 Today's webinar, again, Association of Menopausal Status with Metabolic Syndrome and Depression, CLSA baseline findings. If I can introduce our speakers, Dr. Marie K. Christakis and Dr. Allison shape. So, first I'll just give you a bit of biographies on these lovely scientists. Dr. Christakis is an assistant professor of obstetrics and gynecology at the University of Toronto. She received her medical degree from McMaster University and completed her residency training obstetrics and gynecology at the University of Toronto, followed by a fellowship in menopause and mature women's health. Her clinical interests include menopause, premature ovarian insufficiency, and vulvar diseases. Her research interests include interactions between menopause and obesity, metabolic syndrome and cardiovascular risk. And Dr. Shea is an is an assistant professor in obstetrics and gynecology at McMaster. She received her medical degree from the University of Ottawa and completed her residency training in obstetrics and gynecology at the University of Toronto. Following this, she completed a fellowship in menopause and reproductive mental health. Her research is focused on mental health during reproductive transition. So now I will turn it over to our presenters to take it from here. Excellent. Okay. Thank you, Jennifer. And thank you for inviting me to do this webinar. I was very excited to be part of this, especially the invited with my colleague, Dr. Christakis. We trained in both residency and fellowship around the same time at University of Toronto. So it's wonderful to be invited to hear with her today. I'm going to talk to you about a recent publication in the menopause journal depression hormone therapy and the menopause transition among women aged 45 to 64. The Canadian longitudinal study on aging baseline data. I've mentioned I'm a part of the department of obstetrics and gynecology, but I also have a cross appointment in the department of psychiatry and behavioral and neural sciences. Where I work with that group closely as well at St. Joseph's healthcare. I want to acknowledge my co-authors, Dr. Sohel, Gil Singh, Mayhew Griffith, and Raina who have made this paper possible. And also to acknowledge the CLSA participants for their time and dedication. My disclosures include that I've received honorarium from both Pfizer and biofint. So now this is a particularly interesting time and challenging time to talk about mental health and mental well being given the current pandemic. We know that to mental illness is certainly on the rise in the last 6 months. We've seen an increase in depression and increase in anxiety, increase in substance use and overdose, as well as suicide attempts. This is all due in part, as we know, social isolation. The stress due to the pandemic, many financial stresses, job loss. And sometimes the opposite of social isolation and being with too many people in a crowded place, namely working parents at home with their kids. I'm sort of be happy to have them back at school, but we'll see how long that lasts. And again, that adds to the uncertainty and stress right now. We do know that women are at a higher risk for depression. This is a graph showing the difference between men and women in the instance of depression that starts to occur after puberty. So after women start menstruating, you can see the top line is women. There's a 2 to 1 ratio and that women are much more affected by depression than men. And you can see a few different peaks in the trend. One is around the reproductive years thinking about pregnancy and postpartum. And the second peak, which is actually even higher is around the menopause transition. So a lot of people don't know this and a lot of people don't talk about it is that the incidence of depression and depressive symptoms are actually higher around the transition. It's great that we're hearing a lot more about postpartum depression, but we need to also get the word out that women are suffering greatly around this transition and that there are a lot of treatment options. So the menopause is a normal physiological event, which occurs following the final menstrual period, which represents a loss of ovarian follicular function and ovulation itself. The mean age in North America is 51 years, but it can occur earlier for many women. It's demonstrated physiologically by an elevated follicle stimulated hormone or a lower undetectable estradiol level. The definition of menopause is actually 1 year of a menorrhea. So 1 year of no periods in women with an intact uterus. There are many bothersome symptoms that come along with the menopause and the most common being hot flashes and night sweats, which occur about 75% of women. We get changes in mood and depression changes in sleep, which are partly related to vasomotor symptoms, but are also independently related as well. And that many women suffer with sleep disorders, even after their vasomotor symptoms are improved women experience vaginal dryness, change in libido bone loss and weight gain. Now, I mentioned the average age is 51 in North America, but many women suffer earlier than this. So an early menopause by definition is age 40 to 45 years. And then there is POI or premature ovarian