Did you know there is a connection between mental health and medical disorders like cardiovascular disease or Alzheimer’s disease? Clinical neuroscientist Jill Goldstein, a professor of psychiatry and medicine at Harvard Medical School and the executive director of the Innovation Center on Sex Differences in Medicine, explains why women are disproportionately affected by these co-occurences. They have twice the risk of developing a co-occurrence of heart disease and depression than men do. Goldstein explains how links between the heart and brain can be traced back to prenatal development.
Emily Kumler: I’m Emily Kumler and this is Empowered Health. I remember when I read the book The Female Brain and I was struck by the fact that something like the brain, right, which is an organ, but you don’t think of it as being a sex organ, is so different in women than it is in men. And that was years ago. But I think in some ways it sort of inspired this whole project because it made me realize everything is different in my body than it is in my husband’s. How well do we understand any of this stuff? And as some of you know, who have listened to the podcast, I like to talk a lot about the involvement of women in clinical trials. From 1977 until 1993 women were legally banned from being in any clinical trials. And the reason for that was because they were worried about birth defects on women who were pregnant. And so basically any women who were of the sort of child bearing years, were not allowed to be tested on. Now that didn’t mean that women weren’t prescribed medicine or they didn’t get sick. It just meant that there was really no research during that time. So it’s sort of like the dark ages of medicine when it comes to women or research. And even since then, there have been efforts to try to include women in clinical trials, but the representation of women is much, much lower. Drug companies get around this often by saying that women don’t volunteer as much or they don’t adhere because they’re busy or they can’t commit the time. Whatever the reason is, we have allowed this and tolerated it. So, very often when you go to the doctor and you ask them some question and they offer some treatment, the treatment that they are offering you has not been properly tested on people who look like you. It has not been tested on women. So much of the information that we have and the reason we’re doing the podcast is because we want to get you good information from researchers who are really looking at sex differences. So I was thrilled when we locked in this interview with our next guest who is an expert on sex differences and she’s been looking at sex differences in the brain for 30 years. So she’s sort of been on the cutting edge of this like way before anybody else. And her background is in psychiatry. So she’s fascinating to learn from in terms of the comorbidity phenomenon, which is basically women get cardiovascular disease. We know that heart disease is a leading cause of death for women, but we also know that women are more likely to get depressed. They’re more likely to experience anxiety. And what is the connection between these things? And how much of a greater risk are women put at because of those two or three or more phenomenon? And she’s going to explain this to us in a way that I hope allows us all to leave this conversation just sort of thinking a little bit more about how special and wonderful our bodies are, but also about how to take care of them. Because one of the big takeaways for me in this interview was this idea that if you can counteract depression or anxiety early enough, which may even be sort of shortly after adolescence, it has a long-term impact on the woman’s lifespan, meaning you might be more likely to live longer. So for those of us who are mothers, and certainly for those of us who are depressed or have depression in our family, this is like probably a really important topic to just sort of think about. And it’s like this is a high level conversation that I hope you guys all have really great takeaways from. And then just as a side note, before we kick into the interview, we are hoping that listeners will donate to keep the podcast going. You can do that on our website, Empoweredhealthshow.com or you can go directly to Patreon.com/empoweredhealth and donate there. And you can do it on a monthly basis or on a one time basis or whatever you feel like doing. But we would greatly appreciate your support.
Jill Goldstein: I’m Jill Goldstein, Professor of Psychiatry and Medicine at Harvard Medical School, and the founder and Executive Director of the Innovation Center on Sex Differences in Medicine. I’m also the Helen T. Moerschner Endowed Chair MGH Research Institute Chair in Women’s Health. I’m a clinical neuroscientist. My expertise is sex differences in health and diseases of the central nervous system. In particular, how a disorder like depression co-occurs with cardiovascular disease and diabetes and reduces risk for Alzheimer’s disease. I lead an interdisciplinary program, we’ve been funded for many years, over 30 years. It’s the clinical neuroscience laboratory for sex differences in the brain. That program has really focused on really looking across organs and tissues and combining imaging and physiology and genetics and looking at how it is that men and women, boys and girls, develop differently and function differently across our lifespan. That sets the stage for why we see sex differences across almost every chronic disease we know.
Emily Kumler: Since that is really sort of the point of the podcast in general, is just sort of look at these differences so that women can then make really informed decisions about their own bodies as they navigate the sort of health landscape, whether they’re healthy or sick. I feel like a great place for us to start would be to just talk a little bit about like what are some of the differences in the brain? I know historically, people used to think women weren’t as smart because we had smaller brains. And that that has obviously been challenged, but what are some of the other true differences that you see in the brain?
Jill Goldstein: Let me first say that women’s health has traditionally been thought of as reproductive health. And we’ve learned a lot about women’s health as reproductive health. And there’s been a long history of this and obstetrics and gynecology and very, very important to understand how our reproductive organs really impact our health from fetal development through our aging and menopause and so on. But we have redefined women’s health. And others have redefined women’s health in a way that we look at how it differs from men’s health, because even if you study disorders that only afflict women, we actually can learn some stuff about how we are different from men. And that’s very important because sex differences in chronic diseases are pervasive across almost every disease we know. The brain is just a part of that. So when we think of women’s health, instead of just thinking about reproductive organs, we actually have redefined it across all organs and tissues to understand how our bodies develop in different ways and function in different ways across our lifespan and how that differs from men. So sex differences in chronic disease and in chronic psychiatric disorders are pervasive. And that begins even in development. In development, we see that there are higher rates of all sorts of neurologic and psychiatric issues in boys versus girls. But once puberty occurs, really the sex differences in different diseases start to change. So women have higher rates of depression and anxiety disorders than men. That emerges just post-puberty and actually is retained across our lifespan. Schizophrenia for example, also higher rates in men than in women. Again, emerging in young adulthood, particularly in boys and five years later, in girls. So the age of onset of these disorders actually differs for an illness like schizophrenia. The incidents of all sorts of substance use disorders, higher in boys than girls, except for eating disorders where girls predominate, but substance use disorders, alcohol, drugs, gambling, these are all higher rates in men. Although when we look at these disorders and you dig down deep into them, there can be greater severity with women who actually onset with these disorders in terms of how we metabolize things like alcohol and other drugs really differ from men and can produce a more severe course in some cases than in men.
