Well, good evening, everyone. I hope you're enjoying your dinner. On behalf of the Endocrine Society and Medscape Education, I want to welcome you to our program tonight, Concepts to Practice, the Evolving Landscape of Congenital Adrenal Hyperplasia Management Strategies. First, I'm Rich Aucus from the University of Michigan, and I want to introduce my co-faculty. Phyllis Spizer is Emeritus Professor of Pediatrics from the Zucker School of Medicine at Hofstra Northwell in New York, and Anand Bhaija is Associate Professor of Medicine at Harvard Medical School, Director of the Center for Adrenal Disorders at Brigham Women's Hospital in Boston. So after the welcome, we're going to start with Dr. Spizer talking about children, the impact on growth and maturation of classic CAH, and then Dr. Bhaija will talk about CAH in adults, comorbidities and fertility, and then I'll finish with a discussion of what's next before we have Q&A. Before I go any further, I want to make sure you all scan your QR code that's on the handout you got so that you can respond to the audience response questions. I'm going to give you a second to do that. I'm going to start with this introduction. This is the classic steroidogenic pathway that I teach all my fellows and residents. From cholesterol, conversion to pregnenolone, and then the downstream enzymes that get you to aldosterone or cortisol. Now I've color-coded the enzymes and the steroids and their approximate relative concentrations. The main point being that cortisol is normally 1,000 times higher than aldosterone. So you have to have a real severe enzyme deficiency to be aldosterone deficient, but an incomplete defect can cause cortisol deficiency. These precursors can also get metabolized to androgens, and in the adrenal it's mostly DHEA sulfate. In the gonads it's onto androgens and estrogens like testosterone and estradiol. So 21-hydroxylase, as you saw from the previous slide, is involved in the pathways to both aldosterone and to cortisol, and to aldosterone through progesterone, one key intermediate, and then to cortisol through 17-hydroxyprogesterone, the other key intermediate, and the one that we've traditionally used for the diagnosis of 21-hydroxylase deficiency. 17-hydroxypregnenolone in particular is converted to androstenedione, which can then go on to 19-carbon, which is where the 19-carbon steroids, the androgens and estrogens come from. This is sort of parsed out in the three zones of the adrenal, the zona glomerulosa, fasciculata, and reticularis. Now there is also, if you went to the session on the first day of the meeting, the 11-oxyandrogen pathway, where when androstenedione is present in significant concentrations, that it is also 11-hydroxylated and converted to a biologically active androgen, 11-ketotestosterone, which we recognize now as the very important androgen in congenital adrenal hyperplasia. So the genetics of 21-hydroxylase deficiency are complicated. The CYP21A2 coding gene is the dark orange arrow in this diagram. And it is in a duplicated locus, which is in the chromosome 6 in the HLA region next to the fourth component of complement. Now the light orange CYP21A1P gene is a pseudogene that has 10 parts that are different from the coding CYP21A2 gene. And Perrin White in the background figured out the genetics of this. And overlapping the dark orange CYP21A2 gene is the tenasin X gene, the TNXB gene, which is an extracellular matrix protein. So the reason that 21-hydroxylase deficiency has the same prevalence and the same mutations pretty much everywhere in the world is because most of them are not really mutations, but they are gene conversion events where a piece of the pseudogene is transferred onto the coding gene to make it inactive or dysfunctional. There can also be recombinations in this duplicated locus, which can take out a piece of the 21A2 coding gene. So I've shown you on the left side of the slide different chimeric genes where there is a pseudogene coding gene chimera. Or you can have a complete deletion of the dark orange 21A2 gene. And you can also take out a piece of the tenasin X gene, which gives you a contiguous gene syndrome and an Ehlers-Danlos phenotype. So the treatment goals in children are to prevent adrenal crises, to maintain volume status, to minimize androgen excess. And the treatment is generally hydrocortisone and fludrocortisone, as Dr. Speiser will talk sometimes with supplemental salt, trying to keep the dose down to about 17 milligrams per meter squared per day or less. In adults, we still have to replace the glucocorticoids. We generally use mineralocorticoid replacement, except in some rare instances. We counsel about genetics and fertility. We offer them behavioral health counseling. We try to avoid adrenalectomy. And we look out for both adrenal and gonadal tumors, as well as the long-term morbidities both of the disease itself and of the treatments that we use for this disease. And so my last slide is about the long-term therapy, is that it's kind of a Sophie's choice. I know a lot of endocrinologists are not satisfied taking care of this disease because you basically have to pick between two unpleasant options. One is to give physiologic glucocorticoids to minimize the long-term comorbidities, treat them like an Addison's patient. You can mimic the circadian physiology, and you can have pretty good compliance. But that's at the expense of letting the androgens rise, the risk of fertility problems, and the problems with tumor development. Or you can achieve good androgen control with superphysiologic glucocorticoid doses, maintain fertility, and there is some evidence that this will help prevent tumor formation. But patients will experience the weight gain, myopathy, infections that come from iatrogenic Cushing syndrome, bone loss, and glucose intolerance. So I want to finish my introduction with a question. So when managing patients with classic 21-nidroxylase deficiency, do you tend to favor physiologic glucocorticoid doses, even if androgens rise? Or do you tend to favor control of androgens despite the risk of glucocorticoid excess? Don't manage these patients and punt to a center of excellence, or you don't have any patients with 21-nidroxylase deficiency? Okay, so there is no right answer to this question. And my point is that it's pretty evenly spread. And that's what we're going to talk about next. So I'll use that to turn the floor over to Dr. Spicer. Good evening, and thanks to all of you for being here at this late hour. So this is a brief outline of what we're going to discuss this evening with respect to the pediatric population. I'm not sure how many of you are pediatric endocrinologists. Okay, we have a few. About a quarter. All right. So these will be issues that you're going to face in your everyday practice dealing with CAH patients. So we'll start with a case involving newborn screening. So you're notified of borderline high CAH newborn screen on a filter paper blood sample that was obtained at 24 hours of life. And the exam at three days of life shows a really normal, vigorous, full-term female infant with just this clitoral enlargement. So the next step should be, one, begin hydrocortisone treatment, two, get another filter paper blood sample, three, order a genotype for the responsible gene, and four, perform a cosentropin stimulation test. So please vote. Okay. So the majority said go right to the cosentropin stimulation test. And that's not a wrong answer. And I will just confess that some of these questions, multiple choice questions, don't have a single correct answer, but the polling system wouldn't allow me to let people choose all that apply. So you know, that's not a wrong answer. But I'm going to show you some data to explain why a borderline filter paper result is not going to necessarily tell you the diagnosis or, you know, allow you to go with confidence to the family and say, this is what your child has. So this is a study that we did surveying a total of 17 states, and it was based on a single year's data. And the size of the circles on this graph represent the number of babies screened. So you can see, for instance, on the top portion, left portion of the slide, there's a state that screened about 200,000 infants in a single year. And the positive predictive value is shown on the X axis, and the lines surrounding those circles represent the 95 percent confidence interval. So the more babies you screen, the tighter the confidence interval, and generally you're going to get a better positive predictive value. But what you can see here is that from all of these data, the mean positive predictive value for a single Delthea, which is an immunoassay on 17-OHP on the filter paper, is very widely variable, and it's about 8 percent across these 17 supposedly representative U.S. states, the median being 5.3 percent. So that's not a great positive predictive value for a diagnostic test. Now, you can improve the