Hi, everyone. Thanks for coming out tonight. So I'm recovering from a cold. It's not COVID. I tested myself several times to just to let you know if I cough or sneeze. That's why. So I'm curious who you all are. Are you mostly in private practice or fellows or, you know, I don't know, private practice, most academic. Where where are you? Where are you? Where do you work? Uh-huh. Yeah. And mostly all endocrinology. Any fellow metropolitan? So you're a fellow. Any other fellows? Okay, good. All right. Great. It's where we'll be discussing medical management of Cushing's. So these are my disclosures. So can everyone hear me? Okay. So at the end of this program, we hope that you, the learner, will be able to explain the efficacy and safety outcomes associated with Cushing's disease medical therapy, educate patients on successful management of their disease, review recent advances in medical therapy for patients with Cushing's disease, and identify symptoms of glucocorticoid withdrawal syndrome and complexities of management. We're going to start with a few questions. The first is a 46-year-old woman with Cushing's disease who achieved surgical remission with a post-operative day serum cortisol that was undetectable. She was initiated on prednisone 10 milligrams each morning and advised to decrease prednisone in one milligram decrements weekly until five milligram prednisone dose was reached. At the follow-up visit six weeks post-surgery, she continued on prednisone five milligrams daily and reported severe and worsening arthralgias and myalgias for five days with symptoms... I don't know where that's coming from. Okay. All right. So she's having... She's post-op cured Cushing. She's having arthralgias and myalgias for five days with symptoms becoming intolerable once prednisone was decreased from six to five milligrams. So what's the best management? A, administer injectable glucocorticoid. B, double prednisone 10 and continue until symptoms subside. C, change prednisone five to hydrocortisone 20 daily in divided doses. Or D, counsel about symptoms of glucocorticoid withdrawal and increase prednisone to six milligrams daily. Okay. Yep. 10 seconds to answer. Okay. Great. All right. So 58% said D and we'll come back to this question at the end of the talk. Question number two. A 55-year-old woman presented with persistent Cushing's disease despite prior transmonary surgery and she had an invasive ACTH secreting tumor. Laboratory tests show a plasma ACTH of 76, a high 24-hour urine-free cortisol of 140 with normal liver function tests. She started on ketoconazole 200 milligrams twice per day. Three weeks later, three weeks later, her UFC is still high at 95. Her LFTs are normal. She notes fatigue, dull headaches, poor appetite, nausea, and severe body pain. What's the best next step for her? A, increase ketoconazole to 400 twice per day right away since her UFC is still high. B, stop ketoconazole. She's clearly experiencing AEs and can't take this medication. C, add metyrapone. Or D, continue current dose of ketoconazole. Counsel her on symptom management and repeat labs in two to three weeks with a plan to likely increase her dose when her symptoms allow. Okay, so 10 seconds left. Okay, 73% said D. We'll come back to that at the end. And the final pre-question is a 47-year-old man who presents with recurrent Cushing's disease after successful surgical remission five years ago. No visible recurrent tumor is seen on pituitary MRI. His 24-hour UFC is 270 micrograms with normal being less than 50. He's concerned about his poorly controlled diabetes and hypogonadism. Which of the following medications is most likely to rapidly lower his cortisol values while not worsening diabetes or hypogonadism? A, ketoconazole. B, pasiriotide. C, oselodrostat. Or D, none of the above. Okay, 10 seconds. Okay, 53%. Oh, interesting. Okay, well we're gonna learn a bit on this one. More to come on that. All right, so I'm gonna start our didactic talk now with another case. This is a 28-year-old woman. She presented with irregular menses, dyslipidemia, weight gain. She had a blood pressure of 115 over 87. Her BMI was 32.9. She had facial plethora and rounding. She had pronounced dorsocervical fat pad and abdominal obesity, proximal myopathy, and red, purple abdominal and axillary striae. So we know what she has. And her hormonal workup confirms that she has Cushing's. You can see the very high 24-hour urine feed cortisol values, the high late night salivary cortisol values, and the abnormal one milligram dex suppressed cortisol. So these three tests are the diagnostic tests for Cushing's. The high UFC shows that she's hypercortisolemic. The high salivary cortisol at midnight shows an altered circadian rhythm. And the abnormal serum cortisol after taking dexamethasone shows autonomous production of cortisol. So those are the three ways we interrogate the HPA axis. The random serum cortisol that's high is helpful, but it's not part of our diagnostic criteria. And the plasma ACTH that's not suppressed tells us that this is ACTH-dependent disease. So that's an inappropriately normal plasma ACTH for the high cortisol value. Her pituitary MRI was done, and these are coronal images looking straight through the patient's face. And we can see an area of hypointensity in the inferior right side of her cella, consistent with an adenoma. So she did undergo surgical resection in August of 2020. She had a post-surgical cortisol that was one microgram per deciliter, which is low, and we like to see that, and tells us that surgery put her into