Welcome, everyone. We are starting the ASAP live for 2022. And today's discussion is going to be on reproductive disorders. The board review course leaders are myself. I was the past chair of the fellow education committee. And I am an associate professor of medicine and a division director and fellowship director at Auburn Medical School at Brown University. And the chair of the ASAP committee is Dr. Elias Siraj. He is a professor of medicine and the section chief for the division of endocrinology. He's also a vice dean for research at Eastern Virginia Medical Center. We have two great presenters for you today. The first is Dr. Jessica Perrini, who is an associate professor of medicine and the program director of the endocrinology fellowship program in the division of endocrinology and metabolism at West Virginia School of Medicine. And the next presenter is Dr. Daryl Salen, who is an assistant professor of medicine at Auburn Medical School at Brown University. So I want to welcome both of them for today's presentation. Neither has any disclosures regarding our presentation today. The format for today is there will be a question that's asked, and you will have an opportunity to answer the questions via a poll. And then we'll discuss the answers. During the Q&A part of the section, if you have additional questions to ask, you can type your questions in the chat box, and you can vote up or down your questions. When the Zoom poll opens, please remember to select your answers. The questions from the audience will be answered at the end of each case discussion. So I hope you guys have some questions for us. And Dr. Perrini and Dr. Daryl Salen are ready to answer your questions. With that, I'd like to kind of open it up to Dr. Perrini with the first case to talk about male reproduction and hypogonadism. Okay. Hi, everybody. Please ask any questions you can think of. We like it to be interactive as much as possible. So case one is a 40-year-old man who comes to the endocrine clinic with a three-year history of a lack of libido. He has reduced frequency of morning erections and erectile dysfunction. His medical history includes treatment for Hodgkin's lymphoma five years ago, and he had systemic chemotherapy for that, and it led to successful remission. He also has CPAP use for moderate sleep apnea. He doesn't take any medications. He lives with his wife and his two children. He doesn't smoke, and he has two to three alcoholic drinks per week. He identifies as Black. His physical exam shows bilateral gynecomastia. He has sparse secondary hair, soft testes measuring six ccs bilaterally, and he has a normal digital rectal exam. Next slide. So here are his labs. His total testosterone is 46, and if you look at the normal range on the right, you can see that that's quite low. His sex hormone binding globulin is normal at 33. His LH is 33, which is elevated, FSH is 46, which is elevated. His hemoglobin and hematocrit are both within, well, his hematocrit is a little low and his hemoglobin is a little low, so both are a little bit low. His PSA is 3.3. His breast mammogram and ultrasound showed bilateral subareolar densities that are consistent with gynecomastia. No suspicious masses or calcifications or lumps are evident on either of those imaging studies. Next slide. Okay, so here's where you guys step in. So which of the following findings in this patient's evaluation puts him at a moderate to high risk of an adverse outcome if testosterone therapy is initiated? So option A is gynecomastia, B is prostate-specific antigen levels, C hematocrit levels, and D is sleep apnea. So you pick one, enter that, and then we'll wait and tally up the answers. There's some kind of a timer going right now, even though we all don't know. All right, so here's what we can see. So nobody picked gynecomastia, and good. The majority of people picked a PSA, and then nobody picked his hematocrit and some picked sleep apnea. So now we're going to go through why these answers are correct or incorrect so that you can learn from the answers also. Next slide. So there are details written in these rationales, but we can also discuss them. So you can enter your questions into the chat or the Q&A boxes. So this patient has no doubt about having low clinical and biochemical evidence of primary hypergonadotropic hypogonadism, secondary to the chemo that he got when he had non-Hodgkin lymphoma. So we know that it's primary, and I'm going to kind of put this out there so that you guys can start thinking and answering on your chat and getting rolling with your questions and answers. So why do we know that this is primary hypogonadism? So start thinking about that. You probably all know that, but just start thinking. So he will benefit from initiation of testosterone therapy. However, all patients who take testosterone require some assessment before you start that medication because they may be at high risk for adverse outcomes if they start that therapy. So the Endocrine Society guidelines say that this patient's race, he identifies as Black. Given that PSA that was only a little bit above three and definitely less than four, which we kind of think of as our standard, his PSA was three or 3.3, and that puts him at a moderate to high risk of adverse outcomes. That's the reason why option B is correct. Next slide. Okay. So the precise relationship between testosterone therapy and prostate cancer risk is not clear. We generally counsel people that testosterone is not going to cause prostate cancer, but if there is some seedling somewhere or existent but unidentified prostate cancer, use of testosterone could potentiate the growth of that. So it isn't that we know that it will cause prostate cancer, but we want to look at people who potentially have some risk. If urologic evaluation for this patient is reassuring, he can commence testosterone therapy and will require monitoring with a DREV and a PSA level every