All right, I'm here to introduce the medical updates talk today, and it's going to be presented by Dr. Joshua Safer. Dr. Safer is the Executive Director of the Mount Sinai Center for Transgender Medicine and Surgery in New York City, and Professor of Medicine at the Icahn School of Medicine at Mount Sinai. Mount Sinai has a team of 11 surgeons, 5 endocrinologists, and 20 primary care champions. Dr. Safer sits at the head of this and has organized the transgender program. He was the inaugural president of the U.S. Professional Association for Transgender Health. Dr. Safer has written and published extensively in this area, including co-authoring the Endocrine Society Transgender Medical Care Guidelines Reviews of Transgender Medicine in both the New England Journal of Medicine and the Annals of Internal Medicine. Thank you, Dr. Safer, for being here with us today, and please take it away. All right, oh, and I'm on already, beautiful, thank you. So thank you for the, does this sound good? Are you happy? Okay, perfect. So thank you very much for the kind introduction, for the honor of inviting me to speak to you. I know this is a subject that's a little bit outside the topic of the conference here, but it's an important topic, and so I do appreciate having a little bit of your time to go through it. We have overlap in terms of our patients, of course. So what I, let me just, I have kind of three points, but let me just start to move into some of the slides. So no financial disclosures relevant here, and what I want to do, what I want people to get here is an understanding of gender identity and how, and thinking about it as a biological construct, and I'll go through that in just a little bit more detail in just a moment, and how that can be incongruent with other biology. And then looking through what our typical medical treatment strategy is, so when you have trans patients, what it is that we're doing with them when we're doing anything with them, and then also some of the surgical options that are available to them. I think people think very linearly sometimes in this space, and it's not linear. There's a smorgasbord of things that might make sense given, depending upon the person. So a lot of these talks begin with terminology that doesn't even make any sense, and so I usually ignore terminology or wish I could ignore it, but I'm being forced to talk about it a little bit. And just in the English language, as I was taught anyway, gender was a construct, roughly speaking, and sex referred to biology relating to reproduction. And that's true, but the problem is that doesn't help you when you're thinking about transgender medicine per se, and the words that we're using, because for various reasons, we've or kind of organically used some of the words like transgender and gender identity to refer to things that we medical folks at least think of as biological parts of reproduction, and I'm going to go through that a little bit more. While our social science colleagues are busy using those terms actually a little bit more appropriately to think about gender identity being how you might identify yourself, which is different than your biology. And one other thing I want to reference right now in terms of terminology is gender dysphoria sits in the DSM as a mental health diagnosis, and that in and of itself is a problem because not all people who are trans have any mental health diagnosis, I guess I would say, and incongruence between the biology of your brain and some of the other biology that you might have per se isn't a mental health condition. And it might, you might need mental health support, in fact, many of our patients do, and there might be other mental health concerns, including dysphoria, but frankly, the dysphoria might be more from how society is treating a person than from this incongruence. And so the WHO is already going to change the ICD for version 11, and put gender incongruence into a sexual health chapter, and then the mental health pieces are whatever they would be for the rest of the population, as opposed to suggesting that transgender people have some specific thing that's going to help you. And it's not the main agenda of my talk, because my agenda of my talk is going to be more medical, but I'm happy afterwards to even talk about some of the bugaboos, and I will maybe reference some of the bugaboos of the faulty logic, what ends up happening wrong if you go down the path of thinking of being trans as having a mental health concern. So for the first part of the talk, what I want to do is just go through how we got to where we are in terms of thinking of gender identity as a hardwired biological phenomenon for the relevance of our interventions. And we had the view that it would be environment, or a societal construct, or just a passive response to biology, and we have this shift to thinking of it as biological, and I'm going to walk through a little bit some of the data that got us there. I divide the data into four buckets, and they're kind of listed in the order of the strength of the data from my perspective anyway. So the first is historical attempts to manipulate gender identity really among intersex individuals, and kind of the classic paper that I love, because it's pretty and illustrative, is from about 15 years ago in the New England Journal, a bunch of surgeons out of Johns Hopkins looked at their patients with something called cloacal extrophy, where there's quite a bit of surgery in the GU and GI tracts required, and follow-up visits. And at that time, it was considered, gender identity was considered a passive response to either your environment or your genitals, and so the thought process was if you could rearrange genitals early and get the parents to buy in and raise the child consistently a certain way, they will have the gender identity that you desire. And so the idea then, because of all of these surgeries, was to simply do vaginoplasties in all of the circumstances with these kids, regardless of what gender identity you might have otherwise predicted. And so what these urologists and actually their psychiatrist colleague, their two major authors here, did is they looked at all of their XY chromosome patients who had gone through this process as part of their surgical team, and part of the reason they did it is because junior high age, four of these kids who had had vaginoplasty in infancy, who were being raised as girls in very stereotypical ways, because that was the idea, it was like the Truman Show for anyone old enough to know what that means, and came to them, and they were even getting estrogens as they got to puberty, so they would have a breast development, and they were only going to be told their medical history at age 18. That used to be the program. So four of them said they were boys anyway, and so it got them thinking. And the net of it is that once they started really investigating, all of the kids in their program who knew their medical history said they were actually boys, except there was one kid who refused to talk to them because they were being lied to, and there were four kids who didn't know their medical history, who were still living as girls as when they wrote their New England Journal paper. So very striking. There are not going to be any controlled studies in this space, but it really did set us as a field back in terms of thinking about our ability to manipulate gender identity. So my second category in terms of things that really changed thinking are twin studies, and we get very little data here, just really, this is a look at the case reports that had been published as of around 2011, 2012, of twins where one was transgender. So in a circumstance where the twin was a fraternal twin, none of them were transgender as of the time that they wrote this in the literature. I actually have fraternal twin patients who are both transgender, so it's not absolute, but at least a rareish event similar to other sibling pairs. But notably, when the transgender person had an identical twin, there was a 40% concordance rate with the twin also being transgender. And for, I mean, some of us, we have to take a step back and recognize that identical twins are just really similar and not actually identical. But if we're looking at concordance rates, certainly for me as an endocrinologist, I know that type 1 diabetes has about a 50% concordance rate. I know that PCOS has about a 70% concordance rate, so 40% suggests a really, really tight biological explanation. Going down a little further, the only bucket that gets that mechanism, because what I've just been giving to