B (2:03)

Yeah, I think in primary care, this episode should convince you that we need to be owning at least the first line testing for this before we send them to Dr. Banko's to get their adrenal gland. To convince them to get their adrenal gland taken out. But Paul, what is it that we do on Curbsiders?

A (2:23)

And would you introduce our co host?

C (2:25)

Yeah, Matt we are, as a reminder to our audience, the Internal Medicine podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge as you allude to. We had a great expert tonight, and we also have a great co host. We are joined by endocrinologist extraordinaire, Dr. Mobeen Ahmad. Mobine, how are you?

E (2:42)

I'm doing great. You know, just trying to avoid the. Avoid the snow, I guess. We're recording this right after the snowstorm of the century, I guess.

F (2:51)

Yeah.

C (2:51)

Or the year, at least.

B (2:52)

Hopefully by the time this one comes out, hopefully there will be less snow, but you never know in Pennsylvania.

A (3:01)

All right, so, Mobeen, would you tell us about our guest?

E (3:05)

Yes. So today we have a fantastic conversation with our guest, Dr. Irina Benkos. She is a professor of medicine and an adrenal endocrinologist at the Mayo Clinic in Rochester, Minnesota. She received her medical degree from Yuliu Hatiganu University of Medicine and Pharmacy in Romania, completed her internal medicine training at Danbury Hospital in Connecticut, and completed her endocrinology training at the Mayo Clinic. She truly is a leader in the field of adrenal pathologies and has been a key author of the European Society of Endocrinology's clinical practice guidelines on the management of adrenal incidentylomas. And it's also written a lot about the topic that we will be discussing today. In addition, she has authored over 275 articles. And truly, as a mentor and a role model, I think for countless endocrinologists and endocrinology fellows like myself.

B (4:00)

All right, so without further ado, let's get to it. A reminder that this and most episodes

A (4:06)

will be available for CME credit for

B (4:07)

all health professionals through VCU. Healtherbsiders.vcuhealth.org Irina, great to have you here. Thank you so much for struggling with us through technical difficulties. You sound great. And the audience wants to know what

A (4:25)

is a hobby or interest that you're

B (4:26)

currently enjoying outside of medicine?

F (4:30)

That's a great question. I was thinking about it, preparing for this podcast, and I'll be honest, a lot of what used to be hobby time for me has turned into what I call team science. I spend a lot of time, a lot of my free mental space, thinking about mentorship and team development and how to build projects that can truly transform team care for patients with adrenal disorders, especially in this challenging funding environment. And much of this work isn't formally required, but I do it because I'm deeply passionate about mentorship, career development, and creating team that function sustainably in terms of more traditional hobbies. The one that was a constant throughout my life has been reading or more like listening audiobooks. I have a pretty extensive audiobook library and listen while driving or in between busy and what I would really like getting back to is ballroom dancing. I used to dance quite a bit earlier in my life. That's actually how I met my husband at a ballroom dance school. I also hope to return to clay modeling and painting and learning new art techniques. I think those creative outlets would bring me sort of a different type of joy. Maybe something I'll have more space for later in life. Or at least I hope so.

B (5:47)

I hope you get back to those two. That all sounds wonderful.

F (5:51)

We can all meet and dance ballroom dancing.

B (5:54)

Paul, you're a big ballroom dancer, aren't you?

C (5:56)

I mean, no, Matthew, I am not. I would be if I could be. I was born without rhythm, but I admire those that can.

B (6:04)

Actually, Paul, someone sent me an AI video. A mutual friend sent me an AI video of you doing a wild dance.

A (6:12)

Did that make it your way as well?

C (6:14)

It did, yeah. I found it deeply upsetting as anyone who actually knows me, they know I don't like pictures or videos of me. So the fact that someone went to the effort of actually transforming into something even more egregious, I actually sound hurtful, but glad it made its way to you.

A (6:27)

For the audience, it was former guest

C (6:29)

JJ Nunez and former friend.

F (6:33)

And former friend.

B (6:34)

Okay, but back to Sorry for that detour there, but it just made me think of it.

A (6:40)

Paul.

C (6:41)

Yes, I will ask my standard question. I would love to hear about meaningful advice or feedback either that you've received or that you like to give that you could share with our audience that they find useful.

F (6:52)

Yeah, and I have a good one. The one I received some time ago and the one that I'm frequently giving to my mentees. So one of the most meaningful pieces of advice I received, especially when I transitioned or as I was transitioning from junior to mid career, was to clearly define my vision and mission and to revisit them regularly as my career evolves. And this advice has been incredibly grounding. It helps me decide which projects to take on. Those that are meaningful to me, aligned with my values, and have the potential to make a real difference. It also makes it much easier to say no and avoid being pulled into many directions. For example, when you asked me to record this podcast on mild autonomous cortisol secretion, I said yes almost immediately because it clearly fits within my mission. Disseminating Signs advancing education on adrenal disorders, disorders helping to develop the next generation of endocrinologists are core to what I care about. So using that lens has helped me move forward in a more intentional and sustainable way rather than simply reacting to different opportunities as they come.

C (8:09)

Can I ask your process for revisiting that? I love that so much. By the way. I was just thinking about how sort of writing my teaching philosophy the last time I went for promotions was really clarifying. But I mean, I guess what is your process or do you even have one for revisiting? Like, how often do you kind of go back and check in and say, does this still align with my mission? What is my current mission? Is that something you do with intention or just something that kind of as your career evolves, you think about it Again, both.

F (8:32)

So, for example, last time I had to do it because I had to is when I submitted my promotion package for professor. So that happened now two years ago or so. I really had to think, okay, this is my reflection over the last five years. What is the next five years looking like? So that was a major sort of rethinking and looking forward at opportunities, at what my institution wants from me, what I want from myself, and so on. But I don't think we should be forced to change or to think about our mission and vision. I find it a good time of the year to do it around New Year's time. You know, how people think about new resolutions. I think about, is it still valid what I wrote down one year ago? If not, why did it change? What was my thought process and why? So reflecting on the past and thinking about the future is something that I feel is helping me love what I do.