three to six months after you start the testosterone. Further urologic consultation will be needed if his absolute PSA levels are higher than 1.4 and or his PSA increases after you start testosterone by 1.4 or more during the first 12 months of using testosterone. If the PSA stays stable after 12 months of testosterone use, then you can get back to kind of routine prostate cancer screening as you would for the general population based on his age and race. So because he's a black man, you need to use that lower threshold of PSA of three rather than four for non-African American or non-black people. So why wasn't gynecomastia correct? So gynecomastia is a feature that we can commonly see in people with hypogonadism, but it doesn't represent any kind of a risk for that patient. We don't expect anything bad to happen by initiating testosterone therapy in men who have gynecomastia. In contrast, male breast cancer, which is typically a hormone-dependent cancer, could in fact be adversely affected by starting testosterone. So that's why imaging needs to be done to make sure that what you're feeling on exam and what may appear as gynecomastia is in fact gynecomastia as opposed to a breast mass. Next slide. Okay. So then we get down to the hemoglobin and hematocrit, which in this patient were a little bit low. We know that testosterone stimulates erythroplesis. And so anemia and low hematocrit, which are well-recognized features of the opposite situation, when you don't have enough testosterone, you can get a low hemoglobin hematocrit. On the other hand, if you get extra testosterone, you could have a rise in your hemoglobin and hematocrit. So for this patient, he was starting out already at the low end of the hemoglobin hematocrit spectrum. So starting him on testosterone is at worst going to move him into normal range most likely. You would monitor hematocrit over time, no matter what, and make sure that it doesn't get high above normal and into a range where we would be concerned, but for him, it's not an issue. And then finally, he has moderate sleep apnea. And this is one of those tricks of reading, sorry, my thing, it's like trying to figure out where I am, it's zooming in and out. One of the tricks of reading board review types of questions or board questions is to kind of read between the lines. So it's saying he has moderate sleep apnea, but it says it's treated. It doesn't give you any indication in this scenario that he is suffering, he's still having daytime somnolence or anything associated with untreated sleep apnea. So from this vignette, we have to assume that his sleep apnea by using his CPAP, which we have to presume he is in fact using, is under control. And therefore, of the options, it is not highest in our list of high-risk things going on for him that would make us think twice about starting testosterone. Okay. I think that may be the last slide in this case one. Yep. So are there... Yeah. I mean, let's pause here for a minute, Jessica, maybe, and see if there's any questions from the audience. Okay. And as we're waiting to see if there's any questions, I have a couple of questions. You kind of teased the audience with a comment about primary versus secondary hypogonadism. So can you comment about how you would kind of evaluate and assess somebody with primary versus secondary? How do you make that diagnosis? Sure. So usually, you know, for endocrinologists, we're usually getting people who at least have one plain old testosterone that's come in and it's low, so they send them to us for further evaluation. So our job then is to start figuring out very first, is it actually low? So the very first step is an 8 a.m. testosterone, because it does have this peak in the morning. If they check the testosterone at 4 in the afternoon, and it's kind of low, that doesn't mean a thing. You need to check their testosterone at 8 o'clock in the morning before you confirm that it's low, and then you need to do it again and make sure that, in fact, it's really low. Once you've confirmed that, then you want to know, is it primary, meaning the testes themselves are the primary problem, they've conked out, all the signals from up here are coming to the testes trying to tell the testicles, get busy and make testosterone, or are those testicles ready and waiting to make testosterone, but the signal itself isn't coming for some reason? So primary hypogonadism, you'll see the low testosterone, but all the signals trying to tell the testes, get busy, LHFSH, will be high, and in this patient, he had this very low testosterone, and he had above normal range, LH and FSH. In a central hypogonadism state, maybe somebody who has hypopit, or maybe somebody who's on some kind of medication that's suppressing the LH and FSH to some degree, they will have their low testosterone because that's what came to your attention in the first place, but all of the signals from here are not working in overtime. They are not above normal. LH and FSH in a central hypogonadism situation will be either absolutely low or inappropriately normal. So if testosterone is low, those LH and FSH things should be very high. If they're anything other than high, normal or low, that means they are not working appropriately to stimulate these testes adequately. So inappropriately normal LH and FSH or a low LH and FSH in the face of a low testosterone indicates a central hypogonadism or secondary hypogonadism. You know, with central hypogonadism, a lot of us struggle with trying to figure out when to work on an MRI, considering there's age-associated hypogonadotropic hypogonadism that happens. So what are your thoughts and how do you think about that? So in endocrine, as we all know, we save imaging until the very end. We don't really do a picture until we know exactly where the problem is. So if it looked like a primary hypogonadism where the testes were the problem and LH and FSH were nice and high, we