Hello, everyone, and welcome to our first session of ITE 2025 Live. My name is Hannah Gittner. I am the Director of Education Development and Learning Technology for the Endocrine Society. And I just want to thank you all so much, both for your participation in the in-training exam as well as the Fellows Training Series. So the purpose of today's presentation is just to go over a selection of cases that were included in this year's in-training exam. And so, Madeline, if you want to advance the slides for me, thank you so much. And before I hand it over to our fantastic chair, Nicholas Tritos, I want to just first thank all of the faculty as well. Madeline, if you could proceed. This is our full faculty list who really dedicate a lot of time to developing all of these cases from all of these clinical areas. And it takes a significant amount of time over the years. So a big thank you to all of them. Advance the next slide. Just a quick review of everyone's disclosures for full transparency. You can proceed. And so without further ado, actually, before I hand it over to Nick, a quick a few administrative points before we kick off the case review. For questions about each of these cases, we are having a dedicated Q&A session at the end. However, we encourage you all to submit your questions through the Q&A option at the bottom of your window. So please feel free to submit those in real time as you think of them. And we will address those at the end of the presentation. All right. And without further ado, I will hand it over to Nick Tritos. Thanks so much, Hannah. Good afternoon and welcome, everyone, to the IET live session. I'm Nick Tritos from US General, the IET chair. I would like to thank our dedicated and extremely talented faculty who have really done a tremendous job working on the IET exam year after year, as well as our extremely dedicated and wonderful staff, especially Hannah and Madeline, who have done an extremely good job. So thank you to everyone. And thank you all for being here. So just to remind us all that the IET exam should be treated as a learning exercise by programs rather than a formal high-stakes knowledge assessment, it can be used to provide a general picture of fellows' knowledge base in endocrinology. And review of questions can also help identify gaps in individual fellows' knowledge, but also potential gaps in a program's curriculum. Next slide, please. So this year, we had 804 participants who took the IET examination. And you can see that the average score was 55.2%. There was obviously a range between 44% and 88%. And it's nice to see that there's improvement in scores from first year onwards of training to second year, reflecting improvement in experience and understanding of the endocrine field. There were a few third-year fellows, understandably a much smaller number. Next slide, please. And these are this outline of performance data by topic area. And you can see a number of questions, number of correct answers, 2025, 2024, and before by topic. Clearly, some areas seem to be better subscribed to than others in terms of the correct responses. Some need more attention, perhaps. But I think, again, this is a knowledge assessment tool and a learning exercise. And we hope very much that it helps our fellows and our programs get better. You can get this information and much more through the program coordinators at each training program. That information is available through the endocrine society and the fellowship coordinators. Next slide, please. So today, we're going to be covering topical questions on lipids, obesity, followed by reproduction, male and female reproduction, and then bone. And then at the end, we hope to leave enough time for a Q&A session. So please put any questions in the chat. Without further ado, I would like to pass on to Dr. Dave Saxon, who will review some of the questions on lipids and obesity. Dave. Thanks for having me here. Pleasure to be here. And unfortunately, Rashmi Srinath cannot make it, but I want to acknowledge her for her great work over the years on this section. And I'll be representing our team today for the lipids, obesity section. You can go to the next slide. So I'll read you guys the questions. So this is question one for lipids, obesity. So it's a 20 year, 22 year old woman with class three obesity, complicated by obstructive sleep apnea, impaired glucose tolerance, and polycystic ovary syndrome who underwent gadget bypass nine months ago. She can tolerate small, low carbohydrate meals and has lost more than 50 pounds or 22.6 kilograms. Her current BMI is 36, which is down from 45 before surgery. Her menses are now regular, and she and her husband are interested in pregnancy. She's adhering to a regimen of daily replacement supplements, including a chewable multivitamin sublingual vitamin B12, calcium citrate, vitamin D3, and iron. Next slide. So the questions, or the question, which of the following is the most appropriate advice for this patient regarding pregnancy planning? A, avoid pregnancy until she is weight stable. Use a non-oral contraceptive agent. B, proceed with pregnancy as long as her hemoglobin A1C levels in the reference range, meaning less than 5.7%. C, proceed with pregnancy as long as she increases vitamin supplementation dosages to those recommended during pregnancy. D, proceed with pregnancy, but advise her that breastfeeding after gastric bypass is contraindicated. Or E, proceed with pregnancy, but no need to monitor nutritional or micronutrient status. So we'll give you the answer here. We'll take a second to think about it. And we can go to the next slide. So the answer is A, avoid pregnancy until she is weight stable. Use a non-oral contraceptive agent. And you can see about 55% of people answered this correctly. So we'll go to the next slide that has an explanation. So the rationale for this. So you should all know that non-oral or intrauterine devices are preferred in this situation when someone's had recent bypass surgery. Procedures that create malabsorption such as biliopancreatic diversion, jejuno-allele bypass, or Roux-en-Y gastric bypass may interfere with the absorption of oral contraceptives, thereby reducing their effectiveness. So that's why A is the preferable answer. Why are the other answers not correct? Pregnancy during the time of active weight loss after bariatric surgery is just not recommended. There was a 2013 clinical practice guideline from the