you was really just association so far, the only bucket that gets at any mechanism at all are data relating to androgen levels in utero. And that kind of fits into two very extreme categories. So for individuals, XX chromosome individuals with virilizing congenital adrenal hyperplasia, if they are surveyed, depends whose survey you believe, but maybe 5% of them will say that they have male gender identity. And this is an important point, is that 95% of them say they have female gender identity. I think there's sometimes some anxiety in some of these, especially among parents and such, that their girl isn't thinking that she's a girl, quote unquote. And most of the time, she is, but some of the time, that individual actually has male gender identity, and 5% is a huge number. That's not how many people with XX chromosomes walking around the general population think they have male gender identity, by contrast. And the other side of it is, in complete androgen insensitivity syndrome, when the androgen receptor does not work, we identify these people with very elevated testosterone levels with no androgen action, who then have all of the testosterone-dependent parts of their anatomy appear what we think of as female. So they are born with very conventional, what we think of as female, external genitalia, and are raised as girls. And in puberty, they have breast development, because testosterone is a major factor in preventing breast development. In the absence of testosterone, if you have sufficient estrogen, you do get breast development, and so they get good breast development. But they come to attention, usually when they can't menstruate, because they don't have a uterus, because that's not actually, that's not based on hormones. The point, though, for what I'm saying right this moment, is that those individuals overwhelmingly, there's a case reported to otherwise, but those individuals overwhelmingly have female gender identity. And it just suggests that there may be at least a group of, and maybe it's almost all of us, who depend on testosterone action on the brain in order to have male gender identity. And if you have none, maybe you can't have male gender identity, don't know. But at least we start to think about mechanisms for some folks. Oh, and the other, my last little one there is attempts to, oh, no, let me just, I made a little cartoon here, even, to give a little more detail here. So basically, this is kind of genes in the brain cartoon, and various interventions. So you could have altered testosterone levels. You could have various other factors. I'm just trying to think about how we might study brain biology at some juncture about gender identity. And this is not specific to trans people. This is just for all of us. It's just that trans people alerted us that there even is this biology that might not have been recognized if it weren't for that circumstance. So there are going to be some independent gender identity spectrum genes and factors, and they might be epigenetic factors. I don't want to be overly simplistic. And then you can then envision that you're going to have other phenomena that are dependent on testosterone that will actually influence this. And there are going to be phenomena that are dependent on other factors. I don't even know what those other factors might be. And then there's going to be factors that where it might be some combination thereof. But if we start to think about it, if we do a bunch of brain scans looking for a trans gene, I don't think we're going to find it. What trans people have done is it kind of alerted us that if we start looking at all of us, we might actually have some gender identity stuff that we could learn about at some juncture. So the last category is attempts to find brain anatomy associations with gender identity. And this is mostly what I show people who are not medical because it's pretty, but it's actually very much association data and doesn't give me a lot from a mechanistic perspective. But these are old studies. These are histology studies from the 1990s out of Mayo Clinic. And essentially, they were trying to find the gay gene, quote unquote. Same thing. I don't think they're going to find that either because how you choose your partner might have a significant biological component. But that's going to be true more universally. It's not going to be, oh, gay versus straight specifically. Anyway, so what they were doing, these are staining hypothalamic nuclei of what they perceived to be a heterosexual man, reportedly, because everybody's a cadaver by the time you enroll in this study. And contrast that with an XX chromosome person who they perceived to be a woman. And the idea was that gay was somehow going to be halfway between male and female or something like that. Some of the biases of the era, the era being like the 1990s, which is not that long ago for some of us. And so by contrast, looking at the staining pattern of a cadaver who was reported to have been a gay man, and you see the staining pattern for the two XY men labeled individuals as identical. And this would have been negative research, but back then, they didn't understand the difference between the biology of knowing who you are and the biology of knowing who your partner or your range of partner preferences might be. And so they brought in somebody who was a transgender woman as part of the gay male crowd. And lo and behold, the staining matches that of the cisgender woman. So they did a whole bunch of controls, and they found a whole bunch of other cadavers, including trans people who had not been treated, had been treated, people who had cancers, where they had hormone-blocking regimens and things like that. And that's how they got themselves actually a Nature paper back then with this. But the bottom line of it was a biological association with gender identity independent of any hormone thing or other chromosomes, et cetera. So it gets me to kind of this model, where it's kind of the more we go, the more we learn and the more sophisticated we get in understanding things. And I have a molecular biology background, among other things, in thyroid, of all things, where I remember moving from the thyroid nuclear receptor as a regulatory, as a point of regulation, to understanding that that thyroid hormone is not passively brought across the cell membrane, which we all used to think and we used to say, and it's in textbooks still. But now there are these old transporter proteins that are apparently regulated. And so we learn about all these levels of regulation. And when we're thinking about biological sex, the same is true. And as you start to really think about it, it actually isn't even illogical. So we think about having the right gametes and having the correct organs to share those gametes and having a desire to share those gametes. And that's about as far as we've gone. But it turns out that's insufficient. You also need to know who your choice of partner is. And you also, for the purposes of this talk, need to know what your role is. And although we medical people are using that same word, gender identity, that the social science people are using for how you identify yourself, I think we're talking more about what your brain sex is in terms of conceptualizing this. And any of these things can be coded in different ways. And the ones that are most visible to us are clearly evident as being somewhat variable. Even if 95% of the time it goes a certain way, there is a certain percent of the time that it does not. And it's not at all necessarily linked. And I almost think it's easier. Maybe I'll have to make another slide with another cartoon to think about it in terms of animals. Because with people, we can overthink this. But if you think of like, I'm thinking of like the cardinal. The red cardinal, it's not sufficient for the red cardinal just to have the sperm. The red cardinal has to actually know what it's supposed to do with that, and know what its role is, and know that it's the red cardinal. And it knows that instinctively. It's not like it looked at its wing and figured it out. And so there's an element of that for us too, even if it's more complex, because we're able to manipulate things to some degree. All right. So with that all said, if this is biology, what do we need to know? And so my next part is to kind of shift. So that's kind of framing kind of where we medical folks are, at least in terms of understanding this. Then, two, what is it that we're actually doing with trans people who come to us and say, hey, I'm a man, I'm a woman, or however they say it. And even it's