Thank you all for joining us this afternoon for our webinar on Cushing's Syndrome. I'd like to introduce Dr. Correa, who will now kick us off this afternoon. Hi, everybody. It's a great pleasure for me and all the speakers today to talk about this topic. First of all, we want to thank ACE for this amazing webinar and all the supporters of this. First, our main topic today are these changes in my health, significant, identifying, and treating Cushing's Syndrome. So the next slide, there is activity supported by a grant from Corset Therapeutics and Sears Pharmaceutical. These are the disclosures from the speakers. We have the three speakers today in the upper part, and then you can see that we're bringing this together to all of you. We have multiple planners, and these are the disclosures from all the planners. Before we start, I just want to make sure that some housekeepings, please use the questions and answers setting that is in the bottom of your Zoom for asking any questions during time. You can ask questions in the middle, at the beginning, at the end. We will try to have some space at the end to answer some of the questions. If not, we will try to answer in the middle through the questions and answer. It's much better to use questions and answer from that section instead of the chat. So we just ask you, please use questions and answer settings instead of chat. With this, I want to introduce the learning objective. Upon completion of this webinar, what we want to achieve is describe a diagnosis and texting approach in evaluating a patient with Cushing syndrome, utilize the evidence guidelines, algorithm, and consensus statement to diagnose and treat Cushing syndrome, and identify and treat long-term complication and comorbidities of Cushing syndrome. My name is Ricardo Correa. I'm an endocrinologist by training. I am at the Cleveland Clinic where I'm the program director and the health equity and inclusive initiative director. So it's a great pleasure for me to start introduction and some diagnostic management and diagnostic approach in Cushing syndrome. So the first slide I want to bring that in this webinar, you will hear the word Cushing syndrome. That is the same thing as hypercortisolism. We are trying to use more hypercortisolism now. And Cushing disease, as you all are aware, we will use it as pituitary hypercortisolism too. So both words, you will hear it during the different part of the webinar. And just here to analyze a little bit of the HPE axis that all of you are aware, where the hypothalamus for CRH goes to the pituitary and ACTH, and then goes to the adrenal cortex, basically in the sona fasciculata to produce cortisol, and then there is a negative feedback. So in the next slide, the three types of Cushing or hypercortisolism, as we know, it's the ones that we call ACTH dependent. And then inside them, we can have two of them, the ones that come from the pituitary and the ones that come from ectopic sources, majority of them being from lung cancer carcinoids. And then the ACTH independent, that is the one that comes from the adrenal gland. There is a few cases where it comes from the hypothalamus, but we will consider that as ACTH dependent as pituitary hypercortisolism. Let's start talking about pituitary hypercortisolism. It's the most common cause of hypercortisolism that we know. Approximately 70 to 75% of all the cases are pituitary hypercortisolism, and this represent 0.7 to 2.4 million people per year. It's a rare condition, but that is growing in the last years with all the diagnostic mechanisms that we have been encounter. There are certain theories of what has happened. Some of the ones that I want to bring here is the hypothalamic theory, where there is the ACTH adenomas arising from a dysregulation in the corticotroph cells of the pituitary. And there is a pituitary theory that it says that it's a problem that arise directly from the pituitary and not for any stimulant from the outside. Then we have the adrenal cushing or ACTH independent cushing, the only one that exists, and really is a glucocorticoid excess coming from the adrenal gland. This people has overt hypercortisolism. Majority of the adrenal cushing will present with certain characteristics like dysmetabolism plus certain cushing-coid phenotypes, and then we will have abnormalities in the lab work that we will talk a little bit about that. I just want to bring here another topic that is not hypercortisolism, but that sometimes can be related, but it's a different entity called myelotonomous cortisol secretion. And I bring this in this part because I think that it's very important that we have to recognize that up to 50% of patients will have adrenal incidentalomas. Approximately 2% of the general population can have this disruption in the cortisol secretion that we call myelotonomous cortisol secretion. This will be a different topic, but do not relate it that this is the same as overt hypercortisolism. And then the last type is the ectopic hypercortisolism, where you can see small cell lung cancers, that is the one that has the majority of the prevalence on having co-secretion of ACTH. But then you can see all the other, including some endocrine tumors, neuroendocrine tumors like myeloid thyroid cancer and pheochromocytoma parangliomas. And the next slide. So what is the prognosis? And why is it important that we are talking about here about Cushing? Because we know that people that suffer from hypercortisolism has five times more risk of mortality. We know that these people have more this metabolism and problems in the bone, and we know that these people die more from myocardial infarction and stroke. The cause is a chronic condition. Unless this is a topic in this very acute setting, majority of the others are more chronic conditions. And the prognosis is better if we use surgery and we determine where the source coming from your surgery. But also in the latest years, we have even discovered that some medical treatment are being very useful and have been controlling the patients with good prognosis. Next slide. And her first case is a 38-year-old woman that seeks your attention for a 16-kilograms weight gain. She has type 2 diabetes on sitagliptin. And her A1c in the last seven months has been increasing slowly, but raising even with no changes in her lifestyle to 8.5. Then when it came to you, she just started glyphosate. The physical examination, you can see that she has high blood