American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic and Bariatric Surgery which recommended that women avoid conception for 12 to 18 months after bariatric surgery because this time frame is when women are still actively losing most of their weight. This delay is advised in an effort to optimize weight loss and reduce the potentially adverse effect of post-bariatric surgical nutritional deficiencies. Okay, I would recommend, you know, if you have questions about these, since we're doing questions at the end, go ahead and jot down some notes that you might have and we'll come back to things. But that's the answer rationale for this one and we'll move on to the next. Great, so question two, a 52-year-old man with a history of coronary artery disease status post-stent placement in the right coronary artery seeks consultation for lipid management. His father had coronary artery disease in his late 40s. He has a history of atrial fibrillation, hypertension, and prediabetes and quit smoking 10 years ago. Following stent placement, he was prescribed atorvastatin 80 milligrams daily, was only able to tolerate 40 milligrams daily because of myalgias. Azetamide was subsequently prescribed to achieve target LDL cholesterol levels. His six-month follow-up LDL cholesterol measurement is 90 milligrams per deciliter. He has not been tolerant of evolocumab or allerocumab due to severe injection site inflammation and swelling. Next slide. Which of the following steps would be expected to lower this patient's LDL cholesterol to target for secondary prevention? A, change atorvastatin to resubastatin 20 milligrams daily, B, start bempedoic acid, C, start phenofibrate, D, start icosapent ethyl 2 grams twice daily, or E, start niacin. Go ahead to the next slide. So the answer is start bempedoic acid, and I'll go through the rationale here. Next slide. So firstly, changing atorvastatin to resubastatin would not necessarily cause much more incremental LDL cholesterol lowering that's needed to achieve this patient's targets. I'll just editorialize here for a second. One thing they don't tell you is what would this person's target LDL cholesterol be. There can be arguments and some subjectivity to that. Everyone would say it should certainly be an LDL cholesterol less than 70, but some of our guidelines have moved now towards LDL cholesterol levels less than 55 milligrams per deciliter. So you're certainly trying to get down at least 20 milligrams per deciliter here from starting at 90 milligrams per deciliter, but potentially even trying to cut that LDL cholesterol about in half. So bempedoic acid is the correct answer, and that, as a reminder, is an inhibitor of adenosine triphosphate citrate lyase, which is an enzyme that's upstream from HMG-CoA reductase, which is the target of statins. And another thing I'll say there is that this drug does not work on the muscle. It's a pro-drug, and for that reason, it doesn't have the potential muscle side effects that we see with statins. So in the CLEAR-WISDOM trial, the primary efficacy endpoint of the percentage change in LDL cholesterol from baseline to week 12 was significantly lower with bempedoic acid than with placebo. Specifically, you should know that bempedoic acid alone, when given, lowers LDL cholesterol by about 20%. That medication also comes as a combination with azetamide. So if you, the person was not on azetamide previously, and you started the combination pill of bempedoic acid plus azetamide, that'd be a 40% LDL cholesterol lowering with that. So in this case, we're just starting bempedoic acid, we'd expect about a 20% lowering. There are two other lipid lowering agents listed, phenofibrate and niacin. Those have not been shown to reduce major adverse cardiovascular events in patients for secondary prevention. That's why those are incorrect answers. And then icosapent ethyl decreases elevated triglyceride levels, but not LDL cholesterol. Two more points I'll make here that are not on the slide, but I think are worth knowing. So another answer choice that could have been given here would have been a drug called Inclisirin. Some of you may be familiar with that. It's an injectable medication. I kind of think about it as the denosumab for lipid lowering, because it's something that's taken every six months. It lowers LDL cholesterol by about 45 to 50% in clinical trials. And for patients who are intolerant to the drugs of this person, in the example, were intolerant to evolocumab and alirocumab, that's actually a potentially a decent option choice. So it wasn't a choice here, but it could be on a future test and something you should know about clinically. The last editorialized comment I have is about icosapent ethyl. It's important to know about what's called the REDUCE-IT trial, which was published in New England Journal a couple of years ago. That's a trial that looked at people with high-risk diabetes or secondary prevention patients, patients who'd had heart attacks and strokes before. And when those patients had triglycerides between about one, or not about, when they had triglycerides that were moderately elevated between 150 and 499, and already were on intensive lipid lowering therapy, they found that adding two grams twice daily of icosapent led to reduced cardiovascular events in those patients. That drug does not lower LDL cholesterol, which is the goal here, but there could be questions regarding using icosapent in people with CVD where that could be the right answer. Great. So thanks for bearing with all that, but I wanted to clarify some things and teach a little bit. We can move on to the next question. Question three. 