B (9:36)

Fantastic. And speaking of the future, this thing we're talking about today, it's something that I've been looking forward to because this is something that I only learned about maybe like a year ago or so. And I'm still trying to grapple with like what it means and what we need to do with it. So let's get to a case from Kashlak Mobeen and let's start talking about the main topic.

E (9:57)

So the first case that we have today is Ms. Addie Rennell. She is a 48 year old female with a past medical history of well controlled hypertension, type 2 diabetes, hyperlipidemia and obesity. She presents to the clinic for an annual follow up. She was involved in a motor vehicle accident about a month earlier and was told to see her PCP regarding an adrenal lesion that was noted. Her only medications are amlodipine 5 milligrams daily, atorvastatin 20 milligrams and metformin 1000 milligrams daily. Vital signs are normal with a blood pressure 120 over 75, heart rate 80 beats per minute, respiratory 14 breaths per minute. On physical exam it's positive just for generalized obesity with her BMI being 34. However, there's no abdominal striat, bruising, dorsal clavicular fat padding that you can notice. On review of her CT of her abdomen pelvis without contrast, she is noted to have a 2 centimeter right adrenal lesion measuring 5 Hounsfield units. Workup of the adrenal lesion is only positive for a cortisol of 1 milligram. After a 1 milligram dexamethasone suppression test of 4 micrograms per deciliter with an adequate dexamethasone level of 4 nanomoles per liter. And DHES is also measured and is low at 20 micromoles per liter along with an ACTH level being low at 5 picograms per milliliter. A 24 hour urine cortisol is also performed in all of this and it's normal at 35 micrograms over 24 hours. So I guess the first question that we kind of have for you, Dr. Bankos, is kind of addressing what exactly an adrenal incidentaloma is and kind of what is your approach to patients with adrenal incidentalomas?

F (11:46)

Yeah, thank you. And really well described case. So an adrenal incidentaloma is an adrenal mass that is discovered incidentally on cross sectional imaging, most commonly a CT scan that was performed for a reason unrelated to suspected adrenal disease. That's why it's called incidental incidentaloma. And whenever we see an adrenaloma, we have to approach it from two key perspectives. First, is it benign or is it malignant? And that assessment primarily relies on imaging characteristics, things like size, density measured in Hounsfield units on non contrast CT scan, interval growth over time if available. And actually this part is commonly commented on in radiology reports, so I don't find that this part is ignored. But it's the second question, is Ms. Hormonally active or not that people forget about? Because you know, there are no so many adrenal, not so many tumors in our body that originates from tissue that can produce hormones. Right. So this is one of them. So the second question is Ms. Hormonally Active or not, relies on standard of care work of hormonal excess in three main categories. Cortisol excess, aldosterone excess and catecholamine excess. And just to give you an idea, based on multiple larger population based or system based studies, only around 15% of people with adrenal acidantyloma would actually have at least one evaluation for hormonal tests. So certainly a lot of patients do not get the second question answered or raised. Every patient with adrenal acidantyloma should be assessed along both of this axis, malignancy risk and hormonal activity.

B (13:36)

And this is regardless, regardless of the size of what we see there. Because sometimes they might say nodule, sometimes they say thickenings, sometimes they say mass.

F (13:46)

Yeah, that's a great question. And sometimes different radiologists say different things. So one radiologist may say thickening, that another radiologist may say as a nodule, I guess my recommendation is to look yourself. But not everyone is comfortable interpreting CT imaging and we do rely on radiology reports. So I will answer two different ways. First, the guideline way says that all of those things we should be worried about only if the nodule is at least 1cm in size or larger. So that also means that based on the guidelines, you should ignore a tumor which is 9 millimeters. Right now from my point of view, I think if you see is there, so you cannot ignore it. And even cancer starts small. And we may just be very lucky that we found an adrenal nodule that wants to be eventually a 10 centimeter tumor at 9 millimeters. So I would say that if you see it and if it's described in radiology report, probably deserves evaluation. But again, the guidelines is 1cm and above. And as far as thickening, I think that one deserves probably a discussion with radiologists. What does it mean? Is it really nodular thickening? Is it just maybe a generous adrenal gland for whatever reason? And I guess decision making could be based on that.

C (15:13)

And in terms of the hormonal workup, can you remind us, is it all hormones for all incidentalomas or do certain characteristics sort of push you down a cortisol versus a pheopath? Or what is your approach in terms of the hormonal workup just to remind us?

F (15:25)

Yeah, great question. So actually not every patient needs evolution for all three axis. So just to go with the three, let's start with evaluation for catecholamine excess with plasma metanephrines or urine metanephrines. Only patients with adrenal Tumors in hounsfield unit above 10. So indeterminate adrenal tumors need assessment for pheochromocytoma or catecholamin excise. Because pheochromatomas are not lipid rich, it means if you see a tumor with hans fluid ins under 10, you can skip evaluation for metanephrines. Now, if you're not sure, let's say it's contrast only CT scan, or you're just not sure what the Hans fluid unit is, I guess it's better than to test for metanephrines. But you may avoid testing 70% of people for catecholamine excess because that is a prevalence of patients with lipid range tumors that cannot be pheochromocytoma. So that's one for catecholamin excess. Only those with indeterminate looking adrenal tumors need evaluation for catecholamin excess. Number two, primary aldosteronis. So aldosterone excess Only those patients with hypertension or hypokalemia, usually hypertension less so hypokalemia need evaluation for primary aldosterone. And based on the new guidelines on primary aldosterone, you don't even have to have an adrenal tumor if you have hypertension at least once in your life, you have to be tested for primary aldosteronis. And that would be morning aldosterone and retin plasma activity. And then finally, the easiest one is cortisol excess. Everyone needs it. No matter how the tumor looks and what symptoms you have, you have to have dexamethasone suppression test. And I know this is the topic about max, so we would diagnose MAX based on abnormal dexamethasone suppression test. But we'll talk about it more a bit later. Right.

B (17:15)

That's a fantastic breakdown of everything. And the 10 Hounsfield units, that sticks out in my mind. And it was Dr. Young that we talked about. I think it was number 377 for the audience. And so less than 10 Hounsfield units, that suggests lipid rich. And that's where we're thinking that this could be cortisol producing or aldosterone producing or just producing nothing. But it should be something benign, not a malignancy or a pheo.