pressure. Her BMI is a 37, and she has some characteristics of Cushingley features. Next slide. So this trigger to do a workup on hypercortisolism. So we have an A1c now that is 9.0 compared for the last one. We have a low potassium on 3.3. We have a TSH on 1.2. And then you can see the lipid panel there. Next slide. And my first question here is, which is the next most appropriate test in diagnosis? And we can see a measure, a late-night salivary cortisol, an ACTH in the morning, a random cortisol, a CT, or an MRI. And really, the answer is the late-night salivary cortisol, and we will see the algorithm later. Next slide. The most important characteristics you can see here has the prevalence of those characteristics is this metabolism with obesity in 85% of the patients. When we go to the skin, plethora and hirsutism are the ones that have more prevalence. When we go to osteopenia and osteoporosis, it's very high, and then glucose, decreasing glucose sensitivity, and then diabetes is another condition. So if we think about the phenotypical characteristics in the next slide, we can see that easily bruising, facial plethora, proximal myopathy, one-centimeter purple stretch marks are the most common characteristics that we can see in those patients. And the clinical sequelae will not focus so much because we will talk about this at the end of the webinar, but you can see that every single organ in the body is affected when excess of cortisol. In physiological doses, all of them are beneficial with the cortisol, but in excess of cortisol, you will see all of the side effects. Next slide. So very important is that I always mention this. We don't have an A1c in cortisol. It would be so good to have an A1c and say less than this and more than this is this or this, but we don't have it. So we have some tests that have limitations in accuracy and limitations in sensitivity and specificity. But for that, that's why we recommend it for the diagnosis of the cushion to use the the three tests that we have available for that. And one is the 24-hour urine cortisol, free cortisol, and I try to do two times those. The late night salivary cortisol, and I try to do two times those, and that's the recommendation from the guideline. And one milligram dexamethasone suppression test, depending on the weight of the patient, sometimes you have to use two, sometimes you have to do eight milligrams in patients that have increased BMI. Next slide. So just some caveats from these three tests. The first one is the urinary free cortisol. We know that it's not invasive, that do not influence by diurnal because we're collecting in 24 hours, and it's not affected by the cortisol binding globulins. But it's labor intense for the patients. Many patients do not do their collection very good. They pee sometimes more. Even though you explain, it's some burden to the patient. Patients that are with adrenal failure or dialysis, this is not adequate. That's cross-reactivity with DOC. So sometimes we have to interpret various cortisol or DOC, and then definitely people that pee more. I hear in the literature, the study say more than five liters. I have seen that more than 2.5 to 3 liters per day can start affecting the value of the test. Next slide. The salivary cortisol with sensitivity of 92% and specificity of 96% is not invasive too. Do not increase the stress of going into a lab and then having the pinch and draw the blood. Do not need to keep refrigerator as the urinary free cortisol. Provide a measure of free cortisol and it's correlated very well with a 24-hour period. The pros, the cons is they provide measure of cortisol concentration at a single point. Sometimes we can do diurnals at night and in the morning to have two points. Any patient that have smoking or periodontal disease or brush their teeth prior, even though we explained that this are not adequate practice to do this test, can have some infection. The amount of sample may be low. Sometimes people that suffer from dry mouth, people that are inpatient. In women and patients with hypertension and diabetes, they can be falsely abnormal. And then definitely this is just in people that have a traditional sleep pattern where they work during the day and sleep at night. Next slide. And the final one is the one milligram hexamethasone suppression test, as you are aware. Here I put at 11.30 p.m. This is not strict. We do not, if a person sleep at 9 p.m., we will not make them wait until 11.30 p.m. You can give it 30 minutes before they go to sleep and then you shake the plasma cortisol or dexcortisol the next day. But we have some false positive. For example, patients that are using estrogen or OCPs, they raise the cortisol by the globulins and the cortisol will be raised in the morning. We have some strategies that we can use free cortisol as a measure, but it's very expensive. And then the increase in metabolism of the dexamethasone by some medications. Here you can see the medication on the left. There are some false negative results where the dexamethasone clearance in the hepatic and renal insufficiency. Anyways, with all of this inaccuracy, still we use the one milligram or two milligrams hexamethasone suppression test for adrenal cushing or adrenal hypercortisolism is still the gold standard there. Next slide. And here is a study that I compare different, the three of them, and we can see that the sensitivity and specificity, at least the sensitivity 100% in the one milligram dexamethasone suppression test compared with healthy controls. Next slide. Next case is a patient that comes because of superior sagittal venous thrombosis, also deep venous thrombosis, has a 32 kilograms weight gain in the six months and a fatty liver. You can see here the work, there's two urinary free cortisol, four times upper limit of normal. There is two salivary cortisols that are elevated and ACTH at a 60 and an eight milligram dexamethasone suppression test after doing all this work that suppressed 87%. We have a pituitary MRI that shows no adenoma. Which one is the next next step or a dexamethasone CRA stimulation test, a one milligram dexamethasone suppression test, an IPSS or a pituitary MRI? And the answer is an IPSS. Next slide. So here is how we evaluate patients with ACTH dependent cushing syndrome or hypercortisolism. So anyone that have an ACTH more than 20 with a confirmed ACTH, patients will be hypercortisolemic. So it's not just that we have to confirm first the