Speaker 1:

Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now let's meet the endocrine experts who will be talking with us today.

Dr. Force:

Welcome to today's episode of AACE Podcasts. I'm Bahar Force and I'll be your host today. I'm an endocrinologist, Medical Director of the Pituitary Center, and the Associate Program Director of the Endocrinology Fellowship Program at Baylor College of Medicine in Houston, Texas. Today, we'll be exploring non-neoplastic hypercortisolism, an important yet nuanced topic that continues to challenge clinicians. I'm joined today by two esteemed colleagues, Dr. James Findling and Dr. Ty Carroll, experts in pituitary and adrenal disorders, particularly Cushing's Syndrome.

A little bit about our speakers: Dr. James Findling is a clinical professor of endocrinology at the Medical College of Wisconsin and one of the world's leading experts in pituitary and adrenal disorders. He has authored more than a hundred scientific publications and has helped shape international guidelines on diagnosis and management of Cushing's syndrome. He's especially known for pioneering late-night salivary cortisol testing and refining inferior petrosal sinus sampling, tools that have transformed how we detect and manage this complex condition.

Dr. Ty Carroll is a visiting professor of endocrinology and Chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Wisconsin Medicine. He completed his internal medicine and chief residency at the Medical College of Wisconsin, where he also trained in endocrinology and later served as Fellowship Program Director before moving to medicine. A dedicated clinician, educator, and researcher, Dr. Carroll's work focuses on pituitary and adrenal disorders, particularly Cushing's Syndrome. He has authored numerous publications on the diagnosis and management of this challenging condition and continues to be a leading voice in advancing care for patients with complex endocrine diseases. Welcome, Dr. Findling and Dr. Carroll.

Dr. Carroll:

Thank you.

Dr. Findling:

Thank you.

Dr. Force:

All right, so let's start by setting the stage. Dr. Carroll, could you define non-neoplastic hypercortisolism for us? And among patients suspected to have Cushing's syndrome, how often do we actually see this picture?

Dr. Carroll:

Great. Well, non-neoplastic hypercortisolism is the current term that we're using for cortisol elevations in patients that are not caused by a tumor growth such as an adrenal nodule, a pituitary tumor, or some tumor outside of those organs that's making ACTH. We used to use terms such as pseudo-Cushings and others, but those are really falling out of favor and they're not as accurate as the term non-neoplastic hypercortisolism. And for a long time, we've known that a number of conditions can cause elevations of cortisol, but more recently, there's been recognition of the extent of the problem. So things like alcohol abuse disorder, untreated sleep apnea, advanced chronic kidney disease, untreated depression can all cause significant super physiologic elevations of cortisol, and non-neoplastic hypercortisolism is probably quite common because these conditions and others are very common. The problem is we don't have good studies to give us an idea of the exact prevalence of this disorder. In fact, we don't have great studies to really show us what the exact prevalence of Cushing syndrome is, but it's probably quite common.

Dr. Force:

Interesting. Thank you for that clear definition in describing your clinical suspicions. And for our listeners, to bring it down to a more clinical level, I would love to hear Dr. Findling's perspective on this as well. Are there any particular clinical features or comorbidities that make you stop and think, "Could this be non-neoplastic hypercortisolism rather than true Cushing's Syndrome?"

Dr. Findling:

Well, thank you, Dr. Force, for inviting us to contribute to this podcast today. I think one of the things that's happening now in the United States, and I think probably all over the world, is that the screening for possible hypercortisolism has increased significantly, mostly due to guidelines around adrenal nodules, and now the recognition that hypercortisolism is quite common in patients with poorly controlled diabetes, for example, screening for this condition has increased. And that understandably will lead to probably a lot of patients who have abnormal testing, whether it's dexamethasone suppression testing, salivary cortisol, or even urinary cortisol, that really truly don't have neoplastic hypercortisolism.

And many of these patients have clinical features that are quite indistinguishable from patients who do have neoplastic hypercortisolism. They may have, of course, truncal obesity, hypertension, diabetes, or metabolic bone disease or adrenal nodule disease. So I think this is a consideration that all clinicians, where they do screening for hypercortisolism and have a positive test, need to keep in the back of their minds. Now, in my practice, one of the major contributing factors are alcohol use disorders, which are often covert and not very obvious. Patients often under-report or underestimate the amount of they consume, so I think that's the most common thing I see in my practice, but many other conditions. As Ty mentioned, poorly controlled diabetes, untreated and severe sleep apnea and major mental health disorders are all potential contributing causes.

Dr. Force:

Thank you. Yes, it seems like clinical intuition is key and it should be on our radar as we screen patients. And you alluded to this, but the lab results can certainly complicate the picture. Dr. Carroll, when you're looking at testing, whether it's dexamethasone suppression tests, urinary-free cortisol, or late-night salivary cortisol, what patterns make you lean towards an endogenous Cushing's picture versus something physiological?

