So, welcome to the ACE Rare Diseases webinar series. My name is Dr. Kevin Yuen from Phoenix, Arizona, and it's my pleasure to welcome you to the fourth of the rare diseases that ACE is organizing. This is the fourth of its series and entitled Adult Growth Hormone Deficiency. And I have my colleague here, Chris Yadinak, who is going to be helping me with the slides. So next slide, please. So the title of today's webinar is entitled Fatigue, Abnormal Body Composition and Bone Loss. Is Adult Growth Hormone Deficiency to be Blamed? And I will be presenting this talk together with Chris Yadinak, who's the associate professor department of neurosurgery in Oregon Health and Science University in Portland, Oregon. Next slide. And this activity is supported by an educational grant from Ascendis Pharma. Next slide. And these are our disclosures. And today, our learning objectives will be, upon completion of this webinar, participants will be able to describe the diagnostic and testing approach for the clinician when it comes to evaluating a patient with adult growth hormone deficiency, and then furthermore, to utilize the evidence-based guidelines that are published together with its algorithms and consensus statements to diagnose and treat this condition, and finally, to identify and treat long-term complications and its associated comorbidities of adult growth hormone deficiency. Next slide. So with this, I am going to hand over to Chris to talk to you about the first part of the talk, starting with this slide. Thank you, Kevin, and thank you to ACE for this series and the invitation. So first of all, I think we'll start by looking at what growth hormone is, just as a review. Growth hormone is also known as somatropin. It's a single-chain polypeptide, 191 amino acids long, and it's produced by the somatope cells in the anterior pituitary. So originally, it was discovered around the beginning of the 19th century to regulate growth in children, but by the current time, of course, we know that there are many other metabolic functions for growth hormone. Growth hormone replacement actually started with the human growth hormone from cadaveric sources. However, with the connection between the Human Growth Hormone Administration and Khrushchev Jacobs disease, that was discontinued around 1985, I believe, and at that time, recombinant DNA gene had been cloned, and so there was a switch to recombinant sources. Medical significance, of course, both excess in terms of giantism and acromegaly in what we're talking about today is growth hormone deficiency. In short stature, it's diagnosed in between 1 in 4,000 and 1 in 10,000 children, and usually that occurs about the time that we see this growth deceleration of about 0.3 standard deviations, and this is usually on the regular pediatric auxology exams. As you see here, we see that the child begins to fall off this growth curve fairly early, and at this point in time, this child was actually diagnosed, which was fairly late, but then again, they were able to rejoin the lower level of the growth curve. So, girls' short stature is important to evaluate. I think the other issue that's important to consider is that often girls get less attention in terms of their growth versus boys, and so understanding that that growth can be essential for development of girls as well as boys. There are other ways of measuring growth. Side circumference is one, sitting height to arm space ratio should be a 1 to 1 ratio, and if not, again, there could be a growth issue. So bone age can be evaluated on x-ray, and often we do that to evaluate whether the child is actually growing as expected, and then the status, as we'll talk about later, of the growth plates and growth plate fusion. Big testing is often done, and we'll look at the circumstances around that, but where etiology is unknown, it's important to look at brain imaging and particularly pituitary imaging for a space-occupying lesion. So, evaluation then can be determined. What's the target for growth for a child, and there are several types of equations that can help with this, and this equation is basically mother's height plus father's height, and then add 5 inches or 13 centimetres for boys, and subtract 13 centimetres or 5 inches for girls, and then divide it by 2. This provides the target height for the child or expected growth. So then what happens when the child reaches adolescence? So at that point in time, we can look at the growth plates and see if they're fused. Usually fused a little later than girls, 15 to 17 for boys, 14 to 15 for girls. Treatment of growth hormone in adults as well is an injection until very recently. It's been a daily injection, usually at bedtime, and now, of course, we have a long-acting as well, so a weekly injection. The administration is usually by a pen device, which has lots of advantages. It's easy to manage. There's obviously a window here where you can see what that dose can be, and the advantage for children is, and adults as well, I guess, the spine needle, the needle also can be obscured, so it's not obvious. This device can readily be used by young children, so young children can learn to be independent and self-manage with very little supervision from parents at an early age. So when starting growth hormone, it's a weight-based dosing that's a little different according to some countries and also according to the vendor, so it's important to look at the prescriptive information. So starting at the lowest dose possible is typical as in adults. Again, it's usually given daily, although we can switch to a weekly injection, and it's usually given at night. The height velocity needs to be continually checked, particularly yearly, but again, for children starting growth hormone, that may be more frequent. IGF-1 can be checked at a one- to two-month interval to make sure that it's in the upper limit of normal for age and gender. In transition, if there's a break in growth hormone between the childhood and adult doses, if they're restarting, we usually restart at 50% of the childhood dose. So transition is a tough time. The important part of transition from the childhood to adult treatment for growth hormone is planning, and the planning really needs to start way back early in childhood so that the child understands what growth hormone is, what it does, what it can do, what happens if they don't get it, and also developing this sense of control and independence in administration. What do they expect to have happen? What do the parents expect to have happen? So evaluating these things way before transition is important. There are a number of barriers, unfortunately, to continuing growth hormone in that period. Cost is a big issue, particularly when the child becomes independent and has to transfer to their own insurance plan. If they're moving out of state, if they're moving out of town, if they're going to college, coordinating that care, both with a new provider, endocrine provider, and also with an adult provider in preference to a pediatric provider is important. Getting that