Associations between menopause age and estradiol-based hormone therapy with cognitive performance

All right. Welcome everyone. I'm Sophie Hogeveen, data access officer for the CLSA or the Canadian Longitudinal Study on Aging. Uh thank you for joining us for this webinar titled Associations between menopause age and estradiol-based hormone therapy with cognitive performance in cognitively normal women in the CLSA. Before we begin, uh I'd like to acknowledge that the CLSA National Coordinating Centre and McMaster University are located on the traditional territories of the Mississaugas and Hodenaushounee Nations and within the lands protected by the Dish With One Spoon Wampum Agreement. CAMH is situated on lands that have been occupied by First Nations for millennia. Lands rich in civilizations with knowledge of architecture, technology, and extensive trade routes throughout the Americas. The site of CAMH appears in colonial records as the council grounds of the Mississaugas of the New Credit, as their name in 1860, today known as the Mississaugas of the Credit. We wish to acknowledge that the University of Toronto operates on the traditional land of the Huron-Wendat, the Seneca, and the Mississaugas of the Credit. Today, this meeting place is still home to many indigenous people from across Turtle Island, and we are grateful to have the opportunity to work on this land. As attendees of this webinar, I encourage you to continue your learning following the webinar and to acknowledge the original inhabitants of the lands where we currently have the privilege to research, live, and work, wherever that may be. Before we begin, let's review a couple of housekeeping points. Everyone but the presenters will will muted throughout the webinar. If you need to change or test your audio settings during the webinar, you can click on audio settings on the bottom of the Zoom window. At the end of today's presentation, there'll be a question and answer session. If you have a question for the presenter during the webinar, you can post it in the Q&A box, which is located in the bottom toolbar. We'll address those questions at the very end of the webinar, and the questions will be available will be visible to all attendees. If you have any technical trouble concerning the webinar, please use the chat box to communicate with our webinar team. A feedback survey will be launched at the end of the webinar, and we invite you to complete it after exiting the Zoom session. This brief survey provides us with important feedback we can use to plan future CLSA webinars. Now, today's webinar. As I said, titled Association between menopause age and estradiol-based hormone therapy with cognitive performance in cognitively normal women in the CLSA. This is presented by Dr. Laura Gravelsins, postdoctoral research at the Centre for Addiction and Mental Health, CAMH, and Dr. Lisa Galea, senior scientist at CAMH and professor in the Department of Psychiatry at the University of Toronto. Dr. Laura Gravelsins is a researcher committed to advancing sex and gender-based analysis plus and gender equity in neuroscience. She earned her PhD in psychology from the University of Toronto in 2024 and is currently a postdoctoral fellow with Dr. Lisa Galea at the Centre for Addiction and Mental Health. Her research focuses on how ovarian hormones influence memory, brain health, and quality of life across the lifespan. Her current postdoctoral research in the Galea lab uses mixed methods approaches, integrating large-scale large-scale quantitative data with in-depth qualitative interviews, to better understand menopause-related influences on brain health in older females. Dr. Lisa Galea is the Trail Living Family Chair in Women's Mental Health at the Centre for Addiction and Mental Health and a professor in the Department of Psychiatry at the University of Toronto. She leads the Women's Health Research Cluster, a dedicated network to promote and catalyze impactful women's health research with over 1,000 members across 43 countries. Dr. Galea is a world-renowned expert in sex and sex hormone influences on the brain with a focus on stress-related psychiatric disorders and dementia. She has published over 222 papers and is a fellow of the Canadian Academy of Health Sciences and a top 25 women of influence in Canada in 2025. So, I'll turn it over to you both. Oh, hello. Thank you so much for this opportunity to share our work. Just give me a moment here while I set up the uh presentation, but uh yeah, we're delighted to be here. This is like our favorite topic to talk about how menopause and hormone therapy might influence the brain. Uh and I am Lisa Galea and with me is Laura Cruvels. Hello. >> [laughter] >> Uh and we'll we're going to be doing this sort of in tandem. You're going to hear a lot from me first, unfortunately, and then you will hear from uh Laura and we'll go back and forth um a little bit as we progress. So, you probably already know what our objectives are. Uh by the end of the talk, we are hoping that you'll have gained an understanding of the menopausal transition and understand it as a key inflection point for brain health. Uh and uh while while we're talking about it and studying it, we don't mean to infer that we're pathologizing it in any way. There are many kinds of menopauses. People have different symptoms throughout. Some people sail through, some people don't. And what we believe is that it's an important um time point to uh offer support and intervention so people can thrive during this life stage rather than language and we'll come back to that point a few times. And we also want to be able by the end of this to give you the tools to evaluate discrepancies in findings on menopausal hormone therapy and brain health so that you can account for one of my biggest pet peeves is when you'll see a headline that says menopausal hormone therapy does X. And for me it's well what kind? How long did they take? What age were they in? What went dose were they in? And and you'll learn more about this and that's how we're going to get towards personalized our precision medicine where we're not lumping everything into one group. I have to start by saying that we're going to be talking a lot about a little bit about sex differences, a little bit about gender differences and sex refers to the biological and physiological characteristics that can differ between females, intersex and males. Gender most people will think of as gender identity which is whether or not you identify as a woman, gender diverse, non-binary or man. Now it's much more complicated than that. There are it's also about how society has expectations of you based on your gender identity and that's society at all different levels from home life to being in a supermarket, >> [clears throat] >> your education as well as in your in your work. And there is kind of a big emphasis right now in our research councils to do something called SGBA which is sex and gender based analysis and I I firmly believe that but not everything is about comparing males to females or men and women. It's also about doing deep dives into understanding you know non-binary individuals or gender diverse individuals or or women and that's what we'll be talking about today. The other thing I really want to make it clear is you know