The Ovary’s Job Doesn’t End at Menopause: A Top Neuroscientist Explains

22:08Dr. Mary Claire Haver:let's be fair do we understand more about the what we think of the male hormones that we have testosterone like do we understand male physiology better and this whole cascade and chains of signaling going back and forth? Or is it that we have this unique biological transition that men don't have, and so it's less detrimental to their health? Yeah, that's a really good question. And I would say it's probably a little both. I wouldn't claim that we understand male physiology completely, and certainly around reproductive organs, you know, testes and prostate, for example. We've studied that more, but I think there's quite a lot to learn.

22:48But the real difference, I would say, is that ovaries, which are so important for overall health in females, they are aging faster. And that is the key, right? Two and a half times, right? At least. Let's be clear to listeners.

23:03Dr. Mary Claire Haver:The ovaries are aging two and a half times faster than any other organ system in our body. At least twice as fast. Why? Well, if you can answer that question, then we wouldn't be talking. Like, that's the, I would say that's the biggest question that we could answer. Because there are people in certain areas of the world who say, well, this is nature of God's plan. This is natural. This is meant to happen. But it's not without pathology. So from a functional standpoint, ovaries are aging faster than the rest of the tissue in your body. And aging does happen in male reproductive organs. The difference is that it's really synced up with aging in the rest of their bodies.

23:42So what I mean by that is that if you think about organ function over time, your organs are not aging exactly simultaneously. You know, some things show more signs of aging faster. But if you're lucky enough to live to older ages, most of that decline happens in the last few decades of life for all of your organs. You know, not totally synchronously, but it's happening like that. And so in the male reproductive system, that aging in those organs is synced up with aging in the rest of the body. And so they don't have this differential in health span that we see in females. We all know that women live longer than men.

24:15Dr. Mary Claire Haver:So I've read four years, six years. What's your data say? Well, it depends on what country. It depends on where you live. And it depends on your socioeconomic status. So there's actually, you know. And it depends on if you're a physician. Because women, physicians don't live longer than men. It depends on your job. Yeah. So it depends on a lot of things. But in every country where it's been measured, even in places where the average lifespan is very low, even in places where a lifespan is short, women still live longer than men on average. But it really does depend on where you are and your socioeconomic status.

24:46There's no question that when we talk about aging, you know, whether or not you have a particular level of wealth matters, which is horrifying. Yeah. If we're lucky enough to live to older ages, we will spend more time at the end of our lives in poor health, suffering from one or more of those age-related diseases. And that is, I call that a differential in health span. The number of years that you're healthy if you're female is shorter than the number of years that you're healthy if you're a man. And that is tied directly to the fact that your ovaries are aging at an accelerated rate. And so you asked why?

25:23That is the golden question. If we understood what was driving ovaries, what was it that was causing them to age faster, that would give us a clue about how to change that. And I'm not talking about extending fertility indefinitely. I'm not talking about ending menopause because menopause is really just talking about menstruation. I'm not interested in having a period for the rest of my life. I don't know about you. But yeah, the goal is to really think about how to extend healthspan. That's the goal.

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28:56Dr. Mary Claire Haver:So when I opened my menopause practice, you know, I was a straight traditional OBGYN for 25-ish years. And it was a great, lovely job. But then when I pivoted and decided I just want to take care of these ladies, all of a sudden, every single one of my patients is in perimenopause and menopause. And they're coming in, you know, usually desperate. They've seen six, 10 physicians for various things. And no one was taught to really connect the dots hormonally with their sleep disruption, their weight gain and all the things. So we get them back to functionality. Most of them are in crisis. They're not able to function in the lives they built.

29:32Dr. Mary Claire Haver:their mental health, cognitive issues usually are the two things that bring them in. And they're very frustrated with weight gain. Then we start talking about the next 30 to 40 years. And I don't have a lot, I don't any really of my patients yet have come in and said they want to be the next Brian Johnson and live 250, 120. You know, they look at what the longevity bros, sorry, are spouting online and a few of the women and that has zero interest to them. They don't want to live without their loved ones, right? They don't want to end up alone for 20 years. They don't want to be a burden on their families.

30:06Dr. Mary Claire Haver:They are so terrified of ending up losing their independence from cognitive decline or physical decline. And that is really the focus. And so by the time they get to me, the ovary ship has sailed, right? And we're focusing on all the lifestyle things and maybe hormone therapy that could be helpful here. And when I look at the data on ovarian life, ovarian health, it still seems to be heavily centered on fertility, giving people the ability to get pregnant easier and a longer life because we're delaying childbearing to have kids. I mean, we've just reached where we have more babies over 40 as a population in the U.S.

30:45Dr. Mary Claire Haver:than under 20. So that's what my patients are interested in is they're very aware, looking at their mothers and grandmothers and the women in their family, how they're aging, and they are not interested in what their mothers went through. Unfortunately, we're at a stage right now I mean, it's a good, it's a positive message that we've realized that this is a challenge and everyone has woken up to the idea that we need to think about female physiology, about female health in a different way to consider the female body as a whole system, right? That's like step number one to get medical care to integrate, you know, your brain health and your heart health and your ovarian health and your bone health and think about them as a whole system and a functioning system that we're all talk to each other.

