Menopause Mythbusting | with Why Midlife Changes Your Brain and What Helps | Lisa Mosconi, PhD

0:00So according to my guest today, there is a moment that many women experience in midlife where many things start to just feel off. Memory feels unreliable, sleep gets fractured, emotions feel closer to the surface, and quietly, a question starts to form. What is happening to me? Today's conversation is a deeply grounding answer. My guest is Dr. Lisa Moscone, a neuroscientist at Weill Cornell Medical and one of the world's leading researchers on women's brain health. Her work focuses on how women's brains change in midlife and beyond with a focus on how menopause reshapes the brain and why this transition is far more neurological than most of us were ever told.

0:39We explore why Alzheimer's risk actually begins in midlife, what estrogen does inside the brain, and how brain fog and mood shifts are signs of adaptation, not decline. We also talk honestly about things like hormone therapy, where the science is now, and what questions still need to be answered. This is a conversation about replacing fear with understanding and confusion with clarity, and maybe most importantly, about trusting the intelligence of a brain that is learning how to function in a new way. So excited to share this conversation with you. I'm Jonathan Fields, and this is Good Life Project.

1:21It's fun to have this conversation with you. You were born and raised in Florence. From what I understand, your parents were scientists, so you have been around the world of science and exploration, literally since, you know, the earliest possible days. And as you moved into your career, spending a lot of time studying women's brain health. This is also very personal for you, though, because you could have gone a lot of different directions. But tell me what really drew you to say, like, this is where I want to invest so much of my time and energy. Yes, when I was going through university, I studied neuroscience, and then I was starting my PhD also in neuroscience and nuclear medicine.

2:00So really the apple did not fall far from the tree. That's when my grandmother started showing signs of cognitive decline and cognitive impairment. And that was really shocking and heartbreaking in many different ways, including that she was such an intelligent woman. She was so mentally strong and active and so fiercely independent. She would take care of everything for everyone. She was a little bit like the heart of the house, but also the brains of the family in a way. And then she really started not being able to enjoy her life. And that was terrible. But what was perhaps even more frightening is that my grandmother was one of four siblings, three sisters and one brother.

2:59And all three sisters developed exactly the same kind of cognitive decline and then dementia. My grandmother eventually was diagnosed with Alzheimer's disease and dementia. But the brother did not. so I think for my mom her cousins her female cousins and for myself that was a big red flag it was just is it just our family that is so deeply impacted by Alzheimer's and especially women in the family or is there a bigger lesson that needs to be learned and that's what shaped my trajectory and my career ever since. I mean, when you see that something and it touches you so personally on a day-to-day basis, how could you not?

3:47And especially that ratio that you described, you know, like three sisters, one brother, all the sisters experienced the same thing. And the brother somehow escapes this fate. And I would imagine as a young woman in this family too, you're wondering, how can I understand this? And also, am I going to be okay? Is my mom going to be okay? And is there a way to understand what's really happening here? And maybe we can, you know, understand, is this our fate? Is this, are there other circumstances or contributors? When you eventually decide to say, okay, I'm going to really dive into this question.

4:25I mean, it seems like that really sets your career in motion. It leads you down a path of going deep into exploring women's health with a focus on the brain. But when you do that also, and tell me, correct me if I'm wrong here, carving out women's health or like saying, I want to study women's brains. I would imagine there are a lot of raised eyebrows, people saying, but what's the difference? Like why women only? Isn't it just, isn't a brain a brain? Yes, and you're so right. And this is one of the biggest, or at least one of the earliest pushbacks that I've received back then. So there's this notion in neuroscience, that really, really permeates the field of neuroscience, that sex and gender do not matter one bit.

5:13There are, of course, some neuroscientists that specialize in sex differences, in neurological disorders, in the neurosciences, but we are a minority. And when I started, that was a long time ago I published my very first paper in 2003 so that was a really long time ago and I was still a student I hadn't even finished my PhD back then I had just started and I went to my mentors and to my supervisors who are absolutely fantastic really I was so fortunate and so lucky. And they said, I really want to understand genetic predisposition in Alzheimer's disease, because I thought it's got to be genetic, with an eye on sex differences, and whether or not it matters for women, especially.

6:09And they said to me, and this is something I still get every day, almost in my line of work, and this is more than 20 years ago, right? they said well we do know that more women than men suffer from Alzheimer's disease. So we have known since the 1990s that after getting older after aging itself being a woman is the strongest risk factor for Alzheimer's disease. So much so that today almost two-thirds of all Alzheimer's patients are women. I want to reinforce it. So number one risk is age. Number two behind that is being a woman. Yeah, being born with two X chromosomes, yes. Right. Yeah. But women live longer than men, and Alzheimer's disease is a disease of old age.