Emily Kumler: So we did an episode on the impact of THC on women versus men. And the researcher had started her career looking at sex differences with opioid use, and had, you know, sort of moved on to THC and she explained to us that when you’re ovulating you experience a heightened high and that this puts women at a greater risk for addiction. But, she made the argument that it seems because there’s a cultural taboo against sort of using substances, which she thinks is sort of starting to cave, that you know, there is this idea that men experience more substance abuse than women. But actually she was making the argument that the female brain is more susceptible to it. But we have a cultural protection, which is that girls aren’t supposed to use drugs in a way that, I mean nobody is, right, but it’s more sort of acceptable socially for men to, you know, sort of dabble in substances.
Jill Goldstein: So you’re raising a really important point. What is the difference between sex and gender and how does that inform our health and disease? So, my lab has been studying sex differences, so the biology of sex. And gender is a social construct. Our gender roles, our social roles. And each of these actually can inform the other. But, there are some ways that we can try to separate the two because ultimately our social context is going to be felt through our bodies and in our physiology. So even how the social context affects us. I want to say just a couple of things about this, which is that there’s more variability within sex than there are between the sexes.
Emily Kumler: Oh, that’s interesting.
Jill Goldstein: And that’s a really important point. So I’m going to talk about sex difference in biology, but there’s more variability within the sexes than there are between the sexes. But these small differences between biology of sex provides some really important insights into why we see sex differences in the frequency, the onset, the risks, the presentation, even the therapeutic treatment responses to drugs in men and women. We want to understand what those differences are about. So we also want to understand how we develop differently and how our physiology places us, our bodily context, differently as we move in the world and we’re exposed to all the things we’re exposed to. So the brain actually develops differently in the male and female brain. Now, the primary driver of the sexual differentiation of the brain is gonadal hormones. Now there are some direct effects of genes, and I’m talking about in fetal development, the brain develops differently in the male and female fetal brain. In first trimester, there are some direct effects of genes on the sexual differentiation of the brain. Now, what do I mean by that? How the brain develops differently in male and female fetuses. But at the beginning of second trimester, the testes begin to secrete testosterone. And testosterone can have direct effects on masculinizing the male brain, and also has indirect effects to its conversion into estradiol, which is the primary form of estrogen that works in the brain. And both testosterone and estradiol actually masculinize the male brain. Now about 60 years ago, it was thought because people were only using rats, that it was actually estradiol that masculinized the rodent rat brain. But about 15 years ago, we discovered that in humans and in monkeys, there are direct effects of testosterone and masculinizing the human brain and the monkey brain, but there are also indirect effects. As I say through estradiol, everybody thinks estrogen, which is actually a plural word. Estrogens come in different forms and estradiol is the main form that works in the brain. Now there are other forms, estriol, they work in the brain too, but not as strongly as estradiol.
Emily Kumler: In both male and female?
Jill Goldstein: Yes, in both male and females. So actually estrogen can help to masculinize the male brain. It’s not just a female hormone. And we have testosterone, too. It’s really important. One of the things that we are trying to think about is how to, so estrogens are very important in brain function, let me just put that there. Let me kind of lay out the development and then tell you how this changes over our life course and how we compensate for these changes as our levels of hormones change and our physiology and the aging changes the development of the brain. Again, sexual differentiation beginning at the beginning of second trimester and really going through probably somewhere mid or to late third trimester. And there’s certain things and certain brain regions that are denser in these gonadal hormone receptors that actually differ in men and women later on in life. So these effects of the gonadal hormones in development, called the organizational effects of gonadal hormones, can be set in development and you can have lots of variations on the theme, but some things kind of get set in development that set the stage for lots of things later in life. So if there is dysregulation, we use models of high risk pregnancies, which I’ll talk about in a moment, that can dysregulate or change the course of the sexual differentiation of the brain, these things actually we carry them throughout our life. Now, pregnancy is not deterministic for the rest of your life, but it can set the stage for how our bodies and brain then deals with life after birth. And puberty, by the way, is another really critical period of some organizational effects of hormones. And when we say organizational effects, we mean they can actually change the brain. Then there are activational effects of hormones where we have circulating hormones during, obviously, during our menstrual periods.
Emily Kumler: But when you’re talking about a period like puberty, you’re basically talking about how you’re going through this sort of hormonal change and the makeup of the hormones that are being released at that time period have longer term effects than just through that sort of adolescent period?
Jill Goldstein: Yes, on certain brain regions.
Emily Kumler: And that’s not something that any individual could control? That’s just a natural biological process that happens?
Jill Goldstein: That’s right. Now that can be disrupted by drugs, by trauma, by all sorts of things. So you can change the brain. So the brain, by age four, we sort of have our volumes narrowly developed and then lots of connections are being made, connections are being made and broken. So, neurons are connecting, it’s called synaptogenesis. You know, we’re creating new connections and we’re getting rid of some connections. We’re not using the very front of the brain, actually the prefrontal cortex or even dorsal lateral prefrontal cortex, which is at the very front of the brain is the latest to develop, but it’s the region of the brain that really separates us from our ancestry, our animal ancestry, because it’s the brain region that is really important for executive function control organization, higher order thinking. And that area of the brain does not fully get connected with the rest of the brain until young twenties. So about 18 to 22 in females and 22 to 24 in males, like two years later in the male brain than the female brain.
Emily Kumler: And this is why people talk about impulse control, right? With teenagers?