there will be times that we'll be use binary language, but neither sex nor gender is binary. And it's really important to understand that people of color, transgender diverse, indigenous peoples all have influences of these factors that may differ in very um uh profound ways to affect our health outcomes and and disease risk and and deserve study. But today, we're going to be doing a deep dive into women's health. And for understanding women's health, we also want to make the point that it's more than comparing to men's health. It's more than um having this sort of simple two-way comparison. We already know that these female specific experiences that I've outlined here can influence our health outcomes and disease risks, and not just in the health of what underlies our bikini. Uh for me, it's not just about, you know, comparing apples to oranges, it's about understanding that there are many different types of apples and many different types of oranges, and not everyone has the same kind of pregnancy or same kind of menstrual cycles or even menopauses. And how does that influence our our health outcomes? So, thinking about dementia, uh which is an umbrella umbrella term, there are sex differences in the prevalence of different dementias. Uh for example, in vascular dementia, there's actually a mix. Uh there's, you know, several time points across the lifespan or some one time point across the lifespan, you can see that more males are diagnosed with uh vascular dementia than females. It's at the earliest time point, but there's not really a clear sex difference past that. However, Alzheimer's disease, which is the most common form of dementia, uh does have a very strong sex prevalence. And what by that, we just mean that at every single time point, you see more females than males are diagnosed with Alzheimer's disease, suggesting there's something special about Alzheimer's disease, but also suggesting that we should probably use this to try to understand the disease and disease progression because we might get to answers faster. Now, Alzheimer's disease is a neurodegenerative disorder. Many of you are probably very well aware of this. It's a progressive disorder characterized by cognitive decline and also neuropathological features such as amyloid beta plaques and neurofibrillary tangles within the cells itself which can lead to neuron loss and degradation within the cortical and subcortical areas. And now we know and it's pretty exciting. This comes from a doc tables as people lovingly refer to them as that when we see these cognitive symptoms is cognitive impairment which is in these green dark green lines here. You actually see the neuropathological features of Alzheimer's disease well before cognitive decline. So if you were to look at PET imaging for example. So amyloid beta and tau pathology shows up decades earlier. And now we have some fluid biomarkers that can even show up even earlier than that and by I'm talking about fluid biomarkers, I'm just talking about say blood-based biomarkers. This is pretty new and pretty exciting that we might be able to to detect initial stages of the disease much earlier in the process because that's going to give us the best chance to intervene earlier. Now, in terms of late onset sporadic Alzheimer's disease, about 90% of cases are this late onset sporadic Alzheimer's disease. There are both modifiable and non-modifiable risk factors. And the Lancet has a beautiful series on these modifiable risk factors. In fact, about 45% of cases with Alzheimer's disease are attributed to these modifiable risk factors like how much physical activity you have, how much sleep you're getting, your diet. And there are many other factors like air pollution, diabetes. So I encourage you to take a look at at that uh Lancet Commission. Uh but, there are also some non-modifiable fact risk factors. Uh advanced age, unfortunately, we can't reverse aging. Really wish we could. Uh possession of the APOE4 genotype, that's either one or two of these alleles. Uh you're at uh about 50% of cases of Alzheimer's disease what somebody will have the possession of one or two of these alleles. And female sex. About 2/3 patients uh with Alzheimer's disease will uh be female. And uh and it turns out that sex plays a role in every single one of these factors. And we could do a whole session on the modifiable risk factors, but today we're going to be focusing more on the interaction between female sex and APOE4 alleles. Um now, again, uh as we noted earlier, uh we really think that to to study this, we need to do a deep dive into to females. Like, why are 2/3 of patients female uh of the female sex? Uh can we look at these female-specific factors and understand the disorder better? Can we get other clues on to how we can intervene and more and better therapeutics uh to intervene earlier? And the way we've been doing this in our lab is by looking at um these female-specific factors, but today we'll touch on menopause, hormone therapy, and pregnancy history. Also thinking about this interaction between um uh with APOE4 alleles. So, just [clears throat] initially, what is menopause? Uh well, it's actually defined as 12 months after your last period. Uh so, you're actually retrospectively trying to recall when was your last period. And really, that amounts to one day. Sorry. [clears throat] There are two different periods, either the perimenopause or postmenopause. And the perimenopausal period can at last um anywhere from two to 10 years. And this can differ by uh ethnicity. And the symptoms of menopause transition are on average are uh over in 7 years, but I actually think this is an underestimate because there hasn't been that much research done on that. We'll show you that a little bit later on and I think there's been a lot of dismissal of this as a important variable to variables to study in the literature itself. But there's quite a bit of evidence that menopause is an important flexion inflection point in aging both in terms of epigenetic signaling, immune related changes and even in the brain. And some of these are considered to be transient stages that they can there can be some compensation later on, but there it's certainly an inflection point. And as we noted earlier, the symptoms of cognitive decline are seen you know in the 60s probably average diagnosis in late 60s early 70s and these neuropathological features of Alzheimer's disease either amyloid beta or tau show up earlier than that. So amyloid beta a little bit earlier than that about 20 years prior. So what happens 20 years prior to that? Well, the average age of menopause is 51 years of age in North America. So that's right dab smack in the middle. So when we have these declining ovarian hormones, increase in pituitary hormones also corresponding with increased sleep disruptions, that's when we also it's sort of matching in the sort of timeline with the expression of these neuropathological features. So might this be an important transition point to study? Again, here when we're thinking about menopause and how it influences aging, we are not trying to pathologize menopause at all. What we're trying to do is to identify because there are many menopauses and many types of hormone therapies, we're trying to identify who is at greater risk to develop in our