diagnosis of hypercortisoloma with the first three tests that we talked to you, two of them, two out of the three should be positive. Sometimes it doesn't come though two out of the three and you have to repeat again and repeat again. Sometimes there are some pseudocushions that can be very complicated to determine. So that's why when we decided to go into the route of diagnosis of hypercortisolism, we have to repeat it many times. So we can do a now decimopressin simulation test. In the past, we used to use CRA stimulation test, not anymore. And then some criterias that we can talk later. And then we can do the high dose dexamethasone suppression test that by the criteria of the NIH 69, by the criteria of others is more than 50% suggested that it's pituitary cushion. And we can have an MRI, but MRI has 90% specificity. So if you have inconclusive between all of these tests, then IPSS will be a very good option. If you have very conclusive and you have seen the mass and you see that all of the other dynamic testing, sometimes it's not necessary to go to IPSS, but this is individualized with the patient. Next slide. And in this slide, it looks very busy. I will go one by one. So if you can click the next click. Yeah, so we can go here where we were talking, there's a three test and these three tests needs to be done. And then if two out of the three tests come positive, next slide, then we will have to determine if this is ACTH dependent or not. And here is when we go to the route in the center, where is you measure ACTH, if they're low ACTH or normal and high ACTH, then you can determine if this go through the ACTH dependent or independent. If it goes to ACTH independent, a CT of the abdomen is recommended. If it goes to the ACTH dependent, then pituitary MRI is the next step. Next slide. And then when we go to the pituitary MRI, if there is no adenoma, then we should suspect about ectopic cushion and IPSS is recommended as we were talking about. And then if there is an adenoma present, depending on the size, we can go to the route of an IPSS or sometimes to the route of surgery. So this is a complex and we can send the slides and the article from Dr. Flesser so you can review all of this in detail. I think that this is the very comprehensive, the latest recommendation and guidance for management of diagnosis of cushion. Next slide. And now I will pass the floor to our next speaker, Dr. Atin Moulin. Hi, everyone. Thank you for the invitation to speak in the webinar today. So I will be going through the treatment of Cushing's syndrome. It is a big area to cover, but I will try and point out with a few case studies, the nuances that you need to consider when you're managing a patient with Cushing's syndrome. I'm Shobhana Atin Moulin. I'm an adult endocrinologist and I'm based in Henry Ford Health in Detroit, Michigan. So just to recap what Dr. Correa had said, when we talk about endogenous Cushing's syndrome, we have ACTH dependent causes, which is the bulk of cases up to 85%. And we have ACTH independent cause. Now for ACTH dependent, majority of cases are a pituitary tumour, an adenoma, which makes up about 75 to 80% of the cases. And 10% of ACTH dependent cases are rarer causes such as an ectopic neuroendocrine tumour producing ACTH. You can see here there's a bronchial lesion. And for the ACTH independent cases, the most common cause is a unilateral adrenal adenoma, or you can have rarer causes such as adrenal cortical carcinoma or bilateral nodular disease of the adrenal glands. Now this is an algorithm from the Endocrine Society Guidelines on Treatment of Cushing Syndrome that was published back in 2015. And you can see, regardless of the cause, whether ACTH-dependent or ACTH-independent, surgery is the first line recommended therapy for patients. So it's either resection of the pituitary tumor or resection of the neuroendocrine tumor if it's an ectopic cause, or if it's an adrenal Cushing's unilateral adrenalectomy, and in very select rare cases, bilateral adrenalectomy may be recommended. Now there are exceptions when we don't recommend surgery first. One is if the patient is unfit or ineligible for surgery, if they've got significant comorbidities and they can't go through surgery. Two, if there's a very limited chance that surgery is actually a beneficial result. If someone's terminally ill or if it's a recurrence at very early stages, and you might want to wait and see how they progress. Three is if it is ectopic Cushing's syndrome, but with an unknown primary tumor, then surgery is not an option. And number four, it's probably something more common that one may face where you don't have access, either the provider or the patient, to refer to an expert surgeon. Now in these cases, you could use medical therapy as a bridge to reduce the cortisol burden before finding an appropriate surgeon. So and we'll talk more about medical therapy options. Now when you look at this algorithm for adrenal Cushing's, the treatment is, I would say, a bit more straightforward because if you remove the unilateral adrenal gland that's causing the problem, most times patients develop post-op adrenal insufficiency and then they are in remission. But you can see that for ACTH-dependent Cushing's syndrome, there are a few more steps to the diagnosis and there are a lot more things to consider because there's a higher chance of failed surgery with persistent disease or recurrence. So for the bulk of my talk, I'll be discussing cases with ACTH-dependent Cushing's to point out the different therapy options. So let's start with the case. So this is a 36-year-old female whom I saw in clinic who was referred for an incidental pituitary tumor that's found. She has a long-standing history of irregular menstrual cycles and hirsutism. And she was diagnosed with PCOS, but eventually she became amenorrheic. So her primary provider ordered a pituitary MRI, which found the pituitary tumor. When I saw her in clinic, there was more to the picture. She had uncontrolled type 2 diabetes on three different therapies, uncontrolled hypertension, hypokalemia on supplements, progressive weight gain of 45 to 50 pounds over a five-year period. And she was in the police force and she was undergoing training and had a fall in age. 32, had a non-displaced transverse fracture of her right femoral neck. And she also complained of weakness in her arms and legs and difficulty walking upstairs. So on physical exam, her blood pressure