Jill Goldstein: Yeah, so that’s really important. So here you have these adolescents developing, using lots of substances, and can really change their brain at that point. They can really change their brain.
Emily Kumler: And it’s never changing in a positive way. Isn’t that right?
Jill Goldstein: That’s not true. No, no, no. We can change our brains in really positive ways.
Emily Kumler: Well, no, but I mean like from substances.
Jill Goldstein: Oh, from substances. Not drugs and alcohol.
Emily Kumler: But so then how does that work with things like so many kids taking Adderall or Ritalin or these other things that certainly change the brain?
Jill Goldstein: You know, it’s a very good question. It needs to be studied. It needs to be studied with brain imaging because we have the tools now where we can actually view these things. Now sometimes, because of our genes or exposures early in development, the brain gets changed. And so taking some of these medications early in development actually helps the brain because it hasn’t developed in a healthy way. So it needs a little help. So in fact, with people who have had childhood disorders where their brains, childhood psychiatric or neurologic disorders, brains have actually changed. The enhancement that is produced by providing some of these medications actually can be good for the brain. Of course. Otherwise psychiatrists would not be giving them. Now, is there an overuse of these? That’s a political question. I’m not sure I should answer that one.
Emily Kumler: Well, no, but I mean, I think, you know, what’s really interesting is also, I mean, I would have the same question I guess for trauma too, right? Like people used to think that the brain was sort of once it was wired, it was hard wired. Right? Now we know that there’s a lot more sort of this plastic elasticity or the ability for the brain to change than we once thought. And so, you know, I think part of what we’ll get into when we talk a little bit more about the comorbidity research that you have done, but I do think it’s interesting to think like somebody who’s suffered a childhood trauma that their brain has, you know, changed because of that, but that is now going to be their sort of status quo. And that doesn’t mean that they couldn’t, you know, change it in a way again, right, that would be helpful to them?
Jill Goldstein: Yes. In my lab studies, how do we regulate stress, so stress affects every chronic disease we know, and certainly it affects and is involved with lots of psychiatric disorders. But in fact, it’s involved in every chronic disease we know: cardiovascular disease, I mean everything, cancers. And I’m talking about negative stress, because stress is important, right? If there’s a lion in front of you, you want to get stress response to get out of there. You want to tell your brain and your body and need to move. Your heart rate goes up. You know, you’re ready for flight or fight.
Emily Kumler: One of my favorite books is that book Why Zebras Don’t Get Ulcers, which is all about that. I mean it’s, the Sapolsky I think is the author who wrote it, and it’s really looking at how like we are meant to have these bouts of acute stress, but we’re kind of living this life of chronic stress and how debilitating that is.
Jill Goldstein: Yes, exactly. And stress can be really important actually for imprinting memories, you know, so lots of things, consolidating them, bridging memories. But when it is deleterious is when it’s chronic and an inability to actually regulate it. So what we study are actually prenatal stress models. There can be lots of things that happen in development, high risk pregnancies, personal trauma, death of a spouse, psychological trauma, there can be all sorts of things that happen during pregnancy. The change is the mothers, you know, stress response, sort of high stress response during pregnancy, that also changes other physiologic responses, some of her immune responses as well. And so we look at these as what we call in the literature, prenatal stress model of the development of these psychiatric disorders how and why they co-occur with a number of these chronic diseases in general medicine.
Emily Kumler: And so you’re looking at that in terms of the infant is then born and followed?
Jill Goldstein: Yes, exactly.
Emily Kumler: So it’s not about the mom’s long-term health, it’s about the effect of those hormones being released by the mom while she’s pregnant.
Jill Goldstein: Yes. And so some people look at the mom’s health, which also is really important. So high risk pregnancies like preeclampsia conditions, fetal growth restriction, they actually placed the mother at three to five fold risk for cardiovascular disease afterwards. And in fact, some of my colleagues have really been looking at how the vasculature itself in women after preeclamptic pregnancy actually has changed and that can place that woman at a higher risk for hypertension and into cardiovascular disease later in life in low resource countries. Preeclampsia is a substantial risk factor for mortality in women. In this country, a little less mortality, but certainly this morbidity. And women don’t realize it because after pregnancy we’re focused on the kids’ health, right? We are developing ways to enhance knowledge and develop some therapeutics early so that we can try to prevent this, both in the mother but also in preeclampsia, growth restriction can place the fetus at a higher risk for depression, cardiovascular disease, and even now we’re looking at memory decline after menopause, these prenatal stress models. And that effect differs by sex. That’s how we got into the sort of prenatal stress models of the risk for these disorders over our lifespan. Psychiatric disorders, even cardiovascular disease, they are developmental disorders. So in psychiatry we’ve known that for a while: depressions, psychosis. The disorders we study are developmental, something happens in the development of the brain. Sometimes it’s severe. Sometimes there are a lot of genes involved. You have autism for example, or other exposures, and you have immediate effects, but in most cases you don’t see the effects that emerge until after puberty and into young adulthood, when many psychiatric disorders start to start to emerge. So we think of women’s health and even sex differences in health as a lifespan goal, a lifespan endeavor. We need to think about what happens in development. And then if you create, think that some of these high risk pregnancies or other traumas in pregnancy, actually create a kind of hypersensitivity to stress in the offspring and a hyperimmune response, that depending on whether people are in enriched environments or adverse environments and depending on that child’s genetic makeup will lay the vulnerability for why we see sex differences in the risk for these disorders later in life.
Emily Kumler: So talk a little bit about what does that mean? Like what is an enriched environment? My initial reaction to that kind of stuff is always like people who are of, you know, like have a lower income level or lower socioeconomic status in general are going to be in a less enriched environment because there’s going to be more stress about getting food on the table or whatever than somebody at a higher socioeconomic level. But, I’m not sure that that’s entirely fair because it also feels like if somebody is in a high socioeconomic level, but maybe like an abusive marriage or something like that, that the kid is then exposed to or some abuse in the house. That doesn’t sound like a great environment either.