drug supply and getting it on a regular basis so that the child can receive it, particularly if they're moving frequently, can be a big issue. Substance use, of course, and other substances that the adolescent may use during that period needs to be considered, but there are also a lot of social stigmas associated with administering themselves an injection, and so that can become a barrier for a child continuing treatment. So when would you continue and when would you stop treatment for growth hormone? So typically, idiopathic sources or ideologies, once the height velocity has been achieved, then usually we stop the growth hormone and then reevaluate after one month. If, for example, the IGF-1 is less than two standard deviations or if there's greater than three pituitary deficiencies, then you can simply restart or continue the growth hormone. In other circumstances, you may want to retest to see if there is consistent growth hormone deficiency. If there is, then again, before the growth hormone stimulation test, sex hormone priming is recommended, and if at that point in time, growth hormone deficiency persists, then we restart the growth hormone. Side effects of treatment, short term, some people will experience some swelling, usually that's brief, but often it's associated with joint and muscle pain. Elevated blood sugar is not terribly common, but can occur often, it's again brief. It may be that it's more elevated in the morning because of the growth hormone surge at night, and then we get the dawn phenomenon where we have increased levels in the morning. Allergic reactions are very rare. In 20 years, I've really not seen an allergic reaction, but it's often side reactions if that occurs. Headache is not uncommon, again, it's often transient, sometimes reducing the dose temporarily can be useful in those cases. Long term side effects, greater than 25 years, there's a lot of concern around the potential for malignant tumors, but there's really not enough supportive data at this point in time to indicate that malignancies are increased, and likewise, the pituitary tumors are unlikely again to increase secondary to growth hormone, but we'll talk about other circumstances subsequently. So monitoring every six to 12 months, the key here is using the same lab because there's variability within labs. So understanding what that standard deviation also is within those labs is really important. So where there is concomitant diseases like diabetes, malnutrition, liver and kidney disease, that may impact and lower the IGF-1, so consider that when you're adjusting doses. It's recommended that we evaluate fasting glucose, hemoglobin A1c, and fasting lipids every one to two years, and also serum-free T4, and I recommend TSH and free T4 at the same time after you start, and then periodically every six to 12 months post-treatment. HPA axis should be evaluated with either a morning cortisol ACTH, or if there's symptomatology of concern, then for adrenal insufficiency, a stimulation test. Measurements of BMI, of course, waist circumference, hip to waist ratio, should be monitored on a regular basis. Signs and symptoms, of course, of growth hormone deficiency, and if we're hitting target, for example, in terms of symptoms. And then monitoring regularly for cardiac disease, cardiovascular disease with lipids, et cetera, as we talked about before. Side effects that are very, very rare, bone density, we would like to evaluate that every two to three years just to make sure that the bone density is on track. Quality of life. Chemotherapy assurances require a quality of life done each visit or each year, but it's also nice to be able to titrate medication to quality of life as long as it still remains within the upper limit of abnormal for age and gender. So introducing a 21-year-old female, she has panhyperpituitarism due to a childhood supracellular germanoma. She's status post-chemotherapy. She also had cranial radiation. She's on three pituitary replacements, desmopressin. She is on hydrocortisone for AI and levothyroxine. So the standard deviation is still a little low. She underwent a Massimoralin test, which incidentally is no longer available, but her peak level was still low, 2.27. She complains that she's really more fatigued since she stopped treatment. She's concerned also about what happens with her bones in the future, and rightfully so. She really is amenable to restarting the growth hormone, and as we talked about before, we usually lower that dose, and her dose in childhood was two milligrams a day. So things to think about, the transition, and what are the challenges that this patient and other patients do experience? What are the safety concerns regarding that replacement, as we talked about, fertility in pregnancy, use in sports, and long-term adherence? So what are the challenges? We know that there's significant psychological challenges that occur during adolescence, apart from pregnancy, but forming relationships and being different than other peers is an important issue, considering the concerns, as we talked about, with stigma associated with self-administration of an injectable, particularly growth hormone. Young people may feel more comfortable with pediatric endos, so switching that endos is really challenging at this particular point in life. They've really only had one provider during that period. They trust that provider. The provider themselves may have a little difficulty giving up this patient as they move into the adult arena, and there could be a little dissonance between the way in which the pediatric endocrinologist treats the patient and the adult endocrinologist. The adult endocrinologist may expect a lot more independence from this patient, and so there could be a little bit of dissonance during that period. But the other issues in terms of maintaining growth hormone, about 70%, unfortunately, of patients within this period are actually lost to follow-up. They're tired of getting injections. They don't want any more injections. They don't have access, or they don't want to do the stimulation test. It may be that they're really concerned about, is it really working? What are the side effects that they're experiencing? They want to be independent. They don't want to be dependent on any medication. They don't feel like they're ill. They don't feel like they need that treatment. The cost of the medication and the insurance coverage is a big issue in this country. Are they covered? And particularly after they transition from their parents' insurance, which may be early, or it may be 26 when they leave college, they may not have experience in how to coordinate their care, how to access care, how to continue that care. They may have to establish themselves with a provider in a new location. And again, if they don't understand the metabolic consequences of discontinuing treatment, that can be an inhibitor as well. So ACE recommendations from the 2019 recommendations about replacement in transition. Adults with childhood onset ongoing treatment is important for bone