31:30Exactly. That's happening. Obviously, we're in a place where we don't have the answers yet. We are coming from a place where we're generations behind in the data collection. and you know that's just where we are and so we're we're moving past that and we're starting to like really see discovery in the space but it's going to take a little while for for discoveries at the bench to make their way through to women's hands one of the things that i'm most excited about in my work is to do that to really think about how to change that path and make it to accelerate it and to to make it you know more efficient but while we're waiting for those discoveries to trickle down and for us to collect those large-scale data sets that we need desperately to understand some of the things that you're asking about.

32:15Modern medicine does have a lot of solutions that are available now that are not really being applied. I personally, now I'm not a medical doctor, but you are, so maybe you can say this. I think that at 40, every woman should have a cardiovascular workup. Like you should know what your normal is. You should have a baseline to compare to for when you go through perimenopause and menopause because we know that your cardiovascular disease risk is going to double at least when you enter menopause or go through menopause. What would you say that workup would be? I mean, I personally, especially for someone like I have, you know, a familial cardiovascular disease risk that's pretty high.

32:53And so, and I, you know, I did have to fight with my doctor to get this done, but I mean, the whole gamut to But, you know, VO2 max, not just like a cardiometabolic panel, but like a deep phenotyping of your cholesterol and all that kind of stuff. Thinking through like if you have a risk to have like a calcium scan, right, to get those baselines. Or angiogram. All of it. Like all of it. And right now, I think that if I'm not mistaken, the guidelines are for women at 55 to have a full workup and for men at 50. That's probably also too late. But at 55, like. The train has left the station.

33:32Dr. Mary Claire Haver:So they just changed the lipid recommendation. So that's just in the last two months and it's much earlier. So they're wanting a full lipid panel, LP little a, ApoB, which were never included before, as young as 40. Oh, that's amazing. So we're getting, you know, baby steps. And we've been doing that in our clinic, you know, recognizing the data early. I really feel like cardiology, when I look at all the subspecialties, is really fighting for women's heart health, you know, because it is so vastly different than men's and it's the number one killer of women. Right. Well, not every cardiologist knows that though.

34:06I had to educate mine. So yeah, I'm happy to say he listened. But it was a shocker for me to sit in someone's office who board certified it from a wonderful training background and to say, hey, I'm 40 something and And I'm having symptoms of perimenopause. I definitely think that I should have a full cardiac workup because my cholesterol has been creeping up over the last few years. And cholesterol is a precursor for all these hormones that my ovaries are making. And so I just want to figure out what's going on and get a baseline so that I can watch it change over time. And I said, kind of in an offhand way, you know, because my risk for cardiovascular disease is probably even higher than twofold at menopause because of all of my family background.

34:57And he looked at me and he said, no, that's not true. Your risk of heart disease isn't going to go up when you go through menopause. Really? I was like, what? Oh, my gosh. Okay. But to his credit, you know, he listened, I explained, and then sent him a bunch of scientific literature. But yeah, I really think that there's a lot you can do to monitor heart health that we're not doing today. I mean, lots of us wear wearables, and I'm not, you know, I'm agnostic to which ones, but I think that you have the ability, you know, as an individual to understand what's normal for you in every system, right?

35:34Not just your heart, but in every system, to understand your normal, your baseline. And then when something changes, to really go after it and to, you know, advocate for yourself and talk to your doctors and make sure that you understand what's happening. What about bone health? Oh, my gosh. I mean, DEXA scans are so cheap and so easy. I'm not saying you should do them all the time, but, you know, a couple times a year to look for changes. And for me, the DEXA scan is so much more exciting than just the bones, right? Right. Understanding the muscles. The first time I had a DEXA scan, I was like, oh.

36:03Dr. Mary Claire Haver:They gave you the output. So, I mean, for our listeners, the DEXA is measuring multiple things at once. Depending on what the output is set at, sometimes it will just give you your bone density at the hip and the spine, which is how we measure, you know, for osteopenia and osteoporosis and normal bone density. But it is actually measuring your fat, your visceral fat, and your muscle mass. So you have to ask the tech to give you the report and they have to like flip a button, you know. But then when you have that body composition. Interesting. Yeah. I went to a private company. So yeah, in our clinic, we have an in-body scanner, which is electrical impedance.

36:40Dr. Mary Claire Haver:So I can't give bone density, but I can give muscle mass, fat level, visceral fat, you know, so I'm able to have that body composition conversation. But like most women have never have no idea. They simply go with the scale. Oh, wow. When they're tracking health outcomes. That's insane. It's insane. The technology is so far advanced beyond that. Yeah. And relatively inexpensive. Like there are companies that will, you know, do a DEXA scan for$99 or 50 even sometimes. The competition's getting out there. Exactly. But the muscle, understanding like the fat distribution and looking at the muscle mass.

37:15The first time I, like there was a slight difference in my calf muscle. I was like, ooh, why is that? But then when I was, you know, running or working out, I actually paid attention to what I was doing.