A (17:46)

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B (22:25)

We gave some labs here, right, that we already got for this person and maybe we should start talking about that and how that relates to Max.

E (22:34)

Right? Yeah. So, Dr. Bankos, like we were kind of discussing with this patient, you know, the only thing that came back positive in terms of her adrenal workup was the 1mg dexamethasone suppression test, which was 4 micrograms per deciliter after the 1mg the night before and an adequate dexamethasone level. So, kind of, I guess our next question is kind of, what exactly is mild autonomous cortisol secretion and how does it differ from the traditional Cushing syndrome as has been described before?

F (23:10)

Yeah. So mild autonomous cortisol secretion, or MAX we will call it, refers to cortisol production from an adrenal nodule or nodules that occurs independently of pituitary stimulation. So first, maybe we should remember what is normal. Normal is for pituitary gland to produce acth. ACTH travels to adrenal glands and tells our adrenal glands to produce cortisol, and that cortisol is being produced in a circadian manner with peak cortisol in the morning and then slow decline of cortisol production through the evening and very little cortisol production overnight. While when there is an autonomous cortisol producing nodule, this cortisol will be produced from the adrenal nodule no matter what time of the day or night it is. And in this particular patient with dexamethasone suppression test of 4 micrograms per deciliter, we know that that adrenal nodule produces Constant amount of 4 microns per deciliter of cortisol. And sometimes it's too much, and that would be during the evening and during the night. So, traditionally, MAX has been defined as sort of biochemical causal excess without overt features of clinical Cushing's syndrome. However, our own research showed that the line between what we call overt features of Cushing's syndrome and absence of that is kind of blurry, especially in the current era where a lot of patients take weight loss medications, may not present with abdominal obesity or with sort of classical features of Cushing's syndrome. I think it's more and more difficult to distinguish a patient with just abdominal obesity versus abdominal obesity because of overt Cushing's and classical features of overt Cushing, such as strear or let's say, thinning of the skin, are not that common. So, for example, stria can usually seen in under 5% of all patients with overt features of Cushing's syndrome. So as a result, distinction between MAX and Cushing's syndrome can be difficult to draw. So this is why it's more important to look at our pretest probability at the existence of adrenal mass, at the full workup and comorbidities and Symptoms.

E (25:37)

And I think one thing that people might ask, and I think something that is important to address is they might be thinking, okay, you have this little bit of cortisol excess, you know, like, why is it important for us to recognize that what does it lead to long term in patients? And kind of like how common is it exactly in our adrenal incidentaloma patients?

C (26:00)

Yeah.

F (26:00)

So first of all, how common it is is actually quite common. It's not a rare disorder. So we know based on three very large studies, one population based, one sort of CT based in the younger population, and one of a patient was newly diagnosed with adrenal incidentalom. We know that prevalence of MAX in those study varied between 19% and 44%. So it's certainly at least one in five patients with an adrenal adenoma will have MAGS, maybe higher than that, depending on the setting you are seeing this patient in. So it's not something that is rare. And this is why really screening everyone with adrenal acidantyloma is recommended. Now. Why is it important to recognize? Well, because it's not been a benign biochemical curiosity. It's associated with an increased cardiometabolic risk, impaired quality of life, disturbances in sleep, overall well being. And much like other major risk factors such as diabetes, hypertension, smoking, MAX represents a potentially modifiable contributor to long term morbidity. And recognizing it gives clinicians an opportunity to intervene, whether through surgical consideration, just careful modification of MAX associated comorbidities to improve patient outcomes. Really?

B (27:27)

Yeah, because incidentaloma, adrenal incidentalomas are very common in my experience as a primary care doctor, and so many patients are getting CT scans. So we can expect we're gonna see these adrenal incidentalomas and we'll be working them up in primary care. That's part of why we wanted to do this show and why we've done other adrenal shows. So my question is for this Macs and Cushing's, do we think it's a spectrum where eventually patients who have Macs, they might develop overt Cushing's? We just don't know which patients. And can you tell us? You mentioned that striae are only like 5% of people with Cushing.

A (28:10)

So what?

B (28:10)

But what are the most common symptoms that would make you think someone has overt Cushing's?

F (28:16)

Yeah. So let's start with that. What are the symptoms of overt Cushing? So the list is the supraclavicular pads, dorsace, cervical pad, abdominal obesity, moon Facies, thinning of the skin, easy bruising, maybe thrush, stria. As I've mentioned, those are quite uncommon. And then if it's really severe, you will see edema, you will maybe see signs of vertebral fractures with kyphosis. But as far as how common these in one single patient, very uncommon. So most of the patients with overt Cushing's syndrome probably would have several clavicular pads, maybe there's a cervical pad, maybe a little bit of moon facial and abdominal obesity. And it is a good thing that we are diagnosing patients with Cushing syndrome earlier in their natural history before they develop multiple complications and signs of more overt features. But it also means that it is difficult to distinguish Cushing's between max. Now, how many patients with MAX progress to Cushing's syndrome? It's very uncommon. In a systematic review and meta analysis that I actually participated in as well a couple of years ago, we have demonstrated that it's well under 0.5% of all patients with Max that would progress to Cushing syndrome. In clinical practice, the main group at risk for progression appear to be patients with bilateral macronodular adrenal hyperplasia. Because this is a naturally progressive disease, those patients develop more and more nodules and more and more cortisol production. So eventually, depending on how quickly progressive this disease is, those patients will develop overt Cushing. And sometimes it takes a couple of years to go from MAX to overt features, sometimes couple of decades, depending on individual natural history of that disease. So why some adrenal tumors want to be MAX and other overt Cushing? Probably this depends on why the tumor actually appeared on underlying somatic mutations.

B (30:43)

So our patient, we gave a bunch of labs about this patient. A reminder. This is Addie Rennell, 40 year old woman. The CAT scan showed a 2 centimeter right adrenal mass, I guess we could call it. It's five Hounsfield units. And the workup that was sent was they had a DHEAS that was 20, they had an ACTH level that was low. And then we did a dexamethasone suppression test and that came back at four. So can you talk us through interpreting those labs and if there were any other labs you would have done?

