Good morning, everyone. Please welcome our President of the Endocrine Society, Dr. Carol Weisham. Well welcome to our second plenary of ENDO 2022. This afternoon, we'll be delving into strategies to address health disparities and toward health equity. The Society has championed diversity, equity, and inclusion for more than 25 years, and we are proud to be spotlighting this topic. This afternoon, we'll continue our acknowledgment of our 2022 Laureate Award recipients by recognizing three of our esteemed colleagues. The Bogursky Outstanding Clinical Practitioner Award recognizes extraordinary contributions by practicing endocrinologists to the endocrine and or medical community. The Endocrine Society is pleased to present Dr. David Harris with the 2022 Bogursky Outstanding Clinical Practitioner Award. Dr. Harris is a full-time practicing endocrinologist at the Warren Clinic Diabetes Center in Tulsa, Oklahoma, where he has provided exemplary care for over 30 years. He is a tireless advocate for equal access to care and affordable diabetes medications. He led the Glycemic Management Committee at St. Francis Hospital to ensure consistent treatment protocols for hospitalized patients. He has been instrumental in providing scholarships for medical students and high school students in need. A member of the former Hormone Health Network Committee, Dr. Harris also previously served on the Scientific and Educational Programs Committee. Thank you, Dr. Beverly Biller, with letters of recommendation from Anu Prabhala and Jim Gavin, and congratulations to Dr. David Harris in recognition of his commitment to clinical excellence. Thank you. I first of all want to thank my Lord and Savior Jesus Christ for bringing me to this moment in my life, and most of all, in addition to that, I would say thank you to the Endocrine Society for the award and the Bogursky Award for Outstanding Clinical Practitioner. I would be remiss not to thank my wife, Sherita Harris, and also my family who are here today for putting up with an endocrinologist that's sometimes somewhat cantankerous and with an attitude. I also would like to thank my fellow endocrinologists that I practice with, one of which is here, Dr. Priya Pulapati, and there are six others. The names are too numerous to list. I would thank my family for coming this distance to honor me here today. Most of all, I shouldn't say most of all, but just as much, I want to thank Dr. Beverly Biller. She is oftentimes the brightest, most intelligent person in the room, but she has the rare quality of also being the most gracious and personable person. I stand on the shoulder of previous Bogursky Award recipients. Thank you for this august opportunity and award. Our next award recognizes outstanding contributions in the practice of clinical endocrinology in academic settings. The Endocrine Society's 2022 Outstanding Scholarly Physician Award is presented to Professor Ken Ho, who's Emeritus Professor at the Garvin Institute, University of New South Wales, and Honorary Consultant Endocrinologist at St. Vincent's Hospital in Sydney, Australia. As a globally recognized pituitary medicine expert and a leader in academic clinical endocrinology, Professor Ho developed therapeutic guidelines and advocated for regulatory agencies' decisions geared towards improving patient health outcomes. He established a gold standard measurement for growth hormone deficiency and developed standards for use of growth hormone replacement in adults. Dr. Ho has published over 250 peer-reviewed articles that have directly impacted clinical care. He is a former associate editor for the Journal of the Endocrine Society and currently serves as a member of the nominating committee. Thank you to nominator Shlomo Melmed, as well as Stephen W. J. Lamberts, for supporting this nomination. And congratulations to Dr. Ken Ho, who we are recognizing for his passion for excellence and his commitment to scholarship, enabling outstanding contributions in academic endocrinology. Thank you, Dr. Ho. Thank you, Carol. I'm deeply honored and humbled, after initial disbelief, to be the recipient of the Society's 2022 Scholarly Physician Laureate Award. My sincere thanks and appreciation goes to so many people that shaped my career as an endocrine physician scientist. First and foremost, my mentors, Les Lazarus from the Garvin Institute and St. Vincent's Hospital in Sydney, my home institutions, and Michael Thorner, himself a recipient of this award and who accepted me as a postdoctoral fellow at the University of Virginia. Both taught me how to think and introduced me to the fascinating world of the pituitary gland and within a growth hormone. Both spliced into my DNA, and I couldn't help myself because you would have seen the slide that landed me in trouble with my wife during a vacation in London in a museum where I wanted to know how I would measure up to Robert Wadlow, the world's tallest man. Secondly, a huge thanks to the Endocrine Society. This amazing national society harbors a nurturing and vibrant international culture of excellence and inclusion, provides a global professional home for many like me from the far corners of the world. It gives me enormous satisfaction to know that I have been assessed by my own peers in the awards committee. My gratitude also goes to a special group of people comprising fellows and collaborators who contributed to the work attributed to me. This includes several members of the Endocrine Society. I singled out two colleagues to thank for inspiring and supporting and nominating me. Professor John Walsh and Shlomo Mellman, both deserved or deserved recipients of this year's other Laureate Awards and both previous recipients of the Scholarly Physician Award. I know what you're thinking, no, this is not a pituitary conspiracy. Last but not least, I wish to thank my wife, Tessa, who has traveled all the way to be here with me today. Thank her for unwavering love and support without which my career would not be where it is today. Thank you. Thank you. Our last award this afternoon is the Outstanding Leadership in Endocrinology Award, which recognizes outstanding leadership in fundamental or clinical endocrinology. This year's recipient is Professor John Walsh, a highly accomplished clinical researcher and educator at Oxford University in Oxford, England. The contributions of Professor Walsh have had a significant effect on patients with pituitary disease. His early observations about the importance of a single surgeon expertise for acromegaly paved the way for the adoption of criteria for pituitary centers of excellence, while his early recognition of the needs to minimize neurologic sequelae in pituitary apoplexy paved the way for the studies that are still ongoing to establish best practices in this difficult-to-manage disorder. In these areas, as well as in PCOS, Addison's disease, and obesity, the leadership of Dr. Walsh has enabled endocrinologists to adopt new approaches to improve patient outcomes. Professor Walsh has trained multiple endocrinologists who are recognized globally for their own contributions to endocrinology. I want to thank nominator Shlomo Melamed, and thank you also to Professor Ken Ho for submitting a letter of support. I want to thank Professor Walsh for his dedication to the highest quality training and service, and for his recognition as an outstanding leader in endocrinology. Carol, thank you very much indeed for doing me this great honor. It's something that will be deeply cherished by my wife, Sally, our family, and friends. I'd also like to thank Professor Ken Ho and Professor Shlomo Melamed, who are amongst my best friends and colleagues in the world, highly intelligent, highly successful, and a great pleasure to be working with over many, many years. I'd like also to thank all the people who've come to Oxford during my time there since 1995. I like to think that we've become friends as well as colleagues, and they have written and worked very hard with great intelligence and assiduity to publish papers which I think are fairly widely known and fairly widely quoted. Endocrinology is an absolutely super, super specialty, and I think we're different to some of the other specialties. We're gregarious, fun-loving, sybaritic, and enjoy the good things in life, and I'm proud to be amongst that group of people. And lastly, I'd like to thank the Endocrine Society for its outward-looking approach to our specialty, to science, and all the other things that it does. Thank you all very much. Great. I now have the great pleasure of introducing Dr. Jane Morgan. Jane Morgan is a cardiologist and the Executive Director of the COVID Task Force at the Piedmont Healthcare Corporation in Atlanta, Georgia, the largest healthcare system in Georgia. Within this role, she serves as a system COVID vaccine expert. Additionally, she serves as a CNN medical expert contributor and is the owner and creator of the Stairwell Chronicles, a social media series directed towards addressing questions surrounding COVID vaccines and other medical topics in a conversational format. Further, Dr. Morgan has been named to the Committee of the Department of Health in its Ask the Expert series. Previously, Dr. Morgan was the System Director of Research and Innovation and the Director of Cardiovascular Research, where she oversaw all clinical trials and set the strategic growth of the Piedmont Research Institute. Dr. Morgan has served as a Chief Medical Officer of the American Chemical Council, CEO of 40 Million Beats LLC with clients such as Novartis, Abbott, and Moderna, the Cardiology Advisor to the MitroClip team at Abbott Labs, the Worldwide Director on the Cardiorenal Drug Development Program at Solvay Pharmaceuticals, and is Assistant Professor of Medicine at Cleveland Clinic. She is the Adjunct Assistant Professor of Medicine at the Morehouse School of Medicine, Board Member on the National Diversity and Inclusion Team at the American Heart Association, and the current Health Equity Advisor for Moderna. Please welcome Dr. Morgan. ♪♪♪ Hello and thank you for that introduction. I'm happy to come today to talk with you about health equity and medicine to level set and to give you an idea of really what does that mean currently. These are my disclosures, Moderna, Novartis, and Randomize Now. So