remission. She was started on hydrocortisone from November 2020 to August 2021. She had persistent symptoms compatible with adrenal insufficiency or glucocorticoid withdrawal, despite hydrocortisone replacement. So I'm just going to take a minute to review the guidelines that were recently published on diagnosing and managing Cushing's. And you can see that after we establish a diagnosis of Cushing's disease, pituitary surgery in almost all cases is really the first line therapy for these patients. If surgery is not possible, we may consider medical therapy. We may consider radiation therapy. That would be very unusual. Rarely we give preoperative medical therapy before surgery, but surgery is almost always what we offer first. If we achieve remission, then we continue to monitor the patient over time for recurrence. If surgery is not successful and there's persistent disease, then our three options are repeat surgery, medical therapy, or radiation therapy. So what is glucocorticoid withdrawal syndrome and how is it different from adrenal insufficiency? So we know that adrenal insufficiency on the right is diagnosed with biochemical testing. It's with a low morning serum cortisol. Glucocorticoid withdrawal syndrome is more based on clinical presentation. And this is sort of the reaction that patients have, the symptoms they have when their cortisol is high and it's decreased into the normal range. In terms of the mechanism of adrenal insufficiency, it depends on what type of adrenal insufficiency. But when we're talking about after pituitary surgery for Cushing's disease, you have the suppressed normal corticotrophs present still. The tumor has been removed. The normal corticotrophs are suppressed and they're not making ACTH and they're not stimulating the adrenal glands. So it's a secondary adrenal insufficiency. With glucocorticoid withdrawal, the thought is that patients develop tolerance to high levels of cortisol and dependence. And when there's an abrupt decline of cortisol, there is an induction of cytokines and prostaglandins. That's the thought, although more research is needed on that. In terms of preventing symptoms with adrenal insufficiency, we obviously give physiologic replacement of glucocorticoids for patients. For glucocorticoid withdrawal after pituitary surgery, we need to very slowly and gradually decrease their replacement over time. But even when we do that, often we can't completely prevent the onset of some symptoms. So patients are going to have some withdrawal symptoms, even with a very gradual decline of their replacement. In terms of treatment, we know for adrenal insufficiency, we have them on a plan of physiologic replacement and we educate them on how to prevent adrenal crisis, what to do when they're sick. For treating glucocorticoid withdrawal, a lot of it is management. So we have prepare our patients with Cushing's that after surgery, they are going to have these symptoms of nausea, dizziness, fatigue, aching. So we have to reassure them that when that happens, that's normal. And actually it's a sign of successful surgery. But we can sometimes increase their dose to help reduce the symptoms, but there isn't a clear, we don't always completely get rid of the symptoms and we have to prepare patients that they are going to feel often worse before they feel better after curative surgery for Cushing's disease. So what do we know about how patients feel after pituitary surgery? So this paper was recently published by Irina Bankos and her group. And she looked at 129 patients with all forms of Cushing's, so pituitary, adrenal and ectopic, and she had them fill out weekly ADEQL surveys. So this is a patient reported outcome measure that looks at adrenal insufficiency symptoms. So headache, fatigue, dizziness. So they filled out these surveys and the patients were rated on the severity of their Cushing's and their weaned on their hydrocortisone dose from 50 milligrams down to 20 within seven weeks with five milligram increments. And what I'm showing on the right is there are the scores from this patient reported outcome measure in the 12 weeks after surgery. And you can see that initially patients felt better. And then as their hydrocortisone dose was tapered down, they started to feel worse. So they're developing adrenal insufficiency symptoms as their hydrocortisone was being tapered. And a little bit more on their specific symptoms. So you can see that these are the weeks over time after pituitary or curative surgery, whether it's pituitary or adrenal for Cushing's patients. The black line is the decrease in their replacement dose. You can see that joint and muscle pain actually worsened over time during that 12 week period. Headaches got a little better and nausea, energy and sleep stayed somewhat the same over that 12 weeks after surgery. So back to our case. So remember that she had curative surgery. She had some glucocorticoid withdrawal symptoms as we would expect. She stops her hydrocortisone when she recovers adrenal function. But then in August of 2022, she notices weight gain and she has biochemical evidence of hypercortisolism again. So these are her studies then. You can see that she has a high UFC and a high late night salivary cortisol. One thing you want to notice is that these are not as high as her initial test results. And that's always the case with recurrence because we catch them early. We're always monitoring our Cushing's patients and we're screening them for recurrence. So we always catch them a little earlier. But these are clearly abnormal and this