insufficiency, which means a loss of ovarian function occurring before age 40. The most common reason is idiopathic, which means we don't know, but this is attributed to being autoimmune cause. We are still learning a bit more about that as we speak. There are genetic causes such as Turner syndrome and other. Now surgical causes such as those who had their ovaries and uterus removed from cancer or for pain or for endometriosis. Chemotherapy or radiation induced some medications and other autoimmune diseases can also be associated with an earlier loss of ovarian function. Now, we know that if you have an earlier menopause, there are several health risks that happen and that's because estrogen affects virtually every system in the body. Your skin gets drier, your vagina gets drier, your hair and your nails become more brittle. You have less energy, your sleep is more poor, you have hot flashes, but the more serious effects are those thinking about your bone and your cardiovascular system. We know that estrogen acts on the bones and we also know that estrogen is a potent vasodilator. So when you get a loss of that estrogen, your cardiovascular system really is affected. Now, most of what we know about early menopause, we've derived from studies of women who have lost their ovaries at the time of hysterectomy. We do have some studies on early menopause, but we have much more on those who have lost their ovaries. So this is a very good study done by Walter Rocca and colleagues. This is the Mayo Clinic retrospective study over 1,600 women. And they looked at accumulation of 18 chronic conditions followed for 14 years in women who lost their ovaries before the average age of menopause. They adjusted for other chronic conditions at baseline as well as ethnicity, education, BMI and smoking. So if you can see here, I want to draw your attention to the top line here and this is the risk for depression. Orange is overall and those who lost their ovaries from a surgical menopause before age 45 is the blue line. The brown line is surgical menopause 45 to 49. You see there's significant and strong risk factor to have a depression at an earlier age if you've lost your ovaries. Other significant findings were an increased risk of hyperlipidemia as well as cardiac arrhythmias, coronary artery disease, congestive heart failure, asthma, as well as some of the other chronic conditions. Now back to mood. We know that anywhere from 15 to 50% of women will experience some sort of depression or depressive symptoms during the menopause transition. Studies have shown that up to 30% meet the criteria for a major depressive episode and that would be characterized by the DSM 5 characteristics. The risk of a first episode increases times 2 during the menopause transition and a recent meta analysis showed there was an increased risk overall for depressive symptoms during the perimenopause. So why does this happen? So we know that there are drastic hormonal fluctuations which do affect many of the neurotransmitters that are involved in mood. We also know that women aren't sleeping as well. And so there's a domino effect of that damoline affecting their mood. We know that the motor symptoms increase the risk for depressive symptoms and have been found to both increase the risk for depressive symptoms and depressive symptoms have also found to increase the risk for vasomotor symptoms. We know women's libido is starting to decrease at this time. This can affect their intimate relationships and then affect their self-esteem. Women are having burnout from taking care of elderly parents and sometimes have children still at home. Then there's the phenomenon of the emptiness syndrome. So women are acutely aware of their loss of a role as a mother or caregiver at the same time as they are acutely aware that they no longer have a reproductive potential. And this can be particularly damaging for women who do not work outside the home. We know other risk factors include history of mood or anxiety disorders, but life stressors or any other health issues can put you at a higher risk. Now we're learning more than an earlier menopause may put you at a higher risk as well. So the research questions for the CLSA cohort were what is the rate of major depression among women participating in the CLSA around the time of the menopause transition. And at an earlier age at menopause increase the risk for depression among women living in Canada during this time. And what other factors increase the risk for depression? So as you're probably familiar, the CLSA is a large national perspective study of more than 50,000 people living in Canada who are between the ages of 45 and 85 at the time of recruitment. There are 11 different data collection sites throughout the country and people are recruited and followed for up to 20 years or until death, whatever occurs first with assessments every three years. The CLSA is the most comprehensive and deeply phenotype cohort anywhere in the world and has a multitude of measures, both questionnaires and biospecimen data, which will give us a rich data to use moving forward. The current study we use baseline data of women with the focus of the age of menopause in the early post menopausal years from both