Hello, everyone. Good afternoon from my place in Dallas, Texas, and then good morning, good evening and good night, you know, wherever you are tuning in. Welcome to the Endocrine Society webinar. And this today's topic is the cardiometabolic impact of the gender reassignment surgery, gender affirming hormone therapy in transgender adult. These are my disclosures. I have no financial conflict of interest. And then I did some study with the farmer or the DOD grant. And then I also run some of the VA grant. And then none of them are related to the, you know, this topic. And then today's topic is I will start my topic with the sexual dimorphism and also overall cardiovascular mortality and morbidity and the thromboembolism and then metabolic impact. And then the subgroup subtitle will be the weight gain and adipose tissue distribution and diabetes and insulin resistant blood pressure issue, dyslipidemia. And also I will end my talk with the food for thought. So let me start my topic with the what is a, you know, gender affirming hormone therapy in the transgender care? What are the level of evidence? The level of evidence, it's not very strong because I, you know, another part of my interest is also the research interest is the lipid. You know, whenever I was asked about my colleagues, so what is the most challenging as a provider for the transgender care? And then my answer is one of the most challenging, you know, area for me is lack of the strong evidence-based research. So, you know, I have a transgender clinic at the endocrine clinic at the VA, and also I have a lipid clinic as well. So whenever there is a patient with a statin tolerance or patient who doesn't want to take the statin, who has a misconception about the statin, I can counter these misconceptions with tons of evidence, tons of, you know, a strong level three and level one, the evidence, very strong evidence. But when it comes to the transgender, when the patient doesn't want to take this medicine or when the patient come up with some of the treatment idea, I'm not well equipped to answer the question or the, you know, to satisfy the needs, but, you know, with the evidence-based approach. So most of the transgender medicine we use are off-label use, and they are not, you know, originally approved by the FDA as a transgender hormone therapy. They are almost always studied for the cisgender population. And then the level of evidence is not very strong. Most of them are retrospective data, self-reported data from the population-based survey, and a lot of them are expert opinion as well. And then another problem is a lot of the sample size are small. Until recently, we have a large database, which I'm going to discuss, you know, at the later part of my talk. And then even with the, you know, large database, treatment is a little bit heterogeneous, and then the different type of, you know, estrogen, different type of testosterone, and it depends on the area you practice, and you know, may have a different, you know, cocktail of the hormone therapy. The level of evidence is still evolving, but the science cannot catch up with the need, clinical need of the patient. Let me start my talk with the secular dimorphism. Circulating sex hormones exert a unique effect on the metabolism. The response to the sex hormone testosterone and estrogen mainly vary according to the, you know, sex. Here, sex means native sex or native sex. And there's a fat distribution of the secular dimorphism as well. Woman has a higher fat proportion than the man, 20 to 30%, 25 to 30% of the body fat in the woman compared to the 10 to 20% in the man. Visceral adipose tissue is much higher in the man than the woman. That's why they call that android type. And the visceral adipose tissue compared to the subcutaneous adipose tissue as being strongly associated with the insulin-resistant chronic inflammation, and it can lead to the increase in cardiovascular risk. This diagram tells you that in cisgender, androgen level is negatively correlated to the visceral fat. Why this relationship reverse in the cisgender woman. And then testosterone level in the man with androgen deficiency here, and then the testosterone level in the woman with the PCOS, all the androgen excess overlap here. This area they quite as a metabolic value of that. And this testosterone area somewhere around less than 300 to 100 range. It is low for the cis man. It is high for the cis woman. But in this range, there's increase in the abdominal adiposity, obesity, and the metabolic dysfunction and the diabetes risk. Finally, it can lead to the cardiovascular death and the premature mortality. That's why it is appropriately called a metabolic value of death for this area. Cardiovascular disease occurred 10 years earlier in man than the woman. It is attributed to the high blood pressure, estrogenic lipid profile, insulin resistant, and then increased in the visceral adipose tissue. Estrogen has a favorable effect in the woman. Here is a cisgender woman on the insulin sensitivity by the adipose tissue metabolism, body composition. After the menopause, there's a gradual decline in estrogen value and also increase in adiposity and metabolic syndrome. It can lead the woman to the equivalent risk of the cardiovascular disease and metabolic diseases like hypertension, diabetes, high blood pressure as a man after the menopause. PCOS is associated with insulin resistant and metabolic syndrome. Antiandrogen therapy improves the insulin sensitivity in the PCOS patient. How about in the man? Cisgender male with the hypogonadism because of the low androgen from the androgen deprivation therapy or the age-related decline in androgen has been associated with the central obesity and insulin resistant. Patient with a prostate cancer after getting the androgen deprivation therapy has a higher risk of obesity, type 2 diabetes, dyslipidemia, and the cardiovascular disease. Testosterone replacement therapy in the hypogonadal man improves the insulin sensitivity and the central obesity. It is proven in the study called the T4DM. They give a testosterone replacement in the man to improve the, you know, diabetes progression rate. This study is beautifully done in the Kaiser Permanente in Southern California. Somewhere around 7,600 patients with newly diagnosed prostate cancer. They excluded the advanced prostate cancer who received the other therapies such as radiation, reticuloprostectomy, and chemotherapy within one year after the diagnosis of prostate cancer. And also they also exclude the people who had a patient with an underlying archiectomy or the neoadjuvant androgen deprivation therapy. And the 30% received the androgen deprivation therapy alone. And the patient without the pre-existing cardiovascular disease, androgen deprivation therapy can lead to increased risk of heart failure up to 27%. And with the underlying cardiovascular disease, androgen deprivation therapy can result in arrhythmia and conduction disorder. When they take a look at the stroke and ischemic heart disease, there is no increase in stroke and ischemic heart disease. So that's why low testosterone and also the anti-androgen therapy in the cisgender man has proven to increase the cardiovascular disease and then heart failure risk. This data is done in the mouse model, you know, the archiectomy and the sham operated, you know, mouse. And after the castration, you know, at the age of eight weeks of all these mouse model, and then the castration can reduce, you know, cardiac weight. And they did the stress test for the mouse at rest echo and then pharmacology of stress echo four weeks after the surgery. And then during the stress echo, heart rate reduced, and then they cannot mount enough heart rate and also stroke volume reduced, cardiac index, which is a cardiac output normalized to the body weight also reduced as well. So what does it mean is that this is a, you know, a castration or the androgen deprivation therapy can have a direct detrimental effect on the cardiac function. I'm going to switch my gear to the, you know, transgender hormone therapy. So what is the prevalence of transgender population in the United States? Somewhere around 0.6% of the United States population, 1.4 million adults identify themselves as a transgender. This number has been gradually growing over the years because of change in the, you know, people perception, and then much more increase in awareness and acceptance. The number of the transgender seeking the hormone therapy also increasing, and 80% of the transgender population have either the, they have used a gender affirming hormone therapy, which I use as a GAHT, or they plan to take it in the near future. One of the studies said the majority of, I believe that's a European study that, you know, at least, you know, within three to four years timeframe, almost all the transgender has, you know, received the hormone therapy. Of course, it depends on the way you practice, what's your insurance plan as well. What about the cardiometabolic impact of the sex hormone? Sex hormone has proven to have a significant cardiometabolic impact in the cisgender population already. Years after menopause among the cisgender female, cardiovascular risk increased with the estrogen level, you know, gradually declined. And the female with the history of earlier menopause has a higher cardiovascular risk