F (31:22)

Yeah. So I would like first to point out that the only test that is required for max diagnosis is 1mg dexamethasone suppression test. So in this particular case, this patient's cortisol following 1 milligram dexamethasone was 4 microns per deciliter. Now, in addition to documenting abnormal dexamethasone suppression, tests that you can trust, after excluding false positives or poor absorption of dexamethasone, we have to exclude ACH dependent. So this particular patient had ACTH and DHA sulfate on the lower side. Not completely undetectable from what I recall, but certainly in the lower reference range. So this would be consistent with MAX with autonomous cortisol production independent of pituitary stimulation. So we excluded ACTH dependence. Now, another test that this patient had was 24 hour cortisol. Now, 24 hour cortisol is one of the three recommended tests for evaluation of Cushing's syndrome, but it's actually not recommended or is useful in patients with Max. Why? Because majority of patients with Max have normal 24 hour urine cortisol production. So I find it interesting to explain why, because I think it's important to understand what happens with cortisol secretion in a patient with max. So what happens? Because ACTH production is lower than what it should be. Patients with MAX actually have lower than necessary cortisol production during the morning. So they don't have this peak cortisol that we normally have. They have sort of stunted cortisol production during the morning, and on the other hand, during the afternoon, evening and night, they have higher than necessary cortisol production, but not really into the range of someone with moderate to severe hypercortis. Two to three times higher cortisol production in the afternoon, evening and night. So how does it all translate into area under the curve? Well, if you have lower cortisol production in the morning, when you're supposed to have this peak and slightly higher cortisol production in the evening, at night, area under the curve is actually similar to those without max. It's just redistribution of cortisol is what matters here. So really, MAX is not a disorder of hypercortisolis. It's a disorder of. Of abnormal circadian cortisol production. And I think it's important to note that, because that explains not only that why 24 urine cortisol is normal, but it also explains why patients with MAX present with really what we see with aging. So MAX is sort of like accelerated aging type of disorder, because with age we also have abnormal circadian cortisol production and actually develop those comorbidities that are otherwise associated with Mexico. So to add another test, which is late night salivary cortisol, many patients with MAX would have normal salivary cortisol at night. And I guess I would be wondering why, because this is where the problem is. Right? Patients with MAX have elevated cortisol during the evening and at night, exactly when the late night salivary cortisol is obtained. But the problem there is that salivary cortisol is just not accurate enough test to detect that elevation. For example, in our study that is still unpublished, we found that salivary cortisol in patients with MAX is three times higher than in patients without max. But there is so much overlap and the cutoff for abnormal salivary cortisol is set at a higher level to diagnose Cushing's, not Max as well. So this is why I would not recommend measuring lateness salivary cortisol in patients with max, because it just would not be helpful. Many patients without MAX may have higher salivary cortisol because of stress or insomnia or partying. And many patients with MAX would have cortisol that is lower than what we currently considered cutoff of abnormal.

B (35:42)

Okay, so unless they have clinical symptoms of Cushing's that we went through, we should not be getting that test, the dexamethasone suppression test. Can you talk a little bit about how that's accomplished and any pitfalls in interpreting that?

F (35:57)

Yeah. So dexamethasone suppression test relies on administering 1mg dexamethasone at 11 o' clock in the evening, and then the next morning patient would have their cortisol and dexamethasone concentrations, if available, checked at around 8 o'. Clock. So it's really standard of care test. There's a nine hour difference between dexamedicone administration and cortisol measurement. The idea is that dexametazone, which is a synthetic glucocorticoid cortisol like hormone, as it's being absorbed overnight, communicates to the pituitary gland not to produce any ACTH because it's not necessary. There is floating dexamethasone around and 1 milligram is supraphysiological dose. So once pituitary gland understands that that a stitch production becomes zero, and as such, adrenal glands should produce zero cortisol or at least under 1.8 microns per deciliter, which is considered cutoff of abnormal. So if we measure cortisol and it's actually above this cutoff, then we can conclude that it's crazy, sort of it's autonomous, it's coming from this adrenal nodule and it's not normal.

C (37:14)

And what are we doing with the dhes in the mix? Can you Just remind me the expected physiology and what abnormal would mean with that, please.

F (37:20)

Yeah, so DHA sulfate, I call it hemoglobin A1C of ActHow. Hemoglobin A1C is an average of glucose levels while DHA sulfate is sort of a manifestation of how much ActH adrenal gland is seeing because DHA production, androgen production is fully dependent on ACTH stimulation. So what is the difference between ACTH and DHA sulfate? Well, it's kind of like telling us the same thing. How much ACTH is being produced and how much DHA sulfate is being produced because of ACTH stimulation. But the differences are that ACTH is a worse assay than DHA sulfate and DHA sulfate has less circadian variability and a longer half life. So DHA sulfate is supposed to be a more accurate representation of ACTH exposure. So if there is autonomous cortal production from the adrenal mass that suppresses acth, then adrenal glands see less ACTH than they should and as such, adrenal androgens should be produced at lesser levels. That's the sort of thinking behind DHA sulfate measurement. And indeed, if we look at patients with max, their DHA sulfate levels are much lower as a group than in patients with non functioning adrenal tumors or patient without adrenal disorders. If we look at the average DHA sulfate levels in patients with MAX is anywhere between undetectable and 60. But there is no one specific cutoff that absolutely diagnoses max or absolutely excludes max. In our systematic review and meta analysis we showed that at cutoff of 60 microns per deciliter we have 85 or so percent sensitivity and specificity. But again it means we have 15% or so false positives and false negatives. So I would encourage not to think about any endocrine test as black and white, but as a continuum and look at everything together.

B (39:37)

Was that six zero or one six, 16

F (39:43)

micrograms per deciliter. And remember, but that's, you know, different labs have different units and assays.

B (39:51)

Thank you, that's very helpful.

A (39:57)

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B (42:00)

Why don't we go on a little bit? So let's, let's give you a little more history. We discussed a little further with the patient and she says she's been gaining weight recently and is worried that maybe this is related to this adrenal nodule that we found and she wants to know about treatment. So how would you talk to her about that?