what is health equity? Just to level set, health equity means that everyone has a fair and just opportunity to be as healthy as possible. This requires removing obstacles to health, such as poverty, discrimination, and their consequences, including powerlessness, lack of access to good jobs and fair pay, quality education, housing, safe environment, and healthcare. So imagine a world where the doctor-patient communication is uncomfortable and stilted, resulting in a chasm of mistrust. Breakthroughs in biomedical research only reach a small audience and have only a portion of their potential impact. The most vulnerable patient populations don't have enough doctors dedicated to their care and a patient's race or ancestry influences their treatment plan to the detriment of patients of color. So welcome to my and your world. Many people often ask me, I don't really understand the difference between equality and equity. So if we look at the top of this slide, equality means that everyone has been given the exact same equipment and opportunities. It is fair. That's what we know of as fair. And so when we look at this, we see that there's a child riding a bicycle that's really too big for that child, and they're having difficulty managing it. And then you see a woman riding a bicycle that actually is a great fit for her. And then behind her is a man riding a bicycle who's also struggling because the bike is too small for his frame. And then we have someone who has physical challenges who's unable to ride the bicycle at all. But they all were given the same bicycle, and we expect the same outcomes. Now look at equity. Equity would give each person what they need to reach the finish line and to have those outcomes. So the bicycles fit the size and the abilities of the person such that everyone can move forward. The CDC lists five inequities that put racial and ethnic minority groups at risk of getting sick and dying from COVID. Discrimination, health care access and use we will focus on today, but also occupation, educational, income and wealth gaps, and housing. This is a paper that I published in the Journal of the National Medical Association assessing the impact of insurance type on COVID-19 mortality in black and white patients in the largest health care system in the state of Georgia. The results of that paper demonstrated that when insurance type was equitable, outcomes were equitable. And so the type of insurance that your patient can afford and can access can determine their outcome. It determines how many specialty visits are paid for, what type of copay they may or may not have, what types of drugs are covered, whether they have access to new drugs under FDA development or whether they only have access to generic drugs. And so we looked at the population within the hospital, and when health insurance was equitable, outcomes were equitable. Social determinants of health, childhood experiences. Has a child or a person moved every two or three years throughout their childhood? Has housing been inadequate? Education has been the centerfold of where we can go in life with regard to the income of our family, what type of employment we have, what housing do we have, what kind of communities do we live in, what social support do we have, digital connectivity, type of transportation we can afford, and also access to health services. And that's really why we're all here today. When we look at educational disparities, this slide is actually quite interesting. If we look at the dark blue, that's the black population, and the red is the white population, we see people with less than a high school diploma, and we see the differences in the outcomes with regard to what they will earn. We see it's a difference of $11,000 and $62,000, quite significant. When we go to high school diplomas, that really doesn't change for the black population. White population gains another $40,000 with a high school diploma. Some college, people who've gone to college but haven't finished. We see sort of an equity between high school and college, but look at what happens when blacks and whites graduate from college or get advanced degrees. We see the biggest gap that we see on this chart. And most of that is due to lack of promotional opportunities when people of color get into the workplace. They are unable to move beyond a certain level that then impacts what? The type of healthcare you get, where you live, the communities you live in, the transportation that you choose. And so this is how all of these things come together. Let's take a closer look at racial bias in healthcare. And let's start very specifically with our glomerular filtration rate, our estimated glomerular filtration rate. This is, as you know, one of the key tests for diagnosing kidney disease. The earlier kidney disease is detected, the better the chance of managing it or keeping the condition from getting worse. We generally use two equations, the MDRD, Modification of Diet and Renal Disease equation, or the CKDEPI, the Chronic Kidney Disease Epidemiology Collaboration Equation. Most institutions use one or the other. Both the MDRD study and the CKDEPI equations include variables for age, gender, and race. The only race factor is the African American race, does not impact any other race. And so therefore, if we look at these equations, the MDRD equation, African Americans, when you apply that factor, have an increased GFR approximately 21% greater than whites, and the CKDEPI equation, 16% greater. And you say, why does that matter? It matters because decisions are made based on those numbers. And so here's the equation, MDRD equation, CKDEPI equation, and you can see at the end, there is a factor, a multiplication factor for AA, African Americans. What does that mean? That means if your GFR comes back from the lab higher than it really should be, you're at risk of being triaged to a lower level of care. You may have a late start to your medications, a late start to dialysis, delayed ICU transfer when we look at these objective measures, exclusion from living donor transport, transplant, use of incorrect imaging tests or dyes, timing of referral to a nephrologist is impacted, and then exclusion from clinical trials because your GFR does not meet the inclusion criteria. In 2020, the National Kidney Foundation and the American Society of Nephrology formed a joint task force to review this very factor. And in September of 2021, they announced a new race-free calculation for estimating the estimated GFR. So think about that when you go back to your institutions and when you are managing your patients, ask your lab, are they still applying the race factor? So you can make certain that you are taking care of all of your patients equitably and making certain that they are getting the best care and you are making the best decisions based on equitable and accurate information. I thought this was an interesting slide, a photo that I took myself here in Atlanta, and it shows a dollar store in an area of town that really is a food desert. And so it has dollar stores. This is where people go to shop for their groceries. A lot of high calories, processed foods, cheap foods. And interestingly, because of all of the social determinants of health, the family dollar store sitting right here in the middle of the community, no fresh fruits are available in the dollar store, no fresh vegetables, there are no supermarkets, there's no whole foods. What sits right next to the family dollar store? In fact, they share a wall. That DaVita, that's a dialysis center. So you can shop at the food dollar and slowly kill yourself, and the dialysis center's right there to catch you in an area of a food desert. This is reality. Let's take a look at clinical trials. One of the things that I spent a lot of time talking about, I do a social media series called the Stairwell Chronicles, where I literally sit on the stairs of my house, and I talk with you about medical issues. I generally do them with COVID in 60 second blocks. I ask a question and I answer that question in a very conversational way in 60 seconds, and that includes the salutation. So if you don't like what I'm saying, it's only a minute of your time, you can't get that upset about it. And people have followed along, and it's been a way to educate people, and certainly people in my community, about COVID and to increase the vaccination uptake. I also do something called Stairwell Chronicles Live, where monthly I sit on my stairs for 30 minutes and do an in-depth discussion. On March 28th, I did an in-depth discussion about clinical trials, and what don't we know about clinical trials that people should know? Clinical trials involve our best and our brightest thinking. They have the oversight of multiple physicians, not just your doctor, but the local doctor, and the regional doctors overseeing the local doctor, the national doctors overseeing the regional doctor, the global physician is overseeing the national physician who's overseeing the regional physician who's overseeing the local physician. Where else do you get care like that? You also have access to a nurse or a research coordinator 24 hours a day. We want to know if you're having any side effects. There's something called optimization. We can optimize patients. So for instance, if you are interested in being in a clinical trial, but your HbA1c is too high, we will literally spend two to three months making certain that you have medication to bring your HbA1c down low enough to qualify for that trial. That is great medical care. Without being enrolled in the clinical trial, your HbA1c would have been higher. We have increased touch points with the medical system, and ultimately, with FDA approval or emergency use authorization, all communities can feel comfortable that all approved drugs and therapeutics are relevant to their populations because they were represented. Oncology trials in particular have been shown the trials themselves to increase the rate of remission of cancer just by participating in the trial. African Americans have a higher rate of prostate cancer, colon cancer, some types of breast cancers, and yet we don't participate in those trials despite this type of data. And then lastly, if you are managing patients who are uninsured or underinsured, this is a way to get them coverage because by and large, the companies who are sponsoring these trials will bring you in and cover the costs so you think about that when you are managing your patients who may be struggling to pay or struggling to fulfill their prescriptions. Clinical trials is a way to bring a person into the system and make certain that they are getting care. Another paper that I published, Opportunities and Counterintuitive Challenges of Decentralized Clinical Trials to Broaden Participant Inclusion. And what does that actually look like? It means that we have to have cultural congruence in clinical trials, meaning people need to be able to speak the language of the person who's enrolling. And I don't mean people who speak languages other than English. I mean people who speak English. But there's different body languages and different nuances. We need leadership and research. People like me, people at the top are sitting at the table and can make decisions that impact all others. Principal investigators, the pipeline, starting in medical school, beginning to indoctrinate and introduce the concept of clinical trials to our future doctors such that they can participate. And then obviously trust. 