wouldn't do an MRI of the pituitary because the problem is in the testes. It's a primary circumstance. In central hypogonadism, we may do an MRI down the road, but if the testosterone level is truly low, less than 150 is what our guidelines tell us. If that testosterone is less than 150 and the LH and FSH aren't appropriate, then you do want to look with an MRI at the pituitary to make sure that you're not missing anything centrally. Great. I'm just going to have a quick question. You've made a comment about hematocrit levels and testosterone therapy. Is there a hematocrit level where you worry about that you may not want to consider testosterone therapy for? And on the same sort of thinking, if you have someone on testosterone already and their hematocrit gets above a certain point, you'll either want to decrease the dose or stop it for some period of time. So most of my experience with this is with trans people for whom I'm providing masculinizing hormone. And you do a baseline hemoglobin hematocrit, and then as long as their levels are normal, you can start with the testosterone. And then you monitor that hematocrit. And depending on which guideline you use, it's somewhere around 53%. If the hematocrit is 53% or above, or a different guideline says if it's above 53%, so 54% and above, that's considered too concentrated. And then you have the patient at higher risk for a thromboembolic event. So if it's someone who is a cisgender man and is hypogonadal, I will stop the testosterone for a period of time, let the levels come back down. If it's a trans person for whom gender dysphoria could be worsened by stopping their hormones, I will usually decrease the dose for a period of time, let the hematocrit improve. And if that doesn't work, as long as you've ruled out other reasons for a high hematocrit, you can do therapeutic phlebotomy, where they basically just go and get phlebotomized periodically down to a hematocrit that you write on your prescription. So phlebotomized to a hematocrit less than, you know, 48 or something like that. But 53%, right, or 54 is usually the cutoff. All right. Thank you very much. With that, let's go to the next question. And Dr. Salen is up. Let me see if it'll, okay. So talking about female reproduction and amenorrhea. Okay. So case two, a 20-year-old woman is being evaluated for amenorrhea. She describes the allergy around age 11, but denies any episodes of menstrual bleeding. Her primary care provider recently ordered the following labs. So her estradiol is 42, which is in the normal range. The testosterone, presuming the total testosterone is 610, which is markedly elevated. The LH is 20, also a little bit elevated, and the FSH is 8. The prolactin level is 11 in the normal range, and the TSH is 2.3 in the normal range. And on physical exam, the patient has Tanner stage 5 breast development, which is normal. So no hirsutism, no acne, no virilization, but also no axillary or pubic hair. And on further questioning, she denies ever having any axillary or pubic hair. So for the question, which I'm, yeah, there, the poll popped up. So what is the most likely diagnosis? A, an androgen-producing ovarian tumor, B, complete androgen insensitivity syndrome, C, gonadal dysgenesis, or Turner syndrome, or D, malaria and agenesis. I'm not sure if you can go back to the slide and keep the poll up so they can look at the lab values. Is that possible? It might not be. Oh, yeah, there we go. Okay, so we'll give you time to answer the poll. Okay, so for the answers, it looks like nobody chose A for the androgen-producing ovarian tumor. The majority of people chose B, the complete androgen insensitivity syndrome. No one chose Turner syndrome. And then a couple people chose malaria and agenesis. So we can go through these answers now. And again, if you have any questions, please use the Q&A or the chat below. Okay, so this patient has primary amenorrhea. So she never ever had a period. She underwent pubertal changes. So she had full breast development at an appropriate age, but she never had puberty. So she never, or puberty, she never had periods. And on lab, she had the severe hyperandrogenemia. Her testosterone level was over 600, which is not normal in a female. And, but the patient had no physical exam evidence of hyperandrogenism. She had no hirsutism, no acne, no voice deepening or anything like that. So the answer that was most consistent with this was B, complete androgen insensitivity syndrome. So in androgen insensitivity syndrome, you have a 46XY karyotype and you have testes, which can be in the abdomen or the inguinal region, but there's a loss of function of the androgen receptor. So the body's trying to make a lot of testosterone and is making a lot of testosterone, but it's not having any function. So in these patients, the fetal testes secrete AMH, and that inhibits the development of malarian structures. So these individuals don't have a uterus. And there's also no normal in utero development of the male external genitalia. So as newborns, these individuals exhibit female external genitalia, but they have a blind vaginal pouch and they also have no uterus. So they undergo adrenarchy because they do have some androgens, but they don't go through puberty. And then similarly, despite having increased testicular testosterone, they don't have any virilization because their androgen receptors don't respond to the testosterone. And instead, the testosterone is aromatized estradiol, so they end up with the female secondary sex characteristics. Okay, you can go to the next slide. So like I said before, since they don't have a uterus, they don't have any menstrual bleeding. And even though this individual did have really high testosterone levels, because there was no evidence of the hyperandrogenism or virilization, it's less likely to be an androgen-producing tumor because individuals with a tumor would have functioning androgen receptors, so