All right, should we go ahead and get started? Great. All right, welcome, everyone, to ASAP Live. We will be covering the pituitary, adrenal, and neuroendocrine section for the next hour. This content that we are discussing today is from ASAP 2022, which was developed under the guidance of Dr. Suraj, editor-in-chief of ASAP, as well as Dr. Gopalakrishnan, who is the chair of the Fellows Education Subcommittee. We are the presenters today. My name is Natalia Gennari. I'm an assistant professor of medicine at Washington University in St. Louis, and I practice in the area of endocrine neoplasia, so I take care of thyroid and adrenal tumors. And I'm accompanied by Dr. Lucinda Gruber, who is an assistant professor of medicine at Mayo Clinic in Rochester, Minnesota, working in pituitary and adrenal disease. Our disclosures are listed here. And the way that this session works, we really would love for you all to participate. So if you can type your questions into the Q&A box at any time, you can see the questions. You can upvote the questions by other participants. We will have six questions that we'll be going over, so there will be some Zoom polls opening. Please go ahead and select your answer, and we will try to get to as many questions as possible. And I think with that, we can get started with our first case. I'll go ahead and read this case for everyone. This is a 62-year-old woman with a 20-year history of hypertension presenting for evaluation of possible primary aldosteronism. She takes amlodipine 10, lisinopril 40, and hydrochlorothiazide 25 milligrams daily, yet her blood pressures generally remain elevated in the 140 to 160 over 80 to 90 range. She's otherwise healthy and reports that her father also had resistant hypertension most of his adult life. Her initial screening results are as follows. So renin plasma activity is suppressed. Aldosterone is 12. Potassium is 3.4. Creatinine is 0.9. She started on potassium replacement, and subsequent oral salt loading confirms primary aldosteronism. CT shows a left 1.1-centimeter lipid-rich adrenal adenoma, and then she undergoes cosentropin-stimulated adrenal vein sampling, and the results are here. So this is not part of the question, but I'll quickly go through how we interpret AVS, because this is a very common scenario on board exams. So first of all, it's very important to know if this is undertaken with cosentropin stimulation or not. The numbers we'll be going through are for the cosentropin-stimulated procedure, and there's basically four steps that we go through. So number one is we have to figure out if both of the right and the left adrenal vein were cannulated, and that is basically just a matter of dividing the right or the left adrenal vein cortisol by the IVC, and that ratio should be at least 5 to 1. Oftentimes, it's more than 10 to 1. So for example, 1060 over 27.1 is far more than 5.1, so we know we have adequate cannulation. The second step is getting the aldosterone-to-cortisol ratio, which is already done for us here. The third step is to divide the dominant or the higher adrenal vein by the lower adrenal vein, and lateralization index of over 4 is suggestive of unilateral secretion, less than 3 is bilateral, and 3 to 4 is indeterminate. It's a gray zone. And finally, we can actually do the non-dominant, so the right in this case, AC ratio over the IVC, and that is called the contralateral suppression index. A value of less than 0.5 tells us that there's a higher risk for postoperative hyperkalemia. It also can be helpful in some cases if there isn't adequate cannulation of the other side, but you know that we have the contralateral side suppressed. That can sometimes be used for diagnostic purposes also. I'll keep going with the case now. So in this case, we have a lateralization ratio from left to right adrenal vein that is 2.7, so that is suggestive of bilateral secretion. Spironolactone is initiated with a dose titration up to 100 milligrams daily. Follow-up laboratory samples are collected two weeks after the last dose increment, and the results show potassium of 3.9 with potassium 40 milliequivalents daily. Creatinine went from 0.9 to 1.2. Renin is suppressed. Her blood pressure over the last week is 128 over 74 to 136 over 79. So here's the question. Given her follow-up laboratory studies, what is the most appropriate next step for management of aldosteronism? So you can select your answers there. . . . . . . We have a few more seconds, and then we can go on to the answers. Does anyone else want to answer? Okay. So the group is basically between maintaining current dosing of spironolactone and increasing the dose of spironolactone. So let's talk about that. So we already talked about kind of the beginning of this rationale portion. So we talked about kind of how we interpret AVS. And the reason that it is very important to diagnose primary aldosteronism is that we know that whether aldo is unilateral or bilateral, there's higher risk of cardiovascular disease, chronic kidney disease, and death compared to non-PA-mediated hypertension. For unilateral disease, we have the option of surgery. For bilateral disease, we should be giving patients mineralocorticoid receptor antagonist therapy. And really what this question relies on is knowing what the goals of therapy are, which is bolded at the bottom of this slide. So we want to see normalization of blood pressure, so we see that in this case. We also want to see normalization of potassium without use of potassium supplements, as well as reversal of excess cardiovascular risk factors for PA. And actually, there are several studies that have come out showing that that can be partially sort of evaluated with a non-suppressed renin level, so seeing a renin greater than one, essentially. So in this case, the patient was still taking potassium and still had a suppressed renin, so the best answer to this question is actually increasing the dosing of spironolactone up to 150, and that may require de-escalation of her other therapies, which I can't recall what she was on, but there was space to kind of move those down so that we have more blood pressure room to go. We