F (42:20)

Well, first of all, what do the guidelines say? The guidelines say that if the patient has MAX and we are convinced about it and has at least some comorbidities related to Max, such as obesity, weight gain, diabetes, hypertension, then, then we should consider adrenalectomy. If the patient does not want adrenalectomy after discussing about pros and cons, then we have to monitor for comorbidities associated with MAX and treat those aggressively. So adrenalectomy is high on the list of recommendations. Now, how do I talk about adrenalectomy with my patients? I talk in the following way. So I Say that. Look, as a group, if. If we clone you and we make 100 people just like you, and 50 of you have adrenalectomy and 50 of you do not. The ones who do have adrenalectomy have probably around 20 to 60% chance to improve hypertension, to improve diabetes, to improve obesity, dyslipidemia, or at least stop their progression, but not 100%. On the other hand, in the 50 of you who decided not to have surgery, we know that as a group all of those things would get worse five years later. There is a threefold likelihood that your diabetes will get worse in comparison to those without max. Twice more likelihood to develop worsening obesity, hypertension, and three times more likely to have cardiovascular effects events. But it doesn't mean that it will happen to you specifically just as a group. So why we cannot guarantee success or worsening because we really don't know if that hypertension, for example, is because of Max or would be there independent of Max. So it also means that if we fix it, hypertension may not go away because it was never due to Max. And there is no test that we can do before adrenalectomy to prove us causality, to say that it's because of Max. You have all of this. So I sort of talk in probabilities with my patients and let them decide what they're comfortable with. And sometimes we have other factors such as how young the person is. Maybe adrenal mass does not look completely reassuring. And we would like to consider adrenalectomy also because adrenal mass is indeterminate and we can cannot completely exclude malignancy. Or maybe there is a strong preference that patient has, or maybe there are other things such as insomnia, quality of life issues that we are hopeful related to Max. And that could be a good reason to consider adrenalectomy.

A (45:09)

Paul, does this seem straightforward to you?

B (45:12)

The decision I mean. I'm following the reasoning. I just mean the decision.

C (45:17)

It sounds like a tough conversation, but not that our job is to sell patients on the surgery necessarily, but it sounds like it would be. I'd be curious to sort of see the initial patient reactions to that and what percentage actually offer surgical resection. I'm sure you have those numbers in my clinic.

F (45:32)

95% opt for surgery after I'm done discussing.

A (45:36)

Whoa.

C (45:38)

Better for Mayo.

D (45:40)

Great.

F (45:40)

But you know, I have a presylax. I think by the time patients decide to travel to Mayo Clinic for this opinion, they want to be more aggressive. So I certainly do not think that 95% adrenalectomy choice is what endocrinologists around the world would see. I do want just to add another way to look at it. I feel that whenever I talk about Max, it's very similar how I would talk to a patient about treating their mild diabetes. For example, if we have someone with hemoglobin A1CO of 7.8%, we can talk about controlling the diabetes under a certain cutoff of hemoglobin A1c. And usually we talk not because they'll feel better if their hemoglobin 1C is 5.8, but because we are hoping that by controlling their diabetes those patients will have fewer strokes, fewer heart attacks. So we are talking about the future, right? We are really controlling the risk for those things to develop. I think Max is very similar to the that we don't necessarily guarantee that a lot of things would improve right away, but it's only removing a risk factor. It just sounds a bit more difficult because we are talking about adrenalectomy rather than a medication for diabetes. But ultimately it's the same decision making.

B (47:00)

Well, we have another case that we want to get to. So Mobeen, what does Ms. Renell decide? Is she getting an adrenalectomy? Do we have an end to the case that you want to just make up off the top of your head?

E (47:11)

Oh, yeah, you know, Ms. Renell, she ends up going for the adrenalectomy after talking with Dr. Bankos. You know, she has improvement in her hypertension and is able to get off of amlodipine 5 milligrams daily. And her most recent A1C is 5.7. So things are looking better and better for Ms. Renell and yep, I guess we can go on to the second case, which I think we'll also, we'll kind of talk about kind of like further in terms of like post surgical management. So the second case that we have here, Mr. Max Adamoma, he is a 45 year old male with a past medical history of type 2 diabetes. He's on metformin 1000 milligrams twice a day and dapagliflozin 10 milligrams daily. Also has history of hypertension on amlodipine 10 milligrams daily and hydrochlorothiazide 25 milligrams and also obesity with a BMI of 36. So he presents to your clinic actually for back pain. He presented to the ER last week due to pain that was due to back pain. And Was found to have an L2 vertebral compression fracture on a CT of his abdomen pelvis. The patient denies any recent trauma, previous fractures or family history of fractures or metabolic bone disease. He was also incidentally found to have a 2.5 centimeter left adrenal nodule measuring six houndfield units. Vital signs show his blood pressure is a Little bit high at 138 over 92. Heart rate is normal at 80 beats per minute with a respiratory rate of 13 breaths per minute. Physical exam just demonstrates generalized obesity. However, no obvious signs of Cushing syndrome. Looking for any secondary causes of osteoporosis and evaluating his adrenal nodule. Your workup is only positive for a 1mg dexamethasone suppression test which shows his cortisol is 5 micrograms per deciliter the next morning and his dexamethasone level is adequate. ACTH is also checked in the ACTH level. In this case, let's say it's 4 picograms per milliliter and DHES is 38 micrograms per deciliter. After discussing with the results of the workup with this patient, he is interested in undergoing adrenalectomy for his mild autonomous cortisol secretion. So I guess Dr. Bankos, we kind of wanted to talk about in this case. Let's say this guy goes for adrenalectomy post surgically. What are things that we need to look out for for these patients? Are they at risk of adrenal insufficiency and kind of what is your. Like, what do you look for post surgically in these patients?