80% of all black patients are seen by black physicians in this nation. And that is not by happenstance. The number one reason that black patients choose black physicians as their physician is safety. Imagine that. No other race chooses a doctor based first on where they feel safe. Let's take a look at pulse oximetry, something we use all the time. As we know, low blood oxygen levels harmful to patients can indicate serious illness. Certainly in the middle of this pandemic, we have understood the value as well of pulse oximetry. Again, like the GFR, we use this as a metric to inform our decision-making, admissions, discharge, ICU transfer, intubation, need for supplemental oxygen. Pulse oximeters work by using light that passes through the skin to measure your oxygen levels. So anything that slows that passage of light like nail polish or skin tone can cause inaccuracies. Black patients are three times more likely than white patients to have low oxygen levels that were missed by pulse oximetry. That could translate into as many as one in 10 inaccurate readings among blacks by the University of Michigan study. So black patients and other populations of color can receive inappropriate care. We saw people early in the pandemic who were being dismissed from the emergency room because their pulse oximetry was too high. We have delayed medical care. People are triaged to waiting rooms and lower levels of care and concern if low oxygen levels are missed because of inaccurate pulse oximeter readings. So what does this have to do when we tie it into clinical trials? The first pulse oximeter was developed in 1974. Because the early designers did not use a diverse group of test subjects, sources of error like skin tone were not recognized. Here we are nearly 50 years later. Another sterile chronicle live that I've done clinical trials just in April 25th where I specifically focused on populations of color. By the way, these can all be followed on social media. I'm on Instagram, I'm on Twitter, and I do these frequently. So what should you do when you have a normal pulse oximeter, a pulse oximeter reading, and you've got a patient of color, have a high index of suspicion when the patient presentation does not match the pulse oximeter reading? We've gotten away from the physical exam and our presentation. What does the patient look like? What is the patient complaining of? Don't minimize the symptoms on behalf of the patient. Demand updated technology that's tested on diverse subjects when it becomes available. Treat everyone with care and concern. The lack of diversity in medicine is the healthcare crisis of our times. Medicine will never reach its full potential to alleviate suffering and improve lives until it leverages talent from all backgrounds. On Twitter recently, on a doctor's page, this is what I saw. We cannot have health equity replace excellence in academia. The implication being, when you mix and have concern for black and brown people, somehow the quality of health is lowered for everyone. So remember, doctors are not immune to stereotypes and images that frequently are portrayed in the media which tend to associate blacks with negative and or very narrow depictions. In addition, in-group bias, identifying more with one's own group also influences all healthcare workers' ability to make assessments, especially pain, which I won't go into today. So here's my response to that comment on Twitter and I posted the response there. Equity doesn't mean that we settle for less. It means that we demand more for all of our patients. It's always the right time to do the right thing. That's why health equity. My next Sterile Chronicles Live, I'm focused on women over 50, the lack of clinical trials and participation in this group, the suffering of menopause, the dearth of information and why that isn't happening as we continue to move the topic and the platform of health equity forward. This month, I'm going to be focusing on the health inequities and the inopportune therapies of women over the age of 50 as we approach menopause. Thank you very much. Thank you. Thank you, Dr. Morgan. That was fabulous. Next, we're going to hear from our own Dr. Sherita Golden. Dr. Sherita Golden is the Hugh P. McCormick Family Professor of Endocrinology and Metabolism and Vice President and Chief Diversity Officer for Johns Hopkins University Medicine. In that role, she oversees biomedical workforce diversity initiatives for the School of Medicine and Health System and health equity operational strategy for the Johns Hopkins Health System. She holds joint appointments in the Welsh Center for Prevention Epidemiology and Clinical Research in the Department of Epidemiology at Johns Hopkins Bloomberg School of Public Health and in the Armstrong Institute for Patient Safety and Quality. She served as Director of Johns Hopkins Hospital Inpatient Glucose Management Program and as Executive Vice Chair of the Department of Medicine from 2015 to 2019. The author of more than 250 articles, Dr. Golden's epidemiologic research focuses on two areas, endogenous sex hormones as risk factors for CVD, type 2 diabetes and insulin resistance in post-menopausal female, and mental health complications of diabetes in the biologic, hormonal, and behavioral factors that might explain these associations. Her health services research focuses on understanding and eliminating diabetes health disparities and for the implementation and evaluation of systems interventions to improve patient safety and quality of care in hospitalized patients with diabetes. She serves as the principal investigator of the Johns Hopkins site of the Diabetes Prevention Program Outcome Study and is elected member of the American Society for Clinical Investigation, the American Association of Physicians, and the National Academy of Medicine. Dr. Golden chaired the writing group for the Endocrine Society's inaugural scientific statement on health disparities in endocrine disorders and is a member of the Society's Committee on Diversity and Inclusion. So welcome, Dr. Golden. ♪♪ Good afternoon and thank you for inviting me here. And it's a pleasure to be with my professional society in person for the first time in three years. So I have about 25 minutes to talk to you today about approaching diabetes and endocrinology with a health equity lens. I just want to review my disclosures briefly. So just want to start out by sharing this fairly well frequently quoted manuscript that was published in 2014. And if you look at this, it looked like at the time that the trends and the increase in the prevalence and incidence of diabetes were sort of leveling off. So in fact, to the left, it looked like the prevalence of diabetes was actually reaching a plateau and the incidence of diabetes was going down. So as a diabetologist, I thought perhaps I might actually go out of business one day. But if you actually looked at these analyses stratified, then you could begin to see that in certain subgroups, there was actually a continuing increase in diabetes incidence among older adults, among women and among minoritized populations and those who had less than a high school education. So then I realized that I still had a lot more work to do. And then if you look today, and these are the most recent CDC guidelines, then you can actually see that the prevalence of diabetes is really markedly elevated in all other populations compared to the non-Hispanic white population. And this is really similar for both men and women. So when I look at this, this is my favorite quote of Dr. Martin Luther King Jr. that says, of all the forms of inequality, injustice in healthcare is the most shocking and inhumane. And that's because when people are ill and in their healthcare system, that is when they are their most vulnerable and we should be the most humane. And that has unfortunately not always been the case. So I wanna share an overview of this manuscript that was published in the Journal of Clinical Endocrinology and Metabolism last year, co-authored by two of my outstanding colleagues, Dr. Felicia Hill-Briggs and Dr. Joshua Joseph, casting a health equity lens on endocrinology and diabetes. And to really explore, how did we get here? How do we get to what we see today and what should we be thinking about from an intervention level? So I think we have to really think about this in two ways. How did we get here from the historical, medical and scientific context of health disparities? Again, because we understand our history, then it helps us to design more effective interventions. So as we think back that during the time of slavery, a lot of our current day medical advancements in the United States were made at the expense of slaves, particularly slave women. Dr. J. Marion Sims, who's considered the father of modern day gynecologic surgery and invented the speculum, repeatedly performed those procedures on slave women, not only without their consent, but without general anesthesia. And this was during a time when ether was available as a form of anesthesia. And he was ultimately rewarded with international