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AACE Rare Endocrine Disease Series On Demand: Acro ...
AACE Rare Endocrine Disease Series On Demand: Acro ...
AACE Rare Endocrine Disease Series On Demand: Acromegaly Puzzle - Clinical Clues to Earlier Diagnosis Challenges and Treatment Options
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Hi there, I'm Dr. Susan Sampson, current president of ACE, and it is my pleasure today to invite you to listen about Rare Disease Webinar Series for ACE. I'm here with my colleague, Professor Ranjod Gill. He's in the Department of Internal Medicine and Surgery at Virginia Commonwealth University School of Medicine, and also serves at the McGuire VA Medical Center. So today, we're going to be talking about the acromegaly puzzle, those clinical clues we have, and how they could lead to an earlier diagnosis, and how we choose among the right treatment options for our patients. We want to thank the support that was supplied by CIESI as an educational grant for this activity. And these are the disclosures of the speakers and the planning committee. The learning objectives for this webinar are that at the completion, the learner should be able to describe the diagnostic and testing approach in evaluating a patient with acromegaly, that we should be able to utilize evidence-based guidelines, algorithms, and consensus statements to diagnose and treat acromegaly, and also identify and treat the long-term complications and comorbidities that we see in patients with acromegaly. We're going to start with an introduction, and really a discussion of the recognition and diagnosis, and then we will talk about how we treat patients with acromegaly using a personalized treatment regimen, how we monitor and manage the long-term complications and comorbidities, and we've also included a case-based discussion at the end of the webinar. We just wanted to start with a case that we will revisit at the end of the webinar. This is a patient of mine who is a 56-year-old patient. She'd been on estrogen-containing oral contraceptive pills since the age of 26, so for over 30 years. They were discontinued three years previous on the advice of a primary care provider, given that she was well into the age of menopause. At that point, she describes falling off a cliff. She had rapid deterioration of her health status. She noticed debilitating muscle aches, joint pains in her hands, fingers, wrists, knees, ankles, morning stiffness, and felt like she walked like an old person, she said. She had new onset of paresthesias in her right arm with numbness and tingling and swelling in her hands, and she even had to have her rings upsized. She did seek medical attention. First, she saw rheumatology, and she was noted to have just a mildly positive, probably nonspecific ANA of 1 in 80, and she was reassured that there was no evidence of an inflammatory cause related to her hormonal changes. Neurology was consulted. She had a normal nerve conduction test and EMG studies for the paresthesias. She'd seen gastroenterology for preventative medicine. She had multiple polyps noted, and cardiology was seen because she was having palpitations with multiple PVCs on her Holter monitor. Thankfully, her echo was normal, although she did have a small amount of mitral valve prolapse and mild regurgitation. So this is the opening scenario for this webinar. We will revisit this patient's case at the end. At this time, I would like to turn it over to Dr. Gill to talk about the burden of acromegaly. Thank you for that introduction, Dr. Sampson, and it's a privilege and an honor to be talking about this rare endocrine disorder alongside you. So this case that you described is not an uncommon scenario, and I think a lot of us have had this kind of patient, not necessarily a patient with acromegaly, but other rare endocrine disorders with different representations that are enigmatic. So acromegaly is a multisystem disorder and spans almost every organ, and to name a few, there's coarsening of features from top to bottom. There's frontal bossing, dental spacing, you know, as you can see from the phenotype of the orodental phenotype, the lower jaw growth. So, you know, after one achieves bone growth, mandible is the only bone in the adult body that doesn't stop growing if there's a stimulus. So there's the pronathia, there's tongue enlargement or macroglossia. I want to give you an anecdote, and this may sound unreal. I accosted a patient that was unfortunately lost to follow up, who was complaining of tongue bite for many, many years, and her dentist actually noticed that this, it was a she, had several sort of ulcers on her tongue on both sides, and didn't have any known macroglossia until much later. And she was actually found to have acromegaly years later. So she just presented with tongue bites, which was sort of subclinical in the beginning. Headaches are pretty common. A story about headaches. Patients with acromegaly can have headaches, and when you treat patients, headaches would be the first symptom to go away even before tumor shrinkage happens. That's just an anecdote. Fatigue is very common. Skin thickening, coarsening of skin. Sweating, hyperhidrosis. If you are, hyperhidrosis or excessive sweating is one of the worst nightmares facing any physician, especially endocrinologists. Oily skin, skin tags, you know, acridones, and large visceral organs. Virtually every organ undergoes hypertrophy, including heart, liver. One has metabolic syndrome, insulin resistance, hyperglycemia, diabetes, mellitus, hypertension, or secondary hypertension, osteoarthritis, muscle aches, muscle pain, fractured wrist. Now, with or without, you know, bone loss. Now, here there is some discordance. Growth hormone, axis growth hormone, and axis IGF-1 are associated with, actually, bone building in certain bone areas. But the fracture risk is higher. How does that happen? So there is evidence that the neck BMD, actually, is known to go up in acromegaly. And there's evidence that lumbar spine may remain unchanged. But the fracture risk is higher. And that may happen because of several reasons. Acromegaly patients are more sedentary. They suffer from asthenia, lack of exercise. They have obesity. They have hypogonadism. You know, males have low testosterone. Women often have oligomania or amenorrhea. So several reasons. And also, patients may be treated with, if they are panhypopoietic, they may be treated with glucocorticoids. And sometimes, they may be over-treated. So access of that. Colon polyps and neoplasia and acral enlargement. You know, you can see the hands. Next slide. Oh, and then the incidence you saw, it's pretty rare disorder. Early versus late diagnosis. There are