case is Alzheimer's disease or cognitive issues and the and those people that are not because then we can understand the clues of risk and resilience during this process, so we can give people the tools to thrive during aging rather than languish during aging. And I'm turning it over to Dr. Gonsalves now. Thank you so much. Um yes, so as mentioned by Dr. Glea, uh there's not just one type of menopause or one type of menopause experience. Uh there can be many symptoms of menopause and also many ages of menopause, which we're going to be touching on throughout this presentation. Um as alluded to earlier, menopause is really uh a brain aging inflection point and this is particularly true for earlier ages of menopause, which correspond to earlier losses of ovarian hormones. This has been shown by by several groups. Um for example, earlier ages of menopause have been associated with region-specific increases in tau pathology, so one of those well-established uh biomarkers for Alzheimer's disease. Uh this is data from the CLSA database. Um uh analyses using that data showing that earlier ages of menopause have been linked to accelerated cognitive decline, especially uh in those who have higher vascular risk. And uh data from the UK Biobank, another database, showing that earlier ages of menopause are related to increased risk for developing later life dementia. So, collectively many pieces of evidence suggesting that ovarian hormones are important for uh maintaining brain health. But of course, uh this is a theme that's that's going to be coming up throughout our our presentation. Um in terms of the literature that exists looking at whether menopause is linked to impaired cognition, um while studies say yes, some other studies say no, and other studies say maybe it might depend. Um Um so we're we're trying to understand, well, why why are there these mixed findings and what might be contributing? Uh really focusing in on age of menopause and some of these mixed findings looking at uh risk genetic risk for Alzheimer's disease and pregnancy history. Um So we wondered, how does age of menopause affect different cognitive domains in females? Um so using data from the CLSA, uh rather than looking at a global cognitive score, which is done quite frequently as well, um in investigations of cognition, we were interested in uh cognitive composite. So we use a principal component analysis to derive an episodic memory composite, which is more reliant on medial temporal brain regions like the hippocampus, as well as an executive functions composite, which is more reliant on frontal brain regions. And we wondered whether this relationship between age of menopause and performance on these uh composites might be modified or might be changed by carrying that APOE4 genotype, that genetic risk factor for Alzheimer's disease. So what did we Oh, before that, uh just to give you a sense of of what data we're using from the CLSA, this is coming from the baseline data from the comprehensive cohort. So we have uh rich cognitive assessments, health history data, and after applying our inclusion-exclusion criteria, we had data from a little over 10,000 postmenopausal female participants that were uh cognitively healthy. And just to give you a sense of who's included in this analysis, they're on average 60 years of age, highly educated, um and their age of menopause is close to 51 years of age, uh corresponding with that North American average. So what did we find? Well, on both the episodic memory composite and the executive functions composite, we found that earlier ages of menopause um uh maybe to orient you towards these graphs on the x-axis here we have age of menopause in years and on the y-axis is z-score values such that higher values represent better performance. So, we're seeing on both these cognitive composites that earlier ages of menopause are linked to worse memory. However, this relationship is much stronger in those who carry the APOE4 genotype, so that genetic risk factor um for Alzheimer's disease specifically in the executive functions composite. So, earlier age of menopause and an E4 carrier that leads to reduced executive functions performance, suggesting that genetics, cognitive domain, and age of menopause are all important considerations. So, another factor that I alluded to earlier was pregnancy and you might wonder why we're studying this and we've been studying this in the lab for quite a while. We want to understand how pregnancy could alter the brain in both the short-term for postpartum depression, but also in the long-term. And so, we've seen some signatures in animal models as well as Anne Marie DeLang using the UK Biobank I showed the very very similar things showing a decrease in brain aging in middle age. So, in our animal models we've seen more neurogenesis, which is just means the production of new brain cells. We've seen more or less of a depletion of neural stem cells and more synaptic proteins. So, all indicative of a decrease in brain aging. But there are other signs um that it might lead to an increase in Alzheimer's risk in older age. So, it's like well what what might be going on? And we actually have some other research which we're happy to talk about showing that it might be related to just brain health to begin with. Again, just like there are many kinds of menopause, there are many kinds of pregnancies. Some people sail through their pregnancies and some people have a very difficult time like I had my third pregnancy. It can be the age of when you first get pregnant, the number of pregnancies you have, even whether you or not you give birth to a boy or girl and whether or not you experience gestational disorders. Now in this look at the CLSA using the CLSA database we just looked at the pure number of children but we're planning to look at some other characteristics as well. And what we found here and this is again with your age menopause on the on the x-axis and our z-scores on the y-axis. It only mattered the number of children with the executive functions composite. So earlier age of menopause in combination with what we call grand parity which is four or more children, that was associated with reduced performance on executive functions. And in terms of the Alzheimer's risk, I would say that's probably the clearest signal that's there as well is that grand parity, more children, usually three or more children is associated with an an increased risk. So does menopause influence dementia and brain health? Well, it depends on the a number of factors that we've shown you a little bit that it depends on brain region. So what kind of task we're looking at. We haven't told you about this yet but we're just about to vasomotor symptoms but also the one of the clearest signature is the age of menopause. So earlier age is associated with reductions in scores and and some evidence we also showed you about genotype. So vasomotor symptoms. Sorry, menopausal symptoms. There are a lot of them. There are about 20 to 60 of these symptoms. They aren't well studied. The probably the biggest signature that's studied are these vasomotor symptoms, these hot flashes and night sweats. About 80% of people will say that they experience them. Uh one thing I'll say is there's a lot of dismissal in this area. I'm going to come back