the comprehensive and the tracking cohort. So even though women were recruited up to age 85, I only focused on the age brackets of 45 to 64 to represent the earlier post menopausal years, rather than thinking about other later life effects that could have influence on depression, such as more chronic diseases, death of other loved ones around them, and so on and so forth. Just give us a cohort of over 13,000 women to look at. Now, what we did is exclude women who undergone, but undergone hysterectomy because the question posed out hysterectomy to ask whether or not they had their ovaries taken out. If a woman does have a hysterectomy, but her ovaries are left in she has not rendered menopausal despite a lack of menstrual period. So given the fact that was not known to keep things clean. We decided to exclude those women. Something is not showing up on the side. Anyway, this is the, this is the depression scale that was used, which is the center for epidemiological study depression. The abbreviated version, which is a 10 item scale questions were asked such as I was bothered by things that don't usually bother me. I felt depressed. I felt fearful. I felt lonely or I was happy. And from this, there's a high sensitivity to estimate a major press of episode if you score 10 or more. These scores and we divided the cohort for those who were 10 or more versus those who scored less. And those 10 or more were used as an estimate estimation of those that were clinically depressed at the time. So what did we find? We found that 18 and a half percent of women in this age group scored is being depressed using this one depression scale. Now, this is encouraging because this is actually lower than studies from other countries. Many studies done in the US in Eastern Europe as well as in China show rates anywhere from 25 to 35% around the early menopause years. So this is somewhat encouraging, but nevertheless, almost 20% of women, you know, meet a estimated diagnosis of depression. There were several key differences which emerge between those that were depressed and those that were not. Some of these are not surprising and have been well documented such as the lower socioeconomic status, lower educational attainment search. Certainly our social determinants of health as well as obesity. Some of this may be due to some of this may be due to increased inflammation in the body. There are a much higher proportion, a doubling of proportion of those that smoke versus those that did not. Again, this is not surprising. We do see a higher incidence of smokers and women who are suffering from mental illness. Part of this may be is that when you have a cigarette, you actually increase your brain serotonin, your happy chemical, and you get a little jolt of happiness or a little bit of relief from that feeling of unrest. So it's not surprising. Many of these women were childless and they had a significantly less lower tangible social support. So even though you have people around you doesn't mean that they're actually tangibly helping you. So those that if you needed help, if you needed to drive to the doctors, would they help you? Would they be able to get groceries if you needed that? So that's what we mean by tangible social support. They also had significantly less social interaction. So again, you might be around people, but whether or not you're getting affectionate social interaction really was found to affect whether or not you felt depressed. Part of this may be in due to the fact of being childless. So these are the findings, which I think are the most striking findings from the study. What we did is control for age BMI SES smoking and alcohol use as well as marital status and social support. And we found that women who had their menopause before age 40 had a significantly higher risk for depression in the midlife years with the odds ratio of 1.45. Now, we had another interesting finding when that those that were currently using hormone replacement therapy, which was only about 10% of the cohort had a higher risk for depression. I don't think it's the hormone therapy per se. I think we have to be careful when we see this result. But what I propose is that women who have more severe metaposal symptoms, namely vasomotor symptoms, which is the number 1 indication for hormone therapy are going to be more likely to have depression. As we know, vasomotor symptoms and depression go hand in hand and there are significant independent risk factor. So it's more likely that these women were suffering more greatly in their menopause. So required hormone therapy. And that's why we see this significant effect. So it's on Marie. We found about 18% of women in this menopausal and early menopausal years. And this representative sample of women living in Canada met the criteria for major depression using the CEC 10 several social determinants of health identified. A premature menopause before age 40 had an enduring effect on mental health significantly increasing the risk for depression. So why is it happening? We do know it has been well documented that a longer exposure to endogenous estrogen may be protective. So this was a systematic review looking at the association between your reproductive periods. So