44-year-old man with a history of type 2 diabetes, dyslipidemia, hypertension, and a BMI of 38 presents for counseling regarding his weight and related conditions. He reports reduced energy and low back pain, but is otherwise asymptomatic. He does not use tobacco or drink alcohol. His medications include metformin, atorvastatin 40 milligrams daily, and lisinopril 10 milligrams daily. Next slide. His A1c is 7.2%, LDL cholesterol 95 milligrams per deciliter, triglycerides 320 milligrams per deciliter, and his liver enzymes are normal. Next slide. So the question is, which of the following is the best initial approach to evaluate for metabolic dysfunction associated steatohepatitis in this patient? A, assess for secondary causes of liver fibrosis, including alcohol history, hepatitis, and medications that cause liver steatosis. B, calculate a FIB4 score and consider liver elastography. C, no need to evaluate liver for non-alcoholic steatohepatitis as his transaminase levels are normal. Or D, perform liver ultrasound and prescribe vitamin E as he had high risk for non-alcoholic steatohepatitis. Next. So the answer is B, which most people got right, which was calculate the FIB4 score and consider liver elastography. Next slide. So the rationale here. So although it's important to check for secondary causes of liver fibrosis, which was answer A, this choice does not best address direct assessment of metabolic dysfunction associated steatohepatitis. Second part, screening for metabolic dysfunction associated steatohepatitis, answer B, which is the correct answer, is critical in overweight patients with type 2 diabetes because liver steatosis can progress to liver fibrosis and hepatocellular carcinoma. The next one, metabolic dysfunction associated liver disease or steatohepatitis can be present even when liver transaminase levels are normal, answer C. And then liver ultrasound, answer D, can detect steatohepatitis but does not assess for fibrosis. There's insufficient evidence to recommend use of vitamin E in patients with diabetes. So that's what we have here. And I'll stop there. Thanks so much, Dave. Again, please put any questions in the chat. Next slide. I would like to call upon Dr. Aarti Thirumalai, please, to go over the reproduction questions. Aarti? Thank you, Nick. So yes, thank you, everyone, for joining us today. And I wanted to shout out to Matthew Kemm and Terry Shin, who helped put this section together for male and female reproduction. Next slide, please. So first, we'll look at the questions on male reproduction. Next slide, please. So this is a 35-year-old competitive bodybuilder who is referred for management of infertility. He reports that he has used androgenic steroids since his early 20s, so 15 years of duration now. He typically takes multiple androgens for 12 to 16 weeks, followed by intramuscular testosterone cypionate at a dosage of 125 to 150 milligrams every week for about 8 to 12 weeks. So in addition to some other androgens, even the testosterone that we normally use for hypogonadal creatinine, he is doing at supraphysiologic doses, because the weekly dose is usually about 100 milligrams. He and his wife of two years would like to conceive, so he stopped all of the androgenic steroids about one year ago. He is now reporting low libido, but he and his wife have had unprotected vaginal intercourse one to three times weekly for the past year. He has no history of medical illnesses and takes no medications. Next slide, please. Physical examination. His blood pressure is 128 over 80, pulse is 68 beats per minute, respiratory rate is 12. He has a height of 71 inches and a weight of 144 pounds with a body mass index of 20.1 kilogram per meter squared. He has two and a half centimeters, so about an inch of non-tender gynecomastia. His JVP is normal, heart exam is pretty much normal, no edema. On andrologic exam, he has bilateral 12cc testicles that are normal. He has palpable bilateral vas deferentia and he has no hyperpigmentation. Next slide, please. His lab results show you a hematocrit of 39%. A total serum testosterone is 220 nanogram per deciliter, so a little below normal. This is measured in an assay that has been validated and harmonized by the CDC, and this is important to look for when you're looking at testosterone values because not all assays are reliable. This was repeated, which is the correct thing to do. I always get two measures of total testosterone and make sure you're getting it in the morning, so 7.30 a.m., so before 8 a.m. is what we recommend and usually fasting, and the second one was also low at 206 nanogram per deciliter. And we recommend looking at a calculated free testosterone, not a measured free testosterone, and this was also confirmed to be low. His sex hormone binding globulin is on the low side of normal. His FSH is 2 and LH is 2. His thyroid function tests are normal, prolactin is normal, and his seminal fluid analysis shows 50,000 sperm per mL when the normal is over 15 million per mL. He has a brain MRI that shows a normal pituitary gland and no masses. Next slide, please. So the question is, which of the following is the best recommendation for this patient at this time? Remember, they're trying to conceive, and your options are A, daily oral anastrozole, B, daily oral clomiphene, C, HCG subcutaneously three times weekly, D, reassurance and watch for waiting with serum hormone measurements and seminal fluid analysis every three months. E, referral to a specialist who performs microscopic testicular sperm extraction. Next slide, please. So the correct option is option C, HCG that's administered three times a week, and the majority of people who took the test got this correct. So let's move to the answer slide, please, to look at the rationale. So aromatase inhibitor therapy or anastrozole has been shown to be effective in patients with obesity and obesity-related hypogonadism, but there's really no conclusive data for men who have dyspermatogenesis or subfertility due to a suppressed hypothalamic pituitary testicular axis from chronic androgenic steroid abuse. So there's very little data to support the use of aromatase inhibitors in this population. And then the other thing to remember is that aromatase inhibitor therapy can have significant adverse effects on a man's bone health as well as body composition. So this would not be the correct answer. Selective estrogen receptor modulators such as clomiphene can be useful and they may help restore the hypothalamic pituitary testicular function as well as fertility for men who are recovering from chronic androgenic steroid abuse. However, the evidence to support their use is relatively weaker than that with HCG. The time that it may take to get the desired sperm response may be slower compared to gonadotropin replacement therapy. And so that would not be the correct answer. And another thing to remember is that clomiphene therapy also comes with the potential risk of venous thromboembolism which is not seen with gonadotropin replacement therapy. So when we look at HCG, it is basically simulating the same effect as LH in the male body and it helps stimulate testosterone as well as sperm production in the testicles. And it raises the intratesticular testosterone considerably and therefore it is the most effective at