was uncontrolled. BMI was 38. And she had signs of hypercortisolism, facial flatulence, roundings, supraclavicular fat pads, wide, purplish streaks on her abdomen. So when you look at her lab results here, as Dr. Khoury had mentioned before, all three of her screening tests, the 1 milligram dexamethasone suppression test, 24-hour urine-free cortisol, and late-night salivary cortisol, all three of them are elevated way above the reference range. Now you can see at the top here, she also had an 8 a.m. serum cortisol and 4 p.m. serum cortisol drawn on two different visits, and they are both elevated. Now this is not a screening test for Cushing's, but it is very suggestive because she has lost the typical circadian pattern that you see with cortisol secretion, which is lower later in the day. Her ACTH levels are elevated, so it's consistent with ACTH-dependent Cushing's. And DHEAS is actually an androgen that's produced by the adrenal gland, but its production is dependent on ACTH. So if the ACTH is high, most times DHEAS levels are either high normal or above the upper limit of normal. So her clinical biochemical workup is very consistent with ACTH-dependent Cushing's, and this is the pituitary MRI that led her to me, which shows a 5 by 8 millimeter pituitary tumor. So she underwent pituitary transpinoidal resection of the pituitary tumor, and the pathology confirmed that it was a corticotroph adenoma. But postoperatively, you can look at her labs here. So before surgery, her ACTH and cortisol was very high at 135 and 35, but subsequently after surgery, for the first three days when her levels were drawn, there has been a significant drop in her ACTH levels and her cortisol levels, but they were never totally suppressed. She felt a lot better, and there was a lot of improvement in her blood glucose and blood pressure readings, but she did not develop any symptoms of adrenal insufficiency. So how do we decide if someone is in remission? So it's a combination of their biochemical values and also their clinical picture. So if the serum cortisol the day after surgery is less than 2 micrograms per deciliter, and we are sure that the patient did not receive any glucocorticoids before surgery, and the patient displays symptoms of adrenal insufficiency, we can safely assume that they are in remission and start them on supraphysiological doses of glucocorticoid and provide a tapering protocol. If it is between 2 to 5 micrograms per deciliter, we probably want to observe a bit longer and look out for symptoms of adrenal insufficiency, watch and see if the levels actually level off in nadir or do they actually rise back up again. Now if it's greater than 5 micrograms per deciliter and it's persistent that way for many weeks and the patient does not develop symptoms of adrenal insufficiency, it's very unlikely that the patient is in remission after the surgery, so a repeat MRI and further evaluation is needed. So this algorithm is from the Consensus in Diagnosis and Management of Cushing's Disease, which was published in Lancet Endocrinology in 2021, and it shows here what do we do when we have persistent disease. So we have one of three options. If there is a surgical target, again on imaging we can consider repeat surgery, but if not, radiation therapy is an option, but once again for radiation therapy we want a target, or you may consider in very large invasive adrenomas that are more aggressive to shrink tumour and reduce growth, and the other option is medical therapy. Now in our patient, four weeks after surgery she had an MRI and it did show that there was a small focus of tumour present, but she was not initially keen in surgery because her blood pressures were improving and her blood sugar levels were better, but six weeks after surgery she noticed her blood sugars were uptrending and her ACTH levels were rising and she required treatment for diabetes, so she was agreeable to go in for a second surgery, and this time round it was much better. Her post-op AM cortisol was 0.4 micrograms per deciliter and ACTH was 2, and she had profound symptoms of adrenal insufficiency on her second time of surgery. So at that point she was started on supraphysiological doses of glucocorticoid replacement with a tapering plan, but you can see a year after being on glucocorticoid therapy, this was already from September 2020 to 2021, she had difficulty coming off her glucocorticoid therapy, even though she was on good doses, when we tried to taper her further she would complain of symptoms of myalgia, joint pain, despite being on good doses of hydrocortisone. So her symptoms were very suggestive of glucocorticoid withdrawal syndrome, and I just wanted to kind of talk about what glucocorticoid withdrawal syndrome is, and so glucocorticoid withdrawal syndrome is when the patient has been exposed to high levels of cortisol for a very long period, and then there is withdrawal with an abrupt decline in the level of cortisol, causing them to feel like a withdrawal symptom. So the mechanism, and how is that different from adrenal insufficiency, in glucocorticoid withdrawal, these patients are on good doses of glucocorticoid replacement, but in a true adrenal insufficiency, they have undetectable cortisol levels and they're not on any replacement at that point. So for glucocorticoid withdrawal syndrome, it's thought that the mechanism is not well understood, but it's thought that with the abrupt drop in glucocorticoid levels, there is a cytokine and prostaglandin induction, which leads to these patients having an inflammatory reaction causing these symptoms. So how do we manage them? It's kind of managing the expectations right from the outset. So these patients, before they go for surgery, we want to tell them that you'll be on adequate doses of glucocorticoid replacement, but you know, even though the doses are coming down, you would feel these symptoms somewhat, and that's a good thing, because they are actually in remission and on their road to recovery. And if they are still very symptomatic, you may consider increasing the dose slightly to the dose they were on before for a longer period and then dropping it down back again, because you want to be careful not to keep them on a high dose too long and suppress their HPA axis. So there are other modes of therapy that you could consider when the patients are having glucocorticoid withdrawal and not always turn to increasing the glucocorticoid dose. So if it's