interesting to me now, because people are recognizing that there's a little bit of a spectrum in all of this, whether it's sexual orientation or gender identity. I just saw in the Wall Street Journal last week some reference for business advertising purposes to the fact that younger people, 10% of them are saying that they're in the LGBTQ spectrum of some sort. And so even if people are recognizing a little breadth of that, it's not that all of them are seeking treatment, necessarily, or that you can even predict the treatments that they're going to seek. So question then is, of trans people who are coming for treatment, or I guess I am, no matter how they label themselves. So my patients, some of them come in and say, I'm non-binary, and I have they pronouns. But then I have to ask the follow-up question is, OK, and I'm an endocrinologist, so you're here for some hormones, I presume. So let's talk about what it is that you're thinking. And often, it's very binary, what they're thinking, independent of what they're labeling themselves. So let's get into some of that. So out there, there has been this tension for the past few decades of this being thought of in a mental health paradigm. And if that's the case, then we were stuck with the circumstance of trans people having to go to a mental health person who would validate their being trans, and then would cast about in a somewhat ad hoc way, trying to find people who would take care of hormones and surgeries, depending upon expertise. And so the trans people were felt insulted, and this is what was called pathologization, and a gatekeeper model, which, I mean, all of medicine is a gatekeeper model, I have to explain to folks. But anyway, and then they came up with the idea as they would be in control of their own destiny, they would sign some document and get whatever it is they want. And they called that informed consent with a capital I. And that was kind of the dynamic. So if we're going to move this into medicine in the way we really practice medicine, then it looks a little bit more like this, which is that patients observe that they're trans, and usually the first person they go to is a primary care provider, whether it's at the pediatrician level, or adolescent medicine, or what have you, and then seek support as necessary, which can be kind of variable. So I have, as an endocrinologist, I see young adults who come for hormones with their gender identity very clear to them, nothing else going on, not having suffered much, enough trauma, at least, to have morbidity, let's just say that, where they're seeking mental health support, and looking simply for hormones. And then alternatively, there are people who need quite a bit of mental health support, but it sits in the model of how we take care of people in general. And for kids under 18, because we don't trust them, because we're still limited to people being trans, having to report it, there's no test, nor is there going to be any test that I'm going to forecast anytime soon, especially if it's heterogeneous and on a spectrum, as people say, then there might be extra pairs of eyes, too, in terms of knowledgeable, adolescent, gender-centered mental health people to help with thinking through, not just what people's gender identity is, but what it is they really want to do about it, because those are two different questions. All right, so, treatment. So let me talk about that treatment just a little bit. So it is still the case that most people who present as trans are beyond puberty. They're later adolescents or they're young adults. And why is this? Well, remember, it's self-report. So they have to have a good sense of what gender identity even is. Then they have to be able to say it in a way that convinces the providers to actually give them any treatment. And then there's also the situation of a lot of people want to conform first. In fact, I think that's typical, right? So people who even understand about themselves are maybe in some degrees of denial or at least trying to hide for some period, too. But the bottom line is they present late. Then the second thing which I popped on quickly is that if we get to the happy space where whatever your gender identity is, you're safe expressing it, you say it, you explore, you talk, you work it through with whoever you work it through with, then it's still gonna be the case that for those folks who are looking for interventions to align the rest of their biology with their brain biology that hormones and surgeries are going to interfere with fertility. And we're still kind of addressing that in an ad hoc fashion. And so I think people need to recognize that. And that may be something that we're gonna have to think through a little bit more. So, oh, and here, so when we're thinking about treatment, this cartoon kind of helps me a little bit, which is, and I'll just read it to you. It says, good Lord, Ethel, you can't appear in public like that. And so that's kind of the good news, right? Because as we age, we all begin to look the same. And so there really isn't as much need to shift anything with regard to the external stuff. But along the way, we have more different bodies. And this is a pair of identical twins from, what is that, a little over 10 years ago, where they're just shy of their 15th birthday. They're both XY by chromosome. And the one on your left is the one who is trans. And she's received puberty blockers as of this point. And all she's demonstrating is kind of a linear, what we think of as a typical female puberty, where with what we think of as a typical male puberty, there, where you have this bolus of testosterone, you have all of these features. And I really want you to look at him, at the non-transgender one, and see the impact of testosterone. Because that is going to, that really influences the strategy of some of our medical treatment. And you can just see the squaring of his mandible. You can imagine soft tissue growth in the larynx there, and his voice dropping. You can see the musculature on the side of his neck there, which is all testosterone-driven. This is a known kid. He was actually a bookworm at this point, and not somebody who was lifting weights in the gym with his head. And so those muscles are really a testosterone thing. The, and then the other way to think about it from an endocrinologist's perspective, is that if you actually look at estradiol levels, to the degree that's a legitimate surrogate for estrogens, they're not that different between adult men and adult women, where testosterone is probably 10-fold greater in adult men. And so that actually ends up being an important point too, is these patients are very focused, sometimes in some of us medical folks, on estrogen versus testosterone, when what we're really doing is we're doing testosterone up and testosterone down. So strategically then, for the young people, actually for anybody, we're trying to avoid permanent characteristics that you wouldn't otherwise want. That's actually partly where puberty blockers, for example, come in, is where I have a kid who's pretty clear about being transgender, but we all think they're a little young to be making decisions. Then we can do this very conservative thing by giving them some puberty blockers for a year or two in order to really think about it before we take action that we think they won't want, but we also don't want to do nothing because if we do nothing, they're going to have development that they are likely not to want. And so it lets us kind of live in the middle for a little while. And so basically, when we say GnRH agonists or puberty blockers, we talk about giving them at TANR 2. TANR 2 is when puberty begins, and that's the floor, because there's no point in giving them before any puberty has begun. But I do want to point out that it is the floor. That is, we do have kids presenting later, and I just want to put out something else there, which is for transgender boys, so female to male, excuse me, for transgender girls, male to female, fertility is an issue. And so if I really put puberty blockers in, and most of these kids really are trans, and then I really bring in sex steroids to match gender identity to follow, they're not going to have major testicular development or spermatogenesis. And so if I want those sperm, maybe I want to wait a little later in puberty before I start my puberty blockers. And just things like that become some of what we need to be thinking about right now. And also, puberty blockers, sex hormones give you bone growth. And so we don't want people on extended periods of puberty blockade. We