, what is physiological, and we write with it, and we might take hormones or look at lifestyle to feel better, but we’re just trying to support the brain during this transition. And when instead there’s something a little bit more severe, then it’s addressing in different ways. And that’s when Alzheimer’s prevention comes in handy, or neurological support and other cognitive exams or neurological exams as well. 

Cynthia Thurlow: [00:15:17] Yeah. I think this is such an important discussion because women’s needs have in many ways been misaligned with the kind of traditional rhetoric. I had the honor of interviewing Dr. Avrum Bluming on the podcast, he coauthored the book why Estrogen Matters. And he was talking about the travesty of the post WHI environment that many women were in and that got caught up in that. Maybe they were taken off of hormones or they got to a position where their providers were no longer prescribing hormones based on the results from that. So, I think it’s so vitally important to have voices like yourselves to help women better understand what’s going on with the brain and be able to look objectively at neuroimaging and being able to demonstrate this is normal, this is not normal. What can we do about these things to help navigate this second half of our lives? Because women spend 40% of our lifetime in menopause if we’re fortunate enough to get old enough to get to that point in life. And I think in a lot of ways that one of the things that I found interesting, you mentioned it in the book, but it’s something I’ve certainly noticed as a middle-aged woman myself. There’s a whole language around menopause. 

[00:16:29] There’s a great deal of cultural information that, in many ways, may make women less likely to seek help for some of the symptoms they’re experiencing. I think there’s a lot of shame and dread and ageism, and it shouldn’t be that way. It shouldn’t be looked at any differently than any other transition that women go through, whether it’s puberty, as you mentioned, pregnancy, perimenopause, these are all major milestones in a woman’s life. And so, when you’re looking at these scans of women’s brains, what are you seeing as we are making that transition in the third P, perimenopause into menopause. What is happening in our brains that is impacting how we see the world, how we feel about ourselves and this hormonal fluctuation? Because I think for many listeners, they know that we get these wild fluctuations of estrogen and estradiol in perimenopause, and towards the latter stages, we have less circulating estrogen. And that may be when women start experiencing hot flashes, a lot of those vasomotor symptoms, brain fog, etc. What are you seeing on these scans that are kind of reinforcing this progression neurologically and physiologically as we’re navigating into menopause? 

Dr. Lisa Mosconi: [00:17:46] What we’re seeing is that menopause is a neurologically active state where many different functionalities of the brain are subject to change. And by doing brain scans in women who are either at different stages of the menopause transition or by following the same woman over time, which I find fascinating, we’re able to map out changes that are associated with the menopause transition. And what we have found is that, number one, yes, menopause clearly has an impact on many different functionalities inside the brain, chiefly synaptic volume or gray matter volume, white matter volume, as well, metabolic activity, which we measure in different ways. And I’ll tell you more about it because I think it’s relevant to your line of work as well. There’s definitely changes in blood flow, and we find that for some women who either have a family history of Alzheimer’s disease or have some genetic risks for Alzheimer’s disease, perimenopause is when we are able to detect the very first signs, the very first red flags for Alzheimer’s in their brains, which are amyloid plaques or Alzheimer’s plaques. 

[00:19:07] And another team was able to detect presence of tangles inside neurons. And I’m not saying that all women develop these changes or that these changes mean that they’re going to develop dementia. That’s not the case. It’s more like when you’re looking for risk factors for cardiovascular disease, we look for high cholesterol levels, for instance or presence of plaques in the vascular system. Those are the risk factors for a heart attack. They do not mean that you’re definitely going to get a heart attack. So, the same thing is true for the brain. If you have these signs, then your risk of future dementia is higher as compared to a person who does not have any of those signs. But they are in no way a diagnosis or a prognosis. So, this is really important to clarify. 

[00:19:53] Now, going back to menopause, there are many changes that we see in the brain. In my hands, at least, the clearest change is in metabolic activity inside the brain. And we measure that in two different ways. We use two imaging techniques that I’m sure you’re familiar with, but just to explain a little bit. So, the first one is called positron emission tomography, or PET. And we use a tracer called fluorodeoxyglucose, which is effectively a simple sugar, like glucose. And glucose is the main energy source for the brain. So, we’re able to basically take a glucose and attach a little gamma ray emitter to it, which is like a little GPS that shoots out light. And then we just inject the tracer, it’s in very, very small amounts. Nobody can feel it. It will not give you insulin resistance for sure. It’s like microscopic doses. The tracer goes up in the brain and binds to all the different parts of the brain that require sugar to make energy to convert glucose into ATP. And then the tracer sticks right there, and we’re able to take pictures from the outside of the light that the tracer is sending out. 