mood-related symptoms, you may consider an SSRI or cognitive therapy, and if it's muscle-related symptoms, a non-steroidal. And you know, Cushing's is a very catabolic condition, so some of these patients experience a lot of muscle wasting and deconditioning, so physical therapy can help. So in our patient, she eventually came off steroids about a year and a half after being on therapy, and you know, so this was her picture when I met her in 2020, and 2019 was a year before she had presented to me when she shared the picture, and this was her most recent follow-up. So she had all her antihypertensive therapy stopped, all her diabetes medication stopped, and she was very happy with the progress, and you can see over time some of the physical changes have also improved. Now on to a second case. This is another 37-year-old female who also was referred to me for an incidental pituitary tumor. She had a history of ADHD and bipolar disorder and was followed closely by psychiatry, but she had progressive symptoms despite being on good level doses of therapy. So she had an MRI brain done by psychiatry, which incidentally noted a pituitary macroadenoma measuring 12 by 22 millimeter, and she also, when I saw her in clinic, she was concerned about progressive weight gain of about five to, over the last five to six years. She was 305 pounds when I saw her, pre-diabetic and also uncontrolled hypertension. Now her labs, again, if you look at it, it's very similar to the prior patient. All screening tests were strongly positive with an elevated ACTH and DHEAS, and even her 4pm cortisol was elevated, and that was her MRI. So in her case, she underwent surgery and she had a great outcome right from the outset. She developed post-op adrenal insufficiency, and she was on hydrocortisone therapy, and she stopped it approximately a year after surgery. She was very happy that her symptoms, she came off hypertensive medication, A1C improved, and what she was really happy about was her mood symptoms improved, and she had come off a lot of medications that she was taking while she was following up with psychiatry, and she had lost almost 100 pounds over the next one and a half years. So this is when she had initially presented to me in 2020, and when I saw her in follow-up in 2022, she had lost about 70 pounds, and she was really happy with the progress. But when I saw her more recently this year, she still continued to lose weight, but you can see she's not really as happy as she was before, because she tells me that, you know, it's almost three years after surgery, but she's concerned if she might be having cushings again. She's noticing some emotional ability, and she's feeling like how she felt when she was having cushings before, and this is very common for patients with cushings. They probably know when it's recurring even before the biochemical testing is positive, and so if you look at her labs, the one on the left before surgery, you can see all numbers are markedly elevated, but when she came back to see me between January and June this year, she had testing done, and her ACTH and cortisol levels are not as high as it was before, and her urine-free cortisol is also not very elevated. But she had two late-night salivary cortisol done, and they were elevated, but not as high as it was before. Now, this is very common, at least seen in recurrent cushings, where the first test to become abnormal is the late-night salivary cortisol, because that's what patients lose first, the circadian pattern of cortisol secretion, and the late-night salivary cortisol is the first test that becomes positive. Now, you can see that the levels are not as high as it was back in 2020, and that is because, you know, we're looking for this very closely, and we keep testing them more often, so it's not as markedly elevated as before. Now, at this point, we did an MRI pituitary, but we did not find any evidence of recurrence or residual pituitary tumour. So, back to our algorithm again, so she has persistent disease, or a recurrent disease, and there is, we don't have a surgical target, so not for surgery and not for radiation therapy, but, so the only option available is medical therapy, and we're at this point where she's not very severe and debilitated by her symptoms yet, and the cortisol excess is mild, but we're discussing options with her. So, what options do we have for medical therapy in Cushing's syndrome? So, we are very fortunate, we're at a time where there's a lot of many different options available for treatment of Cushing's, but there are many different factors that we have to look at when we're trying to choose therapy for a patient, so, and such as cost, the side effect profile of the medication, other concomitant therapy that they are taking that may interact with the medication, comorbidities, patient's choice, whether they are okay with an injectable therapy, or do they prefer two times a day tablet, or are they okay with four times a day tablet, and the type of Cushing's syndrome they have, or the degree of hypercortisolism. So, when we look at medical therapy for Cushing's, it can be divided into three categories, either pituitary targeted therapies, where we're targeting the pituitary tumor, adrenal steroidogenesis inhibitors, which target at the level of the adrenal gland, and we're actually blocking enzymes that are involved in the production of cortisol, or glucocorticoid receptor antagonists, which works at the receptor level, cortisol, glucocorticoid receptors in the periphery. Now, there are a few drugs for two of these categories, but you can see that not all of these medications are approved for treatment in Cushing's syndrome in this country, but the ones highlighted in yellow are what is approved in the U.S. for treatment of Cushing's. So, let's go through them. So, we'll start off by the pituitary targeted therapies. So, cabergoline is used off-label for Cushing's disease, and if we do use it, it's usually between the dose of 0.5, we start off with 0.5 milligrams twice weekly. Usually, we don't go up to a very high dose, like 6 milligrams, but when they studied it for this purpose, they found they had used higher doses, and they found about up to 40% response rate, but does not always last. And you can consider this in mild cases of Cushing's, if there's some residual tumor present, because they have been reported potential shrinkage of the tumor. You can also consider this in someone who's