7:04So unfortunately, at the end of the day, more women than men have Alzheimer's disease. And that makes sense in principle. But once you look at the actual data, Women don't live that much longer than men. So in the United States, the difference is four and a half years, 4.4 years. In England, the difference is two years. And Alzheimer's disease is the number one cause of death for women and not men. And the gap in prevalence is, again, is the 2 to 1 ratio. So it can't just be lunged up. also, if it was just aging, then women would also show a higher risk of other age-related dementias. Right, that would make sense, yeah.

7:52Vascular dementia, Lewy body dementia, frontotemporal dementia. There are many different types of dementia. However, we do not. It is only Alzheimer's disease. I could give you counter arguments for the next half an hour because I have looked into this forever, but I'll just, long story short, I decided to look into that. And we can now really say that the field has changed, that our understanding has changed, and that we've all come together to understand that the premise was incorrect. Alzheimer's disease is not a disease of old age. It is a disease of midlife with symptoms that start in old age.

8:39But the actual disease, the process that leads to the symptoms starts decades prior in midlife. So that completely changed the question to, well, if Alzheimer's disease is a disease of midlife and women have a higher lifetime risk as compared to men starting in midlife, in fact, starting at age 45, then the right question is, well, then what happens to women and not to men in midlife? They could explain the higher risk down the line. So many questions. I feel like the last, I don't know, three, four years, this has become a topic of such public discourse in a way that I've never seen before. And you've been become much more forward facing about it.

9:35There are a group of people that seem to be really pushing this and in no small way, normalizing the conversation. Do you feel like that's a right word? I think that's a beautiful, beautiful word. I thought you were going to talk about the menopause wars where people are almost, you know. Yeah, we're seeing that too and we may touch into that. Yeah. I think normalizing the conversation is so important and so necessary. And we should be doing more of that because, you know, all women who live to meet life will go through menopause. It's unavoidable, almost like puberty. Right? There are three major neuroendocrine or hormonal turning points, or there can be, in a woman's life, which are puberty, pregnancy, which is optional, and perimenopause, which is a transition to menopause.

10:32And as a society, we're well-equipped to support a woman as she goes through puberty. And then especially when she gets pregnant, we have parties and baby showers and celebrations and there's zero support in place for menopause, which is a universal event all over the globe. In fact, the understanding of menopause is of something that puts a woman at a disadvantage, right there is so much stigma there is so much bias there are there are stereotypes around menopause and what a menopausal woman is supposed to be or act like that are harmful or demeaning and really need to be addressed when i started looking into menopause as a scientist but also as a woman, what struck me the most was the complete absence of a sense of accomplishment, or even just stardust gained, or the notion that you have reached a very important milestone in your life.

11:46And there's no celebration, there's no acknowledgement, and so many women just go through it in silence. They feel like nobody wants to hear about this. Nobody wants to know my story. And that is not true. That is so not true. I think there's so much desire to learn from older women, from women with more experience. And I find this so beautiful when women do share their experiences and their thoughts and how they have dealt with certain situations. It's such a gift to younger women. For me, it was wonderful when my mother talked to me about her menopause and when her friends would talk to me about it.

12:32And now I talk to my daughter about puberty and pregnancy so that she doesn't have to be confused. She doesn't have to be taken aback when that happens. I want her to be empowered to just take care of herself and get a hold of her life at any age and any hormonal transition point. That makes so much sense, right? Because you were describing, you know, there are these three potential really major transitions. You know, there's puberty, there's childbirth, if a woman decides that that's right for her. And there's, you know, perimenopause or menopause. Should you be blessed to actually live to a point where you move through it?

13:17And we do have, like, there are rituals. There are things where you know what to do and how to handle it in conversations for the first two, but there's really nothing. For menopause, in fact, it's almost like the opposite. Let's not talk about this. It's uncomfortable. So we just kind of push it away rather than you're saying, no, let's ritualize this similarly. Let's celebrate it and let's bring it forward. Yes. And the other thing that we need to do is to provide a framework. We need to formalize menopause in the medical and scientific field first, because that is going to be the backbone for all women that they can refer to.