to that in a little bit. And that might be because some of the symptoms are quite varied. It does make it a more challenging to model um vasomotor symptoms and menopause symptoms. Uh but there happens some very large-scale studies showing that you can cluster these symptoms so that you can accurately identify people that were premenopausal, postmenopausal, and even perimenopausal. Um the the dismissal of the variation in symptoms though uh I think we just have to uh go back just for a second. I think we have to think about this for a minute. Um uh because with menopause we get the uh cessation of uh release of ovarian follicles and with that in concert reductions in estradiol and progesterone, those are the main ovarian hormones. And we have to think about where are these hormones acting? By definition hormones act on receptors at a distant location from their release. That's a definition. That's one of the definitions of a hormone. And these hormone receptors, estrogen and progesterone hormone receptors, are present everywhere in every single organ of our body. So no wonder there's so many different symptoms that are associated with a loss in these hormones. And not just that, there's changes in the density of these uh estrogen and progesterone receptors as well as our own personal sensitivity to these hormone receptors. So that probably will explain why some people have different kinds of symptoms than others. So instead of being dismissive, I think it's really important for us to start paying attention to these different kinds of symptoms. Again, the most well-studied are these vasomotor symptoms. And one of the clearest signals that's coming out from the very few studies that are out there is that particularly nighttime vasomotor symptoms or sleep vasomotor symptoms, otherwise known as night sweats, are more likely associated with uh decreases in episodic memory. By the way, I'm the one that has night sweats only, I don't have uh hot flashes. Also, everyday cognition. So, the more of these symptoms you have, the more likely you'll show some uh differences in everyday cognition. And uh work out of Pauline Maki and Rebecca Thurston's lab has shown uh an increase in white matter hyperintensities, as well as some early data suggesting that uh it it's also increases amyloid beta pathology. So, what can reduce vasomotor symptoms if we know that they might be related to poor health? Well, menopausal hormone therapy is still the front-line treatment for vasomotor symptoms. Um better than any of the herbal remedies that are out there. It is uh recommended by a lot of scientific societies. For people that don't want to take hormones or have a something that's contraindicated, there are some new therapies on the on the market now. Uh they're all neurokinin 3 receptor antagonists. Uh and the first one that was released was something called Veozah. So, does menopausal hormone therapy influence cognition, Laura? Thanks, Lisa. Um similar to before, a common theme again where some studies are finding yes, um it's has cognitive benefits or was related to reduced risk of neurodegenerative diseases, but other studies finding the opposite or no association. So, what might be contributing um or part of the reason we're getting these mixed findings? Um just like there's many types of menopause, many types of pregnancies, there's also many types of menopausal hormone therapy. And for our presentation today, we want to highlight um that there's many types of estrogens that can be contained in those hormone hormone therapy formulations, also many routes of administration or uh ways that you can take that hormone therapy. So, uh transdermally on the skin, uh vaginally, or orally as well. So, um uh we would be remiss if we didn't talk about this study. So, in the US, prior to the release of the Women's Health uh and Initiative Study, about 35% of people were prescribed menopausal hormone therapy. And then with the release of the study, this dropped by about 60%. It still remains there to this day. It's kind coming up a little bit, but not as much as you might suspect based on your Instagram feed. Although, that might just be the algorithm that is showing me. Now, this study has been widely criticized for a number of reasons. Happy to talk about it afterwards. Uh but, one is a critical window. So, the average age of enrollment was 63 years of age. So, that's well and more than a decade past average age of menopause. Another is a healthy cell bias. There were very few exclusions. Um people with hypertension, diabetes were enrolled. Um in fact, people with uh severe moderate to severe vasomotor symptoms were actively discouraged from participating. So, the very people that should be taking uh menopausal hormone therapy were were discl- excluded. Um but, the one the criticism that I'm going to pay attention to is menopausal hormone therapy type. Because uh the Women's Health Initiative used one type of um therapy. It's called Premarin, which is a conjugated equine estrogen, which contains 50% estrone and 3% estradiol. And I'm sure you're thinking, "So what? They're just estrogens." But, we're here to tell you, they're not all equal. So, uh estradiol and estrone both decrease with menopause, but estra- estradiol much more so than estrone. So, there's a flip in the ratio um postmenopause. There's more estrone than there is estradiol. And it turns out that estradiol is a more potent of these estrogens. It binds with greater affinity to the estrogen receptors um than estrone, which is less potent. And so, for the last 30 years, I've been really interested in this question using preclinical models, so using rat models, what we found is that estradiol can dose-dependently influence, positively influence both memory and neuroplasticity in the hippocampus. But estrone, we've only found that it dose-dependently either impairs memory or can impair neuroplasticity in the hippocampus. So we're really interested in like, well, why might why this must explain why they got such negative findings in the Women's Health Initiative study. But when we were looking at some of the randomized controlled trials and the observational studies out there, we didn't always see a benefit of estradiol. And then we started thinking, well, how are people prescribed menopausal hormone therapy? And at least in the past, there were more oral formulations that were prescribed. And in our rodent models, we were always giving a subcutaneous dose, which is basically just under the skin, so like a transdermal approach. And so why would route of administration matter, Laura? Thanks, Lisa. Why would route of administration matter? Well, when estradiol is taken orally as a pill, it's subject heavily to first-pass metabolism, meaning it's broken down by enzymes in the liver. And in fact, 90% of that estradiol is actually converted to estrone, that weaker form of estrogens that doesn't bind to estrogen receptors with the same strength. However, in contrast, when estradiol is taken transdermally, so as a patch or a cream applied to the skin, it circumvents this first-pass metabolism effect, resulting in higher bioavailable or circulating levels of estradiol. But despite these pharmacokinetic differences, route of administration has really been overlooked as a factor of interest in investigations