they would virilize. And this individual did not. For malarian agenesis, it's kind of similar to androgen insensitivity syndrome because they both don't have malarian tubes that form properly. But in malarian agenesis, the chromosomes are normal female chromosomes, so they are XX versus androgen insensitivity where they're XY. But because they have no malarian duct, they have no uterus, they also have a blind vaginal pouch, and they also have primary amenorrhea. But they do have ovaries. And in contrast to androgen insensitivity syndrome, they have testes. So those are the differences between the two, which can be subtle. And I think those were the two options that people picked for this answer. And then, so then such patients can undergo puberty and have underlying ovarian function that's normal and also have testosterone that is in the normal female range. And then for answer C, which was Turner syndrome or gonadal dysgenesis, this can also present with primary amenorrhea, but these individuals, their chromosomes are X. They only have one X, so it's like X and then zero. And they're expected to undergo normal puberty, but then later can have pubertal failure because they have primary ovarian failure. And in those cases on the labs, they would have a high FSH level. And in this case, the FSH level was normal. Yeah, it was eight. And they would not have any hyperandrogenism, which was in Turner's. And this patient had a testosterone in the 600s. Okay, yeah, so that's. And so if, yeah, we'll give you a couple of minutes to put any questions about this case in the Q&A or in the Q&A or chat. So Darrell, thank you for a nice description of the answers. So can you comment again about, you know, complete androgens insensitivity versus malaria and agenesis because those are the two most common answers to how do they present and what should, you know, trainees be looking at as they evaluate patients with this? Yeah, so the difficult thing is they both don't have the malaria system or like the malaria duct system. They both don't have uteruses. They both have the blind vaginal pouch and they can both present with primary amenorrhea. But if you did a karyotype for them, which I know is like, you know, further steps, complete androgen insensitivity syndrome would have an XY and malaria and agenesis would have an XX. And if you searched for gonads, the malaria and agenesis would have ovaries and the androgen insensitivity syndrome patients would have testes. And then in androgen insensitivity syndrome, you would have very high testosterone levels, which you wouldn't have in malaria and agenesis because they have ovaries. So they should have normal like estradiol and progesterone levels if you check those. Great, thank you very much. And then on the flip side, if this was an XX person and they were taking exogenous testosterone, how would the lab tests differ in these cases? If you wanna go, we can pull, if you wanna go back to the slide with the labs, we can pull those up. But yeah, so this patient had very high testosterone and normal estradiol and the LH and FSH levels weren't, were like a little bit elevated, but they weren't markedly elevated or markedly low. But if an individual was taking exogenous testosterone, it would lower their LH and FSH. So I would expect those to be much lower than they are in this patient. And because testosterone is aromatized to estradiol, it's possible that the estradiol level could be normal or it could be high, but I would focus on the LH and FSH because those should be suppressed. Thank you very much, that was very helpful. Any other questions from the audience? All right, hearing none, we'll move on to the next question. We're going back to male reproduction again and Dr. Perini is up next. Okay, so this is a 25 year old trans woman who comes to your office for consultation about her hormone regimen. She uses female pronouns and changed her name and gender marker legally to female. She transitioned to the female gender during college when she was 20 years old. She has not previously had any gender affirming genital surgery. She's healthy and doesn't have any known medical problems and she takes the following gender affirming hormones. Oral estradiol, four milligrams once a day. Spironolactone, a hundred milligrams twice a day and Luprolide, 22.5 milligrams sub-Q every three months. So thankfully for her, she is employed in a tech company and her insurance provides coverage for all of her medications. She feels well on the current hormone regimen and does not report any adverse effects. So here are her labs. Her electrolytes are normal, creatinine is normal. Her total testosterone is 22 and her estradiol level is 197. Okay, so which of the following would be the best advice regarding her current hormone regimen? So should we increase her estradiol to six milligrams daily? Should we increase her spironolactone to 200 milligrams three times a day? Should we decrease her spironolactone to 50 milligrams twice a day? Or should we discontinue her spironolactone? Okay, so nobody picked increase her spironolactone to 200 milligrams three times a day. Thank goodness because no one on the planet needs a dose that high. So we had 22% say increase her estradiol. We had 33% say stop her spironolactone completely. And we had almost half say decrease her spironolactone to 50 milligrams twice a day. So I like this question because although it's a board review question, it's actually a very practical real life situation where you're gonna be thinking about cost and everything like that. This patient was happy, she's feeling fine, her labs look great. So had there been an option E saying don't change anything, that would have been completely reasonable, but that wasn't an option here. So we wanna think therefore not what's harming her because really nothing is harming her. Her labs looked fine, but what's the most practical thing to do, okay? So