typically will recheck potassium and renal function every couple weeks with every dose change, and it is very common to see the creatinine level rise slightly with therapy. With therapy, that is because PA causes glomerular hyperfiltration, and so you can see sort of a spuriously better-than-expected creatinine, and either with surgery or with MRI therapy, you'll see a slight rise. It's important to remember that spironolactone can have some undesirable dose-dependent side effects, including gynecomastia, erectile dysfunction, irregular menstrual cycles, and particularly for men, gynecomastia, first of all, is pretty frequent with the dosing that we need to use for PA, which is oftentimes over 100 milligrams, and it's irreversible. So oftentimes for men, we will reach for a polaronone quickly for treatment purposes. Does anyone have any questions about this case? One question I had for you, Natty, like when you're titrating spironolactone, are you looking for like a potassium goal? Are you like adjusting that basically just to get potassium into the normal range? How do you decide when enough spironolactone is enough? Yeah, so basically my approach is I initiate therapy at about 50 milligrams a day. Many of these patients need between 150 and 250, even sometimes up to 300 milligrams. So I usually will titrate by 50 to 100 milligrams between labs, and I'm titrating for kind of a mid-normal range between 4 and 4.5. And once I get there, just because renin is a more expensive lab, I typically will wait to normalize the potassium first, and then we'll check my renin to make sure it's non-suppressed. And in most cases, when potassium is normalized, at least in my experience, the renin becomes non-suppressed, but I've had a couple of patients that, you know, I'm still kind of titrating even after normalization of potassium. Yeah, that's good to know. That's kind of been my approach too. Sometimes I'll adjust the spironolactone and kind of aim for that like potassium of 4.5. But yeah, it's just sometimes interesting that some patients, you seem to need more spironolactone to get that renin unsuppressed, even when their potassium is like 3.8 or 4.0. Yeah, it's surprising how much they need. Okay, great. Well, let's move on to case number two. All right, perfect. So case number two, we have a 33-year-old woman who's diagnosed with schizophrenia. She started on haloperidol, but unfortunately has excessive sedation. She developed some tremor in her upper extremities, so she switched to oral risperidone. And she's on anywhere from four to six milligrams, depending on her response. About six months into therapy, she starts to notice some changes with her menstrual cycle. So initially, she would go up to 15 days, longer than typical. And now she's having even less frequent menses. So she's only had four periods in the last year. She's also having some galacteria. She's noticed some acne and a little bit of weight gain as well. And so she's really been referred to endocrinology to sort out if this could be hormone-related. When you talk about her a little bit more, so she's previously not had irregular menses. She hasn't noticed any changes in weight or issues with thyroid disease. Started having periods when she was 12. And her menstrual cycles previously have been regular, basically 28 days between cycles. She's otherwise well. So she doesn't have any kidney disease or liver disease that she's aware of, and really no notable family history. So when you meet with her on exam, she weighs about 160 pounds, has normal secondary sexual characteristics. You do see a little bit of mild acne across her cheeks, but no hirsutism or acanthosis nigricans. Cranial nerves are normal. No thyromegaly or cervical lymphadenopathy. And really the rest of her exam is pretty unremarkable. She does have a little bit of nipple discharge that doesn't stain positive for fat. So based on kind of her clinical history, especially with the galactorea, the changes with her menstrual cycles, and you're thinking about hyperprolactinemia. So her lab comes back and her prolactin is 75. Negative pregnancy test. So she goes for an MRI of the pituitary, which doesn't show any pituitary lesions. All right. So this is just kind of a summary of her other laboratory testing. I'll just kind of hit the highlights here. Her estradiol level is a bit low at 25. You can see her FSH is on the low end of normal at 3.1, and prolactin is persistently elevated at 86. The rest of her lab's cortisol looks good. Free T4 looks good. And you can see her total testosterone level is 46. So what do you think is the most likely diagnosis for her? So PCOS, does she have macroprolactinemia, does she have a prolactinoma, or is this non-neoplastic hyperprolactinemia? All right. Perfect. So it looks like 86% of people think this is non-neoplastic, and we have another vote for prolactinoma. So this is a case, very common referral. That I see in my pituitary practice for elevated prolactin. The first slide here, you know, the first half of it is just talking about all the different things that can cause hyperlactin. There are many, but I would say, really, you want to be careful when you work these patients up. If they are premenopausal, you want to be sure they're not pregnant. That's going to be an important one. But beyond that, we start to think with prolactin levels, especially 40 and above, about the possibility of prolactinoma. Medications are a very common thing that can cause elevated prolactin as well. And then you want to rule out these things kind of one by one. So you have to be really thoughtful when you see these patients. So a prolactin level generally has to be pretty elevated to cause hypogonadism. So I'd say, you know, when your prolactin levels in the range of like, you know, 50 to a hundred, sometimes you can see some changes with menstrual cycles. But you typically will not see amenorrhea in those levels. But as the prolactin gets higher, you start to see amenorrhea hot flashes become more common. In those more mild elevations, you typically don't see as many symptoms. So if someone comes to you and they have amenorrhea and their