 This is Jesse LeCasse, is that correct? Well Jesse was an attendee at 2014 AHS in Berkeley and thanks to him attending back in 2014 It now informs his work today. So it had such a huge influence on him And they'll be talking about the pill that Darwin never saw coming Hi everyone, I'm Jesse LeCasse, and I'm coming to you from Montreal, Quebec, Canada Coming from Concordia University in the Center for Studies in Behavioral Neurobiology I'm gonna be presenting to you today as Darrell mentioned the pill that Darwin never saw coming the impact of hormonal contraceptives on the brain Before we start I just want to let everyone know that I'm gonna post all of my slides and references online So you can all have access to that as a graduate student I just plan and don't make money I have no conflicts of interest and nothing to disclose and this is certainly not medical advice the pill Despite the fact that there are so many different pills for every kind of ailment that you can imagine There's only one pill that we call the pill and that's birth control or hormonal contraceptives So what makes this pill so spectacular? Well when this pill was released it was revolutionary for women and really for all of humanity so But the story of the pill doesn't start when it was released in public because no drug is really that interesting Unless it has an endogenous system to bind to Now all drugs work similarly in that they have this kind of ligand receptor action The drug binds to a receptor kind of like a key unlocks a lock You need the special kind of key to unlock a certain lock So this is kind of how all drugs work the same is true about steroid hormones What's a steroid hormone? steroid hormones are these molecules that are derived from cholesterol Broken down through a series of enzymatic processes to form hormones that you might be familiar with like progesterone, testosterone, estradiol Now just like drugs these steroid hormones have to bind at steroid hormone receptors So as an example here, we've got estradiol here coming in and binding at its little estrogen receptor Like the little lock and key stuff that we were just talking about So as an example then let's pull up a cell here and on the membrane is an end Membrane estrogen receptor now steroid receptors can either be on the cell membrane But they could also be found within the cells cytoplasm now when estrogen comes in and binds to this steroid receptor It can alter a certain intracellular signaling cascades or maybe protein synthesis and downstream of that That's going to change things like energy metabolism or maybe the membrane potential It might signal for the cell to grow or repair itself and it could even trigger Program cell death now Depending on where this cell finds itself within an organism and whether it's surrounded by a bunch of other hormonally sensitive cells the role of hormones on Regulating certain cellular processes can become more and more complex These are super super old machinery these estrogen receptors or steroid receptors in general They're found in some of the earliest vertebrates that we know So they've been around for a very long time and over evolutionary time as Organisms became more and more complex the role of steroid hormones and what they were regulating also became more complex So then we fast-forward through evolutionary time and we end up here at the human menstrual cycle You can see that the role of hormones became really complex over evolutionary time. You get these you get these changes in Fluctuating hormone levels that will result in a whole bunch of physiological processes that change Within the endometrium for example So if this cell that's sensitive to estrogen or progesterone finds itself Located in the human endometrium lining maybe that cells responsible for responding to changes in estrogen and progesterone levels And that will actually alter for example the thickness of the lining or maybe vascular or immune processes there so over evolutionary time these were shaped and you could see that it's very complicated but Imagine then if you think that it's complicated all of these things being regulated within the endometrium Well, if you found yourself as one of these estrogen or progesterone sensitive cells within the brain things can get a lot more messy So these are the female rat brain It's a heat map showing you the relative distribution of estrogen receptors different types of them across the rat the female rat brain Only to show you here that estrogen receptors as well as all other steroid receptors are quite abundant throughout the brain meaning that they can regulate Processes that are underlined by the brain of course If you look at the human menstrual cycle you see that there's fluctuations in estrogen levels and progesterone levels across a roughly 28-day cycle, okay And so what you see if you look carefully then for example at brain structure is that across this 28-day cycle There's going to be subtle changes in the brain such that across these 28 days you'll see that there's changes in the shape and the size Roughly speaking of the brain now the same is true of functional activity You might observe that there's differences in terms of glucose metabolism in various brain regions You might see that there's changes in blood flow or blood oxygenation and this all is pinned up to these fluctuations and hormones in women That's something you might be more familiar with the cognitive and emotional processes also change across the the menstrual cycle So