acclaim and presidency of the American Medical Association. So no one saw an issue with this at the time. And then there was Dr. Thomas Perrin, who actually raised awareness of sexually transmitted diseases in the US Health Service. And he, under his leadership, there was not only the Tuskegee syphilis experiment that we hear a lot about, but also the Guatemala syphilis experiment, where individuals in those groups were exposed, they actually contracted syphilis naturally, but instead of being given penicillin as a treatment, they were followed for 40 years to look at the natural history of the outcome of syphilis, and that really wasn't uncovered until 1972, I was only four years old when that happened. Dr. Peron went on to become Surgeon General of the United States, but subsequently issued an apology for this. And then of course at Johns Hopkins Medicine, we have wrestled over many years with the legacy of Henrietta Lacks, and how her HeLa cells were used without her consent to advance medical science. There was also eugenics theory that was purported by Medicine and Science, and Dr. William Welch, who was the first dean of the Johns Hopkins School of Medicine and the founding dean of the School of Public Health, was really an international leader in the science and scholarship of eugenics, which really was considered the quote unquote science of improving the human population through controlled breeding to increase the number of what they called desirable heritable characteristics, which were primarily favored of Protestant, Anglo-Slaxon, and Northern European derivation, and was the foundation of forced birth control and castrations and sterilizations throughout the country that really didn't end until the 1970s. And those who were considered unfit were not only black individuals in the U.S., but those who were Jewish, those who were immigrants, particularly from Eastern Europe and other areas. So this had some very far-reaching implications. And then finally, there was the Flexner Report published in 1910 that supported the biomedical model as the gold standard for medical training and eliminated medical school as a proprietary school. So for all of us in the rooms who trained in the U.S., this is the model that we all trained under, but it had racial implications. So that resulted in the closing of many medical schools throughout the country who couldn't live up to the—didn't have the resources to live up to the gold standard model. But what it meant for medical schools that were training black physicians is that of the seven medical schools that were open at that time, the only two that remained open after the Flexner Report were Meharry Medical College and Howard Medical College. So this means that this was at a time where those who wanted to become black physicians could not gain access to predominantly white medical schools. So not only did that leave black patients vulnerable to medical abuses, but it also impacted biomedical workforce diversity. And this study published in 2020 tried to quantify if those five medical schools had been given the resources to remain open, how many more black physicians would have been trained in the U.S. And it estimated that in 2019, there would have been over 35,000 more black physicians that had graduated, and that would have resulted in a 29 percent increase in the number of graduating black physicians in that one year alone. And because other groups train at historically black medical schools, I really think it would have impacted the workforce diversity even more globally. So those are sort of the medical and scientific contributors. And what those things have resulted in, then, is that the trust of the—in the medical establishment by minoritized communities has been violated, and we really need to earn that back. It's resulted in language and communication barriers, as well as residual healthcare provider bias toward minoritized patients. So that's resulted not only in poor access to healthcare and quality of care, but again, those residual biases. And if we look specifically in the field of diabetes, what that means is that patients with diabetes, particularly those who are seen as poor and less intelligent, they're assumed to be less cooperative, less likely to understand. And so then there's this very paternalistic view in the delivery of their care. And so that—those are just sort of the historical medical contributors. And we think as physicians, well, we use all the guidelines, and, you know, we're not biased. And it turns out that we're not immune, that physicians have the same explicit biases as the general population. So we have a preference for those who are young, thin, rich, heterosexual, and white. We generally do not exhibit explicit race bias. However, there is an impact of our implicit biases on our decision-making. So if it's an objective decision-making, like a urinary tract infection or blood pressure cutoff, there's no impact of racial bias. But when it's subjective, for example, pain management, then those biases manifest themselves. So this is something that we have to be aware of. And even if you control for education, physicians will still rate black patients as less intelligent than white. So that's the medical and scientific context. What about the historical social context of health disparities? As was beautifully laid out in our last talk, how did we get to what we call the social determinants of health today? So this is a map I like to show of Baltimore City, which is where I've spent the last 28 years of my career. And during the Great Migration, when African-Americans, after the Reconstruction period, were migrating up north to escape Jim Crow, they would come to cities in the north. And what happened is that as black individuals were moving into those white neighborhoods, there would be what's called a white flight. The whites would move to other neighborhoods. And so what would happen is they would actually redline those neighborhoods, because now that was considered a minoritized neighborhood. And this is actually the 1910 Baltimore City Housing Ordinance, and this is what was written, to comply by law the separation of black and white races in their places of residence, to prohibit the Negro from having himself and his family present, permanent residence in a district already given over to the white race, and equally to prevent the white man from forcing himself upon a district given over to the Negro. So even though the U.S. Supreme Court determined that this was actually unconstitutional, some of these things are still written into neighborhood ordinances. So what that's resulted in Baltimore City is what you see here is called a black butterfly. The blue dots are where most of our African-American population lives in Baltimore City today. And then there's the white L, which is sort of the more wealthy area. And the previously redlined areas I showed you on that map, those overlap those blue areas today. And the wealthy area, which was the green area on the previous slide, so the green area going up sort of from the middle of the city, that is today's white L, the wealthy area. So if you overlap where are the African-Americans living today, where are their low-income areas in their city, and where is their unemployment, they all overlap and trace back to that redlining. So that's not the only racial residential segregation that happened in the U.S. It also happened with the Native American population, where with the Desert Land Act and the Homestead Act, as there was westward expansion, there was actually the drying up of the Gila River, which was a source of economy, because Native Americans were able to grow their own food and trade with white settlers. And when that river dried up, then they were really relegated to reservations. So what happens is once you've been in a redlined neighborhood and you're on a reservation, there was a decrease in investment and the economic development in those areas, educational resources and the economy, and that really also resulted in discrimination and access to high-quality jobs. And even with the New Deal legislation, farm and domestic laborers were excluded from that, which means they didn't benefit from that. So my grandmother, for example, was a domestic laborer. So those forms of structural and institutional racism have resulted in neighborhoods with poor stability and walkability, a lack of access to healthy food, as Dr. Morgan just laid out, the food deserts, and decreased affordable housing. So that ultimately has led to the obesity, diabetes, hypertension, all of the comorbidities that we see today, and it impacts our field in endocrinology and has led to the present-day social determinants of health. So now what can we do about that? So I'm going to try to bring us up now that we've talked about our history is the first thing we need to do is to incorporate culturally and linguistically appropriate standards into our clinical operations. We really need to redesign how we deliver care. These were developed by the Office of Minority Health in 2000, and what they really do is to ensure that we provide effective, equitable, and understandable and respectful quality of care and services to those that are responsive to diverse cultural health beliefs and practices, our preferred languages, health literacy, and other communication needs. And that's the principal standard, but there are 15. There are four of them that focus on language and literacy support. So this is ensuring that patients have interpreters. We know that Hispanic patients, a lot of our Hispanic patients have diabetes, for example. It's ensuring interpretation services, that those interpretation services are provided by someone who's a certified medical interpreter, and it's also ensuring that we literacy adapt all of our patient educational materials so that they're accessible. This is an example. During the COVID-19 pandemic, we developed a multi-pronged Latinx community anchor strategy support program because there was not only a lot of COVID in that population, there was also a lot of diabetes. So we expanded our language and technology services in collaboration with our senior director of language services, Tina Tolson, and she and her team provided access to over 220 translated COVID documents. We