13:54And right now, we are missing this understanding that we otherwise have for puberty and for pregnancy and for other things that can happen in women's health. But we do need to formalize one thing, for instance, that so many women don't know. There are so many, so many things that most women don't know about menopause. And one thing that is important to me to really explain is that there is a range of symptoms and responses to any hormonal transition state. And I think that that really brings everything into perspective, if I may share. Yeah. Okay. So when you go through puberty, right, a lot of girls experience changes in body temperature.

14:44You start sweating or you have the chills. You start noticing the weather more at that point. You may experience changes in sleep, sleep quality, sleep quantity. How many teenagers just sleep until noon and they're up all night? The pattern is changing. There are changes in mood. For many women and men, puberty is when you first experience anxiety or depression or related symptoms. right? It's a turning point. It's an inflection point for mood changes. It's an inflection point for libido, for sure, right? And it's an inflection point for memory, consolidation, attention, and language. We understand that because it's a system.

15:34There's a system in the body called the neuroendocrine system that connects the reproductive organs with the brain. And as the system evolves and develops and changes, so does part of the brain. So then fast forward to pregnancy, 30 % of pregnant women experience half-flashes, which are changes in body temperature. Lots of women had trouble with sleep. Lots of women had trouble with mood. We talk about the mommy brain, right? We talk about the baby blues. We are aware that when your hormones kick in and then drop out, that can impact a woman's mood. There's brain fog when you're pregnant. Lots of women have brain fog.

16:20They have trouble remembering things. Some feel like they have ADHD all of a sudden. And that resolves over time, usually when the kids are like two years old or so. So the same exact symptoms come back or may appear for the first time in menopause. We have the half flashes and night sweats, which are changes in the way that the brain regulates body temperature. There can be anxiety and depression. There are certainly mood changes. We used to say swings, but that is not really nice. So we say mood changes or changes in mood patterns or mild depressive symptoms. definitely sleep issues, insomnia or fractured sleep.

17:06And then, like you said before, the brain fog is a huge concern. The memory lapses, the attention issues, fluency when you can't come up with words that you're very familiar with. Those are the same symptoms. However, when it comes to puberty and pregnancy, we understand that these things can happen and that there is a range. Some women don't have any of those symptoms. For some women, they may be mild or moderate, or in some cases, severe. When it comes to menopause, there is no formal understanding or framing that there is a range, that some women, about 10 % max, have no particular symptoms other than reproductive changes, but almost 90 % do experience some brain symptoms, some neurological symptoms.

18:00And this needs to be better studied, better researched, better understood, and then shared with women so that nobody panics when these things happen. I was doing a podcast the other day with my friend, Dr. Mary Claire Haver, and she was like, I'm not in menopause, not even close to menopause yet, as far as I know. She was like, are you scared of going through it? I was like, no, why would I be scared? I trust my body, I trust my brain, and I trust my ability to take care of myself and make the right choices. And the point here is that we want all women to feel the same way. And we'll be right back after a word from our sponsors.

18:47This brings us to this moment where we're talking a lot about the physiological changes and psychological, because as you've described in research for so long, this affects the brain too. And I think a lot of times, you know, initially the thought was, well, this is a change that happens in hormones, in reproductive systems. And what you're really saying here is this is actually neurological. This is neuroendocrine. This is like both the brain is deeply affected. And is it right to also, I guess one of my curiosities is what's driving what? Right. Thank you for asking. I think this is so important to make sure that everybody is aware of this.

19:25So we are born with a neuroendocrine system, which is neuro for brain, endocrine for hormones, that connects the ovaries to the brain. It's one actually of the most important physiological highways in a woman's body. And this system is activated during puberty and then is over activated when a woman gets pregnant. Every time a woman gets pregnant and then is at least partially turned off as women go through menopause. And what powers this communication system between the ovaries and the brain is the hormones that we refer to incorrectly as sex hormones, estrogen, progesterone, testosterone. So these hormones were discovered a long time ago in the 1930s by scientists that were studying reproductive function.

20:28And back then, they identified the hormones and said, okay, these are sex hormones. We need them to help children. But it's only in the 1990s, the scientists realized that the same hormones that are responsible for fertility also serve very important functionalities in the brain. So they're not sex hormones, strictly speaking. They're brain hormones too. And estrogen in particular is considered the master regulator of women's brain health because estrogen is a very powerful hormone in many ways for women because it supports a number of functionalities within the brain. It supports brain plasticity, which is a measure of brain resilience.