raising sperm concentrations enough for fertility in a short period of time. So it's going to give you the most rapid response and in someone who's already been trying for a year and the partner is getting up to the age of 35, you really want to move fast on this and so this would be the correct answer. Watchful waiting, as I said, is not really the best option here. This would have been okay a year ago when he was just coming off of the steroids and then you would monitor testosterone, gonadotropins and potentially sperm counts every one to three months. But now that he's been a year out from therapy, men who've been abusing androgens for definitely more than a year and in this case, almost 14 years, they can be hypogonadal and have decreased fertility for a few years before their spermatogenesis recovers to normal. And so this may be too late given the female partner's timeline for reproduction. Surgical extraction would not really be necessary in a person who's already gotten to 50,000 sperm per ml, but we definitely want to increase the sperm count as much as possible. And usually when they get to about three to 15 million, they usually have a higher chance of success. This person is still below that so HCG therapy would be recommended in this person but we wouldn't require surgical extraction or those type of artificial reproductive techniques. I will also add that HCG therapy alone is usually sufficient for the vast majority of men, especially if the combined sort of testicular volume of both sides is over 16 CCs. If, however, in about six months of HCG therapy, you're not seeing the desired sperm response, you can add FSH therapy at that point. Next slide, please. Yeah, thank you. So this is the next question. This is a 65-year-old man who is noted to have marked bilateral gynecomastia and a goiter on routine wellness exam. The patient states that gynecomastia has been present for many years and it does not bother him. He has no history of thyroid disease. He reports good health and states that he takes no regular medications apart from a variety of dietary supplements. He is married and has fathered two children who are now in their 30s and he recalls having normal pubertal development when he was younger. On physical exam, he appears well. On palpation, he has firm symmetric enlargement of glandular breast tissue that is three inches, so that's pretty dramatic, the gynecomastia. There is no axillary lymphadenopathy or distinct breast mass lesions. Testicular volume is 10 cc's bilaterally and no masses are detected. There is no clinical visual field defect and he has full range of eye movements. Next slide, please. His lab results, which were measured 8 a.m. while fasting, show normal thyroid function. His total testosterone is significantly low at 50 nanograms per deciliter and when repeated a week later is still very low at 60 nanogram per deciliter. His sex hormone binding globulin is quite elevated at 12.3 microgram per mL, so almost double the upper limit of normal. His LH is considerably suppressed at 0.2 millius per mL. Kidney function, electrolytes, liver function are normal and his DEXA scan shows a normal bone mineral density with positive T-scores. Next slide, please. So the question is, which of the following is the most important diagnostic test to order now to evaluate his gynecomastia? And your options are A, karyotype analysis, B, serum DHEA sulfate measurement, C, serum estradiol measurement, D, serum prolactin measurement, and E, testicular ultrasonography. Next slide. The correct answer here is option C, which is serum estradiol measurement, which interestingly was not the correct not the answer picked by the most people who took this test. So let's go through the rationale on the next slide, please. So the karyotype analysis or option A is really ordered to look for Klinefelter syndrome, but remember that Klinefelter syndrome is a cause of primary hypogonadism and you would have seen elevated gonadotropins in such a patient. Klinefelter is a common cause for gynecomastia, but those patients, as I said, have primary hypogonadism with elevated gonadotropins. They usually are infertile through their lifetime, whereas this person had a history of normal fertility. And Klinefelter's patient, given again a lifetime of hypogonadism, you usually have low bone mineral density and this person had very good bone mineral density. So option A is incorrect. Now option B, which was DHEA sulfate is not an important initial test when evaluating gynecomastia. The only condition in which this would be elevated they happen to be feminizing adrenal tumors, which are then co-secreting DHEA sulfate as well. Now these are extremely rare, very aggressive, and they can co-secrete adrenal androgens along with feminizing hormones. But this picture doesn't sound consistent with that because remember this person had had a very long duration of gynecomastia that had not been bothersome. So serum estradiol measurement would be the correct answer, which was option C. The reasons for that are as follows. The cues in this case that cue you to excess estrogen exposure are A, this person had pretty dramatic gynecomastia, three inches. Usually you see just about half to one inch in size of gynecomastia. So without some excessive estrogen exposure, it's very rare to get gynecomastia to this extent. And the second thing is that this person had a markedly elevated sex hormone binding globulin, which happens with estrogen exposure. And then thirdly, the bone density on the deck side looked extremely good and positive despite severe hypogonadism. And estrogen is what is very helpful for bone health and even in men. And that's where all of the cues in this case are leading you to think about excess estrogen in this male's body. And in this case, it happened to be actually exogenous estrogen exposure. Option number D, which is prolactin is incorrect because the prolactin excess would not really explain the degree of gynecomastia this person had, the highest HPG or bone mineral density preservation. And then the option E of suspecting a testicular tumor doesn't make any sense because there's no real testicular masses. It's not enlarged. So an ultrasound is not really indicated here. Next slide, please. So with that, we're gonna pivot to the female reproduction questions. So next slide. So the first question is a 24-year-old woman who presents with a change in her intermenstrual interval. Menarche was achieved