F (49:57)

Yeah, that's another great case. So just a comment. First, both of the cases had dexamethasone suppression test at a higher degree. Cortisol was really four in the first case and in this particular person it was 5 microns per deciliter and that's above average. The median dexamedazole suppression test would be around 3. Just again give a feel to people. So most of the patients I see with MAX have cortisol between 2 and 3.5, I should say. So this particular person definitely has a higher degree of MAX and as such more likely to develop postoperative adrenaline insufficiency, especially with very low acth. We recently published a multicenter cohort study, believe five centers participated and contributed. In that that study we showed that 55% of patients undergoing unilateral adrenalectomy for MAX developed postoperative adrenal insufficiency and on average, if the person developed adrenal insufficiency, it would last around four months. Although there was a wide variability, some patients recovered sooner, some patients took longer. Several factors were associated with a higher likelihood of postoperative adrenaline insufficiency. Patients who were younger, women who had higher cortisol after 1mg dexamethasone suppression test, higher biochemical severity score of hypercortisolis, and those with unilateral disease, meaning they have just one single nodule rather than bilateral nodule, where the ones more likely to develop postoperative adrenaline sufficiency. But that said, none of these factors were sufficiently predictive on their own. They don't allow us to reliably identify pre surgically who will and who will not develop adrenal insufficiency. Which is why post operative assessment for cortisol status is essential. Now, before we go to how we would assess for postoperative adrenaline insufficiency, I just wanted to highlight the high percentage of patients with max developing Adrenal Insufficiency. 55%. What does it mean? It means that the contralateral adrenal gland, the normal gland, the one that is left behind, is atrophic. So that mild degree of cortisol production from that nodule was enough to completely suppress cortisol production from the otherwise normal adrenal gland. That by itself should tell us that MAGS is a significant, clinically significant disorder. And the 45% of those who did not develop adrenaline insufficient. The question is why? Is it because we diagnose it earlier, before that adrenal atrophy occurred? Or is it because those people have bilateral max, they have nodules on both sides. So something to be clarified in future studies, but just wanted to point out that at least in right retrospect in these patients, we can understand even more how clinically significant that Max was.

B (52:57)

Yeah. Wow, that's a great point. I mean, 55%, that number.

A (53:02)

That seems high.

C (53:03)

It's a big number.

B (53:04)

Yeah. Paul, you know, like we've talked about this with other conditions where sometimes people don't know that they feel off until like you kind of like diagnose or just fix the problem. And then they're like, oh, I feel totally different. I think we talked about this with like parathyroidectomy maybe. So I wonder if this is a similar thing where some people just have some of these symptoms you can't quite put your fingers on. And then when they get the adrenalectomy, they feel better.

F (53:32)

Yeah. And I think that deserves a bit of a longer answer, so I'll get there. But maybe should we first talk about how do we assess for adrenaline insufficiency? Because opinions vary there. Again, I should just say that the guidelines say, stop, start. Everyone on steroids don't test. But I think it's because in many centers in the world, and the guidelines are written for the world, not just for United States, there is no possibility to test cortisol quickly the morning after surgery. I think here in the United States, most settings, hospital settings, are able to measure cortisol the morning after surgery and get the results quickly. And this is what we do at our institute. We would measure cortisol the morning after surgery to decide who needs steroids and who doesn't. Those who have adrenaline insufficiency based on the testing, get started on glucocorticoid replacement therapy until they recover. And those who have excellent testing, meaning that their remaining adrenal gland is functioning properly, do not need to be studied on glucocorticoids. So around half of the people would be saved from unnecessary glucocortico therapy if we do that. Now the question is like, how do you assess? Do you just do cortisol in the morning? Do you do casintropine stimulation test? I think we have not yet reached final conclusion on that. I know that as of now, until we determine what's best for our patients, what we do at our institution is do cassintropine stim test. So we look at both baseline cortisol and peak cortisol, and actually, if any of those abnormal, and we use cutoff of 10 for the basin, cutoff of 18 microns per deciliter for the peak. So if any of those are abnormal, we would diagnose adrenaline insufficiency and discharge in glucocorticoids and reassess in outpatient setting. But I think as we get more data, we may be able to maybe simplify the assessment for cortisol production. I think if we had at least basal or basal and cortisol in the morning, that would be good enough to diagnose most of the people with adrenaline insufficiency after surgery.

B (55:37)

And the stim test, is that just giving, like, synthetic acth?

F (55:41)

Essentially, that's right. So we use a standard kaisinterpropin stim test, which is, again, synthetic ACTH, as you said, 250 micrograms being injected. So what does it really do? Remember, this person have only one adrenal gland. If it's atrophic, adrenal gland. Whether you measure cortisol based on or you inject a person with a lot of acth, synthetic acth, cortisol production would be abnormal because. Because the adrenal gland is atrophic, so it just cannot produce cortisol. But imagine that it's not completely atrophic or there are some nodules that are capable of cortisol production. In that case, base on cortisol could be still low because it's not enough to produce sufficient cortisol, but it would respond perfectly to casintropine because as nodules are capable of cortisol production and responding to actual. It's just this person does not have their own endogenous a stage production. So despite an optimal response to gesintropin, they would not do well on their own because their own pituitary gland is not producing enough ACTH in this case.

E (56:52)

And I think another question that comes up, Dr. Vankos, at least when we've seen it in the hospital, is when we have patients who have overt Cushing's syndrome, people feel really terrible once you take out their adrenal gland. If you were to just put them on what we consider physiologic doses of hydrocortisone or prednisone with glucocorticoid withdrawal syndrome. In terms of patients with this mild autonomous cortisol secretion, what dose are you often sending people on? And also, are these patients at risk of developing glucocorticoid withdrawal syndrome as well?

F (57:28)