than those female with the regular menopause. According to WHI data, a woman's health initiative data, conjugated equine estrogen and metoxyprogesterone acetate in elderly women can result in higher MI and stroke risk. Higher testosterone in women with the PCOS already associated with the, you know, cardiovascular risk, such as hypertension, obesity, insulin resistant, dyslipidemia. And again, I already mentioned in the previous slides, low testosterone in hypogonadal men associated with the higher cardiovascular risk as well. How about the cardiovascular event in the transgender? Earlier study increased in the cardiovascular mortality and morbidity among the transfemme. They attributed to the use of the ethanol estradiol, which is a much more thrombogenic, you know, estrogen formula. It no longer used in, since in the early 2000. And now we have a much more larger data cohort, much more bigger data population-based registry compared with the general population, cisgender population. We have more information, but the data is still not uniform and consistent. And data cannot solidly point out to the gender affirming hormone therapy attributed to the cardiovascular event in the transgender population. This data is from the, you know, Amsterdam cohort. It's a retrospective data from the 1972 to 2018 mortality trend over five decades of gender affirming hormone therapy. They have a significant number of dead in the, you know, population, much more significantly higher to a patient in transfemme and the 44 patient in transfemme. Compared to the general population, transfemme has the highest mortality, two-fold higher than the general population. Transfemme is similar to the cis-femme, but higher than the cis-femme. And then they noticed that, you know, high mortality is much more high in the last decade. Of course, the patient are getting older than the earlier decade. They break down the cause of mortality. So all the mortality causes are the lung cancer, HIV, suicide, and cardiovascular diseases. And then HIV suicide happened in the first decades of the, you know, gender affirming therapy. This is a breakdown of the, you know, cause of mortality. You can clearly see the highest mortality in the transfemme. And then even though you can see here in the breakdown cardiovascular disease as a statistically and numerically increase in the risk among the transfemme compared to the general population, the author, you know, attributed that it is not from the gender affirming therapy because there's other causes of high mortality are the external causes or the suicide, depression, or maybe HIV-related diseases. And then most of these HIV-related diseases and suicide occur in the first decades. And then because HIV treatment improved over the years, people do not die with HIV any longer. And also the awareness of the, you know, gender of transgender medicine has been improved. So the suicide prevention might be getting better. Another here is that there's no difference in the smoking status. So compared to the general Dutch population, they have a almost like 40% smoking prevalence among the Dutch population. What about the data from the UK GP data? This data is retrieved from the UK GP database. And one of the, you know, weakness of the study is 90% population are white. And the study is done from the 1988 to 2019. They retrieved the data from the diagnosis code, but there is no confirmation of the, you know, use of the hormone therapy. And they got the data from the death certificate. Transgender population has a higher mortality, 5 to 19 times than the cisgender population. Majority of the causes of the mortality are attributed as external cause. Here you can see the suicide, accidental poisoning. And then, interesting enough that here, they also document it as one of the causes, endocrine disorder. So I'm not quite sure how they, you know, these are breakdown for the endocrine disorder. Maybe all these physician or the provider who are filling out these because the transgender, they include as endocrine disorder. It is not quite clear what kind of endocrine disorder is. It is not unusual to have a poor documentation of the cost of debt or the medical record among the marginalized or underprivileged population. And there is no increase in the debt in the cardiovascular disease. And again, in this data, the trans female has a higher mortality than the cis male and cis female. It is also interesting to see the lower cancer mortality among the trans female. Trans female has a much less cancer mortality than the cis female, but the same as a cis male. And the cis male has a same cancer mortality than the cis gender. The number of the cancer they noted are, a lot of them are GI cancer and lung cancer. This is a United States data. This is a Kaiser Permanente, which is a HMO system in healthcare system. Very large, one of the largest HMO system in America for the audience who are not familiar with the American healthcare system. They have a well-documented medical record and they are very heavily present in the California. There's a three HMO center, Southern California, Northern California, and then Georgia as a Kaiser Permanente data. They have a 2,800 trans female and then somewhere around 2,100 trans male. And the majority of them, 60 to 70% are between the age 18 and 45. The mean follow-up is a four to 3.6 years, respectively. They match to the cis gender population from the medical record, somewhere around 4,800. They noticed clearly the higher rate of MI among the trans female compared to the cis female, but the MI rate is similar to the cis male. So it's questioned that it is not purely from the gender affirming therapy and that it might be because of these trans female, despite of endogen deprivation therapy and the estrogen hormone therapy. You know, they still have inherent risk of, you know, cardiovascular death and MI because they are exposed to the higher testosterone, you know, throughout the life until they got into transition. This is a Danish cohort, you know, 2,600 transgender. They use the ICD-10 code and then legal sex change, you know, paperwork. And then they got the cardiovascular disease from the diagnosis code. And then the first time they got the cardiovascular medication prescription related to cardiovascular disease, somewhere around 2000 to 2018. And then trans male here, they use a term called the sign female at birth, median age is 22 years. And the 1,200 patient and the trans female, the term they use is assigned male at birth, median age is 26, relatively, you know, younger than the American cohort. And then the 26,000 age match population, follow-up is pretty good, somewhere around four to six years. And cardiovascular disease has been noted increase in both trans male and trans female compared to the cisgender. But here it's different from the, you know, strong cohort is trans male has the highest cardiovascular risk compared to the cis male. And then hazard ratio is 2.2%. How about the ischemic stroke? You know, trans female has a high incident of ischemic stroke compared to the cis male and the cis female. The stroke incident is significantly higher, you can see, compared to the reference male, which is a cis male, compared to the reference female, which is a cis female. This data is from the Swedish National Healthcare Registry. Interested to see that the cardiovascular incident in this registry are relatively low. We have overall number of 18, mostly is a conduction disorder, mostly atrial fibrillation. Trans male has a 3.7%, 3.7,000 person year, trans female has a higher number, 7.1,000 person year. That's why they concluded that cardiovascular disease risk is highest in the trans female, 2.4 times higher than the cis female, and the 1.7 times higher than the cis male. But when they take a look at the transgender taking the hormone therapy, not taking the hormone therapy, the risk is similar. So that's why they cannot make any causal relation between the gender affirming hormone therapy and the cardiovascular disease. This data is from the Dutch cohort, and then Amsterdam Transgender Clinic in Netherlands from the 1972 to 2015, have a significant number of the follow-up. Again, you may notice that they are relatively younger population, 20 and 30 years of age, and that they excluded the trans female who started the gender affirming therapy before the 2001. So 2001 is a time, you know, when the ethanol estradiol was noted to have a thromboembolic risk and MI risk, but they tried to replace the ethanol estradiol with the other much more natural estrogen estradiol. But that's why they do not want to have an effect of the ethanol estradiol in the data, but they excluded those trans female who has been started the hormone therapy before the 2001. Even after that, even after such exclusion, trans female has a still higher risk of stroke and then thromboembolic risk compared to the cis male and cis female. And then trans female and both trans male, both transgender has a higher MI risk compared to the cis female. But here, the weakness of this study is they cannot adjust the psychosocial stress, smoking. Again, Danish population, they have a pretty high prevalence of smoking, 40 to 46%. So that's why they could not adjust these population. They believe that cardiovascular event has reduced over the time. It's not that higher anymore because