patient has recurrent Cushing's. So she has recurrent Cushing's. We do another MRI, but nothing is seen. So there's no clear tumor that's visible on her MRI. And this is not an uncommon situation that patients with Cushing's have biochemical recurrence without a clear surgical target. So what do we do in the setting of persistent or recurrent Cushing's disease? So if we have persistent or recurrent disease, we have persistent or recurrent disease. If there's a target, if we see the tumor there, if we see that it's recurrent, if there's something on the MRI, we can suggest another surgery. If there's no target, then we might likely recommend medical therapy. Radiation is also an option, but this is really typically reserved for people with very aggressive tumors. Radiation is very effective for tumor control and less effective for biochemical control. So we tend to really give radiation to the people with aggressive tumors. But in most cases, we'll consider medical therapy. We'll start a medication. If there's partial control, we may either add a drug or consider a combination therapy. If there's control, then we're going to monitor patients over time for corticotrope tumor progression. And we'll monitor other outcomes, which we'll talk about. If there isn't control and we've tried several, maybe all the therapies available, at that point, we might consider bilateral adrenalectomy, which will cure the Cushing's in nearly 100% of the time. I say nearly because sometimes there actually can be adrenal rest cells or some adrenal tissue in the bed that's left over. But nearly 100% of the time, we'll have a biochemical remission. But there are obviously issues with bilateral adrenalectomy. Patients have primary adrenal insufficiency for the rest of their life. And you can also have Nelson's or develop corticotrope tumor progression after a BLA. So there are some issues that we need to consider before going into bilateral adrenalectomy. As I tell my patients, if we take your adrenals out, we can't put them back in. So it's kind of a final measure. So what are some factors that we need to consider when we're choosing medical therapy for our patients? So there are a lot of factors to think about. We have to think about the patient's medical history and their comorbidities, the side effect profile of each therapy, obviously, the cost and is it available? Can we get, sometimes it comes down to just that, can we get the medication for our patient? What other medications are they on? And are there any interactions? And obviously, patient wishes. So there's lots of things to consider. So these are the three main targets for treating Cushing's. We have pituitary-directed targets. These take advantage of receptors present on the corticotrope tumor. We have adrenal-directed targets, and these are straight agenesis inhibitors. And then we have a peripheral target that blocks the glucocorticoid receptor peripherally in the body. And I'm going to be discussing these therapies. I'm going to focus on the ones that are FDA approved, which are the ones with the check marks, and I'll also mention the other ones as well. So first, some general considerations with medical therapy. So what do we need to think about? If we need to rapidly normalize cortisol levels, we will likely consider an adrenal stratagenesis inhibitor because they work pretty rapidly. Oselodacetamotarapone are the fastest action in their oral therapies. Etomidate can be used in very severe cases. This is only given IV, and it's given in the ICU, so that's a very select situation. If there's mild disease in a residual tumor and we want a tumor-directed therapy, we'll consider a pasiretide or cobergeline. We do need to remember that, and it's come out more recently with cobergeline, that there's a risk for impulse control disorders. So we want to avoid this in a patient with bipolar illness or someone with a history of impulse control disorders or someone on a dopamine antagonist. For women who are pregnant or are desiring pregnancy, we could consider cobergeline or metarapone. Please note, these are not FDA-approved for pregnancy, but we have used them during pregnancy and there are case reports of these medications being used successfully in pregnancy. We need to consider drug intolerances, side effects, comorbidities, and particularly diabetes and hypertension because some of the medications make those worse and some make them better, and we'll discuss that. And again, cost, also what's the duration of therapy? Is this going to be a long-term therapy? Is it just temporary and we're planning adrenal surgery? Is it someone who received radiation and we're waiting for the radiation to take effect? And so it might not be a forever therapy. Those are some of the other considerations we need to think about. So I'm starting with our pituitary directed therapy, starting with cobergeline. So we know cobergeline well. We use it for prolactinomas, of course. We also use it for Cushing's disease, but it's off-label, so it's not approved for Cushing's disease and we don't have any clinical trial data. So the data we have is just from small observational prospective and retrospective studies. And overall, we see a 25% to 40% response rate in patients taking cobergeline. This sort of modest response may be related to the fact that each study had a different dose that was being used, typically lower doses. When we're using cobergeline for either Cushing's or for acromegaly, we tend to use higher doses than the ones needed for prolactinoma. We don't have predictive factors for