mineral density, for adverse body composition, which also feeds in, of course, to self-esteem for young adults and then for cardiovascular risk markers. So resuming that, there's good studies now that indicate that there's improved body composition, there's improved bone mineral density, quality of life improves, particularly after continuation of growth hormone for at least two years. So the other importance is main or establishing a high enough peak bone mass during the developmental period. So that's between the ages of 20 to 30. So if the adolescent continues growth hormone, they're more likely to reach an adequate peak bone mass so that as that age-related decline occurs, particularly for females, then we see less osteoporosis in later years. So again, the recommendations on restarting and maintaining growth hormone in transition, we start at 50% of the childhood dose. IGF-1 should be monitored to avoid exceeding the upper limit of normal. So we want to keep it in the upper limit of normal, but we don't want to exceed that limit. So it's not that a little is good and more is better. Growth hormone should be modified based on the clinical response, the serum IGF-1, and then some individual considerations from the patient themselves in terms of quality of life, et cetera. So measurement, as we discussed, should happen at least annually, height, weight, BMI, waist circumference, lipid profile every two to five years, quality of life with the AGHDA questionnaires, and monitoring at least yearly to make sure that we're reaching that target. So this is just an algorithm that discusses what we talked about previously, idiopathic forms of isolated growth hormone deficiency may not need further evaluation if the IGF-1 is actually in the normal range. At that point in time, we can discontinue treatment. However, if there's suspicion for the low growth hormone, IGF-1 should be evaluated, and if it's low, we can go to further testing. Macromoralin at this point in time is not available, a mesomoralin, so we use either an ITT and most commonly a GHST, and that's with glucagon at this point in time. But again, on the other side of this algorithm, congenital defects and hormonal deficiencies greater than three hormonal deficiencies, we really don't need further testing. So we can go ahead and restart the growth hormone at 50% of the childhood dose. With organic causes of GHD, we may want further testing, and again, the GHST is important. Now, what level is important? And so a peak of less than three is considered diagnostic, but that is really BMI dependent. So with a BMI that's as high as over 30, then that peak level less than one is diagnostic. So effects long-term on secondary neoplasms, there's not a lot of data that's really indicative of higher risk. However, there is one study, Urgen, et cetera, that indicates, it's a fairly large study, an increased risk of meningiomas, and that was supported by Wood-Mancy, and that meningiomas were the most common risk. Other than that, most of the studies that have been done are equivocal, and so don't show an increased risk of neoplasms or secondary neoplasms. Again, childhood cancer survivors, there's an increased risk if they started on growth hormone related to previous exposure of cranial irradiation. However, this is very individually defined, and so at this point in time, the Endocrine Society in 2018 recommended careful consideration of growth hormone if the child is a survivor of cancer. The use of growth hormone for fertility during pregnancy and for increased fertility, although it's not FDA, it has been used. Several studies support the use of growth hormone because it actually increases oocyte viability and FSH stereogenesis, but again, it doesn't appear that it impacts either the mother or the fetus, but there's no significant data at this point in time to support it. So, more data is needed on the safety and use of growth hormone in women with GHD to assist conception during pregnancy. So, the GHD and sport activities, GH does seem to improve body composition, but may not improve strength. It may worsen exercise capacity, particularly post-adolescence, and it may increase the risk of AEs. So, it's not recommended for treatment during, for sports activities, and it certainly isn't effective in increasing sporting prowess. So, detecting growth hormone is, in abusive situations, is challenging. It has a very short half-life, even the exogenous administration. Urine sampling is difficult. There's no specific biomarkers at the moment for testing, but again, it continues to be illegal and discouraged. But it becomes challenging for those people that have growth hormone deficiency, bona fide growth hormone deficiency, and are treated with growth hormone, exogenous forms of growth hormone deficiency during sporting activities. So, with that, I'd like to turn this over to Kevin to talk about adult growth hormone deficiency. Thank you, Chris. So, the question is, what is adult growth hormone deficiency? And I think many patients, and also even some providers, get confused simply because the name growth hormone is confusing, and people tend to think that it's only responsible for promotion of longitudinal growth. Well, actually, as this entity has actually been around now for several decades, it's characterized by pathologically lower growth hormone levels, more so than the physiological decline in growth hormone IGF-1 levels associated with aging. And so, this could be usually typically as a result of pituitary tumors or radiation or both that is causing the excessive decrease in growth hormone, more so than the physiological decline associated with aging. And then the other question becomes, well, if that's the case, then what do you typically see, or what types of clinical features do you see in these patients? As you can see, this is generally very different to children, because with children, you have problems with growth, but then you don't see that in adults who are already fully grown. So, these are these parameters that are associated with adult growth hormone deficiency. You have a reduction in lean body mass with an increase in central fat mass. You have a tendency for a reduction in bone marrow density. There's also studies showing the reduction in cardiac capacity. The change in the body composition with a reduction in lean body mass and an increase in fat mass predisposes patients to the metabolic syndrome-like features that is predisposing that is predisposing patients to cardiovascular disease and diabetes, glucose intolerance. And there's also significantly, especially for those with severe growth hormone deficiency, they not only have a reduction in terms of their cognition, but also studies that have shown that they also impaired both in social isolation, they have mental fatigue, they're more prone to develop depression, and also have dissatisfaction with their body image and low self-esteem. Next slide. So, as you can see here in this picture here, with the associated comorbidities associated with growth hormone deficiency, what