currently no tools for early identification. Often, the diagnosis is delayed by 5 to 10 years. That's pretty unfortunate. And that's one reason why we are presenting this webinar, to increase awareness. Development and progression of comorbidities with greater delay in diagnosis. So later, the diagnosis, the higher the risk of comorbidities. And the comorbidities not only increase, but also increase in number. And that was data shown by Asposito in their paper. And Bolfi et al. showed that the standardized mortality ratio also increases by at least two-fold. There's a 10-year delay in diagnosis. In cancer, there's increased cause of death with the longer life. People are living longer. There's also a similar increase in cardiovascular disease. Now, mortality has decreased in the last decade with the medical therapy, of course, you know, with decimerostatin receptor ligands. And then more difficult to control disease. And you can see the graphical representation. It's more clear in the next picture. Next slide, sorry. So here is a graphical representation of the frequency of comorbidities with the delay in diagnosis. Most of them are statistically significant. So even with no delay in diagnosis, the number of comorbidities and the increase in comorbidities is significant. And so the local effects, which is edema and the pronathia, the acral features, they are pretty high. And then hypopituitarism is the only phenotype that is not statistically significant. And it's not clear why it is not, but it's still a pretty high number. But you can see that all of the other phenotypes are pretty significant. And then also, for the longest time, it was known that people often come to cardiovascular risks. But lately, it's been shown that people die more from cancer than from cardiovascular risks. Next slide. So diagnostic delay results in deleterious effects of both IGF-1 axis and multiple organ systems. And some are irreversible. And I would say most are irreversible. And mortality in patients with uncontrolled acromegaly is approximately two times higher. And this goes, you know, it's just belaboring the earlier fact. And survival improves after biochemical control. But the emphasis is on earlier detection and earlier intervention. And the patients with the diagnostic delay of greater than 10 years have higher chances of cardiovascular and musculoskeletal comorbidities and have higher mortality than patients with a shorter delay, which is less than one year. Next. So what can you do to reduce diagnostic delay? Right now, we don't have much to talk about. But some of the strategies that can be employed can be and should be to include stuff in the medical school curricula. And we should be teaching our students to recognize early symptoms and signs of acromegaly. We should be educating physicians and other providers at the primary care level. We should be spreading awareness in the gastroenterology arena. Dentistry. Dentistry, it's sad that, you know, patients that, you know, have acromegaly, they are often seen by dentists and still not recognized, whereas they can be and should be. Cardiology, you know, there's no reason why they can't be sort of identified and alerts can't be generated through cardiology. Orthopedics is another area where we can have intervention. Pulmonology, because a lot of these patients have respiratory symptoms. Neurology, as our patient, index patient, had symptoms pertaining to neurology. Ophthalmology, similarly, and dermatology. Patients have these coarsening features, skin tags, etc. And we have to have heightened alert and low threshold to refer these patients out and to screen these patients. Should have focus on specialty-specific criteria to identify early disease and to screen them. And screening is pretty easy, you know, but we have to have low threshold. Should have emphasis on early signs and symptoms with less reliance on morphological changes of late disease. By that time, it's too late. I should rather say early emphasis on early symptoms and signs. And collaboration with patient advocacy groups and organizations. And I can't, you know, talk about the names, but there are several organizations, including pharma companies, that are out there who are willing to help. And then there are technology interventions that are way of the future, including artificial intelligence, facial recognition, and EMR and EHR alerts that can be helpful in alerting us about the presence of not only acromegaly, but about other rare disorders, medical disorders. I'll hand it over to you, Dr. Sampson. Thank you, Dr. Yeo. So, when we think about confirming that a patient that we suspect has acromegaly, or we are seeing patients with pituitary incidental loma, or other ways in which these patients are identified, the diagnostic criteria have really evolved over the years. And if you think back, this table kind of summarizes some of the major consensus and guideline documents that have been published in this area. And what's really important to remember is that the assays have actually evolved as well. And that's one of the reasons our threshold for the diagnosis of acromegaly using oral glucose tolerance tests have a decreasing threshold over the years. And so, I think early on, we were seeing the one microgram per liter threshold. And as you go through time with these guidelines, you're seeing a decrease down to 0.4. To show that the patient does or does not have acromegaly using a GTT. But then as you get down into the most recent consensus, which was just published here in 2024, in the Pituitary Journal, the oral glucose tolerance tests, growth hormone thresholds have shifted down even further to 0.4 with a normal BMI, or if in overweight or obese patients, down to 0.2. So, it's important to keep these moving targets in mind as the assays evolved. But I think most importantly, is we used to use the glucose tolerance tests frequently to confirm when we already had an elevated IGF-1. And for the most part, IGF-1 is an excellent measure of integrated growth hormone activity. So, if we have an IGF-1 that is at least greater than 1.3 times the upper limit of normal for that patient's age, and the patient has the characteristic clinical signs of this disease, we don't need to continue on to additional confirmatory testing, particularly when they already have a pituitary adenoma. But the growth hormone suppression test may be helpful in those cases where it is somewhat equivocal. Also wanted to just touch on some of the caveats in the use of the diagnostic tests that we use. So, the assay methodology for IGF-1 can be highly variable from lab to lab. And the consensus is that we should be using the single WHO international standard. So, you want