who might respond and there's a variable time to achieve control and also some people escape control. So you can see in this small study of 18 patients, this is UFC over time, you can see that seven of these 18 patients escape control. And so that's 39% of patients escape control. So it's something to consider when we're thinking about using cobergeline. So what about Passyriotide? So this is approved for Cushing's disease. Remember lanriotide and octriotide are first generation somatostatin receptor ligands. They work primarily on SST2. Passyriotide is our second generation SRL, and it works on four of the five SST somatostatin receptors, but it has high affinity to the fifth somatostatin receptor. And that's very relevant for corticotrope tumors, people with Cushing's, because corticotrope tumors tend to highly express this fifth somatostatin receptor. So this was the study that was conducted that led to Passyriotide approval in 2012. It was a randomized study where people with Cushing's disease were randomized to one of two doses of Passyriotide, either a low dose of 600 micrograms sub-Q twice per day, this is the short acting form, or 900 micrograms sub-Q twice per day, or a quarter or 25% of the people who got the higher dose achieved control. And that was measured by a normal 24-hour urine pre-cortisol. There were also clinical improvements seen in this study, improvements in blood pressure, cholesterol, weight, and quality of life. You can see here as the UFC decreases in light purple, the weight in dark purple decreases over time, and this is a health-related quality of life score that's improving over time with this treatment. For patients who had a visible tumor, remember a lot of patients with Cushing's disease have a tumor that's so small you can't even see it on the MRI. Those with a visible tumor, it decreased by 44% in the patients getting the higher dose. In terms of safety, the GI side effects are very similar to first-generation SRLs, but what makes this different is the high rate of hyperglycemia. So almost 75% of people in the study had elevations in their glucose levels, 43% became pre-diabetic, and 34% became diabetic, and it's thought because of this SSTR5 action on the beta cell, it inhibits insulin secretion. So that's the main thing that differentiates pasreotide from the first-generation somatostatin receptor ligands is the risk for hyperglycemia. Also we saw in this study a higher response rate in people with mild Cushing's. So about half of the people with milder Cushing's were able to normalize their UFC. And we also have long-acting pasreotide, so similar to octreotide and lanreotide, it's a long-acting monthly IM injection. And a study was published in 2018 that showed overall 40% of people achieved a normal UFC. But when we stratify patients by the severity of their Cushing's, so these two bars are people with milder Cushing's, they had UFCs less than two times above the upper limit of normal, and these are people with UFCs two to five times the upper limit of normal. You can see that the people with milder Cushing's, about half, 52% of them were able to normalize their UFC, and that's on either the 10 or the 30 milligram dose. And a fewer, 35 to 37% of the people with more severe Cushing's normalized their UFC. So when we're thinking about pasreotide, we want to think about our milder patients that might have a better response. We also have long-term data on pasreotide, and we see that over time, these are the UFCs over time, they're decreasing and remaining normal. BMI decreased also and kind of remained lower over time. We see as expected when we start pasreotide that the A1C increases, but over time it stabilizes. So it doesn't continue to increase, it stabilizes over time. So how do we prescribe pasreotide LAR? So we start at 10 milligrams IM every four weeks, and we adjust based on the 24-hour urine-free cortisol and the clinical response. The maximum dose is 40 milligrams IM every four weeks. We have to measure before we start the fasting glucose, the A1C, and the liver function tests. And then we measure them every two to three weeks after starting, and monthly for three months, and then according to clinical indication. We have to check the ECG. We have to make sure the magnesium and potassium are normal. We follow IGF-1 and thyroid function. Considering we do get gallbladder sludge and gallstones with somatic center receptor ligands, typically it's not considered very clinically, you know, it's not as strong. People disagree on whether we get gallbladder ultrasounds, but in most cases it's subclinical, so we don't do them routinely in all patients. But patients do need to check their fingerstick glucose values at least once a week after starting pasreotide, and then less frequently thereafter, depending on what we see. Okay, so next I'm going to discuss the adrenal stratagenesis inhibitors, and I'm going to focus on the two FDA-approved therapies, osteologistat and levoketoconazole, and I'll mention the others as well. So I'm going to start with levoketoconazole. So you're probably very familiar with ketoconazole, which is an antifungal therapy that we use off-labeled for Cushing's. So ketoconazole is a racemic mixture, so it has both hands of the molecule. Levoketoconazole is just one enantiomer, and that's the side of the molecule that is more potent. So levoketoconazole is a more potent version of ketoconazole, and it's been FDA-approved to treat Cushing's syndrome. The FDA approval was based on two phase three studies, Sonics and Logics. This is the Sonics