[00:21:06] So, I think it’s beautiful, and I’ve been doing it for many, many years. I’m a total nerd [laughs] when it comes to imaging, but I think it’s fantastic that we can do it. And what we’ve seen is that the metabolic rates of glucose in the brain decline as women go from premenopause to perimenopause and then the postmenopausal transition. And actually, the phase that is most sensitive to these changes, where we can see the biggest jump is not menopause or after menopause, but it’s before. So, it’s what we call perimenopause which is the transitional phase when you start skipping your periods in estradiol, like you said, “Is all over the place.” It’s like peaks and valleys, peaks and valleys. And progesterone is already going down. And other hormones, like the follicle stimulating hormone, is actually starting to increase. So, your brain is a little bit in a flummox because all these different hormones attach to different parts of the brain.

[00:22:07] And then one second the estrogen is saying, “Work harder,” and then the minute later, the estrogen is saying, “No, actually, you know what? that just flushed off for the night, and you crash and burn in a way, because estrogen– One of the many functionalities of estradiol is that it increases energy production in the brain. It’s like an activator. It makes your brain cells work harder. And so, it’s like pushing you to work harder, and then it’s telling you to stop and then push and stop, and push and stop. It can cause a lot of confusion in many ways. So overall glucose metabolism, the overall concentration goes down by about 30% and this actually varies. There are women who show no changes and women who show more severe changes that tend to correlate with the severity of the symptoms that they report.

[00:22:57] Women who tell us, we have very severe hot flushes, maybe they’re more frequent or maybe they last longer, maybe they’re more intense. They tend to show a little bit more of these changes in their brains. There are women who just don’t have any issues during menopause, which is amazing. It’s about 10% of women, and that correlates with lack of strong changes in the brain. So, then the other thing that we’ve been doing just recently is to use another technique that’s a little bit newer in some ways, or at least has been improved technologically very recently. It’s called magnetic resonance spectroscopy, MRS. And we’re one of the few centers in the states, as far as I know, who has the 31-P coil. So, it’s a phosphorus-31 coil. So, we’re able to actually map ATP directly in the brain, the intracellular concentration of ATP in the mitochondria. And what’s really interesting is that if you do that, you’ll see that women’s brains are actually pushing out more ATP relative to the phosphocreatine bank that we have.

[00:24:03] So we all have a certain amount of phosphocreatine. So, it’s creatine with a phosphate attached to it, and we need to have a little buffer. It’s like a little piggy bank for energy. And then when the brain needs energy, converts that into ATP very, very quickly. You want them to be in a balance. You don’t want to exhaust your reserves, you don’t want to run out of cash. And what happens in women’s brains in menopause is that they spend too much money relative to how much money they have in the bank. So, they try to overproduce ATP as a compensatory reaction probably, relative to the phosphocreatine buffer. So, the ratio goes down, which was a very interesting study. We published it in Scientific Reports, which is a Nature journal. And yes, so basically bottom line the brain is under metabolic stress during menopause, especially during the transition to menopause, which I think is the most novel aspect of a research, because when I started looking into menopause, that was 2016, there wasn’t a single imaging study that looked at menopause like before and after. 

[00:25:10] Everything was done after, but a long time after, like in women who were in their 70s and 80s. But menopause is like 50, and you need to start in your 40s if you really want to understand what’s happening. So that was incredible for me, that I had absolutely nothing to compare our data to, which is stressful [laughs] if you’re a scientist, like, “Oh, my God. Do I need to rely on mice?” And basically, the answer is, “Yes.” So, we switched gears and we applied a translational approach by working with one of my mentors, Dr. Brinton, at the University of Arizona, whom I absolutely adore. She’s such a rock star. And we’re able to base our hypothesis driven studies on her preclinical work. So, she provides the mechanistic analysis and the knowledge, and we’re able usually to test it in humans, which I think is a wonderful approach. So, it’s a very comprehensive look at menopause. And I think the bottom line is that there are changes in everything we’re measuring, also connectivity. The connectivity of the brain also changes.