37:26Dr. Mary Claire Haver:I can often show my patients that, you know, have a life, a job or something that has led them to be more sedentary than they realize. And then they'll see this amazing upper body muscle mass, but their legs are falling behind like 10%. And I'm like, this is your sign, you know, get up every hour and do 10 squats, like take the stairs, like you're really going to have to work because of your job that's requiring you to sit or, you know, make some lifestyle changes because this, you're going to be the woman who won't get off the toilet. it without help. Yeah, exactly. At 80. Yeah. You know, and if that's your goal, like this is a gift.

38:01Yeah.

38:02Dr. Mary Claire Haver:That now we can put some changes in place that will. Yeah. And this is easy, right? It's not, there's no, it's, it's non-invasive. It doesn't take very long. You don't have to do it very often. Yeah. But when you see changes, especially in bone density, you know, that's a, that's a warning flag. Very few things. When they see their visceral fat, a red flag, you know, alarms go off in their head. And when they see their muscle mass, you know, and when they see their bone density, they're like, I don't want to fall and break. I'm like, just being a woman, it's a 50 % chance you're going to have an osteoporotic fracture before you die.

38:30Dr. Mary Claire Haver:The younger you are, the more we can put - Hopefully not. I mean, we've got some time before - Right. But now that you know you're a little bit higher risk, we can make interventions. And then to be clear, we can grow bone and muscle at any age, right? With or without menopause. It's just harder because of the aging process. Yeah. So here's a fact that I think is probably going to make people listening angry. And it should. The main body that funds biomedical research in this country only required scientists to include, required them to include females in their studies starting in 2016. That is true.

39:07We're talking about the NIH, which is the largest biomedical research funding body in the world. And NIH is amazing. It funds a lot of research, mostly preclinical research, meaning not in humans, right? So it's kind of early stage stuff, but it also funds clinical research as well in humans. And the clinical research part of it had been addressed through an act of Congress, actually. It's also sad that that had to happen through an act of Congress. But in 1993, there was an act of Congress that said you must include females in clinical trials, which is important. But for this kind of preclinical research, All this work that we do to establish, to test really crazy ideas and hypotheses.

39:48Dr. Mary Claire Haver:So to the listener, we usually don't start testing things in humans. We use animal models for safety. And cells and lots of different... Hela cells and yeah. So preclinical means before we get to humans. So before there's a human trial, typically, there's been decades of research done in cells and animal studies before we take it to humans. Exactly. And so that work, which forms really the, that's like the foundation for all of biomedical research and for all of the sort of clinical things that happen with like drug discovery, for example. Because there were no rules and because there was a really, there was the mistaken assumption that female systems are somehow noisier or have, you know.

40:32Dr. Mary Claire Haver:Complications. More complicated than male systems, which is not true, by the way. It's been shown completely, like, totally myth busted. But that was the assumption. And because of that, a lot of people just defaulted to using males, right? Right. And, you know, I think it's important to acknowledge that when you have a limited amount of research funding, it can be expensive to try to study something in both sexes. And so if you have to make a choice and you think that females are complicated and noisy, then you're going to default to the males. But because there was no rule in place, what it meant is that historically 80 % of those preclinical studies were done in male animals and male cells.

41:12and that has implications beyond just thinking about you know women and female health when we miss the differences between males and females it really changes our ability to make interventions for both sexes we were talking about the immune system earlier right female immune systems are different from male immune systems right for whatever reason we don't understand it very well but we're better at dealing with viruses. Like we just, our immune systems respond differently to viruses. So the male cold, like the man flu is a thing?

41:47Dr. Mary Claire Haver:Apparently, yeah. I mean, we saw it during COVID, right? Men died at twice the rate of women, right? Independent of age. And that is likely due to differences in immune system, like immune function that we don't understand. But if we did understand those differences, that would have given us a lever to potentially save the lives of men. And when you think about response to vaccines, right, when we talk about autoimmune disorders, right, 80 % of the patients who have autoimmune disorders are female. And your risk of autoimmune disease goes up dramatically at and after menopause. And that is directly linked to this ovarian aging question.

42:24And again, no idea, like, what's driving that, but we know that that is, you know, there's a link there. And so this is a place where there's a huge amount of opportunity to make discoveries that will impact so many lives.

42:37Dr. Mary Claire Haver:One thing surprised me in my research for this is that when we look at the menopause model, so say you are going to study a female in the lab with an animal model, and you're going to study a female, you're going to study a menopausal female. The only model for menopause female is they go and remove the ovaries. So they have an iatrogenic surgical menopause. That's not the only model, but yeah, that's the dominant model. Would that be fair to say? And there's no perimenopause model. So we're missing a seven to 10 year gap in animal studies where they're going through this, you know, predictable decline where there's lots of things going on, especially with cognition and mental health and bones and the general urinary system that we can't study because we don't have a model of a declining, you know, rapidly declining ovary.

43:27Dr. Mary Claire Haver:It's either the female model is premenopausal or postmenopausal. That is true. It's important to say that there are models that are being developed. So an animal model is never going to recreate everything that happens in a human, right? So we have to acknowledge that up front and we have to just like acknowledge that up front and then be smart about using models in the context of their limitations, right? And so, for example, a rodent model, like you said, doesn't go through menopause. And so you can take out the ovaries and that is, that's a really good model for POI or POF, right? Or for someone who's...