newborn screening efficacy by doing several other maneuvers. So once you have the initial filter paper immunoassay, several programs in different countries have looked at whether if you add on gestational age and or birth weight, could you improve that? And the answer is yes, you can raise that positive predictive value from a mean of 5 to 8 or 10 percent up to as high as 26 percent, and this is all with a single screen. And there are the references in the published literature. Now, if you did a second tier test on that initial filter paper using the liquid chromatography tandem mass spec system, which is now active in many newborn screen labs, not just for CAH but for other diseases, inborn diseases that are screened, you can improve that positive predictive value even further, and this is from a study that was done in New Zealand. Now, the second tier test has an additional advantage to it besides improving the positive predictive value for diagnosing CAH, and that is that you can look at multiple steroids with this system of tandem mass spec, and you can do steroid ratios. And as Dr. Orkus and Dr. White were discussing earlier in a session on CAH today, that the 21-deoxycortisol happens to be an excellent diagnostic marker for CAH, probably better than 17-hydroxyprogesterone, and the positive predictive value in one of these studies went up as high as 100 percent. And then there are other ratios you can look at, and you can actually diagnose other types of CAH using this type of system. Now, genotype is attractive, but the problem is that it's more costly, at least as of now. It's also more time-consuming, and it's not been in general use, so there's very little data on its use in real live, large-scale newborn screening programs. So here's some more history, some imaging and labs on this particular newborn. The gestational and birth history, pretty much unremarkable. There was no known exogenous hormone exposure, no maternal virilization during the pregnancy, and the post-discharge course at one week of age is that the baby is nursing normally, no vomiting. When the baby was examined, the weight was slightly below the birth weight, but no signs of dehydration, and the ultrasound showed a normal uterus and ovaries. And the lab results from a venous blood sample done at one week of age, which is when we would typically get to see these babies who screen positive or borderline positive, normal female karyotype XX, 17-hydroxyprogesterone that is well above the normal range at more than 15,000 nanogram per deciliter, a testosterone that's also quite generous at 88, a DHT at 61, a slightly elevated cortisol that's relatively low, given those other numbers, and normal electrolytes and a slightly elevated plasma renin activity, which for the pediatricians in the audience you'd know is not so unusual in newborns. So this child does have classic simple virilizing CAH, and the recommended starting treatment is one of the following. So please vote for hydrocortisone given in what would be considered more than a physiologic dose in an older child or adult, prednisolone, one milligram twice a day, which would be even more than physiologic, fludrocortisone and sodium supplements, or number four, some combination of the three, and then monitor lab results. So please vote. Okay, so the majority voted for option four, which was to include a glucocorticoid as hydrocortisone, fludrocortisone, the mineralocorticoid oral replacement, and sodium chloride supplements until the lab results improve. And that's what we generally would recommend according to the CAH practice guidelines that the Endocrine Society has put out. You know, hydrocortisone alone is given in some institutions by some endocrinologists. The official recommendations of the Endocrine Society are to include fludrocortisone in the newborn period along with sodium chloride supplements as needed because babies are generally resistant to the effects of mineralocorticoid that they produce endogenously, and the typical newborn diet does not include much in the way of salt. So once you see that the plasmarin inactivity is trending back toward normal, you can probably cut back. Usually we'll cut back on the sodium chloride supplements first and then on the fludrocortisone as the plasmarin inactivity is maintained at a stable level. And prednisolone is not recommended in infants or young children because it is more toxic in terms of its long acting profile and the possibility of accruing cushingoid features over time. So we spoke about the problems inherent in newborn screening based on a Delthea 17-hydroxyprogesterone filter paper assay. And the data have shown, interestingly, that depending on one's genotype, the 17-OHP can be quite variable in the immediate newborn period. So what you see here is that for classic simple virulizing patients who often carry the isoleucine-172 disparaging mutation, that they have significantly lower initial 17-hydroxyprogesterone levels compared with people who have either null mutations, deletions, or a splice mutation. Now people who have other mild-type mutations, for instance, the typical non-classic mutation, which is valine-281 to leucine, also have even lower initial 17-OHPs. And I might point out that the object of the newborn screening program is really not to diagnose non-classic forms of CAH because that's not a life-threatening type of CAH. But they do show up from time to time, and people are often quite confused as to what to do with those data. So that's part of the rationale for needing to go forward with further evaluation of the newborn. And so I just present here some data on the utility of second newborn screens. And this was a publication from a number of years ago that was collected by investigators in Wisconsin. And what you see here is that in states that do a single newborn screen, they pick up most, the vast majority, on the first screen. But if you do a second screen, then you have even more cases picked up and very few cases that are not detected at all. But interestingly, what you're picking up with the second screens often are the simple virilizers. And some people would argue that simple virilizing CH is not such an emergency to diagnose because eventually they will make themselves known, although that is itself a problem because of the cases that we may see later on that show that if you diagnose a patient later, they do tend to get behind the eight ball as far as inhibition of their growth and other issues that come up. Non-classic CH, as I mentioned, not life-threatening, not prone to salt wasting, not an object of the newborn screen. So do we really want to diagnose those? And there's a debate ongoing and still a minority of states do two separate screens, which means bringing the baby back to the pediatrician's office at about two weeks of life. So it's a little bit complicated to get that done. So probably the focus will be for the future on improving the first screen. So now I'd just like to go on and discuss a slightly older child. This is a three-year-old boy who's been adopted and presents with a six-month history of penile enlargement, pubic hair, and underarm odor. And his exam shows normal blood pressure. He's got some facial comodones, a little bit of pubic hair, Tanner stage two, with small testes, 2ml, which would not be considered pubertal, a stretched penile length, which is generous at eight centimeters, and a normal meatal position. And the lab values here show a 17-hydroxyprogesterone done by liquid chromatography tandem mass spec at 5,200 nanogram per deciliter, an elevated androstenedione, which is 250, and a testosterone of 30, all quite high for a child this age, and a DHEA sulfate that is not particularly notable. The gonadotropins are not elevated. They're mostly really suppressed. The bone age is also somewhat advanced beyond his chronologic age. So the diagnosis here is, one, premature adrenergy, two, central precocious puberty, three, classic 21-hydroxylase deficiency, CAH, or four, the condition formerly known as testotoxicosis and now termed familial male-limited precocious puberty. Please vote. All right. So I'm just going to go ahead and say that this is a symposium on CAH. So this is classic 21-hydroxylase deficiency, CAH. But in some cases, you might not be mistaken by choosing one of those other possibilities. Actually, the testosterone is probably not high enough to see in testotoxicosis, and it's sort of beyond premature adrenergy, and the central precocious puberty doesn't quite match with the gonadotropin levels, and certainly not with the elevated adrenal androgens. So let's just get beyond this one. And the advancing slide is not... Oh, there it goes. Okay. So now we have another dilemma. The same child comes back at age eight. The bone age has advanced to 13 years, and the growth rate has slowed. Here, hydrocortisone is still being prescribed, and the parents say they're giving it. It's now up to 17 