to check that your lab uses the standard for their normal range. These assays can also differ in terms of the methodology that is required to remove the IGF binding proteins from IGF-1. Some of them use IGF-2 for displacement or other extraction methods. That could definitely lead to some variation among different assays. We used to say that we needed a normal range stratified for age and sex. We now know that after adolescence, it's really just an age-specific range. And you really want to try to use the same assay as much as possible. Now, sometimes it's not possible. And it's important to think about what that upper limit of normal is to be able to compare directly to two different assays. And I always educate my patients, please look at the normal range because they'll see a large swing in the IGF value when I test them without realizing, okay, the upper limit of normal is very different from assay to assay. As of right now, there's no evidence that liquid chromatography mass spectroscopy is superior to immunoassays. But I do want to give you an example of why we have to still be vigilant when switching between these two methodologies. Similar to IGF-1, growth hormone also has a WHO international standard. So you want to choose a lab that is using that. And you want to think about the other factors that can impact IGF-1 and growth hormone. Things that might lead to a false negative or false positive. For example, patients with higher BMIs may have a lower IGF-1. We can talk a little bit about the impact of estrogen on IGF-1 levels. And also nutrition, metabolic disease, hepatic dysfunction, and genetics can influence IGF-1 levels in our patients. When we think about the factors that impact our growth hormone testing results, estrogen can also play a large role. So it's important to take note if you have a patient on estrogen therapy. I wanted to just give an example here of one of my own patients. So this is a patient that presented with a pituitary incidental loma. And so she had the pituitary panel, as she should, that included an IGF-1. And at her baseline, the IGF-1 was normal. And it was just under the upper limit of normal, 0.99. However, when she came faithfully for her one-year follow-up, the IGF-1 levels were much higher. So the question is, which one of these was wrong? Well, really, neither. And we know that this tumor did not progress in the course of one year in terms of the size. So what happened here? Well, the patient was on hormone replacement therapy for the first IGF-1, and she stopped hormone replacement therapy for the second. So in her case, what we were seeing was the impact of oral estrogen therapy dampening IGF-1, keeping it just within the normal range. But when she came off that estrogen therapy, the IGF rose significantly. And she manifested the laboratory values for acromegaly. She later went on to have surgery, which was a proven growth hormone secreting tumor. So it's important to think about the impact of estrogens on IGF-1 production. Now, estrogens can impact growth hormone secretion from the pituitary, actually can stimulate it, but it's really counterbalanced by the fact that particularly oral estrogens affecting the liver are able to inhibit that JAK stat pathway, that signal transduction that is induced by growth hormone signaling. And so what you see is inhibition of IGF-1 production in patients on estrogen. And also you have to remember that the CERMs, the Selective Estrogen Receptor Modulators, also do this and inhibit growth hormone impact on IGF-1 levels. The other key point I wanna raise about diagnostic assays. Now, we talked about the fact that if the right standard is used and you're consistent with your assay can be very helpful, but just a word of caution that there could be very wide variations even for the same patient. This again is another example of a patient of mine who had IGF-1 drawn on the same day from one lab with an immunoassay and one lab using liquid chromatography mass spec. And you can see that the levels are highly concordant. So they both measured her IGF-1 to be very similar, but look at the impact on the upper limit of normal. And that's because the range for this particular immunoassay is much lower than for the LC-MS assay. So if you used this assay only, you would think her pituitary adenoma may be making growth hormone. But if you looked at this one, you would say she doesn't have a growth hormone secreting tumor. So this is a diagnostic conundrum. And one of the things I think that explains this is in many of the immunoassays used commercially in the US, we're using a European standard at patient values. And what has been discovered and was published here in 2022 is that in the USA, both females and males actually have a higher upper limit of normal in the normal population, almost 14% higher for females and 23% higher for males. So what that means is if a patient tests in this range in the United States, they may look like they have an elevated IGF-1 by an immunoassay. But in fact, that is well within normal limits for the US population. So this still remains a problem even now with the current commercial labs that we use in the US. So I just ask you to be very aware when you're using an immunoassay that this is a concern versus LC-MS, which seems to have less issues with the normal ranges. So now I wanna turn it over to Dr. Gill to talk about management. Thank you. Thank you, Dr. Sampson. So acromegaly is a surgical disease. So whenever possible, you want to find a good surgeon and try to resect as much of the tumor as possible and leave no tumor behind. So that's the first-line treatment. Now, the exceptions to surgery as first-line, of course, it's an operable tumor if patient has any contraindication to surgery. Patients with the limited chance of obtaining a beneficial result from surgery. And the patient have no access to a surgeon, which is pretty rare. You can always find a surgeon. It'll be unfortunate if patient, we can't find a surgeon, or if there's lack of insurance, that'll be pretty unfortunate. Another indication to treat medically before offering surgery would be to optimize for reasons of obtaining a good airway access, because we know that acromegaly is associated with edema almost everywhere, including upper airways. So it may behoove, it will behoove to treat medically and to lessen that edema for a few weeks and make intubation easier for the anesthetist. So after surgery by an experienced surgeon, either complete or debulking, then you assess if patient has a persistent active disease, then either offer re-operation, medical therapy, or radiation therapy with the interim medical therapy. But if patient is in remission, then monitor for disease