prolactin level is like two clicks above normal, unlikely that it's related to the prolactin. So, you know, when we think about hyper-prolactinemia in the case of this patient, she's had a pituitary MRI. So we know she doesn't have a large pituitary mass. So we can rule out stock effect in her case. They didn't note a small adenoma. So it doesn't appear that she has a prolactinoma either. So then you start to think, well, you know, could this be a medication effect? Cause I would say those are kind of the two big buckets that we think about if we've ruled out things like pregnancy. For her, she's on risperidone. So most of the anti-atypical antipsychotics are going to cause some degree of hyper-prolactinemia, but especially risperidone commonly causes a prolactin levels of a hundred or more. The other one that I'll, I'll add in paliperidone often doesn't show up on lists for hyper-prolactinemia, but it's common to see prolactin levels above a hundred with, with that one as well. So in her case, you know, we have a culprit medication. We ruled out anything really worrisome on blood work, worrisome on the MRI. So this is most likely non-neoplastic hyper-prolactinemia. If you can, you can stop the medication and we would expect the hyper-prolactinemia to go away. But often that's just not really practical for these patients. You know, if they're in a good place in terms of good control of their psychiatric disease, usually you need to find an alternative way to manage the hyper-prolactinemia outside of discontinuing the medication. As you see on the bottom of the slide there, whole bunch of other medications that can cause hyper-prolactinemia. So I typically will just like take their medication list before I meet with these patients and just go through with kind of a fine tooth comb and make sure that we're not overlooking something medication-wise that can cause the hyper-prolactinemia. Awesome. I have, I have questions for you. I don't see these patients very often. Is there a certain threshold of prolactinemia where you wouldn't do an MRI? Is it any elevated level ultimately if you cannot find a cause or, or is, is there a certain threshold? Yeah, it's a great question. I'll be honest. I have a pretty low threshold to do a pituitary MRI for these patients. If it's a single prolactin level that's elevated, I always recheck it just to be sure it's not a weird, you know, stress effect or, you know, they were racing to get to their blood draw or something. But if it's, if it's elevated above normal on two occasions and I can't find a clear indication, I generally will go ahead and get the pituitary MRI. And it's primarily because I don't want to miss stock effect. That's really the thing that I'm worrying about. I'm not missing, you know, if it's a small prolactinoma and, you know, it's unlikely that that's the case with the prolactin level of like 20, you know, 28, 32. But I'm always worried that I'm going to miss, you know, a giant pituitary macro adenoma that's causing stock effect. If, if I can't discontinue a medication for a patient, I generally will do the pituitary MRI for the same reason. I do find a lot of these patients have had cross-sectional imaging of their pituitary at some point, maybe, you know, an emergency room visit. So if you can look at old imaging and say, oh, no, eight months ago in the emergency room, you didn't have a large pituitary mask, then you don't necessarily have to get that. But otherwise I have a pretty low threshold. Great. And one other question just to follow up. So let's say that this is drug induced hyper prolactinemia and you're deciding to treat either because of hypogonadism or symptomatic breast discharge. Can you talk about kind of your decision-making about OCP versus Cobergoline versus this kind of no treatment at all? Yeah, it can be really tough for some of these patients to sort out, well, what is the best thing to do? If they can't stop their medication that's causing the hyperpolactinemia, that's usually a good sign that they have psychiatric disease that's going to make starting Cobergoline problematic. I have yet to find a psychiatrist who's super excited about starting Cobergoline in someone who has stable psychiatric disease. But in theory, that's something that can be introduced really carefully. But I would say with the agreement of the patient psychiatrist, I generally will treat the symptoms and will opt to do either an OCP or testosterone replacement. You may have to balance that a little bit with if they're having really symptomatic galacteria that's impacting their quality of life, that's not really going to improve with testosterone replacement or an OCP. So then it may be worth circling back to their psychiatrist. The other thing that I'll throw out, aripiprazole or vilify may be a nice thing to add on to whatever antipsychotic they're taking. So a vilify has some dopamine agonist, dopamine antagonist activity. So sometimes you can add that to their atypical antipsychotic and you can see the prolactin level will be a bit more blunted. So that's another thing to talk with their psychiatrist about. If we can't stop the risperidone, can we add on something like a vilify and maybe bring down that prolactin level and improve their symptoms that way? That's a great point. Thank you. I have a question in the chat. Yep. I think that's what we just covered. Awesome. Okay. All right. So we can probably move on to case three. This is a 50 year old man who is referred for an incidental finding of an adrenal mass. He had a CT during an evaluation of a ventral hernia. He complains of pain associated with the hernia, but is otherwise well. He denies significant weight change, palpitations, anxiety, tremors, headaches. His history is significant for hypertension diagnosed five years ago, which has been challenging to adequately control. He's taking amlodipine and metoprolol. On physical exam, his BMI is 24. Blood pressure is 160 over 98. Heart rate is 80. He appears healthy. He has a reducible ventral hernia. Yay. But otherwise abdominal exam shows normal findings. He does not have moon facies, dorsal cervical fat pad, or abdominal