Yeah, great question. So I do want first to point out there is a difference between adrenaline insufficiency and glucocorticoid withdrawals. So adrenaline sufficiency is a biochemical diagnosis that clearly shows that remaining adrenal gland does not produce sufficient amounts of cortisol. And if we just replace it, physiologically, the patient should have no symptoms. Glucocorticoid withdrawal syndrome is a phenomenon that happens with any addiction. For example, alcohol withdrawal, smoking withdrawal, heroin withdrawal, or as I like telling my patients, coffee withdrawal. Whenever someone is used to to a particular substance in amounts that are supraphysiologic, we develop tolerance to it. And then if we withdraw it, you develop symptoms. For example, if I no longer drink my six cups of coffee a day and tomorrow I wake up and say, okay, I'm quitting coffee cold turkey and I drink zero cups of coffee, I'll probably feel quite unwell. I'll develop coffee withdrawal with fatigue and irritability and severe headache. And I probably would feel this way for weeks until I finally get used to living without coffee, without caffeine. While really the same concept applies to patients recovering from Max or Cushing. We take away what they've had in supraphysiological amounts, at least at some parts of the day, and they may develop glucocorticoid withdrawal that is characterized by arthralgias, myalgias. Patients often say that I feel like I have a flu. Without a flu, my whole body aches, fatigue, nausea, palpitations, sometimes some other symptoms as well. So yes, it certainly can happen in patients with Mex. It's less likely to happen in patients with Max and in patients with overt Cushing's. But sometimes I'm surprised. I think what we cannot assess is duration of Max and for how long a person has it. And I suspect that those with long term undiagnosed Max may have more severe withdrawal, despite the fact that biochemical degree of Max is actually not that bad bad. So we should counsel our patients about it. And what helps in this case is a slower taper of glucocortico. For example, I would start with 10 milligrams of prednisone rather than 5. Five would be considered physiologic for most patients, but I would start with double of that and then slowly go down to 9 milligrams each morning, then one week later, 8, then 7, 6, 5, and stay on 5 until they recover from adrenaline insufficiency. Why this gradual taper is because we need to give that body some sort of time to get used to lower and lower or healthier and healthier levels of cortisol. I think to make a parallel to my coffee addiction, if I wanted to quit coffee, instead of going from 6 cups a day to 0, I probably would go to 5 cups a day for a week, then to 4 cups a day for a week, Then to 3 cups, perhaps then to 2, then to 1, and then quit. And probably I would feel less rough doing it this way rather than just going to zero.

E (60:39)

Sure. Yeah. I think that's an excellent point and I think something that we definitely see. And I guess thinking about the future, let's say you have a patient who you've diagnosed with adrenal insufficiency after adrenalectomy, kind of. How do you decide that the patient is able to come off of the glucocorticoid months down the line? Kind of. What testing do you do?

F (61:06)

Yeah. So you could do it different ways. What I do is I rely on cortisol testing. So once my patient is on 5mg of prednisone each morning for at least two weeks to give a chance for HPA access to recover, I I ask my patient to hold their prednisone in the morning until after they provide blood for cortisol testing. And if that cortisol is 10 microfarms per deciliter or higher after holding those glucocorticoids for 24 hours, we generally feel comfortable stopping glucocorticoid therapy completely. So we go from five to zero if cortisol is lower than that, certainly if it's lower than 5. But even if it's between 5 and 10 10, I continue 5 milligrams of prednisone a day and then retest again maybe six weeks later, and then again, if cortisol is 10 or above, I would, I would stop prednisone and declare recovery from adrenaline insufficiency. And if it's not, I will continue the same approach. I very seldomly do casintropus stimulation tests in this cases, but I do find it useful to at least occasionally to measure ACTH in addition to cortisol because we are seeing that acthe becomes high, normal, even above normal ranges right before cortisol recovery. So pituitary gland remembers how to produce optimal ACTH a bit earlier than obviously adrenal cortex remembers how to recover from Atrophy.

B (62:37)

And 5 of prednisone is not enough to suppress the ACTH from the pituitary and just endogenous cortisol production.

F (62:46)

Not enough if it's administered in the morning, morning only as one single dose, because the half life or how long it's sort of in the body is usually 16 hours. So by the time the patient is falling asleep in the evening, they don't have any prednisone floating around. And then they have what, eight, 10 hours of no cortisol whatsoever coming exogenously. And that's the time when pituitary gland recovers. In fact, that's a common question that I get. Is it better to be on prednisone or hydrocortisone for glucocorticoid replacement after curative surgery for Max or Cushing's. And we've recently published a paper showing that it does not matter as far as recovery whether you start prednisone or hydrocortisone at equivalent potency dosing, which is 5 mg of prednisone to 20 mg of hydrocortisone recovery or duration of adrenaline Insufficiency is identical between patients.

C (63:38)

I'm kind of assuming postoperatively smart people like you and Mobeen will be sort of managing the steroids and figuring this stuff out, doing the testing. It's. So my question for you is sort of longer term, this patient comes to see their primary care doctor and follow up. Are there circumstances where we should be worried about delayed adrenal insufficiency? I guess what should prompt testing? What is the long term kind of evaluation of this look like? Because oftentimes after the acute stuff's done, specialist physics kind of taper off. So what should I be worried about in the long term for these patients?

F (64:04)

Yeah. So adrenaline insufficiency, if it happens, it happens right away. So really we should diagnose it as soon after adrenalectomy as possible. And if the patient recovered from adrenaline insufficiency and prednisone is stopped, that person is no longer at risk for developing adrenaline insufficiency unless we give that person another risk factor, such as exogenous, I don't know, glucocortic injections or opioid therapy and so on. I also think that this cutoff of cortisol of 10, let's say you inherit a patient on prednisone 5 and no one knows whether they still have adrenaline sufficiency or not. And that doesn't have to be after adrenalectomy for Max or Cushing's. It could also be a patient on long standing prednisone therapy tapered down from 20 milligrams to five. And you're wondering, can I stop prednisone from the adrenaline sufficiency point of view. That cutoff of 10 microns per deciliter is in the guidelines for glucocorticoid induced adrenaline insufficiency. It's also in several papers for recovery. And I would say it's pretty safe to remember for any clinician and not relying on endocrinologists. So hold prednisone for 24 hours, measure cortisol in the morning. If it's 10 or above, the person does not have adrenaline sufficiency.

B (65:18)

Is there anything else that in primary care we should look for? There's a lot of overlap, like some of these things that we're not sure if Max, you mentioned high blood pressure, dyslipidemia, diabetes, of course, obesity. These are things we're used to dealing with. And it's so common that I think that's maybe why you were suggesting. It's hard to know if that was the cause and that therefore, if having an adrenalectomy is going to cure those things or make them better. But is there anything else we should be monitoring in primary care, like DEXA scans or something? We mentioned bone is something that can be affected by Cushing's, but what about max?