want to come to a decision at some point and go one way or another with sex steroids. And so we were talking about those sex steroids at earlier ages with those kids whose gender identity is sufficiently well-established. For transgender men at the adult level, I think the only thing to say is androgen supplementation can be lifelong. For the purposes of this talk, I'm going to be completely agnostic about how you give testosterone. I think that's beyond scope for what we're talking about right this second, but that's really all we're doing. And then all the typical end points for testosterone and the monitoring like we would for any other person who requires testosterone therapy. For transgender women, the thing is we're blocking testosterone. And I think conceptually that's the main point I want to be making with these few slides. And we use estrogens as the tool because estradiol feeds back centrally, suppresses testosterone in a beautiful way. And if I'm worried about bone health that where you need some sex steroid, then what better suppressor of one sex steroid than a different sex steroid that's gonna do lovely work with those bones. And the only reason we don't just give transgender women boatloads of estrogens is we worry about clots. And I'm gonna walk through that just a tiny little bit here to see how that although we're worried, we're probably more worried than we need to be. So for transfeminine folks, we give other agents so that we can give lower estrogens. And so if you're looking at your transgender patients, what you're seeing, the transfeminine folks are getting estrogens, and then they're getting adjunct and androgens to help the estrogen a little bit so that they don't have to have quite as much estrogen and have a slightly lower clot risk. And one of those agents is spironolactone. That's the one we use mostly in the United States. It's a big, long safety profile that's gone back about half a century, where frankly, if you develop New York Heart Association class three or four failure as you age, you actually live longer with spironolactone, which is like the best safety profile. There are a couple of other agents out there. The same puberty blockers, GnRH agonist, can just block the entire axis, and then you can add back the hormones you'd like. And that is not a bad concept anyway, and is popular in the UK. And then progestins are used as well, especially in Europe, an agent called cyprotoronacetate. It's got some side effect concerns, and therefore is actually losing favor. But those are kind of the three categories. And so, bottom line, estrogens, feedback centrally, very powerful. They'd be the only agent we were using for transfeminine folks if we weren't so worried about clotting. So let me talk about clotting just a little bit. So not that you should look at all the details of the slide, because you couldn't read it anyway. But if you look at the purple lines on your right, basically what they're demonstrating is they go farther, further, farther, farther to the right. They are, that's just more blood clots. And basically the point of that is that no matter what estrogen product you use, the more of it you use, the more risk of blood clots. There's a second point on this slide, which is no matter what estrogen product you use, if you add a progestin, the blood clots get even worse yet. And then there's one other item here, which is using transdermal estrogens patches versus oral agents, you have fewer blood clots. But nobody has ever actually measured the amount of estrogen that's getting delivered. And so it could be the case that all that's happening is these products are inefficient, and we're only, and really what we think of as a patch, as a different route of administration, is really just a lower dose of an estrogen. And it's all just part of the dose situation. But I wanna say this, this is a, the blood clot risk might be there, but it's modest. This is 700 transgender women on oral estradiol for about two years, where they had one person have a thrombotic event. And so it's hard to do statistics with that. Or at Sinai specifically, we looked at our, many of the surgeons were arguing that our transgender women should not take estrogens in a perioperative period, because that's another thrombogenic period. So we actually, we looked when we did really do that and hold the estrogens in the perioperative period, and with about 500-odd surgeries over 18 months, we had one recorded thrombotic event. But we have a very aggressive DVT protocol at Sinai, like a lot of academic institutions, early ambulation, blood thinners as necessary. And so when we just continued the estrogens right on through and didn't make the patient stop them, which is much more comfortable for the patient, you might imagine, we had no recorded events. And so the manipulation of the estrogen seems to be irrelevant, at least when you're being aggressive with your DVT prophylaxis anyway, and torturing the patient, maybe we should not be doing. So bottom line, well, let me just go through. So spinal actone acts on androgen receptors in addition to lowering testosterone. So for patients of yours who are on these agents, one thing to know is that their benefit from a decreased masculinization perspective is greater than the blood levels would suggest. GnRH agonists, I think I referenced already, they're kind of attractive, very clear mechanism, they're effective. The main concern with them isn't even safety, it's more, and it isn't even cost, it's that they're an injectable agent. And so that might be a barrier for some patients, I guess I would say. The cost issue is relevant in the states where there's still hostility to providing care for trans people, is less of an issue in the states where the atmosphere is friendlier because all of these things, surgeries included, are actually not very expensive in the greater healthcare universe, not compared to heart surgeries and cancer treatment and hepatitis C, et cetera. And so an insurance company doesn't care about costs that much for gender-affirming care for what it's worth, but some of the patients with fewer resources do. All right, so one comment on progestins, because you might hear about patients on that, and I already said that our data are that no matter what estrogen product you use when you add a progestin, people do have more blood clot risk. And there are also some other data for various insundry, other negative things, including some increased virilization, kind of the opposite of what people want, increased prolactin levels. There's a small association with meningiomas with the Cyproterone they're using in Europe. And for postmenopausal cisgender women, to the degree that it's a useful comparator, if those women have had a hysterectomy and take only estrogen with not a combination product, they have less heart disease and less breast cancer than the postmenopausal cis women who take nothing. So back, I don't know, those of you who are old enough may remember that we used to think that postmenopausal estrogen was the best thing ever, and then we decided it was a hazard. But the real data are that it's kind of neutral for when you do the combo product, at least in early menopause, and it's actually beneficial like we used to think if you do estrogen alone. And part of my point in saying, and so we're probably torturing our postmenopausal cis women more than we need to, but I also, if some of this is all about how anxious I am about clot risk with estrogens with trans women, I'm not very anxious. That's what the summary of all of these slides is. All right, I said, I would say surgical options, that isn't a big chunk of the talk. That's like a slide, just to go through this quickly. And basically, for the transgender guys, there are three things, and I think the main point to know is this. Chest reconstruction surgery is super popular, at least among people who are already getting hormones. That is, when I look at the people who come to me for hormones, more than 90% of them are getting chest surgeries. It's a clean, straightforward surgery, works pretty well. Genital surgeries, phalloplasty, metoidioplasty, those reconstruction surgeries, much less popular. They're not as well-established. I think it's beyond scope for me to go into the nitty-gritty of that, but I'm happy to share. But the bottom line is it's true, the patients know it, and under 10% of the patients who come to see me for hormones are looking for those surgeries. It's the same bugaboos that were true for the kids with the intersex situation, which is why vaginoplasties were being done and not