44:01Dr. Mary Claire Haver:Sorry, premature ovarian insufficiency. Or failure. Failure, yeah. So this is premature menopause. Or for women who have to have their ovaries removed for cancer or for some other reason. And so that's a great model for that patient population. But for normal perimenopause and menopause, it doesn't, you're right, it doesn't recapitulate anything about what happens in a human. So there are models that are being developed where they're trying to sort of mimic a more gradual decline in ovarian function, as more scientists and clinicians focus on this problem, as more people come into the field, as more people understand that this is an important question to ask, we'll get better.

44:41There will be better models.

44:46Dr. Mary Claire Haver:Can we talk about something that catches so many women completely off guard? You hit your 40s, and suddenly your skin feels different. It's drier, thinner, or maybe even a little crepey. So you do what we've all been taught to do. You buy the expensive moisturizer, upgrade your retinol, and hope for the best. But here's the thing. It's not that you're doing skincare wrong. For many women, these changes are happening because estrogen is declining during perimenopause and menopause. And if the root cause is hormonal, it makes sense that products designed for aging skin can only do so much. I noticed this myself.

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48:43Dr. Mary Claire Haver:so back to funding billions of dollars have gone into studying erectile dysfunction oh yeah which is important not knocking that which affects less than 20 percent of men your entire consortium which i think is absolutely amazing raised 14.5 million dollars we raised a little bit more than that, but we gave away 14 and a half. Okay. And you called that basically a rounding error. Well, yeah. I mean, when you think about the NIH budget, for example, in 2024 was$47 billion. So, yeah, there's a few orders of magnitude there difference. The consortium was designed to, again, stimulate research in the space, to build a new field.

49:25And we gave away$14 and a half million to 49 scientists all over the world from 37 different institutions and eight countries. And I'm really proud of that. So the consortium existed for five years. It doesn't exist anymore. Partly because there are other institutions and other foundations that have taken over and are funding research in the space. And they're bigger and they're doing more. Yeah, I mean, but you kicked it off. So amazing. I'm very excited about that. But yeah, it's a challenge. What we fund dictates what we know.

49:58Dr. Mary Claire Haver:So I want people to understand when we talk about the data here. And I knew the data from 2023. The NIH budget at that point, I think, was$43 billion. And women's health, what they called women's health, was 10 % of that. And the majority of that went to pregnancy or breast and ovarian cancer. Three, very important, you know, but everything else, things like polycystic ovarian syndrome, which affects 10 % of the population. Endometriosis, which affects at least 10 % of the population, probably more. Menopause, which affects 100 % of women who live long enough, got all collectively less than 1%.

50:32Dr. Mary Claire Haver:Yeah, that's the women's health budget, which was 10 % of, you know, so it's like 0.003%, I think, is what menopause got. So how that translates, when I pulled the data a couple days ago, and I just go to PubMed, PubMed is where we look up research articles, right? Like legit, peer reviewed research articles. And I just type in the word pregnancy. Right now, it's about 1.2 million articles that say the word pregnancy in it somewhere. Okay, great. Labs, brains, money, HR, all the things. Okay, I type in the word menopause, and we're about 104 ,000. Okay, I type in the word perimenopause, and I just wrote this book, and it right now is at 7 ,000.

51:11And if you type in ovarian aging, it'll be in the hundreds, probably. Yeah. Yeah. Which is, you know, it's very reflective of where we are as a field, And we're at the very beginning. And at this stage, I track those numbers for women's health and NIH funding. And I think at some point we have to just stop calling it women's health. It's the health of women. It's human health. Human health. I mean, honestly, or precision medicine or something where we're talking about understanding these sex differences in a way that doesn't make it seem like some special thing that we need, right? It should command a large part of the budget because it's half the population.

51:53Dr. Mary Claire Haver:Right. And women aren't aging well in general. That last decade is rough for most of them. Yeah, that's true. My patients don't want to live forever. They just don't want to be a burden, right? They don't want to end up in a long-term care facility. They don't want to have to have their children scrambling to care for their needs for a long period of time. Yeah. And that is happening in so many families. It is such a topic of conversation in my friend group of our parents, our parents, our parents. And usually, not all men, but the men kind of function pretty well. Wives are taking care of them.

52:22Dr. Mary Claire Haver:And then they die with a very short, you know, again, not all families. This was certainly my family. And then the women live a really long time requiring lots and lots and lots of intervention and care. Yeah, that's right. So I think that is the downstream of the lack of all of this study. And now that we're educated and we're understanding and we're in positions where we are caring for our parents, we're like, no, please. Right, because you're watching it happen in real time to someone that you care about deeply. And who never wanted, my mother never would have wanted to live like this. Right, yeah, I understand.

52:55If she had the choice. You were talking about philanthropic or governmental funding for research, right? So that's - That's one way we get things funded. That's one way. But, you know, the numbers are not so different if you look at private investment. Okay. Right? Which is also horrifying. I just ran these numbers from 2020 to 2025. If you look at investment in companies focused on the health of women across the board, I think it was something like 23 billion total. So not a lot. should be more, but you know, it's, it's going up. But of that 23 billion, most of it, like most of it, 22 billion of it went to those three, those three things, um, female specific cancers, maternal fetal health and fertility.