recurrence and consider laboratory monitoring of IGF-1 and occasionally with the growth hormone and pituitary MRI if evidence of biochemical recurrence. Next slide. Now, we also have to take into consideration what the patient wants. And in a sense, it's a shared decision-making. And also, we have to consider what the patient can afford. Unfortunately, we are in the sort of different times and medical managed care era. And these are the various options. A lot depends on patient preference, patient comorbidities. We just learned that if a patient has an inoperable tumor or has comorbidities that increase the risk of surgery, then you have to treat medically. Then amongst medical therapies, frequency of administration of medical treatment, safety. You have to visit or we have to discuss the benefit versus risk of any intervention for any disease. Insurance coverage and cost. This is an important discussion to have for any intervention we have to decide about. Biomarkers, how to manage or how to monitor the disease progression. How to monitor IGF-1 and growth hormone in half and whether it will be paid for. How to monitor a tumor volume. Availability of therapy, availability, whether it can be given in the office or at patient's residence. Efficacy of the various treatment options, route of administration, et cetera. So it's not just one factor, it's a multitude of factors that affect our decision-making. All right, I'll give it over to you, Dr. Sampson. We can't hear you, you are on mute. Appreciate that discussion of all of the different things that go into making these decisions together with our patients. And so I did wanna talk a little bit about the different therapies that we have and that we're able to use and that has been really expanding over the last few years. On this slide, this just summarizes and I'll go through the medical therapies in a little more detail, but just on this one, radiation, especially stereotactic radiotherapy can be very successful in these patients. And we just have to think about the fact that it can retake some time for the therapy to have an impact of one to two years. And then during that time, we still need to consider what medical therapy might be best for our patient. We also have to kind of have that informed discussion that if the patient does have pituitary function, even after surgery, that some of that could be lost depending on the radiosurgery. So maybe up to a third of patients could lose some pituitary function. But if we choose the right target, the right type of patient for radiosurgery, I've found it to be very useful. But for the most part, if patients are not cured by surgery, we do turn to medical therapies, somatostatin receptor ligands, cobergeline and growth hormone receptor antagonist are the two approved therapies. Cobergeline is not FDA approved for this use, but it can be helpful in a subset of our patients. And of course, earlier we discussed the impact of estrogen and serms on IGF-1 production and there are some patients that benefit from this as an off-target effect. So cobergeline is not FDA approved for acromegaly, but it does target the tumor. And we know that these tumors can have dopamine 2 receptors. It doesn't work for everybody. And the data based on meta-analyses of over 149 patients would tell us that the patients that might be most successful are those with a very mild elevation of IGF-1. And if you look at the data from the French meta-analysis on cobergeline in acromegaly, those with an IGF-1 below 150% of the upper limit of normal, about 50% of those were able to respond, which you can see on the left side of this graph. Now, overall in the entire patient population, about 30% will achieve IGF-1 control as monotherapy with cobergeline. But when you add it to somatostatin receptor ligands to patients that are not yet controlled on the somatostatin receptor ligand, another 50% can gain control. So it also works in concert with SRLs. Now, of course, we have to think about the fact that we may need a little bit of a higher dose than we're used to for prolactinomas. And we also have to be able to counsel our patients to be aware of adverse effects that include some of the impacts on impulse control disorders. I've also had patients talk to me about depression and anxiety and suicidality. So we have to make them aware that if they experienced those symptoms, they reached out to us. And of course, we also have to do informed consent about the impact on the valves. Now, the doses of cobergeline that were used in the older studies showing valve thickening were for Parkinson's disease. And we're in the milligrams per day level. We use low milligrams per week. And our patients do not seem to manifest the same type of clinically significant valve disease as was seen in patients using cobergeline for Parkinson's. But it's always good to make sure that you have a baseline knowledge of your patient's heart's function and their valve function in order to make an informed decision. But the mainstay of tumor-directed therapy are somatostatin receptor ligands. And that is because these growth hormone tumors express both somatostatin-2 and somatostatin-5 receptor on the majority of tumors. Over 90% will immunostain for these receptors. And that these agents have octreotide, lanreotide, which some may call first-generation, or passereotide, which some may call second-generation SRL, have high affinity for the SSTR-2 receptor. And the passereotide medication actually adds higher affinity for SSTR-5 and has its place in the hierarchy of therapies for acromegaly. So the value of these are that they can shrink tumor and they can control the growth hormone, thereby controlling IGF-1 in patients with acromegaly. Now, when you actually look at the clinical trial data for octreotide and lanreotide, I think the control rates are probably lower than we think they are in the sense that about 30 to 50% of patients in these trials demonstrated control of both IGF-1 and growth hormone. That's really been supported by a meta-analysis by my colleague, Dr. Carmichael, and colleagues at Cedars-Sinai, showing that IGF-1 and growth hormone control was about 50%. Now, what is the place of passereotide in this hierarchy? Well, we know from the clinical trials on passereotide that if you compared it directly to first-generation octreotide-lanreotide, more patients showed control that could be in surgery or naive patients that had never been on somatostatin receptor ligand. And the PAOLA trial took patients that were not controlled on first-generation and randomized them either to passereotide or to stay on their current therapy. And for many of these patients, passereotide was then able to go on to normalize