all of this to say that over evolutionary time as women were exposed to these fluctuations in steroid hormones Certain processes in the brain and cognitive functions were kind of tacked on to that over the course of evolution Now this is the underlying process that we think might be real related to a lot of this This is a finding from woolly and McEwen in 93 what they found here is that actually the neuron the brain cell is Sensitive to fluctuations in estrogen and progesterone So again, this is a neuron in a female rat brain on the left here We've got the neuron and branching out from it are these things called dendrites now These dendrites are actually reaching out trying to form a connection with another neurons dendrite So that they can connect with each other and form a network of neurons This is basically the under the underlying process under learning and memory if this goes awry You see a lot of problems, especially in neuropsychiatric conditions Now if you look carefully here at the dendritic spines, you'll see that there's these little stubs that are reaching out from them These are called dendritic spines These are finger-like protrusions that are reaching out and these are actually the Little points that are going to form the synapse if the dendrites end up connecting with one another from two different neurons And so what you see is that there's actually fluctuations Well, there's fluctuations here in the number of dendritic spines that are forming across the female rat Estrus cycle such that when they have high levels of estradiol circulating They have more of these dendritic spines and you actually see improvements in learning and memory and stuff like that Now in the estrus phase when you get this rise in progesterone What you see then is that you get this stripping away of these dendritic spines And so all of this to show is even at the level of the neuron The neuron is sensitive to these fluctuations in estrogen and progesterone So now let's take a step back and let's make a timeline here We've got all of human evolution and all of hominid evolution if you really want to think about it even further back than that But where women would have been exposed to these cyclic fluctuations in estradiol and progesterone and other various hormones But over all of evolutionary time, they would have been exposed to this these cyclic changes now Then in 1960 what you see is that we flip this whole system on its head And the United States approves the birth control pill as a contraceptive now This is revolutionary because for women this really propelled them to this was really what led to the women's Liberation movement and allowed them to enter the workforce and really have access to higher education But it also gave them a choice over the number of offspring that they would actually be able to have And so it was really revolutionary for women's health in that sense However, we've now gone through all of evolutionary time with these exposures to these cyclic changes in hormones and all of these Processes at the level of the brain and cognitive functions that dissociated with those changes and yet we flip the system on its head in 1960 So I like to juxtapose the release of the hormonal contraceptive pill with this fact in 1968 which is the discovery of the estrogen receptor in the female rat brain by Don Faff and so what you see is that I like to juxtapose these two facts next to each other because it really shows you where the thinking was in terms of neuroendocrinology At the time of the release of the birth control pill We discovered the estrogen receptor in the brain eight years after it was released into the public So we just weren't thinking really about the brain necessarily at the time of its release So let's continue our timeline then and we end up here in 2019 with the release of this graph from the United Nations Showing the different types of contraceptive methods that are used around the globe If you look carefully here, you'll see that about half of the methods include a hormone in them one that you'll be more familiar with Obviously the pill, but there's other forms like injectable methods or implantable methods as well as intrauterine devices That can either be hormonal or copper now this figure actually doesn't Break up between hormonal IUDs and copper IUDs But if we take about half the number there that gives us an estimate that about 250 to 300 million women around the globe are using hormonal Contraceptives and this number is growing as the drugs become generic and as they enter countries that didn't have access to them before So what is the pill? Well like you saw in the last slide the pills not just one thing There's no one entity that is the pill there can be a lot of different forms of the pills and Really what the combined oral contraceptive pill is that everyone's familiar with would be a Combination of a synthetic form of estrogen and a synthetic progesterone molecule Now the most frequently used estrogen in hormonal contraceptives is something called ethanol estradiol. This is a very potent estrogen It has twice the binding affinity for an Estrogen receptor then does the endogenous 17 beta estradiol now in addition to that It has about a hundred times the biological activity that you see with 17 beta estradiol Now if you look at the progestins that are used in hormonal contraceptives what you first notice is that there's a whole bunch of them So to try and build a framework around how to think about these progestins There's