[00:26:16] Like, the brain is rewiring itself a bit. And that comes with pros and cons. The cons are obvious, the symptoms and the mental fatigue and the brain fog and just not feeling like yourself. So, it’s really important that we have this data showing that we’re not making it up. This is actually changing. Your brain is changing. Most women can feel it. And it’s important to have this information because it validates what women have been saying for thousands of years really and medicine just won’t listen. So, I’m hoping that this is helpful. Many physicians and many clinicians reached out to us by saying, “Thank you. This is the hard evidence that I needed to really be a better doctor for my patients, because now I know what’s happening.” It’s insane that that happened in 2017 for the first time.

Cynthia Thurlow: [00:27:06] It’s hard to wrap my head around this because there’s multiple layers to why there probably wasn’t enough study and focus. It starts with the fact that clinicians, residents in obstetrics and gynecology, get little to no training around women in menopause. I think it’s up to the residency programs, whether or not the physicians even get training around this. And then even I think there might have been a sentence in my nurse practitioner training. [Lisa laughs] It was like, “You drop off a cliff.” And I was in my 20s, and I was like, oh, I’ll eventually worry about that. But I think that there was this lack of information and then obviously lack of research, and that’s why your research is so needed. And I feel like women in middle age are perhaps having a moment. There’s a lot of women that are using their voices and speaking up. And so, I think that future generations will really benefit from the work that you’re doing. And certainly, when I look at the work that you’re doing, and just from a personal perspective, for me, it really opened up my eyes to why it is so important to focus on lifestyle and then the additional considerations, which I’m sure we’ll probably talk about. Let’s talk about hormones. 

Dr. Lisa Mosconi: [00:28:16] Everybody is like, “hormones?” [chuckles] 

Cynthia Thurlow: [00:28:18] Yes, let’s talk about hormones. Because you touched on some of the hormones that are changing in perimenopause, reduction of ovarian function, less circulating progesterone, wild fluctuations in estradiol, high FSH, etc. But I think that the conversation would be remiss if we didn’t kind of walk through why lab work is helpful. And you mentioned quite a bit of information about the severity of symptoms during that transitional period and the impact on brain health. I think that’s quite significant. I know that one of the things that I talk quite a bit about is usually the women that have the worst vasomotor hot flashes symptoms are also women that are more likely to be insulin resistant. So metabolic health becomes very, very important. So, when we’re talking about the hormone piece, is it just estrogen that is impacting the changes that women are feeling in their brains? But is there also contributory things relevant to testosterone and progesterone that you’re seeing in your research.

Dr. Lisa Mosconi: [00:29:21] Yeah, for sure. Estrogen is by far the most studied and best characterized of hormones, but it is by no means the only one important. I think in medicine and in science, we have this tendency to just focus one thing at a time because you really have to go vertical, you really have to go deep. And estrogen is extremely bioactive, so it’s easier to see an effect statistically in some ways. And I’ll go back to Dr. Brinton, who’s done such incredible work for decades about estrogen in the brain. And she came up with this expression of estrogen as the master regulator of women’s brain health because it is such a versatile hormone in such way, it’s implicated in a gazillion functionalities that the brain needs to really thrive and remain healthy over time, from neuroplasticity to having a neurotrophic effect, to reducing inflammation and improving blood flow and also energizing the brain. However, progesterone is also very important and so is testosterone in some ways for women’s brains. What I would say is that in here the words become a little bit tricky, I believe. But when I use the term women, I’m referring to cisgender women at this point. So, individuals who were born with two X chromosomes and the female reproductive system, which I’m perfectly aware it is not a universal definition of women, but just stay with me for now. 

[00:31:03] So if you’re born with two X chromosomes that give you, in part a reproductive system is considered female, so ovaries, uterus, breasts, tissue, then these organs come equipped with estrogen receptors, very abundant receptors throughout the [unintelligible 00:31:24] again, reproductive system. But at the same time, those same receptors are found in your brain in very high concentrations relative to the androgen receptor. So as women, we have a lot of estrogen receptors in our brains. We have also quite a lot of progesterone receptors, but not quite as many as the estrogen receptors. And we have receptors for the gonadotropin releasing hormones as well, FSH and LH for just the pituitary gonadotropin. We have receptors for testosterone, which are called androgen receptors. But if you look at the big picture, the estrogen receptors are really running the show in some ways. And I think that’s one reason that a lot of research has been done on understanding estrogen functionality and replacing estrogen as the primary hormone that we’re trying to supplement during menopause.