also established Juntos, which I'll talk about in a second, and then with Dr. Kathleen Page, one of our bilingual Latina physicians, helped support Baltimore City in our bilingual contact tracing support, ED follow-up, and meal delivery, and she also did a biweekly Ask Your Doctor session in Spanish on Facebook that was well received. So the Juntos consultation service was in response to the unprecedented volume of Spanish-speaking patients who had limited English proficiency that we were seeing in our hospitals in Baltimore. So we were able to really leverage the diversity of our workforce, those who were Latino and bilingual, and what they did is they complemented interpretation services by going in and explaining to patients in their own language what intubation actually meant for them, and they were able to call their patients' family members in Spanish and explain what was happening. Because remember, no one could access the hospital with the patient at that time. So this was a way to provide culturally tailored, appropriate care. So this is what this looks like, the class standards look like operationally. The other thing we did is we recognized that we needed to communicate to the community the importance of, for example, the COVID-19 vaccine. You can understand why there was existing mistrust, I hope, based on what I've shared with you, and as much as we thought our great Johns Hopkins media, our website was terrific, because we're not going there to get information. Where our black and Hispanic patients in Maryland get their information from is Urban One Radio, Afro News, and El Tiempo. So we set up Facebook Live education with our experts, and we were able to reach the community by using community partners, and through these three programs last summer, we were able to reach over 200,000 Marylanders with these programs. So that's really the importance with the communication and doing it culturally tailored. It's also important to collect and maintain accurate patient demographic data, and this is particularly important because if you can't accurately identify patients, you don't know where the disparities are. So we really focused on training our access services staff and race, ethnicity, and language training to help them understand why this was important and how to ask the questions appropriately. So these were our real questions. How do you identify your race, just so we don't look at people and guess? Do you consider yourself Hispanic or Latino? And what is your preferred language for medical care? And in doing that training, which we started in 2018 and really reactivated in 2020, we at one point had about 10% of our patients had missing data on race, ethnicity, and language. We're now down under 1% with missing race data. And then similarly with ethnicity data, close to 20% of our patients were missing data on race and ethnicity. Now again, we're less than 1% are missing those data. So that's sort of how we can think at the health system level. What can we do to address the social determinants of health? Because that's the real issue, and that's what I'll close with. So there was a really excellent review article written on social determinants of health intervention and diabetes by Dr. Felicia Hill-Briggs, who is past president of health care and education for the American Diabetes Association, and I just want to summarize some of the key tenets of addressing the social determinants of health. So the first is that we've got to intervene at more than one level. It can't just be one thing. So we start at the patient level. We know that interpersonal connections rather than computer-based approaches really help to improve glycemic control and diabetes knowledge. This is an example of a study I collaborated with her on called DECIDE. The intervention is decision-making education for choices in diabetes every day. And what it did is it was an intervention that used a culturally tailored approach to really educate and provide patients with problem-solving skills who had diabetes. These were low-literacy urban African-Americans. And what you see in the graph is there was a significant reduction in hemoglobin A1C over the course of the intervention at six months post-intervention, and there was also an improvement in systolic blood pressure and lipids as well. And then in addition, we also have to intervene at the provider level, and studies show that in-person feedback rather than computerized decision support changes provider behavior. And then we've got to think about the microsystem level. So what about the healthcare organization? So we know disease management approaches that use registries, incorporate clinical practice guidelines and use health IT to track and monitor patients, improve diabetes outcomes. And then at the macro level, incorporating the community with the health system, then that enables us to do community coalition building and advocacy to continue to address the social determinants of health. And that improves healthcare and minoritized populations and reduces racial and ethnic disparities. So really, if you look at the cross-cutting themes, it's important to target multiple patient barriers rather than a single solution, to use culturally tailored interventions, to use multidisciplinary teams, so, you know, health extenders like community health workers, to employ interactive skills-based patient training rather than passive approaches, use patient navigators and involve the family and the community. And then what about the social determinants of health themselves? So we've talked a lot about the health system and healthcare access. So what about housing and food insecurity? And, you know, what do we need to do there? So here are some examples of interventions directly to social determinants of health that have improved outcomes. So an intervention on housing called Moving to Opportunity, published in the New England Journal in 2011, looked at 4,500 families who were randomized to three groups. So either they had to move from a high-poverty area to a low-poverty area and were given a voucher. They had a traditional voucher that didn't have any location restriction, and then they got a control voucher where they got no new assistance. And those who moved to the low from the high-poverty to the low-poverty neighborhoods, they had a lower prevalence of extreme obesity and diabetes compared to control. There was another initiative, Address Housing, called the Initiative to End Chronic Homelessness, and it placed individuals in permanent housing. But in addition to placing them in permanent housing, it gave them access to primary and mental healthcare. That resulted in a reduced risk of new-onset diabetes. We looked at the what about the built environment? So I talked about the green spaces. We know that policies to improve the walkability and green space infrastructure also improve obesity, which is a strong risk factor for type 2 diabetes. And then finally, the food environment. If we increase grocery store presence in low-income neighborhoods, that's been shown to reduce diabetes prevalence, and also diabetes-targeted food and self-management care at a food bank. So you have a food bank in the pantry, but you're also teaching diabetes self-management skills. That's been shown to improve not only blood sugar control and nutritional consumption, but it also improves food insecurity. So the last thing I want to talk about in terms of what you can do, this is what we can do individually. So the Endocrine Society has a very strong advocacy arm, but we as individuals can be very strong advocates to address health equity in whatever sphere we find ourselves in. So I show this picture of Queen Esther, because many of you, I don't know if many of you know the story in the Bible where Queen Esther was married to the king, and there was a plan to annihilate all of the Jewish people. And her cousin Mordecai came to her and said, you know, Esther, perhaps you've come to the kingdom for such a time as this, but you've got to go to the king and tell him to save your people. And she said, well, I haven't been invited. I could get killed. And she said, perhaps you've come to the kingdom for such a time as this. If you stay silent, a voice will come up from another place. So the reason I share that story is I found myself in 2020 stuck between a pandemic that was disproportionately killing my own community, and also sort of we also had all of the civil unrest in the country. This is not a position an endocrinologist would normally find herself in, but I thought this is a time for me to use my voice as a scientist and an advocate. So I'm very fortunate to work with our government and community affairs team at Hopkins, our assistant director for state affairs, and we were able to work collaboratively with three of our outstanding leaders around health equity in our Maryland state legislature. And I know that all of our institutions have a government and community affairs department. And through this effort, we were able to testify on behalf of and provide written testimony for five pieces of health disparities and health equity legislation that passed in the state of Maryland in 2021, and many of those are actually being implemented right now. So our voices as scientists really do matter. So I think it's also important from an advocacy standpoint to recognize that while we spend a lot of our time thinking about what are we doing at the provider level, and maybe we're better now about thinking about what do we do at the system level for our individual patients, we have to move really far upstream and think about the community impact. And so that's a different level of advocacy because we actually need to change the environment in which our patients live so that we can influence their health behaviors in a positive way. So that really calls upon us to be a bit nontraditional in how we deliver care. And during the COVID-19 pandemic, when we had to roll out the vaccines, everyone thought, well, how are we going to reach many of our marginalized communities? They don't have access to health care. We went to them. We vaccinated. I know our Johns Hopkins Medicine operation, we vaccinated people in church basements and schools and gyms and strip malls. Literally, one of our medical