happens when you replace growth hormone? On the left-hand side are the comorbidities and the symptomatology associated with the syndrome. And on the right-hand side is a combination of studies that have shown that growth hormone replacement does improve the cognitive function and psychological well-being. The study results on the right-hand side you see can be variable. So are the effects of growth hormone on lipids and cardiac function and exercise capacity. In terms of its effects on gluconeogenesis, it is very dose dependent, meaning higher doses of growth hormone used is associated with higher risk of glucose intolerance, and lower doses generally tends not to be the case. But importantly, the effects of growth hormone in previous studies have consistently shown that body composition, particularly increase in lean body mass and a reduction in fat mass, provided adequate doses are used, have consistently shown that there is improvement in body composition seen in most, if not all of the studies that have been published so far. Likewise with bone marrow density, where the effects of growth hormone on the bones are consistently shown that it does improve BMD if used long enough. So then the question becomes, well, now that you know the effects and how do you counsel your patient, then the next thing is what are the types of patients that you would consider screening? So obviously you'll need to know the potential causes of growth hormone deficiency in adults. And here in this slide here is divided into both acquired and congenital. And the ones that are highlighted in the red arrows are the causes that are most commonly associated with adult growth hormone deficiency. Although in the recent years, there's also increasing recognition that growth hormone deficiency can be manifested following head injuries, strokes, and even some arachnid hemorrhages. So the lesser known causes are now becoming more and more recognized. Next slide. So with that in mind, so I'd like to discuss a case example that is slightly different to the case that was described by Chris earlier. This is an adult onset growth hormone deficient patient. So he is a 54-year-old male who initially presented with a non-functioning micro-adenoma affecting his vision and therefore resulting in him having underwent a trans-funnel surgery four years ago. But because of the nature and the invasiveness of the tumor, serotectic radiosurgery was also performed three years ago. And now he has deficiencies in his thyroid and cortisol axes, which is why he's on stable doses of thyroxine and hydrocortisone. And he presents with an IGF-1. SDS is in the lower half of the normal range, minus 1.7, but presents to clinic with increasing weight gain, 10 pounds over the past six months, despite his best efforts in trying to control and also finding it difficult with energy levels, particularly in terms of his jaw, where he's finding it difficult to focus and concentrate as a relevant family history of osteoporosis, hyperlipidemia, and cancer. So he read on the internet about the syndrome of adult growth hormone deficiency and that this may be related to what he may be having. So he comes to you and he wants to discuss this syndrome further and also wants to know more and is keen to know whether he would be a candidate for growth hormone treatment. Next slide. So in a patient, when you see such as this patient in clinic, there are several important points that needs to be discussed and thought of. Firstly is who to screen for adult growth hormone deficiency, because it's clearly not realistic to screen every patient that walks through the door who complains of fatigue and weight gain. So you kind of need to know who, and in my previous slide, I alluded to earlier, the typical patients are those who have had a history of pituitary surgeries or pituitary tumors or anything that affects the pituitary gland in that area. And then there's the question is, once you've decided who to screen, then the question then becomes, how do you screen these patients? What types of tests would you use? And if you diagnose the patient, then how would you start therapy and monitor treatment efficacy? And then also, this is a treatment that is not a short-term thing. It involves many months, if not years of growth hormone replacement. So there's also the safety aspects of growth hormone that needs to be discussed with the patient. And finally, there's also the use of growth hormone, which is highly discouraged for anti-aging purposes that I think in some cases needs to be emphasized that the use of growth hormone in bona fide growth hormone deficiency in adults is really to replace the deficient hormone and is not used for anti-aging purposes. Next slide. So to screen a patient, the first test that you would consider using would be the serum insulin micro factor one. And here in this slide here, in this figure, you can see of patients, a totaling of 152 patients, 81 men and 71 women who have had the diagnosis of growth hormone deficiency following pathology to the hypothalamic pituitary area. And what you see that's very notable is the fact that between the ages of 40 and 80, the patients who have been diagnosed with growth hormone deficiency can have IGF-1s that actually fall within the lower half of the normal range. Whereas the younger patients between the ages of 20 and 30, if the IGF-1 is low or at least below minus two standard deviations, there is a higher likelihood that younger patients with very low IGF-1s are more likely to have growth hormone deficiency. And this is where the IGF-1 becomes more reliable when they're in younger patient versus in patients who are in the age range between 40 and 70 years old. Next slide. As you can see here, this is to emphasize that point. Okay, next slide. So this is an algorithm, again, from the ACE 2019 guidelines that breaks it down into three groups. So on the far left, you see that those patients who have three or more pituitary hormone deficiencies and a very low IGF-1, by definition, they have a 95% chance that they will have growth hormone deficiency. And as a result, no further testing is needed. They can be treated based on the these findings. Whereas for those who have two or less pituitary hormone deficiencies and low IGF-1 below zero standard deviations, further testing is required. Likewise, for patients who have a history of hypothalamic pituitary tumor surgery, radiation, or any form of insult or structural abnormalities in the hypothalamic pituitary area, and you have a high suspicion and find that the IGF-1 is actually below the lower half of the normal range, those patients also may need further testing. This is obviously in the form of growth hormone stimulation tests. And as Chris mentioned to you earlier, in the U.S. there's only widely available tests, the insulin tolerance tests of which the peak growth hormone of 5 micrograms per liter is used as the cutoff, and the glucagon stimulation tests of which is BMI-based of less than 3 for normal weight patients and less than 1 for overweight