Dr. Carroll:

Yeah, it's really a tough situation because the biochemical testing in terms of the screening test for hypercortisolism don't really define neoplastic versus non-neoplastic. When we look at patients who don't have clinical features, there are certainly patients who have clear neoplastic hypercortisolism, those individuals who have mild cortisol excess or max. And so we also have to keep in mind, there may be patients who have no clinical features but have real biochemical disease. So certainly, the picture or the pattern that I see when I see a patient has normal salivary cortisol, normal dexamethasone suppression testing but has some other abnormal tests, whether it's urinary free cortisol or some other testing, that really gives me pause.

Patients that have real neoplastic hypercortisolism generally have an abnormal salivary cortisol or dexamethasone suppression testing. It's very unusual for a patient to have both of those be normal and have true neoplastic hypercortisolism. So I think it's important that if we have discordant tests, that we really look harder into do those patients have some of the known conditions that can cause neoplastic hypercortisolism, like we've mentioned previously, alcohol abuse disorders, mental health disorders, chronic kidney disease. If individuals have those, we need to keep neoplastic hypercortisolism in the back of our minds. Not to say that those individuals can't have Cushing syndrome or neoplastic hypercortisolism as well, but we really just need to consider it even more strongly.

Dr. Findling:

Yeah, I agree completely with Dr. Carroll. Patients who have prodigious hypercortisolism, that is, say, urine cortisol, late night cortisol greater than five times the upper limit of normal and who have overt clinical features, obviously, those patients are much higher risk to have neoplastic hypercortisolism. And since neoplastic hypercortisolism by definition is ACTH dependent, patients with low ACTH levels of course probably do not have non-neoplastic hypercortisolism. But patients with non-neoplastic hypercortisolism may have elevated ACTH levels occasionally, so ACTH levels alone may not be helpful if they're elevated, but prodigious cortisol excess is much more common in patients with neoplastic hypercortisolism.

Dr. Force:

Excellent. That was in fact going to be my next question for you, Dr. Findling: if there is a degree of positive testing that makes you favor neoplastic hypercortisolism over non-neoplastic. So it sounds like five times upper limit of normal for sure puts that in the neoplastic bucket. That's a really helpful framework for interpreting mixed results. Let's shift to one of the newer tools in this space, the desmopressin stimulation test. Dr. Findling, can you walk us through how this test is used in clinical practice and where it fits in your diagnostic algorithm? I know you've published on this before.

Dr. Findling:

Yes. This test has become somewhat invaluable in making this distinction in selected patients. CRH show the Dexamethasone CRH test was in favor back in the eighties and nineties, but CRH, as you know, is no longer available in the United States and in most parts of the world, so the Desmopressin Stimulation Test has now become, I think, the standard of diagnostic care to make this distinction. Like all tests for Cushing syndrome, it's not perfect.

Now, vasopressin has three receptors. One, the V1 receptor, mediates the hepatic effects and glycogen analysis. The V2 receptors is the antideirac and hemostatic effects, which of course DDAVP binds to the V2 receptor, and the V3 receptor mediates or helps the pituitary make ACTH along with CRH. And for reasons that are not real well known, for some reason, DDAVP augments a dramatic increase in ACTH and cortisol in patients with ACTH screening tumors, particularly in the pituitary and occasionally in ectopic tumors.

Now, the reason for that isn't clear. It's not clear to me whether some cortical adenomas express the V3 receptor or the V2 receptor. DDAVP does bind weakly to the V3 receptor. So in corticotropic adenomas, you presumably just have a lot of ACTH secreting cells. So this test helps to distinguish neoplastic from non-hypercortisolism because patients typically with non-neoplastic hypercortisolism do not have any ACTH response.

Now, the problem with this test, of course, as with all tests with Cushing's, there are some overlap. There are some patients with proven Cushing's disease that do not have a response, and occasionally, patients with non-neoplastic hypercortisolism may have a response. But it helps us in our clinical decision making about which patients we should pursue more closely for either pituitary or non-pituitary ACTH screening tumors.

The other issues with the test is how do you interpret it, and I get asked this question frequently. It turns out in patients with pituitary Cushings, the ACTH response in the majority of them is very dramatic. It occurs quickly after the administration of desmopressin, within five to 20 minutes, and it's really not equivocal. Usually, the response is very, very robust, and there are some other caveats. One is the test should be done in the morning before nine o'clock. It should start in the morning when there is more glucocorticoid negative feedback generally on the HPA axis, and there are some side effects, the most common of which is, well, unfortunately, is hyponatremia as you might expect. So patients probably should have electrolyte profiles done prior to the test to make sure they don't have hyponatremia before you start. Fluid restriction, where we use 40 ounces or about a little over a liter over the next 24 hours after the test is important to avoid hyponatremia.

But I think anyone who's interested in this problem and doing the differential diagnosis should have this set up in their clinic. It's not any more complicated than doing a cosyntropin test, and I suspect most endocrinologists have access to that. So I think this is a test that will be increasingly used, and I think we'll have more and more valuable data in the future as this gets implemented more, particularly in the United States. This test has been around a long time in Europe. It's been, for 10, 15 years, been well established in many parts of Europe, but not widely used in the United States.