the next slide, please. So the answer is to stop her spironolactone, okay? And here's why. So it tells you, it highlights the significance of the antiandrogen therapy, which were for this patient spironolactone and luprolide and the target sex steroid hormone, which for this patient is estrogen. So she's doing well, like I was saying, on both the estrogen and the antiandrogen therapy. But if you think about it, she's taking two different antiandrogens and although her labs looked great, so again, you don't have to do anything, she's getting more medication than she needs. So there are potential consequences, either side effects or costs, or some, even if insurance is paying for it, which is a great and unusual thing, it's still costing somebody money along the way. So she doesn't need two antiandrogens. Her lupron is working perfectly well. It's easy, it's once every three months. And although spironolactone is very cheap if you're paying cash out of your pocket, it's still a twice a day medication. And she's taking estrogen only once a day. So she's taking pills, two types in the morning, one in the evening versus one type of pill a day and one thing every three months. So since your options were really only to adjust spironolactones, not stop the lupron, luprolide, our best answer then is to stop the spironolactone altogether. Decreasing the dose of the spironolactone won't add anything for her. It's a cost issue and a hassle issue as opposed to really a medical issue at this point. So if a lot is doing no more than a little, just stop it altogether. That's really the logic behind this. Her total testosterone concentration was within the target that we tried to get. So with feedback mechanisms and the effect of spironolactone and the luprolide, we've gotten her testosterone suppressed significantly and the target there according to the guidelines is less than 50. And her estradiol level, the reason option A was not the correct answer, which offered the option of increasing her estradiol, the maximum estrogen level you want in your trans women is 200. And so anything up to 200, as long as they're feeling well is your target estrogen and she's already in the 190s range. So increasing the estradiol dose is not the correct answer simply because she's already getting an adequate amount. Next slide. Okay. So we'll open it up for questions if anybody had some burning questions, but as we wait for the questions, the question I'd like for you to answer is how does Lupron work in this population and what are the benefits of using such a costly drug? Sure. So I personally very rarely use it in my trans people simply because of cost. In the state where I live, most insurances do not cover luprolide, but spironolactone again is either covered or it's very inexpensive if you pay out of pocket. So typically I don't even go to luprolide as an option, but if I could more often I would simply because it's very easy, it's very effective. So luprolide is a GnRH agonist. And therefore if you take it, it basically is gonna, you remember that the LH and FSH are kind of working in a cyclic sort of way. So if you agonize them with a GnRH agonist and you give a chronic stimulation to the LH and FSH as opposed to a pulsatile stimulus, instead of helping the LH and FSH be released in the proper way that it's always been released, if you chronically stimulate it, you actually down regulate all the receptors and things like that. And then the LH and FSH levels go down. Therefore they're no longer gonna stimulate the gonads in their making of either estrogen or testosterone, depending on what gonads the person has. And then you've suppressed that person's endogenous gonadal hormones. And then when you give them their gender affirming hormone, in this person's case, it's estrogen, it's not fighting with the endogenous hormone. You have just the estrogen effect in this patient working and doing its estrogen things. And this brings up an interesting point that I debate with people a lot in that the target testosterone of less than 50 is something that I personally, I have about 500 trans people that I see in my clinic. And I very rarely check in trans women, their testosterone levels. I monitor their estrogen levels. And if they are feeling well and feeling like their gender dysphoria is significantly improved, phenotypically they're looking how they wanna look. I honestly don't care what their testosterone level is. I'm giving them their spironolactone, 100 milligrams twice a day, and it significantly inhibits the effects of any circulating testosterone. Spironolactone also, in addition to just blocking the androgen receptors in some way that we're not quite sure of yet is also down regulating the actual amount of circulating testosterone. So it seems to also have some effect on some of those, if you imagine those adrenal pathways with the 17-hydroxypregnolone going over, and those are those 17, 20 lyase hormones. It looks like spironolactone actually blocks that to some degree as well. So then there's less shift in the adrenals towards the androgen pathway. So not only is spironolactone blocking the effect of circulating androgens, but it's also down regulating the amount of androgens in addition. And so between those two things, you're having a great effect. And I don't care what the testosterone levels are then because people, if they feel well, I don't need to go chasing a number. Great. So then what do you use for spironolactones in terms of starting doses and how long do you kind of process that? Sure. So I start with 50 milligrams twice a day, but then I increase it within the month usually as long as their potassium is fine and they're not lightheaded to 100 milligrams twice a day as my standard dosing. Okay. I used to be afraid of 100 milligrams twice a day, but now it's routine and people almost always do great with it. Perfect. All right. Thank you very much. We'll go to our