at 13 years of age and she had regular menses during her high school and college. She took an oral contraceptive pill from age 20 to 22 years. And after stopping the oral contraceptive, she initially had 28 to 30-day cycles. But more recently, she has been having menses every 22 to 23 days. She has autoimmune hypothyroidism and takes a stable levothyroxine dose. She exercises for about one hour, three times a week. She has mild acne, no hot flashes, and no galacteria. Her body mass index is 20 kilogram per meter squared. Next slide. Her lab results, which are drawn on cycle day three, show an FSH of 20 and LH of 60, both of which are considerably elevated for when in her cycle she is. Her estradiol is on the lower side at 28 picograms per ml. Her anti-malarian hormone or AMH is again at the lower end of normal at 0.9 nanograms per ml. And remember that AMH is sort of an indicator of ovarian reserve. Her TSH is normal. The karyotype is normal at 46XX and FMR1 gene testing was negative for any premutations. Next slide, please. So which of the following is the most important next test to perform here? Options are A, GAD-65 antibodies, B, IGF-1, C, inhibin B, D, serum ovarian antibodies, and E, 21-hydroxylase antibodies. Next slide. And the correct answer is option E, 21-hydroxylase antibodies. And there was a pretty even split among test takers between D and E. So let's look into why the correct answer is E. Next slide. So what would the GAD-65 achieve here? That would maybe give you insight into this person's risk of developing type 1 diabetes down the road, but that's not really essential either to make the diagnosis of why she's having her menstrual changes or other risks in the current moment. So that would not be the correct answer. IGF-1 measurement would really not be helpful in someone who's having menstrual changes, but not really showing you any signs of sort of acromegaly. Inhibin B levels, now this is an interesting one because in patients who have autoimmune premature ovarian insufficiency, inhibin B levels are actually normal. So they don't really help you make that diagnosis, but they can be low in women who have primary ovarian insufficiency of other causes. And the affected women often will present with serum LH concentrations that are higher than FSH concentrations like here. So in autoimmune oophoritis or as a cause for primary or premature ovarian insufficiency, there isn't really much utility for the use of serum ovarian antibodies. These are usually measured with an indirect immunofluorescence assay, but it has a very poor predictive value for autoimmune premature ovarian insufficiency. And the presence of these antibodies, they can be present even in women without POI, and they're not really the most sensitive way of diagnosing this condition. However, because in this person she had another autoimmune condition, Hashimoto's, and she's now presenting with elevated gonadotropins, low estrogen, menstrual irregularity, she is behaving like someone who is developing autoimmune premature ovarian insufficiency. So once you've sort of presumed that diagnosis, you have to understand that a lot of these patients they need to be screened for autoimmune adrenal insufficiency because about 3% of patients will go on to develop autoimmune adrenal insufficiency. And so 21-hydroxylase antibodies are actually a good screening test for patients with autoimmune primary or premature ovarian insufficiency. And about 50% of women who have 21-hydroxylase antibodies that are positive will go on to develop actual adrenal insufficiency. And so then you would test for a cosyntropin stimulation test as well. So the antibodies are a good screening test. Now this patient had already had a karyotype that would have been done for POI evaluation to look for turners. This patient had already had a fragile X syndrome screening. Those are all important other steps. So the next step in this person was the 21-hydroxylase antibodies. Next slide, please. So our last case here for Repro is a 19-year-old patient who was referred to discuss transgender hormone therapy. The sex assigned at birth was male. The preferred pronouns in this case are female. She has disclosed her gender dysphoria to family and close friends and is seeing a therapist. For the past year, she has experimented with wearing makeup and dressing in feminine clothes on the weekends. Her medical history is notable for heterozygosity for factor V Leiden pathogenic variant, which was identified on screening after her mother had a non-provoked pulmonary embolism. She does not smoke cigarettes and takes no medications. Her therapist is supportive of her decision to start hormone therapy to alleviate her gender dysphoria. Next slide, please. Which of the following would be the most appropriate initial hormone regimen for this patient? Your options are Luprolide, which is a GnRH agonist at 3.75 milligrams IM, along with Estradiol 50 micrograms by transdermal patch. Option B, Luprolide with Estradiol two milligrams orally. Option C, low-dose birth control pill containing 20 micrograms of ethanol estradiol and rosperinone plus spernolactone. And option D, spernolactone plus finasteride. Next slide, please. The correct option here is option A, which is the GnRH agonist Luprolide along with transdermal estrogen, which was the correct answer that was selected by 47% of test takers, but let's look into the rationale. Next slide. So this is a patient who wants gender affirming therapy for transitioning to female. And the important thing to remember is the factor V Leiden mutation in this patient really changes how you decide which agents to pick. So patients who have a factor V Leiden mutation or a family history of thromboembolism are at higher risk for venous thromboembolism themselves on estrogen therapy. However, this risk is specifically associated with the use of oral estrogen formulations. And that's why answer B would not be correct because the risk of VTE would be high in this person, almost six fold elevated with the use of oral estrogen preparations. This actually is also true for ethanol estradiol, which is a synthetic estrogen. And so this also option C would also be avoided, right? However, transdermal preparation such as the estrogen patch has not actually been shown to increase VTE risk because it bypasses the liver and therefore doesn't lead to an increase in clotting factors. So that will be the safer alternative. Now, the reason we picked