stria. The abdominal CT shows a well circumscribed two centimeter right adrenal mass that is five Hounsfeld units on pre-contrast imaging. I will say that there is an error in this question. So there's two sets of labs, but this is the appropriate set of labs that we're using for this question. Potassium is 3.6. Creatinine is 0.9. Aldosterone 20. Renin 0.4. Plasma METs and NORMETs are negative. And cortisol after dex suppression is 0.9. Which of the following is the next best management step for this patient's adrenal mass? I'll give you about 40 seconds to answer this. So we have a few different answers kind of all across the board. So this is a good one to talk about. And I think really what this question comes down to is going through the evaluation of an adrenal mass and particularly kind of launching down the pathway of aldosterone evaluation and kind of appropriate steps in that. So I guess where I would start is that adrenal incidental lomas are really common and they're becoming a lot more common because we're doing a lot more cross-sectional imaging. Whenever we see an adrenal incidental lomas, there's two questions that I ask and answer for the patient. The first one is what is the risk of malignancy? And the second one is what is the likelihood of hormonal hypersecretion? The question of malignancy is driven a lot by the radiographic indicators, but there's some additional adjunct tests that are sometimes performed. And the overall prevalence of malignancy in adrenal tumors is less than 10%. It's not very common. But the problem is that the types of malignancies such as adrenal cortical carcinoma, which would be the minority or metastatic disease to the adrenal gland, which would be more common, they're pretty bad. And so we want to identify those quickly. As far as hormone excess, overt hormone excess is pretty rare, but max or previously called subclinical Cushing's can be seen in up to 30% and in some studies even more, a higher percent of patients. And it's not subclinical. There's a lot of metabolic complications relating to max. And so we also want to identify the patients that would benefit from removal. So in this case, it was very appropriate to screen with a deck suppression test and with an Renin-Aldo screen because the patient is hypertensive. Now the tumor is less than 10 Hounsfeld units. So it's actually quite unlikely for it to be a pheochromocytoma, but we have the negative screen already. As far as the Renin and Aldo, so there's a few ways that we can interpret this information. And previously an Aldo-Renin ratio was quite commonly used. It depends on which Renin assessment you use in terms of the specific cutoffs. But in my practice, I typically use absolute values of suppressed Renin and aldosterone levels of over 10. And this has been argued in more recent studies as a great way to not kind of falsely hyper elevate the ratio. With that being said, we diagnose a very small minority of patients with aldosteronism. So this is a very large need in our field. There is a paper by Muatero and colleagues that look at how different medications and other studies as well, how different medications impact the Aldo-Renin ratio and both the Renin and the Aldo values themselves. And it is true. So first of all, the common medications that we use such as ACE inhibitors, ARBs, MRAs, diuretics, those can increase Renin. But the nice thing is that if the Renin is suppressed, you don't have to worry about it. The other very important cause of false negative screens is that if hypokalemia is left untreated, this can suppress aldosterone synthetase and give you a falsely low aldosterone level. So I think those are two very important things that I look for every single time. Beta blockers as well as clonidine and NSAIDs can actually cause false positives. Typically mediated by Renin, in this case, the Aldo level is very high. So although, yes, it is possible that the beta blockers are responsible for this elevated ratio, I don't think that's the most likely situation. Our pretest probability is pretty high with resistant hypertension and an adenoma. So I don't think for that reason that B is the best answer here. Now for patients who have spontaneous hypokalemia and a suppressed Renin and an Aldo over 20, you can forego confirmatory testing. Or if the Aldo is over 30, even without spontaneous hypokalemia. But in this case, we don't have spontaneous hypokalemia. It's a little bit tricky because we're right at the 20 mark. And so this patient would benefit from confirmatory testing, which can take the form of either an oral salt loading or an IV saline suppression test. Among, there's some less commonly used options as well. And only after that would we do an AVS and an adrenalectomy. All right. Let me see if there's, sorry about that, if there's a slide. Okay. Okay. And those are the references. So there's a question about what max is. So it's MACS. I'm sorry. I should have clarified that. That is mild autonomous cortisol secretion. And that is becoming a more commonly used term instead of subclinical Cushing's. But basically this, this refers to patients who do not have any overt features of Cushing's like the patient we're discussing in this, in this question stem, but who may have metabolic complications such as hypertension, hyperlipidemia, diabetes vertebral factors, or osteoporosis sleep apnea, cardiovascular disease. Any other questions? One, one thing that I have kind of interested to get your take on this it, it's really common actually for people to fall into the gray area, just like this patient, where we can't really confirm the diagnosis without doing something like the salt loading test. Are there situations where you use the salt loading test cautiously, or where you think about skipping the salt loading test because of a patient's comorbidities or situations where you feel like it's just not safe to do something like the salt loading? Yeah, I, I actually see a lot of Aldo patients. And so this, and many of these patients have chronic kidney disease because they've had Aldo for many, many years that has been on undiagnosed or have hypertrophic heart disease or