21:22is the ability of neurons to connect with each other and talk to each other. And if something goes wrong, you just reroute your pathway. You've remained supple and flexible over time. But also estrogen supports blood flow to the brain, which is important for oxygen, for nutrients. It's an antioxidant hormone. It reduces free radicals impact and oxidative stress. It's an anti-inflammatory hormone. It does a lot of beautiful things inside the brain. And that happens throughout a woman's life until menopause. With menopause, the ovaries stop producing the most powerful form of estrogen, which is called estradiol.

22:09And it's almost like for the brain, it's almost like your CEO that's been there for 50 plus years is now gone, right? And there's a new CEO that's taking the lead. It's called Estrone, but it's not nearly as powerful or as knowledgeable, you know, if you're a CEO, as Estradiol. And so things don't quite work or as present, let's put it that way, as Estradiol. And then things just don't work the same way that they used to, which means that the brain really has to reset and switch gears and adjust to functioning without Estradiol. And the wonderful thing is that women brains do have that ability.

22:53We and others are showing increasing evidence that the human brain has the ability to basically recalibrate itself, rewire itself and switch gears metabolically so that it can keep going. Even though your ovaries are closing down shop, your brain carries on. And then I have to say, as a woman, I thought it was really amazing to learn that this is not universal. Most animal species, most females in different animal species just die soon after the end of the reproductive span. There are just a few species where females outlive their menopause, like whales, killer whales, norwals. potentially some elephants, some Asian elephants, a bug, the Japanese aphid, for whatever reasons, and women.

23:55So we are fortunate in many ways that our bodies and brains have the ability to just renovate themselves and carry on. I think that's something that is important to be aware of. I never really heard it explained like that. So it's like as this hormone is being downregulated in your body and just not being produced at the same level, your brain is forced to figure out how do I keep on keeping on without this thing that is so critically important to all of these different functions from cognition to mood to regulation. so now i'm fascinated you're you're sharing that we do actually have the ability to kind of like through neuroplasticity rewire and be able to function at a very high level and regain mood and without that the estradiol present do we understand how yes how deep do you want me to go i mean like on on a level that that a non-sophisticated person like me might understand.

24:59But I'm just really curious now, like, how does that happen? It's fascinating. So I think one part of the puzzle is that I should explain is the neuroanatomy of menopause. So this neuroendocrine system connects the ovaries to the brain, but to very specific parts of the brain. And those are the brain parts that are specifically in charge of very ancient functionalities like memory and mood and sleep and wake and regulating heartbeat, but also thinking and reasoning the frontal cortex. So the reason that we have the symptoms is that those specific parts of the brain are very responsive to estrogen levels, but not only estrogen levels.

25:46There are many different other factors that support health within those brain regions. So I think it's important to think of estrogen as an activator. In a way, one of the most important functionalities of estradiol in particular, which is one type, is the most powerful and more abundant type of estrogen, is that it supports energy production in the brain, everywhere in the brain, especially in those brain regions, but also a little bit everywhere in the brain. And the way it does that is by supporting glucose metabolism. So the human brain, men and women, the human brain runs on glucose for energy.

26:33Glucose is a simple sugar. Your neurons, actually your astrocytes use the glucose and then feed energy to neurons. but even neurons take the glucose and turn it into energy. For women, that changes with the menopause transition because at that point, estrogen is no longer there to push the glucose into your brain cells. So the fuel that it needs to function, all of a sudden one of the major mechanisms that makes that available falls away. Yes. And what my colleague has shown, Dr. Roberta Diaz-Brinton, she's a preclinical scientist. She does a lot of mechanistic work. What she has shown is how resilient the brain is.

27:21And the brain at that point in time is thinking, well, if glucose doesn't work for me anymore, I'm going to turn into a hybrid. it, I can no longer depend on glucose, I'm going to start using something else for energy. And the something else is first protein, amino acids, which is not the best choice if you're a brain, because you really need the amino acids to make neurotransmitters. And so then you see how the brain will switch to fat. And so then the brain starts using fat as a major source of energy. which is very smart. The rest of the body can do it too. But in the brain, this mechanism is very delicate.

28:08And the switch is prone to glitches, which manifest themselves, at least in part, in the head flushes, the night sweats, the depressive symptoms, the brain fog and whatnot. For many women, this process, it needs to be better, better studied. But what we're thinking is that for some women, the process is more efficient or perhaps is faster. For other women, it may be slower or not as efficient. And then the long-term effects are different. We do believe that part of the reason that women have a higher risk of Alzheimer's, for instance, is that estrogen also prevents the formation of Alzheimer's plaques and Alzheimer's lesions.