Dr. Force:

That's a really practical perspective. You also answered one of the questions that I had about the reliability of the tests, and it sounds like overall it seems to be quite reliable. But as all tests, this can have some pitfalls and the hyponatremia risk is real, so we need to be very careful about that. Let's talk about those tricky cases with cyclical or intermittent hypercortisolism. Dr. Carroll, in patients with intermittent or cyclical Cushing's who happen to be in the biochemical nadir, is the desmopressin stimulation test still informative or are there alternative approaches that you might recommend?

Dr. Carroll:

Yeah, this is a great question. I wish this is one that we had a really clear answer for. There's not great data on this. We don't have large scale studies. There was a recent publication from the NIH group that showed a patient that was in a biochemical nadir with clear cyclic cushings and had a desmopressin stimulation test that was positive, so it was helpful in diagnosing that patient actually in a recurrence at the time, but it was an individual with cyclic cushings. So it looks like this test may be helpful even in biochemical nadirs in patients with cyclic disease, but we don't have large scale data about this.

Part of the problem is cyclic cortisol excess is a pretty uncommon or very uncommon condition, and we just don't have the bulk of data to let us know if this test is adequate or not. Certainly, finding patients when they're in a biochemical peak is ideal because that's when patients have symptoms and they need to get treated, and being able to arrange a desmopressin test at those times might be ideal, but even in a nadir, it may be positive and it may lead us to show that a patient has neoplastic hypercortisolism.

Dr. Findling:

Yeah, I completely agree with Dr. Carroll. This problem is generated a little bit by social media of course, because patients who have or think they have hypercortisolism or Cushing's syndrome frequently go on these social media sites and find out it can be cyclical, so the normal testing doesn't necessarily exclude the problem. So it is a challenge, many clinicians when they're confronted with this, about what to do. I routinely do this task with the full understanding, as Dr. Carroll said, that it's not perfect, and patients who are in a nadir may or may not respond, but anecdotally, a case that Dr. Carroll mentioned, I know of another case in Washington D.C. where the same thing happened, so that this is still a test that you may use to help make that distinction, but I certainly wouldn't rely on it without more information and retesting in patients in whom you suspect may have this phenomena of cyclical or intermittent hypercortisolism.

Dr. Force:

Yeah, that really highlights how dynamic and complex this physiology can be. To summarize then, we've talked about distinguishing physiologic from pathologic hypercortisolism, through nuances of biochemical testing and how tools like desmopressin stimulation test may add insights, but also raise new questions. Looking ahead, let's talk about the future of this field. Dr. Findling, what do you see as the biggest unanswered questions, particularly regarding the metabolic and cardiovascular impact of mild non-neoplastic hypercortisolism? Are there any ongoing or recent studies looking at this question?

Dr. Findling:

Well, I think this summer, many of you are aware of the Catalyst study, part one and part two, that may transform how we evaluate and manage patients with particularly poorly controlled diabetes mellitus. Part one of the study, of course, showed that 24% of patients with poor glycemic control hemoglobin A1Cs greater than 7.5% had abnormal dexamethasone suppression testing, and many of them had adrenal imaging abnormalities. Part two of the study demonstrated in a randomized placebo-controlled double-blind study that cortisol-directed therapy, glucocorticoid receptor antagonism, resulted in dramatic improvement in the patients who receive that and compared to placebo. So this study shows that, maybe for the first time, that non-neoplastic hypercortisolism, that these patients may benefit from cortisol-directed therapy, at least in this circumstance.

But now one of the legitimate criticisms of this study is that of course they did not clearly distinguish neoplastic from non-neoplastic hypercortisolism, and so some of those patients may truly add neoplastic hypercortisolism. Nonetheless, many of them surely did not, and I think this opens the door to further evaluation of patients with known non-neoplastic hypercortisolism for pharmacotherapy. Most of the time, it's pretty straightforward. If you have an alcohol use disorder and you have hypercortisolism or Cushing syndrome, I think we know what the treatment for that should be, reduction in alcohol consumption. But in patients with poorly-controlled diabetes, for example, maybe even patients with end-stage kidney failure, there may be some benefit from medical therapeutic interventions in the future. So I think this is an exciting time for hypercortisolism, neoplastic and non-neoplastic hypercortisolism, so stay tuned.

Dr. Carroll:

Yeah, I would echo that. I think the real interesting thing about the future is currently, we're talking about making this distinction between neoplastic and non-neoplastic, and this study looks to show that perhaps treating non-neoplastic hypercortisolism improves diabetes control, so maybe treating hypercortisolism, no matter what the etiology, will be beneficial. We just don't know that yet and I think we need further investigation to find out if that's true or if there are select causes of hypercortisolism that we need to focus on.

Dr. Force:

Excellent. This has been a truly enlightening discussion. Thank you, Dr. Findling and Dr. Carroll, for sharing your insights and experiences on such an evolving topic. And to our listeners, thank you for tuning in. We hope you enjoyed the conversation and found it thought-provoking. I'm Bahar Force, thank you for joining us, and have a great week.

Speaker 1:

Thanks for listening to another great AACE podcast. Join us for another episode at aace.com/podcasts and help us in our mission to elevate clinical endocrinology. Together we are AACE.