milligram per meter square per day, which, as Dr. Orkus pointed out earlier, is kind of the upper limit of where we like to be. It's a little super physiologic, and we don't feel comfortable in young children giving them much more glucocorticoid than that on a daily basis. And the predicted adult height is now about two standard deviations or maybe a little bit more below his mid-parent target or target height, and his testicular volume is now a little larger, three to four ml, borderline pubertal. His LH is higher at 2.5. His testosterone is 50, and his early morning serum 17-OHP and androstenedione are about 10%, the upper limits of normal for his chronologic age. So at this juncture, the option includes adding growth hormone, GnRH analog, aromatase inhibitor, nighttime prednisolone, or five, nothing, just continue the hydrocortisone. So please vote. Let's see if it works this time. Okay, good. So in this case, a lot of people asked to add GnRH analog. Some suggested growth hormone. A few of you wanted an aromatase inhibitor and minority nighttime prednisolone, and then 15% said just continue the hydrocortisone. So this is one of those questions where, you know, there's probably no exact correct answer because I think it will depend a lot on the personal approach of the endocrinologist. So the growth-enhancing pubertal suppressing therapies and aromatase inhibitors, there's very scant, robust, and long-term data to recommend the use of any of those. And again, in the Endocrine Society's clinical practice guidelines on CH, these are not strongly encouraged. The nighttime prednisolone is one option, I think, that in the older adolescent than the adult population, that is something to be considered. But really, the mainstay of therapy in the growing adolescent should still be hydrocortisone, trying to maintain just slightly above physiologic levels. And I think, you know, what I want to point out here is that sometimes people jump to making therapeutic decisions based on one set of data, one bone age x-ray that disturbs them, or one set of lab results that's out of line. And you really have to look at the long view and see what is going on over time. At age 14, this boy is now 167 centimeters, which is about one standard deviation below the mid-parent height. And he's not been treated with any medication to enhance growth or delayed puberty. And in fact, this is basically the outcome that was shown in a meta-analysis of growth in CAH with over 1,000 patients collected in the published literature. And that was done by a set of data experts at the Mayo Clinic in conjunction with the Endocrine Society clinical practice guidelines. So being one standard deviation below your mid-parent height is not a terrible outcome. Of course, it might be possible to get a better outcome if you were to apply aggressive therapy. I know Dr. Cutler was advocating for, you know, polypharmacy and treating CAH with some very good clinical trial results. And the question is whether in the real world it's possible to get people to take three and four drugs. And I think that, you know, part of the discussion at the end of this symposium is going to be what are we doing to try and improve CAH treatment so that we can look forward to better outcomes without having to give so many different drugs at the same time. So now at this point, the child is nearing his full adult height. How would you manage his glucocorticoid treatment? I'd like you to choose either continuing the hydrocortisone three times daily, switching to prednisolone twice daily, dexamethasone once daily, or for stop the glucocorticoid treatment. Okay. So again, a plurality of people said just continue the hydrocortisone. Some people wanted dexamethasone. Now, the practice guidelines based on expert opinion and some information in the literature show that when you get to drugs like dexamethasone, very potent, very long-lasting, very much more bioactive than a hydrocortisone, you're going to accrue long-term changes that will give you what looks like an atrogenic Cushing syndrome, and that's not really a favorable outcome. If you must use a longer-acting glucocorticoid, it's probably preferable to use prednisolone. And stopping glucocorticoid treatment really should not be an option because of the complications that we are aware of now with testicular adrenal rests in the young men and the problems that accrue with the suppression of normal fertility in both sexes. So the pitfalls of glucocorticoid treatment in childhood simulate those in adulthood except that we have the added problem of the premature cessation of growth with the advanced bone age and the pseudo-precocious puberty that happens if they're not appropriately treated or treated timely, and the atrogenic Cushing syndrome, and the inadequate glucocorticoid dosing, which will, of course, lead to excess sex steroid production, virilization, adrenal rest tumors, and the atrogenic adrenal insufficiency in some cases. Okay, so some take-home lessons. If you have a strong suspicion of CAH in an infant, as in the first case, go beyond the newborn screening to get a proper diagnosis, and oftentimes you can get that with a second filter paper assay. Of course, the gold standard hormonally is to do the ACTH stimulation test if you have a high enough initial venous 17-hydroxyprogesterone. Some endocrinologists might argue that you don't need the cortisone stimulation. The newborn screen is mandated in the USA, but just remember that it's not standard in all countries, and so if you have a child who comes to you adopted and you suspect CAH, you have to go back and do the workup. You can't rely on one set of lab values or a single bone age x-ray to make a therapeutic decision. You have to look at the long view over time and take the whole child or the whole patient into consideration, and the Endocrine Society guidelines are not at present recommending growth-enhancing drugs for most children with CAH. Of course, in the context of a clinical trial, that may be another kind of question. So I think I will stop at this point and hand the presentation over to my colleague here. Well, thank you, Dr. Spicer. I think many of you know that Dr. Spicer headed the development of the Endocrine Society clinical practice guidelines and the rewriting of them a few years ago as well. So now that that child has reached adulthood, we'll turn it over to Dr. Vaidya to talk about CAH in adults. All right. Hello, everybody. So as was mentioned, I'm an adult endocrinologist, so we'll move to the next phase of life, and I think both Dr. Alkisan and Dr. Spicer already touched on this conundrum with glucocorticoid therapy. You're balancing the very effective and necessary role glucocorticoids play in treating adrenal insufficiency, their effectiveness in lowering ACTH, lowering downstream androgens, and their potential role in improving fertility and rest tumors with the counter Cushing syndrome and cardiometabolic disease. And balancing this is a challenge, if not impossible, so it's always about picking what's the best for your patient in that particular clinical context. And that clinical context changes depending on who the patient is and what phase of life they are in. So we'll see a few examples of that. I did want to touch on, we've mentioned the guidelines, so at the top there is the Endocrine Society Guidelines. There are some other great resources, New England Journal Reviews, Endocrine Reviews. I'm going to focus on the Endocrine Society Guidelines just so you can see what the specific recommendations were as we review the cases, but it's important to note that CAH in children and in adults is a heterogeneous syndrome. There's so many unique considerations, and part of the problem with making guidelines, as is quoted inside the guidelines, is there's very little high-grade evidence in terms of randomized control trials and high-grade studies. Therefore, the recommendations that have emerged are at best low or moderate quality, often relying on the opinions and experiences of experts like the one sitting next to me. So what I'm going to share with you are three mini cases, and I really chose these cases to reflect what you are most likely to encounter in adult practice, as well as trying to cover as many elements of what you might cover as well. There will be two cases of non-classical CAH in women in different clinical contexts, and a case of a classical CAH in a young man desiring fertility. Okay, so this is a 25-year-old woman. She's complaining of new facial hirsutism, acne, and amenorrhea. Her history is she had an unremarkable birth, normal genitalia, no salt wasting, normal growth, menarche at age 13, and thereafter irregular menses and oligomenorrhea, and now amenorrhea. Oh boy, this is going to be a long night. Oh man. Sorry. Okay, so she was tested for CAH. 17-hydroxyprogesterone is above 1,000 nanograms per deciliter. She does not have adrenal insufficiency. You can see