53:42And so there was something like 800 million ish, 900 million ish that went towards everything else. So like 4 % ish of the funds went to all of the indications that cause more than 50 % of the disease burden. So everything you just talked about, endometriosis, PCOS, POI, all of these things that are not cancer, fertility, or pregnancy. Why do you think that is? I think it's because, I mean, woman is incubator. This is how medicine has characterized female bodies forever.

54:17Dr. Mary Claire Haver:Yeah. You gotta be your own advocate. Moving into the biggest wealth transfer in the history of the world to women. Yeah. Okay. So when they get those paychecks, and none of these women that I see who are getting these windfalls are building rockets or buying yachts or anything. I mean, maybe a couple are. But what I'm seeing is Alice Walton building a medical school. It's beautiful. That's going to specifically serve the underprivileged. I see Melinda Gates. I see Mackenzie Scott, like, donating heavily to health. Where would you tell, if anyone out there is listening with a deep pocket suddenly, where would you have her invest for her?

54:52Oh. That would serve her.

54:54Dr. Mary Claire Haver:If she's like, keep me out of a nursing home, Jennifer. Where should we invest? I mean, there's a long list of academic labs that I can talk to you about. And, you know, I am in the middle of raising money and what we're building is something new. And so it's, you know, we're trying to build something that is at scale. So one of the things that's frustrated me a lot over the last eight years watching this space grow up is that there are so many parallel tiny efforts. Siloes. Yeah. And just a lot of very small things happening. And I think that's because women, when we realized, I call it the four stages of grief.

55:38At 42, I was like, oh my God, I'm so embarrassed as an intellectual, as a scientist. I quite literally didn't know how my ovaries worked. I couldn't even tell you what they looked like or even necessarily exactly where they were. They were down here somewhere. But I was like horrified and embarrassed that I didn't know anything about my ovaries. And then when I went to learn something, I was second stage of grief, which was like shocked, like really shocked at how little there was for me to learn. Right. And then the third stage, which I got caught in for a long time, was like abject rage at why we are here.

56:16Right. Once you understand why, why there's such a lack of knowledge. and then I think the fourth stage that most women end up in is like all right it's a problem like let's roll up our sleeves and fix it and the challenge with that is that then you get like 20 women all working on the same problem independently instead of like joining together and building something massive and for for the health of women I think we need not just a new model, but we need to stop trying to like shoehorn it into the system that was never built for women in the first place and just make something new. If it's broken and it wasn't made for us in the first place, like let's just make something new and let's not be bashful about it.

57:02And let's not pussyfoot around and say like, oh, we're just going to do this tiny little thing. We're like, let's really do it at scale in a way that's going to move the needle.

57:11Dr. Mary Claire Haver:So you did something in your lab that had really never been done before. You started mapping what is happening inside of the ovary as it ages. I should say me and several other wonderful and amazing researchers all over the world. So group effort, lots of different techniques, lots of different ways to do this. Just imagine, so swap out the word ovary for heart. In the last five years, we have gotten the first pictures of how nerves innervate the ovary, how the lymphatic system innervates the ovary. Yesterday, like quite literally yesterday, I was at an all-day symposium about ovarian health, which was put on by QB3 and Baker Labs, which is the incubator that works across UC Berkeley and UCSF.

58:00and I saw Diana Laird present beautiful data, the most detailed data I've ever seen for the innervation of nerves and blood vessels into the ovary. And it's 2026. And it's 2026. And the kind of mapping that you're talking about that we're doing, where we're quite literally asking, what are the cell types that make up the ovary?

58:24Dr. Mary Claire Haver:I only learn those cell types in reference to cancer. Uh-huh. and all the different ways the ovary can develop cancer. That's the only way someone taught me what the cell types were. Yeah. There's a lot of depth to how the ovary looks in terms of how many types of cells there are in it. And what's cool and also complex about the ovary is that if you think about, so most people will understand ovulation, right? I think I do, but I realize I don't know a damn thing. But what ends with ovulation begins in humans a year earlier, right? So a year earlier, every cycle, so for humans, every cycle, your ovary, my ovary used to recruit about a thousand primordial follicles.

59:17So these are the things that are dormant.

59:20Dr. Mary Claire Haver:I thought that happened on day one of your cycle. I didn't realize it was a year in advance. Okay. So let me blow your mind. I also didn't know this, right? This is something that I learned when I was 40. So every cycle, you recruit about a thousand primordial follicles to start growing. And they all start growing together, but across a slightly longer than a year, like 375 days. From the moment they get recruited to the moment of ovulation, that's how long it takes. And so what's happening across those 375 days is that those thousand are going through the stages of development, right? Like primary, secondary, you know, all the stages.

59:59So essentially they start to grow and then they change and, you know, all kinds of things happen. But along the way, you know, you're losing at every stage many, many dozens, if not hundreds of follicles, right? So they die through atresia. Atresia, yeah. And eventually the winner gets ovulated. So imagine now, so that happens with a thousand. And so you've got not just the follicles that are developing through different stages where there's different cell types, all kinds of things happening, right? But then there's all these cells that are dying through atresia that have to be resorbed, right?