their IGF-1 levels over time. And about at any time, 37% of patients, more patients, achieved IGF-1 control and growth hormone less than one during the core or extension of the PAOLA trial. So there is a place for passereotide. And one of the things we think about when choosing this medication is, could this tumor be somewhat resistant to octreotide or lanreotide? One of the clues can be, what does the tumor look like on MRI or on pathology? And we know now that T2 hyperintensity, so this is a T2-weighted MRI image of one of my patients that shows similar hyperintensity or hyperintensity compared to gray matter. So over here on the MRI, those particular tumors can have sparse granulation on pathology and may not always respond to octreotide, lanreotide, but can show good response to passereotide in some cases. So this might be a tumor characteristic you would take into consideration. And you can see here where the tumor is hyper or iso-intense to gray matter. But we have to use caution with passereotide because we know that it can induce hyperglycemia. It is manageable, but you wanna think about that in your patients who already have glucose intolerance or diabetes on oral medications, because it will increase the fasting blood glucose very soon after starting the medication and increase the hemoglobin A1c by week 12. Now, if you stop passereotide, this also can reverse. The main mechanism here is a dampening of ancretin secretion through the somatostatin 5-receptor and a dampening of insulin secretion. So that little bit of difference between passereotide, octreotide, lanreotide in terms of receptor affinity impacts the glycemic status of the patient. So really important to keep that in mind if you do start this medication. And with pigviscimont, which is a growth hormone receptor antagonist, it inhibits that JAK-STAT pathway as well to lower IGF-1 production. And we know from meta-analyses of several clinical trials, as well as the long-term real-world ACRO study, that IGF-1 control can be achieved in over 70% of patients with pigviscimont, that there is some improvement in glycemic control in some patients, including the fasting glucose and the A1C, and that patients tolerate pigviscimont well. The discontinuation rate is very low due to adverse effects. We did not see the signal in terms of hepatic, any kind of hepatic disease with elevated liver enzymes. And the other fear about removing that feedback on that tumor was never really realized and we did not see in this data, we did not see increased tumor growth in the majority of patients. So this is the data we have for pigviscimont. And you could say to yourself, well, if I'm not controlled with one, I need to use combination therapy, and that could be a really extreme expense. But there's studies now showing us, for example, this one from Cedars-Sinai and collaborators, Vivian Bonart had published this in 2020 showing that you can use a lower dose somatostatin receptor ligand with weekly pigviscimont, even though pigviscimont is approved for daily, and cut back on the cost of the dual therapy quite significantly. So we do have to think about combination therapies for some of our patients to achieve full IGF-1 control. And there are ways in which we can think about a personalized regimen that might also decrease cost for our patients. So a couple more words about some newer options. Do we need more? Well, we do know from data from patient-reported outcomes that have been published here by my colleagues, Dr. Strasburger, Dr. Geer, that patients do have concerns with the injections, which can cause pain for hours or days and cause nodules or swelling or bruising, that they may feel like they have decreased liberty because they are having to schedule their injections and they may perceive that they have less independence. They have to take time off work. They may have to miss work to get that injection. And also as that injection, the long-acting injections wear off, some patients may experience breakthrough symptoms, which could be anything from a manifestation of increased headache or sweating, joint pains, tissue swelling. So with this in mind, there are some, an oral option was approved in 2020. These are oral octreotide capsules. And the kind of proprietary transient permeability enhancer allows for the opening of the tight junctions in the intestine so octreotide can pass through. And octreotide has been really protected by an enteric-coated capsule. So we know that this allows for active octreotide to be absorbed into the bloodstream and have a pharmacologic effect on patients with acromegaly. And some key trials proved this, and this is what led to FDA approval, showing that in patients on oral octreotide versus placebo, the oral octreotide was able to control IGF-1 levels and the mean IGF-1 was way lower than the placebo. So patients on oral octreotide capsules and the mean IGF-1 was within the normal range versus patients on placebo showed an elevation of IGF-1 at the end of the 32-34 week trial. And another trial here, the Empower trial, showed that oral octreotide capsules achieved non-inferiority. So patients came into the trial on injectable, switched over to the capsules, and then spent capsule time back onto their injectable or stayed on capsules. And those on oral octreotide capsules were able to maintain their IGF-1 within the upper limit of normal. And also on capsules, they had a decreased symptom scores at the end of that treatment period. And the symptom scores were looking for on a scale of zero to three, how bad are your headaches, joint pain, swelling, sweating, and fatigue. And so this data was very positive with regard to the impact of oral octreotide capsules. I did wanna make a note here about an investigational drug Pathfinder. One is testing the use of paltucetine in acromegaly patients. And in this case, again, the primary endpoint is an IGF-1 less than one times the upper limit of normal. And for those patients on paltucetine, over 80% were able to keep their IGF-1 within that upper limit of normal versus 4% of placebo patients. And the IGF-1 control, you can see here that for paltucetine, IGF-1 stayed in its range, just increased a little bit, 0.04 versus the placebo patients showed an increase in their IGF-1 of a mean of 0.83 times the upper limit of normal. So this is very promising as well as an oral medication for our patients. So I wanna turn it over to Dr. Gill just to remind us about what are our goals when treating with these medical therapies? So, yes, our goals have actually evolved over the last 25 years or so. It sort of reminds me of an exercise we went through with other disease states, particularly Cushing's syndrome. When I was training, we