if you had an earlier period and or a later menopause. So a longer duration that you were exposed to your own estrogen, you had a significantly reduced risk being around the early post menopausal years. So why is this happening? As I mentioned earlier, we do know that estrogen influence important neurotransmitters involved in mood regulation, namely serotonin and norepinephrine. When we have estrogen present, it modulates your serotonin neuronal firing increases serotonin synthesis. It decreases serotonin breakdown. We also know that have an effect on the noradrenergic or norepinephrine system increases the availability increases the synthesis. So as you can imagine, if women who've had an earlier menopause have a much less time being exposed to their own estrogen, they have much less time to have these positive effects of these neurotransmitters on mood. So what are the implications of this? So certainly proper identification of an early loss of ovarian function may lead to replacement of important hormones, particularly estrogen to mediate this. Hormone therapy, I've got a better map, but it really is often to initiate 10 years of menopause in the right person without contraindications and can have huge health benefits. It will help other systems, the body to reduce health risks. So, namely, what we're most worried about in these women is osteoporosis and early early cardiovascular disease, but certainly protection of mental health is very important as well. So, what can we do to treat these women once they already are depressed? So, there's a recent can that clinical guideline, which you can refer the references there. And this goes down all the 1st and 2nd, 3rd line treatments for depression in a perimenopausal depression. Certainly want to stop start by optimizing exercise and sleep. And there are good evidence for several psychotherapies and pharmacotherapy, both SNRI, SSRI, as well as treatment with estrogen. So, in terms of future directions, knowing that an earlier menopause is associated with many poor health outcomes, we're now looking at the risk for osteoporosis. And when there's an earlier menopause in the CLSA cohort, as well as the cardiac disease risk, which is looked at using the carotid into the media thickness. So these will be the next few papers coming out. And we're also going to look at the rest for multi morbidity. Thank you. Great. Thanks so much. Um, I also want to echo how much of a treat it is to be invited to talk here, especially with Dr. Allison shape. I do want to recognize the CLSA for building such a wonderful database for both of us to access. And also my co-authors. So I work out of the menopause and mature women's health clinic at St. Michael's hospital in Toronto. And my co-investigators included Dr. Lindsay Sheriff, who's at Mount Sinai Hospital. And some of our team, our research team at St. Michael's, Dr. D'Souza and Haruna San. So, I don't have any conflicts of interest to disclose. My, you know, one of my biggest interests now is on metabolic syndrome and how this, how women at menopause are particularly vulnerable to metabolic syndrome and changes. So, we know that metabolic syndrome is a combination of dysmetabolic criteria that includes abdominal obesity, dyslipidemia, hypertension, and insulin resistance. And astoundingly the estimated prevalence of metabolic syndrome in Canadian women, the latest data of, which was in 2012, 2013 was 20% overall. And in women who are certainly post-menopausal in the 60 to 79 age range, we see that 38% of them fit criteria for metabolic syndrome. So, certainly this is a huge health risk. And the significance of it is that it increases the risk of both heart disease and cancer, which are the two leading causes of death among women. So, specifically, we've seen up to 78% greater risk of cardiovascular events and death compared to controls. And more recently, metabolic syndrome has been associated with increased risk of breast cancer development, poor prognostic characteristics, including triple negative hormone receptor status and increased likelihood of recurrence and higher mortality. So, certainly if we know that there's this correlation between menopause and metabolic syndrome, it could propose a very important time to introduce preventative care. So, there has been conflicting evidence regarding the association between metabolic syndrome and menopause. Several cross-sectional studies in Europe and Asia have demonstrated an association, and this is independent of aging. So, in a 2008 current study of two women, menopausal women, were looked at, and this was their baseline data, similar to what Dr. Shea and I looked at with the CLSA data. And post-menopausal women had a 2.93 times greater odds of developing metabolic syndrome even after controlling for age and BMI. We also know that increases in systolic and diastolic blood pressure have been shown to be associated with metabolic syndrome. This is also independent of age and BMI. And the data from the study of women's health across the nation or SWAN in the United States had looked at 949 women, and they reported an association between menopause and development of metabolic syndrome that was independent of aging, but had in fact been altered