one way to think about it, which is how are they derived? Well, if they're derived from a synthetic form of testosterone like 19 or testosterone What you'll see is they actually carry with them this androgen or testosterone like effect they have binding affinities for androgen receptors and they can carry with them these effects that you might expect of the Androgens like DHT or testosterone Now if they're synthesized, oh God here we go. Okay, if they're synthesized from an Synthetic form of progesterone. Well, then what you see is that they actually what is going on here? You actually see that they carry with them these anti-androgenic effects where they have and Effects that oppose those of the androgens or maybe might be more similar to what you observe with estrogens The general mechanism of action for hormonal contraceptives doesn't apply to all forms of them But the vast majority work in this way So in a naturally cycling woman what you'd have is ganatotropin releasing or ganatotropin releasing hormone would be released from the Hypothalamus to stimulate the pituitary to release follicle stimulating hormone and luteinizing hormone These will travel down to the ovaries which will stimulate the release of estrogens and eventually it'll stimulate the release of progesterone downstream from that Now with hormonal contraceptives We close off this feedback loop by saying to the hypothalamus listen We've got a whole bunch of estrogen and progesterone on board here We don't need to make any more and so you get this reduction in ovarian hormones and ganatotropin hormones as a result of the hormonal contraceptives So then keeping this mechanism in mind. How do hormonal contraceptives impact the brain? Well, let's start by looking at brain structure and function starting with brain structure. Well There's a lot of changes that they observe in terms of brain structure relative to natural cycling women with hormonal contraceptive users However, what you see is that some studies report that there's larger gray matter volume in certain parts of the brain and then other studies Report that there's smaller gray matter volume in other parts of the brain now I've underlined here a couple of different brain regions that show that depending on which study you read You actually get the direction of the effect going in opposite directions here So the jury is really still out in a lot of ways now a recent study that came out in plus one showed that using a really highly high-resolution type of MRI showed that there was a total volume reduction In the hypothalamus and pituitary gland of women using hormonal contraceptives compared to naturally cycling women which is interesting for the reasons I Related to the mechanism that I just showed you so you get this less total volume in hypothalamic and Pituitary gland tissue so Moving on to brain function then the two ways that we tend to think about brain function is Resting state the brain at rest or during a task during a cognitive task or while the brain is doing something And you want to see if there's changes in functional activation Now in terms of resting state and task-based Assessments what we see is mixed results and no differences. What do I mean? Well in terms of mixed results you see that hormonal contraceptive users in some cases have higher levels of functional activity in Various brain regions either at rest or during a task and then the opposite is also found depending on which study you read So the effect of hormonal contraceptives on the brain in terms of structure and function is complicated Let me explain why Now let's say you want to run a study to assess the effect of hormonal contraceptives on the brain. What do you do? It's not necessarily it's been done But it's not necessarily ethical to randomly distribute people to receive a contraceptive hormone And so what you get then is that we all recruit these types of convenience samples Well, who are you recruiting? Are you recruiting anybody on a hormonal contraceptives? I hope I've shown you that there's not just one thing that is a hormonal contraceptive And so do you have IUD people with IUDs as well as implants? Are you including people who have? using Androgenic forms versus anti-androgenic forms are you throwing them all into one group? So that's part of the problem. Are you comparing them when they're using the active pill or the sugar pill? Are you looking at people who started using them when they were adolescents or are you looking at adult onset users? There's other studies that also just look at women who experience negative mood effects of the pill and they only look at those women So there's a lot of really cool findings out there in the brain structure and function literature However, they test all of these really unique samples and you know not necessarily a single type of Contraceptive hormone and so it's really hard to weave the needle and try to get this kind of global effect of what's going on to brain Structure and function. However, we do see that relative to naturally cycling women. There are changes in brain structure and function It's just that we don't necessarily have a good finger on the pulse in terms of which direction those effects are going in just yet If we do observe these effects in structure and function though, maybe you'd expect that there would be an effect on Cognitive function or cognition okay Remember earlier. I told you that a progestin depending on how it's derived can actually come from Synthetic forms of