Jill Goldstein: Yeah. Your enriched environment I believe is really about your relationships. Obviously there are pressures from social class and it’s nice, you know, and critical if you don’t have to worry about getting food on the table. But the relationships between the parents and the child are absolutely critical to what will create an enriched environment or not. Exposing that child to words, reading, libraries, exercise, playing, and connection with the parents. Whether if it’s a single parent household, that parent or a dual parent household, that there is a connection and attachment. It’s really absolutely critical in development regardless of social class. So, what we have looked at is if we’re looking at something that happens in development that changes someone’s physiology, what is it about that that gets carried throughout life to produce these, you know, the onset of these illnesses later on? So the stress circuitry in the brain, which is what we study, so we study the kind of gonadal hormone regulation of the brain, the stress circuitry in the brain, that is the brain regions we use to regulate stress are some of the most highly, what we call sexually dimorphic regions in the brain. That is they develop differently in the male and female brain and they function differently across our lifespan. They even activate differently across the menstrual cycle, which was just in the healthy brain. Just in the healthy brain, they activate differently to stress under hormonal conditions. So hormones are really important. That same circuitry not only regulates our gonadal hormones, it regulates our stress hormones. And it also regulates, it’s tied in with our immune responses. And so those immune responses, there are immune receptors that sit in the same brain regions that are regulating our other physiology, our stress hormone physiology, our gonadal hormone physiology, and they’re regulating the heart. So, the brain talks to the heart, physiologically. Think about the stress response. We have a negative stress, our heart rate goes up, our respiration goes up, and then we have to regulate that. We have to use certain brain regions to say, calm down. We don’t need to go anywhere. Everything’s okay. We just need to function. This is stressful, but my brain can regulate and inhibit the arousal. In a number of these disorders like depression, like anxiety disorders, even it’s been shown in cardiovascular disease, the regulation of that response, that stress response to negative stress is off. It’s dysregulated. And we’ve shown that it can be dysregulated in sex dependent ways, and that has been related to the higher risk for depression in women. So those brain regions that are developing are getting preferentially affected in the female brain than the male brain to lay the vulnerability to that dysregulation of that stress circuitry for why it is that we see higher rates in females later on in life. And that same circuitry is regulating our cardiac control. So the brain talks to the heart both physiologically, but even electrically. There’s a primary nerve that connects directly from the brain to the heart, from the brain stem, a set of nerve cells in the brain stem, and that set of nerve cells in the brain stem connects directly to that stress circuitry in the rest of the brain. And that set of nerve cells is connected to this miracle, the vagus nerve, which is the primary electrical conduit from the brain down to the heart. And what’s cool about this vagus nerve, as it kind of wanders over the body, it also goes to the gut. So when we’re stressed out, we get the stuff in there and gut feelings, and the immune system affects the gut and the heart and the brain. There is a physiology, an electrical connection between these three organ systems. And so effects that can happen early in development to these brain regions not only may affect the regulation of mood and the risks for depression or anxiety, but the regulation of the heart and even the regulation of the gut.
Emily Kumler: And so the vagus nerve is developmentally different in males and females in utero?
Jill Goldstein: I don’t know the answer to that. That’s a really good question. I haven’t read that. It’s the brain regions that it’s connected to are developed differently in the male and female brain. They all connect to the vagus nerve.
Emily Kumler: Just so that I make sure that I understand this correctly, the sex differences then are in the brain. The way the brain responds to stress is different because it’s then translated differently when it’s going from the brain through the vagus nerve to the heart and gut. So we have different gut responses or different heart responses. And this becomes incredibly significant because obviously heart disease is the leading cause of death. And we know that there are higher instances of anxiety and depression amongst females.
Jill Goldstein: Yes. And what we also know is depression is almost twice the risk in women than in men. And heart disease, although it’s number one killer of actually women and men in the U.S., the co-occurrence of depression and cardiovascular disease, which is going to be the number one cause of disability next year, is almost twofold in women than in men. And people who have depression who have cardiovascular disease, they have a three to five fold risk of death from cardiovascular disease. So we believe that death from heart disease in women may in part be due to unrecognized and untreated major depression. Now there’s also a difference in the development of the vasculature in men and women and how heart disease is expressed, how our vessels actually express heart disease is different in men and women, which is really important to understand because even though the rates may be the same in terms of overall heart disease, actually the timing of that heart disease, so hypertension occurs earlier in men than in women. Maybe in their forties men become at risk for it, or in the fifties. Women become at risk after menopause. You know, they’re at much higher risk for heart disease, but there’s a lot of unrecognized and untreated major depression among women who have heart disease.
Emily Kumler: We did two episodes on, or we did one episode on SCAD, and we did another one on small vessel blockages because I really wanted to look at heart disease and I sort of was like, wait, what is heart disease? It’s all these different things, right? It’s sort of like a catch all for all of these other, you know, sort of diagnoses and with SCAD certainly, it seems like there is usually some sort of big physical event or a big emotional event that happens right beforehand.
Jill Goldstein: Yes. And women with SCAD have very high rates of anxiety and mood dysregulation, very high rates.
Emily Kumler: Then the other thing that comes to mind, which I would love to have you talk a little bit about, is I know that there was some research, I don’t know, this may even be going back 10 years now, about people taking antidepressants and that it allowed the brain to kind of take a break and heal? And your brain health was actually better if you had, when you suffered a depression, taken medication for it. Does that research still hold true and is that true in women as it is in men?