LVH. So I think about that often. I tend to be pretty aggressive. I have them contact me every week or sometimes more with blood pressures. And I, I tend to get their blood pressures very well controlled first. That can include MRAs in some cases at low doses, as long as their renin stays suppressed, because you know that it's still going to be a diagnostic test as long as the renin is suppressed. And I try to get their blood pressures to the one less than 140, at least, maybe even lower, down to the 130 systolic. And I still do the oral salt loading in those cases. Patients who have a history of volume overload, pulmonary edema, heart failure with reduced ejection fraction, I tend to not do the IV saline, just because it's a very high volume over a short period of time. But yes, there are some patients that, that I struggle with and, and I would rather take my time and, and do it once and do it well and do it with very well controlled blood pressures than, than to have a patient have a complication from that. And their potassium has to be very well controlled because a high salt diet can induce kind of increasing potassium losses. And so you, we got to make sure that their potassium is well controlled. Perfect. Thank you for that. I feel like I have this dilemma fairly often myself. Yes. Okay. Go on to case four. All right. So for case four, we have a 34 year old woman who's being evaluated for oligomenorrhea. So she started having periods when she was 12 and had normal development. She's basically had regular menses until age 33. And since then they've started to be irregular. And now she's had amenorrhea for the last six months. She's had about 20 pounds of weight gain over the last couple of years, has some intermittent mild headaches. Otherwise no mood changes, hirsutism, acne, galactorrhea, hasn't noticed any cold intolerance, constipation, polyuria, vision changes, um, and no increase in libido. Um, she shares with you that she's had hypertension since she was around age 30. Um, and she has obesity, but otherwise has generally been pretty healthy. Um, about three years ago, um, she was in a minor car accident, didn't have any loss of consciousness. Otherwise it's not had any, um, head trauma. Um, she's not taking any medications at this point. And she has a family history of hypertension in both parents. When you see her in the clinic, her blood pressure is 145 over 92. Heart rate is 85. Um, she does have a BMI of 38. Um, her visual fields are full to confrontation. You don't see any terminal hair growth or acne. Um, she has a small dorsal cervical fat pad, but nothing else to suggest clinical Cushing's thyroid exam is normal. Um, and her breasts are Tanner stage five. So here are her test results. Um, so you can see she has a negative pregnancy test. Um, TSH is in the normal range. Testosterone is eight nanograms per deciliter FSH and LH are, um, undetectable. Estradiol is undetectable and her prolactin is slightly elevated at 33. So you get an MRI, um, and you can see that she has a fairly thin pituitary stock, but it's midline. Um, but the pituitary gland itself, um, is really kind of a flattened rim along the floor of the cellar. And you can see the majority of the cellar is filled with CSF. So what is the most likely cause of this patient's clinical presentation? Okay. I thought this would be one that, uh, we'd have kind of a nice mix of things. So I can see, um, really the first three answers, um, were, were popular for this one. Um, so this is actually a patient who has partially empty cellar syndrome. Um, so one, one thing that's helpful to look at here. So even if we look kind of separate from, um, the MRI findings, so she essentially has undetectable LH FSH undetectable estradiol. Um, so what, what we're looking for, when we look at the pituitary, we're trying to rule out a large pituitary mass, um, that's causing issues. Um, for her, she had normal development up until this point. So it's unlikely that this is related to something genetic. Um, we would expect that should present earlier in life, um, delayed puberty, um, or other, uh, pituitary deficiencies for her. She has this kind of flat rim of pituitary gland. And so what we were trying to describe there, um, was, uh, an empty cellar, um, where there's not a lot of pituitary tissue. We don't really know why this happens. Um, there's, uh, a lot of debate about this, but it's thought that maybe there's some incompetence in the cellar diaphragm. Um, and then the cellar over time kind of fills up with CSF and kind of pushes, um, down the pituitary stock. Um, many of these patients will have some form of pituitary dysfunction. Um, it's not always necessarily going to be complete hypopituitarism, um, but hypogonadism is common. Um, growth hormone deficiency actually is very, very common in these patients. Um, so maybe as high as, uh, 20%, um, we'll have growth hormone deficiency, um, potentially in combination with another pituitary deficiency. Um, so when, when you see an empty cellar, it's just helpful to kind of think through the different, uh, pituitary hormones and make sure you really do a complete assessment. Um, if this were a rathies cleft cyst, um, we would have described this differently. Um, so it would have been kind of a, often they'll say a cystic structure, um, but, uh, the, the T1, T2 weighted images, um, often will appear fluid-like. Um, so that's how they would kind of feed it to you on a STEM. If you were taking boards, um, often it's going to be midline. Um, and I would say for the purposes of boards, they're typically going to describe it in the classic way. So something midline within the pituitary, um, as opposed to kind of the flattened rim of pituitary tissue that we're describing here. Um, now the traumatic brain injury, I don't think anyone selected that one. Um, traumatic brain injury certainly can cause hypopituitarism. Again, it may be one axis. It may be multiple axes that are affected. Um, but in her case, they were very clear to say, you know, Oh, she had a single motor vehicle accident, but nothing else. Um, so in her case, you know, we weren't really, really pushing you in that