study, and it was an open-label study looking at 94 patients with Cushing's syndrome, and it showed that after the dose titration period, 81% normalized their urine pre-cortisol, and then after the maintenance period, it was a six-month maintenance period, 31% had a normal UFC. So this is obviously lower than 81%, and part of the reason for that is that the primary endpoint was specified that they had to be on a stable dose during that six months. So if you adjusted the dose in the trial, they couldn't qualify for the primary endpoint, and it was also intentioned to treat analysis, but the study did meet its primary endpoint. It was significant. There were also clinical improvements seen, improvements in glycemic control, cholesterol, and weight. You can see here that acne scores improved over time, hirsutism decreased, and edema decreased. And this was a composite clinical assessment looking at plethora, striae, and other measures that did, this wasn't significant, but there was improvement in these other clinical signs and symptoms. We also have the Logics study, and this was a randomized withdrawal study of levoketoconazole that also met its primary endpoint, and you can see that 95% of people that were randomized to placebo lost urine-free cortisol control, and that was compared to 40% of people who were maintained on treatment. So that did meet the primary endpoint of that study. And we also have long-term data on levoketoconazole. So this is from the extension study, and we can see that over time, at month 12, 41% of patients on levoketoconazole had a normal urine-free cortisol, and there were also continued clinical improvements with improvements in hirsutism and acne scores as well. So how do we prescribe levoketoconazole? So we need to measure liver function. Like ketoconazole, levoketoconazole can affect the liver function, so we need to monitor that. We need to check the ECG, and before we start, we need to make sure they have a normal potassium and magnesium level. We start at 150 orally twice per day, and we titrate by 150 milligram increments every two to three weeks. And we titrate based on the rate of cortisol changes, individual tolerability, remember those glucocorticoid withdrawal symptoms, so we want to manage those, and improvements in signs and symptoms. The maximum dose is 600 milligrams twice per day, and we also need to be careful about drug-drug interactions. Okay, so again, as with ketoconazole, there's an LFT warning, so we do need to monitor for that. About 11 to 15% of people do have an increase in their liver enzymes. In the trials, any increase was reversible, so every patient, it was a reversible situation. There is also the risk for QTC prolongation, so we need to follow ECG. And also, for people on other medications that could prolong their QTC, we need to be careful about that. With any treatment of Cushing's, and particularly the adrenal striatogenesis inhibitors, we want to make sure we're not over-treating them and causing adrenal insufficiency. So we need to monitor for signs and symptoms of adrenal insufficiency, and we may need to reduce or interrupt the dose if it looks like we're over-treating them and their cortisol values are becoming too low. Questions on levoketoconazole? So the question was titrating based on rate of cortisol change, and how much do we expect? So there isn't a specific number, but if we're seeing that, sometimes we're surprised. So we see someone with very severe Cushing's, and we start them on treatment, and they have a dramatic reduction. We think, oh, they're going to need a high dose, but their UFC decreases dramatically, we may want to slow down the taper. So we just have to be aware of not just the starting point of the UFC, but how much it decreases. We don't have a specific number, but it's sort of part of the clinical picture we need to look at. Any other questions? All right, so next I'm going to discuss osteologistat. So that's another recently approved adrenal stratagenesis inhibitor, and this inhibits 11-beta-hydroxylase. For some of you who may be familiar with metarapone, it's the same enzyme that metarapone inhibits. This is a very potent stratagenesis inhibitor. So while we don't have head-to-head data, this is really the most potent of the therapies, and it was recently FDA-approved. We have—LINK-2 was a small phase 2 study that showed 79% of patients achieved a normal UFC. LINK-3 and LINK-4 are two phase 3 studies, and you can see that the rates of control were varied depending on the study. These were slightly different protocols and populations, but overall we're seeing UFC control in 72% to 81% of patients. We're also seeing clinical improvements. So on the right, you can see improvements from baseline in hirsutism, supraclavicular fat pad, striae, muscle atrophy, ruber, ecchymosis, and dorsal cervical fat pad. And this is based on how much these clinical signs improved based on their UFC. So the people in dark purple had a normal UFC, and the people in light purple had partial control of their UFC. So you can see that even people with partial control had some clinical improvement. But obviously you want to get the UFC into the normal range, but even with decreasing the UFC, there's clinical improvement. So this is data on the left from LINK-4 showing individual UFC normalization from baseline to week 12. And what about adverse events? So not surprisingly, we're seeing these cortisol withdrawal symptoms. So patients are showing that they have decreased appetite, arthralgia, fatigue, nausea, and these are occurring in