Jill Goldstein: Well, let me take the first part, which is treatment actually does help. We do have treatments that can help. And the earlier these things are treated, the better. Because with any other chronic disease, we know the earlier we treat the more we can enhance resilience and the more we are able to prevent or attenuate disability and ultimately prevent recurrence. So earlier is better because the brain as we know is more plastic at that point. So yes, treatment earlier and identifying these things earlier, really just post-puberty. There are a lot of boys and girls that are on setting with these disorders and they don’t know what they are. They don’t know what’s happening to them. Because many of the symptoms are kind of common symptoms that many people have and they don’t realize that some of these are actually kind of precursors to eventually a chronic debilitating disease like major depression. I’m not talking about depressive symptoms that many of us feel at different times, or anxiety symptoms. I’m saying the real clinical depression is a chronic debilitating disease, twice the risk in women and number two cause of disability worldwide, which is pretty amazing and it’s pulling women out of the workforce, and men as well. But it has a major impact on our economies, on work productivity, and our economic health. In fact, the co-occurrence of depression and cardiovascular disease is really going to be an economic crisis because those are the people who are also at risk for Alzheimer’s disease later in life. So these are the three chronic diseases. They’re the major public health challenges of our time. And they co-occur really frequently.
Emily Kumler: Right. And we know that two thirds of all Alzheimer’s patients are female.
Jill Goldstein: They’re women. And in the field used to just say, oh, it’s just because women live longer, but it’s because we weren’t studying it over the life course and looking at timing. Timing is everything when you’re going to identify whether men and women, boys and girls, male or female. The brain differs. Timing is everything. So if you look much later in life, let’s say when a person is in their eighties or nineties, maybe the brains really look similar or more similar. But really, if you looked at people, while women were going through the menopausal transition as part of early midlife, compare those to age matched men, you see sex differences in memory, circuitry changes emerging. So timing is everything even later in life, let alone within gestational periods.
Emily Kumler: And you know, one of the things that I feel like is often said, whether it’s accurate or not, is that people say women have more depression because women are more likely to go to a psychiatrist or a therapist and ask for help than men are. So when we’re talking about these kinds of figures, where is that data coming from? And I also feel like it’s important to mention that the suicide rate amongst middle aged men or even younger men, I think in the 20s it’s like the leading cause of death for men. You know, it’s not to say that men don’t suffer from depression. So just I’m curious about like in terms of when we say like women are, you know, more likely to develop anxiety and depression. Like how are we, where are those figures coming from? Is that self reported in terms of people who report?
Jill Goldstein: No, no, no, no, no. There have been population studies done around the world, actually. This is not just in the U.S. This is a world figure and people define it differently. So if you just took a screening instrument and kind of looked at a set of symptoms and asked for current depression for the number of people that met criteria for a certain number of symptoms. Sometimes that’s the way it gets defined. What we’ve defined it as is actual clinical depression, something that emerges just post-puberty, and actually is long lasting, recurrent.
Emily Kumler: And how do you define long lasting?
Jill Goldstein: Well it could be for their lives. And how to control that or how to live with it. How to control the symptoms is a constant battle. Now, there are people with a major clinical episode that occurs that lasts for a year or two years and resolves. So that is also true, but there is a group of people that have lived with this throughout their lives. We know that all these disorders are complex, so there are some genetics involved and even the genetics, very complex. What do these genes actually do? In fact, some of the genes related to depression are actually in our immune system. Not surprising, right? Because the circuitry that regulates mood actually can regulate some of our immune response. Those are things we’re looking at. As I just said, that stress circuitry. There are certain receptors that are also immune receptors that sit right in the same circuitry that regulates mood and regulates our hormones and regulates the heart and also regulates the vagus nerve, which also regulates our immune system. So these things are tied in with each other. Our physiology, our brain, they’re tied in with each other and it is important to actually separate out what is causing what, what is producing what, what is regulating what, and how do men and women do this differently and what goes awry at different periods of development that may set the stage for why they have these different risks. The lifespan perspective on looking at sort of development and risk over one’s lifetime, I find is a really optimistic way to look at these disorders because the sooner we can pick up biomarkers for risk, the sooner we could develop therapeutics to target that. And the sooner you target that you’re going to attenuate disability and hopefully eventually prevent disease. And we need to think about those biomarkers for risks in a sex dependent way. They may differ for boys and girls and men and women. We believe they do.
Emily Kumler: So I don’t know if you’re familiar with Cindy Morshead, but she’s somebody else that I recently just interviewed. We’re going to do an episode, probably before the end of the year, on Metformin, which I’m sort of obsessed with us like this wonder drug.
Jill Goldstein: Oh, I’ll really be interested to hear that one.
Emily Kumler: Yeah, well you know, I mean I feel like most of the research is really good and then there was just some research that came out a week or two ago saying that it may have a negative impact on the ability to put on muscle, which I think in terms of aging is pretty important, but I was really excited to talk to her because she’s at the University of Toronto and she had done this study looking at traumatic brain injury and the use of Metformin. They found like basically no statistical significance until she had a research student who was like, what if we take apart the female versus male? And she’s looking at mice and they found that in the females there was a dramatic improvement in cognition and brain repair and all this stuff. But, then they retested and they looked at it post-menopause, or they induced menopause in the mice and the result went away. So there’s some connection which she was, you know, this is at its infancy. I think she just got some money to start looking at humans. But like it’s fascinating to me, right? That there’s some interplay that like with testosterone that blunts the effects of Metformin or that with estrogen allows for brain repair.
Jill Goldstein: Yes. Well, estradiol is really a primary driver of many causal pathways, which is why we’re really interested in looking at these shared causes across organs and tissues. And the causal pathways we believe are really important are obviously hormones and genes, but the vasculature, how the vasculature develops differently. Actually one of the primary regions that drives the stress circuitry, a little set of nerve cells in the hypothalamus called the paraventricular nucleus in the hypothalamus. It’s an amazing set of nerve cells with lots of different chemistry in it, but it also is the densest region of the brain that’s vascularized. And the vascularization that region differs in the male and female brain, which just kind of blew me away.
Emily Kumler: So what does that mean? Like, explain it to me like a kindergarten. What does that mean?
Jill Goldstein: That brain region is more highly vascularized in the female brain than the male brain.