by how long it had been since menopause. So, the timing of menopause may also be important, and that was something that we were hoping that we might also look at when we examine the CLSA data. So, the contrasting data is from Europe where there have been several longitudinal studies showing no significant differences in metabolic syndrome in triglycerides or HDL levels. And so, what they had found really was that even though they saw this increase, once you adjusted for age, it disappeared. So, we took this opportunity to examine a large cohort of Canadian women and see how do these findings apply to our women nations. So, we wanted to gain some demographics on metabolic syndrome. We also, our primary interest was to evaluate whether menopause is an independent risk factor for metabolic syndrome or its components that I previously described. And we wanted to know whether the age of menopause influenced the risk of developing metabolic syndrome. So, the last piece was whether hormone therapy influenced the risk of developing metabolic syndrome. And this was convenient that this information had been collected as part of the CLSA baseline data. So, similar, our approach was very similar to Dr. Shea and her team's approach. So, we started off with about 30,000 patients, but of course eliminated males. And then, because of the exact same reason that Dr. Shea had eliminated patients who underwent hysterectomy, we also did so. Certainly, it would have been inappropriate to include patients who we really could not pin down the age of when their ovaries started to decline. So, even though we know they weren't bleeding anymore, that doesn't give us the information we need when we're looking at hormonal changes and metabolic syndrome. So, we also ended up excluding women with a history of cancer or an onset of menopause at 40 or less. And this was also because of uncertainty around what their ovarian function had been like if they had undergone chemotherapy or radiation. So, our final cohort had 12,611 women and of those 10,035 had undergone menopause. So, pinning down the definition of metabolic syndrome that we wanted to use is actually a bit trickier than it seems. So, a unified set of criteria were developed in 2009 that resulted from collaborative efforts of the International Society of the Federation of the American Heart Association and the National Heart Lung and Blood Institute. So, this set of unified criteria, which is under definition one, has been adopted in Canadian literature. So, we felt that this was the most appropriate starting point, but the unified criteria when they were developed, they had encouraged a secondary analysis using a lower threshold for waist circumference. And this is because waist circumference is very sensitive to ethnicity groups. And so, we have the second set of criteria where we used a lower waist circumference. So, from 35 to 32 inches, and that's really the difference between definition one and definition two. The other piece that we had to modify from a unified criteria is that we used a glycated hemoglobin because this was available in the CLSA data set, but this is also supported in the literature. So, and it's also supported by the American Diabetes Association. So, when comparing these two groups, the pre-menopausal and post-menopausal patients, of course, we saw that women who were post-menopausal were older. And one thing that I should point out is that we use standardized differences or D values to report a lot of this data, because although P values can inform us about whether an effect exists, it doesn't reveal the size of the effect often. And so, this is kind of a newer wave in reporting these kinds of results. So, any standardized difference of greater than 0.1 denotes an important difference. And so, when we looked at these, when we compared post-menopausal women to pre-menopausal, we found that they were more likely to be older. They had higher hemoglobin A1Cs, higher triglycerides, higher systolic blood pressure. So, no real surprises here, but also in this group, in the CLSA group, they were less likely to be in a relationship, more likely to have a smoking history, have a lower household income, a lower level of education. So, they were less likely to be regular drinkers and less likely to have reported weight gain in the last six months. And that piece was actually interesting to us as an aside, because certainly there is a lot of data surrounding weight gain at menopause. So, I think that whenever we're comparing post-menopausal and pre-menopausal women in any study, there certainly are generational variations that we have to be careful about and control for. So, the prevalence using definition one, where that's a higher waist circumference, overall 30% of the CLSA participants that we included fit criteria for metabolic syndrome. With definition two, it was higher, understandably, because we're including more women at 35%. So, this is actually, you know, this is higher than what the previous statistics had noted from 2012 to 2013 among post-menopausal women with definition one, it was 32.6% and 38.2% using definition two. So, these are, you know, a significant portion of a very large population that had been sampled