option A over D is so just using spironolactone or spironolactone with finasteride would not be feminizing enough as a therapy. And so what you really need is something that blocks their endogenous to androgens, which preferably is the GnRH agonist like luprolide. And that allows you to get away with a lower dose of estrogen to get the desired feminizing effects. And that is why option A is the correct answer. With that, I thank you. You can move on to the next slide. Thank you. Thanks so much, Arthi. And again, please be reminded to put any questions in the chat and we will get to them at the end of the session. I'd like to call upon Dr. Partha Sinha to review the poll questions. Partha? Hello, thank you so much, Dr. Traitos, and welcome everybody. My name is Partha Sinha and I just wanna acknowledge the other members of our team, Dr. Alan Malabanon and Dr. Jad Spheer. Working with them to come up with these questions and a great experience and wanna acknowledge their outstanding contributions to this. So with that, we can begin if you can go to the next slide. So this is a 28-year-old woman, G1 para-zero, currently at 11 weeks gestation, presenting with nausea and vomiting. She was told that she had mild hypercalcemia a few years ago, but had no follow-up from that. She reports she's feeling tired. She generally is arousable. Next slide, please. And here are her laboratory results. We see her serum calcium is frankly elevated at 13.9 milligrams per deciliter, and she has an elevated parathyroid hormone at 75. The rest of her labs are remarkable for a moderately elevated activated vitamin D at 125 vitamin D. She has normal kidney function and also nodal and urinary calcium is also elevated at 321 milligrams on a 24-hour urine collection. When they correct the calcium for the albumin it's still markedly elevated at 12.9. She was given intravenous fluids. She did feel somewhat better at that time. Next slide, please. So which of the following choices would you pursue to match this patient's disorder? The first choice being Sinocalcite, the second choice being Denosumab, third choice being surgery, parathyroidectomy to be done in the second trimester, D, parathyroidectomy urgently or now, or E, prednisone. So I'll take a few, a little bit to think about it and choose your answer. And we can go ahead to the next slide. Yeah, so the correct answer is C and the majority of you got this correctly that pursuing parathyroidectomy the second trimester is the best and actually a safe option for this patient. So if we go on to the next slide and go with the rationale of each of these choices. So Sinocalcite is currently a category C in pregnancy. It does cross placenta. There really is a very limited experience with this medication. So I would have best to avoid this medication in pregnancy. Bisphosphonates or any anti-resorptive during pregnancy should really be avoided. They're both category D as they could have an adverse effect on the fetus. And this is in line with animal studies, skeletal outcomes and preclinical studies. I'll skip over the last answer, prednisone, this is something you would consider if the patient was having something like sarcoidosis or other granulomatous disease, it is not indicated in this because the 125 vitamin D is not from aberrant conversion, but rather from activation by PTH and PTH-related peptide. So going back to the third and fourth answers, so surgery actually is the modality of choice to treat this, now the important thing is that when you pursue surgery you want to try to aim for the second trimester, studies have shown that the CPTP generally safe and the outcomes are most favorable, first trimester there is increased risk of miscarriage of the fetus, so second trimester is your really time to try to target this, and I will say that treating hypercalcemia from primary hyperparathyroidism is quite important for pregnancy, it is associated with a high risk of miscarriage and fetal demise, so it is important to address, this is not something you want to watch, but again you do have the option of parathyroidectomy in the second trimester, for this particular patient she would have to be watched carefully, progressively hydrated until she got to the point where surgery can be safely performed, lastly I would like to make the comment that pregnancy, one of the most important hormones that we need to think about is PTHRP, which is made by the placenta and actually induces some hypercalcemia locally, and this is done to enable calcium transit to the fetus, so it is something to think about in primary hyperparathyroidism, even patients who are on high doses of calcium during pregnancy, PTHRP does not respond or responds very little to negative feedback from calcium levels as opposed to PTH, so it is something always to think about in any patient with a calcium disorder who is anticipating pregnancy. So with that we can go to the next slide, and the next question, so this is a 42 year woman who is presented with a bilateral hip pain and the radiographic findings are shown here, I would direct your attention to the medial femur, take a look at that for a few seconds, and then we can go on to the next slide, and here are her laboratory results, she has a borderline low calcium, phosphate is also borderline low, normal kidney function, and markedly elevated alkaline phosphatase, so with that we can move to the next slide with the question, measurement of which of these will most likely provide you with a patient's diagnosis, fibroblast growth factor 23, question, choice A, intact parathyroid hormone, question on point B, choice C, 125, dihydroxyvitamin D, choice D, serum or electrophoresis, for the last 25, dihydroxyvitamin D, let's take a few seconds to think about that, and then we can go to the next slide, so there's a split between choice A and choice E, which is the correct answer, 25, dihydroxyvitamin D, this is osteomalacia from inadequate vitamin D intake, so we can go on to the rationale at the next slide, so a lot of people chose FGDF23, which is something to consider, since you did have a slightly low phosphate, however, you already have a much more clear reason for that, being the low vitamin D leads to a slightly low phosphate, and the alkaline phosphate is being elevated, it also would not explain the finding on the x-ray, which is what they call a looser zone fracture that is secondary to osteomalacia, it can be fairly subtle in this particular image, it