of cognition. So we wondered, does menopausal hormone therapy route of administration influence cognition. And to do this, we use data from the CLSA and comb through medication records of postmenopausal females and categorize them into one of several groups. So, a group taking oral estradiol, a group taking transdermal estradiol, or a group that has never used menopausal hormone therapy. And we looked at their performance on the same cognitive composites that we described earlier, that episodic memory composite and executive functions composite. And what did we find? Well, to orient you on these graphs again, we have Z scores, higher values are better performance. Our group that has never taken any hormone therapy is in gray, the transdermal estradiol group is in orange, and the oral estradiol group is in blue. And what we found on this episodic memory composite is that those who are taking transdermal estradiol specifically outperformed those who have never taken any menopausal hormone therapy. And interestingly, we don't see any group differences on the executive functions composite. So, importantly, a few takeaways here. First off, none of the hormone therapy formulations were associated with worse cognitive performance than having never used hormone therapy. And interestingly, this transdermal estradiol group, which we know has higher bioavailable circulating levels of estradiol, is really showing benefits for episodic, more hippocampal dependent memory. So, um does menopause hormone therapy influence cognition? Well, it probably depends on the route of administration, the type of estrogens, but also the cognitive domain as well. Of course, there's not only estradiol-based formulations of hormone therapy. So, we wanted to see what what would we find by potentially expanding this analysis and looking at estrone based formulations as well. So again, using the same CLSA data, we have a group of oral estradiol, transdermal estradiol, same as before. Now we're incorporating a group taking oral estrone, a group taking transdermal estrone, a group that has never used any menopausal hormone therapy, and additionally, a group that has previous history or use of menopausal hormone therapy trying to understand whether past use might have continued lasting benefits for cognitive performance in the brain. And again, looking at these same cognitive composites. To give you a sense, this is a very busy table. I want to draw your attention here to this kind of overall average column on the right to give you a sense of who's in this analysis. So they're on average 65 years of old old, highly educated, low vascular risk, and age of menopause close to 50, and they initiated their hormone therapy a very close to their age of menopause as well. So what did we find? Well, again, Z scores on the Y axis, which means better performance, and we can see the different hormone therapy groups here, the estradiol groups in green, the estrone groups in purple, this past group in blue, and the group that has never taken any hormone therapy in black. And we're seeing the same pattern of results with respect to the hormone current hormone therapy use, such that transdermal estradiol's outperforming those who have never taken any hormone therapy on this episodic memory composite specifically, not seeing that any of the other current hormone therapy groups are outperforming the never use of hormone therapy, but interestingly, on both these cognitive composites, we're seeing that past hormone therapy users in the blue are significantly outperforming those who have never used any hormone therapy in black. So, um suggesting that there might be lasting benefits of previous use of hormone therapy for cognitive performance in later life. Um now, one of the things that we'd like to do and we know we know that the ZELSA database is uh starting to collect some brain imaging data, but to really get a handle on this uh Matea Petravic um I started to look at the knock uh which is the National Alzheimer's Coordinating Center data. And here's a we know this is a very busy slide. We understand that. This is just looking at estradiol therapy and unfortunately we can't see whether it's transdermal or oral, so that is a limitation to this particular study, but in this case it didn't seem to matter. Here we're looking at APOE4 status. Um it's mostly this is mostly thickness of certain areas or or volumes or the last square here on the bottom right is white matter hyperintensity. So, more would be um worse I guess you could say or poorer brain health. And what we saw was that estradiol based therapy was beneficial for E4 carriers. So, the same people that are at risk for um Alzheimer's disease and it didn't matter if we're looking at cortical thickness, white matter hyperintensities or even uh volumes. So, again we come back to this question of are estrogens neuroprotective? And it's going to depend. You it's again it's not a one size fits all. We've shown you some evidence that the type matters, uh the brain region that you're looking at matters, uh the genotype matters, and the route of administration matters. And at some other point we can tell you about how all the other um variables can matter. So, again when you see these headlines, who what type of hormone therapy who did they actually uh examine in the in the studies themselves? And uh at least on my Instagram feed there's a lot of stuff about how we have to pay attention to randomized controlled trials, but we want to make the point that these cohort longitudinal study databases like the CLSA are really rich databases where we can get a lot of really great information. Unfortunately, in clinical trials, just by the virtue of how they're designed, as they're designed this way, they don't have a lot of diversity in their samples. Um and in fact, um I can tell you more about this, but I won't. Um there's a lot of past hormone use even in the placebo uh groups in all of these different um trials. Um now, there's a lot of people that say we should only pay attention to randomized controlled trials and no no observational studies, but we would argue that we can get a lot of really good information from databases like the CLSA, probably because of the diversity that's there. And in fact, there are there's a book, I haven't read it all the way through yet, just read the first chapter, but it's quite interesting about how this is written by a journalist and from the UK, just about how the menopause movement has um led to these sort of different camps of you should take hormones or you shouldn't take hormones and uh you know, science is never as clear-cut as that, and that's why we think that it's so important to do these deep dives into um what kinds of hormones and for whom. And in fact, when you look at the randomized controlled trials, um uh Mateus is also doing a deep dive into this and finding that there are very few studies that are looking at APOE4 as a predictor, for example. Am I doing these slides or you? Um there are very few do looking at reproductive um uh history collection, so it's about 60%, that's not too bad, but they're really only looking at past hormone use, and very few are looking at pregnancy history. And in terms of menopause symptom collection, uh again, only half of the studies have looked at this