are fitting these criteria. So, this is very hard to see here, but essentially we looked at the relative risk and we adjusted for several factors. So, we adjusted for body mass index, age, highest level of education, household income, marital status, type of drinker and type of smoker. And this was based on previous literature and also what we were finding there were some differences. And so, when we adjusted for all of these variables, we, I wanted to point out with the red circles, the items that did end up being significant. So, there's a summary on the next slide for ease. So, post-menopausal women were, they had a significantly higher relative risk of metabolic syndrome using definition two, so the lower waste circumference, but not using definition one. And this was after adjusting for all of those variables that I had previously listed. They also had a higher risk of impaired glucose tolerance, elevated blood pressure and elevated triglycerides. So, we wanted our next goal was to look at age groups. And I would direct you to the, each of the points are in clusters of three and the bottom of each third, every cluster of three is the adjusted relative risk. And all, you can see that all of those are crossing one. So, there it for in our population, we did not see that when we broke these women up into when, what age they had undergone menopause. It had not impacted whether or not they developed metabolic syndrome. So, no significant difference in risk of metabolic syndrome by age group. So, the next question was around hormone therapy, menopause hormone therapy and whether women who were, had, had been on hormone therapy versus women who had never been on hormone therapy if there were important differences there. And what we saw was that there's really only one difference and this was that women who had taken hormone therapy had a lower risk of impaired glucose tolerance. Now, this may be because the effect of hormone therapy is transient and based on our data, we could only categorize women as ever users or never users. We couldn't say whether they were currently taking hormone therapy. And so it's very possible that, you know, the changes that have been substantiated and other literature to changes in triglycerides changes in HDL changes in blood pressure for women who are on hormone therapy that perhaps we were just not. At the right time point. So we're limited by the cross sectional nature. And then this table just breaks down the types of hormone therapy that women were on and certainly the literature on hormone therapy impacting metabolic syndrome. Is in women who use some form of estrogen, so not progesterone only patients. And so we analyzed this group of patients with and without the progesterone only group. And we found the same. It hadn't impacted any. So, overall, the prevalence of metabolic syndrome is 35.1% by definition to postmenopausal women have had higher levels of hemoglobin A1C triglycerides, systolic blood pressure. And we had adjusted for all of these variables and found that they, that postmenopausal women had a higher risk of impaired glucose tolerance, elevated blood pressure and elevated triglycerides. And they also had an elevated risk of metabolic syndrome by definition too. So, a really important point here is that 96% of the CLSA cohort reported a European origin. So, using this ethnically sensitive lower waste circumference value gave us the significant, the significantly higher relative risk. And so I do think that this, this is an appropriate interpretation of the findings, but certainly the effect size was not large and it disappeared when we used a lower waste circumference. So, you know, this is important information for people reading our study to know. But likely this, you know, the criteria, the reason why there's so much conflict over which criteria to use is because it is so sensitive to these small changes. So, the age of menopause and use of hormone therapy really did not have any effect on the risk of developing metabolic syndrome. But again, we are limited by the way that data was retrospectively collected regarding the age of menopause. And also the fact that hormone therapy may produce a transient effect. But of course that's important to know because if you're looking at patients, if you're, if a patient is wondering, you know, long term will a short course of hormone therapy be helpful for my longevity. The answer from what we've found is it doesn't change your risk of metabolic syndrome long term. But of course, perimenopause may be a very important time to institute preventative care to identify patients that are higher risk. And this is especially alongside high obesity rates to improve the health and longevity of Canadian mature women. So, I really appreciate everyone's time and attention and I guess now we'll take questions. Both very much for your presentations. I also just wanted to note too that we appreciate you coming together to do this. Both of your topics seem to work well very together. I feel a say webinars will often only focus on one topic, but with one core research team. So it was really great that that the both of you could collaborate and share share the findings from two different studies in one