about a third of the cohort. So it's pretty common to see these symptoms. A little bit more on hypocortisolism-related adverse events, because remember, oselodracet is a very potent medication, so we need to be careful. We're not inducing adrenal insufficiency. So this is data from LINK-3 and LINK-4. You can see that in LINK-3, 51% of patients had a hypocortisolism-related adverse event, whereas in LINK-4, 27% of patients did. So two things to know. One is that these are high rates of hypocortisolism-related adverse events, because this is a very potent medication. But then you might wonder, why is it different? This is the same medication. Why is it 27% in LINK-4 and 51% in LINK-3? And most likely the reason is that in LINK-3, the dose was titrated every two weeks, whereas in LINK-4, the dose was titrated every three weeks. So we think that a more gradual titration of this medication is going to help to mitigate some of these hypocortisolism-related adverse events. And the recommendation is to start at two milligrams twice per day. I will say that for mild patients, you're going to start even lower than that. And I'll talk about that, I think, in a minute. So we also have long-term data on ocelotristat. This is from the extension study. You can see that over time, the UFC in black is staying controlled. What's interesting to note is that this is the dose of ocelotristat over time here. You can see that, actually, there is a decrease in requirement of medication over time. We're seeing that in our patients, that over time, they're actually requiring a lower dose of medication. So be careful if you start ocelotristat. Many, many months later, you might notice that you actually need to decrease the dose a little bit. We also saw long-term benefit in terms of cardiovascular-related metabolic parameters in this extension study. The median average dose was 7.4 milligrams per day. And in this study, 81% of patients had a normal UFC at week 72. So a very high rate of UFC control with ocelotristat. All right, so how do we give ocelotristat? We need to make sure that potassium and magnesium are controlled before we start it. We need to get a baseline ECG. We start, I mean, the official starting dose is 2 milligrams twice per day. Like I said, with a mild patient, you're going to start lower. I've started at 1 milligram once a day or 1 milligram twice per day. So just be careful and look at the clinical situation of your patient. It's a very mild Cushing's. You want to be careful that even a milligram of this drug could help lower their cortisol level. So we titrate by 1 to 2 milligrams. And I would do, again, a very gradual titration, unless it's a very severe patient, every two weeks or maybe every three weeks or even every four weeks, depending on the patient. And we titrate, again, based on the rate of change. How is the patient tolerating the medication and the clinical improvement? The maximum dose is 30 milligrams twice per day. That's a very, very high dose. I use that only really for my ectopic patients, my very severe Cushing's patients. A typical Cushing's patient is going to be on a much lower dose of osteologistat. And we need to always check for drug-drug interactions. This affects the CYP3A4 enzyme, as do many medications. So you need to think about not only when a patient adds another medication, but when they stop another medication, you need to reassess for any drug-drug interactions. Again, we need to monitor for hippocortisolism, especially with this drug, because it's very potent. And if we're seeing that the patient has clinical signs and symptoms of adrenal insufficiency, if they have a low morning serum cortisol, we may need to reduce the dose or interrupt the dose. We need to check the QTC interval. And we should be aware that like metyrapone, because you're inhibiting the final step of cortisol synthesis, there can be precursor buildup. So mineralocorticoid and androgen precursors can build up. And so we can have mineralocorticoid excess, like hypokalemia, hypertension, edema. And we can have androgen excess symptoms in women, like hirsutism and acne. So we want to monitor for those things. So we also have our off-label therapies, ketoconazole and metyrapone, which probably these are the drugs that you're more familiar with. And we use these widely. So these two drugs, ketoconazole and metyrapone, are approved in Europe for Cushing's. They're not approved here, but we use them off-label. Both of them have rapid onset and rapid action. Ketoconazole is typically given twice per day. Usually we start at 200 milligrams once or twice per day. We can go up to a max of 1,400 milligrams per day. We want to be careful with ketoconazole. Like levoketoconazole inhibits multiple enzymes in the steroidogenesis pathway. So we're not just inhibiting the final step. We're also inhibiting 17-alpha-hydroxylase, which goes over to the androgen pathway in the adrenal gland. So men can develop hypogonadism. And so we need to be aware of that. For women, it might be beneficial because they're not going to have your hirsutism and acne. We need to monitor liver function with ketoconazole and they need gastric acid. So they can't take an H2 blocker or proton pump inhibitor. Metarapone is a very effective medication. It does have a short half-life, so it's given three to four times daily. And you can, again, have buildup of the mineralocorticoid and androgen precursors. So we need to monitor for that and some GI side effects sometimes with metarapone, usually just transient when you start it. Mitotane is really