of the people has increased awareness and improvement in the cardiovascular disease treatment modality. So this is a United States survey with the help of the CDC. They sent out the questionnaire for the transgender population, the cross-sectional survey among the transgender. They asked if they had a patient with a stroke and MI, they adjusted the age, diabetes, chronic kidney disease, smoking, hypertension, hyperlipidemia, exercise. MI risk is highest in the trans male and then trans male has a four times higher than the trans female. Trans male has a two times higher than the trans male. Trans female has a two times higher than the trans female. But trans female has not much of difference from the cis male. This data, the weakness of this data is it's a volunteer information and then not everybody they sent out for the survey answered this question. I'm going to shift my gear about the treatment of the estrogen and then the thromboembolic risk of the estrogen. Trans female needs a lifelong estrogen therapy. The aging is a major risk factor for the thromboembolic risk. Estrogen dose in the gender affirming hormone therapy is much higher than the usual HRD dose of the hyperbolic cis female. There's no study comparing the long-term safety and efficacy and effectiveness of the different estrogen formulation. The oral estrogen, 70 beta estradiol has a lower thromboembolic risk compared to the ethanol estradiol, six to 8% risk of the thromboembolics. So that's why it is reserved for the people with the low risk. And the transdermal estrogen patch is suitable for the high-risk patient. And injectable, it's a quick onset. Some of the transgender patient will request to get the injectable, but associated with a cyclical fluctuation, it is believed to have a much more high advanced effect. And then it is also sometimes, you know, it's a little bit tricky to avoid the supraphysiological estradiol level with injection. If you have a patient who has a major surgery or immobilization, and then with the underlying risk of the thromboembolic disease, you have to hold the estrogen during those major surgery. This is a study, these are the study, take a look at the thromboembolic risk. 676 transfemales taking the estrogen-based hormone therapy, only one has the thromboembolic event. The incident of 7.8 event per 10,000 person year. And another study shows that, you know, 1,000 transfemales follow up around five years, again, 1%. So lifetime risk is very low, 1% to 5%. But here, these two studies are mainly coming from the European country, and then the patient are much younger than the United States counterpart. And then here is a Dutch cross-sectional study. As you know, they noticed that 5% of the transfemales has a thromboembolic event. You know, five event occur in the first year, three event occur during the gender affirming surgery. So that's why it is included that most of the thromboembolic event occur in the first year of the gender affirming therapy or initial year of the gender affirming therapy. So they also noted that these patients may have underlying risk factors, such as obesity, smoking, immobilization, and hypercoagulable disorders. This is the data from the United States database. You know, again, this is from the strong database. You know, our database from the United States has a relatively older population compared to the, you know, European counterpart. And also we have a high risk of a higher number, high prevalence of the obesity as well. And two and eight years risk difference event per 1,000 patients. Transfemales has a significantly higher than the cystomates, and, you know, and also the, you know, cystomates as well. A transfemales, there is no conclusive data. So here, if you take a look at the graph, you know, compared with the cyst men, transfemales has a higher number. And then compared with the cyst female, transfemales has the highest number. So transfemales has a higher MI and higher thromboembolic risk in the, at least in the United States database. What about the hemoglobin value? You know, this data is from the transfemales. And then, you know, before and after the hormone therapy, these hemoglobin values shifted closer to the, you know, cyst female after taking the gender affirming therapy. Transmale, again, their hemoglobin value shifted closer to the cyst male after getting the gender affirming therapy. That's why most of the experts suggest that the hematological parameter or lab value of the transgender receiving the gender affirming therapy should be interpreted based on the affirmed gender rather than the sex documented at birth. Still, it is quite, you know, debatable for the, what about the other chemistry? What about other creatinine value? So this is a little bit, you know, tricky area. You know, I cannot cover in this topic, at least, you know, from the hemoglobin, hematocrit value, we should use, you know, the affirmed gender when you interpret the result. You can see here that, you know, after getting the gender affirming therapy, trans female developed anemia relative to cyst male, but the value has become much more similar to the cyst female. Trans male developed erythrocytosis higher than the cyst male. It's interesting to see because they are taking the testosterone, maybe exogenous testosterone caused the erythrocytosis more than the similar level of testosterone than the cyst male. And then here it says 83-4, significantly increased erythrocytosis in the cyst female. What about the coagulation profile? These are the coagulation profile. This part is a trans female, this is a trans male. And the green lines are the anti-coagulation changes. These are the coagulation factors here, factor two, factor nine, factor 10, and all these are protein C, protein S. These red are the pro-coagulant changes. The trans female, they become more pro-coagulant profile. It's influenced by the route of administration, oral versus transgender and age. On the trans male, there's no significantly pro-coagulant, but influenced mainly by the age only. There's a small difference between the route of administration compared to the transdermal versus intramuscular injection. So the take-home message from this slide is trans female has a much more higher coagulation profile, and then their high coagulation profiles are much more influenced by the age and then route of administration. Oral has a much more high risk than the transdermal. Older age has a much more high risk than the younger age. Estrogen therapy, we have been using estrogen for many years. Before the 2000, early 2000, the main estrogen used in the United States was a conjugated equine estradiol. But in Europe, they use the ethanol estradiol was most frequently prescribed. WHI data show the excessive stroke in the compared... These data are from the cis female. Because of that, they move the use of the ethanol estradiol has been moved to as a much more estradiol, 17 beta estradiol. And also if the patient is an older high risk patient, they are using more of a gel or the patch. So transdermal estrogen has been known for the less risk of MI, stroke and then venous thromboembolism compared to oral, because of course we use that data from the WHI data from the cisgender female. Oral estrogen can raise the triglyceride and also can cause a reactive oxygenation free radical compared to the transdermal estrogen. That's the endocrine society recommended to adjust the estradiol E2 level, not to exceed the 2,000 picograms per mil. The blue pad suggested that titrating the hormone level to achieve the E2 level in the pre menopausal cis female range, but it should be below the supraphysiological level. And then keeping the testosterone level below the upper limit of the cis, you know, you know, female range as well. But here is a question is, yes, if your transgender population is, you know, a younger population, premenopausal hormone level will be appropriate. What is the appropriate level of hormone estrogen level for the trans female who are 60, 70? And a lot of the transgender population are getting older. Are we supposed to give the same level of hormone therapy or will they have a different, you know, side effect once they get older? You know, here you already saw in the slides that the age is a major risk factor for the thromboembolism and MI. So with the aging transgender population, we still need to do more research. So who are high risk for the thromboembolism? Patient with the personal history of thromboembolic diseases, hereditary thrombophilia and strong family history of thromboembolic disease, they should get the proper evaluation of the coagulation disorder before the start of the gender affirming hormone therapy. These are the known risk factors, smoking, older age, age is like 35. So most of the transgender here, they start the hormone therapies between the 20 and 30. And then postpartum period, major surgery with a prolonged immobilization, you know, inflammatory bowel disease, IBD, inflammatory bowel disease, SLE with the antiphospholipid antibody. If the patient has a modifiable risk factor such as obesity, sedentary lifestyle, smoking, we should encourage to adjust or correct these risk factors as much as possible. If the patient's at risk, if you feed the patient at risk, we encourage to use a transdermal estrogen. And sometime, you know, if the patient has a known