patients. And this is because Macy Morellin, who at one point was available, is now no longer available. We are hoping that it would become available, but we just don't know when that's going to happen. Next slide. So screening for growth hormone deficiencies in adults can be complex and challenging. And why is that? It's because, unlike children, this condition has no single distinguishing clinical feature. And you can see that many of these features are subtle. They can be very difficult. And many patients that you see in most endocrine practices have very similar symptoms, particularly weight gain, fatigue, brain fog, tiredness. And so it's really hard to pick patients out to screen them appropriately. Secondly, when there is a possibility of assessing for growth hormone deficiency, unlike assessing for hypothyroidism, where you measure free T4, which is the hormone, the direct hormone, you cannot measure growth hormone directly because randomly measured growth hormone levels are usually not diagnostic because as you know, from physiologically, they can be episodic and pulsatile. Thirdly, it's also that the other biochemical markers can also be problematic because they are not well validated. And also they have assay issues as well. So this makes it somewhat challenging when you're using other biochemical markers to assess for growth hormone deficiency in terms of screening purposes. Then the other issue becomes also is the performing growth hormone stimulation tests. And it is quite a cumbersome process because this is not a test that can be done with a patient going into a lab and having his or her blood drawn randomly. It requires a provider to actually order, perform and interpret these tests and also requires, and many times requires prior authorization with insurance approval before these tests can be performed. These tests are particularly like the insulin tolerance test is contraindicated, particularly in patients with cardiovascular, unlike cardiovascular disease or predisposition to epilepsy. These tests also require multiple IV access and blood draws and therefore requires these tests to be performed in an infusion unit in most cases, and also requires the possibility of having the cardiac facilities to be present in case there is a cardiac arrest. Because again, when you're performing an insulin tolerance test, in theory, you're lowering the blood sugars of these patients to very low levels that can potentially promote a cardiac event. So appropriate measures need to be present and in order for these events, and therefore this is often challenging. Next slide, please. So there are several tests, as you can see here in this table. Again, mesimorelin used to be available, certainly now it's actually becoming available in Europe. One of the caveats when it was available in the US is the fact that it was expensive. But if you take out the availability and cost issues, you will see that the accuracy, safety, tolerability, simplicity and the speediness of the tests, it actually does fulfill all the criteria making it a very easy and user friendly test. So with the two tests that we have in the US, again, you'll see particularly the insulin tolerance test is challenging, although it's the gold standard test. And it is available, insulin is available anyway. So but again, it may not be available because the provider may not be able to perform such tests because it requires a hospital cardiac trolley to be present. And so that can be tricky, particularly in a private practice setting. GHRH arginine is not available in the US, it is available in Europe. And again, also very user friendly tests like the mesimorelin. So we are more or less left with only one test, which is the glucagon test, to be honest. And, and that's why we have to kind of make use with that. And hopefully we'll someday we'll have an alternative test, maybe hopefully mesimorelin would come back or the GHRH arginine would be available in the US. But for now, these two tests are not available in the US. Next slide. So the issues with the stimulation test is that there are several concepts, inaccuracies and limitations. So one has to understand that growth hormone deficiency like is basically like a disease, it's just like diabetes. It's a spectrum you have, it can't be patients that have deficiency and patients don't who don't have deficiency. It is a spectrum. And the base, but unfortunately, the basis of testing for growth hormone deficiency is binary, meaning it either it's it classifies patients as either having deficiency or no deficiency. And that's typically not the physiology of the disease. All other growth hormone stimulation tests is based on the concept that you administer a pharmacological agent, often a growth hormone secretogoc, which can range from a weak to a strong secretogoc. And you simply stimulate the pituitary growth hormone secretion and you measure the growth hormone levels with sequential blood sampling. But don't forget that these tests also you must factor in each individual patient characteristics, whether they are suitable patients or not. The validity of the chosen test is also different growth hormone cutoffs. And also there are different sensitivities of the growth hormone assays used by different labs. Next. So in terms of growth hormone replacement, it's important that there are studies that have shown that it also improves the quality of life. And here you can see in this study published where they looked at the effects of growth hormone over seven years, you can see the quality of life actor score actually declines. And the lower the number, the better the quality of life. And you can see there's this statistical significance of the reduction in the scores immediately from year one up to year seven, although it doesn't quite reach the general population that is seen in the stipled lines around about a score of four. And in terms of sick day leaves, you'll see here on the right hand side of the figure that patients who are taking growth hormone and certainly after two years, you will see that the sick day leave numbers are gradually less starting from 12, 18 and 24 months compared to baseline. Next slide. And this is a very nice study that was published in Scandinavia quite some years ago, but it's still a study I like to discuss and highlight the point. So this is a study where they looked at patients with growth hormone deficiency and they gave them a questionnaire and they also gave the patient's partners a questionnaire. And those who were treated with placebo and growth hormone, you can see these are the patient's partners ratings of the health questionnaire. And you can see that the patient's partners actually felt that the patient themselves were more alert, more active, had better endurance, essentially better quality of life when they were receiving growth hormone versus those who were on placebo. Next slide. So again, as for use of anti-aging, there are no good studies that have assessed the long-term efficacy of safety. And in fact, there's one study that did a