Emily Kumler: Meaning like there’s more blood supply?
Jill Goldstein: Yes. And one of the reasons we think that is, is because it drives so many of the hormonal regulations. So it drives the stress circuitry. So the hypothalamic pituitary adrenal access that releases stress hormones, we’ll call them that. It regulates our gonadal hormone. And as I told you, it regulates the heart and regulates some immune system function. And so it’s a really critical brain region that needs the blood supply, right, to you talk to the rest of the body. Sort of to drive physiology and the rest of the body. That’s a bit on the vasculature, but the metabolic function and brain metabolic is a hot topic right now, really important for understanding the risk for Alzheimer’s disease. And we believe really important for understanding some of the sex differences that are occurring over the menopausal transition. Estrodiol really can enhance metabolic function in the brain in a really important way. And so one of my trainees is looking at how that’s happening and what are the brain regions it’s affecting and how might we try to intervene to try to maintain intact memory function after ovaries decline. So we study sort of windows of opportunity of studying sex differences in fetal development, in puberty, in pregnancy, and in menopause, sort of perimenopause to menopausal transition. And in menopause, so, these are periods in which the brain and the body are either differentially flooded with gonadal hormones or depleted of gonadal hormones during menopause. So these are really critical periods of shifts in the brain that can change the setting of the brain and can have good effects, you know, advantageous effects, but also some deleterious effects. Now during menopause, after the ovaries decline, the ovaries can actually produce weak androgens up to 10 years after menopause. And those weak androgens can get converted into estradiol and help what we call maintain estrogenicity in the brain. Well, one of the questions we have in my lab is how can we maintain intact memory function in early/mid life so that we can attenuate the risks for disorders of aging, but memory decline with Alzheimer’s disease.
Emily Kumler: And so you’re looking at preventing the decline?
Jill Goldstein: Yes. We’re trying to identify early biomarkers during that period that we could target for therapeutics to help maintain intact memory function. Now, estradiol is really critical for just the healthy memory circuitry function. So we study the stress circuitry and memory circuitry and they’re actually cross talk with each other. So some of the same brain regions that regulate stress and regulate all these hormones we’ve been talking about or regulate the heart, they also regulate memory function. They’re actually shared. That kind of makes sense, doesn’t it? Because stress can affect your memory when you’re highly stress, it can be really hard to remember things and concentration and things like that. And it also can affect how we consolidate memories. So they really are related to each other in the way that we regulate them in the brain. So some of those same brain regions, as I said, are the most highly sexually dimorphic in the brain. So they’re the densest regions in the brain with gonadal hormone receptors, which are really important in the regulation of memory function. And some of those brain regions actually can produce these gonadal hormones in the brain. So we can produce estradiol in the brain itself, even without the ovaries. So we can maintain some estrogenicity in the brain with the conversion of these weak androgens into estradiol in the brain. And also, we have what’s called an adrenal cortex that’s part of the HPA, that stress circuitry that produces the cortisol, which supposedly we call it the stress hormone, but also produces a weak androgen called dehydroepiandrosterone, and that weak androgen continues to be produced after menopause. So it’s a really important hormone that can get converted again in the brain into estrodiol. And again, estradiol, really important in the regulating memory circuitry. In our brain imaging studies, we’re brain imaging group, we’ve shown over the menopausal transition, that higher levels as the ovaries decline, as estradiol goes down, higher levels of DHEA, the dehydroepiandrosterone hormone, DHEAS, higher levels actually help to maintain intact memory function and intact activity in that circuitry in the brain. So we’re trying to think about ways that actually, naturalistically, we function so that we can enhance those later on for people in which these things have been dysregulated.
Emily Kumler: And so is there any research that has looked at hormone replacement therapy? We always say that it’s like bones, brain, and heart in this podcast are the big ones when your estrogen starts going all wonky in perimenopause or menopause. Has anybody looked at any sort of like longitudinal study of women, like Women’s Health Initiative obviously wouldn’t have because it would’ve been too late, but like is there anything else where they’ve looked at women who have done hormone replacement?
Jill Goldstein: Oh yes, this is a hot topic, and one that is absolutely critical for much more research than is out there right now. There are groups doing this, looking at women over the menopausal transition, following them prior to menopause, after menopause. There are groups that really follow them in brain imaging, brain structure, brain functioning, looking at functional imaging components and structural imaging components, how the brain changes just naturalistically over the life course and how we might be able to change that with hormone therapy. With the Women’s Health Initiative, they kind of put the kibosh on the field and on a pharmaceutical companies to be producing these hormones because they just decided that, you know, hormones were bad because they were going to cause breast cancer or heart disease.
Emily Kumler: Right. Which has now been completely reversed.
Jill Goldstein: So the problem is we need more work to discuss, you know, of course. Even in those same data, what was found later on, JoAnn Manson, one of the principal investigators of this study who actually published this, that when you took the women who were younger, not the 65 and older women, but the younger women, and you looked at the different impact of hormone replacement on cognitive function. In fact, they did better. So that has now spawned a number of people really focusing on this kind of window of opportunity for hormone replacement therapeutics. And I believe it’s absolutely critical for helping to maintain memory function. So there are some theories out there that when you, those who can actually take these hormones, that it will depend on the route of administration. So whether you use a patch, whether you use it orally. If you use it orally, it’s going to be metabolized in the liver and there may be more systemic effects than using let’s say a transdermal patch. These are things that one would need to talk with their physician about, about their risks for all sorts of illnesses that they’ve had family histories for. So it’s not for everyone, but that doesn’t mean we shouldn’t be studying who it is under what conditions and what is the duration route of administration and type, type of hormone type of neurosteroid we can be giving women. These are the questions that are still out there that are absolutely critical given the tsunami of Alzheimer’s disease approaching.