direction. Um, but if you are seeing someone who has unexpectedly at least one pituitary axis, that appears to be involved asking about traumatic brain injury. Um, I do this a lot for like low cortisol patients. And every now and then you, you learn something sort of interesting where you're like, Oh, you know, maybe that explains why your pituitary gland looks normal, but you have secondary adrenal insufficiency. If they've had, um, a severe traumatic brain injury, um, can happen with less severe, uh, TBIs as well. Um, the one thing that I'll say for, for this patient, her labs were kind of a slam dunk, uh, just in terms of the, the LHFSH and estradiol all being undetectable. Um, and I find in clinical practice, it's never this easy. Uh, so let's say, you know, if she had had an estradiol level of like 75, her FSH is three, her LH is three. Um, this is a patient where I would have actually thought about doing something like a progesterone withdrawal test and given her 10 days of progesterone. And if she had a menstrual cycle, then, you know, she has adequate estrogen and you need to be looking outside the pituitary gland. Um, but if she did not have a withdrawal bleed, um, after progesterone, then you need to sort out like, okay, this looks like secondary hypogonadism, um, looks to be related to a true estrogen deficiency, um, and kind of sorting out what, what to do next. Questions about this case at all. We don't get any, I have one. Uh, I, in, in patients, let's say her prolactin was normal. Let's say it was 29 instead of 33. Um, is your first go-to, uh, to evaluate for hypogonadotrophic hypogonadism a progestin challenge? And in, are there any cases of oligomanorrhea where you do proceed with pituitary imaging irrespective of the prolactin level? Yeah, I, I think for her, if her prolactin had been normal, I probably still would have gone to the pituitary MRI just because all of her gonadotropins were completely suppressed. But if they'd been kind of in an equivocal range with a low-ish estradiol, I probably would have gone with the progesterone withdrawal first. You know, sometimes with women who have PCOS, you know, it can be mild enough that they don't have a lot of acne, a lot of hirsutism. And I find that the progesterone withdrawal can be helpful to kind of sort out those cases, just to be sure you're not ordering a pituitary MRI on someone who actually has normal estrogen status, but it just doesn't look like it based on their test results. But yeah, I feel like this case is a little bit more cut and dry than what I typically see clinically. But I'm a big fan of the progesterone withdrawal test because it can give you a lot of information and it's easy enough to do. And often will save patients getting a pituitary MRI when they don't really need it. Great, awesome. Okay. I think we can move on to case five. 57-year-old man with neurofibromatosis type 1 presents for follow-up of type 2 diabetes. He also has peripheral neuropathy, hypertension, and insomnia. His current medications include dilaglutide, nortriptyline, lisinopril, hydrochlorothiazide, and trazodone. Since his last visit, he has gone to the emergency department with complaints of right flank pain and imaging has confirmed nephrolithiasis. A CT with contrast revealed a two and a half centimeter adrenal mass with enhanced Hounsfeld units of 63. What is the next best step in evaluating this adrenal mass? Okay, this is kind of what I expected. And that's that there would be a mixed bag of some of the things that we're going to be looking at. So we're going to be looking at the adrenal mass of the patient. And then we're going to be looking at the adrenal mass of the patient. And then we're going to be looking at the adrenal mass of the patient. And then we're going to be looking at the adrenal mass of the patient. And then we're going to be looking at the adrenal mass of the patient. And then we're going to be looking at the adrenal mass of the patient. So this is a mixed bag of answers. So some people selected CT without contrast, some selected plasma meds, some selected urine caps and meds. So we can go through this question. And I have to say that I think there's a few different ways that this can be approached. And I'll kind of talk through the reasoning that our group discussed in preparation of this question. So I think we can start with just talking about neurofibromatosis type 1 and what endocrinopathies we should be aware of. And then kind of broadening it out to a question of what to do with adrenal incidentalomas with certain hereditary patterns, I guess. So first of all, neurofibromatosis type 1 is oftentimes managed by pediatric endocrinologists, but maybe not as commonly seen in adult endocrinology. And that's because NF1 is, as we know, a hereditary disorder that can be associated with central and peripheral neuro tumors, neurocognitive issues. There's an increased risk for breast cancer. In kids, there's actually frequently seen changes in both growth, either early or late, or puberty. In this setting, many of these patients encounter a pediatric endocrinologist. From the adult endocrine perspective, there is an increased risk for pheochromocytoma. So it occurs in about three to 5% of patients with neurofibromatosis type 1. So that changes our pretest probability whenever we see an adrenal tumor in these patients. And what to do in terms of screening is still a little bit unclear. And there have been different suggestions by different groups. I think that all groups sort of agree that before something stressful like surgery or pregnancy or labor and delivery, patients with NF1 should have a metanephrine screen, or of course, if they are having symptoms of a pheochromocytoma. There are also some possible intervals at which we should be screening that have ranged, I've seen values from yearly to every three years by Dr. Gruber's recent publication. So it's, I think, still a question of what the optimal follow-up for these patients is as far as pheochromocytoma. There also is likely an increased risk for osteoporosis. So that's another area for monitoring this group. Now, as far as what to do for