was a little bit more obvious, but again, FGDF23, wow, reasonable thing to think about, it would only explain maybe the phosphate, but none of the other findings really, parathyroid hormone might get you to the diagnosis, but by itself it wouldn't, if it was elevated it could be from inadequate calcium intake or inadequate vitamin D intake, so while it's another thing you would probably check in tan with most of these other tests, it won't give you the diagnosis, 125 vitamin D, again, probably less of a helpful test and something we don't check very often, it would not explain much of these findings as well, it will say that in vitamin D deficiency, 125 vitamin D can actually be elevated, which is just sort of a compensatory mechanism mediated by parathyroid hormone, it's not your first test of choice, and then serum electrophoresis would not explain this finding either, you might see hypercalcemia, but you wouldn't see this type of lesion in the bone, and wouldn't really give you much information in terms of osteomalacia, so the quick choice was choice D, and as an important point, this particular patient was found to have celiac disease that was causing malabsorption of multiple nutrients of clean calcium and vitamin D, so it's something to keep in mind, particularly if you have a patient with a very low vitamin D, particularly if they have abnormal bone findings such as a loose ozone fracture, or even low bone density, so celiac disease is something to keep in mind when you come across patients such as this, and we go on to the next slide, and the last question, this is a 55-year-old woman with ESRD, Ancid Recony disease, second year to hypertension, has been on hemodialysis for 10 years, she's had multiple vertebral fractures and a low T-score in her femoral neck and her DEXA scan, leading to referral to you, you see her long-term medications there, calcitriol, 0.5 micrograms twice daily, as well as sinicalcid, 60 milligrams twice daily, so we can go on to the next slide, and here are her laboratory results, I guess slightly low calcium, slightly elevated phosphate, if I went to a low-ish 25 vitamin D, a 24, slightly elevated PTH, and a relatively low total alkaline phosphatase, the patient undergoes a iliac crest biopsy after a double tetracycline labeling, go on to the next slide, so while you're awaiting those bone biopsy results, which can take weeks to perhaps even a month or two, what are the following changes imagined would you pursue immediately, would you start the patient on denosumab, start the patient on teriparatide, decrease the calcitriol dosage, increase the calcitriol dosage, or increase calcitriol dosage, take a few seconds to think about that, okay, and we can go on, yes, so the correct answer is D, she's a little bit hypocalcemic, and we'll go on to the rationale on the next slide, most of you got that question correct, so going through the incorrect answers, so denosumab, it is indicated for patients with CKD and can be used in ESRD, but needs to be used as caution, particularly in this patient, in this current setting, a patient with hypocalcemic and a low alkaline phosphatase, and a lower than expected parathyroid hormone, there is a possibility of a dynamic bone disease, this is not the time to administer denosumab, and then teriparatide, which has been used in inpatient ESRD and evidence of a dynamic bone disease, could be considered, but it's not yet reached to the point where it's approved for general treatment, additionally there are other things you have to consider, like dealing more directly with the low calcium, but it is something you can keep in mind, perhaps, if after you do these other maneuvers, you still appears to have a dynamic bone disease, so then in choice C and E, making adjustments to calcitriol dosage, so decreasing the calcitriol dosage is not what we want to do, because if the calcitriol is low, that could make things worse, increasing the calcitriol dosage won't help the calcium, but may suppress the PTH, which is another thing you don't want to do, so again, I should stress that in end-stage renal disease, or stage 4 CKD, that PTHs are usually in the hundreds, even 150 to 200 ranges, so when you see even a normal or slightly elevated PTH in a patient at the ESRD, you worry a little bit about a dynamic bone disease, so here, what you're trying to do is trying to rule out a dynamic bone disease first, and your first maneuver is to decrease the syndecalcidose to see if that, number one, relieves the hypocalcemia, and number two, relieves the relatively low PTH, and that's your first maneuver, both therapeutically and diagnostically. Once you get to a point, if, say, you lower or even eliminate syndecalcidose, and the PTH is still low, then you have to sort of think about a dynamic bone disease, and your decision-making and strategy becomes much different, as opposed to if the PTH started to rise quite, and the calcium normalized, and you can kind of think of these other options. Okay, so with that, I think we can move to the next slide and conclude this, the bone session. Thanks so much, Partha, so I'd like to thank you all for your kind attention. We have a few questions we can go through in the remaining time. The first question in the chat, can you just do estrogen patch without Luprolide for the question on transgender care in clinical practice? Yeah, thank you. So, yes, you absolutely can. I think the nuance in this clinical case was that in a patient with a known factor V Leiden mutation or at risk for thrombophilia and venous thromboembolism, you want to keep your estrogen dose as low as possible, and for that reason, having a JNRH agonist that's oppressing the testosterone, endogenous testosterone, will allow you to get away with the lowest dose of the estradiol patch, rather than if you just do the estradiol, you're going to end up needing a much higher dose of exposure. Thank you. Thanks so much, Arati. We have a number of questions on bone. The first question is, can any of the other acute treatments be used in a pregnancy, like calcitonin? That's a good question. So calcitonin could be used acutely. It's a limited experience in their literature. However, it is, as you said, an acute treatment. You can only do it for a few days before it starts to undergo tachyphylaxis, and it is no longer effective generally after 72 hours. So you could consider it as probably not going to bring a whole lot, much benefit over that time. Thank