1:00:34You have to clean up that mess. So there's a lot of immune infiltration of the ovaries that's important for normal function. So you've got not just like the follicle cells, but you've got the cells that are dying. So over the course of a year, this is 12 ,000 cells. I mean, if we've got a thousand for each cycle. Hold on. I'm going to make it slightly more complicated, but just stick with me for a minute. Stick with me. So you've got, let's just, that thousand cohort. So it's not just those cells. It's the cells that are dying. It's immune cells coming in to clean up the mess. And as they're growing, you get blood vessels coming in to provide nutrients.

1:01:09So there's blood vessels growing and retracting. There's the lymphatic system. Like, it's all dynamic. Okay. So that's one cohort, right, from one cycle. Now, 30, 28 days later or 26 days later or 24 days later, however long your cycle is, another 1 ,000 get recruited. So now imagine your ovary has so many different cohorts that are going at the same time and all of these dynamic processes happening. And it's, I mean, it's amazing. It's so beautiful what happens, but it's also amazingly complex. Now, what we wanted to do and what others wanted to do was to understand, like, what are the identities of all those cell types, right?

1:01:53And what are they making, for example, right? At a resolution that we've never been able to see before, right? The technology has gotten to the point now where you can sequence a single cell and understand everything that it's doing. But in the ovary, if you dissociate everything and just look at the cells individually, you don't know. So maybe at any given time, there's a few hundred eggs that are developing in different stages. But each one of those eggs is different because it was in a different kind of follicle. It had different cells around it. It was doing different things, but you would never know that if you didn't capture the whole structure.

1:02:32And so spatial transcriptomics allows you to basically take a slice of the tissue. So you maintain, you understand the structure, and then you sequence directly. So you know that this egg, which came from like, you know, a month secondary. Yeah, exactly. Has these cells around it, and they're doing these things in this context. And so the data is beautiful. And there's so many labs now that have done this. and in 2024 so again just swap in heart here like if if i had just told you that this is where we are with understanding the heart you'd be horrified so swap in the word heart right now in 2024 we got to this place where you know so some of the grants that we gave away in 2020 in the first cohort were to fund some of these like really deep phenotyping and spatial transcriptomics and this kind of this like just cataloging what the cells are and what they're doing.

1:03:28It's the basic, most basic function of the ovary. And everyone did comparing it to the data that already existed that had been generated in those previous few years. We couldn't compare across the data sets because we quite literally had never agreed on what to call these cell types. And so in one data set, you know, they made up because we had never talked about it before. And so trying to compare across the datasets was impossible. So the Chan Zuckerberg Initiative, they basically paid for a meeting. We called it a cell types jamboree, the reproductive tissue cell types jamboree, where they paid for 60 researchers from all over the world to come and bring one person from their labs to the people doing the actual data analysis.

1:04:12And we sat together in a room for three days, and we talked about cell ontology, which is basically what do we call these cell types, and agreed on what to call them and how to categorize them so that now we have a common language. And a similar thing happened a few years earlier across a different group of researchers where they went in and assigned landmarks to the ovary so that when, for example, you dissect out an ovary from a human, if you're going to cut it up into different pieces, you orient it the same way so that, you know, this piece here is the same as the piece you take from this over here.

1:04:52It's insane. It's so, yeah. It's amazing that we're, like, I'm so happy that we're making all this progress, but it's also, it just kind of highlights how far behind we are in understanding things. Wow.

1:05:08Dr. Mary Claire Haver:Welcome back to another MidiPause. I'm Dr. Mary Claire Haver, host of Unpaused. One of the most confusing parts of menopause is knowing which lab test you should actually be asking for. If you've ever gone to the doctor with symptoms like fatigue, brain fog, weight changes, low libido, or mood swings, you may have been told, that's just menopause. And while hormones are a big part of it, that doesn't mean you shouldn't get a full picture of what's happening in your body. During your annual exam, your clinician asks how you've been feeling. does a brief exam, and usually orders blood work. He or she might rattle off the names of a couple of lab tests to be ordered, like a CBC, Complete Blood Count, or CMP, Comprehensive Metabolic Panel, but rarely has the time to explain what exactly these tests are looking for.

1:06:01Dr. Mary Claire Haver:So, you get your blood drawn, get a call a few days later that things came back normal, and you don't really think much about it until the next year. Sound familiar? If you want to be more proactive about your health in menopause and perimenopause, where should you start? Hormones are one piece. Looking at estrogen, progesterone, and FSH can help identify where you are in the menopause transition. But don't stop there. Thyroid testing, including TSH, T3, and T4, is important since thyroid issues can mimic menopause symptoms. You'll also want a broader metabolic picture, including blood sugar and markers of insulin resistance, and a full cholesterol screening, including LP little a, a genetic risk factor, and ApoB, which shows the total number of particles putting pressure on your arteries, especially since menopause can increase cardiovascular risk.

1:07:00Dr. Mary Claire Haver:and don't overlook vitamin levels. Low vitamin D, B12, or ironed and ferritin levels can affect your energy, mood, and overall well-being. The bottom line is this. You deserve more than a quick dismissal. You deserve data, context, and a plan. That's where MidiHealth can help. Their clinicians specialize in midlife care and take a more comprehensive approach. They help you decide which labs make sense for your symptoms and explain your results clearly and build a plan tailored to you. Because this isn't just about checking boxes, it's about connecting the dots. If something feels off, advocate for yourself.