disease of the thromboembolic disease already, you should consider giving the anticoagulation. Depend on the bleeding risk factor, you can start with, you know, aspirin or some low molecular heparin. Here, I want to change my gear a little bit, you know, talk about the breast development. Most of the reason a lot of the transgender patient, they want to get on the higher dose of the estrogen or the intramuscular estrogen therapy, mainly because they have expectation for the breast development. This breast development is investigated in the 300 and somewhere around 30 transgender women. Very young, average age is 28 years, and after one year of gender affirming therapy, the treatment is oral estrogen, estrogen patch, and estrogen gel, but combined with the, you know, ciproterol acetate or spironolactone. So in European transgender hormone therapy, they use heavily of the ciproterol acetate, which I'm going to discuss a different, you know, result of these affirming therapy. In United States, we use more of the spironolactone, because spironolactone has more data, and plus it's easily available in the United States as well. So transgender estradiol was used in the older woman because of the risk of the autoimmune, the cutoff is 40, because of the risk of the thromboembolic. And then they measure these, you know, breast development per centimeter, and then chest and the breast different size, but they do see some difference in the somewhere around eight centimeters after one year, or somewhere around four centimeters. They do have some modest, you know, breast size changes. Most of the changes occur in the first six months of the therapy, and then majority of the changes, somewhere around 50 percent are the, you know, small size. So a lot of the patients are not, you know, happy with their breast development, and then they ended up requesting the gender affirming therapy. They try to correlate the breast size and estrogen level, and the route of administration, age, weight, because of the, you know, change in weight can influence a breast development, and the smoking. You know, they did not see any significant, you know, correlation. You see that. The two-third of the trans female in this study group proceed to the breast augmentation surgery. If you have a transgender patient who is pushing you or requesting you to give you higher dose of estrogen, you know, for the sake of breast development, you can assure them from this data that, you know, estradiol level does not directly correlate with the breast development. How about the weight and adipose tissue changes? There's major concern for the transgender population is weight and adipose tissue changes, and the data is still, you know, not well set, but they do agree on one thing is that they do weight gain on the transgender population. Depending on the data, you know, somewhere around 1.3 kilo to somewhere around, you know, 4 kilogram change in weight, and then they cannot attribute to the gender affirming hormone therapy directly for the weight. Some of them are age, some of them are lifestyle, diet, exercise, which is hard to tease out from these retrospective analysis data or the, you know, population-based data. So compared to, you know, general population in the United States, obesity rate is similar in the trans male, in the trans male and the general population, but much lower in the trans female. It is not surprising, they notice this kind of, you know, intentional weight loss in the trans female in the adolescent population because of the preoccupied, you know, body weight image, and then they want to look like a, you know, skinny woman, so they actively try to lose weight in the trans female population. This data is from the, you know, United States, Washington area, and they follow up, you know, over a few years for the weight changes. Significant change in weight noticed in the trans male within the few months of the initiation of the hormone therapy. In the trans female, it takes longer, almost two years. The trans male has a much more quicker weight gain than the trans female, and of course, this data, they cannot exclude the, you know, lifestyle modification, exercise, and diet, and the more than five kilogram weight gain is after 21 months, it's much more higher in the trans male. Obesity rate is significantly increased, 50 percent of the trans male and 30 percent of the trans female. Baseline weight has American transgender population is much higher than the European counterpart. From the strong database, up to 70 percent of the, to 80 percent of the population, this transgender cohort and strong database has been overweight or obese. This is data from the, you know, cross-sectional case control data, Melbourne, Australia, smaller database, and the one year of hormone therapy, 40-41 transgender population, duration somewhere around two, three, four years of the hormone therapy, and the trans female compared to the cis male, the lean body mass reduced, fat mass increased, and android and gynoid ratio reduced, and also it leads into the increase in insulin resistance. Trans male lean body mass increase, significant increase, somewhere around eight kilogram, and then despite of, you know, android fat, which is insulin resistant, so there's an android and gynoid ratio increase, but there is no increase in the, you know, insulin resistance. This is a, you know, HOMA-IR, they take a look at the insulin resistance from the same data, HOMA-IR correlate with the android and then gynoid fat mass in both male and trans male and trans female. Android fat has a much more strongly correlate with the, you know, gynoid fat, you know, to come close to the insulin resistance, and the trans female has a reduced lean mass, increase in fat mass, that's why, then they lead to the reduced android and the gynoid, it's most likely because they're reduced in lean mass, it's an increase in insulin resistance compared to the cis male. On the other hand, trans male, they did not show any increase in the insulin resistance, despite android fat mass increase, might be the protective effect of the increase in the lean mass. So this data is from the European Network of the Investigation for the Gender Incongruent, you know, E-N-I-G-I project, it's embedded in the study, one year of the gender affirming hormone therapy, there's a, they take a look at the fat distribution by the, you know, Texas scan, body fat distribution changes before and after Texas, and both group show, you know, reduced in the, you know, visceral adipose tissue changes, and, you know, and then the trans male has a total fat increase, and then trans female, the total fat reduced, but the lean mass trans female has a reduced lean mass, trans male has an increase. So here is, if you take a look at it here, and then, you know, there's no significant change in the visceral adipose tissue fat in both groups. They take a look at the different BMI for these fat changes, and not much of the difference between the different BMI, the same changes, you know, visceral, you know, adipose tissue and total fat, you know, ratio has been the same between the trans man and trans woman, it does not affected by the change in the different BMI as well. So since the data is not quite conclusive, you know, some had a, you know, systemic analysis, and then once you take a look at the 26 study, two cross sectional, 21 perspective, uncontrolled, and then three perspective controlled data, it is concluded that testosterone treatment, increasing lean mass, reducing fat mass, no impact on the insulin resistance. Feminizing gender affirming therapy, increasing fat mass, and then reducing lean mass, feminizing gender affirming therapy, increasing fat mass, and then reducing lean mass, and it might cause a worsening of the insulin resistance. Trans man, not the trans woman, increase in the waist and hip circumference ratio, and then 12 months after the gender affirming therapy. Since, you know, there's a transgender can cause a weight gain and fat distribution changes, can it cause a diabetes and insulin resistant risk? This is also, again, from the behavior risk, you know, survey from the United States, they did not see any increase in the diabetes risk among the transgender compared to the cisgender population. But this study is most of the, you know, question and survey, and patient response survey, you cannot make the final conclusion. The other study showed a different effect of the gender affirming therapy on the weight and body fat, glucose metabolism, insulin resistant, but all these studies did not show that any significant increase in diabetes risk, and after taking the gender affirming therapy. This study is earlier study from the insulin resistant, take a look at insulin resistant and metabolic syndrome by using the eucalyptus insulin clamp. After four months of gender affirming therapy, which is relatively short, and the sample size are very small, you can see, and the sample size are very small, you can see 18 and 13, that's increase in insulin resistant. Another study, they did it, but a little bit, you know, higher number of population, 37, you know, non-obese transgender using the ethanol estradiol separatorome, because of this older study, that's why they use ethanol estradiol, and the testosterone, the follow-up for the longer duration before two months and 12 