next case. And we're going back to female reproduction again and Dr. Salen is up. Okay. So a 22 year old woman seek treatment for hirsutism. She has a well-documented history of PCOS with moderate hirsutism and oligomenorrhea. She has about six to eight menses a year. She has been given a combined oral contraceptive with 30 micrograms of estradiol and 0.35 milligrams of desagestrel, which is a third generation progestin. And then she also takes spironolactone, 50 milligrams twice a day. And sorry, that was four years ago. So then three years ago, the dose of spironolactone was increased 100 milligrams twice a day. And this is relevant to what Dr. Perini was just talking about. It can be used for the trans population and it can also be used for PCOS to block or to decrease androgens. So these medications improved her hirsutism and resulted in regular menstrual withdrawal bleeding. However, they were both stopped a year ago when she had an unprovoked proximal DVT. She was given anticoagulation and completed that nine months ago. However, now she's reporting worsening hirsutism over the past six months. She's managed her hirsutism with daily shaving, but is interested in a medication to improve it and minimize the shaving. She's only had four to five episodes of menstrual bleeding with variable flow over the past year. She's sexually active and does not desire pregnancy. She also doesn't smoke and her BMI is 26. Next slide. So which of the following is the most acceptable therapeutic combination for this patient? A, spironolactone with a copper IUD, B, spironolactone and a low dose OCP with a first generation progestin. So 20 micrograms of estradiol and one milligram of norepinephrine, C, spironolactone and a progesterone only pill, which is 0.35 milligrams of norethindrone, or D, spironolactone and episodic micronized progesterone. So 200 milligrams at bedtime for 10 to 14 days each month. So we'll let you answer those with the poll now. Okay, so it looks like no one picked answer B, which is good, spironolactone in the OCP. Fifty percent of people picked spironolactone in the copper IUD, which was A, 38 percent picked spironolactone and a progesterone only pill, C. And then D, 13 percent of people picked, and that's spironolactone with the episodic micronized progesterone. And we can go through these answers because I think this one was definitely a tricky question. So this patient is PCOS, and there's three things we're trying to accomplish with her treatment. So she has hirsutism, which we want to treat and get rid of. We want to prevent her endometrial hyperplasia, and we also want to provide her contraception because she's not interested in becoming pregnant at this time. And there will be a table further on that we can show with the different treatment options, but there are a bunch of treatment options available. So spironolactone is expected to improve her hirsutism, but having androgen receptor antagonists can disrupt the sexual development of a male fetus, so it is a teratogen. And therefore, while on spironolactone, individuals need to have effective contraception. So one option, which was the correct option in this case, is to do a progesterone only contraceptive pill with the spironolactone, and that was choice B. And the reason for this is that you need the progesterone to prevent the endometrial hyperplasia, and in choice A, which the majority of people picked, the IUD had no hormone, it was just copper, so it's not providing any endometrial protections. But if that answer choice had been spironolactone with a progesterone-containing IUD, such as like a Mirena or Skyla, then that would have been the correct answer. And I think that's why this one is more of a trick question because a lot of, like a good treatment for PCOS is an IUD with spironolactone, but you just have to make sure that the IUD actually has hormone in it. So for this case, it's spironolactone and then a progesterone-only pill because we want to prevent that endometrial lining buildup and endometrial hyperplasia, especially since this patient has oligomenorrhea, she only had a few periods in the past year. And even though the norothendrone in the progesterone-only pill won't address the hercutism, the spironolactone will, so this is the best option for this patient. But it is important to note that progesterone-only pills aren't ideal because you have to take them at like the same hour every day, and if you forget, and if it's a patient that isn't good with remembering to take a pill at the same time every day, it won't provide effective contraception. There is a new progesterone-only pill that does work, or that lasts a little bit longer. It's called Flynd, but a lot of insurances don't cover that right now. Hopefully in the future they will, but right now the progesterone-only pills need to be taken at the same time every day to be effective. Okay, next slide. So then the other answer choices, so combined OCPs do improve hercutism, but no one picked that answer choice because we know that this patient had a DVT, and even though the answer choice said a low-dose OCP, it still has a high, still has a risk of DVT in this patient, especially since she had an unprovoked DVT. So it's not a good choice to give her any more estradiol, so that was good that no one picked that answer choice. And then for answer D, the episodic micronized progesterone, that will prevent endometrial hyperplasia, but that does not provide any contraception. So that's also important to note, when this patient wanted the contraception. And then, like I mentioned before, a copper IUD does provide contraception, but it has no hormones, so it will not prevent any endometrial hyperplasia. So this is the option, or the answer choice for this question of spironolactone with the progesterone-only pill is one option, but it's not necessarily the only one or the correct one for all patients. So there's other options