F (65:56)

Yeah. So I feel like there are two settings where appropriate monitoring and primary care is essential just because there's not enough endocrinology in the world. So one is a bit more urgent after adrenalectomy. Let's say your patient had max, had surgery in a referral center and maybe tapering prednisone and maybe did not have adrenal insufficiency. So if that person had hypertension and diabetes, especially if diabetes was treated with insulin or sulfonylurea type of drugs, that patient is at risk for hypotension from the hypertension point of view or hypoglycemia from diabetes point of view, if the medications are not being tapered down. Because if that person's hypertension and diabetes were partially or fully due to max, that should improve and potentially no longer require that therapy. So I feel like monitoring of blood pressures and readjustment of antihypertensive, monitoring of blood sugars and readjustment of hypoglycemic therapy is quite important in, in this acute situation, usually the first three months is when most of the changes occur.

C (67:08)

And this was a question I meant to ask before. So for say the patients don't see you and so we don't have the 95% success rate of going to surgery and instead they opt to not be surgerized or they have contraindications for whatever reason. Are there preferred agents for managing the sequelae of max? Are there preferred medications for the hyperglycemia seen with MAX or for the hypertension? Or does it you just treat it the same as you would hypertension diabetes elsewhere?

F (67:33)

Yeah. So definitely in the second setting would be conservative follow up of Max. And in that case we have to treat hypertension, diabetes and everything else with standard of care medication. There is not something like specific to Max that those comorbidities need different treatment. I know that you asked also about bone health. The guidelines actually were not very clear on the follow up with DEXA scans, mainly because MAX impacts quality much more than density. But bone density does not look at quality, it looks at density. So you're actually missing an opportunity to see or to predict fractures. Having said that, if you can get a bone density with trabecular bone score measurement, that's much better. TBS trabecular bone score. That's a much better assessment of quality and more appropriate for cortisol induced bone disease. But otherwise it's really monitoring for hyperglycemia, hypertension, obesity, osteoporosis and counseling of management of depression, anxiety, that is potential to max. Management of insomnia, potentially due to max. It's a lot of work. If you don't do adrenal ectomy for max, I'm not sure if it's easier.

E (68:48)

And Speaking of that, Dr. Benkos, mild autonomous cortisol secretion. Obviously it's a new and very emerging and exciting field. One thing that I was curious about is have there been long term studies now in patients who have had adrenalectomy me in terms of the various outcomes like cardiovascularly, in terms of vertebral fracture risk, thromboembolism. Kind of curious what the data has shown there.

F (69:16)

Yeah, this field really exploded in the last five to 10 years from renaming subclinical Cushings into Max in 2016. Why the rename? Because it's not really subclinical. It's a clinical, very evidently clinical problem. Then to sort of renaming ACS to Max and then all of the clinical trials and systematic reviews, what we currently have is actually short term clinical trials. Five maybe in total, if I'm counting correctly. But most of them have like six months follow up. So really short term follow up. And they all do show improvement in cardiometabolic risk. If you do adrenalectomy versus you conservatively manage. You usually see improvement in hypertension and diabetes and dyslipidemia, at least in one trial. But really we need longer term trials and we need to also look at other outcomes our patients care about. What about sleep? What about quality of life? What about bone disorders? There is one clinical trial looking at vertebral fracture that shows decline in vertebral fractures with adrenalactomy, but that's it. Now we've recently published a prospective cohort study and I think the only prospective cohort study of sort of unselected cohort of Max and Cushing and looked at what happens 12 months after and we have shown again anywhere between, what was it, 15 and 50% improvement in this cardiometabolic risk 12 months after surgery. Yeah. But we do need many more studies. Yeah, yeah.

B (70:50)

Well, I thank you for coming on and talking to us about this. Primary care doctors need to know about it because as obviously we see a lot of adrenal incidentalomas. And since this is the most common way that those might be functioning, we should know about this. So thank you for your time on that. At this point, I want to ask you for your take home points that you want the audience to remember. Just maybe two or three things if they don't remember anything else from this talk.

F (71:18)

Yeah. So number one, just a general adrenal acidantyoma take home point. Remember that any person who has an adrenal mass needs evaluation for malignancy risk and evaluation for hormonal excess. Not just max, but also primary aldosterones and catecholamine and excess. That also means that some patients may not need to be monitored because we can actually exclude some of the things right away and discharge them, at least from that point of view. So my second take home point is that everyone with adrenal meds needs 1mg dexamethasone suppression test. And consider Max as a cardiovascular risk factor, quality of risk, quality of life risk factor, sleep factor in your pain patients with adrenal nodules. And number three, remember that we endocrinologists love Max and talking about it.

B (72:11)

Yeah, well, we love talking to you about it. Is there anything you would like to plug before we let you go?

F (72:19)

I think I'm okay.

B (72:24)

Thank you so much.

C (72:25)

Perfect answer. Thank you. This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole.

E (72:37)

Yummy.

C (72:39)

Thank you. So every time we have a co host on, their job is to preempt Matt from saying holes. So strong work, mission accomplishment. Bean, still hungry for more. Join our Patreon and get all of our episodes ad free, plus twice monthly bonus episodes@patreon.com curbsiders. You can find our show notes at the Curbside. And while you're there, sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the practice, changing articles, guidelines and news in internal medicine.

B (73:01)

And we're committed to high value practice, changing knowledge, and we want your feedback. So email us@askcurbsiders gmail.com reminder that this

A (73:09)

and most episodes are available for CME

B (73:11)

credit for all health professionals through VCU health@curbsiders.vcuhealth.org special thanks to our writer and producer for this episode, Dr. Mobinad, and

A (73:21)

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B (73:22)

Our technical production is done by the team at Podpaste. Elizabeth Proto does our social media. Jen Watto runs our Patreon Chris the Chew Manchu moderates our Discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto, Dr.

C (73:37)

Mobina Moth, and as always remain Dr. Paul Nelson Williams. Thank you and goodbye.

G (73:57)

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I (74:57)

Hi, this is Alex Canceroitz. I'm the host of Big Technology Podcast, a longtime reporter and an on air contributor to cnn. And if you're like me, you're trying to figure out how artificial intelligence is changing the business world and our lives. So each week on Big Technology, I bring on key actors from companies building AI tech and outsiders trying to influence it, asking where this is all going. They come from places like Nvidia, Microsoft, Amazon, and plenty more. So if you want to be smart with your wallet, your career choices, in meetings with your colleagues and at dinner parties, listen to Big Technology Podcast. Wherever you get your podcasts.