Emily Kumler: And so we did an episode on Alzheimer’s when we first launched and I talked to Dale Bredesen who’s done some really interesting work looking at a lot of different factors, and he really has like a very multifactorial approach to how the disease happens and why and things you can sort of do to try and prevent it if you know you’re like, you know, a four, four genetically or even three threes who have, you know, high risk. But I was sort of curious, one of the big things that he really talks a lot about is the role of inflammation in general. And I’m like a huge, I like if I could do my CRP every day at home, I would because I think it’s such an interesting internal way of looking at how healthy you are. And obviously if you’re sick or you have a cold or I have two little kids, so there’s always germs going around. So it’s really interesting to sort of see how my levels do change. But, I was sort of curious like when you’re talking about immune function, is that not synonymous, but is that part of that inflammation?
Jill Goldstein: Absolutely. That’s right. One of the pathways we believe are really shared with why it is that depression, cardiovascular disease, diabetes, are independent risk factors for Alzheimer’s disease. Why is that? Independent of smoking and other things. They’re independent risk factors. So we are really interested in why that is because depression emerges just post puberty, so if they’re shared causes across these three chronic diseases and the immune system is one of those absolutely critical pathways, right? We are looking at disruption of the immune system in prenatal development and we’re looking at how that gets disrupted in the offspring who are exposed and unexposed to high risk pregnancies and how that change in their immune system, even in their innate immunity, they carry throughout life into the risk for these three different diseases across life. So if we could intervene early, prior to depression or even after depression, 94% of cardiovascular disease is modifiable, we could be changing the life course of that person by intervening early. This is why we need to take a life course perspective and we need to think about the impact of sex, because it’s different, sex and gender because it differs. How we’re going to intervene will differ depending on whether you are a man or a woman. And it doesn’t mean that it may differ in total quality, like here you have this risk factor and you have that, maybe you will, but even quantity wise, how our hormonal systems regulate these things, the dosages of these things. We need to think about how our bodies are different in the healthy sense, how they get dysregulated in a sex dependent way, and why we need to develop what we call sex dependent therapeutics and sex dependent approaches to really thinking about intervening early. We want to reconceptualize, at the Innovation Center on Sex Differences in Medicine and our initial focus on the co-occurrence of these three chronic diseases. We believe we need to reconceptualize illness as crossing organs and tissues. So medicine needs to get out of its departmental silos, differing by sex, and begins early in development prior to the manifestation of disease. So we like to say, what if we could predict and prevent an adverse future? How cool is that? We could be preventing Alzheimer’s disease by focusing in after pregnancy in this woman and preventing her hypertension potentially.
Emily Kumler: Well, and I think taking this whole body approach makes so much more sense to me. Right? It’s like this idea like that you’re saying silos, but I always have loved that definition of health that’s like health is the absence of harm or whatever. It’s like, you know, it’s what happens before you get sick, but it’s sort of like we have this inevitable. And when you’re thinking about taking any of the, not the hormone replacement stuff obviously, but pharmaceuticals that would help with the depression, is there any sort of consumer advice or patient advice you have in terms of sex differences there? Like, I know often women aren’t involved in clinical trials, especially women of childbearing years, and that people are trying to change that. But that’s still, unfortunately the vast majority of the testing is done on men for a number of reasons that people justify. But, I’m just sort of curious, knowing as much as you do about the female brain, are there things that you feel like are more dangerous or drugs that are more dangerous for women or that haven’t been as well studied or ones that you feel more confident work the way they’re supposed to work or the way they’re touted to work on women versus men?
Jill Goldstein: Yes. I mean you’ve said so many things I want to say yes to. First of all, medicine has been built in silos, departmental silos, and we need to break down those silos. But medicine has also been built on models of male animals and men’s health. And women are not little men. And in fact, what we like to say, this really places both women and then at a disadvantage because for example, if you have a drug that may be more effective in one sex than another, and you combine those sexes in a clinical trial, you likely will attenuate your result for both sexes. So we believe that in industry there are likely molecules or not just even at the molecule level, there are probably therapeutics they’ve spent billions of dollars on that they think are ineffective, but they have not designed their study by sex. One of the things that the Center is actually focused on is to educate the public about the importance of sex, not only as a gender equality thing in clinical trials, which is really important and really initiated by the 1993 NIH Revitalization Act that women need to be included in clinical trials. That was a game changer, but we are now at a point where we need to design our studies to look at the impact of sex and gender, both sex and gender are complicated constructs. One should not just throw in a bunch of female animals or throw in a bunch of females and then separate their data by sex and see if there’s a difference. They need to design the studies to actually focus on the impact of the sex or gender. Most animals used in basic cardiovascular disease research are male or they’re unspecified. And even in neuroscience, there are like five and a half animal studies that are exclusively male for every female. And that even includes depression where less than 45% of studies on depression, which is a higher risk in women, use female animals. This is even true in eating disorders where girls totally predominate. It’s mind blowing.
Emily Kumler: It is mind blowing. It feels so irresponsible.