she has a normal morning cortisol. Her androgens were reported as elevated, and as a result she was diagnosed with a non-classical CAH. So what treatment should be offered? I'll just tell you all our multiple choice questions from now on are going to be in alphabetical order. So the options are dexamethasone in the daytime, dexamethasone at night, split dose hydrocortisone, estrogen contained in oral contraceptive, plus or minus an anti-androgen, or prednisone either in the morning or in the evening. Okay, so spattering of answers. As with all of these questions, there are many potentially right or appropriate answers, and I think that's true here too. I would say that maybe the least right is dexamethasone, as Dr. Spicer was alluding to earlier, and I would say if there was anything that was absolutely wrong, it would be nocturnal dexamethasone, although I think you can justify it with the right caveats and conversation. So I'm glad to see that the majority of you said oral contraceptive and anti-androgens and maybe hydrocortisone. So let me tell you what happened. She was started on dexamethasone 1 milligram at night, and this is an extremely effective glucocorticoid because her 17-hydroxyprogesterone plummeted, androgens normalized, clinical hirsutism resolved, and her menses initially returned. But then she was continued on this indefinitely, right, because all the numbers got better. And she was on this for 30 years. During this time, gained 100 pounds. I cannot fully describe how teary and emotional she was, but has tried to lose weight, very challenging, no success, major depression, PTSD, oligomenorrhea, infertility, now in menopause, severe osteoporosis, and as expected, chronic secondary adrenal insufficiency and many other issues, all reflecting the Cushing syndrome. So I actually saw her at the end of that 30 years at age 55. I took her off nocturnal glucocorticoids and put her on daytime glucocorticoids and switched her to a short-acting hydrocortisone and then ultimately weaned that off and showed that her HPA axis had normalized. She didn't have adrenal insufficiency. And with that wean in the course of about a year and a half, she lost 75 pounds. Her major depression improved, but she's still stigmatized and has tremendous PTSD from this decades-long journey. So glucocorticoid therapy in adults with non-classical CH I think should be reserved for three situations. Invasive or suspected adrenal insufficiency. Suspense. What is it going to be? What I would call resistant clinical hyperandrogenism where you and your patient decide that the risks are outweighed by the benefits and or, in rare cases, unexplained infertility or unexplained recurrent miscarriages. So here's actually what the guidelines say on this topic verbatim. In asymptomatic, non-pregnant individuals with non-classical CH, we recommend against glucocorticoid therapy, which I just mentioned. In previously treated patients with non-classical CH, which you will see, we suggest giving the option of discontinuing therapy, presuming they don't have residual adrenal insufficiency or their HPA axis recovers when adult height is attained, which I just showed you in the resolution of this case. In adult women with non-classical CH who have patient important hyperandrogenism, I call that resistant hyperandrogenism or infertility, we suggest glucocorticoid treatment. So what does this mean? The translation. If your patient is not desiring to get pregnant, they're not pregnant at the moment, you should try using a non-glucocorticoid anti-hirsutism or anti-androgenism approach like an estrogen-containing oral contraceptive with or without an anti-androgen like spironolactone. This therapy can take months to work, sometimes up to a year, and if at the end of that time the benefits are not satisfactory to your patient, you can prescribe a glucocorticoid. You need to discuss the risks of Cushing's, make sure your patient understands what those risks are, and then ideally prescribe what's the least amount to get the best effect. So I would say non-dex, non-nighttime, ideally something daytime like hydrocortisone or prednisone if you can get away with it. Predefine the clinical objectives. Your goal is not to normalize the labs. It's to address the clinical complaints without suppressing the androgens in 17-OHP to avoid Cushing-lite effects. Okay, so in asymptomatic, non-pregnant individuals with non-classical CH, we recommend against glucocorticoids, and adults with non-classical CH will also have patient-important hyperandrogenism or infertility. We suggest glucocorticoids. And then finally, for men, which we'll talk about the specific case in a moment, with non-classical CH, we suggest clinicians generally not prescribe daily glucocorticoids, except if there's an issue with infertility or breast tumors, and I'll show you an example of that. I like to show this curve because this table shows you the relative potencies of glucocorticoids against one another. If you look at the second row, hydrocortisone, it's assigned a potency of about 1. If you go all the way down, you'll see dexamethasone is approximately 25 to 30 times as potent, but it's more than that. You know, the dynamics of hydrocortisone, it's relatively quick on, quick off. Prednisone has a kind of longer, smaller peak and longer tail. Dexamethasone, it's almost like insulin analogs. It's like a basal insulin. It doesn't have a large peak, but it has a very long duration of action. So it's not only much more potent, it's almost like giving a continuous infusion. So this is why it's very effective as a glucocorticoid, as an immunosuppressant and anti-inflammatory, but it's also why the Cushingoid effects are tremendous. Okay, I'd like to just point out that we typically don't think of patients with non-classical C-H as having adrenal insufficiency, but there are really nice studies like this one that tease out by stressing the system that many patients with non-classical C-H have mild or subclinical insufficiencies of cortisol or aldosterone that typically are not clinically relevant on a day-to-day basis, but because of the pathophysiology, they do have enough of an enzymatic defect that they may not mount the full cortisol response, and that might be relevant when we talk about infertility and miscarriage in a minute. OK, we'll go to the next case. 35-year-old woman, G0, P0, she has non-classical CAH and wants to start a family. Again, normal birth, unremarkable genitalia, no salt wasting, normal reported growth, menarche at 12, and then oligomanorrhea till 18. And then she developed mild hirsutism at a young adult age. It was tested with a 17-hydroxyprogesterone, which was already 1,000. The stim confirmed that she had CAH. She did not have adrenal insufficiency, as you can see with her cortisol and stim values. And her testosterone was reportedly slightly elevated. She also had genetic testing and was diagnosed with non-classical CAH. OK, so how was she treated? I went to a multiple choice here. She was actually also given nocturnal dex. But unlike the first patient, she was given 0.25 milligrams, which is better, although I would say not ideal, in addition to an estrogen containing oral contraceptive. She was started on that at age 20 and continued on that till age 32, so 12 years. Her hirsutism did resolve. Her menses normalized. 17-OHP was undetectable, and androgens normalized. When I saw her at age 32, she didn't have any overt stigmata of Cushing syndrome that I could see, or even on labs and metabolically. So we discussed that nocturnal dexamethasone might be overkill and switched her to daytime hydrocortisone and then weaned her off completely. She, on her own, decided to stop her oral contraceptive because she wanted to get pregnant. Once she stopped the oral contraceptive, months later, she was still having irregular menses. Whether they were ovulatory or not, we never got to assess. But she had been trying with her partner for six months without any luck. So here are her morning labs, six months after being off dexamethasone and off oral contraceptives. 