months, and they take a look at the insulin resistant by using the insulin clamp as well, and the trans-female has a fasting insulin increase, and then reduced glucose utilization, they come up with the, they usually show with the M value, which is a mean glucose infusion rate, you know, it reflect the measure of the whole body insulin sensitivity. So the greater insulin sensitivity is reflective of the high rate of the exogenous glucose required to maintain the target glucose value during the eucalyptus insulin clamp. It concluded that it's a trans-female increase insulin resistant, trans-male no effect on the insulin resistant, and then they take a look at the weight gain, they do have a weight gain and the visceral adipose tissue gain, but there's no association of the insulin sensitivity as well. So conclusion is that they cannot make the final, you know, strong association with the weight gain and visceral adipose tissue fat. They take a look at here for the transgender population from the European Network, you know, Transgender Study Group, and then one year of gender affirming therapy, they give these patient for the OGDT and assess the insulin sensitivity, and then assess the increase in response. So insulin sensitivity and post OGDT increase in response, increase with the muscular hormone therapy and reduce with the feminizing therapy. So estrogen based therapy, hormone therapy can reduce insulin sensitivity. So insulin sensitivity improved in the trans-male, it's parallel with the lean body mass changes increase in response. Here the conclusion is that testosterone based therapy can increase the muscle mass, it might have some influence through the body increase in response as well. So adipose tissue changes and insulin resistant. This is a, you know, I split the, you know, finding of this Dr. Cleaver group into three portion, fat changes, adipose tissue distribution, and then the lipid level. The adipose tissue distribution, the trans-male increase in lean mass and the reduce in HOMA-IR because the increase in lean mass, but there is no association with the fat distribution and body composition of HOMA-IR. Trans-female reduce in lean mass and then increase significant, almost 50% HOMA-IR associated with the total body fat, but not with the visceral adipose tissue. In both groups, visceral adipose tissue and total body fat did not show any association with the lipid level changes or the HOMA-IR. So the lean body mass increase can have impact on the HOMA-IR. The author concluded that these adipose tissue distribution changes may not directly result in the insulin resistant in the transgender population. They concluded it might be the other target organ involvement. It makes sense if you look at the previous data with OGTT and the oral glucose increase in secretion, it might be the part of the reason as well that it is more than the fat distribution. This data is from the Dutch study. And then all these patients who referred for the specialist transgender assigned center, they compare with the age match and then gender match, cisgender book control, one, two, three matching. They sent out the survey questionnaire. The weakness of the study is only 54% response rate. Not everybody responded. All the patient should be on the transgender hormone therapy, average of seven years. And more than half of them had an orchiectomy already. And then almost 90% of the trans-me has a dystrectomy and oophorectomy already. Diabetes prevalence, you know, part thousand person population, both transgender, cis-me and much higher in the cisgender population. 42 in the trans-female and compared to the cis-me and then, you know, cis-female. And then trans-me also higher than the cis-female and the cis-me. This is a strong database from the Kaiser Permanente healthcare system. It's a longitudinal data, but they are much more robust in the diagnosis of diabetes because they have a disease, you know, HEMR. They can take a look at the diagnostic criteria for the diabetes A1C value 6.5 and higher and fasting glucose 126 and the random glucose more than 200 and the patient who are receiving the diabetes medication and also of course with the diagnosis code. So they have much more robust diabetes incidence. The baseline prevalence, and they also take a look at the prevalence as well. Baseline prevalence is somewhere around 6% and then diagnosis of diabetes after the gender affirming therapy increased 18% in the trans-female and the 27% in the trans-female. That's why they take a look at, after the gender affirming therapy, trans-female compared to the cis-gender, there is no difference. But they compare with the trans-female with the hormone therapy, but they do have a higher than the cis-female. Maybe because these trans-female has been exposed to the testosterone or they have been made genetic sex throughout their life. So that's why they have an inherent risk of the diabetes risk compared to the cis-female. Trans-female compared to the cis-male, there is no difference. Trans-male compared to the cis-gender, there's no difference. The final conclusion is that gender affirming therapy cannot be attributed to the, cannot be the direct causation of the diabetes risk in the trans-gender hormone therapy. This is the Amsterdam cohort. So they take a look at the data from the Nationwide Health Registry. Relatively younger population, 30 and 23, pretty good follow-up. And then somewhere around, you know, 11 to five years. Observation year is pretty good as well. And then 90 trans-female and then 32 trans-male develop diabetes. Mean age or onsets are somewhere around 50 age. And then how they come up with the diagnosis incident, diabetes incident is a dispense of the glucose lowering agent, the first time they dispense. There's no difference in diabetes incident when they take a look at it and compared with the trans-gender and gender test population. The weakness of the study is that 90% are the white ethnic group, very homogeneous population. And then the younger age, so they have a lower type two diabetes prevalence compared to the United States population already to begin with. That's why they may not see the significant increase in the risk. Some of the author said that maybe because of the difference in the hormone therapy, compared to the separatorial acetate and luprolide, they take a look at the 50 trans-gender female, five years of the trans-dominant estrogen plus separatorial acetate or the luprolide. Either or, they take a look at the HOMA-IR and the separatorial acetate group has a higher number of insulin resistant. The author explained that separatorial acetate is a progestin with the anti-androgenic activity and lower the gonadotropin hormone, it causes reduced testosterone. At the same time, it also has a competitive binding of the androgen receptor. Another side effect is that these people with the separatorial acetate has increased the waist circumference attributed to the glucocorticoid activity and also it in turn leads into the insulin resistant. So it might be the reason that different hormone therapy might have a different impact. How about the blood pressure? There are trans-gender population has a higher risk of undiagnosed, untreated cardiovascular disease, such as blood pressure, hypertension, hyperlipidemia, compared to the cis-gender population. Blood pressure datas are inconsistent and then both trans-gender has a minimum blood pressure changes after the gender affirming therapy. Blood pressure changes may be statistically significant but small effect in size. And that's why it is questionable that whether these are the clinically significant. This is from the European Network of Investigation of the Gender-Congruent Study. They follow up the patient over the years after the year of gender affirming hormone therapy. And then trans-male has a no change in systolic blood pressure, two, three millimeter increase in diastolic. Trans-female has a little bit drop in systolic blood pressure, three, and then drop in diastolic blood pressure as well. But there is no correlation between the mode of delivery and no correlation between the hormone therapy and also blood pressure changes. This is a United States database from the Washington, D.C. area. And then 200 plus trans-gender patient, mean age is 28 years, almost five years follow-up. No significant change in blood pressure. Trans-female has a four millimeter marguerite reduction of the systolic blood pressure. Trans-male has increased in systolic blood pressure. It might be due to because of the use of the spironolactone which is the antihypertensive agent in the trans-female and also might be effect of the estrogen. And also there is a increase in the blood pressure in the trans-male might be because of the testosterone effect as well. But they know that there's a change in blood pressure very quickly within two to four months of the hormone therapy these such kind of blood pressure changes maintained throughout the follow-up period. Dyslipidemia, how about the dyslipidemia in the trans-gender? Both testosterone and estrogen-based hormone therapy can affect the lipid metabolism but it is difficult to make that conclusion because of the heterogeneous demographic with the underlying variable diseases and the different hormone therapy with the different motor delivery, particularly aura versus the trans-dominant