had, when we did dexamethasone suppression tests, we had five milligram and then three milligram as the threshold. Now it's 1.8. I wonder how many Cushing's disease or Cushing's syndrome patients we missed by not having the strict goal. Anyway, so as you can see, the first acromegaly consensus guidelines had the goal as IGF-1 normalized for age and sex and growth hormone less than 1 microgram per liter. And in between, you can read, but the latest guideline is simplified. And as of 2022, 14th acromegaly consensus guidelines say you just look at IGF-1 and normalize for age, which is, I think, I agree. And we need to have simplified the goal, which is to just normalize IGF-1 for age. How to monitor for comorbidities, as we know, it's a multisystem multi-organ disorder. I won't belabor. You can read for cardiovascular disorders, you obtain, you know, for BP measurement, you know, just, you know, do baseline measurement and periodic assessment. For respiratory, you know, you do assessment for sleep apnea and other measurements. For glucose metabolism, fasting glucose, A1c, you know, you do screening measures. Other endocrine disorders, for hypogonadism, you do appropriate measurements. For hypothyroidism, other endocrine, you know, pituitary disorder, pituitary abnormalities, you do the appropriate hormone assessments. For musculoskeletal disorders, for bone health, you know, obtain DEXA scan and vertebral morphometry as needed, if and as needed. For cancer screening, we know that colonic, you know, cancer risk and polyps risk is higher. And then quality of life measures, you know, it's important to have the questionnaires and also ask at each visit about their symptoms, about quality of life. So physical symptoms and treatment effects on patient psychology. So we have to assess not only the physical symptomatology, but also psychological symptoms, as well as effects of the treatment. You know, we have to assess both efficacy and safety measures. I won't belabor the physical aspects, but the psychological effects, you know, patients often suffer from poor body image. They may have negative perception, may have poor coping measures. They often suffer from depression and anxiety. They may have a cognitive dysfunction. Of course, you know, on the left side, we've gone over those before. And then treatment effects, you know, the intervention that we employ, they have their own, you know, outcomes and may have negative outcomes. The chronic medication burden, the other intervention, including radiation therapy may have, you know, if it's a cranial radiation may cause, you know, memory impairment, may cause other, you know, cranial deficit. Cranial deficit. Of course, hypopituitarism, if it wasn't already there, may result as a consequence of radiation treatment. Although our radiation treatment now is more focused and stereotactic, but still there's a risk of causing, you know, damage to the surrounding areas. Next, you can take over Dr. Sampson. Thank you. So I think with all of those considerations in mind, Dr. Gill, I wanted to just show a slide about how I might think about different patients who need further treatment for their acromegaly. And then we'll go back to that initial introductory case that we started. So when I think about what I might use and what kind of benefits I may talk to my patients about, and also the risks with octreotide and lanreotide, I think I use them as first line when I've got a significant remnant tumor to shrink. And I also want to achieve IGF-1 normalization. Of course, we talked to patients about the gastrointestinal side effects they may experience, which often can be transient. Passereotide is a drug I also use quite frequently, particularly as a second line after octreotide lanreotide, if I'm unable to achieve control in their characteristics of that tumor, such as a lot of tumor burden, sparse granulation on the immunohistochemistry, that might hint they would respond better to passereotide. But I pay really close attention to baseline glycemic function and monitoring. And given the impact of passereotide on ancretins, we've actually published a study showing that ancretin therapy, specifically GLP-1 receptor agonists, can be really helpful in mitigating the hyperglycemia if first line metformin doesn't completely control glucose. Oral octreotide is a good option for patients who've responded to octreotide lanreotide, that is the FDA requirement that you've responded to first generation somatostatin receptor ligands. And it may be really helpful for patients who experience those breakthrough symptoms and also just, you know, tired of injection fatigue or pain, but they have to be very adherent because it's an oral medication and it requires the empty stomach for absorption. Coberglyne works great in patients with low-ish IGF-1, as we discussed. I particularly think about it in a patient with mild IGF-1 elevations, but also who had some prolactin characteristic of their tumor, perhaps a smaller remnant tumor, and particularly for patients that have extreme cost considerations and don't have access to some of the other medications. But of course, we always think about the valves and psychiatric background when making that decision. Pegvisumab works great in our patients, especially if there's, I'm not worrying about shrinking a tumor remnant. And post radiotherapy, it can be very useful as you wait for that stereotactic radiotherapy to kick in and also can help a little bit with the glycemia of the patient. And then radiosurgery, I like to have a very particular target and the ideal target is the part of the tumor that's over to one side of the cell and the pituitaries over to the other, which does happen. Those with calvernous involvement, and you want to make sure that that tumor remnant is away from the optic chiasm, which can be impacted by radiation therapy. So those are kind of the ways I think about the use of each of the therapies we talked about. I just want to return to this case. If you remember the patient who fell off the cliff after stopping her estrogen therapy and had saw numerous specialists without a diagnosis. So Dr. Gill, what kind of things explain her sudden onset of symptoms? And you can come up mute. Yes, I think after having gone over the presentation, I think it's probably very obvious that stopping the estrogen, the hormone replacement therapy explains. Yeah, I completely agree. And I've had numerous patients with this story and also not just post menopausal but pre-menopausal patients on oral contraceptive pills. And remember that she had all of these consults and because she felt so unwell and still didn't have a diagnosis, she actually asked to go back on the estrogen therapy and that kind