17-hydroxyprogesterone is 638 nanograms per deciliter. Testosterone, androxine, and dione are elevated. Her cortisol is normal. That should be ACTH, 34 picograms per milliliter. And her ACG is negative. Both she and her partner have undergone genetic testing and her partner does not carry any pathogenic CYP21A2 mutations. So they want to get pregnant now. You discussed referral to reproductive endocrinology. But in addition to that, what would you recommend? Seen here alphabetically, your options are clomiphene, dexamethasone, gonadotropin therapy, hydrocortisone, no treatment, or prednisone. OK. All right, I was not expecting that spray of answers. I wish we had time to unpack why everyone chose what they chose. So let me show you what happened. And I think you could justify almost any of these. Maybe dexamethasone is the one I would say is the most incorrect. But I think you could justify almost every other answer, depending on your thought process and what conversation you will have with your patient. I will move. There we go. OK. So we started having the conversation on whether we wanted to initiate treatment and what to initiate. But six weeks later, she calls you and tells you that she is pregnant. And so we're definitely going to run out of time today because of this remote. OK, so you got your chance to pick a treatment. But before you even get to implement it, she's pregnant. Now, at six weeks gestation, what would you recommend? Your options are a little narrower. Dexamethasone, hydrocortisone, nothing, or prednisone. OK, so the vast majority of you said to do nothing, followed by hydrocortisone. Great. So we discussed that her baby will be a carrier for CH because she carries the mutation, but her partner does not. We discussed the pros and cons of empiric low-dose glucocorticoid therapy, essentially hydrocortisone therapy that a lot of you chose, non-dexamethasone since hydrocortisone does not cross the placenta. And we discussed that the reasoning for this might be the risk for miscarriage prevention. It can also be the risk for miscarriage prevention It can also be used for infertility, which is not an issue since she's pregnant. We discussed that this is very low-quality evidence, and we did not prescribe the glucocorticoid at her choice, which I was fully supportive of. She went on to have a normal, healthy pregnancy, delivered at 40 weeks, and had a healthy baby girl. Could you have given hydrocortisone? Absolutely. Here's what the guidelines say. In individuals with congenital adrenal hyperplasia and impaired fertility, we suggest referral to a reproductive physician. We suggest referral to a reproductive endocrinologist, which we did. And women with non-classical CH who are infertile or who have a history of prior miscarriage, we recommend treatment with a glucocorticoid that does not traverse the placenta, in other words, not dexamethasone. And the idea here is that maybe the cause of the infertility or in part or in whole or the cause of the recurrent miscarriages in part or in whole might be a subtle unmasking of adrenal insufficiency that might be clinically relevant. Providing a glucocorticoid to treat that that doesn't cross the placenta is probably low risk and might help a patient get pregnant or maintain a pregnancy. So that's what that says. And women with CH who become pregnant, we recommend continued pre-pregnancy doses of steroids if they were already on them, as you would with any patient who has adrenal insufficiency and is treated. And then if you do decide to treat with hydrocortisone, as many of you chose, the recommendation is that a stress dose hydrocortisone be given to people who have documented adrenal insufficiency. So if you chose to give this patient hydrocortisone, it wasn't for the indication of documented adrenal insufficiency. It was for this more nebulous miscarriage protection. So when the OBs call you and say, do I need to give them stress dose steroids in labor, the answer is no. Sometimes you have to do it to make everybody happy, but they don't actually need it, like she didn't need it. OK, so we'll go to our last case. This is a 36-year-old male with classical CH. I guess his past medical history is on the side. So he was born with a salt-wasting crisis at birth. Actually, his older sister was also born with a salt-wasting crisis. So this should have been predicted, but I think that he was born at a different hospital. He was treated with glucocorticoids and mineralocorticoids. He thereafter had what was reported as normal growth, development, puberty. He's currently on hydrocortisone 20 and 5. He's on 0.2 of flugocortisone. He says he feels great. He has good energy strength, normal libido. He works as a carpenter. He has no problem with making it through his day and doing his work. His issue, the reason he's coming to established care right now, is him and his wife have been trying to get pregnant without success. She's 35. They've been trying for a year. She's had a full infertility workup, and it's been negative. And at their age, they're a little bit anxious that the time is of the essence here. Okay, so here are his morning labs. His 17 OHP is 18,000. His androstenedione is nearly 1,400 nanograms per deciliter. His total testosterone is actually low at 180, and his free testo is also low. So his androstenedione to testosterone ratio is approximately eight. And you can see his gonadotropins are very low. His testicular ultrasound shows no rest tumors, a relatively normal testicular size. His heart rate is about a hundred and fifty. There's no rest tumors, a relatively normal testicular size and volume. And there's a semen analysis which shows a low sperm count. Almost all abnormal morphology, and half of them are immodal. So what would you do? Here in alphabetical order, you can increase his daytime glucocorticoid dosing. You can give him clomiphene. You can give him HCG. You can initiate nocturnal glucocorticoid therapy, or you could refer him for a testicular biopsy or aspiration. All right, so it looks like almost 60% of you wanted to either increase the daytime glucocorticoid or initiate nocturnal glucocorticoid therapy and a spattering of other answers. So that's great. So he has hypogonadotropic hypogonadism. He doesn't appear hypogonadal, because his androstenedione is very high. And that's suppressing his gonadotropins, resulting in a low testosterone and a low sperm count, inhibited spermatogenesis. So we discussed that we can fix this problem by suppressing the production of androstenedione. And you could do that with daytime glucocorticoids. I chose nocturnal glucocorticoids in part. And so this is the conversation to have. They were anxious to get pregnant as quickly as possible. And I think the most effective way to reduce ACTH in androstenedione is nocturnal glucocorticoids. But the highest risk of developing Cushing syndrome, he was completely on board with that. I chose three milligrams of methylprednisolone. You could have chosen another formulation as well. And five months later, you see his biochemical labs are much better. His 17-OHP went from 18,000 to 3,000. His total testosterone has risen now from low to 550, mid-normal. His androstenedione has come down nicely. His A to T ratio is 0.3 down from 8. And his gonadotropins, you can actually see them. They were gone before. And I think the real success here is his semen analysis, which he now has a robust sperm count. They're moving, and they're moving in the right direction. But he gained 15 pounds in five months. So there was a price to pay for this. And ultimately, this price, which we had discussed before starting this therapy, was worth it for him. They got pregnant spontaneously. After they had the first baby, we discussed reversing his glucocorticoid regimen. But they wanted to get pregnant again. And they did about eight, nine months later. And now they don't want to have children anymore. So we're back with the same conundrum of how we should manage his glucocorticoids. So this was successful, but it still came with adverse effects. So here's what the Endocrine Society's guidelines say. In adults with classical CH, we recommend using daily hydrocortisone plus mineralocorticoids, as we've discussed. In all individuals with classic CH, we recommend monitoring for signs of glucocorticoid excess, as well as signs for inadequate androgen normalization to optimize the steroid treatment. In all individuals with classic CH, we recommend monitoring for signs of mineralocorticoid deficiency or excess. And in adults with CH, we recommend that clinicians do not completely suppress endogenous adrenal steroid secretion to prevent adverse effects of overtreatment. So translation, treat the primary adrenal insufficiency and educate about stress dosing, just like you would with a patient with Addison's or primary adrenal insufficiency. But at the same time, balance between physiologic glucocorticoid replacement and suppressing the sequelae of hyperandrogenism to induce Cushing's, which is, of course, easy to write, but extremely difficult to execute on a case-by-case basis. And so really, the message here that's kind of synced across all of our presentations here is you really need to customize the goals on a case-by-case basis. Do you want to get pregnant? Do you not want to get pregnant? How old are you? What point in your life are you? What's important to you? And the goal is not to make the biochemical numbers better, but to achieve the clinical objectives. So I'm going to turn over this wretched remote back to Rich. OK, thank you, Dr. Vaidhy for that very enlightening presentation. OK, so what's next? So there's many ways where you can conceptualize attacking the hypothalamic pituitary adrenal axis and treating this disease that's due to androgen excess from the adrenals. And