more for adrenal cortical carcinoma. We don't use it for benign Cushing's. These are really for our adrenal cancer patients. And etomidate, as I mentioned, is used in the ICU setting for very severe patients. It's only given IV. So this is a very fulminant patient who's in the hospital, you give etomidate IV. Any questions on those therapies, on the adrenal striatogenesis inhibitors? So how do we select our adrenal striatogenesis inhibitors? We want to consider how rapidly they work, how tolerable they are, how easy they are to use, how effective they are in normalizing the UFC, and what clinical improvements we're going to see. Levoketoconazole and ketoconazole are very easy to titrate. We do need to remember about hepatotoxicity with both of those therapies. We need to monitor liver enzymes. And we need to consider drug-drug interactions. And with men with Cushing's, they can either develop, or they're hypogonadal. Usually with Cushing's, men are hypogonadal already. And sometimes that can improve when you treat them. Often it does improve, but with ketoconazole, they may remain hypogonadal. Osteologistat, remember, we're seeing very high rates of cortisol normalization. We just want to be careful about over-treating our patients. There's a more convenient dosing scheme versus metarapone, which is given multiple times per day. Osteologistat is twice per day. But neither metarapone or osteologistat is going to cause hypogonadism. So they're good for our male patients. So finally, we have our glucocorticoid receptor blocker. So that works peripherally in tissues to block cortisol action. And this is mifepristone. So this is a very strong antagonist of the glucocorticoid receptor. It's 10 times as strong as, it has a 10 times higher affinity for the receptor compared to cortisol. It also blocks progesterone, as we know. And this was FDA approved for hyperglycemia due to Cushing's. And that's the label because we're not actually lowering the cortisol levels. We're blocking the receptor so levels actually go up. So we can't check levels. So that's the indication for mifepristone for Cushing's. We start at 300 milligrams per day and we can go up to 1,200 milligrams daily. So this was the study from 2012 that led to approval of mifepristone for Cushing's syndrome. This was 50 patients with Cushing's syndrome. They were all treated with metarapone. And you can see, again, we're looking just at the clinical improvements. We can't look at cortisol levels with this medication. We see that the A1C improved over time in patients on mifepristone. And this is looking at a clinical composite score, including weight, blood pressure, oral glucose tolerance tests, and Cushing's weight appearance. And you can see that over time, there's improvement in these clinical outcomes. So patients who had these findings were much improved are in dark purple. Patients who had somewhat improvement in these findings are in light purple. And you can see that over time, more patients are noting clinical improvement in these features when treated with mifepristone. In terms of side effects, of course, we worry about adrenal insufficiency. We're blocking the cortisol receptor. Patients can also develop hypokalemia on mifepristone. And again, we're just determining efficacy by clinical parameters. So we can't measure UFC. We can't measure serum cortisol. We can't measure ACTH. So we're a little bit, you know, as endocrinologists, we like to look at those numbers. We can't look at the numbers, but we look at symptoms, blood pressure, weight, glucose levels, and that's what we use to titrate mifepristone. TSH can go up, so we want to monitor the TSH. And this is not a tumor-directed therapy. So people with a pituitary tumor, we need to monitor for any progression of their tumor. Again, so we check the potassium, and we need to monitor potassium. If they become hypokalemic, we can give spironolactone with mifepristone, and that works well. There's a lot of interaction, so we need to be careful about that. Women can develop, because of the progesterone receptor antagonism, they can develop something called benign cystic dilatation of the uterus. So it's not a malignant process, but it's proliferation of the uterine lining, because we're blocking the progesterone receptor. So any woman with a uterus on mifepristone, if there's any bleeding, you need to do an ultrasound and biopsy, and you need to monitor for that in women. And we also need to be careful about signs and symptoms of adrenal insufficiency. And remember, we can't use cortisol as a marker of efficacy with mifepristone. All right, so some general recommendations for follow-up for patients with Cushing's who are treated with medical therapy. So remember that we need to always remember that there's, for Cushing's disease, there's a pituitary tumor that we need to monitor, particularly if they're not on a tumor-directed therapy. Remember, the only tumor-directed therapies are cabergoline and pasireotide, so anyone on an adrenal serratogenesis inhibitor or on mifepristone, we're not having any tumor-directed treatment. So the recommendation is for an MRI six to 12 months after starting treatment. And then after that, every few years, it depends on the clinical situation. How big is the tumor? Is it small? Has it changed? So it really depends on the patient. And it's hard to know if we do see progression of that tumor, is that loss of feedback, kind of like in Nelson's with bilateral adrenalectomy, or is it just the natural history of the tumor over time? And most likely it's the natural