28:57So when you lose this protective layer that estrogen provides, the brain is left in a more vulnerable state, which is when we, my team and I, and other teams as well, using brain scans, this is when we see the lesions of Alzheimer's disease, the Alzheimer's plaques really starting to accumulate in some women's brains, not all women. But for some women, we and others have shown that menopause is a tipping point or an inflection point for Alzheimer's risk. So every brain is different. And we're trying to really better understand what leads down this pathway, or a better pathway, and how can we intervene.

29:45It's like everything has to get rewired. Everything has to be rewired. Can I tell you my theory about? Yeah, yeah. I'm so curious. Oh, thank you. So this is what we've learned from puberty and pregnancy. When you go through puberty, you actually lose half of all your neurons and connection between neurons. Whoa. Yes. This is actually, so before puberty, you have the most neurons you will ever have in your life. As you go through puberty, they drop, which sounds really alarming, right? In reality, that is very smart because the brain is very metabolically active. It's the one organ in the body that takes up the vast majority of energy.

30:33And it's really hard to just maintain functionality over time. So if you're a brain, it makes sense to say, oh, wait a minute, from now on, we may get pregnant here. We may have a baby. We're grownups. We're members of society. I no longer need all these neurons and connections that I needed to learn to ride a bike. I know how to write. I know how to use a credit card. I know how to do all these different things. I can go in autopilot. So I'm going to get rid of all the things I no longer need, right? So it takes remodeling, there can be glitches, there can be symptoms, but you also end up when the transition is complete, which by the way, can take up to eight, nine years, I'm going to have a really mature, very well-connected, very cost-effective brain.

31:30And this new rewiring that happens during puberty also allows me to develop theory of mind, which is the ability to put myself in other people's shoes. In fact, what we've learned is that all this rewiring that takes place during puberty, I promise is relevant to menopause, really supports your ability to have a good place in society. It helps you be a good member of society. It's wiring you for compassion and pro-sociality. Yes, exactly. The same thing happens during pregnancy. We lose neurons. We lose white matter for at least a few years after the baby is born. And then there's a rebound in the recovery.

32:14Because there's a lot of rewiring that takes place where your instincts need to be stronger. You need to, again, you need to be able to mentalize that kid won't speak to you for years. You need to literally learn to read minds. You become even better at dealing with people, but you're losing neurons and you may have those symptoms that are upsetting and difficult and disruptive. Menopause is no different. Menopause is actually when you no longer have a reproductive life. So all the neurons that were necessary to get pregnant in the first place, to grow a baby, to take care of the baby later, those can go.

32:59So my theory, at least, is that the rewiring that takes place in the menopause brain is number one necessary because you do need to get rid of the neurons that you no longer need moving forward with your life. But at the same time, it seems to strengthen the deepest parts of your emotional brain, like the amygdala, the brain structure that is involved in empathy, like you said, compassion, just being more emotionally in tune with other people. And that's something the studies have shown in postmenopausal women, that empathy is of the charts. Post-menopausal women are by far the most empathic individuals in any gender and age groups globally.

33:51And there's also this ability, at least preliminary studies show, that the ability to sustain happiness is improved after menopause. You are less impacted by negativity, by things that may have upset you. But at the same time, you are more likely, at least in those studies, to be able to sustain happiness. Just stop sweating the small stuff. You know what matters. There's more clarity towards yourself and your life. And that could be psychological, but there seems to be a neurological basis because we do find changes on the brain scans. That all sounds powerful. And it makes so much sense. There's sort of like this evolutionary reason for these changes.

34:41It shifts at each one of these major phases. But also within each one of them, there's this window where everything is sort of thrown to the wind, where there's a lot of disruption. There's a lot of upheaval. It's probably physiological and psychologically uncomfortable, concerning on varying different levels while you're in the middle of that window, which could last anywhere, could last years. Let's just be clear. It can last anywhere between two years and 15. Wow. That's a long time to be feeling that way. It's a very long time. The average is seven years. Okay. And that's only to get to the final menstrual period.

35:24Your brain, your ovaries are done at that point, your brain is not. So there are more years afterwards, it's called the early postmenopausal stage, where your brain is still rewiring. So the whole process can spend a decade, if not longer. And women don't know. Women don't know. We should know, because we should be able to plan for that. We should know what's happening. We should know that it could take time. Hopefully, it doesn't take that long, right? But there's a possibility and we need to know, we need to be prepared. Do doctors know? Yes. So there's a staging model for menopause that is not about the brain, it's only almost about the ovaries.