pregnant. Now, just as a disclaimer, none of these medications approved for Cushing's syndrome is approved in pregnancy, but there are some case reports or reported cases where they have used it, so it can be considered, but you would avoid use of cabergoline in anyone with a history of bipolar or impulse control disorder, because it can cause these symptoms to recur, and it can be quite debilitating for the patient. So, in my patient, which I just saw, I would not consider cabergoline, because she does have a history of psychiatric disorder, and she was treated and followed up for quite a while. So, persidiotide is the other pituitary directed therapy. It is approved for Cushing's disease, and we use it in usually mild Cushing's disease, and the data shows that in up to 50% of patients, there was a 50% reduction in 24-hour urine-free cortisol in six months, and even normalized in up to 40% if it wasn't very severe Cushing's to start with. Now, the main thing is, persidiotide works on the somatostatin receptor 5, and this receptor also is present in the pancreas and can actually inhibit, using this drug can actually inhibit insulin release. So, one of the common side effects is worsening glycemic control. You can have higher blood sugars in patients, or worsening of pre-existing diabetes. The patients can develop gastrointestinal symptoms, or in prolonged use, there's also reported cases of gallstones. But it is a pituitary directed therapy, and there is potential for tumor shrinkage in up to 40% of patients. Now, moving on to the adrenal steroidogenesis inhibitors. So, there are quite a few medications in this class. So, levoketoconazole and ketoconazole, which has been around for a long time. So, levoketoconazole is approved for Cushing's syndrome, and ketoconazole is used off label. Now, potency-wise, in animal studies, it shows that levoketoconazole is much more potent, but we do not have any head-to-head comparison study to suggest if one is stronger than the other. But both have been shown to be beneficial in improving, in treating Cushing's syndrome. Now, the thing to be cautious about is hepatotoxicity. So, if someone has pre-existing abnormal liver function tests, or if it's a case with malignancy with ectopic Cushing's and liver mets with higher LFTs, you might not consider these medications because it can worsen their liver function tests. With any adrenal steroidogenesis inhibitors, there is a risk of adrenal insufficiency. And one thing to consider is that levoketoconazole is twice daily dosing, but ketoconazole might be up to four times a day dosing. Now, metiropone is off label used for Cushing's syndrome in the US. It is used more widely in Europe. It is 11-beta-hydroxylase inhibitor, and it is a very potent adrenal steroidogenesis inhibitor shown to normalize urine-free cortisol in up to 50% of patients. So, the side effects is adrenal insufficiency and gastrointestinal side effects. One thing to consider is the consensus statement does say that if we want rapid normalization of cortisol in a patient, we should consider either ocilidrostat or metiropone because they are very potent. With metiropone, the dosing, four times a day dosing, may be a concern if you're worried about patient's compliance. Ocilidrostat is an approved medication for Cushing's syndrome, and it's also 11-beta-hydroxylase inhibitor, and it's considered the most potent of the adrenal steroidogenesis inhibitors, as it has shown a rate, about an 80% rate of urine-free cortisol normalization in patients. And the side effects is adrenal insufficiency, QT prolongation. And once again, if you want rapid normalization for it to act very quickly and bring down high cortisol levels in moderate to severe cases, you should consider either ocilidrostat or metiropone. And in ocilidrostat, it's a twice-a-day dosing. Now, there are other adrenal steroidogenesis inhibitors available. Mitotane is usually used for adrenocortical carcinoma. It's a very slow onset of action, and it has got quite severe side effects associated with it. So we tend to use it more in cases of malignancy. And etomidate is usually used, it's used IV, and it requires an ICU setting for monitoring, and it usually reduces cortisol level very rapidly. But once again, it's used for very severe cases, and these both are off-label use. Now, the final class of medication is mifepristone. Mifepristone is a glucocorticoid receptor antagonist, so it blocks the glucocorticoid receptor in the peripheries. So ACTH and cortisol levels in these patients will always be high, and we can't use those values to assess how efficacious is the treatment, but we should actually measure other clinical parameters, like their blood sugars or blood pressure and weight. So mifepristone is actually approved in patients with Cushing syndrome and hyperglycemia. It's also a potent antiprogestin, so in female patients who are on these medications, we need to monitor them for vaginal bleeding, and side effects also include adrenal insufficiency and moderate to severe hypokalemia. So, you know, there's a lot of different medical therapies, but just as a quick summary, like, how do you choose it? If someone has mild disease and there's a little bit of, there's a residual pituitary tumor, you may want to choose a more pituitary-directed therapy, like Pocidiotide or Cobergoline, and you can monitor their MRI to see there's progression, and consider reassessment and a change in their plan. If it is a moderate to severe case of Cushing's, and you need to rapidly normalize their cortisol levels, you would want to choose a more potent adrenal steroidogenesis inhibitor, Ocilidrostate or Metirapone acts quickly. It's an oral option. In very severe cases, you can use Ibuetamidate, and levoketogonazole or ketoconazole, the doses are increased by every two to three weeks, and it's more favored for how easily we can titrate the dose, but the main concern is hepatotoxicity, and sometimes people may underdose because of that, and you want to consider drug-to- drug interaction because it is a severe inhibitor. And once the patient is on medication, you keep them on it, and you get them up to maximum tolerated dose, and you see how their treatment, doing on the medication, and if the cortisol levels are persistently elevated after two to three months, we may want to consider changing treatment, but if there is improvement but not optimal, you can also do a combination therapy. With that, I'll