estrogen may have a different effect on the triglyceride. Underlying age may be different, genetic factor, family history, lifestyle, diet also play a role as well. Last but not the least, there's a concomitant use of medication that can have an effect on the lipid level. Aura estrogen increase the triglyceride, different route has a different effect on the lipid level and pre-existing cholesterol disorder can affect the lipid level as well. That's why people who has uncontrolled or the poorly controlled lipid disorder, trans-dominant estrogen is suggested. If you give a testosterone, especially in higher dose, reduce the HDL and as they have a variable effect on the LDL and triglyceride. If you use an extended intramuscular dosing, definitely it can worsen the lipid panel. So those, but the trans-dominant testosterone patch and gel has a more of a lipid neutral. This data, take a look at the different cholesterol value and trans male reduced in HDL. They had a subgroup of the HDL2, HDL3, both of them has reduced, increased in hepatid lipase and also increased in triglyceride and LDL particle size also reduced. Trans female has a totally opposite effect. Both group has a no change in total cholesterol, VLDL3 fatty acid. There's no correlation between the hepatid lipase, lipoprotein lipase activity and then LDL size and body composition with the hormone therapy. This is a European gender congruence network study. So two year study and there's a full European clinic and then they calculate the cardiovascular risk using the Framingham 30 years cardiovascular rate according to the lipid value. You can see the trans female has a favorable lipid profile. This is the LDL value reduced and then this is a triglyceride also reduced and this is not significant. HDL changes are not significant. Total cholesterol also reduced. But the trans male has other opposite effect. Unfavorable lipid profile, LDL increased and total cholesterol increased, HDL reduced. By using these lipid base, lipid value, they calculate the 30 years cardiovascular risk and the cardiovascular risk high in the both trans male and trans female compared to the cisgender. Lipid changes has much more increased cardiovascular risk in the trans male. If you take a look at it here, this is a trans male graph, increased significant. But trans female has on the downward trend, but it's slightly coming down from the baseline 30 years risk, cardiovascular risk, but not statistically significant. The conclusion is that trans male has an unfavorable lipid profile. By using the lipid profile, they calculate the cardiovascular risk, the high risk of cardiovascular risk. They particularly pay attention to the trans male and then all age group has increased and a different age group has increased in the cardiovascular risk. But interesting enough is that the youngest group has a significantly increase in the cardiovascular risk compared to the older group as well. If you take a look at this last line here, this is the confident intervals, it's lowest and then narrowest and then increased. This is another data from the Dr. Claverin group. They take after the one year of gender affirming therapy using the ciprodermal acetate and estrogen and they're using the testosterone. These patients within one year, they're not supposed to get the gender affirming surgery. Again, they see the trans male has increased in LDL and triglyceride reduced in HDL. Trans female has reduced in all these opposite end as well. So the strength of this study is it's a longitudinal study, it's relatively large sample size, 180 and then 160. And the weakness is there is no control. And so, but they believe that these changes are much more than the incidental finding because of these opposite trend of the lipid changes. And then, even though they said is it more than the age-related changes? So they contributed much more of the hormone therapy effect. Testosterone formula, different formula can have a different effect on the lipid panel. So 45 patient and then 15 each arm, injection every 10 days, intramuscular gel every day and on decanoate every six week for the, every 12, six week and the first and then six week and then every 12 week is a long acting. Then here again, they see the similar trend but they do not see any changes in the triglyceride but the less changes with the HDL and the LDL with the transdermal and gel compared to the intramuscular injection. But one interesting finding is after 54 weeks, every subject become a minority. So there's no difference in the onset of the imminoria between the three group. So another take-home message for this, regardless of what type of injection or formula of the testosterone, you use injection or gel or the long acting. After 54 weeks, almost after a year, everybody got into, they become a minority. And then the time become a minority has not much of the changes. The different dose of the estrogen can affect the different level as well. If you take a look at it, black bar is a higher estrogen, six milligram. That's the lowest number of total cholesterol. The HDL changes are not that significant but the lowest number of triglyceride, lowest number LDL. So estrogen definitely has a lipid friendly pattern even with the higher dose. So this data is from the United States data from the Washington DC area and the much more mixed population, only 40% are non-white, 15% lactase. And then the follow-up for the almost six years, a majority of patients are overweight. And you can see that within a short time, two to 10 months of gender affirming therapy, significant lipid changes are noted. All of them has a high triglyceride in both arm. But interesting enough that severe triglycerides only one patient who has a history of alcohol use. No significant change in LDL value, significantly high LDL, which is 160. It's a very rare in both group. But another interesting finding also that they have a very low rate of taking the lipid lowering medication. Maybe because they don't see the doctor regularly or maybe because they don't get attention for lipid changes. This is a trans-female data from that United States database. And as you see that HDL slightly increased, triglyceride not changes. This is a trans-male data, HDL reduced and triglyceride increased. So meta-analysis, since the data is a little bit tricky, they combine all the meta-analysis. Trans-male has a high triglyceride. This is a meta-analysis data. Increase in LDL, reduce in HDL. No change in total cholesterol. Trans-female has not much of the changes, but they have an increase in triglyceride. So increase in triglyceride due to the oral estrogen is much more high than the trans-dominant estrogen. Some of the experts believe that trans-dominant estrogen can even lower the triglyceride value. So this is a trans-man using from the data from the European data. Again, reduce in HDL, increase in LDL, high in triglyceride, but there's not much of a difference between the different formula. And then there's no correlation and lipid changes and hormone level as well. They use at least three form of testosterone gel injection and long-acting testosterone. This is a trans-female using estrogen and subrotron acetate. And all the lipid panel has been reduced. Interesting that there's a slight reduction of the HDL as well. Again, they don't see any correlation between the lipid panel and then hormone level as well. So I give you a lot of data. It can be confusing. So before I finish my talk, I'm going to summarize as much as I could. In cardiovascular risk, transgender is higher compared to the cisgender. MR and stroke are much more high in the trans-female, at least from the strong data. They may not 100% contributed to the gender-affirming hormone therapy. The reasons are not quite clear because these are not mechanistic study. These are more like a population-based study. And venous thromboembolism, trans-female are higher. Most of them they attributed to the estrogen use, especially in the ethanol estradiol, which is used in the past. And then erythrocytosis is much higher in the trans-male and the anemia is more common in the trans-female. And then these effects are because of the level of the testosterone. And weight gains are very common in the transgender population. Body fat distribution cannot attribute to the insulin-resistant directly, even though these transgender has body fat changes, but they cannot directly cause insulin resistance. Increasing lean mass and mass because of the testosterone-based therapy has more of a protective effect as well. And they may be because of other factor play a part, other target organ, liver, and then a gut hormone play a part as well. The diabetes risk possibly increase in trans-female, but the data are not uniform data. Blood pressure slightly increase in both group, but not quite clear for the clinical significance, even though you may have a statistical significance. Dyslipidemia are very common in the transgender. Low HDL with the testosterone. High triglyceride is commonly seen in both trans-male and trans-female. Mind you, triglyceride is not only for the one estrogen-based therapy, it can be from the diet and the underlying genetic factor as well. Testosterone-based therapy can cause atherogenic lipid profile in the trans-male. And injection, especially long-acting supraphysiological dose testosterone can