phalloplasties. And then on the other side of things, same thing, just really a couple of points for the transgender women, and that is this. Vaginoplasty, by contrast to phalloplasty, is a pretty good surgery. If you've got a good surgeon who knows what they're doing, you're basically preserving all those tissues, rearranging and making the penis inside out, if I'm gonna say it in the most simplistic sort of way, preserving, taking the glands and making it into the clitoris, and basically preserving sexual function and getting good appearance. And so those are considered relatively successful surgeries and they're pretty popular, actually, among transgender women. And the only other point is facial feminization surgeries. Harking back to my comments earlier about the impact of androgen and how these people present after puberty, facial feminization surgery can be more important for a given transgender woman than even vaginoplasty, especially if she's a little older. She may have, you know, what's in her pants is between her and her intimate others, but walking down the street and successfully appearing masculine versus feminine is a huge deal for comfort and for safety too. And that's actually something we need to be working on a little bit because transgender, we look at the surgeries through a cisgender lens, that's what I was gonna say. So people are like, oh yeah, vaginoplasty, in a friendly environment, that should be medically necessary because who would rearrange their genitalia otherwise? But facial feminization in a cisgender world is a cosmetic procedure, but at least once or once in a revision or something like that for a masculinized transgender woman, that can be equally if not more important and we need to kind of think that through and adjust that in terms of how we approach it. All right, so summarizing a few things, I got health concerns with gender affirming therapy are really very modest, that is hypogonadism with a little osteoporosis concern, so we don't want that. And so when I have non-binary people who want to be, I do have to talk through with them that we still want some sex steroid on board for them. And we're avoiding super physiologic hormone levels, specifically with androgens, there's urethrocytosis, that's part of it. Men have higher hematocrits than do women. And we can talk about the relative concerns there if people are interested. And then that thrombosis risk, where I spent a fair amount of time, because I wanted to point out how small it is, actually, even though I do believe that it's there with exogenous hormones. All right, so one last thing in terms of research future thinking. I put up that brain biology thing. And then the other model in my mind, there's quite a bit of focus right now on thinking about the relative harms of hormones and maybe thinking that that's a reason for caution in terms of treating transgender people. And so basically, there's a lot of cross-sectional data with transgender people having more heart disease and having more harms of various sorts. And then saying, oh, to what degree can we attribute that to their hormones? And I think that's kind of a false framing. And really, what we've got is a huge population of people who are being denied care or who are feeling unsafe getting care. And what we're seeing then is various stressors, what we consider to be minority stress or lack of access to care. And if you look at the increased morbidity amongst transgender people, more of it associates with that and is completely accounted for by that. And very little is accounted for with the hormones. So if we're looking at two research topics, we're looking at the disparities research as explaining a lot of what we observe in terms of the morbidity differences for trans people relative to the background population. And we are also kind of interesting to me as an endocrinologist, I'm kind of pushing it, is our interventions for those who are looking for interventions include big hormone changes for folks, which gives us an opportunity to look at hormone action on all sorts of tissues that would generally be true for everybody. It's not really trans-specific. It's not so much looking at harms and trying to find a way not to treat people. It's really taking people where the treatment, the current treatment models actually give us opportunities to explore yet new things and to learn more about all of us because of our awareness of the trans people who are among us. And I think I tried to speak quickly enough to give plenty of time for questions because I understand that being the format. So thank you for your attention. Thank you. I want to thank Dr. Schaefer for giving just a wonderful talk and an overview of this very timely topic. We now have 30 minutes for questions. So we were counting on having a lot of questions. And please line up at the mics and we can start to ask questions, especially clinically relevant questions for those in practice. Thank you. Dr. Schaefer, that was an excellent primer for those of us not in the field. Thank you. Based on your years of experience, are you convinced that there is a biological basis to gender identity? Yeah. So the question is, am I convinced? And I hope I was clear that I'm convinced. And the question really is whether I am convincing with regard to the data we have so far. I got into the field about 15 years or so ago. You heard I had a molecular biology background and a thyroid background, even. And I started to look at this really with some of that lens, because that influences approaches. And so short answer, very much so, which then influences the model of our approach. Yes. So it's our goal, our responsibility to help patients go where they want to be. Yes. It's our... Exactly. And a caution, though, with that statement, which is that I don't want to overly protocolize things because... And especially now with young people who are coming forward and saying that they're on a spectrum, both in terms of sexual orientation and gender identity, where I think as we create a safer and safer environment, people are feeling more comfortable observing that. But that doesn't necessarily mean that the people who are going to be looking for medical intervention is going to change to include that entire group. Thank you. Hi. Thank you for this chat, this talk. And I am acutely aware that we're in a state where the medical board has really denounced gender affirming care for children who want puberty blockade. And so in your practice and in your work, how do you work to educate people on the indications for puberty blockade and the risks and benefits that might be associated with it? And have you been able to change hearts and minds, either in the clinical practice or those who are legislators and create public policy and impact clinical practice? Yeah. Thank you. So I've been trying to educate people with regard to the logic pattern for treatment, including puberty blockers for youth, including both medical folks and our government leaders. And my thought process all along for myself in the field has been to try to think about this in a nonpolitical, relatively, as evidence-based way as I can be. And that, by the way, includes not being necessarily PC in any particular direction so that if data went a different way, maybe we need to listen to those data. So the negative data with progestogens, for example, is something to make us reflect. You heard my little aside comment, not getting too much into detail, about maybe we're putting for trans feminine folks. We don't want to start puberty blockers at 10 or 2, actually, for many of them. So it's not all being aggressive about interventions. But that all said, right, the data for this being biology and this being the logical approach and for those of us who are in the field being open-minded to doing more studies and adjusting the nuance of it as we go in a medical framework. And I think because most of us in the field actually do talk that way, that's why there is pretty wide acceptance in the medical world. That is, endocrine society meetings, we don't debate whether we should provide gender-affirming care. We talk about the subtleties just like I did. And that you can find some endocrinologist who's not connected with the field and bring them out and say nasty things. I can do all sorts of things like that. But that's not really where we are as a medical community. And I feel like the medical community is pretty aligned in that space. The problem I have is with those who think that demonizing vulnerable people is a legitimate political maneuver to get them votes on other issues. And