meta-analysis of 31 studies in healthy elderly subjects, and they reported some changes in body composition, but unfortunately, as we get older, we will see that growth, we can become more sensitive to the effects of growth hormone and therefore the adverse events were more noticeable in elderly folks compared to younger patients, which is a huge limiting factor. So as a result, growth hormone is really not approved and certainly should not be considered for use for anti-aging purposes. Next slide. So more recently in the last two years, this is a study where we looked at over almost 16,000 patients in the KIMS database. KIMS is the Pfizer International Metabolic Database. And this is the largest number of patients of growth hormone treated patients followed up for just over five years. And the bottom line is that the long-term effects of growth hormone on de novo cancer was actually, there was no difference compared to the general population. And certainly there was a neutral effect of growth hormone on glucose and lipids, indicating the safety aspects of long-term growth hormone replacement in a very large cohort of patients. Next slide. What about mortality? And this is a nice study published by Van Bundren and from the Netherlands three years ago, where they looked at all the publications of those who were treated with growth hormone. And you can see in the top half of the figure, the standard mortality ratio really crosses one, whereas those patients who were not treated with growth hormone replacement, you can see that the SMR ranges between two up to four times higher than the general population, suggesting that there is an increased risk of mortality in untreated growth hormone deficient patients. And the question is, is this due to unphysiological replacement of other hormones, which could be the case? It could also be the effects of CNS radiation effects. Don't forget that there are also differences in terms of the etiologies of growth hormone deficient patients. Could there be gender differences? Could there be surveillance bias or selection biases in all these publications? And also the fact that when you're asking the question of mortality, patients need to be followed up for a very long period of time. And certainly in the real world, following these patients up may not be long enough, or there's that possibility. And finally, there's also the fact that is it also because of the fact that is it purely because of growth hormone deficiency? So all these questions need to be answered. And we still don't quite know the exact answer to the possibility, but at least from previous studies, the indication is that it may be a suggestion that untreated patients have a higher mortality rate. Next slide. And there's also, you can see here several studies that have been published that looked at the non-adherence rates. You can see for patients taking growth hormone up to 71%, non-compliance. So the non-compliance rates are high, not only in children, but also in adults as well. And because of the high non-adherence rates, then the question then is, is there another way of giving growth hormone? Next slide. And which is why in recent years, there has been quite a number of studies looking at using or utilizing long acting growth hormone preparations. The thinking behind it is to overcome the problems associated with daily growth hormone injections, which is, as you can see, is inconvenient, painful, distressing, and has a high non-adherence rate. And the thinking behind long acting growth hormone preparations is that it might mitigate the problems associated with daily growth hormone by giving less number of injections. Next slide. So how do we make the growth hormone action longer? There are several new formulations, either the reduction in absorption from the subcutaneous tissue or the depot preparations. There's also the pegylation and the prodrug, where you can actually reduce the clearance of growth hormone from the circulation. Or you can have fusion proteins, which actually binds to albumin, for example, to prolong its action. And there's also the non-covalent albumin binding by changing the binding or the reversible binding of the growth molecule to the albumin. So there are many clever ways nowadays of using technology to increase the duration of action of growth hormone to prolong its action. Next slide. So you can see here in this table that there are the approved long acting growth hormone preparations. There are several approved ones. More of them are actually approved in children, where compared to adults, only somepacetan is approved for adults. The expectation is that in the next few years, hopefully there would be approvals of somatragon and lonopexomatoprine as well for adults, at least in the US. So, however, when you look at these products, they are slightly different in that you can see, because they are long acting, so the starting dose can be different because they are, as you can see, there are different technologies in prolonging the action of growth hormone. The good thing about long acting growth hormone is that it can be administered at any time of the day because it's administered at any time of the day because it's long acting. However, when you're checking and measuring IGF-1 levels, it is recommended that depending on the PKPD of the drug, generally it's measured in between the two injection times, which is usually between three and four and a half days, but it can be variable from product to product. And when you're interpreting the IGF-1, you also want to know that the timing of when IGF-1 was measured, depending on the time of draw in relation to drug administration, because that can actually skew the results slightly if you are not aware when the IGF-1 was drawn. So, the long acting products, they also have non-growth hormone components here in this table. You have the differences in terms of the preservatives and also slight differences in terms of storage. You can see some apacetan requires some degree of refrigeration. There's about three days of stability if taken out on room temperature stability. Lonapeg has room temperature stability for up to six months, and somatogon requires refrigeration. Next slide. Now, in terms of long acting, so somapacetan, you can see here the previous studies have shown that in general, they have shown the improvement in body composition, which is why somapacetan, based on the body composition and as the primary endpoint, there's improvement in body composition, which is comparable to the daily growth hormone. There are really no noticeable changes in bone parameters, but then again, it's probably not assessed long enough. In terms of the lipids, fasting glucose and adverse events, again, the outcomes are very stable and overall, there hasn't been any signals to indicate that it's detrimental in these aspects, which is why, again, that I think also is why it got its approval for its use. Next slide. And when the patients were asked in terms of the convenience factor, most of them actually reported they prefer that