1:07:43Dr. Mary Claire Haver:Ask questions. Request the labs. You're not just managing symptoms. You're taking ownership of your long-term health. For more support, you can find a free lab checklist to bring to your next appointment that will be linked in the show notes. This clear and concise checklist explains why these tests matter and includes simple language to use if you feel you're not being heard. Go to joinmidi.com, join midi.com, and connect with one of their clinicians today.

1:08:17Dr. Mary Claire Haver:what i want you know people to understand is the health of the ovary is tied to yes fertility irregular periods polycystic ovarian syndrome and fertility miscarriage early menopause perimenopausal symptoms but you know and as you touched on before metabolic problems you know we see the rate of metabolic syndrome in women doubles or triples 2.3 across the menopause transition, we see rates of depression and mental health double across the perimenopause transition. The most likely time for a woman to, you know, trigger warning, commit suicide is between the ages of 45 and 55. The fastest rate of bone loss is in perimenopause, you know, two to four years before your periods end.

1:09:02Dr. Mary Claire Haver:Like this is so far reaching, way more than we ever, ever, ever understood. And to quote Moscone, we're owed centuries of research here. Yeah. We're generations behind. Yeah. Yeah. And that they're all connected. They're all connected. Don't know how yet, to be perfectly honest. How close do you think we are? Well, if you were listening through this whole time, through this whole discussion, it's complicated, right? Female physiology is complex and we have to treat it that way. And so it's not like we're just going to solve it tomorrow, but every day we're gaining more knowledge. And as we gain more knowledge, we will be able to, you know, act on that knowledge and to really leverage that knowledge to create solutions for women.

1:09:51And while we're waiting for that, you know, I think what most women need to do now is to think about themselves as like an N of one experiment and understand everything about their own biology and to find doctors who, you know, who are up to date on the latest research and who listen to them. I think that listening is probably the most important thing.

1:10:11Dr. Mary Claire Haver:True. You're talking about perimenopause and the hundred and I don't even know how many symptoms there are now. At least 125. Okay. Probably more. Probably more. But the reason there's so many, right, is because of this, because ovaries are so important for so many different things. and because you know that the aging trajectory is so different between individuals right like when you entered menopause it's going to be different from when i enter menopause and the changes that happen during perimenopause right it's not that graph that we always see this like gentle slope that's an average and um you know but at the level of the individual it's like this and it's like this chaotic that's why i call it the zone of chaos right and we we graph out the zone of chaos for like two or three hormones, right?

1:11:00And we show that. But now imagine that what I told you is true and there's a two dozen hormones that are changing in different directions at different times in different people. And that's why there's so many different symptoms because, you know, those are chemical conversations that are happening with different tissues in your body.

1:11:16Dr. Mary Claire Haver:I mean, I've had, you know, Vonda Wright talking about some of these myokines and individual cellular responses that she sees in the musculoskeletal system. I've had Jane Morgan and hopefully soon Jeremy London, he's a cardiothoracic surgeon. You know, I think we're getting there. The understanding is getting there, but like you talked about translation, you know, from bench to exam room is 17 years. I'm not going to wait a whole generation to begin to utilize and wait for guidelines to catch up to help women stay healthier. so what does the future look like if we get it right you know what frustrated me was when i really understood that the majority of any research in menopause was done around the hot flash and just this one tiny symptom very disruptive i had them they're horrific they disrupted my sleep and so many things and so they are important but i would say 90 of research funding went into hot flashes, presence or absence, and stopping them.

1:12:21Dr. Mary Claire Haver:But what do you think if we get this right? What is women's health going to look like? I mean, honestly, I think if we can understand how ovaries work at baseline at every age, not just in midlife and beyond, but at every age, like what's normal for ovaries? What are they making? Who are they talking to? What's happening? I think It will unlock so many things, so many potential interventions, but also just so many places where we could think about female health in a different way, right? And I think this message is important for very young women, right? The people who can benefit most from this message, honestly, are the women in their teens and early 20s who have the opportunity that I never had to really tune into their bodies and understand what their normals are and then leverage that information, right?

1:13:12And to use it like as a superpower as opposed to thinking about it as some sort of burden. are waiting till things break before you go and have it fixed, which is the worst way to do things,

1:13:23Dr. Mary Claire Haver:I think, in medicine. You've made a plea, a direct plea. So you have a microphone now to advocates, women who have said loudly that they care about women's health. You know, we've thrown out some names, but there's several. And I'm going to quote you here, and let me know if I get this right. Imagine what would happen if those people actually put their money behind what they're saying. What would you change, you know, if the right person came and made this their cause. Yeah, it can't be just one person. I mean, honestly, I'm certainly looking for partners personally, but it can't just be one person.

1:13:52It has to be bigger than that, right? In terms of like research funding for the foundational science, that has to explode. And there are foundations, there are people stepping up to fill those gaps, but the amount of money that's been put forward so far is pretty minuscule. I mean, I'm not knocking it. I'm so excited and so grateful and so happy that people are paying attention to us. But it's not enough. To be clear. Not nearly enough. Not nearly enough. That's one piece of it. But the other piece of it is we have to think hard about what we're doing in terms of building those solutions, those not just clinical solutions and not just drugs.