progesterone or testosterone So they can either be androgenic or anti-androgenic well It turns out the best way to think about the effect of androgenic and anti-androgenic hormones on Cognition is by thinking about them through the lens of cognitive sex differences. And so what do I mean by that? So it turns out that there's a whole bunch of cognitive processes that in some cases males excel and in other cognitive Processes women excel so for example men are really really good at these visual spatial tasks like mental rotation For example where you have to rotate this 3d object in your mind and match it up with a couple of different options Now on the other side of the spectrum women are really really good at these cognitive processes like Emotional facial recognition. So if you were to give a woman this Image here her reaction time would be a lot more quick and she'd be a lot more accurate at recognizing those emotions than a male Now let's take mental rotation then as an example For how these androgenic and anti-androgenic hormones work. So here's a Block here, and I'd like you to rotate it in your mind and match it up with either option a b or c Okay, so for those of you who chose option C. This is the correct answer A lot of you look disappointed especially the men okay, so So what do we see with mental rotation and hormonal contraceptives? Well, what you see is that if you give an androgenic form of these hormonal contraceptives then well It slides Performance towards this male phenotypic end of the spectrum where you see this lower reaction time and higher increases in accuracy Now with women, it's a little bit more complicated. I said with females. It's a bit more complicated So what you see in naturally cycling women is that women with higher levels of Estradiol actually show worse improvement or sorry worse Performance on a mental rotation task lower reaction to our slower reaction times less accuracy So it's driving them towards that female female phenotypic end of the spectrum now if you look at ethanol estradiol the hormone in or this Synthetic form of estrogen as you drive up that dose of ethanol estradiol What you see is that it actually drives you towards this female phenotypic end of the spectrum as well Now if you look at this study here, which along the x-axis This is the angle at which the block is turning so it's getting harder and harder So what you could see is that accuracy in all groups is declining as they make the task harder But what you see is that males are having the highest level of accuracy followed by naturally cycling women and women using anti androgenic forms of hormonal contraceptives are all the way at the far end of this female female phenotypics End of the scale where they have the highest reaction times and the less of the least accuracy Now it turns out that this actually applies to several other cognitive tasks in my own work. I've actually shown that This applies to 3d navigation as well So males tend to complete these mazes a lot more quicker quickly They learn the Environment a lot more quickly and what you see is that if you give an androgen or women using an androgenic form of Hormonal contraceptives will tend to have lower latencies depending on the form that they're using Some latencies that are exactly what we observe in men Another form of cognition that I briefly mentioned before is this social cognition facial recognition facial emotional recognition This is something that we probably take for granted a lot of the time But you'd really want to be able to tell the difference that these are two different people And if you knew them you'd want to be able to look at their face and recognize who they were as an individual In addition to that you'd want to be able to see the emotion on their face and recognize what that might mean And so as I mentioned females really excel at this They can really detect in a shorter reaction time and highly more accurately what the emotion is on these face now If you give an and or women taking an androgenic form of the hormonal contraceptive You could see where the story is going they get or yeah They get worse at this more towards the male phenotypic end of the spectrum And there's actually this other finding that women using hormonal contraceptives tend to have this bias towards negatively Valence to stimuli so they'd be a lot more quick at reacting to this negative face the angry face Versus reacting to the happy face and so they seem to have this bias towards negatively valence stimuli Now in terms of executive functions from my own work as well, this is stuff that we've found was that sure the androgenic Forms of hormonal contraceptives drive performance towards this male end of the spectrum But what you need to do is look at whether they're taking the active or sugar pill And you see that the effect that we observed only occurs if they're taking the active pill not the sugar pill Meaning that there might be kind of short-lived effects on cognitive function as it relates to taking these hormones That being said a couple of studies that have come out in the past ten years or so have shown that there might be benefits for cognitive function in the long term for women who have used hormonal contraceptives what they showed was that these improvements in cognitive function were actually duration dependent such that women using hormonal contraceptives for greater than 15 years Actually had better performance on these cognitive tasks relative had the greatest performance I