I feel terrible about that. I'm kind of surprised by it, honestly. That is, we medical folks range politics. I don't know. We could poll the room here. But certainly in my lifetime, we can have serious debates among presidential candidates and blah, blah. But this is not that. This is health care. And I don't know. And that's all. I try to keep just having that message. And I look to allies, especially allies in places that are not politically aligned with that, to say the same thing in the AMA, in our own organizations, where it's like, no, this is health care. What are you doing to the political people? And hoping some of them will listen. Yes. Thank you to speaking to that nuance. Thank you. Yeah. Yeah, I know that this topic is, yeah, it is so politicized and so corrupted by politics that it gets difficult to understand. And I know you said that the 5% congenital adrenal hyperplasia that thought they were female is way too high of a percentage. But as an adolescent psychiatrist, that's pretty much the exact proportion I'm getting among 13, 14-year-olds that are presenting. And I think one of the questions I had is, as we're talking about the possibility of social contagion and maybe putting some reasonable barriers in there, often when I'm talking to other clinicians and I say, OK, this patient has just had a sexual assault, has rapid onset gender dysphoria, I'm kind of accused of doing reparative therapy or advocating for reparative therapy about that. So I'm wondering, is there a moderate proposal about what kind of safeguards we need in these 13, 14, 15-year-old natal females? Yeah. And what do we do with some of the fears we know are true and where the extent of them is a little bit less true but could be confounding things? So the rapid onset thing is kind of a hostile phrase, I guess. So I have a... OK. So is there a different way I can say it? It's non-long-standing, non-persistent gender dysphoria? Yeah. Well, we don't have... There isn't a... There's a term for it, and where we might need to go, honestly, is gender dysphoria not necessarily being associated with whether you're trans or not. I'm just thinking in my own head. And the bottom line, though, where you're going, I think, is that we need... This is part of... Because we're dependent on self-report, when we're dealing with adults, that's a pretty safe space. That is, it's vanishingly rare for somebody who does not... Even for a non-mental health person, a non-mental health provider, I mean, it's vanishingly rare for a person who does not have any indication of any mental health concern to come forward as an adult and say, in all seriousness, that I have such and such gender identity, and I want to have this intervention, and not have that really be where they are. One issue, though, is when you go to what you're saying, 13-year-olds, where you're more suspicious of their ability to report both what they're thinking and what they want. And part of the point, then, is that that's why more people in the field who... We want the... We want those kids to be able to go to people in the field to help suss out where they fit in that place. And I guess I wanna say one other thing, which is, to me, part of how we got here is thinking of being trans as a mental health concern, per se, as a mental health morbidity, where if we could parse it out a little better, I think... Because you can be trans and have mental health concerns, and you can have other mental health concerns, and we wanna label that a little separately. We don't wanna accidentally have the kids who you just described, who are not trans, be treated as trans, because people are just throwing anything at it. And at the same time, we don't want to take the trans kids who have fewer of these issues and tell them that they have to have some degree of suffering for us to have an intervention. And so both are wrong. Hi, thank you. Deborah Barnett from Tampa, Florida. Another unhappy Floridian with this atmosphere this last year on this issue. One of the reasons, apparently, that the boards and the Department of Health decided to go the direction that they went, again, one of the reasons purportedly, was that they heard anecdotally from people who had regret, who had gone through some form of gender-affirming care. Scientifically, where does that stand? What's the data on regret? Yeah, so what are the data on regret is the bottom line question there. And the best study right now, everything in gender-affirming care is more modest than we'd like, but the best current study is an ongoing, I don't know whether she's calling it gender dysphoria, by Christina Olson, where she's following kids who came to her as transgender, and that's it, just simply following them. She's not the one who does the medical treatment. And about five years, and she has, I don't even remember what her N is exactly at this juncture, but all are accounted for. And so now she's getting five and 10 year data, and she's seeing teeny tiny numbers, like 1%, not so much regret, but people who are coming off their medication, if they were on medication. So that's about our hardest data, because we're not missing anybody in her cohort. There were older data from Boston Children's Hospital, where they were very conservative. I would argue overly conservative, but again, it was earlier times in terms of their being willing to treat trans kids. And they had a much bigger mental health approach before they got to a medical approach. But bottom line of it is, at least in that very conservative framework, when they put their data together, they had about 160 or so kids who'd gone through their program who they were able to follow something like 10 years later, and identify all of them. And they too had, I think, one or two individuals no longer on treatment. It wasn't even regret. And so it looks like it's a very small thing. Those of us who are doing this clinically seem to anecdotally feel like we're observing the same. I have seen maybe five people, and I used to be a safe person to come to. I might be less safe now that I'm running a transgender program, but I used to just be some random endocrinologist who wasn't very dogmatic, and who was willing even to do things a little under the radar for people who were in a more conservative universe. And I wasn't really pushing people to be anything politically. It was just, what is working for you? So in that environment, I did have about five people come to me who were trying to get off of their hormones or switch their hormone therapy, because they thought I would be safe and I wouldn't be judgmental. But that's all, for what it's worth. And notably, among them, none of them were telling me that they're, well, that's not true. There was one of them who interestingly had kind of a schizophrenic background, and with a long hospitalization even, like a year or two, which sounds long to me as a non-mental health person, who actually said that her gender identity changed. But the other four of them, it was mostly that they couldn't get societal acceptance with their treatments, and were abandoning treatments for that reason, and still didn't want to be judged. So those three different kinds of answers, I hope, to that space. Low, and a big chunk of it, might still be societal acceptance, and not even a gender identity or lack of clarity in terms of what people want to do about it. Thanks very much. Hey, good morning. I'm Kate Reen from Seattle. My question is not about transgender medicine, actually, but since I have an endocrinologist. You touched on it briefly, hormone replacement therapy for postmenopausal women. I've had a handful of patients who've been taken off of it. After several years, they were told, it's not good to be on long-term, we've got to get you off. And now they're depressed and can't think clearly. And I'm just curious what the current guidance is on duration of hormone replacement therapy in menopause. So I don't know if I can give you a guidance answer, but I can give you a data answer. And the data answer is, at a most superficial level, so this is postmenopausal hormones for cis women, which also could be for trans women, actually, at the relevant ages. And the data are this, per the Women's Health Initiative, which is the biggest data run out of Brigham and Women's Hospital in Boston for, I don't know, a decade plus, the women who are on combination product, estrogen and progestins, because you have to be on both if you have a uterus, it was somewhat neutral, their health experience, in young menopause. So 55 to maybe as high as 70. But beyond the age of 70, things like, it's