pass it on to the next speaker, Chris Yedinac. Thank you very much, and thank you for this invitation. I'm most recently from OHSU and also adjunct faculty at Mount Marty University, so I'm going to be talking a little about what happens with comorbidities in Cushing's disease, and we know that excess glucocorticoids drive a lot of comorbidities. So first of all, I'll look at some highlights in the interest of time, and also of recent data, and also in uncontrolled, and then subsequently in controlled or remitted disease. So cardiovascular comorbidities are foremost, and in particular, we talk about recently more about thrombotic events, and if you look at the cartoon here, and at the foot of our cartoon character here, we see there's a significant increase in thrombotic factors. So in a meta-analysis that was done by Wagner in 2019, this included over 6,000 patients, and that just found that there was an 18-fold increase in the risk of VTE for patients over the general population. 50% of deaths associated with Cushing's syndrome are related to pulmonary emboli. The critical period seems to be perioperatively, with 50% of those events occurring within one to two months, and we'll look at that in more detail in the next slide. So in terms of treatment, there's some recent data that suggests that low molecular weight heparin perioperatively in selected patients can actually decrease the incidence of VTE, although more data is needed at this point. Also, driving cardiac issues, of course, is arrhythmias associated with hypokalemia, increased renin angiotensin activity, and mineral corticoid activity, and we know that there are significant coronary events, so 75% of patients present with hypertension and dyslipidemia. Next slide. So this is a study that was a retrospective study done at OHSU. We see here there's a significant increase in patients having VTEs preoperatively, but again, that perioperative period immediately post-op, there's a significant increase, but the incidence decreased for this population about 60 days post-operatively and then stayed stable for at least three years, but it still remained elevated. Next slide. So arguably, metabolic issues drive many patients to seek care. The Cushing Support and Research Foundation actually assessed or surveyed their membership and found that on average, patients gained about 55 pounds. Mass General also did a study and looked at Cushing syndrome patients who actually had a 4.4 pound gain more than the control group over about six-month period. We've also got to keep in mind that patients delayed significantly in diagnosis, up to four years or more in some cases, and so there's increased incidence of weight gain during that period. Glucocorticoids also decrease the brain sensitivity to adipokines, appetite increases, and particularly a desire for higher sweet and higher carbohydrate foods. And anecdotally, that increases in the evening, so patients snack more in the evening on higher carb foods. We don't have time to go into a lot of the details, but hyperglycemia is present in upwards of 34, but in some studies, up to 83% of patients. And so there's multiple issues, including decreased intake of glucose by the GLUT4 transporters. That then drives lipolysis and proteolysis in the cell. Coupled with decreased insulin resistance, there's an increased fatty deposit both centrally and in the liver. Next slide. We know that there's muscle catabolism and particularly proteolytic effects which drive muscle atrophy. Patients report significant fatigue and weakness. They have difficulty performing a sit-to-stand test in particular without using their hands. They have difficulty walking up one to two flights of stairs. We also know that osteoporosis is common in up to 65% of patients with uncontrolled Cushing's disease, and that's secondary to prolonged osteoclastic activity and also decreased osteoblastic activity in the bone. 50% of patients have been shown to have some kind of non-traumatic fracture. Often these are vertebral, thoracic, lumbar, and rib fractures, but adrenal causes of Cushing's seem to have a higher incidence. So in addition to sleep architecture changes, patients have a high incidence of both obstructive and central sleep apnea. 88% of patients indicate they have insomnia. So the etiology of obstructive and central weight gain is really not clear, but certainly myopathies and weight gain contribute. Next slide. So chronic exposure to high levels of glucocorticoids both inhibits adaptive immunity and promotes pro-inflammatory cytokines. So we have susceptibility to fungal infections, viral infections, bacterial infections, and also there's rebound autoimmunity in symptoms after glucocorticoids are withdrawn. But of more importance is the perioperative period with a high risk of pneumocystis pneumonia in patients that have five to 10 times the upper limit of normal urinary free cortisol. Those patients should be prophylaxed with treatment preoperatively. Next slide. So we talked a little bit about mood changes and some patients are actually diagnosed as in the previous patient example with psychiatric disorders. 50 to 70% of patients report or are treated for depression and significant numbers up to 80% actually are treated for anxiety and panic attacks. Cognitive effects are significant. Patients report brain fog, difficulty with executive function, difficulty with decision making. In terms of a survey that was also done by CSRF, they found that 50% of patients surveyed had actually contemplated suicide. So there's a significant low quality of life. There's also sex-based comorbidities that contribute and amenorrhea, infertility, erectile dysfunction, and within the family and intimate relationships, there's significant dysfunction as a result. Next slide. So looking at what happens postoperatively, this study by Van Halen and cohorts assessed what the overall mortality risk was after biochemical remission. They looked at studies from 1994 to 2020 in their meta-analysis and discovered that in response, there's still significant elevation in probably cardiovascular risk and mortality associated compared with standard mortality ratios. Next slide. So I looked at about 11 studies to look at what the changes were in those comorbidities postoperatively and what I found was although diabetes did change significantly and significantly improved in over 60% of patients, and of course thrombotic events decreased at that 60-day or