[00:32:17] But obviously all hormones are important and it’s important to realize that the neuroendocrine system involves so many different moving parts and is this incredible system that we never talk about that we are born with, that connects the brain with the ovaries and every other part of the hormonal system that gets activated during puberty, it gets overactivated during pregnancy, and then is in part deactivated and turned off after menopause at least for the reproductive part. And this activation and deactivation has an impact on the entire system. So, it just makes sense that whatever happens in your ovaries will have an impact in your brain and will have an effect in your brain as well. So, yes, I think estrogen is very important. All hormones are important. And at this point in time, we’re focused on replacing estrogen primarily. But I think that’s a reductive way to think about menopause. 

Cynthia Thurlow: [00:33:18] Yeah, it’s really interesting. And for listeners that are probably familiarized, there’s different types of estrogen, and our body makes predominantly estradiol prior to menopause, I’m probably oversimplifying things and then our body will try to make its own estrogen source. So, we’re talking about estrone. What has your research shown about making estrone, which is a weaker form of estrogen our body will make, unfortunately, in fat tissue, adipose tissue. I know women loathe and hate suddenly feeling like they’re a little more fluffy, or there are changes in body composition relevant to this, changes in sex hormones. What helps differentiate estradiol from estrone in menopause, like, from your perspective as a scientist? 

Dr. Lisa Mosconi: [00:34:01] Well, they are different forms of estrogen. So, estrogen is an umbrella term that includes many different types of hormones. And estradiol is the one that we all want, and we all talk about the hormone everybody loves. But estrone is also just as important. It’s just that before menopause, the concentration is fairly low relative to estradiol. But starting in perimenopause and more so after the menopause transition is complete, then estrone becomes the most abundant form of estrogen in your body. And like you said, “It does not come necessarily from the ovaries, but it’s made by using body fat and other sources.” It’s important to have estrone and I think nobody tries to supplement it, which I think is funny. [chuckles] Although there is a formulation of HRT that’s called CEEs, conjugated equine estrogens that were used in the Women’s Health Initiative as the only source of hormone that is a combination of different estrones that come from the urine of pregnant horses or pregnant mares. And that seems to be helpful in many, many ways. But there is a tendency right now to move towards bioidentical estrogen, which is actually estradiol, because that’s really what we’re trying to maintain for as long as possible. 

[00:35:22] And I think you’ll appreciate this. There’s accumulating evidence that longer estrogen exposure throughout the lifespan seems to be protective against dementia and cognitive decline and also depressive disorders, anxiety, osteoporosis, and other diseases of old age. Depression is not a disease of old age, but diseases then impact you more, I guess, as you get older, may impact you more at that stage. And I think that’s one reason that we’re trying to really find the best way to keep your estrogens high and strong for as long as we can, even after the ovaries stop producing estradiol. And, of course, this is very controversial because it’s good to go through menopause. It’s actually a wonderful thing. I know this may sound very strange, [chuckles] but from a scientific perspective, it’s a wonderful thing, because menstruating is extremely demanding metabolically, energetically, not just for the body, but also for the brain. You need to have a huge amount of neurons in your head to support having a menstrual cycle and host a pregnancy, in case the menstrual cycle turns into a pregnancy. And it is arguably better to stop doing that when you’re done having children. 

[00:36:48] So, from an evolutionary perspective, menopause is a really good reason to be. The point is we don’t want to suffer. So, menopause is one of the very few scenarios in medicine where silent suffering is not only accepted, but is actually encouraged, and that is unacceptable. While at the same time, women are taught from a very young age to doubt our hormones and our brains, actually to fear our hormones almost and doubt our brains. So, we’re really left in this terrible situation where there’s hardly any information given. So, you don’t know what’s happening to you. Your doctors don’t really want to talk about menopause that much, unless maybe you want a prescription, which a lot of women don’t want, especially in this country, because they’re scared of hormone therapy for reasons that maybe we can discuss. And so, we’re really in the soup, and we’re trying to revamp menopause as something that is not alien, there’s a reason for it. There’s a reason for the symptoms, nobody’s hijacking your brain.