not known actually what the mechanism is, but and so stroke and heart disease and such started to actually appear more in the people getting products than people who didn't get products. And so that's the basis for stopping people early. It's not huge. And so I think there's also a sex bias going on, bluntly, where the same exact risk for prostate cancer is accepted. And we give much more testosterone to older men with prostate cancer. We're much less, we're much more protective of their sexual function. If you take a poll of older male endocrinologists, they'll all be really supportive of that very laid back approach for prostate cancer. So I think that actually is an element of what we're seeing here. For the women who've had hysterectomy, the data are really good. They have less breast cancer and less heart disease from age 55 to 70 than the people who don't take hormones. And they go to neutral from 70 to 80. And so for them, it almost looks like they should be pushed to take hormones. And yet, we're not even doing that. Hi, Charlie Silberstein from Martha's Vineyard. I'd like to tell you about a case that I saw a couple of years ago. And in it is embedded a couple of questions. This was an 18-year-old trans man who I saw once in consultation. And what he described was getting very agitated on testosterone. And so he went on it and off of it. He was agitated, impulsive, perhaps hypomanic. And before I could see him again, he committed suicide. And of course, I've wondered what could have I done differently? I really didn't know what to do with somebody who was on testosterone and had that kind of reaction. So one of my questions is, how common is that reaction? Is that something, a well-known phenomenon of hypomania and impulsivity on testosterone? The other thing I wonder about is this trans man was kind of quiet and restrained. And I had the sense that there was a lot brewing under the surface, as turned out to be true, I suspect. And he was in therapy. And it seemed to me that there was no room for ambivalence in his choice of being a man. And as you said at the beginning, we all are on a spectrum. We all have various feelings. And I think ambivalence must be embedded in all of us in terms of who we are and finding our identity. So I found myself wondering, was there room for him to explore the part of him that might not have wanted this surgery and might not have wanted to be a man who might have wanted to remain female? Anyhow, so my two questions are, how I might have dealt differently with this response to testosterone? And also, what about that ambivalence that I think exists? I liked what you said or a questioner said, that our job is to help people go where they want to go. But the question is, where do they exactly want to go? And what parts of them want to go to different places? Yeah, thank you. Yeah, so your question, there are a couple of key questions in there. So first and simplest, is testosterone associated with impulsivity to the degree that there's a mental health component, I guess, is I'm going to add a little bit to it. And there, I would say no. But is it associated with certain behavior patterns, even though this is not studied? And there's something we should study. When I put that research stuff up at the end, it's not even as a basis for not treating people. It's things we can learn from people who are going to do this treatment anyway. And it is, I mean, I know this as an endocrinologist. I have two anecdotes, but I think they illustrate what my thinking is, at least even though there is no study. One is a, actually, they're both cisgender guys. One is a young cisgender guy, hypogonadal for various reasons, came for hormones when he hit college, was only about five feet tall, also connected to his hormone status, was attending college in the area, got on testosterone. The very first day he got on testosterone at the height of five feet, he got into a fight at a bar. And the second is another hypogonadal guy who we used to not be able to find in the waiting room when he first started seeing me, because he would be in the back asleep, having showed up too early for his appointment or something like that. And once he got on his testosterone, he would come, if we were 10 minutes behind schedule, he would be coming up to the registration window and just asking how late the doctor was going to be. And so there's clearly something there, but I don't have data in that space. In terms of the mental health thing, I think this is part of the reason why I want to really separate the idea of being trans with mental health morbidity per se, because the people then might make the mistake with your patient of thinking that giving him that testosterone would somehow help with some of the other mental health morbidity, which more conventional mental health approach is independent of the hormones. And I've certainly seen kids where they need to work on that piece first before we start with the hormones, because they are going to have a little bit of an emotional effect on them. And I want them to be in a stable place with the rest of themselves before we start layering in hormones. And I kind of have a third thing in that space, which is I definitely see, and I'm sure familiar to you, but rarer to me, where people are so depressed that when it begins to lift, that's when they take action, because they kind of unmask their ability to take action before they unmask their desire to take action. And so I definitely have seen that with trans people, where they're low, and we start them on hormones, and we weren't attributing anything, and we weren't making a depression diagnosis necessarily, and we start them on their hormones, and they make a suicidal gesture. And I've had several calls from hospitalized patients terrified that their hormones are now going to be discontinued, because they're going to be blamed. The parents are blaming it, et cetera. And they're like, no, that was the only thing going right, and they're already, you know. But it was just an element of what I guess is clearer probably to the folks in the room than to me even. So those are my three thoughts. Thanks so much. Hi, I'm Liz McCord from Emory University in Atlanta. This is piggybacking on the regret question. So I recently came upon a news article of an 18-year-old individual who was born biologically female, who wanted to change genders, and had a chest reconstruction at 15, and went through with the surgery, and is now regretting that choice, and is suing the institution and the surgeons to perform the surgeries. And so my question really is kind of two-part. Is their fault in that situation? And also, when we are advocating for minors who are going through these really life-altering decisions, how do we not only protect them, but also protect ourselves? Yeah, so another regret question, and protecting the kids and ourselves. So in terms of protecting them, because I'm more focused on protecting them, actually, it's all biology, so just a little terminology thing, the way I'm thinking, right? It's brain biology, too. So it wasn't biologically female, per se, right? It was an XX. I use slightly different words for the parts that you are connecting with the biology, but the other parts that are also biology. And this particular person, we're dealing with kids at ages where there is some lack of clarity for some about what they want to do. But on the other hand, we want to be respectful. And we can't be perfect. And so there's a bit of a hierarchy in terms of how invasive we go. And so that's the reason why there are puberty blockers. It's kind of funny to me that puberty blockers are the thing that are under attack in some places, because puberty blockers fit exactly in that space, where you don't want to do the disservice to the kid of not doing anything and letting them develop characteristics they don't want, when 99% of the time, they really are trans, and they really do want these treatments. But you're nervous about the 1% chance that they don't really know what they want. And that's what puberty blockers do. It gives us a little more time to think about that. It's the conservative maneuver, honestly. And it's what we should be promoting when kids are at that stage where we're a little bit more nervous. And then we move on. And hormones move in slow motion. And there are some things that are of greater consequence and some things that are of lesser consequence. And even chest surgery, the reason why we do chest surgeries, maybe even in late high school, for kids who are very well-established and clear appearing in their gender