would say on cognitive tasks relative to women who never use them now two other studies out of China had come out recently Showing that there was a decreased risk for cognitive impairment in women above the age of 60 using hormonal contraceptives Compared to those who had never used them Okay Let's get into mental health And I'm going to double-click on depression here because this is the area that's received the most attention as it relates to the link between hormonal contraceptives and mental health In 2016 in JAMA psychiatry this paper came out as showing an association between hormonal contraceptives and depression Now this paper and some others have received quite a bit of criticism down here in the reference section here I know you can't really see them too well There are four reviews here that really attack the literature on hormonal contraceptives and depression So I want to make sure that that is included in your reading after the fact But really the issue is essentially the absolute risks are a lot less impressive than the relative risks But overall what you do see is that there's this story emerging where it looks like there is a population of women who might be particularly vulnerable to this risk and It looks like that might be women For example closer to the age of 16 years old young women showing a greater propensity to have this association come to life The other thing is that women using Forms of hormonal contraceptives that include only a Progestin rather than this combined form with the estrogen and the progestin. They actually show a greater risk as well, so Of course though in 2021 a study had come out from Sweden in a large sample showing that there was absolutely no association between depression and hormonal contraceptives and then of course there's this study in 2013 that continues to throw a wrench in Everyone else's research that showed that there was a reduced effect of Sorry reduced depressive symptoms in women using hormonal contraceptives and so really the jury is still out in the epidemiological literature They are still hot at it and I am not an epidemiologist And so I backed off and I turned to the neurobiological literature to try and find some putative link between depression and hormonal contraceptives Now sadly, I don't have enough time to present to you all of the different Neurobiological changes that occur in a woman using hormonal contraceptives But I will present to you the one that has received the most research Which is the link between cortisol stress and hormonal contraceptives Cortisol is our main stress hormone. It comes or it's produced in the adrenal glands and released from the adrenal glands And it's released in times of acute stress The classic example walking through the jungle tiger jumps out of the bush You want to get this big spike in cortisol levels and this is really gonna You know pull glucose into your bloodstream and direct blood flow to your major muscle groups in order so that you could fight Or flight if you really needed to Now if you're exposed to cortisol over the long-term chronic long-term exposure to cortisol I mean, it's probably not a better group to try and explain that that is not a good thing too But if you're interested, I would Recommend reading the book why zebra don't get ulcers by Robert Sapolsky It's a great place to start in terms of connecting cortisol and health In people with depression you see that there's disrupted cortisol on a few different levels So what you see first is that they have a blunted cortisol response So when provoked with a stressor someone with depression is not gonna get for the most part is not gonna get this big acute stress Responses big spike in cortisol. You see that they have a blunted cortisol response in addition to that They just sit at a higher elevated baseline of cortisol levels to begin with people with depression Just have more cortisol circulating through at any given time They also show a Disregulated cortisol awakening response when you wake up in the morning for the first 15 or 30 minutes You want to get this big spike in cortisol? And that's really going to kind of engage your faculties and get you ready to start your day in people with depression. You don't see this It's disrupted. It's dysregulated. So I'm sure you could see where the story is going here. What do we see with birth control? What do we see with hormonal contraceptives? women with hormonal or who take hormonal contraceptives you could see that in this figure here that Okay, so I'll walk you through this then on the x-axis You got two baseline measures of cortisol followed by two provocations with a stressor and what you could see in the HC negative group That's people without hormonal contraceptives on board that they get this big spike in cortisol when provoked with those two stressors What you see in the HC plus group, that's people who have HC on board hormonal contraceptives They don't get this rise in cortisol when provoked with a stressor Now another thing that you'll observe if you look there's this recent study that come came out showing that Hormonal contraceptive users just sit at a higher baseline of cortisol levels what you saw from this study was that? Hormonal contraceptive users had cortisol levels that were one standard deviation higher than their non hormonal contraceptive using counterparts this was actually oh little box there to illustrate that for you and this was actually replicated recently in a paper that was just came out last month showing