36:08So when you start around age 35, that is considered the early premenopausal window where you are almost, you know, you're effectively midlife, but you have a regular menstrual period. A little bit later on, you may notice as a woman, I don't know how comfortable you are talking about periods and menstrual. Okay, fantastic. When you can feel like your cycle is a little bit different, it could be slightly shorter, slightly longer, just a couple of days, it may be lighter, it may be heavier, but it's still regular. That is the late premenopausal stage. And many women start reporting sleep disturbances at that point or irritability.

36:52So there are symptoms already that may or may not be menopause, but we're investigating that. Afterwards, you start skipping periods. So your period is no longer every month. It could be every two months, every three months. That is the early perimenopausal phase. And that's when the actual symptoms of menopause can start popping up here and there, not consistently. Once you start skipping periods for more than three months at a time, especially if it's more than six months at a time, that's the late perimenopausal stage. And that's usually when the symptom hits you hardest. Okay. Before the final menstrual period, years prior, that's when most women have a harder time or can have a hard time.

37:42The hot flashes are at the worst and the other sleep disturbances, mood, brain fog, that's when they are more likely to impact the woman. Then there's the final menstrual period. For whatever reason, that is menopause in clinical terms, right? Just that one day on the calendar when you're like, oh, I haven't had my period in a year straight. Now I'm in menopause. What most people don't realize is that there are other phases afterwards. words. There's an early postmenopausal stage that could be anywhere between two years and six. And the symptoms are still present, but usually they're kind of dissipating and fading.

38:23And then more than six years after the final menstrual period, that's your late postmenopausal stage, which is going to be the rest of your life. And this is all based your menstrual cycle, pretty much, and your hormone levels. The brain does not necessarily follow the same dynamics. And we are trying to better understand what happens in the brain and when relative to ovarian function. They're not like hand to hand. There's a disconnect that needs to be better understood. So it's like your reproductive physiology has a certain time cycle and it's related to changes in your neurological physiology, but they're not the exact same.

39:07They're both working in parallel, but also going through similar, but related, but not the same processes. And they have slightly different timeframes potentially. Oh, for sure. Because otherwise we will lose our minds every time we have a period. Right. The brain needs to be connected to the ovaries and needs to be informed of ovarian function, but it cannot be dependent on. In fact, something that most women don't realize is that when you measure hormones in your blood, if you have estrogen levels measured or progesterone, that doesn't tell you anything about the levels of hormones in the brain.

39:48They're different. They're two separate systems. The brain keeps whatever concentrations quite stable by shielding itself chemically from the rest of the body. and we'll be right back after a word from our sponsors one of the questions that always comes up is like as you're experiencing all these different symptoms these changes and these season of where there's a lot of things that don't feel good in the moment because your body is in the middle of shifting and rewiring and adapting how do we navigate that with as much ease as possible one of the things that has become a real source of controversy over the years.

40:28You know where I'm going with this is hormone therapy. Of course. And for decades back, it was prescribed. And then there was some research that came out that basically created a lot of fear in a lot of people. And it feels like we're now in this window where you brought up earlier in our conversation, the menopause wars. There's a real difference of opinion about the role of hormone therapy in helping to navigate this moment. Give me some context here. Yes. So like you said, this is quite unprecedented in medicine, but what happened is that hormone therapy was prescribed very commonly to women before clinical trials were run to test the efficacy and safety.

41:19In the late 1990s, the NIA decided to start to launch the largest clinical trial of women's health in history, which is called the Women's Health Initiative. And they were not just testing hormone therapy for half-lashes. They were also testing hormone therapy for things that were already in the headlines that you should take hormone therapy to be young forever and to prevent heart disease and to prevent dementia, right? And so they were like, well, this has to be tested. And so they launched this enormous clinical trial that unfortunately did not work for those specific endpoints, dementia and heart disease.

42:03And so the trials ended in 2002 and then in 2003. What the headlines, however, ended up reporting on was the increased risk of breast cancer in one specific part of the clinical trials. So this is what's important to know in a nutshell. Those were clinical trials of women who were mainly in their 70s and 80s, many years after menopause. First thing, that's very important. Number two, the type of hormones tested were not the same that we typically use today. They tested high doses of oral conjugated equine estrogens or CEEs. We still use CEEs today, but not at those specific dosages. And most importantly, a type of progestin, which is a synthetic version of progesterone that has been discontinued because it was later shown to sometimes potentially increase the risk of vascular damage.