identity, is because it's not likely that they're going to regret it. But if they do, we'll at least have a plastic surgery option. And I'm not suggesting that's what we would want, but it's there. And for genital reconstruction surgeries, by contrast, we move it a little further. We say, OK, you have to be 18 for this. We just need you to mature more. And we create these somewhat artificial lines to get a little more maturity, a little more maturity with the more invasive things, knowing, again, the whole while and being mindful of the fact that 99% of the kids who are coming to us, or the people in general, are going to want these treatments. And so we don't want to torture them forever by not doing the treatment. And that's it. It's just that basis. And if you're thinking about regret, yeah. I mean, I read all the same papers I've had a handful of people come to me. I referenced already. I want a safe space for them. The transgender program should be where those people go, because we know how to do the hormones, and we could go the other way with it. And I don't want them to turn into political arms themselves where it's unsafe for somebody who's having that. On the other hand, I don't want the people who are having those experiences to be some sort of wedge to deny care to everybody else. And the rates of regret, it's funny, because I live with plastic surgeons among my team. And in plastic surgery, the rate of regret for anything is way, way, way, way more than 1%, no matter what you do. And even people who do a hip or a knee replacement, it's way more. Go talk to your orthopedic surgeon. They're like, oh, that was not worth it. And so actually, even then, it's a lowish thing. It's just that as an endocrinologist, I want perfection, because I deal with people a little long time with our interventions. And so we want to strive for it. And I don't want to stop striving for it, but I do want to be mindful of where it sits. I think we have time for two more questions, and then people can speak privately. So why don't we do one, two, and then we will stop. And I'm happy to not run out of here, either, if people want stuff that they want to say more on the down low. Thanks. I'm Jen Creeden. I'm at LSU New Orleans. And I am child and adolescent in addiction psychiatry and have the privilege of being the psychiatrist for our adolescent gender clinic. So I was very grateful for your talk today, and it was great. In Louisiana. Tell me your last name again. Creeden. Oh, Creeden. I know your last name. I met your husband this morning while I'm swimming. So in Louisiana, we're in this weird limbo where we've been protected from some of the more insane restrictions because we have a Democratic governor right now, and that's unlikely to be the case next time around. And so within our small but mighty clinic, we're already kind of in discussion of what do we do when these inevitable laws come to us and our patient population. And we're already seeing one kid that we were treating who got started on testosterone, which had him, he went from being hospitalized psychiatrically multiple, multiple, multiple times to no psychiatric hospitalizations. His family moved to Texas. And now that his treatment's in limbo, do you have experience or do you know if there's any data of what kind of the outcomes for particularly young people who are stopped from their gender-affirming hormone treatment or blockers because of external forces? Yeah, so do I have data on what happens to kids where they were treated appropriately and then we took their treatment away? I don't. Right, I think we can anticipate terrible to a degree because some of our worst data, the 40% suicide thought process among trans kids is among people getting no acceptance at all. And so good parental support and fighting the fight, I think, is the area where we have the best data in terms of improved mental health independent of what interventions we're able to achieve. And so I'm hoping, you know, that's my one little, that's the one little cushion, I guess. But yeah, I don't have more to answer in that space other than I'm hoping we don't learn too much. I'm hoping that courts consider this attack, can see that it is as irrational as it seems to be. The lawyers tell me you need a rational basis for discrimination. And I'm hoping that even in the most labeled conservative jurisdictions that that understanding of law will at least be predominant, if not a complete. We'll see. Thanks. Let's have our one final question and then we'll have lunch. Carol Weiss from New York. I know we haven't talked much about the non-binary space here, but in our clinic, one of our clinics at Cornell, there was an interesting situation to me in a non-binary situation that I think speaks to the issue of surgery and regret and all of that. This is someone born XX who in late teens, early 20s, as part of a binary path, did have chest surgery and went on testosterone. Goes by pronouns they, them. And after a number of years, also like Charlie's case, went on and off the testosterone, didn't really like the feeling of the testosterone and specifically didn't like the feeling of affective blunting, is what they reported. But they also didn't like feeling so emotional as an XX. So after a period of time, they came to the realization that what they don't like is the hormonal changes associated with menses. So they were able to, I didn't realize this, but implanting an IUD was able to impact that such that they weren't having the emotional, weren't having menses and the emotional shifts of menses. And now they're feeling very good about where they are. So though it is a non-binary case, it is kind of an interesting example of fluidity as opposed to regret, if you will. Right. And I guess I would say a couple of things in that space. So changing thought and not wanting the treatment, but is from an endocrinologist's perspective, on the continuum of what we consider conventionally male to conventionally female, I don't have a really good health reason why you need to be in one place versus another versus anywhere in the middle. The only health comment I can make is I don't want you to have no sex hormones. Sex hormones have a little bit of a binary character to them. And so that's kind of what I'm advising patients. I'm like, look, if I give you testosterone, you're going to have to be OK with getting some facial hair because that might be what happens to you. And if you're not going to be OK with that, then maybe let's pause for a moment and think that through. But if you're OK with that, but then you come back and you're like, eh, I don't need so much, whatever it is, I don't mind backing you off. It's a reason for somebody who's more in that space not to rush to more permanent things like surgical interventions. And it does point out, and the other thing, too, I don't talk about non-binary specifically because from a medical perspective, I'm customizing to the person anyway independent of how they label themselves. And I had plenty of people come to me some years ago with very binary labels and say, I am a transgender woman, but I only want low-dose stuff, or I am a transgender man. Same. And so I haven't really changed my treatments a whole heck of a lot, even though half of my kids come to me now and they tell me they're non-binary and they're using they pronouns. And it means I just have to ask the next question, which is, OK, and what are you looking for? And then most of them are still looking for pretty binary interventions. But you heard my parameters in terms of what's a safety issue and what's not a safety issue. I don't have to pigeonhole them and force them to go down a certain specific path. I have a non-binary person who had an ophorectomy because they're BRCA positive, and they were doing that as a prophylactic move, and they're non-binary and we're not going to use ovaries for fertility anyway. But then they were having difficulty getting on estrogen because the assumption in the trans framework was you must be transmasculine. Why did you take your ovaries out when you already had estrogen? You must want testosterone. And it wasn't quite that. You need to think a little bit in a more customized way to what's really going on with that person's biology and risk patterns for other disease. What an enlightening presentation. Thank you both, Lisa and Dr. Safer. It was wonderful. Thank you.

transgender healthcare

gender identity

comprehensive care

hormone therapy

surgical options

gender affirming surgeries

health concerns

regret rates

restrictive laws

Dr. Joshua Safer

Mount Sinai Center