that women in the follicular phase and luteal phase of their menstrual cycle had about half the circulating levels of cortisol compared to hormonal contraceptive users This was associated with increased scores on questionnaires related to depression and stress but not anxiety Now lastly the cortisol awakening response, of course And so we get to the cortisol awakening response and this is what a healthy one should look like you get this spike in the morning Like I mentioned and then after about the first hour or so you get this gradual decline throughout the rest of the day And of course in non hormonal contraceptive users That's exactly what you see you see this rise in the morning followed by that gradual decline in cortisol throughout the rest of the day Okay, here we go What do you see with hormonal contraceptive users? You get a roughly kind of blunted cortisol awakening response They don't get this big spike in the morning They kind of get this little rise and then it kind of tapers off from there Actually more gradually than the rest than then you'd observe in non cycling or sorry naturally cycling women so All of this to say that we obviously see some connections between what we observe in a depressed Depressed population and then what we observe in a hormonal contra contraceptive using population I'm not necessarily saying that this is the exact connection But in a particularly vulnerable group of individuals this cortisol dysregulation could be What's kind of leading to this association that we're seeing with hormonal contraceptives and depression in? General though the science of hormonal contraceptives is just emerging now This is a brand-new field and so since their release in 1960 when we flipped the menstrual cycle Physiology on its head. We're still catching up as a science to figure out what kind of impact that might have had on women's brains hormonal contraceptives do impact the brain compared to naturally cycling Women but the results are subtle and they're mixed There's no real clear direction yet as to where that's going and that's likely due to the fact that Most studies are just grouping all of these hormonal contraceptive users together and not accounting for the different pharmacological Pharmacological properties within each unique formulation That being said unique types of hormonal contraceptives are going to produce unique types of effects as I mentioned There's different effects of anti androgenic and androgenic hormones used in hormonal contraceptives And then you saw that there's different risks of depression in combined users versus progestin only users So the type really really matters here So I don't want everyone to forget that while there's so many different unknowns about the brain and how hormonal contraceptives might affect it They've been they've benefited women in so many different ways. And so we really have to appreciate that as well now, thank you all for your attention and I'm actually going to skip the question slide because I have a little bit more time So I'm going to plug a couple things. I was associated with a Journal a special issue in a journal recently that is going to be covering all of the different Research on hormonal contraceptives in the brain and we're calling for translational research because we really don't know much about Mechanisms here and so really we're looking for animal work as well to try and decipher really what's going on at the level of the brain And so if you're interested in the stuff I presented to you today I highly encourage you to follow up with this special issue. It's being released as we speak Another thing that I've planned recently in collaboration with a great team at the women's health research cluster is a Virtual conference that is entirely dedicated to hormonal contraceptives and brain health And so we've got an amazing lineup of speakers of all of the world-class scientists from around the globe who are going to be speaking on this topic and Now I will thank you all for your attention and if you have any questions I'd be more than happy to try and answer them for you and occurred to me that these would be That this would offer some opportunity for very strategic strategic use of of these as a neotropic and I Was imagining for example a med student might want to take an androgenic version while they were Taking the boards and then when they're doing patient interview testing they would take the The anti-androgenic version. It's wondering what you think of that And and if so, what would the would the timing be would you use it as an acute dose a day of the test? Or would you want to take a preparatory lead-up lead-in phase? Thank you. Well, thank you for your question, Chris Honestly, I think that the literature is still too scarce in turn to make any I Mean yeah, I definitely don't think we should be using these things as cognitive enhancers until we have a bit of a better understanding of their function, but yeah too early for that Hi, thank you very much. This was excellent Having been on various forms of it whether it was the pill or the nuva ring for a total of 24 years in which no one thought to take me off it Initially it was to protect my bones Even though I wasn't ovulating, you know, you using it it was suppressing all the ovulation. I Have been musing about the connection between Well, you see a higher resting cortisol in people who are taking it Is that connected perhaps to like vagus nerve suppression which might then play into Like the development