so far, and this is only the ones that are looking at randomized controlled trials. So, so all of these all of these variables are important in terms of the outputs um and how we can understand what the results are giving us. And one uh really exciting opportunity with the CLSA data is that there is information available on self-reported reasons for medication use. And we've been able to leverage this data looking at self-reported reasons for menopausal hormone therapy to better understand what types of menopausal symptoms are the female participants experiencing. Um and I'm sure as you can appreciate by this very colorful uh graph, um the these menopausal symptoms really affect all body systems. Uh and are quite rich. Um so just to give you a sense of of what types of information we're getting, um people are taking without their menopausal hormone therapy they're they're experiencing quite intense cognitive emotional symptoms. Thought they were depressed, thought they were dying without their hormone therapy. They're using hormone therapy as a sleep aid, using it for menopausal dry eyes or to support their immune system, uh using it for even cardiovascular benefits. Um and then also other systemic uh reasons like fluid retention or even migraines. So um there's quite diverse menopausal symptoms and this makes sense given that we know that there's receptors for these types of hormones all over our body. So uh we just wanted to make this point um because this was a really lovely survey that was released from the IWK and they're based in uh Halifax in the Maritimes. Uh they got 27,000 responses and I hope we get to do something and across Canada. Uh there are talks to to release this survey everywhere. And um we really want to make sure that women are heard. So this is um what people are self-disclosing. So look at those numbers. I'm not going to read them all out, but just look at the left side. Over half of the people are saying that they're downplaying their health concerns. Uh 77% carefully consider what symptoms are worth mentioning and over 50% are also worried about being heard when they're discussing their symptoms with their doctor. Now, why does this matter? On many, many, many levels this matters, but one of them is to be prescribed menopausal hormone therapy, you have to say that your symptoms are bothering you. And my plea to any health care practitioners that are out there is um if somebody's in your office complaining about vasomotor symptoms, all signs point to the fact that it's bothering them. They shouldn't have to then expose again that it's really bothering them, please prescribe me menopausal hormone therapy. And there are there are it's not just my uh feelings or our feelings about this. Uh there are uh um please to revisit the recommendations for initiation of menopausal hormone therapy. The other point we want to make is that we're sent to our gynecologists when um we're undergoing uh menopause, but at least in the US, less than a third of the programs have any menopause curriculum, [clears throat] any. Only 7% of uh uh gynecologists in the US feel that they can support their menopausal patients. And in Canada itself, uh 72% of individuals felt that the menopause advice from their health care practitioner wasn't helpful. And we're losing at least half a million work days a year due to menopausal symptoms. It's probably an underestimate. So, we were really fortunate to receive um a grant from the Welcome Leap. We were the only Canadian team to do so. Um it's a really fantastic program that's only given it was only money given out. It's called CARE, Cutting Alzheimer's Risk Through Endocrinology. So, just looking at uh females. And so, we're uh the idea is to build a predictive calculator for Alzheimer's disease risk specifically for women tailored to female specific factors. And we're taking a a big databases, crunching some numbers, looking at some machine learning, doing some fancy stuff to try to come up with um giving people the best um clues based on a number of factors like genotype, like their hormone history, like their pregnancy history to understand what type of menopausal hormone therapy, if any, might be beneficial for them. And the other point we want to make is that um and this is work that's really led by uh Laura. Do you want to talk about it? I [laughter] feel like you should go. I'm a roll. Um we looked [snorts] at over 10 She looked at over 10,000 project uh grants from CIHR. CIHR is the Canadian Institutes for Health Research. Uh it's our major um health funding agency in Canada. Um only 6.4% of funding over 15 years went towards women's health kinds of questions. And um what we found was for menopause, look at that percentage. 0.18% of of studies that were funded were on menopause. If you're just looking at menopause hormone therapy alone, it was 0.04%. And and we deserve more than 0.18% of the funding for, you know, 100% of um females will go through menopause if they live longer. So, we need more than 0.18% of the funding. And we just want to end by saying um again, we're not trying to pathologize. This is again from IWK, the number one issue that women want prioritized is menopause. Menopause hormonal health and perimenopause. And I think it's really an opportunity for us scientists and politicians and funders to recognize this. Um menopause is an opportunity for earlier intervention, not probably not just for Alzheimer's disease, for many uh disorders that can um rear its head during this aging process. So, that we can more of us can thrive during this process rather than languish. Uh and with that, we want you to be curious and not judgmental just like Ted Lasso. Um menopause is an important inflection point for aging. We need to embrace that complexity. That's the only way we're going to get towards precision medicine and please study women. And thank you very much to our funders and especially the Catalyst Grant that started us on the journey with uh the CLSA database. And that's it. Thanks so much for yeah, interesting presentation. So, we'll now open it up for questions. Just a reminder to everyone that muting will remain on. Please leave your questions in the Q&A box. Um so, not the chat box. It's a separate box that yeah, so that's Q&A. Uh in the bottom of the Zoom window. So, we have one question already. Um Do you know anything about the effect of testosterone therapy on cognition? Is that also something Is anyone studying that? >> different question so I was gearing up for that. That was a Oh, sorry. What counts as early menopause and we I apologize that we didn't define that. Um do you want to do it? Oh, sure. I can Yeah, sure. Thanks. Yeah. Um so, early um the cutoffs there would be uh 45 uh sorry, 40 to 45 um and then it's pre-40. That's considered what some people call premature or primary ovarian insufficiency. Um yeah. Yeah. Uh testosterone um Oh, that's a good question, Parminder. Um uh testosterone uh actually, how much do you know Have you looked at that at all in terms of the CLSA database? I know more and more people are being are using it. Um, I have feelings, but I don't have scientific feelings, so so but I you know, I think this comes down to um there's some a long time ago some great work by Barbara Sherwin who is at McGill University who was probably