webinar. So I think it's greatly appreciated that you're able to do this approach with us. So, before I have a couple of things jotted down, but I always like prefer if questions come from the audience, so to speak. And we had a question from Jean Lou and I believe it was during yours, your presentation, Dr. Shea about comorbidity. So could you maybe speak to that a little bit about when I think it was when you were presenting the initial results. Yeah, I saw that question about comorbidity and I wasn't quite sure if that was comorbidity of other mental illnesses. I'm assuming that's what it was. Now, the issue is we only had specific measures for depression. We didn't have a clinically validated tool for diagnosis of anxiety or other mental illnesses in terms of a history of depression anxiety. We certainly showed that those who had a history of depression anxiety were at a higher risk. But given the fact that we didn't have a clinical tool for the other. The other mental illnesses or any other comorbidity, we can't, we can't necessarily comment. It just wasn't included as one of the measures. And so also just a reminder that you can put your questions into the chat box. Everyone, everyone will be remain muted, but you can all put your questions into the chat box as some have been doing already. Okay, we have a question from Roberta now. If you had been able to identify those individuals who had undergone menopause due to cancer treatment. How do you think it would have impacted your results? I can say had undergone cancer treatment or had undergone premature ovarian insufficiency or even surgical menopause. I think that it would have, you know, would have been really interesting to look at that group. Of course, we would have had to look at them separately because of how young they were. And the fact that it was, you know, an iatrogenic menopause. But there is certainly data showing that women who undergo iatrogenic menopause at age 40 or less are at higher risk for the schemic heart disease. So I would expect that those women, if we had been able to identify them accurately and report on them accurately, would likely have fit been at higher risk of metabolic syndrome. But I think that, you know, we do already have some data showing us a much harder outcome of the schemic heart disease is more likely in those patients if they aren't treated with hormone therapy. And so I guess the focus of our study became more what about these women who are undergoing natural menopause and should we be looking out for them and identifying them as high risk? I don't know how that would like Dr. Shea. I don't know if you feel if you had more data on earlier patients, how that would have impacted your results. Well, we didn't exclude those patients. Anybody who stopped their period before age 40, whether it be from a natural menopause for age 40 or from surgical or cancer treatment. We're all grouped as one thinking of them all of having a loss or varying function at that time. But stay tuned because we have we have permission to look at those early menopause, depending on all group together and looking at their cardiac into the media thickness. So, stay tuned. We'll have a look at those results and maybe we can have a further discussion. Great. Thanks. Usually at the end, I asked what your what your next steps or plans are going to be following this research. So you've already alluded to that a little bit. So maybe I'll come back to that in a second. Just 1 question I had while we wait to see if anybody else has any other questions and I apologize if it doesn't completely make sense. This isn't 1 of my obviously areas of content expertise by any means. But I noticed in the 1st presentation, you seem to be learning more about who the ideal patient would be for hormone hormone replacement therapy, and you seem to have some more insights. And I also thought in in Dr. Christakis is you also perhaps are learning more about who that ideal patient might be. I'm just wondering if you could speak to that a little bit. And do you see both of your these research studies actually contributing to that? Or is that something we already know? And it's not something we don't necessarily need to know more about. Oh, I'll go first. Yeah, I think we certainly. This, we need to keep learning and we need to get the word out 2002. The study came out that. Misconstrued the effects of hormone therapy and make blankets statements that everybody got afraid of hormone therapy. The biggest disservice those results did is to women who had an earlier loss of ovarian function before the average age of 51. Because you cannot be generalized to that, but people still Google hormone therapy or hear from their mothers or grandmothers, but hormone therapy and white bed. So, certainly those who have lost. Normal ovarian function for age 50 certainly should be replaced provided the reason for the loss was not an estrogen dependent cancer. And they don't have the other contraindications, which. Usually include a history of stroke blood clots or significant cardiovascular disease. A large majority of women can take them and same goes for women in early postmenopausal years in the first 10 years. You know, they're they're a very