I'm going to talk about a couple of these now. So I'm going to talk about studies that have been published or that are in progress, modified-release hydrocortisone, an ACAT1 or SOTE1 inhibitor called nevanamide, the P45017A1 inhibitor abiraterone acetate that is involved in the biosynthesis of testosterone, and the CRH receptor antagonist, which is crineserfant or tildeserfant. So this is the phase three results from the modified-release hydrocortisone that is now approved by the European medicine agencies as FMODE. You see the 24-hour curves for 17-OHP and androstenedione with the standard hydrocortisone in the open circles and the modified-release hydrocortisone in the filled circles. And you see the problem with the standard-dose hydrocortisone is that escape in the early morning hours when the circadian rhythm is driving the ACTH up. And that is suppressed with the modified-release hydrocortisone that has a delayed onset of absorption and then is available during those early hours of the morning. The dose, though, was about 30 milligrams a day at the end of the study in both groups, so still high. But during the extension phase, where the investigators had the option of changing the dose, they were able to slowly whittle away the dose down to about 20 milligrams per day and still maintain quite good control of the 17-hydroxyprogesterone. So I think this is one theme, is that once you get people into control, they tend to remain easier to control as you get some atrophy of the adrenals, but when they're in very bad control, it takes a lot of big guns to get them into control. They have so much adrenal tissue, they're making steroids. So what else can we do? So here's the hypothalamic-pituitary-adrenal axis, supposed to make cortisol, instead it's making androgens that have these unwanted effects, and we've been using glucocorticoids to suppress that axis. So why don't we just block androgen synthesis? So one way is to use a drug that will be adrenolytic, and this drug called nevanamide is an ACAT-1 or SOAT-1 inhibitor. So cholesterol is taken up from LDL, hydrolyzed in the lysosome, and then re-esterified by this ACAT-1 enzyme into cholesterol esters, that's the lipid droplets that you see in adrenal cells. And if you block that enzyme, then free cholesterol is elevated, which becomes toxic because of its effects on membrane stability and on protein synthesis. So a dose escalation study was completed for dogs. If you give this drug to dogs, it basically destroys their adrenals in a week. So a dose escalation study was done in adults with 21-hydroxylase deficiency, where the dose was escalated from 125 milligrams twice a day to 1,000 milligrams twice a day, interleaved with two weeks of placebo. And every time the patients were on drug, there was a lower 17-OHP than when they were off drug. But there was not a good dose response curve, and there was not a meeting of the desired primary endpoint. This drug is no longer in development. But conceptually, you could do this. So the other way is to block the enzymes that are making androgens. So there's a very good drug called abiraterone acetate now that's used to treat prostate cancer by suppressing testosterone synthesis. And so the idea is that with the block in 21-hydroxylase, the overflow going to androgens, you would just add abiraterone to block that overflow and lower the testosterone. So we did a study of six adult women who were treated with either 100 or 250 milligrams a day of abiraterone acetate in conjunction with 20 milligrams a day, a physiologic dose of hydrocortisone. And you can see how high the androstenedione was at baseline. And it normalized by day seven in all these patients. And there were also parallel reductions in testosterone and urine androgens. Now I also mentioned about 11-ketotestosterone. And we were able to get leftover samples and measure 11-ketotestosterone. And they suppressed in parallel because all androgens have to go through P450-17A1. All right. So again, instead of using glucocorticoids to suppress the axis, can we suppress the axis in another way? Well, it's CRF from the hypothalamus that drives ACTH production from the pituitary. And the type 1 receptor is found in the pituitary. And drugs that block this receptor were developed originally for the treatment of depression. And though very safe, they were not very effective in this condition, unlike in rats. So they were now being repurposed for the purpose of suppressing ACTH production and therefore inhibiting adrenal steroid production and the resultant androgen. So I'm going to go through a couple of studies that were done. This is the phase 2 study done with Crenesifon. It was a 14-day study where patients were screened and then brought into the clinical research unit for 24-hour steroid sampling and then treated for 14 days and brought into the clinical research unit again for 24-hour sampling. There were four cohorts going from 50 milligrams at bedtime to 100 milligrams either at bedtime or in the evening to 100 milligrams twice a day. The primary endpoints were 17-hydroxyprogesterone, but we kind of measured everything else. So what we saw were consistent reductions, greater than 50% reductions in ACTH and 17-hydroxyprogesterone in all cohorts. And we saw a dose-dependent reduction. These build slides are going slow. There we go. A dose-dependent reduction in androstenedione up to 64% from baseline as we went up to 100 milligrams twice a day. Clinically meaningful reductions. Now what does that mean in terms of numbers? So ACTH going from several hundred down to less than 100, 17-OHP going from tens of thousands to a few thousand in androstenedione where the upper limit of normal being about 200 coming into the normal range in three out of the four cohorts. There was a pediatric study that was done with Cornesor-Fond in eight adolescents that has just recently gone online for the JCNM where we delayed the morning dose of glucocorticoid until 10 o'clock in the morning. So we really saw the effect of the drug itself. And you can see these substantial reductions in that morning rise in ACTH, 17-OHP, and androstenedione in these children. So also to show percent changes in baseline, now we've looked at added testosterone levels in the females. Now in the males, the testosterone levels didn't really change much. They may have gone up slightly. But the androstenedione went down. And the androstenedione to testosterone ratio improved. And one interpretation of that is that testicular function is improving and that the testes are making that testosterone is no longer coming from the adrenals. We don't have direct evidence for that, but that's a very reasonable interpretation. So post hoc analysis was recently conducted to assess whether the baseline hormone levels or the glucocorticoid dose predicted who would have a treatment response. So of these 18 participants distributed throughout the four cohorts, the regimens included hydrocortisone, prednisone, or something like prednisone, and combinations with a total daily dose of about 14 milligrams per meter squared per day. And we found that the correlation between the baseline concentration and the change from baseline. So in other words, the higher it was, the more it came down. But there was no correlation between glucocorticoid dose and change in baseline. So this is encouraging to suggest that it doesn't matter what you're taking. It just matters how high your androgens are. The higher they are, the more the reduction we saw. Now Tildastrofant was studied in a 14-day study in adults and in a three-month study. So this is the data from the 14-day study. Changes in ACTH, 17-OHP, and androstenedione. These are waterfall plots where you see the individual patients as they came down. And you see nice reductions in the three biomarkers over a variety of doses in these cohorts. And then in adults with poor disease control who went into the three-month study, you see ACTH came down and it stayed down. 17-OHP bounced around a little bit but came down nicely by the end of the study. And androstenedione kept continuously dropping over time. So again, good control begets more good control over time as you induce the adrenal atrophy. So this is kind of a list of the drugs, the status of the trials, the NCT numbers, and the phases and the age groups that these populations are in. I'm not going to talk about the gene therapy trial with BBP631 here because it's too premature. So with that, I'm going to start the questions by asking my colleagues, to get a 70% reduction in androstenedione in an adolescent, how much would you have to raise their glucocorticoid dose if you have someone in poor control? So Phyllis, what do you think? Well, that's a tough question. And again, I think it's something to be decided on a case-by-case basis. So adolescent is a broad-range term and it could be somebody who's 10 or 2 or it could be somebody who's at the end of their growth. So I