[00:37:50] But at the same time, we want to make sure that nobody suffers, that we are providing the education that women need so that they’re not fearful to use the tools that we have available and also then provide the tools like hormone replacement therapy if appropriate, lifestyle interventions when appropriate. There are so many things that one can do that I discuss in detail as well in the book. And then as a scientist, we’re trying to develop new formulations, estrogens in particular, that are very selective for brain health and do not touch the rest of your body. In fact, what we’re trying to do is to develop an estrogen that supports brain health and supports brain energy levels, but has an inhibitory effect on reproductive tissue. So, it decreases risk of uterine cancer and breast cancer while potentiating brain health. And we’re doing a clinical trial right now. So, I’m very excited about that. 

Cynthia Thurlow: [00:38:46] That’s really exciting. And I think for everyone listening, whether you are in your 30s, not yet thinking about perimenopause, you’re in the throes of perimenopause or in menopause, understanding that there are options and being able to work with practitioners that can help you navigate, what are your best options available. Now, I do want to kind of quickly touch on the HRT piece, because you and I both know, post Women’s Health Initiative, there were a lot of women taken off of HRT. My mother was one of them. We were talking about this before we started recording and how different her life was before and after. She went through debilitating pain and arthritic-type symptoms in her hands and in her feet. She was a very high functioning person, had a very demanding job. And she would be the first person to tell you at 77 how different her life has been because she’s got everything that happens in menopause if you’re not on HRT. She’s osteoporotic, she’s becoming frail. And she would talk about this openly and she’s given me permission to talk about it more inflammation, lipid issues, etc. 

[00:39:53] So let’s talk about some of the benefits of HRT from a broad perspective and then some of the new treatments. You kind of touched on this new type of estrogen that is going to be brain selective, which is certainly really exciting. But let’s talk a little bit about HRT because I think this is still important even to hear about it from a research perspective. Where have we gone post WHI, because HRT was used quite frequently. I think it was in 1942, that Premarin was the number one prescribed drug in the United States, and in 1992 had a billion dollars in revenue. And then we go to Women’s Health Initiative and things shifted quite extraordinarily.

Dr. Lisa Mosconi: [00:40:33] Yes. I mean, to the point that today only 4% of all women of menopausal age are prescribed hormone therapy for menopause in the United States. It’s more like 50% in England, but only 3% to 4% in the United States, which is really a handful of women in the end. And even then, reluctantly, I think a lot of women, at least from what I’m hearing, a lot of women have to really beg or push or change practitioner, which is always challenging for a number of reasons. So, I think the education around the history of HRT is also interesting, it’s really important to have. It’s important information to have. So, the Women’s Health initiative was a major fail in many, many ways, but it does– I really want to acknowledge the fact that the individuals who planned the study were nothing short of visionary in so many ways. I appreciate them so much because the study started in 1993, which means that they had at least two years prior to the start date to just come up with a study design. So, we’re looking at the early 1990s when, for example, no one was talking about prevention, certainly not in neurology. The idea that Alzheimer’s disease and dementia could be prevented was like completely– Nobody would use the word prevention, but they did. 

[00:42:03] And they did an entire huge clinical trial to try and see if taking hormones could be preventative against dementia, as well as cardiovascular disease and other risk factors and other chronic diseases. And of course, if HRT could reduce hot flashes. So, we’ve learned quite a bit from the Women’s Health Initiative. Mostly we learned what not to do. We learned very clearly that starting hormones late in life, like over a decade past the final menstrual period, comes with risks. Some benefits, for sure, but also some risks. We also learned that some formulations are safer than others. Back then, the trials use the CEEs, the conjugated equine estrogens at high doses and take it orally by mouth, which is a little bit harder on your system because it has to go through the liver, so it increases the risk of clotting, which is a risk factor for heart disease and stroke and heart attacks in turn. And then they were using a very specific type of a progestin, which is a synthetic formulation that mimics the effects of progesterone in your body called MPA. And that specific type of progestin has been linked with an increased risk of vascular damage relative to other forms of progesterone, like micronized progesterone, which is known as bioidentical progesterone, and also other progestins, which are gentler somehow on the vascular system. 

[00:43:37] So we’ve learned that specific combination is perhaps not the one we want to use today. So, most OB-GYNs are switching towards bioidentical estradiol and progesterone, which haven’t been as well studied in clinical trials. But they think they have been studied well enough to know that they are much safer than other formulations that were used in the past, especially when– estradiol is now given transdermally rather than orally. So, there’s the patch, there are creams, there are sprays. And I’ll tell you this, I have two colleagues I work with, Dr. Brinton and Terry Milner at Weill Cornell Medicine, who are pioneers in the studying of estrogen and estrogen’s effect on the brain. And I asked them, “Hormone replacement therapy, yes or not?” And both of them are like, “Yes.” I said, “Okay, when and how?” Because whatever you’re doing, I’m doing, they’re fantastic. And transdermal, either patch or even a spray, you can spray it if you want to have a very gentle start of your therapy and bioidentical progesterone by mouth, orally.