three-month period postoperatively, BMI did change but only in around 10% of patients and return to normal was difficult for a lot of patients. Dyslipidemia was decreased in about 20%, 25% of patients, and the same with hypertension. Sleep apnea and sleep issues didn't significantly change. Next slide, please. So in summary, the message I think in terms of postoperative is we need more studies. So we need more studies related to treatment, but to educate patients about what it is that they should expect postoperatively and be realistic about their expectations. Once treatment occurs, and primarily we're talking about surgical remissions, it's really the beginning of the journey of treatment and remission. The patients need control of a number of comorbidities that remain elevated and this requires decision making from the family, the patients, and multidisciplinary approach. Next slide. So postoperative treatment recommendations in summary, we talked a little bit about glucocorticoid withdrawal syndrome. Patients need to be monitored for those symptoms as the replacement dose of glucocorticoids are withdrawn and that can take one to two years and more in some patients. They need to be monitored particularly immediately, but long-term for different coagulopathies. Lipids and cardiovascular disease are a driver of elevated mortality risk and need to be monitored long-term. Blood glucose may improve, but not everybody achieves a normalization of their glucose levels and do require probably very rapid reduction of hypoglycemics immediately postoperatively. Blood pressure also can be rapidly changing, but again may not return to baseline postoperatively. Patients may have restored fertility, so a discussion and monitoring around the need for contraception and also there's a 30% lifetime chance of recurrence. So re-evaluate sleep function, re-evaluate hyperpituitaries and that may be worse postoperatively. Re-evaluating bone density and once glucocorticoids are withdrawn, re-evaluation for persistent Cushing's disease is necessary. So autoimmune disorders may resurface once that glucocorticoid is withdrawn and may require follow-up with other professionals. So treatment, ongoing treatment is necessary for weight management strategies, strength and endurance therapies and because of the high risk of suicidal ideation, patients need to be monitored for ongoing depression and the involvement of partners and family are really important in the treatment plan and should not be underestimated. So thank you for listening and we can open the floor for questions. Thank you so much everybody. We will open the floor for questions. At this time, I have a question for Dr. Atimulan. How do you use combination therapy for suppression of cortisol? Which are the most common that you use? How do you start looking at when I need to add an extra one if I'm not achieving the goal? Yeah, so usually if you start them on medical therapy and you have escalated the dose as per what's recommended to the maximum dose and you wait to see if the patient has, we target usually for normalization of urine-free cortisol and sometimes you can also look to see if the late-night salivary cortisol falls into normal range. None of the medications so far approved actually corrects circadian pattern but in some patients you may achieve a normal late-night salivary cortisol. Now if you are able to achieve that then the patient has a good response and if they are feeling better, it's a combination of how they feel clinically and biochemically better. Now if there's good response and it's come down a certain level but they are not totally in the normal range, they still have some improvement but the levels are still not good and they still have some persistent symptoms, you can add on a second therapy. So for example, I've started off with levoketoconazole or ketoconazole and then we've added on like materiopone therapy and if they have a better outcome, sometimes we can even stop one and just continue with the other one. So that's when I would use a combination therapy but if despite being on it for two to three months and there is no improvement at all, then you consider that treatment resistant and then you might either stop and move on to a completely different therapy. Thank you so much. Just a follow-up question there. You say you target this to urinary free cortisol. When the patient is unable to do urinary free cortisol, I have multiple patients that they cannot collect a 24-hour urinary cortisol. What is this other strategy that you use? Yeah, so I've used late-night salivary cortisol in those cases and the other thing is also their clinical parameters like they have hyperglycemic, all other comorbidities and their symptoms. So it's tricky. I mean most of the studies we have with all these drugs are urinary free cortisol but I've used these as other parameters and most times I'm hoping that we get a surgical target evolving soon and we can switch back to a more definitive therapy. Great. Last question for Chris. Should all patients be put on PCP prophylaxis? So those patients with higher levels of glucocorticoids, five to ten times the upper limit of normal on UFC should be prophylaxed, yes. Okay, so I know that there's so many other questions in the chat. We will try to answer by typing it because we are at the end of the hour. It was a great pleasure to be with all of you today. I think that we really enjoyed this starting from what is the diagnosis that it is basically have not changed in the last 20 years but learning again and then going into the treatment and finally the comorbidities and all the complications that we have with these patients that are not easy not even to diagnosis or to manage. So it was a start all the journey on the cushion on patients that suffer from this disease and hypercortisolism. Thank you so much Dr. Atimuland, Chris Jedinak for joining us in today. Thank you to ACE to organize this. Thank you to all the sponsors and thank you to all of you for participating in our webinar and I hope that this will be recorded. You can continue listening and if you have any questions please feel free to reach ACE staff. They will most likely reach to us. So thank you so much everybody. See you soon. Thank you everyone.

Cushing's Syndrome

hypercortisolism

diagnosis strategies

ACTH-dependent

ACTH-independent

treatment options

glucocorticoid withdrawal

comorbidities

long-term management

thrombotic events