43:09So those women were too old for any preventative effects to have a chance to occur. And number two, those results do not apply to women in midlife who take hormones for menopause as they go through menopause. And most importantly, the results do not apply to the type of hormones that we use more often in clinical practices today. However, what everybody was scared about was the risk of breast cancer. Now, there were two different arms, or there were two different trials in the Women's Health Initiative. There was one trial with the conjugated equine estrogen and the progestin, and one trial with only estrogens, okay?

43:57Estrogen plus progestin, 26 % increased risk of breast cancer. Estrogen only, 22 % reduced risk of breast cancer. But what the media picked on was the increased risk of breast cancer. and all women, many women, get really, really scared and they stop using hormone therapy and hormone therapy's reputation really has not recovered since, which is a problem. One thing I want everybody to know, I'm a scientist. I love statistics. I have studied statistics the vast majority of my life, including dinners and my parents' conversations with friends. Those clinical trials were not looking at breast cancer as an endpoint.

44:47Those were incidental findings. Those were not results of the study. What the trials really show is an association, not a causative effect. I think this is important to understand for many women. All of us have heard that hormone therapy can cause breast cancer. That is the wrong word. Hormone therapy does not magically generate cancer. It's not like radioactivity. It's not like chemical compounds that can change the molecular structure of your cells. What can happen, which is important to know, is that you may have precancerous cells, or you may have a small tumor, and you don't know. If you add hormones, if those are hormone-receptive cells and you add hormone, that may grow.

45:42That's what estrogen does. It makes things grow, right? So that is where prevention is really important. That's where mammograms are really important. Ultrasounds, MRIs, we have a lot of options today for screening and prevention. That's one reason I believe that professional societies now say, as of 2022, Two, the guidelines have changed. And professional societies, which are appropriately very conservative, do say that the risk of breast cancer is rare for most women in midlife who take standardized, carefully controlled doses of hormones that we have tested in clinical trials. So as long as you follow the guidelines and you work with your physician, that the risk breast cancer is considered a rare occurrence.

46:36I think that is very reassuring because it means that hormone therapy is on the table, but at the same time, it's not like a silver bullet. It's not magic in any direction. It's one tool that we have to support and alleviate specific symptoms of menopause for women who are eligible. Yeah. And of course, just to put this out there, this is not medical advice. This is just really good information. If you're in this moment and you're trying to figure out what's right for you, sit down with your qualified healthcare provider, practitioner, and just have a really good, deep, rich conversation about what is appropriate for you in this moment.

47:19As you're describing this, something else kind of pops up also, which is if, as you mentioned earlier, without hormone replacement therapy, over time, your brain will eventually move through all these changes and kind of rewire itself. So you're functioning at a high level again and feeling the way that you want to feel without the same level of estrogen. And granted, this may be really uncomfortable while you're moving through it. It may last a really long time. Is there a risk if you introduce hormone replacement therapy that that organic rewiring won't actually happen? The organic rewiring is something that we have the potential to go through.

48:03As I mentioned before, for some individuals, again, a lot more research is needed to really understand, right? So the preclinical work that's been done is in rats. In women, And we still need to do a lot of the work. But our understanding is that hormone therapy could be, and this needs to be tested and proven. We're doing it now. This is the kind of research myself and others doing now. Hormone therapy will support the transition by not letting your brain go through the crash. That's one theory, right? That it can sustain functionality for longer. It needs to be proven. We and others are working on it.

48:45There are many different types of hormone therapies as well that are worth investigating. And there is, however, no evidence that that would impair your recalibration. But I think what's missing in our field has been a tool that allows us to look at what estrogen is doing in the brain. Like I said, you can measure it in blood, but we do not yet have accurate ways to measure estrogen activity in the brain. So what my team and I have done in the past is that we've been able to use positron emission tomography, PET imaging, which is the kind of technique where the brain looks like red, yellow, blue.

49:27We were able to use one tracer to measure estrogen in the brain. And we've done it, but we're still the only one, the only team who have looked into that. And right now, as part of my new program of research, we're trying to develop more ways and more techniques to really look at estrogen in the brain, because that is important to test the effects of hormone therapy, right? If we don't have a way to measure what these hormones, endogenous, exogenous, are doing in the brain that we're really, we're flying blind when it comes to prescribing hormones for brain health. So this is one of my next steps in research.

50:12I will be following along with your research closely. I'm fascinated by this. I want to maybe start to close the loop here. The earlier part of our conversation, we were talking about Alzheimer's and cognitive decline. And that brought us into this conversation of this notion that this is actually a disease of midlife. It starts in midlife. And what is one of the primary differences between women and men in midlife? It is moving through menopause. If we come back to the conversation around Alzheimer's here, and we're trying to look at the experience of menopause and help people not just navigate the discomfort or the changes in the brain, but also navigate in a way which maybe minimizes the potential for dementia or Alzheimer's.