Jill Goldstein: But you know, it just wasn’t thought about. So many years ago, before we had the field of pediatrics, children were just thought of as little adults and that the medicine would be the same. But now we know development is really different and we developed a whole field of pediatrics. So I think it’s similar to that. We just assumed that human beings were the same. And so we didn’t focus on what these differences were and how they could implicate disease. But we know there are so many sex differences across every chronic disease. So even though primarily men and women are really similar, as I said before, these small differences in our brains and our bodies, and I’m not talking about the reproductive organs, I’m saying all the other tissues and organs, those are the ones that are going to tell us about how to develop new therapeutics that are sex dependent. Absolutely critical that these studies need to be designed and the Innovation Center on Sex Differences in Medicine, we are a resource for our hospital or people that are crossing fields. We brought in psychiatry, neurology, cardiology and OB/GYN, obstetrics and gynecology, and we have investment from all these fields to actually rethink about how we can look at shared causes across these fields to try to understand this issue of comorbidity. From a global point of view, they use the word multimorbidity, that these are going to be the number one causes of death worldwide and morbidity by next year. It’s a particular crisis for women in terms of depression, cardiovascular disease, and Alzheimer’s disease because there are higher rates, much higher, substantially higher rates of this comorbidity in women. And the comorbidity, just a few facts, which I think your audience may be interested in, I don’t think people realize how costly these multimorbid conditions can be. If you just looked at cardiovascular disease, cardiovascular disease alone, the annual global economic impact they have at 863 billion back in 2010 and it’s now over a trillion, it will be over trillion in 2030. Or Alzheimer’s disease is going to tank our economy if we do not find therapeutics. Even now it’s about, it’s estimated to be about a trillion and by 2030 up to like $2 trillion and the costs are highest with people with multimorbidities. That accounts for over 90% of Medicare spending. So these are highly infused with women. We believe that this multimorbidity condition or threat is an economic threat. So women’s health is also our economic health. Women are the primary drivers of health care utilization. They bring their families in for treatment. So it’s not only themselves but actually all their family members. Over two thirds of them are the caregivers for ill relatives with chronic disease. So they are leaving the workforce. Mean age of caring for their ill relatives with dementia is 49 years of age. This is at the height of their economic success. So they’re having to leave the workforce. This is a major economic issue for businesses. So we not only want to talk about, at the Innovation Center, about the impact of sex on the biology and really enhancing discovery, translating discoveries. We are about action now. Translating that discovery into therapeutics, into programs, into policies. We want to educate the next generation to think differently than my generation about the impact of sex and looking at across organs and tissues, which is really important. And then we want to develop those to try to prevent these illnesses. So I just wanted to say a little bit about, you know, how we’re trying to make an impact not only on the biology of sex, but trying to understand and impact how gender also affects our health care and economy in terms of these multimorbidity conditions.
Emily Kumler: I just did an interview for another podcast and they asked me at the end like, what are some actionable items that you could tell people you know, to do, to change in their life? And I was like, go enlist to be a subject in a clinical trial because people make all kinds of arguments like, women are too busy or you don’t know about it, but I feel like, yeah, you know, if you’re not a researcher or you don’t have a lot of money to donate, then the easiest thing that we can all do is donate our bodies. Right? So that you all have people that you can study.
Jill Goldstein: The other thing is ask your doctor. Say, gee, you know, how was that drug developed and is it good for someone who is a woman at my age?
Emily Kumler: Right. Yeah. No, I feel like you always want to know like has there been like a double blind clinical trial done on people who look like me, right? Because oftentimes there is not. And I think sometimes doctors aren’t even like that familiar with some of that research, which you can usually look up on pub med or find somewhere. But I think that’s very helpful.
Jill Goldstein: Yes. Do a little research, you can get online. There’s so many things online. There’s a lot of false information online, but you can also get good information online about your condition and what are some of the options for therapeutics and then you could ask your doctor, gee, did they ever test this on women my age?
Emily Kumler: Yeah. There was a 60 Minutes like, I don’t know, maybe 15 years ago where they were talking about Ambien and sex differences and it was like mind blowing that the Ambien stays in women like two to three times longer than in men.
Jill Goldstein: Yes. Ambien is a story that fortunately came out in the public because it happened to a famous person. And there are multiple drugs, Ambien works on certain neurotransmitters in the brain that actually is regulated by estradiol. It came obviously to the attention because of the car accident of the Kennedy family member and it turned out that the dosages should differ by sex and probably by sex and age. There were a couple of other drugs that were going to be thrown out, but they tended to work better in the female lung, for example, a lung cancer drug, than in men with lung cancer. And the same thing for strokes, which women have higher rates of stroke. There was a drug discovered that really only worked in females than in males. And so it’s really important for investigators to actually study these things and the FDA to actually require trials to be designed by sex. And if you have designed the trial by sex, we want to see the results reported by sex. That’s the other thing. People don’t report their data by sex.
Emily Kumler: Yeah, I mean that seems just like lazy really from an outside perspective.
Jill Goldstein: They don’t think about it.
Emily Kumler: No, I mean it’s obviously it’s just so dogmatic or something. I mean I that Metformin study really was so fascinating to me that it was like they were going to just sort of say that they didn’t find anything. Right? And then this research assistant was like, well hey, you know, like let’s just separate by sex and see if there is anything. And it was like that’s everything.
Jill Goldstein: I’m not surprised.
Emily Kumler: Yeah, no, and I mean you just sort of, I think your point earlier of like how many drugs have they spent billions of dollars testing only to say it didn’t have an effect when really it may have had an effect on one of the sexes? What a waste.
Jill Goldstein: Exactly. There are a few examples in the literature on this, but there likely should be many more. It is just that we still need to do a lot of education in the field. That is part of our mission as well. Part of our mission, as I said, is discovery, but it’s also about educating not just the next generation of people in medicine, but really the public really needs to understand these things because it’s the public that will then demand that the National Institute of Health study these things by sex and gender and that our healthcare systems, the FDA, start to deal with this.
Emily Kumler: I mean I feel like you and I could literally talk for hours.
Jill Goldstein: Oh, I could. I kind of went from topic to topic. I don’t know how you’re going to put this whole thing together, but you’re the professional, so I’m sure you will. You’ve done beautiful work.
Emily Kumler: Well, thank you. I have like a list of a hundred things that I still want to cover, so the sex difference stuff is so, I don’t know, it’s definitely the obsession for me right now.
Jill Goldstein: I love it. You sound as obsessed as I do and I’ve been doing this for 30 years. I’m still obsessed.
Emily Kumler: Well that’s a compliment. I appreciate that. I’m Emily Kumler and that was Empowered Health. Thanks for joining us. Don’t forget to check out our website at empoweredhealthshow.com for all the show notes, links to everything that was mentioned in the episode, as well as a chance to sign up for our newsletter and get some extra fun tidbits. See you next week.