students was driving a van around, and we were able to vaccinate over 35,000 people in Maryland who were in minoritized communities. So I say that to say that what we're thinking about now in our organization is how do we take that model and now expand it to address diabetes, obesity, hypertension, and other chronic diseases? So we really have to deliver health care outside of our brick and mortar and really can't go back to doing business as usual if we want to achieve health equity. And this is my favorite pandemic quote. It says, nothing should go back to normal. Normal wasn't working. If we go back to the way things were, we will have lost the lesson. May we rise up and do better. So I'd just like to thank my family, who's a tremendous source of support to me. My parents, who are in their mid-80s and really instilled in me the importance of serving my community. And my husband and my son, as you can imagine, my 22-year-old has a lot to say about what we should be doing to achieve equity. So that's been very interesting as he's coming of age, but very grateful for their support. And I thank you so much. Thank you, Dr. Golden. Next it's my honor to introduce Dr. Shlomo Mellman, the inaugural winner of the Transatlantic Alliance Award. The Transatlantic Alliance Award recognizes the international leader who has made significant advances in endocrine research on both sides of the Atlantic, in Europe and the United States. Dr. Mellman is dean and distinguished professor of medicine at Cedars-Sinai Medical Center in Los Angeles. He's an international endocrine leader and receives this award for his pioneering research in pituitary medicine and endocrine tumors. He has received the Endocrine Society Clinical Investigator and Scholarly Physician Awards and awards by the European Society of Endocrinology, Royal Society of Medicine, and Pituitary Society. His NIH-funded laboratory is devoted to pathogenesis and treatment of pituitary disorders, and he has trained over 70 fellows who are now leading endocrinologists worldwide. His translational achievements include elucidating the mechanisms underlying growth hormone and ACTH regulation and adenoma pathogenesis, and has spearheaded investigator-initiated, as well as registration clinical trials for treating pituitary adenomas. He co-edits Williams Endocrinology textbook, edits the pituitary, and was editor-in-chief of Endocrinology and the editor-in-chief of Pituitary. He served on the Endocrine Society Council and was president of the International Society of Endocrinology, president of the Pituitary Society, and is director of the California Institute of Regenerative Medicine. Welcome, Dr. Melman. Thank you. Thank you very much to Carol, and thank you to the society and to the European Society of Endocrinology for this inaugural award. I am extremely humbled, and thank you so much. I'm proposing a provocative question as the title of my talk. Is adult growth hormone an endocrine misnomer? I'm not going to answer the question for you. I'm going to give you the data, and let you decide at the end. These are my disclosures for the talk. The first time that we see in the literature the term growth hormone really was alluded to by Harvey Cushing in 1910, when he spoke about a hormone of growth which he realized must exist because of the fact that patients who underwent pituitary surgery for acromegaly appeared to be cured by his surgery. But it was Herbert Evans, who really was one of the giant fathers of our society, who in 1921 discovered growth hormone. In fact, the six other hormones were all founded and, in fact, invigorated by his discovery. In fact, invigorated by his imaginative ideas and experimentation indirectly, but directly he discovered growth hormone. And he writes about growth hormone only in 1935, when he talks about the growth hormone of the anterior pituitary after he'd injected daily rat pituitary extract injections for six months, and the rats grew. And we fast forward to 1988, when the concept of growth hormone and IGF-1 both being growth factors when injected into hypophysectomized mice was, in fact, elucidated. And then it took him another 20 years or so for the isolation of pure pituitary growth hormone, published in 1944. And then we spring forward to 1996, when growth hormone and its receptor were, in fact, crystallized by Sandstrom and colleagues. And today, we know that growth hormone is, in fact, regulated by multiple central and peripheral factors, impacting the peripheral JAK-STAT receptor signaling pathway on ubiquitous tissues, expressing the growth hormone receptor through the heart, the bone, adipose tissue, pancreas, muscle, kidney, colon, and, of course, the liver, which generates IGF-1 in response to growth hormone. What I'd like to do today is focus on the colon as a model for growth hormone action. And the question that we've been asking ourselves in the lab for several years now is, in fact, growth hormone implicated in cancer development. And, of course, this was generated by the observation clinically that patients with acromegaly harbor soft tissue tumors. And the clinicians in the audience are all aware of the fact that soft tissue tumors are so ubiquitous in patients with acromegaly, especially colon polyps as so elegantly demonstrated in this image on the bottom right. But in 2010, an intriguing paper came out, which was an elucidation of breast cancer pathways. And it turned out that growth hormone signaling pathways were the third most ubiquitous pathways uncovered in this observational study. And this set people thinking that perhaps growth hormone itself was involved in signaling in some way towards the pathogenesis of a malignancy. And the epidemiology of acromegaly has not been very helpful. And there have been multiple epidemiological studies both supporting and not supporting the fact that acromegaly patients harbor more malignancies. This recent study from Scandinavia is, in fact, probably the most comprehensive, studying 1,296 patients showing that not only were malignant tumors more prevalent in acromegaly, specifically renal and colorectal and brain tumors, but most significantly, benign tumors were more prevalent. And this really was a reflection of what we see clinically. No apparent epidemic of malignancy in patients with uncontrolled acromegaly. And perhaps the reason is that the growth hormone receptor sees a ligand which does not necessarily derive from the pituitary. So in addition to pituitary endocrine growth hormone, paracrine, autocrine, and intracrine growth hormone all express the ligand which binds the receptor and results in a pro-proliferative action. And many of my colleagues listed on the slide over here have utilized this concept to study growth hormone impact on transformation, on EMT transition, migration, stem cell regulation, chemo-resistance, radio-resistance, tumor growth, all derived from the fact that the receptor can be activated by the ligand regardless of its source. And the concept of autocrine and paracrine growth hormone was really developed by Bill Odell when he was actually doing a sabbatical in New Zealand in 1981 when he ground up human tissue and using, at that time, a crude raniobino assay, was able to identify growth hormone in peripheral tissues that was actually endogenous to that tissue, not derived from the pituitary, and the colon was particularly rich in growth hormone. And this has been exemplified clinically. When you look at paracrine or autocrine or intracrine growth hormone in malignancies, on the left I've shown you hepatocellular carcinoma, on the right, mammary carcinoma and endometrial carcinoma. Within these malignancies, the abundance of growth hormone actually can correlate with survival. And in these studies, survival is now plotted over 70 months, and you can see the curves of survival are shifted dramatically to the left for each of these cancers if the tumors express abundant growth hormone. So the question that we've been asking is, what is the mechanism for this endogenous growth hormone to apparently be associated with an adverse outcome for a malignancy? And Mike Waters in 2004 really set the platform for this science when he hypothesized that both endocrine growth hormone and autocrine, paracrine growth hormone, or even perhaps intracrine growth hormone, could all impact the growth hormone receptor, and he used breast cells as the model for his hypothesis, resulting in ductal elongation, EMT, increased proliferation, increased invasiveness, and immortalization of a cell. And this was really a revolutionary platform at the time, hypothetical, and I'm going to try and develop Mike Waters' hypotheses to show you that, in fact, he was quite correct and prescient in his predictions. His first experiments, which really drove the field forward, were when he took a lymphoma and he was able to target the growth hormone receptor to the nucleus of these lymphoma, injected it into mice, and you can see that the lymphoma cells that had been targeted with the growth hormone receptor actually resulted in a very, very much increased tumor volume as compared to the control animals. And this really was the first demonstration that nuclear targeting of the growth hormone receptor could, in fact, drive a malignancy. Again, this is not dependent upon the pituitary. So we asked the question, does growth hormone directly regulate the cell cycle itself? And we utilized the p53 pathway as our model. And just to recap for the audience, that aging, aneuploidy, and DNA damage all activate the p53 pathway through p21 to regulate the CDKs, to regulate the phosphorylation of RB, which ultimately drives the cell cycle. And if p53 is activated, acting as a tumor suppressor, premature cell cycle arrest occurs or, in fact, senescence. So the question and the hypothesis that we posed was, is growth hormone action mediated by p53 as it would appear to regulate the cell cycle? And the first set of experiments that we performed were to see whether growth hormone was, in fact, activated and whether p53 was involved in this activation. And it turns out that DNA damage induced by chemical or non-chemical factors does, in fact, result in growth hormone induction. And this is an example of colon carcinoma cells, which are either wild-type p53 or mutant p53 knockouts derived