you. That makes sense. There was another question. I'm still unclear why we won't consider sarcoidosis in the pregnant patient, given the high 125 vitamin D. Yeah, so you have to sort of figure out why the high 125 vitamin D is what's driving it. In this case, it's clearly the parathyroid hormone. If she had sarcoidosis from a burned 125 vitamin D, that should negatively feed back on PTH, and you expect a lower PTH. I mean, it is always possible that she has both, but it's not likely. Yeah, that makes perfect sense. Thank you. And what is the more appropriate treatment option for osteoporosis in patients undergoing dialysis with high risk of hypocalcemia? So this is a very difficult question, because many patients with end-stage renal disease are at risk for hypocalcemia for a variety of reasons. There's also this entity of adenamic bone disease, which is really poorly defined. So your antiresorptives can all be problematic. Denosumab would seem the most obvious choice, but then we still have the worry about fatal hypocalcemia, particularly in end-stage renal disease. But it is a possibility, but you would have to be very aggressive with both calcium and vitamin D repletion. And really, that's the only thing we have. I mean, there are some case studies of using very low dose bisphosphonates in this situation, or Pimidronate. Again, you still have to worry about hypocalcemia, even adenamic bone disease. You can make the argument that those are less potent antiresorptives, but again, there's just no data to really support using any of these medications besides denosumab. And then the other one, which we briefly mentioned, would be teriparatide, which would solve your hypocalcemia issue and potentially help adenamic bone disease, or overcome adenamic bone disease. And so Paul Miller, who is a nephrologist at the University of Colorado, has done a lot of studies about this. Someone could look up, and he has several anecdotal cases where it actually has been effective. It is a temporizing measure for those patients, and it's really only for those patients that have clear adenamic bone disease and do not have high PTH. And most end-stage renal disease patients have high PTH, which generally precludes using agents like teriparatide or valparatide. Thanks so much, Dr. Sinha. That's clearly a very tough choice, a tough situation clinically. You're very popular today, I have to say, with all these bone questions on tough topics. There are two related issues about PTH, two questions. How long after decreasing sinacalcet should I reject PTH level? It's one question. And the second question, what is the goal PTH level for patients on dialysis? Sure thing. So for the, sinacalcet doesn't have a very long half-life. I generally wait about a week in the outpatient setting. You could do it in two or three days to recheck PTH levels, but I think a week or two should be enough if you're trying to really closely follow them. Thank you. And what is the goal PTH for a patient on dialysis in general? So this is somewhat controversial. On dialysis, you're trying to, the goal, the historical goal has been 200 or less, or in the 200 range, and to keep it somewhere above 100. So roughly 100, 100 to 200, maybe 140 to 200. This is a very, the literature is all over the place as to who, what's the best PTH to target. Some nephrologists will target a normal PTH if they think they, if they have metabolic bone disease, there's no evidence to show that actually helps with low bone density. So, so historic, so I should just say, there's not great evidence as to what should we target. But generally speaking, if their PTH rises above 200 on their own dialysis, that's when we recommend starting activated vitamin D, such as calcitriol or hectordoxacarbicliferol. Thank you. And one last question, because we're at the top of the hour, for the pregnant patient, what if surgery is, she's high risk for surgery, would you consider senacalcite until delivery? And is it okay for her to wait for it with a calcium of 12.9 until second trimester? Two related questions. And this will be the last questions for today, because we're running out of time. Yes, so you're weighing the risk of fetal demise from hypercalcemia versus the risk of surgery on miscarriage and fetal demise. So it's not an easy question. You can probably, if you can keep it at least below 14, you should be okay, but it's not ideal, obviously. So if you're balancing the risk of hypercalcemia and the risk of surgery, most surgeons will not be comfortable doing the surgery until at least reaching, maybe if you reach like 20, like 13 or 14 weeks, then they may, I'm sorry, like maybe they'll be more comfortable with it. But the problem is that many of the agents they use for a surgery also cause the placenta and can cause problems for the fetus. So it's not an easy question, but generally speaking, you can hold, if you can hold them at least around 12, definitely keep them below 14, preferably below 13, they generally should be okay. Again, there is not a huge statistical population about this to give us great guidance, but that's sort of the thinking. Okay, thank you. That was excellent. And finally, would you ever use in a calcet, if for some reason she cannot have surgery during pregnancy? Well, I could consider if there is absolutely no way to do any procedural on the patient. I would actually think about doing ablation, either with the radiofrequency ablation or ethanol, if they're at a high surgical risk. Again, there's no data about that whatsoever. There might be that, I'm not aware of, but that's what I would actually try to consider because, you know, the ablative procedures have advanced and that's what I would consider before using sinicalcet. Again, sinicalcet, we just don't have any idea what it would do long-term for the fetus and it would be, I think it would be a choice, but I would actually say it was third line after surgery and ablation. Okay, thank you. Thanks so much. Excellent discussion, excellent questions. I would like to thank our participants. I would like to thank our excellent faculty, Endocrine Society staff, and everybody else who is on this webinar. Thank you for your attention and we look forward to seeing you again on Friday, April 11, 3 p.m. Eastern Time to talk about adrenal diabetes, pituitary, and thyroid questions. Thank you again and have a good rest of your day. Bye-bye. Thank you.

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