one of the people that studied testosterone quite a bit in terms of postmenopause more related I think to mood and and sexual function like libido, uh sexual desire. I think that's partly what her data suggested. Um I you know, testosterone most of testosterone's actions uh are via it doesn't matter if you're male or female actually via estrogen receptor. So a lot of testosterone gets converted to estradiol that really potent estrogen which is really interesting through a process called aromatase. Um that doesn't mean that it doesn't have um effects just on its own because it can work through androgen receptors as well. It's just not something that we have looked at yet. Um but certainly there are more and more people that are taking either um not usually alone but in in with in supplement with the HP. Uh the HRT the sorry MHT menopausal hormone therapy. I'm trying not to look at the chat but I'm looking at it and it's distracting me. Um Yeah, everyone ignore the chat. Focus on the Q&A. >> [laughter] >> Focus on the Q&A. I'm looking at the chat. Sorry sorry sorry. Um Uh Um so wait, this is a good question for um Laura. So I don't know if it's in the Q&A yet but we're going to answer it and then we'll look at the Q&A. Um did you look at the bioidentical um menopausal hormone therapy and synthetic hormone therapies and its effect on brain health in the in the database? Can you look at it? Um we can look at it. We have not yet looked at it. So I think that would be a good next step for us. Um cuz surely we know that there's going to be probably effects on the brain and they're probably going to be distinct from what the data that we've shown, given that we know that they're acting potentially on different receptors and with different strengths to those receptors as well. >> And don't you have it you have a little bit of preliminary data, but like don't you know, don't scoop us. On non-hormonal, yeah, there is some evidence there anyway. You don't have to tell us what you found, but Yeah, um but I I guess for very generally, I think we we see that the benefits tend to be the greatest with more of those like estradiol, more hormone-based uh medications rather than with the kind of herbal remedies. And I think it's too early to look at the beta-3 receptors, yes. But we really we do have them there, too. Um I see Can I Can we just go to the questions? Like I I can see them now. I put it up, so it says Daniela asked, "Do you have any idea why your findings seem to be kind of domain-specific?" Yes, we do. >> [laughter] >> Some of it's in the uh in the uh I think it's a good question though. We don't have all the answers to that. We just suspected that that might be the case based on animal literature because we do see a stronger signal of estradiol in the hippocampus than we ever do in the frontal cortex. And I'm going to give you another little um which is always a little perplexing, right? Like we want something to affect everything all beneficially, but sometimes we see an opposite signature in the frontal cortex than we do in the hippocampus. So, I mean, the nice thing about animal models is that we can, you know, actually grind up the brain and look at like things like inflammation and plasticity markers. So, we've done a a lot of those studies and we do tend to see just a a larger effect size in the hippocampus than we do in the frontal cortex. The other thing and I can't we can't prove this yet and Laura might remember more in our discussion, but one of the one of the other interesting findings is, and this comes from Lisa Mosconi's work, um looking at PET imaging and estrogen receptor densities across the menopausal transition. And uh what they showed is that there was a uh more of a What happens when often when a signal is decreased is that more of these receptors come out because they're trying to compensate. Like we don't We don't even see it. We need to We need to We need to find it. We need to find the signal. So, there's an upregulation of these um and it's just ER alpha. There are many types of estrogen receptors, so that makes it even more complicated. So, it's just the ER alpha we know about now um that is uh upregulated in the frontal cortex, but you don't in this in humans, but you don't see that same upregulation in the hippocampus. So, um I mean, it kind of it goes counterintuitive, but the fact that you see a difference between those two different areas might be why we also see um we also see different signatures in in terms of the frontal cortex versus medial temporal lobe. Um Wow, that's a lot of questions. You we shouldn't have made it so short. Um do you know any research that looks at hormone therapy and brain health for those with brain injury and concussion? A very, very, very good question. All we did in this case was did a sensitivity analysis, so we um we took out people with um We We kept everybody in, and then we we we took them out, and we didn't see a change, but we didn't look directly at TBI or concussions. I I And you maybe you already know this, but uh certainly concussion outcomes tend to be uh and maybe this isn't super surprising, but tend to be worse in people postmenopausal than they are, like accounting for as much as you can, um than they are pre uh menopausal, and even can change depending on uh menstrual cycle phase of when that So, there is going to be a link, but I don't know very much about it yet. Uh how do you disentangle the effects of vasomotor night sweats? Damn, that was night sweats. Sorry, I swore. Um, on cognition from the potential effects of sleep disruption on cognition. I'm passing this to Laura cuz that's her expertise. That's a great, uh, question. Um, so generally speaking, um, it's true that vasomotor symptoms can occur both during the day as well as at night. I think, um, one common way to measure vasomotor symptoms is, uh, or ambulatory hot flashes and nights and and sweats is through actually like a monitor where they look at skin conductance changes rather than like subjectively asking, "Oh, how many hot flashes did you have, uh, that day?" Um, so that's a way that you can actually measure them also throughout the night, sometimes a bit more accurately where it can be I I think harder to subjectively report those those types of symptoms during the evening. Um, so they they try at least in analyses where we're looking at vasomotor symptoms on cognition to control for some of these sleep disruptions. So things like sleep fragmentation or like sleep duration. And these, uh, associations tend to still hold up even when we're we're trying to account for that um, in the analysis. I don't think there actually has been a really, um, certainly sleep disruption, that doesn't mean that it doesn't have any effect on cognition that vasomotor symptoms during the sleep is not is not a big issue. Um, I I think both are important, but they're also distinct is I think what that what that, uh, those studies are really telling us. >> Yeah, it's really like, honestly, there aren't that many people that are really doing these kinds of deep dives into into menopause, um, in this way. So we we just need more people interested, but we also need more funders to fund this kind of research. And I can tell you I'm fighting with CIHR right now to fund to fund some, uh, more work on