from bird Vogelstein. You can see that when these two cell types are treated with nutlin, a DNA damage activator, p53 is increased. And to our surprise, growth hormone was increased. And the growth hormone increase and the p53 increase were obviously not present in the knockout cells. Furthermore, it turns out that p53 directly activates growth hormone independently of IGF-1 to activate transcription and production of growth hormone in these cells. DNA damage induction of growth hormone also is evident in human samples. So this is an example of human colon adenocarcinoma. On the left, you can see the pre-radiotherapy and post-radiotherapy. The expression of growth hormone in these colon epithelial cells is quite abundant after radiotherapy. And another patient example on the right of DNA damage once again. Chemotherapeutic induced DNA damage results in an induction of post-chemotherapy growth hormone in this tumor sample. We then resorted to studying human colon organoids derived from induced pluripotent stem cells. These are normal, non-transformed human colon cells. And you can see that using etoposide, which induces p53 in terms of a DNA damaging agent, also induces growth hormone. And the induction of growth hormone was really functional because STAT5 was in fact also induced by the DNA damage induced by etoposide. And when these cells were subjected to inhibition with siRNA, you can see that inhibiting growth hormone also inhibited STAT5 and abrogated the effects of etoposide on these cells. To our surprise, within the culture of the human colon organoids, growth hormone was also detected in the medium in response to the DNA damage activity of etoposide. And this led us to suspect that growth hormone in response to DNA damage was in fact being secreted in a paracrine fashion, and we could actually identify growth hormone by Western blotting in the medium of these, again, non-transformed human colon organoids. So the question is, what is growth hormone doing in the circumstance? So, again, using non-transformed human colon cells, either transfected and overexpressing human growth hormone or treated with human growth hormone, you can see that the induction of growth hormone actually suppresses p53, suppresses p21 in both these models, and this observation can be reversed using the SI growth hormone. In fact, in vivo, if animals are injected with tumor cells overexpressing growth hormone, you can see the growth hormone levels are extremely high, and the colon p53 in these animals is in fact suppressed. So these two sets of findings led us to conclude that p53, the tumor suppressor, actually induces growth hormone, and growth hormone, the apparent growth factor, blocks p53 in an auto-regulatory loop, and this auto-regulatory loop formed the basis of several of our subsequent experiments. So the first question that we ask is, if that is true, does growth hormone deficiency associate with induced p53, the tumor suppressor? For this, we utilize the PROP1 knockout mouse, which this audience knows very well. The PROP1 mouse has no somatotrophs, increased longevity, reduced incidence of cancers, and delayed aging. Sure enough, growth hormone is absent, and to our surprise in the colon, supporting our previous in vitro findings in both murine and human models, the PROP1 knockout mouse has no growth hormone and high p53 levels, high p21 levels, likely explaining what is in the gray box. Furthermore, the growth hormone receptor knockout mouse, the GHRKO, p53 is high, and not surprisingly, Ki67, a marker of cell proliferation, is completely absent. As clinicians, we all know the syndrome of the APC mutants when patients with the APC mutation develop polyposis colon cancer, and this is the pathway which induces APC, the tumor suppressor gene, which is mutated in families with adenomatous polyposis coli, and we reasoned that perhaps growth hormone could be implicated in this cascade model, again using normal human non-transforms colonocytes treated with growth hormone. You can see that CDX2, the precursor of APC, and APC itself are totally suppressed when treated with growth hormone, and in fact, if you look at the organoids in terms of their expression, their immunofluorescence, you can see that CDX2 is suppressed and p21 is suppressed, supporting that notion. Do mice have functional implications for colon tumors? We then resorted to answer this question by crossbreeding transgenic mice which are very prone to colon tumors, the APC min mouse, with the Prop 1 knockout growth hormone knockout mouse, and you can see that the compound transgenic, so this is now a mouse which is prone to colon cancer and deprived of growth hormone. P53 is markedly induced. P21 is induced, and you can see the difference in visualizing the gastrointestinal tracts of these mice, and you can see on the top the min heterozygote compared to the transgenic, which has now been deprived of growth hormone, and the question is, is there a difference in tumor formation? And small intestine tumor number and size were dramatically decreased by depriving the compound transgenic mouse of growth hormone. Tumor size was increased, and most importantly, colon tumor prevalence, which was so abundant in the transgenic APC min mouse, was almost wiped out by depriving the mouse of growth hormone. So then we asked, well, is this true for the human? And these experiments were extremely challenging, but the question that we asked in human patients were, does colon growth hormone receptor signaling function as a pro-proliferative system? We performed a clinical trial with pegvisimant treatment of acromegalic patients who received 20 milligrams a day for eight weeks, and asking the question, does growth hormone receptor signaling blockade induce P53 and APC in the human colon mucosa? And that was the question we asked, and we biopsied these patients before treatment, and then we did a repeat colon biopsy eight weeks later. A very, very challenging experiment. We tested seven patients. In all of them, P53 was induced by pegvisimone. By blocking growth hormone receptor signaling, you could actually upregulate the expression of the tumor suppressor P53, as well as the suppressor APC and P21, supporting the animal findings in the compound transgenic mouse. And this is a demonstration in humans that we can actually regulate P53, the tumor suppressor, in human colon mucosa by blocking growth hormone receptor signaling. Well, what is the significance? Now I'll just refer you to an older paper, really a beautiful clinical study by Dr. Guevara in science translational medicine 10 years ago, showing when he looked at his patients who were growth hormone receptor deficient and compared their mortality and their morbidity to their unafflicted relatives, you can see that the unafflicted relatives of the growth hormone receptor deficient patients died of cancer and of stroke. And in contrast, the patients with growth hormone receptor defective signaling died of convulsive disorders and alcohol, and there were no cancer deaths, supporting the observation which we had shown in terms of the biopsy of the patient's mucosa in response to growth hormone receptor blocking. Not only was this observation supportive of what we'd seen in vitro, but Ron Roosevelt was kind enough to send us some fibroblasts derived from one of these patients. And you can see on the left, we found supporting our animal data and our previous human data that in the mutant patients, P53 was very high as compared to their unafflicted relatives, which could provide a mechanism as to why they don't develop cancer. Not only was P53 high, but when we took these fibroblasts and we retransfected intact growth hormone receptor, P53 was suppressed. And so this was a further affirmation of the mechanistic findings, which led us to affirm our hypothesis. So at this point, we felt that we really had shown both cellularly and in animal models and in the human models, restricted as they are, that this loop was in fact operative. That P53 maintains proliferative arrest, whereas growth hormone eludes proliferative arrest, so there's this auto-regulatory loop that is operative in epithelial cells. And that growth hormone, in fact, now the term that we use is NPGH, non-pituitary growth hormone, actually enables a pro-proliferative mucosal field change. So the question is, how does growth hormone deficiency induce P53 to buttress this appropriate anti-tumor defense? Do we have a mechanism? And I'm going to show you some data which would be suggestive of a mechanism for these observations. So again, to remind you, after DNA damage, the cell responds to try and repair the DNA. And whether the DNA damage is due to a DNA break induced by multiple factors, including ultraviolet light or chemical breaking or any other environmental triggers, aneuploidy itself will all result in the DNA damage response mediated largely by the key factor of ATM, phosphorylated ATM, acting through the cascade through to P53 to result in cell cycle arrest. Non-homologous end joining or homologous recombination results in repair, hopefully, of this DNA damage cascade. And the marker of DNA damage, which I'm going to show you in the data that we used, is gamma H2AX. In fact, taking those human colon organoids, once again, these are organoids that are not transformed, if you treat human colon organoids, non-transformed organoids with growth hormone in vitro, PATM, the DNA damage response factor responsible for this entire cascade is virtually wiped out. Gamma H2AX, PCDNA, P53, the whole pathway is suppressed and DNA repair is reduced at least by measuring non-homologous end joining. So it appeared to us that growth hormone suppresses the DNA damage response, resulting in high accumulation of DNA damage. And measuring DNA damage by the comet assay, this is looking at the intensity and the length of the comet's tail in the single cell electrophoresis as a reflection of DNA damage. You can see that transfecting these human organoids with lenti-expressing growth hormone, antiviral-expressing growth hormone, DNA damage is high. It accumulates in response to growth hormone, likely because the DNA repair pathway is suppressed, abrogated by growth hormone. It's also true for exogenous growth hormone. So this is now mimicking endocrine growth hormone