history of the tumor, but we do need to monitor for that. And how do we monitor? So we do look at the ACTH level. Remember that plasma ACTH has a very short half-life and it's pulsatile, so you're going to see a lot of fluctuations in ACTH levels. If we see that it goes up, it does not necessarily mean that the tumor has gotten bigger. But if we see a progressive increase in the plasma ACTH, it could be a sign of tumor growth. And we do at that point want to get an MRI if we see that happening. And if we see that the adenoma is growing, we need to reassess our treatment. We may need to suspend treatment and reassess our management. The patient may need surgery or radiation or both. So what are some factors to consider when we're using combination therapy or switching to another therapy? So we can use these therapies in combination. We don't have trial data that looked at which combinations we can use, but it is often used. You can use medications with different, like a tumor-directed and adrenal-directed, or even to adrenal-directed therapies. It kind of depends on the clinical situation. But we look at all the various clinical outcomes that we are using to assess how our patients are responding to therapy. Their phenotype, their weight, their blood pressure, their glucose levels, quality of life. We look at biochemical endpoints in anyone who's not on mifepristone, but everyone else. And for mifepristone, just the clinical outcomes. Typically except in people on mifepristone, we use the UFC to monitor response. So that's really what we're trying to get into the normal range is the 24-hour urine-free cortisol. And if we're worried about adrenal insufficiency, we look at the morning serum cortisol. Remember that the 24-hour UFC is good on the high end. On the low end, it's not very accurate. We don't use it to assess adrenal insufficiency. In that case, we look at the morning serum cortisol value. And if the patient is continuing to have persistently elevated cortisol levels on maximum tolerated dose, then we will consider changing our therapy. If the cortisol has improved and there's some clinical improvement, but it's not normalized, we could add another therapy and we could do combination therapy. And if there's clear resistance to treatment despite dose escalation, then we'll want to switch to a different therapy. So this is just to remind us, actually I'm getting towards the end of the talk, and then we'll go back to our questions and then you can have dinner. So we always, as endocrinologists, we focus on our biochemical outcomes. We want to see a normal UFC. We'd love to see a normal salivary cortisol value, but we need to remember that patients with Cushing's, this is really a lifelong condition. I never use the word cure, except if it's adrenal Cushing's, then you can cure them if they have an adenoma and you remove that adrenal. But for most Cushing's patients, this is really a lifelong condition and we can put them into remission, but they often unfortunately continue to have signs and symptoms that may persist. And this was a study I published a bunch of years ago in 102 patients with Cushing's disease who had achieved remission. And you can see that despite remission, 60% said they had poor energy, half of them had body aches, half of them had poor memory, difficulty losing weight, muscle weakness. You can see a high rate of hypertension, dyslipidemia, diabetes, depression. So we need to remember to follow these symptoms and comorbidities over time. And along those lines, so this is a figure that's adapted from a paper published by Susan Webb. And just to remind us that we really need to follow all these clinical outcomes for our patients. These are some of the issues that people with active and treated Cushing's suffer from. So insulin resistance and diabetes, dyslipidemia, hypertension, we know that cardiovascular risk remains high over time, mood and quality of life and cognitive function can remain impaired. And there's also the complications of the treatment itself, hypopituitarism from surgery or autoimmunity that can happen after you treat patients. And over time, there is still increased mortality. So it's important to remember that we need to follow these other signs and symptoms of Cushing's long-term in our patients. So in summary, treatment of Cushing's syndrome is multimodal. While surgery is generally first-line treatment, there are several second-line therapies, including repeat surgery, medication, radiation, or bilateral adrenalectomy. There's been a lot of progress recently. So 10 or 13 years ago, before 2012, we had no FDA-approved therapies for Cushing's. So in 2012, we had Mifepristone and Passeritide. So we had two. And then the past two years, we have two more, Osteologistatin and Levoketoconazole. So there's really been a lot of progress in medical therapy for Cushing's. And luckily now, we have a lot more therapies to consider for our patients. We should warn our patients that their symptoms might worsen before they improve when we treat them. And that's from glucocorticoid withdrawal symptoms. We should know that impaired quality of life may persist even after long-term treatment. And patients with Cushing's really need a multidisciplinary care that's individualized and patient-centered. And we do need to monitor patients over time for recurrence. And long-term follow-up is needed.

medical management

Cushing's disease

case study

treatment options

pituitary-directed therapy

adrenal-directed therapy

glucocorticoid receptor blockers

efficacy

safety outcomes