that can work, such as spironolactone and a progesterone IUD, such as Mirena. They can also, if they're fine with the hair removal, just do a progesterone IUD, but sometimes that can actually make some acne and hair growth worse, so a lot of times that isn't a great option for patients. Or they can have the direct hair removal and the progesterone-only pill, or direct hair removal, episodic progesterone, and then a non-hormonal contraceptive option. So there are lots of options, and if you go to the next slide, there's a table with them on it that's a little bit cut off, but basically for this patient in the far right, the low-dose OCP is the only thing that's contraindicated, so you could give them a different combination of the other options. And yeah, if anyone wants to take screenshots of this, feel free. I think this is the last slide, yeah, of this case. If anyone has questions. Yeah, so we'll open it up to the audience for questions. Again, if anybody has any more burning questions as we go through these cases, please put it in the chat. But as we're waiting, Dr. Salen, can you comment a little bit about, we're talking about endometrial hyperplasia with PCOS, what's the mechanism for that? Because that's what we're worried about in this case. What's driving that? So it's actually, it's not completely clear what's driving it, and there's been research into whether it could be the high unopposed estrogen levels that are causing it, or, because some individuals with obesity or who are overweight but don't have PCOS are also at an increased risk of endometrial hyperplasia. So there has been some research into whether it could be insulin as a growth factor for the endometrium, because there are insulin receptors on the endometrium as well. But it is either unopposed estrogen or insulin resistance and high insulin levels in some of these individuals who are insulin resistant and also tend to be, or have overweight or obesity. And then that unopposed estrogen, and then without having the regular withdrawal bleeds, the lining just continues to build up. So for some of these patients, we can have them just do a withdrawal bleed every, like if they hate having periods every month and they don't like the idea of an IUD, we can do just like give them a withdrawal bleed every three months. So you could have like a progesterone withdrawal with just like Provera every three months. So at least they're having withdrawal bleed because some people don't want to be on any hormones or they don't want an IUD, but you could just say, okay, if you don't have a period in the next three months, just like take a 10 day course of Provera, shed your lining, and then, and that's usually sufficient. But yeah, in a lot of these cases, we just want to make sure they're regularly shedding their lining. Perfect, thank you. In the interest of time, I'm going to go on to the next question and turn it over to Dr. Parini again, talking about male reproduction and infertility. Thank you. Oh, you're on mute, Dr. Parini, sorry. Thank you. In the interest of time, I read without anyone hearing me. So a 39 year old man is referred for evaluation of infertility. He has regular intercourse with his wife over the past two years, at least four times a month. His wife is 34 years old and has two children from a previous marriage. His medical history is significant for attention deficit disorder for which he has received treatment since adolescence. He shaves daily and reports normal pubertal development. He has noticed enlargement of his breast tissue over the past few years, and he denies any visual symptoms or evidence of loss of the sense of smell. Next slide. On exam, his vitals, his blood pressure's 132 over 76. Heart rate is normal, 84. Respiratory rate, 12. He is five feet, 10 inches tall, and he weighs 204 pounds. His BMI is 29. His visual fields are normal. He does have bilateral gynecomastia. He has sparse body and axillary hair, and he has normal pubic hair. Genital exam reveals Tanner stage five, and his testicles feel firm and have a volume of two ccs, and his penis appears normal on exam. Here are his labs. His total testosterone is 326, which according to this normal range is at the lower end of normal. His sex hormone binding globulin is 25, normal. FSH is 40, which is high. LH is 20, which is high. And prolactin is 18, which is upper normal. And the couple desires a pregnancy. Okay, so which of the following would be the best recommendation for this couple? Testosterone therapy should be initiated because it may increase the husband's sperm count sufficiently to result in conception. They should consider adoption because of the 25% or greater chance of a male offspring having the same condition. Microscopic testicular sperm extraction and subsequent in vitro fertilization intracytoplasmic sperm injection should be attempted. Or the final option, stimulation therapy should be initiated with intramuscular or subcutaneous HCG 1,000 to 2,500 IUs twice per week. Thank you. Thank you. This seems like extra long, doesn't it? I might keep going. Sorry, I can see the answers, so I can say them. I don't know. We've read through them, but do you see the polling? Yeah, yeah, I see the poll. Okay. I don't know. Oh, wait. Okay, well, I remember what it was. So no one picked the first two answer choices. The majority of people picked answer C, so doing testicular sperm extraction and then IVF and ICSI. And then a few people picked the last option, which was stimulation therapy with HCG. Okay, thank you. So answer C is the correct answer. And I think this is a tricky question, simply because first you have to diagnose the patient with what he has, and then you have to know what has, from research, been shown to be the most beneficial and likely to create a pregnancy in a person with this diagnosis. So as you all know, word questions are not straightforward. There's usually first this, then this, then