in vitro, where you actually add the growth hormone to these non-transformed cells. You can see that the cells were treated with a toposite for up to three hours, and growth hormone was either added or vehicle in the control. And you can see that the dramatic induction of PATM in the control cells is attenuated by growth hormone, DNA repair is suppressed, and DNA damage accumulates supporting the previous findings that I showed you. And in vivo, those mice that are experiencing high levels of growth hormone from an inoculated tumor-expressing growth hormone, and you look at their colon, their colons, besides having high P53, suppressed P53, have high levels of DNA damage. And in order to try and understand a mechanism for the paracrine growth hormone action in the colon, we resorted to these microfluidic chips, which have dual chambers, where we were able to co-culture colonocytes, again, non-transformed hewlin colonocytes, with lentigrowth hormones secreting fibroblasts. So the fibroblasts are making the paracrine growth hormone, and the colonocytes in this experiment are the targets. And you can see that the target colonocyte, seeing paracrine growth hormone expressed by the lentigrowth hormone fibroblast, has suppressed P53. So we've now recapitulated in vitro a paracrine suppression of P53 by paracrine growth hormone. The cells proliferate, and again, going back to looking at the response to this DNA damage, you can see the DNA damage in the fibroblast-derived growth hormone-targeted colonocytes is high. And so the cartoon image shows you on the left the impact of the lentiviral control expressing fibroblast versus the lentigrowth hormone expressing fibroblast expressing paracrine growth hormone. You can see that the paracrine growth hormone suppresses the entire DNA response pathway. Then because of these observations, and actually this was almost serendipitous, growing these colon organoids in vitro for two months in an attempt to mimic, a mimic of aging in vitro. Again, these are human cells, they're non-transformed, they're aging. We were surprised to find that after two months in the green, the expression of growth hormone, endogenous growth hormone, was very abundant. In fact, telomere length in two months, after two months culture, was also suppressed as a marker of aging. Growth hormone mRNA increased dramatically, IGF-1 mRNA was unchanged, and again, as they grew in culture, as growth hormone levels became more abundant after eight weeks, P53 was suppressed, as we'd seen in our earlier models, and in this model of aging, the time in culture of eight weeks also resulted in a suppression, attenuation of the DNA response pathway. Well, this was an in vitro improper model of aging. What about in vivo? These are now age 24-month-old mice, and you can see, not surprisingly, in the blue, that after 24 months, the colon of these cells expresses abundant DNA damage in the blue dots. However, the growth hormone receptor knockout animal does not express the DNA damage. So, after 24 months, you can see that P53 is high if you deprive the aging animal of growth hormone receptor signaling, whereas the wild-type animal has low P53 and high levels of DNA damage. Is this true in humans? Well, we were surprised to find that in humans, growth hormone expression in the colon is also age-dependent, and you can see the growth hormone mRNA in a 50-, 60-year-old patient on the right compared to a 22-year-old patient on the left, far more abundant. Not only is growth hormone higher in the aging colon, but DNA damage is higher. Sixty-six-year-old male with expressing gamma H2AX, a marker of DNA damage, compared to a 17-year-old patient. And so, this was affirmation that what we'd seen in the growth hormone receptor knockout animals was likely true in human ex vivo specimens as well. What is the mechanism? Well, we believe that the mechanism is that the non-pituitary growth hormone is induced in senescent cells, and these are four examples of senescence. Medication-induced senescence by a RAS mutation, ultraviolet-induced senescence, replicative senescence replicating these cells for 61 cycles, and medication-induced senescence in this circumstance, etoposide again. And you can see in each of these senescence models in vitro, growth hormone, non-pituitary growth hormone is increased dramatically together with beta-gal and P16, the markers of senescence. And if you look carefully, you can see that in these senescence models, growth hormone and beta-gal are expressed in the same cell. And once again, we saw the paracrine growth hormone secreted in the medium, which was actually blocked by the siRNA for growth hormone, and so we believe that this could in fact be the mechanism for the data that I showed you previously in the mice, and possibly for the data that we've seen in humans. Well, this mechanism could also explain what we've known now for many years in the literature, especially by the beautiful work of Andrei Bartki, that mutant growth hormone results in enhanced survival of mice, whereas excess growth hormone reduces murine survival. Dramatically, you can see the shift over here to the left by excess growth hormone reducing survival in these experiments, and the data that I've showed you for senescence could in fact explain the longevity. It may also be true in humans, and this is a beautiful clinical study performed in the Rotterdam Aging Study by van der Spool and colleagues, which shows by measuring growth hormone in the offspring of individuals who are centenarians. So on the left, we have the offspring, and on the right, we have the controls. These offsprings in the red circles all had first-degree relatives who lived over 100, and their growth hormone is lower. Leading these authors to conclude that low growth hormone entropy in fact enriches familial longevity, and this was really a very elegant study where they measured growth hormone every few minutes over 24 hours. This just isn't a single spike of growth hormone, which we are all aware of, and once again, we believe that the data that I've showed you could explain a mechanism for this observation. And finally, as a supporting evidence, there's a really fascinating study published last year from L. B. Ali looking at acromegalic zebrafish and comparing them to aging zebrafish, and you can see that surprisingly, the deleterious genes found and expressed in acromegalic zebrafish and aging zebrafish overlap. And the aging and the acromegaly gene profile appears to overlap in at least 50 percent of the expressed genes, both upwardly expressed and downwardly expressed, being a very intriguing model supporting the notion that in fact aging and growth hormone overexpression are in fact deleterious, deleterious outcomes. So in summary, what I've shown you is that we have evidence that DNA damage and aging is the example, but chemotherapy could also be an example, ultraviolet light could be an example. Any DNA damage with an altered DNA structure, which causes cellular injury, reducing the viability of the organism, induces growth hormone. And this non-pituitary growth hormone dampens, suppresses, blocks the DNA damage response, blocking the entire response pathway, and I've given you supporting data to affirm this box and the hypothesis in this box, resulting in the fact that DNA damage abundance, DNA abundance appears to increase in response to growth hormone. And if you look at Francis Crick's original definition, DNA repair mechanisms protect DNA from assaults, radiations, and all the hazards that I've mentioned, including aging. And this is exactly what evolution by natural selection would have led us to expect. And the data that I've shown you and the data in the literature supports the notion that growth hormone receptor signaling accumulates DNA damage, leads to chromosomal instability, and does enable cell transformation by changing the microenvironment to enable mucosal field changes, favoring an age-associated cell transformation. So growth hormone is really a hormone of growth, but is it an adult endocrine misnomer? We know that we need growth hormone when we are young. Differentiation, growth, and adult homeostasis are vital functions of growth hormone. In the symmetrical mature adult, the organism integrity of which we all achieve at maturity is in fact enabled by growth hormone. But as we age, DNA damage, epithelial proliferation, and decreased longevity all appear to be triggered by growth hormone. So there does appear to be a switch. Now our challenge as endocrinologists interested in pituitary hormones is to understand why this switch occurs to turn growth hormone from a true hormone of growth to a hormone of DNA damage. And in fact, if you look at yeast, this is an example of a yeast with a disrupted growth hormone IGF-1 mutation. These yeasts, which are mutant growth hormone signalers, are in fact more long-lived and protected from what the authors call inflammation. And these two oldest ladies in the world record, in fact, reflect that. Jean Calment was apparently the oldest lady in the world. There was some controversy about whether it was really her or her daughter who kept herself with the same name to get her social security checks. Nevertheless, she lived for almost 120 years or more. And Kani Tanaka, unfortunately, I wanted to talk about her, but she passed away just a few weeks ago. And you may have seen the reports about her. Nevertheless, these two wonderful ladies avoided disease and disability. They maintained their cognitive function until the very end. And they really were fully engaged in life. And remember, we all know as endocrinologists that our growth hormone levels decline with aging, likely contributing to the fact that these women lived so well. So I would only end off by suggesting to you and wishing you a healthy somatopause. And may you all live so long and healthy as these two ladies. And I really wanted to thank and acknowledge the wonderful collaborators of mine, my colleagues in the lab who are responsible for the original data that I've shown you, and especially to mention Vera Chesnikova, Svetlana Zonas, and Rob Barrett for their terrific work, much of which I've shown you today. So thank you very much.

Dr. Kathleen Page

Johns Hopkins Medicine

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