this. Um, uh, there's there's uh, there's one also in the webinar chat that I want to answer, but uh you spoke extensively about estrogens, you know, oral and transdermal, yes, E2, what's the role of progesterone? Which we always get, and often we have a slide, but we didn't uh throw it in there. Um if you have a uterus, you have to take progesterone. Um we didn't find in our analysis that made much of a difference. Uh there is very good evidence that medroxyprogesterone acetate, which is the one they used in the Women's Health Initiative study, uh doesn't have a lot of beneficial effects. Um in fact, it has quite negative effects. So, most of the negative effects, I would say, argue that this is I'm going to give give you a sweeping statement, but otherwise I can't get through all the questions. Um uh uh what word was more due to the medroxyprogesterone acetate than it was to um Premarin. Um so, again, we're in our infancy because some people take it cyclically, you know, only certain times during the month for a progesterone. Some people take micronized uh progesterone. Some people take I have an IUD. Um uh which is another very common form right now. Uh and uh and some people are are taking some other synthetic um progestins or progestins, I should say. Um so, in our analysis, it didn't make a difference. Again, it did you when we used it as a sensitivity analysis, it didn't change the outcomes. Uh but um uh And some people only take progesterone, so that's another thing to look at. So, I think I I have some other thoughts about it, but they're not necessarily baked in good science. So, maybe I should keep them to myself until I have the uh the evidence. But, it's very important to look at the role of progesterone. So, thank you for your question. But, I think it's going to have different effects based on cyclic versus chronic, and based on the formulations of the same kind of thing. Ah. Um so yes, vaginal estrogens, first of all, they're very good data to indicate they're safe for a long, long time. They reduce UTIs, urinary tract infections, are really important um for vaginal health. Uh obviously, UTIs also are for the, you know, related to to delirium anyway, and more so in women apparently than men, although there's not a ton of great data around that. So I do think it's really important to um if it works for you to to keep up with vaginal estrogens. And um and there's good evidence that even if you've had breast cancer, um that it's it's not associated with an increased risk for recurrence, uh at least the vaginal formulations. Uh but I've heard people say, "Well, there's no biological explanation why vaginal estrogens would support brain health." Um and we're still we're working on that, but I think there's actually really good biological explanations for why they would support brain health, and you can just think about what I just said about you know, if it reduces urinary tract infections, that's reducing systemic inflammation, which we also know can influence brain health. So So we're working on that question, but um vaginal estrogens is another thing that we have looking at in the CLSA as well data set. Um which one should we I'm going to answer the question about men. There's a question about men in the in the chat that probably you can't quite see. Um I think there's a really So I gave uh a version of this talk at um endocrinology in San Francisco, and I had a trans uh man come up to me afterwards saying, "Look, we Sorry, trans woman come up to me afterwards and say, "Look, we've known in the trans community for a long time that transdermal estradiol works better than oral formulations." And it depends on how it's conjugated, by the way, that oral formulation, so just to make that point. Um, but I said, "This is fantastic. Like if you're seeing the same thing that that we see, I would really like to be able to say to each other and like talk about it more and and and and, you know, the community of best practices kind of thing." And uh unfortunately, a lot of that information is on the dark web. Now, the question in the chat's not about uh trans individuals, but I I I'm saying that we can learn a lot from each other, right? The trans community to the cis community and and even cisgendered men to cisgendered women. So, um in the chat, it says that there's value in transdermal estradiol in post uh prostate cancer treatment. Um the evidence suggests it's highly beneficial in men with um prostate cancer um as well, PCA. I'm not really sure. Do you have any data plans to include men in your research? And I think we've actually looked at it in terms of not pregnancy history, but child uh how many children you've had. And somebody else would have published on it, so we sort of abandoned that for now, but we are planning to publish that, but you actually see a beneficial signal in um and and men and women with uh uh you know, children, which I think is really interesting. Um but um I I think that's something that's an open question that we are not averse to to answering. I think it's a really important thing cuz we can learn from each other, 100%. I'm loving this conversation. So many great questions. We're actually running out of time. Um did you have any last comments you want to make or was there any last question you saw that you really wanted to answer? I couldn't even read them all, but um I just want people to study women. To think about these questions, to think about cisgender, transgender, and see the value see the value in studying this kind of work. And so, please lobby the government. Please lobby Yeah, your MPs. Please lobby CIHR to um you know, we're I guess our NATO spending is 2%. I would love to see that same kind of funding for medical research as well. Great. Well, thank you again to both of you for your participation in our webinar series. Um and just a reminder for everybody that our next deadline for data access applications is April 8th, 2026. Um there's more information on the data access section of our website. Um we just announced that follow-up three data, a questionnaire data will be available for request with this next deadline, so that's exciting news. Um also just a friendly reminder, please keep us updated if you've had any changes that affect your data access agreement. So, have you moved institutions? Has your team changed? Um and you can always reach us at access@clsa-elcv.ca with any questions or updates. Um and please do complete the anonymous survey when you exit the Zoom session. So, um thank you again for attending and participating in our webinar. Um to to everyone who joined. Our next webinar, social adversity is causally linked to multimorbidity including oral, will be presented on Tuesday, April 28th at 12:00 p.m. Eastern but by Dr. Noah Goma, assistant professor and associate director for dentistry research at the Schulich School of Medicine and Dentistry at Western University. Registration details are posted on our website and in the chat box. Um and if there's anyone who is interested in presenting a CLSA webinar, we please reach out to the team. Um the link also in the chat box. All the links are in the chat box. And the recording for today's webinar and the slides will be available in the coming days on our website. Thanks again, everybody. Have a great day. >> [music]