50:57Yes, absolutely. What are we thinking about here? What are the changes that we want to explore? What we're thinking here is the program that I just launched in July. I was so fortunate that Dr. Regina Dugan, who is the former director of DARPA, the advanced research program agency for defense, is now working in health. And she launched Wellcome Leap, which is an independent subsidiary of the Wellcome Trust, one of the world's largest charitable organizations. And she reached out to me and she asked me to develop and run and direct a program of research that they funded is a$50 million research program, which is entirely dedicated to women's health, hormones, and Alzheimer's risk for women.

51:50So it's called a sprint. We have a three-year grace period and$50 million to what I love about this project is that I'm running it, but it's effectively, it's a network of scientists from all over the world working together to address a difficult question that none of us alone could hope to really answer. And so all together, there's strength in numbers. And we have 70 leading scientists from all over the world working together to address exactly these questions and bring clarity on questions that have been very controversial in our field. Does menopause really increase the risk of Alzheimer's disease for all women or is it just some women?

52:39How does it do if so? and can we offset the risk using hormone therapy in menopause? And what kind of hormone therapy is best? And for which women? And what are the genetic markers of susceptibility? Does lifestyle play a role? What are all the different risk factors that we need to address and balance out to really protect a woman against Alzheimer's? So our goal, the name of the program is CARE. It's my idea. It means cutting Alzheimer's risk through endocrinology, C-A-R-E, care. And our goal overall, and we have done PNLs. We know that this is potentially going to happen, has the potential to happen if we've really hit all the marks.

53:25Our goal is to reduce the risk of Alzheimer's disease for an estimated 330 million women globally, and given current conversion rates to Alzheimer's, hopefully prevent almost 55 million new Alzheimer's cases among women by the year 2050. Powerful. And it sounds like you're in the early stages there. But the ability to, I mean, it's both funded and the ability to, you know, one of the biggest problems in science is siloing, like everyone's protective and they're just working their own lives and sounds like you've brought together a network of 70 scientists from around the world who are breaking the silos and sharing and exploring this um i'm excited to see what unfolds from your research in the coming years and i think uh me too it's because it's such an important set of questions that we need answers to you know to first understand what's really happening here what is the connection and then what interventions might be effective?

54:27Because, see, as women, and this is the problem we're having today, that the awareness has increased exponentially, but the science hasn't quite caught up with the questions that women now have. And that's when people just start sharing opinions, right? And everybody's now a menopause expert and an Alzheimer's prevention expert and the brain expert. And then we get confused because one person says, take hormones. The other person says, don't take them. The other person is like, it's all about magnesium. And it's just, it's terrible. So we are building the science that women deserve. And I understand that we all want answers now.

55:09You know, so do I. But it's important to have the right answers that are based, grounded in evidence, not fear, not marketing, not soundbites, and certainly not other people's opinions. So it's a privilege to be able to do this kind of research. And we're all very motivated. We work really, really hard. And I am quite confident that we're going to have good answers in the next three years. That feels like a good place for us to come full circle as well. So final question in this container of Good Life Project, if I offer up the phrase to live a good life, what comes up? Oh, for me, being with my family, I really, for me, living a good life is hopefully being healthy and just as in love with my family as I am right now.

55:58Thank you. Thank you. Thank you so much for having me. My pleasure. Hey, before you leave, be sure to tune in next week for a conversation with psychiatrist and mental health educator, Dr. Tracy Marks about what anxiety really is, why it feels so physical, and how understanding your brain can actually help you feel steadier and more at ease. Be sure to follow the show so you don't miss that episode or any new episodes we share. This episode of Good Life Project was produced by executive producers Lindsay Fox and me, Jonathan Fields. Editing help by Alejandro Ramirez and Troy Young. Christopher Carter crafted our theme music.

56:35And of course, if you haven't already done so please go ahead and follow good life project in your favorite listening app or on youtube too if you found this conversation interesting or valuable and inspiring chances are you did because you're still listening here do me a personal favor a seven second favor share it with just one person i mean if you want to share it with more that's awesome too but just one person even then invite them to talk with you about what you've both discovered to reconnect and explore ideas that really matter, because that's how we all come alive together. Until next time, I'm Jonathan Fields, signing off for Good Life Project.