think if it's somebody at the end of their growth period and they're pretty close to their expected adult height, you feel a lot more comfortable raising their glucocorticoid dose or switching over to a more potent long-acting glucocorticoid than you would in a younger child who has a lot of growth potential to either gain or lose. So I think it's very encouraging that the trials are headed in the right direction in terms of looking for something that can be not a replacement for glucocorticoids but sparing the practice that we've all done, whether we wanted to or not in the past, of raising the glucocorticoids to try and achieve better control. And I think my policy and what I think my colleagues on the task force for the clinical practice guidelines thought about was that in certain patients, pediatric patients, you have to sacrifice control a little bit in order to allow growth to go unimpeded and not worry so much about looking at individual steroid measurements to assess control. So you're going to relax control at some point in the child's life, and you probably do in an adult's life, too, depending on the individual circumstances. Right. And, Anand, you basically got a 70% reduction in intrastein dione in your patient, but you have to add three milligrams of methylprednisolone at bedtime. Yeah. I effectively doubled the dose and added it at a nocturnal dose. So the answer is a lot, and a Cushingoid amount. Yeah. All right. So if you double their hydrocortisone dose instead and nothing happens, what would you do? You'd probably add a nocturnal, right, long-acting glucocorticoid. Sure. They'll bite the bullet and do what you know is going to cause them to gain 15 pounds, right? Sure. Okay. All right. So now we have some questions from the audience. There was a question about stress dosing in non-classics, but I think you answered that as you got to the end of your second case. Dr. Van Rossum from Erasmus is saying that their group often treats non-classic CAH 10, 5, and 5 of hydrocortisone, and that seems to be very successful. This wasn't an option that we gave, but it's certainly reasonable. I think, you know, if you have a patient, this is where the art of medicine comes in. If you have a patient that's willing to take three doses a day and they are very concerned about their androgen excess, very sensitive to it, sure, that will work just fine. But I think that's the most I would use. I think it's probably overkill in some people, but it's certainly reasonable. Those are the only questions I have on the board. If anybody has any other questions, I don't think we have microphones out in the audience. There's anything we skipped, or there's a question up front? The question was what steroids do not cross the placental barrier. That would be hydrocortisone, prednisone, prednisolone, methyl prednisolone. It's really only dexamethasone, maybe betamethasone, and some things we don't generally use orally. When we say cross the placenta, it's that they're not inactivated well by the 11-beta-HSD2 enzyme. So prednisolone gets converted to prednisone, which is not an active drug, which is why I don't use it much, as it crosses the placenta, because the enzyme metabolizes it back to the inactive prednisone, and the fetus gets exposed to the inactive drug. The easier way to think about it is dexamethasone does cross the placenta, and betamethasone by design is given to get to the fetus. So everything else you would typically use would be okay. Yeah, well, or beta-methadone is what the OBs have been traditionally using, but they give it particularly for that reason. It gets across the placenta. It has an active agent when it gets to the fetus and helps surfactant mature in the fetal lungs. There was a question in the back, I thought. Yes. You're asking about 21-deoxycortisol and using it to monitor treatment. Well, okay, Phyllis, you want to handle that? I don't think there are any published reports on the use of 21-deoxycortisol for that purpose. So we're still looking at a panel of hormones and generally it would be 17-OHP, which is not the most reliable. Androstenedione was a little more stable as a marker and in the pediatric population, in the older women, it would be a testosterone measurement as well. And in the classic patients, particularly if you're monitoring their fludrocortisone treatment, you want to look at plasmarin inactivity. And we did a study with Debbie Merck where we looked at the 11-oxygenated androgens in kids where there's discrepant biomarkers because we always have these cases where this is high and that is low. Which is it? And you don't really know. And we were actually able to adjudicate most, but not all, of the cases with 11-ketotestosterone and so on. So I think that, you know, I think the panel approach is still better. It would be even better if we could use drugs that would get people in control. We didn't have to measure all these things, but we're not there yet. And you can get those 11-ketotestosterone measurements at Esoteric's lab and possibly other commercial labs. Right. Currently, I know of Esoteric's lab course offering that commercially. Yes. How often do you see adrenal crisis in these patients? Yeah. So, I mean, I think there's some good data from Europe about this. You know, that adrenal crisis is still the number one cause of death in CAH patients, both in children and adults, even if they're educated, even if they have injectable hydrocortisone and live in a metropolitan area. It's still, and I know we have some patients in the room, and it's a terrifying experience. So I think that that education is still an issue. Whether they have fewer than Addison's patients, maybe slightly fewer, because they have, you know, the progesterone from their adrenals can be metabolized by the liver to deoxycorticosterone, which has a little mineralocorticoid activity. So they have a little bit of a safety net. And some of them, especially with the Intron 2 or the I-172N, they have a little bit of activity and make a little bit of cortisol. So, but, you know, when they get sick from a GI illness, when they're throwing up and they can't control their volume and they can't keep their pills down, they need to take their shot and get to the emergency room. So it is unfortunate that people still die from adrenal crisis. Well, I think everybody wants to, oh, there's one more question over here. So, the question was, how low do you need to get the 17-Hydroxyprogesterone? Oh, okay. Okay, there's some more questions. Okay, sorry. They came in after I stopped looking. So, the question was, how low do you need to get the 17-Hydroxyprogesterone? All right. So, Phyllis, in children? Yeah, we're reluctant to suppress it into the so-called normal range for age and gender. So, I think we're most comfortable when it's slightly above normal. So, again, we're not looking at a single value. We're looking at values over time. We're looking at usually a panel of hormones that will give us an idea of where we stand. And, of course, we look at the growth curve. We look at bone age from time to time. And, as I said before in the case discussions, we don't want to use any single value to make a therapeutic decision without considering the whole picture. So, 17-OHP, as I alluded to earlier, is not the most stable of the biomarkers. And we probably favor the androstenedione as a more robust marker. Right, and has a lot of pathways for its metabolism. So, it's sort of the tip of the iceberg. And you don't know which ways it's going to 21-deoxycortisol, to androgens, and so on. This is a good question for Anand. How do you manage an infertile male with adrenal rest tumors on testicular ultrasound and poor semen analysis? Prayer, mostly. Yeah, well, that patient, I thought he was going to have adrenal rest tumors because his control was so poor when he came to see me, but he didn't. I would have actually started the same strategy. I would have really tried to lower the ACTA 17-OHP and get biochemical control and hope that there would be reduction in the rests. And if not, then we'd have to go get our urology colleagues involved and see if we can deal with it surgically. But I would try to normalize biochemically first and see if we can get resolution that way. Right, and then you have the issue of looking at both the shrinkage of the rest and the restoration of the normal sperm, and then which one's more of an issue. So, I think we answered that 17-OHP question. There's two questions. There's one. Well, hold on one second. I'm going to take two from the board first. There's two questions about tildesifon and crinesifon. One about any concerning adverse events in the published trials. There wasn't really anything seen consistently. And the related question that says, assuming approval of either or both of these drugs for classic CH, who wouldn't you prescribe them for? Well, somebody who's on a physiologic dose of hydrocortisone and well-controlled