because of the convenience versus the daily growth hormone, which again, is not surprising. Next slide. But there are slight differences between the daily versus the long-acting preparations. Although long-acting preparations, they definitely do not mirror the physiological aspects of the growth hormone secretion. There's also the long-acting growth hormone preparations. The patients tend to be exposed to growth hormone longer. There's also highs in peaks and trough levels, and there's also differences in tissue distribution, especially if the growth hormone molecule from the long-acting technology is modified. Next slide. And so here's a cartoon to show children with GHD versus adults with GHD, and you can see there's the peak and troughs. And so if you're measuring IGF-1, it's important to note when you're measuring it. So generally in time point B, which is roughly about four days in between from the last injection is usually the recommended time to measure IGF-1. That gives you the average IGF-1, but if you're measuring IGF-1 at time point A for childhood, for kids who generally have higher doses, then you'll see that the IGF-1 levels could be a little bit higher than say at day four. And likewise, if you're measuring at day seven, it could be lower. So it's really very dependent on which day the IGF-1 level is drawn. Next slide. So in terms of patient's perspective, this was a study that was published not so long ago, where patients were interviewed, and these are some of the comments that we received. So newly diagnosed patients, they actually don't know which provider to see. They can be sometimes dismissed or underappreciated by some providers. They find that negotiating with insurance is an exhausting process, and repeating growth hormone stimulation testing to validate the diagnosis can be cumbersome. There's also often treatment gaps or delays, cost is a big, big issue, and risks of illicit use may underlie suspicion amongst clinicians and insurance companies as well. And finally, not every patient develops or actually experiences positive effects, which is another thing that patients can report. Next slide. So in a nutshell, there are challenges and unknowns that are still present in this field. For starters, for challenges, there's perception, the perception of adult growth hormone deficiency as a disease state is still not known amongst some providers and certainly in some patients. The methodologies for screening and testing can be quite challenging, as I alluded to earlier. Transition of patients from pediatrics to adults, again, is something that has been seen known now to be a challenge for some years. There's also the lack of adherence, the misuse of growth hormone, and also performing and obtaining tests to confirm the diagnosis can be challenging as well. There's also some unknowns as well, certainly in terms of the data of some growth hormone effects are still inconsistent, particularly the mortality and cancer data. Long-term effects on safety, there's also the effects of growth hormone on fertility and pregnancy, which is not currently approved, but it has been used by some providers. Long-acting preparations are still fairly new, and so we still need to study them and have a good database to actually collect the data of patients that are going to be given long-acting preparations. So with that, thank you for your attention and happy to answer questions. And going into the question and answer, I have a question here. It says, in your young-led patient with post-pituitary symptoms and diagnosis, there's three pituitary hormone deficiencies and low IGF-1. Do we still need dynamic testing to confirm the growth hormone deficient state? Well, technically, no, because three hormone deficiencies and low IGF-1, we don't need to. However, in practice, I still do it because I feel that it's often very helpful to have a growth hormone stimulation test result because sometimes insurance wants it. And particularly, I've had cases where patients have been on growth hormone for some years, and then when they change insurance and insurance companies, and they want that test result, and we have that handy. So that's why it's more of an insurance thing that we perform the test rather than, but really, you don't really need to have that test because 95% of the times, patients with three hormone deficiencies and low IGF-1, they are considered growth hormone deficient. Yeah, Chris. I would think it's also important that the patient have that because finding that data many years later can sometimes be challenging. So asking the patient to keep that information, I think is a key. Yeah. Second question, could you comment on using growth hormone for muscle wasting treatment that may occur with rapid weight loss using GLP-1 agonist or bariatric surgeries? Do you want to take that, Chris, or shall I take it? I think that's a good question because there's not a lot of data to support that. So what's your gestalt on that, Kevin? I feel that in theory, yes, there is data on the use of growth hormone in improving muscle mass. But again, when you're trying to use that particularly for muscle wasting with rapid weight loss, again, I don't think we have good evidence in the literature to support that use specifically to mitigate the muscle wasting certainly with weight loss. So we don't have good data to support that. But in theory, it's plausible, but we still need data to support that. This third question is, would you recommend screening for growth hormone deficient patients with no risk factors presenting with extreme unexplained tiredness? What do you think, Chris? I would think an IGF-1 is a fairly benign evaluation, and at least it can give you an appreciation for one of the factors that may be contributing. But there's so many factors, it's very difficult to say. I would not choose that as a first choice, no. No, no, I agree. I think it has to be in the right context. So if the patient has had a history of surgery or head injury or radiation with those symptoms, I think that is reasonable. But if the patient has absolutely none of the above in terms of the history, I think I would not actually screen them for growth hormone deficiency. I think one of the issues is a chronic fatigue syndrome. And is growth hormone deficiency related to that? And there's no real supportive data at this time. Right, right. Yeah. And then the fourth question is, what are your thoughts on replacing growth hormone in patients treated for acromegaly who are clinically and biochemically growth hormone deficient? I think there's data to support that. Yes, yes. And there's data to support that. We have written a paper using the ACRO study cohort patients and particularly patients with acromegaly who have had radiation. Those are the ones that are at risk of developing subsequent growth hormone deficiency. So you would obviously go through the normal channels of screening them. And then if they are found to be deficient after screening them and performing stim testing them, then you would treat them. And I would