[00:44:41] So, according to the Menopause Society, for most healthy women who are going through menopause, taking hormones is effective and safe. You can start them as early as perimenopause. You don’t have to wait until you are postmenopausal. Actually, technically, they’re designed to be taken during the transition because you want to counterbalance the fluctuating effects of estradiol. You want your concentration as stable as possible and then support your levels over time. So that would be ideal at least from a scientific perspective. And you can keep taking those hormones for as long as you have symptoms, which is another change from the previous version of the guidelines of professional societies, which were amended in 2022. 2022 was a big year for HRT. And also, another thing we learned is that if you want to start taking hormones a little later, more than 10 years after your final menstrual period, if you have symptoms, that’s actually an opportunity to address the symptoms. So, you’re never too old to start taking hormones as long as you’re eligible. And you have active symptoms of menopause. 

[00:46:00] So that’s also something that I find very encouraging and very interesting. I would say, be careful, be smart. Go for your mammogram. If you have a high breast density, go for a sonogram as well, just to be absolutely safe. Pap smear tests, really, really important, especially as we get older. And I will throw some brain scans in there, because one thing we learned from the Women’s Brain Initiative is that those specific hormonal formulations that were used in the WHI actually increased vascular damage in the brain. They have been associated with an increased risk of vascular damage in the brain, if you had it already. So, if you already harbored an impaired vascular system or perhaps if you had the plaques of Alzheimer’s disease already, then the hormones will make it worse in those women, at least. We don’t have any information with the newer formulations, other than studies showing that they are broadly safe at any age. But again, you want to be extra careful. So, I would also do a brain scan and just make sure that my brain is 100% fine. If there’s anything that needs addressed and we address it, and then you start therapy. But I know we’re not there yet. 

Cynthia Thurlow: [00:47:10] When you’re saying do a brain scan, you’re talking about a PET scan. 

Dr. Lisa Mosconi: [00:47:14] No, I’m thinking MRI scans in this case.

Cynthia Thurlow: [00:47:17] MRI. Okay. 

Dr. Lisa Mosconi: [00:47:18] Yes. At older ages, like, if you’re older than 65, make sure that there’s no sign of vascular damage. 

Cynthia Thurlow: [00:47:25] That certainly makes sense. 

Dr. Lisa Mosconi: [00:47:25] For me. I mean, it’s not necessary, and it’s not something that people say you should do, but I think at some point, it’s something we want to do anyway for screening, right?

Cynthia Thurlow: [00:47:35] No, absolutely. And just to kind of tie up our conversation today, a lot of what we talk about on this podcast is lifestyle as medicine. And I know in the book you do spend some concerted amount of time talking about lifestyle and how that can manage and mitigate that transitional period in our lives. Give me two or three of your favorite lifestyle recommendations that we can take away to kind of pack along with the HRT, thinking about imaging, etc. 

Dr. Lisa Mosconi: [00:48:03] So, number one is exercise, and I think it may be helpful to tailor the exercise to your symptoms or concerns, because we know that cardio, for instance, cardiovascular fitness, is effective. It really helps balance thermoregulation. So, it seems to be especially effective at relieving hot flashes and night sweats. And it has been shown time and time again to support cognition and reduce, hopefully, brain fog, but then strength training or resistant training is associated with better metabolic activity and also better mood in women going through menopause. So, I think that’s also important information to have. Whereas flexibility exercises, including yoga, Pilates, tai chi, are not just good for flexibility, obviously, but also for sleep and stress reduction. So, in an ideal world where every woman in midlife has a ton of time to take care of herself, you would do all three. But if you can’t, then I think it’s good to either switch it off or tailor your exercise routine towards really supporting your health and addressing your health needs. I just bought a reformer machine– 

Cynthia Thurlow: [00:49:29] [crosstalk] Pilates. 