and normal fertility, no androgen excess, and good luck with that. And so, yes, go ahead. What happens to these patients when they get COVID? Well, you know, COVID, some people get GI manifestations and diarrhea and vomiting, and they need stress dosing, hospitalization. A lot of them are getting dexamethasone now. So, they call me from the hospital, like, are you going to give them dex? They say, yeah. Well, then don't worry about it. You know, they give them six milligrams of dex and they're covered. But others, you know, just have the upper respiratory tract and sore throat like I did. And if they call me, I wouldn't stress dose that because I tell them to stress dose like you would for an illness that wasn't COVID, right? You know, because it's not about whether it's COVID or not COVID. It's do you have diarrhea, vomiting, volume depletion, high fever, or do you not? And if you just have a head cold and a low-grade fever, you don't need stress dose. So, yeah, but that's a good question. And, you know, if they have pulmonary symptoms, they're going to get dex. Yeah, I would say during these last three, I have a very large population of patients with Addison's or primary adrenal insufficiency that's not autoimmune. And we really bolstered our sick day teaching for them. That was previously for flus and GI illnesses. And I think all of them probably got COVID during those last three years, almost all of them. And only one was hospitalized. Almost all of them staved off hospitalization by doubling, tripling dosing. And we gave the same advice to our patients with classical CH, and they did the same thing. Go ahead. Yeah. Right, right. So the question is, is there like a long COVID affecting the HPA axis and so on. I haven't noticed anything. No. Okay. I've had several CH patients come down with COVID. And I think it's interesting to think like what happens to the axis in general, like you know, does their control deteriorate because they have a significant febrile illness and things like that. But that's short term. I'm not aware of any long term complications. Okay. In the back. Well, that was that BPP-631 at the bottom there. It's actually just getting started. I mean, conceptually, it's great because, unlike the other treatments, it actually will restore cortisol production, right, which is where the home run is. But, you know, the systemic agent is delivered, and then it will get to the adrenals. That's been shown in animal models. But it will also go to other places, and it has to be expressed long term. So, if it works, it's great, but it's too early to know. Yeah. think everybody wants to go watch the baseball game at this point. So, I want to thank Dr. Vijay and Dr. Spicer for their excellent presentations and I want to thank you for your attendance and your participation. Oh, actually, there is, oh, so there are... People keep coming in. So there's two more questions. How often should we do imaging for adrenal rest tumors? Anand, what do you do? I do ultrasounds every two years in men and kind of a little bit less predictably in women, but roughly every two years. Yeah, I make sure they have a baseline when they come to as adults. And then if they don't have any and they're in good control, I don't necessarily re-image. If they have them, I do every two years, yeah. I think it's pretty similar in the pediatric population, but they have been shown in fairly young children. So if you have a patient who comes to you and had been out of control for some time, then I think it's worthwhile to think about it. And certainly when they get to a peripubertal age, you should get at least one baseline to look at that. Right, and somebody's asking about MC2R antagonists. That's just getting going. So we don't have any data on that yet, but it's also, it was on the list of possibilities of, yes, and you had a question? In women? Yeah, so do you do any imaging routinely in women? And I don't. I mean, not routinely. In men, I'll use ultrasound. In women, if I do imaging, it is ultrasound. Yeah, but it would have to be like, you know, for amenorrhea, like it would be like a woman that you would do an ultrasound for if they didn't have CH, you see? So like, you know, like they have amenorrhea and they don't respond to a progestin withdrawal. And you want to know, are they blocked? Do they have an endometrial stripe? You know, then you would do a vaginal ultrasound or an HSG. But I don't think we routinely image the women. I think if everything is going well, then I think it's easy to not image, but usually things are not going well when they're seen. Well, yeah, that's right, yeah. There's always things to think about, and I do keep it on the annual checklist of things. So, you know, every once in a while, if your 17 OHPs are way up there, there's medication adherence issues, a whole broad series of complaints and lifestyle issues that change with every decade of life. I do keep it on the list because periodically, just knowing that there aren't any rest tumors or that they are does change my management. When 17 OHPs are that high, you just don't know what the chronic effects are. So I think there is a reassurance, at least for me practicing, to know that that's not an issue and we can focus on the other things that we can see. Might be overkill, it's true. Yeah. What's the problem with rest? In women? Well, no. In men. So, you know, the testis is confined to a capsule. So if you have a mass growing, it impairs the blood flow to the normal cells. And so they can have high FSH. So, you know, every time I get, see somebody with rest and I measure the first gonadotropins, I hold my breath, you know, and I pray that they're low, like in that case. But if they're high, it's too late. And you know, you're not going to recover function at that point. So that's why testicular rest are particularly bad. Ovarian rest, we actually don't know how common they are. They're probably as common as adrenal rest. But they're harder. You can't palpate them, right? And we don't routinely image them. And the ovary has more room to grow in the retroperitoneum. But I think what Anand was saying is that it's additional mass of tissue that's making androgens. And so if you're having really hard control, that could be one reason why. And the fertility, just the underscored fertility, oligomenorrhea, fertility, and then mass effect. Not to mention the fact that they can grow quite large. They may be very hard, and these people may end up in the hands of a surgeon, not realizing what the condition consists of. Well, I had one patient who, you know, had rest tumors. The pediatric endocrinologist that referred them to me knew he had rest tumors. And you know, he was seen by a urologist at an outside hospital close to town before he got to me. And the mother told the urologist that he has 21-hydroxylase deficiency. Do you think this is related to it? He still got both his testes removed. Yeah, I have the same situation. Yeah. I think, yeah, so good question. The question was, do drugs that lower ACTH have any effect on pigmentation or vitamin D metabolism? I think if people are hyperpigmented, that should reduce. But again, even when we use glucocorticoids to lower ACTH, people don't get hypopigmented. Vitamin D metabolism, we know the effect of glucocorticoids on vitamin D absorption. But I'm not aware of any effect on like hypopituitarism on causing vitamin D absorption. There's another question. How do you work up a woman with an elevated DHEAS but normal testosterone to rule out CAH, any role in CAH patients? So yeah, elevated DHEAS is typically PCOS. But if they come to you, I'd work them up like you're supposed to work them up. You get a stimulated 17-hydroxyprogesterone, baseline follicular phase 17-hydroxyprogesterone and ACTH stimulation test if it's borderline. If it's normal, they don't have CAH. Do you see Nelson syndrome? No. Well, I think, Chairman Dowery, the question was Nelson syndrome. But there was one case report that I'm aware of from Greece, Chairman Dowery, of a corticotrope adenoma. Like, if a patient with CAH had Cushing's, how would you know? Right? I mean, how would you know? Because they don't make cortisol. And so there was one example of a very difficult to control person who had a corticotrope adenoma. And I have had one patient with Addison's develop a corticotrope adenoma. So it does happen. But it's not Nelson's. You know, Nelson's is, like, invasive, you know, vision loss and stuff. They're just, you know, modest-sized adenomas. Well we've managed to get down to the last minute of the time. I think we'll adjourn here. If anybody has any other questions, we'll be around for a little bit. Thank you all for coming and participating.

congenital adrenal hyperplasia

CAH

management

fertility

glucocorticoid therapy

pregnancy

anti-androgen

adrenal androgen production

gonadotropin therapy

in vitro fertilization

adrenal function monitoring

classical CAH