of mitigated her symptoms. But three years later, she went off again. And at that point, she had new snoring, increased shoe size, change in her bite, and again, worsening headaches. And this then prompted imaging. And you can see here that she has a pituitary macroadenoma, extending supracellar, it has both cystic and solid characteristics. And so basically six years delay from that initial presentation after coming off of estrogen containing birth control pills. This is the T2 showing you the cystic areas and the chiasm kind of draped over this tumor. So she was referred to a pituitary center, mine, and she really didn't have a lot of overt acromegaly features. So it's possible that some of that dampening of IGF-1 production was actually keeping some of that those changes at bay. If I had to say anything, she had mild prognathism and increased finger width and palmar tissue. But not every patient you see with growth hormone excess actually has the classic features of acromegaly, particularly if it's a little earlier. And these were her labs that were performed because of her pituitary macroadenoma. You can see her IGF-1 more than three times the upper limit of normal for her age, the growth hormone of 37. And also you see this mildly elevated prolactin, which could be stock effect versus the fact that this could be a co-secreting tumor. So at this point, Dr. Gill, what do you think would be your next step with this patient? The tumor has to go. The tumor has to go. Right. We have surgery as first line with these patients, unless there's the contraindications that Dr. Gill talked about. And here at post-op day one, you could see the cavity where the tumor was. It's relieved all that pressure. And she actually shows a significant drop in her growth hormone, although not to the level that is in the literature for possible cure, which would be closer to 1 to 1.2 nanograms per mil. Of course, IGF-1 is a more stable hormone and can take longer to drop. I do measure it early, but if it hasn't dropped, I wait for the six, three to six months that are recommended. This was a mixed lactotroph-somatotroph tumor. It was CAM 5.2 negative, which was referenced to sparse or dense granulation. And in her case, at post-op month three, she still had dropped. You can see her pituitary gland here. You see a hypo-enhancement here. What kind of things might you think would be a good option for her, Dr. Gill? I'm sorry? What would be a good option for her to treat this elevated IGF-1 at this point? Oh, so she has residual tumor, then? I don't know that it's clear. I mean, she does have some hypo-enhancement here, but we're now three months out. She still has high IGF-1. Yeah. So medical treatment, you know, versus radiation, you know, you have a variety of choices. I would offer medical treatment. Okay. I mean, I thought about a number of options, too. I started her on cobergoline because this is a lady who had a mixed lactotroph-somatotroph tumor. She's a very small area that could be the remnant. And perhaps we can achieve control using cobergoline. And she did achieve control. You can see here where her IGF-1 is getting closer and closer, even just after the first three months of therapy. But really, unfortunately, she had some symptoms from cobergoline. We had to stop it abruptly. And you see that rise in the IGF-1 again. So you know that cobergoline was having an impact, but it's just not the appropriate medication for her. And so at that point, thinking about this possible tiny remnant here, the other options for her, you can see it's consistent even now post-op month 10. So it's starting to look more suspiciously like remnant tumor. Again, thinking about other options, well, this was a small remnant. And so after discussion about all the options with her, we started pegviscimont. And the other thought about why we chose pegviscimont, she was wondering about doing stereotactic radiosurgery to this small area. And of course, with somatostatin receptor ligands, you might have to stop them for a period of time to increase the response to radiation. And you can see she responded well to pegviscimont with full control. But she did decide that she would have reoperation on this area with a cavernous wall resection, which was 1.5 years after her first surgery. And the exciting thing is that she was able to have a cure after that surgery. So you can see her IGF-1 was normalized. And so this is a really good outcome in this patient, although it took a long time from their presentation. And she is now has a controlled IGF-1, and we just monitor her on a yearly basis. So these are the, you know, the thoughts I had about that particular case, and I appreciate you listening. And just to finish off with some take home points. Delayed diagnosis in our patients with acromegaly can lead to increased number of comorbidities, and increased standardized mortality, we really need to work on better strategies to educate our field, the field of medicine and all the specialties therein and dental specialists as well. And we need to start thinking about how we can leverage artificial intelligence and the electronic health record we use every day to do that. As a clinician, we all need to have a deeper understanding of the tests we use when we are testing for and monitoring our patients so that we can detect when the lab value just doesn't fit the clinical picture. And I would just encourage you to think deeply about your patients' characteristics and their own experience in order to shape a patient-centered personalized approach to their medical management. And with that, I'm going to thank you, Dr. Gill, today for being here with me. And I think we're at the end of our time, but if anyone wants to stay over, we're happy to answer any questions. There are a couple of questions in the Q&A. Excellent. Shall we answer? Let's see here. So Dr. Ibrahim asks, Do you suggest any adjustments for estrogen therapy prior to ordering IGF-1? So I think this may be asking if, do you take your patient off of therapy, perhaps if they were on a birth control pill and reorder testing? Well, I think you'd have to take them off for at least four weeks to know. And you know, if you think about doing a glucose tolerance test, it can also impact the growth hormonator and raise it a little bit. So it can be challenging when patients are on estrogen. I guess the way I think about this is, you know, it can be very disruptive to take someone off of estrogen. So you have to consider the whole picture. I don't know, Dr. Gill, how you think about this. No, I agree. You have to. If you're seriously considering, then you have to take them off. Depends on your threshold and suspicion. Well, so Dr. Ibrahim has a