generally treat them with the conservative doses just to make sure that they don't get or develop the side effects that they've had from having acromegaly in the past. Next question is regarding the effects of growth hormone replacement on body mass, on BMD, on bone mineral density. What could be the possible reasons leading to differential effects on BMD in male versus females? Well, I think from the differences would be obviously in females. We know that especially the estrogen effects are actually much more potent on bone BMD effects, whereas for males, not so much. So I think, and certainly women are more prone, particularly postmenopausal women are more prone to lower BMD. So I think, and women tend to have obviously high risk of fractures from that as a result. So I would say that treating them, certainly most women need higher doses than men as well. So treating them is important, particularly for the bones, and particularly you might need to use higher doses than men. Chrissy, any thoughts? No, I think it's certainly age related and also probably somewhat activity related as well. So encouraging patients, particularly females to increase their activity level is important. Yeah. And also the, you know, adequate consumption of calcium and vitamin D. Why was Macy-Morellon discontinued? It was discontinued because the distributor for Macy-Morellon in the US, Novo Nordisk, actually decided to release the contract that they had to distribute that in the US back to the parent company, which is Atenas Antares in Germany. And I think really it was also because of a business decision. So they decided not to continue distributing Macy-Morellon in the US. So currently they are still looking for companies to take over that mantle to provide or take over the mantle to provide or supply Macy-Morellon to the US. And as far as I know at this moment in time that they have yet to be successful in getting another company to take over. Next question, how long should growth hormone replacement be continued in adults, specifically in the elderly folks, Chris? I think we need a lot more data. You know, I think it really depends on the individual. So some people can discontinue treatment without any significant effects. But again, I think you've got to consider the stability of the individual and the risk of fracture, bone fracture, particularly considering an elderly female that may actually be osteoporotic. So it's a very individual decision and strength may be an important factor and risk of fall. So we need more data, definitely. Yeah. And I usually say that there's no obviously end point to when you're going to, I would say long term when I put a patient on it, but certainly there's no data in patients above 83 on growth hormone deficiency. But I do have patients as old as 85. But then again, you know, so there's really no stop date as long as the patient is tolerating and wants to remain on it. And I do say that if you're practicing evidence-based medicine, there's no patients that study beyond the age of 83. So but if they're benefiting from it, I generally will not stop the treatment. Next question, any role of IGF-BP? No, I don't usually use IGF binding proteins. It's typically used in pediatrics, BP-3, but they are less robust, they're less reliable compared to IGF-1. Not that IGF-1 is perfect, but they are less so compared to IGF-1. So we generally do not use binding proteins in assessing for growth hormone deficiency. Next question, could you comment on the use of growth hormone for treatment of MASLD, M-A-S-L-D, not previously known as non-alcoholic fatty liver disease. So basically the use of growth hormone for treatment of fatty liver. Chris, any ideas? I mean, when you've got liver disease, then the IGF-1 is usually lower. It's very difficult to determine whether that's going to be effective or not. I don't know of any other data. Do you, Kevin? Yeah, actually, there are some Japanese data that have shown that the use of growth hormone actually does improve fatty liver, and they actually did some liver biopsies. I'm not sure how they were able to convince the participants to undergo liver biopsies, but they did. And these were mostly Japanese studies, but they did show that there was actually improvement in fatty livers in some growth hormone deficient patients, knowing the fact that the condition is actually more commonly seen in severe growth hormone deficiency adults. So the answer is, it's not something that we would actively treat for, but if the patient already has fatty liver, and if the question is, does growth hormone improve the fatty liver, there are data to show that it actually does improve fatty liver. Not a lot, but certainly there are a few papers out there. The next question, do you routinely adjust other pituitary hormone replacement doses when you introduce and use GH for hypopit patients? Yes. Re-evaluate particularly testosterone doses and thyroid doses. It may be that the patient then needs to be re-evaluated for adrenal insufficiency, particularly if they start showing some symptoms of HPA axis dysfunction. Yeah, I agree. And also cortisol as well, hydrocortisone, because the effects of growth hormone on the 11 beta HST type one enzyme that is responsible for the conversion of cortisol to cortisol. So it inhibits that. So sometimes patients might need a little bit of higher doses of hydrocortisone to help overcome that little bit of a block there that growth hormone actually induces. So thyroid as well, sometimes we may have to adjust those as well slightly. And the last question is, if a patient underwent surgery for acromegaly, can we prescribe growth hormone if he has growth hormone deficiency now? So this is the same question, so the answer is yes, provided they have the symptoms and they have the biochemical confirmation of growth hormone deficiency. The answer is yes, we can prescribe growth hormone and we treat them as like we would for a growth hormone deficient patient. Although, like I said earlier, maybe I'm a little bit more conservative in the dosing, but certainly, yes, we will treat them. So I think that is the last of the questions. One more, it would be difficult to monitor for access. Not sure what that means. But certainly we use IGF-1 so that we don't overtreat patients, just like you would do with your free T4 when you're treating a patient with levothyroxine. And also the symptoms, you assess the patient's symptoms, you talk to them and see whether they would be experiencing some of these symptoms or not. Okay, I think that's all the questions we have. Yes, thank you so much, Dr. Yuen and Chris Jednak. We really appreciate your time this afternoon and thank you all for joining us. This concludes our webinar on GHD today. I hope you all have a great rest of the afternoon and a wonderful weekend. Thank you again. Thank you.

Adult Growth Hormone Deficiency

AGHD

fatigue

abnormal body composition

bone loss

growth hormone therapy

IGF-1 levels

diagnostic strategies

long-acting growth hormone

hormone replacement therapy

pituitary surgeries