1:14:31I'm talking about direct-to-consumer products. I'm talking about devices and biomarkers and diagnostics, like how we're investing. How are we investing in companies that are making those things for women and for females. Do you think that women's health just isn't valued enough yet outside of reproduction? I mean, in terms of the amount of money, it's just as poultry on this side in terms of the investment. And what's happening, what I've seen, for the tiny amount of investment that is happening and the exits that we should all be celebrating, it's in a really narrow, shallow sandbox that all of these companies are playing in.

1:15:08And that is where we're going to stay until we basically unlock some of this. There's like a deep divide between what we want in terms of solutions for women and what is possible right now in terms of the intellectual property and, you know, the discoveries that have been made. And so there's a lot of work to be done.

1:15:28Dr. Mary Claire Haver:Explain how shallow, like talk to me about the sandbox. Yeah. Where is the money going right now? Fertility. Which is important. It's super important. I don't want to discount that. It's really important and so important for so many women. But honestly, if you have infertility or you have issues with fertility, that's like a biomarker for lots of other things. women don't realize that. Your period is a vital sign. It's a vital sign. Yes, exactly. All of that is tied together in the same way that we were asking earlier about ovarian aging and fertility. They're tied together, but defining that is difficult.

1:16:07But digital health, right? How many apps are out there? A zillion. Wearables. And so these are all great things. I'm not knocking it. It's just lots of things in the diagnostic space. Certainly, we're pretty good at making drugs for cancer, right? These are places where we're pretty good at doing these things. But everything else, all the things that we were talking about, you know, this sort of 50 % or more of the disease burden and 4 % of the investment. Like this is the challenge. And it's not because we don't want to do those things. It is because we quite literally do not have the knowledge to build on, to make those companies.

1:16:45And so that's the gap that I think we really need to bridge. That's that's where I'm focusing anyway.

1:16:50Dr. Mary Claire Haver:What is the take-home message you want women to understand from this conversation? Your ovaries are for more than baby making. Essential for baby making, don't get me wrong, but your ovaries are for more than baby making. And your health is tied to your ovarian function, far beyond fertility. And understanding that and then thinking about like your body, wherever you are, whatever age you are, thinking about like what's normal in your body. That's by far the best thing that you can do for yourself right now. And working with physicians who really understand and listen to you. And for the women, we have a lot who are postmenopause.

1:17:31Dr. Mary Claire Haver:I'm postmenopause. Yeah. Our ships have sailed. What advice would you give them? Work with someone who understands that this is not, you know, it's not something horrible that's happen to you, but rather like you are just in a different part of your life and your health risks are, you know, accelerated, but in some areas, and we have some band-aids available that are good for most women that you should think about. But also just, I would say to women that we are in a place where the medicine is imperfect. The solutions are imperfect. And so it takes a while, you know, do have to do end of one experimentation to try to find, for example, with hormone therapy, 18 months, it took me 18 months with all of my knowledge, with all of my access, with my relative comfort, I had to fire two doctors and I had to play around with lots of different things to find what worked for me.

1:18:29And so a lot of women, I think, start hormone therapy and then they stop because they have a side effect. And the challenge is that we haven't innovated in that space almost since it was introduced in the 40s, right? Hormone therapy came online in the 40s. And the only innovation that I'm really aware of is the introduction of the estradiol patch, which is an important one, right? Transdermal delivery. But there's a lot of opportunity there. And the way that we administer it now is kind of like a sledgehammer. And not because that's how doctors want to do it, just because that's what's available.

1:19:03That's what's available, yeah. And so understanding that going into it, I think is really important. And knowing that it's not you, there's not like, it's not something wrong with you or it's not something wrong with the process. It's just kind of where we are. And the hope is that in the next five to 10 years that we will have completely changed that landscape because there's a lot of opportunity for innovation there. but right now you know for women who are in our shoes this is what what's available and so finding physicians who understand all of that is really important awesome well dr jennifer garrison will

1:19:37Dr. Mary Claire Haver:in the show notes have everywhere that people can find you and your website but thank you so much for sharing your innovations your research and how hard you are fighting for the health of women thank you for coming on on past thank you for the conversation that was really really fun you can find dr garrison through her website at dr jennifer garrison.com or at jennifer garrison.bsky.social or on linkedin at dr jennifer garrison i'd love to hear from you about this topic and anything else that's on your mind you can find me on instagram at dr mary claire and get honest and accurate information on health fitness and navigating midlife at thepawselife.com.

1:20:18Dr. Mary Claire Haver:My new book, The New Perimenopause, is available now everywhere you buy books and through our website. If you're loving this podcast, be sure to click follow on your favorite podcast app so you never miss an episode. You can also find full episodes on YouTube at Dr. Mary Claire. Unpaused is presented by Odyssey in conjunction with Pod People. This episode was sponsored by MidiHealth, the first virtual clinic created for women, by women for the treatment of menopause. Don't let anyone tell you menopause is something you have to suffer through alone. Midi can help. Visit joinmidi.com to learn more.

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