of dysbiosis because that's something I've also had a lot And I've heard from various sources that it plays a big role in in the production or the development of dysbiosis so There's not enough work done yet that I could say whether or not it actually is affecting a vagal stimulation or not It could be and I know that there is work that showed that in general women using oral contraceptives had dysregulated microbiome whatever that might mean though, you know in terms of Yeah, compared to naturally cycling women I Again, I couldn't speak to the mechanism of that because the research is just lacking in a lot of ways And it would be so hard to do a mechanistic study. Exactly. And so I don't know again I Yeah, the gut connection is interesting and there's a lab in Ottawa right now That's working on just that question, but I think it's too early to say. I'm sorry. Thank you Canadian apologizing I thanks for that so I guess my question is I saw the The blunted cortisol response Would it Basically, I've got this sort of image in my mind that like Essentially the natural circadian rhythm itself is sort of messed up because of this because of how much You know cortisol and many other of these hormones are affected in that and so I'm curious if there's been other studies around sleep And how sleep has been affected There have to be honest. I haven't read all of them They're really kind of coming out in the last year and I'm trying to wrap up my PhD But there are associations with increased insomnia and women using hormonal contraceptives That's something I know and that association with this insomnia is also associated with increases in depressive symptoms That's basically all I know in terms of the sleep There was one study that came out about sleep sleep architecture being different But again just because things are different between a naturally cycling woman and a hormonal contraceptive user in the laboratory setting When you walk out of it, would you be able to kind of spot that? I don't know and so Yeah Thank you Hi, thanks for the talk. I have sort of an adjacent question. Actually, it does have to do with cortisol I know there's a connection between cortisol and fat storage particularly belly fat And so I'm curious if you can speak to that at all and then also Is there a connection between? Hormonal birth control and insulin resistance and there's a very particular example I'd like you to speak to which is a friend of mine Was just told by her doctor that she is pre-diabetic Even though she works out and generally lives a healthy lifestyle Could hormonal contraceptives contribute to that? Okay Well in terms of the obesity thing it depends on the progestin because what you see is that with the androgenic forms There does seem to be a bit of weight gain and in rats that I've tested myself giving them 11 or gestural is a They put on 30% more body weight and giving them only ethanol estradiol. They lost 30% of body weight So there does seem to be a body weight effect, but again, it's to be investigated further The second part about insulin resistance So This is a little bit outside of my domain First of all, but second of all, I do think there is an effect on insulin resistance Especially because what you see is that women are typically prescribed women with polycystic ovarian syndrome Which do have disrupted insulin they tend to be prescribed hormonal contraceptives in Combination with metformin and so I can't speak to the mechanisms, but I do know that hormonal contraceptives I think are actually showing to be depending again on the type that you're using in some cases beneficial on insulin resistance Thank you Thanks very much Jesse Yeah, yeah, so I'm so with chronically elevated cortisol levels. Do you see down regulation of cortisol receptors? That has not been tested yet, but that you would expect that you would expect that that is yeah Very interesting question to be honest, you know folks I'm about to start my postdoc and I think some of the questions that I have are these real basic questions where you know Not only cortisol receptors. I want to see our estrogen receptors and progesterone receptors being As you get a reduction in them when you introduce these potent steroid hormones and so The answer is still not there. There's one study that showed that There was reduction in estrogen receptor alpha MR mRNA in the hippocampus with the introduction of leaven or gestural, but that is about it So in postmenopausal women the use of topical e2 Mm-hmm is at least anecdotally and there's some data to support it Associated with improved cognition and improved sleep cycles. Yeah Totally different from birth control situation. I mean estrogen in general is I Mean it seems like a cognitive enhancer at some level, you know, that's why we give it to women a postmenopausal women and so Yeah, I mean There's definitely a case that can be made for why we're observing these potential effects of improved cognition Long-term if you're giving a real potent estrogen and there's also recent literature Documenting a probable cause-and-effect relationship between decreased risk of cognitive impairment age over 60 in the duration of E2 replacement for postmenopausal symptoms And sorry, what direction is the cognition going in? It's improved a decreased risk of cognitive Dysfunction as we age as women age and that's with giving a biodynamic Biogenical topical to avoid the breast cancer or ovarian cancer issues. Yeah Cool. Thank you Thanks very much. Just a round of applause