Dr. Lisa Mosconi: [00:49:30] Oh, my God. I adore it. And that was our gift to me for Christmas, was this reformer. My daughter enjoys kind of playing with that with me, but for me, it’s been really life changing. It makes such a– I’m sitting all day in front of a screen, so my neck, my shoulders are always like, “Oh, God, this is not good.” Inflammation to the top part of your body is too close to your brain, in my experience. So, inflammation in your mouth, inflammation in your neck, has a preferential access to your brain. It’s too close. So, it’s really important to stretch and make sure that everybody addresses that. But so that would be exercise for me. Number two, diet because everybody eats every single day. So, every day we have an opportunity or maybe three opportunities, to make a smart choice and really support brain health or not. And every person has different diets and dietary habits. But I think one thing that seems to be important for women’s brain health is to eat more fiber. If nothing else, I would say fiber and antioxidants. So eat whatever you like. I never say you should be eating one diet over another, but I find that a lot of people do not eat enough fiber-rich foods for whatever reason. 

[00:50:58] In that case, I think that even a fiber supplement might be helpful for some. And then antioxidants, antioxidants, antioxidants. So, the brain and the ovaries have one more thing in common, which is that they’re both born with a finite number of cells. So, your neurons are born with you. They stay with you for a lifetime. Yes, you can regrow some synapses and some neurons here and there, but for the most part, your neurons are born with you and die with you. And the same happens in the ovaries. That we’re born with a certain number of egg cells, and at some point, we run out, and that’s why we go through menopause. So the best way to preserve cells and reduce cellular aging and insults or damage to your cells is to consume antioxidants, one of the best ways is to consume antioxidants from your diet, because these high metabolic cells, unfortunately produce a lot of oxidative stress just by virtue of being very active. Therefore, we need to import the antioxidants from the diet and vitamin C, vitamin E, vitamin A, beta-carotene, selenium. These are the key antioxidants that mostly come from plant-based foods. So, it’s important to eat the fruit, veggies at least if you don’t eat fruit, but yes. So that’s for diet.

[00:52:22] And then my third tip would be stress reduction. So, your sex hormones, like you were saying before that the hormonal system works as a whole. So, your sex hormones work in balance with your stress hormone, as well as other hormones as well. So, when you’re too stressed, when you have too much chronic stress in your life, your body needs to increase the production of cortisol, which is the main stress hormone. In order to do that, it needs to draw away from the hormone reservoir, which is called pregnenolone. So, there’s a pregnenolone steal by which the body reroutes resources towards cortisol, which means that there aren’t enough resources left for your sex hormones, like estradiol, which really plummets as your cortisol goes up. So if you can reduce your stress and your cortisol goes back down to normal levels, then your body has a chance to up the production of sex hormones that we want. Whereas the cortisol, we don’t really need that much of. So, I think stress reduction is becoming a very important component to brain health as well as overall health. And we’re all really stressed. I know everybody I know is under stress. So, it’s important to think about stress reduction techniques and try to find something that really works for you that is sustainable over time and that you can do consistently. 

Cynthia Thurlow: [00:53:44] It’s really the key finding things that are sustainable that we enjoy doing. Dr. Mosconi, it has been such an honor to connect with you and share your amazing new book but obviously, all of your work with my community. Please let my listeners know how to connect with you on social media, how to get access to your new book, which will be out in March.

Dr. Lisa Mosconi: [00:54:03] So, The Menopause Brain, I have it here with a beautiful forward by Maria Shriver-

Cynthia Thurlow: [00:54:08] I saw that.

Dr. Lisa Mosconi: [00:54:08] -which is such an honor. She’s such an incredible person and just an incredible woman, and one of the fiercest women’s health advocates out there. Goodness, she is a powerhouse and she’s so sweet. I’m really, really happy that she’s on the book. And she wrote the foreword for The XX Brain as well. She was a little good luck charm. I’m super blessed. So, the book comes out March 12th, can be found online on Amazon or any bookstores and online retailers. Finding me is easiest on my website, which is just my name and last name, lisamosconi.com and on Instagram @dr_mosconi. So, it’s D-R, I have no idea why they put an underscore in there, but there is an underscore, Mosconi. M-O-S-C-O-N-I. 

Cynthia Thurlow: [00:55:01] Well, this has been such a pleasure. Thank you again. 

Dr. Lisa Mosconi: [00:55:03] Thank you for having me. It was so nice to see you almost in person. 

Cynthia Thurlow: [00:55:08] Yes. 

[00:55:11] If you love this podcast episode, please leave a rating and review, subscribe and tell a friend.