second question. And I think this is illustrated, perhaps in some of the data I showed for the upper limit of normal from Dr. Martin Bidlingmeier's paper. Do you think there is any racial ethnic differences in terms of IGF-1 levels? I don't think we have data on racial and ethnic differences. But the data I showed you did show a difference between European and U.S. values. Now that data, it was not available to dive down into what the different backgrounds of the patients were. And it may actually be geography. There was some thought that it could be related to body mass index, but that actually did not prove to be true. That was looked at. There was some thoughts also on vitamin D and could vitamin D be affecting IGF-1. So I don't think we know the answer to that question. But it is important to understand the normal ranges in your area for the assay you use. Dr. Gill, this question asks, what approaches would you recommend in terms of educating primary care and other specialties regarding acromegaly? Just to be on the alert, if you have any, for example, hyperhidrosis, you've looked at the common causes. IGF-1 is not an expensive test. Or just refer. If you've excluded thyrotoxicosis, if you feel chromocytoma, just think outside of the box. If there's no other plausible cause, just think of it. I'm interested in how we might leverage the EHR for specific constellations of symptoms, right? So there are those we think about that are so specific to IGF-1, like ring size, shoe size. And then there's the nonspecific of things like headache. Or you might have a patient with cardiology, you might have a patient with concentric left ventricular hypertrophy. Should we be looking at how we create alerts? I'm not saying for each one of those things separately, but when they come together as a constellation, and maybe that starts to show up in people's radar as they care for their patients through the electronic health record. Right, right. You know, shoe size, head size, we often don't measure, but we ask them. Those are so subjective. But, you know, the reason why I mentioned hyperhidrosis or sweating, I've had so many patients referred for that, and we picked some patients that had acromegaly. So, you know, then certainly alerts about secondary causes of hypertension, you know, diabetes, we've seen those patients being diagnosed, you know. So having a low threshold. A low threshold for testing, I agree. I've appreciated, we have a headache clinic here at my institution that also looks at pseudotumor cerebri, and they have actually been successful in finding, case finding for me and referring to me, where they've looked at IGF-1 and growth hormone excess as a cause of headaches, as well as increased intracranial pressure. And that's very interesting. I mean, they see a lot of patients, and I'm talking about maybe a handful have been sent to me, but they were still the first line in finding those patients. So that's really exciting. A couple more questions here. One patient, one person asked with the case, could we have used Passyriotide? And I think this is a great question. Now with the case, there was very tiny amount of remnant, and I think Passyriotide is extremely powerful. And I would try the first generation somatostatin receptor ligands first, because, you know, there is the risk also of hyperglycemia. So if I use Passyriotide, I want to really do it with purpose in choosing the right patient, I would probably use the first generation first in that case. And then another case, another question is a significant number of patients have symptoms, even after surgery and therapy. And the benefits of oral Octreotide, is this something you see often? So this is a good question. It's just, you know, we're gaining more and more experience, because oral Octreotide is kind of the new kid on the block. It's been around for since only since 2020. And it takes a while to get that integrated into clinical practice. But certainly the data from clinical trials would speak to the fact that there can be a decrease in those acro symptoms compared to injectables. That data comes from the Empower trial. I just wanted to say a word about growth hormone and prolactin co-secretion for the endocrinologist and the audience. They both arise from acidophiles. We've seen commonly that, you know, if one has acromag, I mean, if there's, you know, growth hormone over secretion, or prolactin over secretion, they often have both. I mean, not uncommonly. So, and Octreotide actually can be effective in some of those patients. Well, I think, I think we'll stop there. And we appreciate the audience's attention and also their excellent questions today. And I wish you all to have a wonderful weekend. Thank you so much.
Video Summary
Dr. Susan Sampson and Dr. Ranjod Gill discussed acromegaly, a rare endocrine disorder, during ACE's Rare Disease Webinar Series. They emphasized the importance of early diagnosis and evidence-based treatment, noting that the condition affects multiple organ systems and can lead to increased mortality if not properly managed. Typical acromegaly symptoms include coarsening facial features, muscle aches, insulin resistance, and cardiovascular issues. Delays in diagnosis, often spanning 5-10 years, contribute to the development of comorbidities. The webinar emphasized raising awareness among medical professionals through education and leveraging technology, such as artificial intelligence, to aid in early identification.<br /><br />Management options for acromegaly vary. Surgery is the first line of treatment, with medication options like somatostatin receptor ligands, Pegvisomant, and Cobergoline available for persistent cases. The speakers stressed personalized treatment plans considering patient-specific factors such as tumor characteristics, cost, and patient preferences. They discussed newer options like oral octreotide and highlighted the need for regular monitoring of comorbidities, including cardiovascular and respiratory issues, along with psychological and quality of life assessments.<br /><br />In a case study, a patient experienced a delay in acromegaly diagnosis after discontinuation of estrogen therapy. Her symptoms markedly deteriorated, highlighting the role hormones can play in modulating disease manifestation. Emphasizing the impact of different assays and evolving guidelines, Drs. Sampson and Gill concluded by stressing the need for a holistic, individualized approach to acromegaly management.
Keywords
acromegaly
endocrine disorder
early diagnosis
evidence-based treatment
medical education
artificial intelligence
personalized treatment
comorbidities
hormone modulation
individualized approach
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