cause atherogenic lipid profile, more common than the trans-dermal. So what are the food for thought? What is the age appropriate hormone level value? What is the optimal level of value? I just mentioned in the beginning of my talk that are we going to continue the same estrogen to the transgender woman when they got to 60? And then is it a different effect compared to the transgender population who started the hormone therapy at the younger age or who started hormone therapy after the age of 40 or 50? And then what are the optimal choice of the gender-affirming hormone therapy? Now we know that ethanol estrodiol is a bad choice for the estrogen. And how about the spiritual acetate? Should we use it or should we change it different? If the spironitone is a better alternative than the luprolide, we don't know. And is there any difference in the mode of delivery? You see the data is still murky. And it's hard to, yes, there is an increase in the cardiovascular risk, but it's hard to attribute to the gender-affirming hormone therapy per se because there are other factors we cannot uniformly control like an inherent risk. Trans female who has been exposed to high level testosterone throughout their life after getting the anti-androgen therapy and the estrogen therapy at the age of 20 or 30, are they still high risk than the cis female? So all these complication and cardiovascular risk outcome depend on the age of concept and duration of therapy underlying comorbid condition. Last, not the least, we should not underestimate the minority stress. All these transgender population, the marginalized population, they don't see the doctor regularly, they don't get the best head care, or they are usually unseen population until recently. There are a lot of healthcare disparity and then socioeconomic status differences as these population. Substance abuse and the mental health issue also play a part. You saw a lot of the mortality, cause of mortality and the transgender are suicide. And the interesting enough that it's a gender poisoning and for these mortality. So current data we have is a retrospect analysis data or expert opinion. How about the long-term randomized control study, just like lipid or the diabetes medicine? It may not be the ethically acceptable because if you want to do the, you know, gender affirming therapy, placebo control arm or the different treatment arm, you know, some of the patient, you know, may want to be on a different arm or, you know, a lot of the patient may not want to be on the placebo arm for at least two, three years. So that's why it is unethical to get the randomized control study. We should not forget the complex interplay of the ethical, psychosocial and lifestyle, which limit the conclusive data. So we ended up doing the shared decision-making and then we have to counsel the patient about the realistic expectation from the gender affirming therapy. Gender affirming therapy is only one aspect of the transgender transition hormone, transition process. So it is not the only transgender treatment. Since there's a very limited, you know, data and scientific-based fact, we have to counter a lot of misinformation at the age of the internet and then we have to counsel the misconception. So current political situation, political climate, depending on where you practice, it can affect the transgender healthcare policy and access as well. So with that, you know, I'm going to finish my talk and, you know, please let me know if you have any questions. So I'm going to read through the question here. And the question is, do you recommend that major surgery is limited with the low estrogen portion? Do you recommend that major surgery is time with the low estrogen portion of menstrual cycle in cisgender women? Do you recommend that major surgery is time with the low estrogen portion of the... I'm not quite sure about the first question. If you can type up a little bit more. Major surgery is time with the low estrogen portion. I'm not quite sure. You mean, do you recommend major surgery time with the menstrual cycle? I'm not quite sure about this question. How much you can really establish the cardiovascular risk if all the studies are so many different type of gender affirmative, meaning previous treatment with progesterone, having different type of the combination, having not the same medical treatment. Yes, that's a thing pretty much. We cannot just attribute it to the, you know, cardiovascular risk, but the thing is, they do have an increase in the cardiovascular risk compared to the general population. Initial study is a little bit murky. Now is that, you know, now we have a much more established database from the Scandinavian database, Netherland data, and also the Kaiser Permanente data. They do have increase in cardiovascular risk, especially with the Kaiser Permanente data, even though they cannot attribute to the gender affirming therapy, they do have increase in the, you know, increase in the, you know, MI risk and thromboembolism risk in the trans-female. And then, yes, the previous treatment has a progesterone, true, but then it's not all the transgender patients are progesterone only. I hope the potential transgender patient are informed correctly that all the patient highest level, what is the highest level estrogen achieved with the breast development? And is there any, this is a question I don't really know. And then I have to take a look at a supplement. I don't remember the highest estrogen they achieved. What's the level, three years old to address that. Is there any three-year follow-up for this? They might have this one for the breast development. And again, you know, estrogen level and breast development is that you can take a look at the cisgender population. Cisgender population, healthy cisgender population, this cis woman has a high estrogen level. They do not correlate with the breast development size. And so some woman has a, you know, a small breast size. They may have a high estrogen level. Some woman has a, you know, a large breast size. They may have a low estrogen level. So breast size, it does not even properly correlate with the, you know, estrogen level, even in the cisgender population. So it is, it will be the fast stretch to make the conclusion for the transgender, you know, breast size and the estrogen value. What is the difference in the pharmacodynamic between the supernatant and the value rate? That's a question I don't really know. And then I don't think there's a much of the thing, but I don't want to tell you wrong. What is the expert opinion on endocrine society, estradiol goal? Yes. Yeah, so the thing is, you know, they put the 200. So the reason they put the 200, 250 for the estradiol level, what is the expert opinion in the endocrine society, estradiol coverage, is that this is the upper limit of estradiol level. You know, people who are familiar with the estradiol level, it depends on the lab. It's heavily influenced by which assay you use. It also depends on the menopausal, premenopausal status. It depends on the pre-puberty status. And also depend on the, you know, even in the, you know, puberty and between the age of 20 and 35, the estrogen level can fluctuate very, you know, depend on the pre-menstrual cycle and the menstrual, luteal phase and follicular phase. So even in the cisgender population, what is the appropriate, you know, estrogen level? It's a very wide range, depends on how you measure. And also you got to understand the cisgender estrogen value are quite cyclical and quite fluctuating, but we are giving the estrogen level continuous daily dose. So is it even the physiological? That's a food for thought. I don't know what's the right answer. Should we give it a cyclical estrogen level for the transgender? I don't know. And then definitely they want to put the 200 more of expert opinion, is that they don't want to overshoot 300, 400 because they said the higher level might be associated with the thromboembolism and all of these. How can we establish a category because of the persistent high-level estradiol not having the different level of age initiation, not just because of tobacco? Yes, they do adjust the tobacco and then all these things, and some of the data to smoking. And then so far they did not see any estrogen in level directly correlated to the cardiovascular risk. Some of these European data and the Scandinavian data, they compare with the transgender population with or without gender affirming therapy. They do see the increase in the cardiovascular rate compared to the cisgender population. So they do have increase. Can it be because they don't see the doctor or they don't take the cholesterol medicine just like one of the US data? Yes, maybe. And then they neglected these other health issue, maybe. So it may be the major reason. But definitely they cannot see the high estrogen value is causing the cardiovascular disease. Do you recommend stopping the estrogen? That's a good question. Stopping the estrogen therapy prior to the gender affirming surgery to prevent the DVT and the PE. It's a good question. Breast, we don't recommend that for the stopping the gender affirming therapy because I was part of the transgender council, quality care delivery at the VA as well. But if the patient going through the pelvic surgery, just like any pelvic surgery, and then if there's a