this, all in your head. Then you get to the actual part of the question that you have to answer to pass the board. So this question, you have to first figure out that the patient has Klinefelter's. This is the most common chromosomal disorder in men, affecting approximately one in 600 people. So Klinefelter's can be missed until adulthood. It's a 47 XXY karyotype, and it results from the non-disjunction of the X chromosome, either in meiosis or mitosis. And although that may seem like a, don't worry about that, it actually matters when you're thinking about whether this can be transmitted to your offspring. So when it occurs in mitosis after fertilization, a mosaic form can occur, and that accounts for about 10% of cases. So the typical clinical features of Klinefelter's include tall stature, and he's five foot 10, a unicoid body habitus. And so they look quite tall. Their arms and legs are, look at those pictures and memorize them because those things even can be on boards. Gynecomastia, symptoms and signs of hypogonadism, including reduced body and facial hair, poor libido, erectile dysfunction, infertility, and small testes. Now remember, this patient had a normal testosterone. It was low end of normal, but it was still within the normal range. So we often think of primary hypogonadism in people with Klinefelter's, but this person did in fact have at least measurable and in fact normal testosterone. So you might not think about it right off the bat in a real life situation, but if you see that LH and FSH, you're gonna wonder why in the world are the LH and FSH so high in someone with testosterone levels at that low end of normal. They're working hard to keep those testes functional. So let's see, boys with Klinefelter's enter puberty as expected. I think I'm still on the previous slide, I'm sorry. And they have appropriate initial rise in their testosterone concentrations, but then eventually they drop in hypergonadotropic hypogonadism, so primary hypogonadism ensues. So the concentrations of testosterone in adults are usually in the low or in low normal range, and infertility is a consequence of germ cell degeneration that actually starts back in utero and progresses slowly through childhood and accelerates during puberty. So even though their testosterone levels are okay, those germ cells are not actually okay. Next slide. Early comorbidities include concurrent cognitive, behavioral, or psychiatric disorders. He didn't seem to have anything bad, just ADHD. Affected boys can present with learning difficulties, particularly with verbal skills and behavioral issues, and later on they could develop thrombotic disease, metabolic syndrome, diabetes, and cardiovascular disease. Because the sperm from men with Klinefelters start in the eucloid germ cells, then ICSI or intracytoplasmic ICSI does not increase the risk of having a child with Klinefelters or other chromosomal abnormalities compared with using sperm from a man who does not have Klinefelters. And the technique of the microscopic testicular sperm extraction and in vitro fertilization appears to be the most successful strategy in helping people with Klinefelters actually have a viable pregnancy and actual offspring. Okay, so if you start this person on testosterone, it may alleviate some of his symptoms of low libido and things like that, but it could very well and very likely impair sperm production, whatever sperm production there might be, because exogenous testosterone will go and suppress LH and FSH, which will then suppress any other endogenous testosterone, and you need that local neighborhood testosterone in the testes to help stimulate spermatogenesis. Male offspring of men with Klinefelters are most likely to have a normal karyotype, so you can counsel your patients on that. HCG would likely result in an elevation of endogenous testosterone, but unfortunately there just isn't enough research to show if that in fact is enough to help with potentiating pregnancy and offspring down the road. So the ICSI and IVF strategy for Klinefelters seems to be the most appropriate step in helping the couple conceive and have a child. Okay. Looks like it's eight o'clock. I know. So I'm gonna ask you one more question and then we'll probably finish up the hour if that's okay. Sure. As far as testicular size, what's a normal testicular size and when do you think about Klinefelters? Yeah, so that's a good question, because you know, in all of these questions, they always mention the testicular volume, and unless you really go look it up, you kind of get a sense of, okay, this one says 25 milliliters, this one says six, what's normal? And if you have that little necklace of beads in your clinic where you can actually go and measure, it's kind of hard to know, but it's actually less than five, or sorry, 15 I believe is considered, and above is considered normal. And so five cc's is absolutely very small. In people with Klinefelters, you will suspect it when you feel these very, very small testicles. You wanna have that in your mind, because that's not someone who developed normal testes that then kind of started to fade away, for lack of a better term. And these are people who were sort of born with gonads that weren't going to function properly. And so they started out small and they really didn't meet full size so that they were starting from a larger starting point. All right, thank you very much. I wanna take this time to thank Dr. Perrini and Dr. Salem for a great presentation on walking us through these questions and answers and the audience for attending. And so hope you found this helpful and we wish you a great Thursday evening and best of luck in your board studying. Thanks everybody. Thank you everybody. Thank you. Thank you.

infertility

reproductive disorders

Klinefelter's syndrome

polycystic ovary syndrome

treatment options

specific symptoms

goals

diagnosis

management

valuable information