this specific adrenal tumor, I think we have to go back to our question about how we evaluate adrenal incidentaloma. So one, risk of malignancy. That cannot be assessed without a non-contrast image, or I suppose an MRI as well. So we have a single contrast-enhanced image. And so in order to adequately answer that question, we need a non-contrast CT. And so that's actually the answer that this question was looking for. Now, there can be other very informative information, and that is that this particular tumor, when it was evaluated, had Hounsfeld units of five, non-contrast Hounsfeld units of five, which effectively excludes pheochromocytoma. So by doing an additional scan, you can effectively rule out malignancy, and you can rule out pheochromocytoma for this patient without having to mess with the plasma and urine metanephrines. And the reason that I say mess with is because this patient is actually on two different medications that can significantly increase the risk for false positives. Now, I will say that in my clinical practice, I often do check, but I tell the patients, this is likely going to be positive, and then we're going to have to take you off of medications. But tricyclic antidepressants account for a very significant proportion of positive metanephrine screens, and this patient is on both nortriptyline and trazodone, so there's a pretty high chance that if we were to do this, it would be positive, and then we would have to taper the patient. And I find that tapering psychiatric meds is just tough and really has to be done very cautiously or pain medications, depending on the indication. And you can see here, there's a list, amphetamines, ADHD medications, psychoactive medications, tricyclics, all can affect false positives. Levodopa can increase, of course, dopamine levels. And so the best answer they were looking here for was to do a CT for that contrast. MIBG has very, it's going to cause false positives and false negatives, so that's not the best answer here. And basically, the end of the stem says that the CT scan without contrast had a household units of five, and it oblivated the need to basically need to take this patient off medications. Okay, and we, I think we have time for our last case. Can I ask you a quick question? Oh, yes. Just in general, so when you're working up like an adrenal incidental wellness, we're going to say like separate from NF1, when you're checking either plasma or urine metanephrines, what levels are what you consider kind of false positive? What levels make you concerned like, oh, wow, like this incidental adrenal mass actually is a Pheo? Yeah, so it's very challenging. So I think two times above upper limit of normal, kind of below that is very oftentimes false positives, but it depends on the size of the factory. So the larger the factory apart from necrosis, and some additional factors, which can affect size, but not productivity, I suppose. The larger the size, the larger the factory, the higher the metanephrines, normetanephrines will be. So I actually have seen patients who have two centimeter adrenal masses who have a risk factor like SDH that would increase their risk for this being a Pheochromocytoma, and they do have a positive metanephrine screen, but it is within that less than two times upper limit of normal. But I think it's just because they have a very small tumor. And we've taken these out, and they have proven to be very small Pheochromocytomas. So I think it depends on which patient we're looking at, and what the imaging characteristics are, and what the pretest probability is. Perfect, thank you. All right, so case number six. So we have a 28 year old, so she's following up for type one diabetes, takes no other medications other than insulin, and she's been on multiple daily injections. She's telling you that over about the last three months, she's had a lot of nocturnal hypoglycemia. She's lost about 10 pounds of weight, she's fatigued. She's noticed a little bit of nausea, over this time, some poor appetite, and she thinks that's what's causing the weight loss. She's had to reduce her doses of insulin pretty significantly, but still is having a lot of hypoglycemia overnight. So when you see her in clinic, blood pressure is 102 over 67, heart rate is 98 beats per minute. She weighs 119 pounds and has a BMI of 21. She is not in acute distress, but you can see she has very dry mucous membranes, pulse is regular, but again, a little bit on the fast side and no edema. She does have orthostatic vital signs. So blood pressure drops to 80 over 60 and heart rate increases to 818. She maybe looks a little bit hyperpigmented over a previous appendectomy scar, but otherwise doesn't really have any hyperpigmentation on exam. So her laboratory testing shows a sodium of 1.5 mg and a potassium of 128. Potassium is 5.0, glucose is 109, TSH is normal at 1.7. She did have a celiac disease screen because of the weight loss and that's negative. And her morning cortisol is 8.2. And she does have a normal sleep-wake pattern. So you get some additional testing because she has the hyponatremia and you can see her serum osmolality is a bit low at 262. Sorry, it's high at 44 and her urine osmolality is 520. So based on these results, what do you think is the most likely cause of her hyponatremia? All right, perfect. So a little bit of background information. So she has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. She has a normal sleep-wake pattern. So a little bit of a split between SIADH and primary adrenal insufficiency, and I can certainly see why. So I thought this would be a good case to go through. So this is a patient who has primary adrenal insufficiency. It's a tough case, though, because her low sodium and then her serum osmolality, urine osmolality, certainly look a lot like SIADH. But what we have to kind of sort through is, clinically, this is someone who has autoimmune disease. So she has type 1 diabetes and has a lot of other symptoms that we can't necessarily chalk up all to the hyponatremia. So the weight loss, the recurrent hypoglycemia, the nausea, the pigmentation. I'm going to say plus or minus because