small, much smaller list of contraindications for hormone therapy than there are for the for the birth control pill. But a lot of family doctors seem to not know that. And so, Dr. Christakis and I probably get a lot of referrals, but for saying, bother some hot flashes in a smoker or bother some hot flashes and somebody with high blood pressure. And those aren't certainly contraindications. You want to get the blood pressure under control, but smoking is not a contraindication. High blood pressure is not diabetes. Certainly it's not. And just as a family physician really is just to go and just review those lists because a lot of women are suffering needlessly. I think for us, we certainly, one of our future directions is is looking more into how the dose and length of time that a patient is on hormone therapy can impact the cardiovascular risk. I think that it's there is some data on this, but longitudinal data is difficult to collect and and certainly there is a lot information still pending. I think there is a suggestion that it hormone therapy is at least neutral for your cardiovascular health. It, there is evidence that it benefits patients like Dr. change that who are less than 10 years from their menopausal transition and are less than 60 that in fact their cardiac their cardiac event rates are lower. But because the event rates are so small in this group of women, because of their age and risk factors anyways, it's hard to know whether that effect is clinically significant. And it's also hard to recommend hormone therapy as a preventative approach for cardiac health. But I think we're going to, I hope that we're going to learn more in the future about how hormone therapy interacts with cardiovascular risk because it is the number one cause of death in Canadian women. And, and so we need to, we need to do better and know more. I think you've also alluded to some, some future areas of research, which is great. Hopefully you both continuing on those lines along with your clinical practices. We maybe we'll just, well, we may have time for a couple more, but we, Roberta also asked another question. Is there an interaction between depression and met on and onset of menopause, particularly earlier menopause from cancer treatment? Would you suggest suggest your research, would you suggest your research suggest that. Yeah, I don't, we weren't, we didn't actually get the data that Dr. Shea had, like the portion of data that was collected from the CLSA to look at whether that impacted metabolic syndrome to look at the two of them together. I do think that early menopause probably does have a big impact on on cardiovascular health, but again, it's, it was very hard to draw appropriate conclusions based on the way that the data was collected with the CLSA cohort. And so once we have more longitudinal data, we may actually be able to draw more conclusions. Yeah. Certainly, I mean, there's, we do know that there is a connection between depression in general and cardiac disease. We are seeing emerging interactions. I don't know necessarily between depression and met, but it would be interesting to look at, you know, but both met and depression, you know, do have inflammatory states. We do know that if you have more inflammation in your body or more risk for depression through the inflammatory cytokines and perhaps there could be interaction that way. I just don't know if it's ever really been looked at. Maybe we should. Perfect. If there's anything good that has come out of this webinar is a future collaboration. Perfect. I love it. Okay. I don't see any more questions coming up. So I think this is probably in its right about time. So this is probably a good time to close. If you do have any questions, you can still post them and we'll have the presenters get back to you with a response. But first of all, thank you again to our presenters. We definitely appreciate your participation in these webinar series and hopefully we can have you back when you share your, your collaborative research project in the future. I'd like to remind everyone that CLSA data access request applications are ongoing. The next deadline is quickly approaching and that's October 7th of 2020. You can visit the CLSA website under data access to review available data for their information and learn about the application process. I'd also like to remind everyone to complete the survey located under the polling option. If you don't see it beside the chat button, please click the drop down arrow and then you should be able to see it. And stay tuned for our upcoming CLSA webinar. The next one on October 20, 2020. It will be anticipating new weights in the CLSA unpacking sampling weights and their youth. And Dr. Lauren Griffith, who is the associate scientific director with the CLSA will be the lead on that presentation. And I know that there's been a lot of people who have wanted that topic presented at a webinar. So we look forward to having Dr. Griffith with us, Dr. Griffith with us. And remember the CLSA promotes this webinar series using the hashtag CLSA webinar and we invite you to follow us on Twitter at CLSA underscore ELCV. And thank you again for attending today's presentation. We will see you next month.