major gender reassignment surgery, usually it is recommended to stop it. Some of the surgeon want to stop it two weeks before and the two weeks after. And even for the breast, some of the surgeon want to stop it. For me, my take is, yes, the patient may want to continue throughout the hormone therapy. The safety comes first. I want the surgeon to be comfortable as well. I don't want the surgeon to be not comfortable. So that's why, if the surgeon said to stop it for a few weeks, I'm okay. But usually these estrogen are short-lived. After they stop for the two weeks, the risk may be reduced significantly. Of course, we got to use other measure for the DVT prophylaxis and then ambulation and then lapthena. What is your thoughts about the ciprotron causing the excessive risk of cardiovascular disease seen in the... Yes, this is more like a hypothesis rather than the proven formula. They take a look at the ciprotron group has a higher risk because of the a little bit glucocorticoid effect. Can it make a concrete solution? No, because they need the larger data. Because at the same time, a lot of the European study, they use a ciprotron-based therapy. Initial data did not show the increase in cardiovascular risk. So I doubt that ciprotron alone is a major driver for the cardiovascular risk. It might be the subtle differences. What is the highest level of estrogen achieved in the breast development? How long trans male or trans female have the gender affirming therapy to start the weight gain analysis compared to that? Yeah, they notice a weight gain compared with gender and muscle. How long does the trans male, trans female have to have the gender affirming therapy to start the weight gain analysis? How long trans have to have a gender compared with the gender? How long compared with the gender to start the weight analysis? They do see the change in weight within the few months of starting the gender affirming therapy. And then especially in the trans male, they see the weight gain within a few months. So that's why the trans female take longer when they compare with their cisgender counterpart. The weight is always a tricky event for any study. What are the next step of the gender surgery? It seems like you cannot cancel out the effect of the chromosomal. Yes, it is true. Men are inherently high risk for the... Men are inherently high risk for the cardiovascular risk compared to the female. That's why even after the hormone therapy, even after you suppress the testosterone, we cannot exclude the fact of this chromosomal effect on the body cardiovascular health. So that's why I end my talk with the food for thought. That's why I don't know. And then currently we can manipulate the hormone level, but some of the inherent risk, we don't know. That's the thing we might able to get the better study in the future, hopefully. Did you run across any effect of the thyroid function either trans male with the acute? I did not notice any abnormal thyroid function, maybe just accidentally, it just noted. And then do you measure the baseline lipid? Yes, I do measure the baseline lipid panel. And then I check it in the three to six month because these are the time they check for the hormone level as well. I pay attention to the lipid panel. I do pay attention to the weight. And then I pay attention to the diabetes. So these are the thing, at least part of the endocrinologist, I pay attention to them. When are we going to do the bone density? It's a little bit tricky question. Sometimes, since I practice at the VA, so I don't have to worry about the insurance, I can check the baseline bone density just for the sake of monitoring. But usually, if the patient is young and I got the good bone density value, and then as the patient is getting older, after 40, 50, I do check the bone density for almost everyone, especially if the patient after the hysterectomy or if the patient has a lower estrogen value. What is the legal age to start the hormone therapy? And yes, it is true. In the United States, you depend on where you practice. In Texas, if you give hormone therapy at the teenager, you can be sued by the state government, but in the other state, it is approved. So I asked this question to one of my pediatric endocrinologist. Usually, they start at the age of 12, 13, 14, but before they do that, they have extensive counseling, they have a psychiatric, they have parents come in and the endocrinologist, they have extensive counseling. And then they try to wait as long as they could. Usually, they don't wait until like 20, but the early hormone therapy has a much more impact on the body changes. So they try to delay the puberty with the blocker androgen, GNI's analog, and then they start the opposite sex. And somewhere around 14, I asked my endocrinology colleague who take care of transgender, they rarely give anybody less than 12 or 14. The role of the progesterone on the cardiovascular risk, lipid and breast development. Yeah, that's a good question for the progesterone on the cardiovascular risk, lipid and breast development. I purposely did not touch that topic. It is a dicey topic. Yes, after Dr. JC Pryor published the opinion in the GCEM about this progesterone, and then a lot of my patients showed me that paper. So usually at this point, the standard is that we start with the micronized progesterone and then we start with the low dose. And then before we started, I counseled them, the data is not there. And then of course, I don't have enough data to say that, oh, if you take progesterone, that dose, you have MI, all these things. But most of the progesterone data are from the WHI data with the methoxyprogesterone. Can it be the micronized progesterone or different formula progesterone will be safer? I don't know. And then even in the transgender, I don't know. So I asked them what their expectation. A lot of patients, they want the progesterone because they want to have a lower testosterone. Yes, progesterone can lower the testosterone. But breast development, I don't think any literature support of this progesterone effect on breast development. But if you give a long-acting progesterone, there's a risk of thromboembolism for sure. For those using the progesterone in addition to estrogen, are they increasing risk if the patient is using the progesterone for many years? In other words, there's some worsening risk of using the progesterone. For example, if any different, if the patient is, yes. So this is a very good question, the progesterone use in addition to estrogen. Yes, because the progesterone use has been concerned for the cardiovascular risk from embolism, mainly from the WHI data. So if you look at the WHI data, cardiovascular risk is mainly noted in the women 65 and older. So if you have a younger patient, age itself is a major protective risk, major protective factor. Younger patient, you can do a lot of bad things or you can smoke, you can drink, you don't have a side effect. So that's why even if you give us some of the treatment that might impose a cardiovascular risk, if the patient is younger, they don't see the effect. That's why some of these data, they published many years ago, they don't see the cardiovascular risk. But now if they publish again after five decades, they see the increase in cardiovascular risk. That's when the patient, their patient cohort is getting older. It is true, age is a major risk factor. And then it is also proven at the cisgender female. And then can it be the progesterone is the driving the cardiovascular risk? We don't know because we don't have a progesterone plus or minus, you know, randomized control trial. And I wish there is, you know, and then your data's are reassuring from the physiologic perspective, number of progesterone is used in the female when intact uterus progress instead of... Your data's are reassuring for the physiological perspective when the progesterone replacement is used in a female to male transgender, female to male transgender with integrity is appropriate to use instead of the... Yes, you know, you can use that data for the WHI data. What is the low dose of testosterone in the male to female trans individual who undergone the surgical castration? I don't know for sure. That's a good question. Now is the question come down to number two question is what is the appropriate testosterone value, you know, in these people? And then, but the male to female, you know, even after you did the orchiectomy, testosterone level is reached to the female range. So I don't know whether these testosterone level in the female range are good for the trans female or the bad for the trans female. But if you take a look at this, you know, prostate cancer data, orchiectomy range testosterone has a bad cardiovascular outcome. Are we going to give a testosterone replacement for those patient? It is tricky. So I'm not quite sure. Is there any question? Thank you, Dr. Seow. This was a great presentation. And you answered all the questions. So we want to go ahead and end it now, okay? Thank you so much, Jessica. Really nice talking to you as well. Have a great day, everyone. Thank you.

cardiometabolic impact

gender reassignment surgery

hormone therapy

transgender adults

evidence-based research

fat distribution

weight gain

metabolic function

thromboembolic risk

cardiovascular risk

individualized care

health outcomes