it was just around a single scar. But that really makes primary adrenal insufficiency the most likely diagnosis here. Her cortisol level was not especially low, and sometimes that will be the case for these patients. So you really have to have a high index of suspicion because they may not have a cortisol of 2 or 3 that makes it really easy to say, oh, you know, I think this could be adrenal insufficiency. But just kind of piecing it all together, clinically, this is the most likely thing. So she's otherwise a pretty healthy person. So there's nothing that's jumping out here that's going to cause a pseudohyponatremia in her case. Now, what's really interesting is that mineralocorticoid deficiency and SIADH have very similar lab tests, and it can be really hard to tell those apart. The key here is that she really has signs of hypovolemia. So she has orthostatic vital signs. She has dry mucous membranes. And so we basically, in the pathway, working up hyponatremia, she breaks off into that part of the algorithm that is hypovolemic hyponatremia, whereas normal volemic hyponatremia is going to be more of an SIADH pattern. So the reason I'm making this designation, in her case, because she has orthostatic vital signs, because she's volume depleted, her ADH response is appropriate. So she should have high ADH because she's volume low. And so that's really what you have to kind of sort out. This, again, I think is a very tough question, but in her case, that's how we kind of make this designation. Other things that can cause SIADH are not necessarily obvious for her. So she's not on any medications other than insulin. She doesn't have lung disease or other situations where we can see SIADH come up. So in her case, primary adrenal insufficiency is the most likely diagnosis. You know, secondary adrenal insufficiency can present with hyponatremia from SIADH. So that's why cortisol is on multiple pathways in our hyponatremia algorithm. But in her case, it's really the difference that this is hypovolemic, not normal volemic. And that's the distinction here. At the end of the day, we're going to check the cortisol no matter which pathway you're in. So that's the important thing here. And the ACTH is obviously going to be really helpful in her case, which should be elevated if this is primary adrenal insufficiency. Any questions about this case? It's a tricky one. That was great. And I actually also use that, is it appropriate or inappropriate ADH secretion, just like we talk about hyperparathyroidism or really anything else in endocrinology? And sometimes that's so hard to tell on the inpatient service, right? Yes. Everything with cortisol gets very cloudy once someone's in the hospital. Any other questions? I guess I will ask the final question unless something else comes through. When you're seeing patients with hyponatremia inpatient, do you think all of these patients require cortisol assessment? And what is sort of the pretest probability threshold, I guess, that you use to make that determination for hyponatremia patients? Yeah, I'll be honest. I tend to test it for everybody because it's something that they're ill enough to be in the hospital. They have a sign of low cortisol. So I check a cortisol level in all of these patients. Now, what is an appropriate cortisol response for someone is very tricky to interpret on the inpatient setting. And I think sometimes we get caught in this trap. At least I feel like this, where the baseline cortisol sometimes is not as robust as what we would expect. And the primary team often has already ordered an ACTH stimulation test, which looks normal. And then you're like, well, but was there a critical illness kind of in and of itself? So I think it's always helpful to check the cortisol level. And if they're sick, I mean, we should see a cortisol of like 15, 18. I would argue often much higher than that, depending on how sick they are in the hospital. Full disclosure, I also have a low threshold to start hydrocortisone if someone's critically ill and their cortisol is a bit equivocal. But I think it makes sense to check it in these patients with hyponatremia if they have SADH or if there's kind of a question of, well, are they volume depleted and they have primary adrenal insufficiency? I kind of have the same approach. And it's hard to know if there could have been a secondary insult where the stim test may not be reliable in those first couple of months. So I have a very low threshold to discharge patients on 10 milligrams once daily of hydrocortisone if they have very borderline testing and kind of assessing a couple of months post-hospitalization. We have one other question that came in about a prior case for case four, which I think you also covered. For empty cella, what treatment do you typically advise, OCP or HRT? So I am in the hormone replacement camp rather than the OCP camp within reason. The reason, I feel like if we can use a bioidentical hormone, we should. And for a lot of these women, I think the patient in that case was like 33 or 35 years old. So oral estrogen really isn't that risky. But as a woman gets older into her late 40s, 50s, you're kind of nearing the age of menopause. I do worry about the risk of DVT with oral estrogens with an OCP. So I tend to offer everybody hormone replacement first. And I typically will use an estradiol patch with oral progesterone or progesterone IUD. If it's a younger woman and she's wanting to do something that's maybe more simple, she's wanting to do something with birth control built in. Because in theory, even though you have secondary hypogonadism, pregnancy is still possible, very unlikely. Then sometimes I'll use an OCP. But I like bioidentical hormones. So that's typically my go-to. It's a good question. You might get a different answer depending on who you ask. All right, perfect. Well, thanks so much for joining us. Everybody have a good night. Bye-bye. Have a good night.

endocrine conditions

adrenal mass

malignancy evaluation

hyperprolactinemia

neoplastic causes

primary aldosteronism

hypertension management

pheochromocytoma

primary adrenal insufficiency

differential diagnosis