My name is Larry Lehman. I'm a reproductive endocrinologist and geneticist at the Medical College of Georgia at Augusta University. And what we're going to talk about today is primary ovarian insufficiency in the adolescent. So the management strategies for primary ovarian insufficiency in adolescents protecting long-term health. So the QR code is here. Many of you have already gotten that. But to ask any questions, and there are going to be four questions that we'll ask that, you know, we can take a poll. So I'll give a few seconds for people to be able to get the QR code if you desire. And then we'll take questions at the very end. And I remind you, too, there's only one microphone in this room. So if you have a question, either please come to the, well, please come to the microphone. It's the easiest thing. All right. So the learning objectives are shown here. We'll discuss the clinical presentation of primary ovarian insufficiency, describe a rational diagnostic approach to the patient with POI, explain how POI affects long-term health, and guide the management of POI. So primary ovarian insufficiency, or POI, has been formerly known as premature ovarian failure, and it occurs in about one to three percent of individuals. It's usually defined as three to six months of amenorrhea and hypoestrogenism under age 40 with elevated gonadotropins at least twice, four weeks apart. Something to keep in mind is it can occur prior to puberty, during puberty, or after puberty as well. And it's important to pay attention to pubertal development and stature. That helps guide the management, especially for secondary amenorrhea. Potential etiologies, a few are shown here. Most of them are going to be either chromosomal, genetic, autoimmune. But you know, certainly if the patient has had cancer and has had chemotherapy or radiation, that should also be obtained, that history. So I have the first question here. An 18 year old woman seeks your evaluation because she's never had a period. She gives a history of partial breast development. Her referring physician gave her medroxyprogesterone for seven days and she did not bleed. On physical exam, she has 10 or 3 breasts and a Q-tip was able to be inserted into the vagina. Her estradiol is 10 picograms per ml, with 30 to 50 being normal in the early follicular phase. So which of the following is the next best step? A, expectant management. B, karyotype C, serum FSH. D, transabdominal ultrasonography. So if you want to go ahead and answer if you'd like on using the QR code, I'll allow a little time for that. So she has some evidence of breast development. She didn't bleed to a progestin, has 10 or 3 breasts and a Q-tip was able to be inserted into the vagina. So I'll allow a little bit more time. Okay, so we have about 70% saying serum FSH, 22% karyotype, 7% abdominal ultrasound. So let me go through this. The correct answer is C, an FSH. So she didn't bleed to a progestin. She had a low estradiol level and so she has hypogonadism. So we need to determine the etiology of hypogonadism and an FSH with usually with an LH, we would do to determine if it's hypothalamic, pituitary, or gonadal. So C is correct. Expectant management is not a good option. No one chose that, which is good. She had some breast development, which says she's had estrogen exposure at some point. Delayed puberty is usually defined as age 13 to 14 without breast development, age 15 to 16 without absent menarche. And she's clearly beyond this and needs evaluation because there could be pathology. So expectant management is not correct. Outflow obstruction is unlikely. She has a vagina, so you expect a uterus and ovaries at this time. So transabdominal ultrasound really won't add much here because the uterus and ovaries are often small in anyone with hypogonadism. Hypogonadotropic or hypergonadotropic hypogonadism. And sometimes the sonographer doesn't see the uterus when it's there. So even though this will be useful later, right now it's not terribly helpful. And a karyotype is not needed yet because we don't know about the gonadotropins. When gonadotropins are elevated, then there's a higher chance of a karyotype abnormality. Whereas with hypogonadotropic hypogonadism, that's much less common. So here are her laboratory values. She has an FSH of 57 MIUs per ml, with normal being 3 to 10. An LH of 33. And these are repeated four weeks later and her gonadotropins are still elevated. FSH is 25 and LH 22 MIUs per ml. Her vital signs are normal and we have her height now. It's 155 centimeters or 61 inches and her BMI is 22 kilograms per meter squared. So this patient has hypergonadotropic hypogonadism. Which is the next best step? Is it a brain MRI, a DEXA, a gene panel, or a karyotype? So think about that and we'll register those answers and talk about it. Okay, so we have karyotype is the most common answer. And let's go through it. So the correct answer is D, a karyotype. It's important to rule out Turner's syndrome in primary amenorrhea with gonadal failure because of their cardiac and renal anomalies they can have. Most patients with Turner's syndrome are less than 60 inches. She's 61, but she still could have Turner's syndrome. She doesn't have Turner's stigmata by what we've told you, but it's still worthwhile to make sure of that. Normally you want to ask the lab to count more, to count chromosomes in 50 cells. 20 may not be adequate to detect low-level mosaicism. So counting 30 cells excludes about 10% mosaicism, whereas if you count 50 to 60 you get down to the 5% detection rate. And remember 45x can occur with or without mosaicism. You can have mosaicism with 46XX or 47XXX, and you can also have B45X, 46XY. That's less likely in this patient because she had breast development, unless she had a gonadoblastoma and a predisposed to a germ cell tumor. But that would be very unlikely. You can also have a deletion of the short arm or the long arm of the X chromosome, or you can have an isochromosome where both short arms are lost and you have two long arms. And there are translocations of autosome to X and X and Y that result in gonadal failure as well. So a karyotype is definitely an important component of the management. So A is incorrect. An MRI is important if gonadotropins are low or normal. So in hypogonadotropic hypogonadism we would do an MRI, but not here. A DEXA scan would be important for long-term management, but it won't help us for the diagnosis right now. We know she's hypogonadal, and this won't help tell us that any more detail. A gene panel is not appropriate yet because we don't know if she has Turner syndrome. If she has Turner syndrome, she doesn't need that. So a few brief overview of pubertal milestones. I'm sure this audience is very well acquainted, so I'll go through it quickly. But you know normally breast development is variable ages 9 to 11, earlier in Hispanic and black girls. Growth spurred at about age 12, and on the deceleration of the growth, peak growth velocity, menarche occurs. And in males the growth spurt, as we know, is a couple years later. Tanner staging, we said our patient had Tanner 3 breasts. Remember Tanner 1 is no breast bud, so it's totally pubertal. Tanner 5 is adult. So breast bud is Tanner 2. She had Tanner 3, so she had enlargement of the breast and areola. And in Tanner 4, the areola protrudes and then later recedes when it's Tanner 5. 3 and 5 are often difficult to discern if you haven't followed the patient longitudinally. So I was taught to use age 13 as no breast development and no menarche by 15. You see 14 in the literature and 16 for menses. But we usually rule, you know, begin thinking about seeing patients when this is the case. And what I learned as a fellow, it works incredibly well here with Paul McDonough and Richard Rheindoller. And in patients who have amenorrhea or delayed puberty, it works the same. The same algorithm or flowchart is similar. It's actually similar in males. So you're thinking about getting prolactin and thyroid studies are important, and then you determine if they're hypogonadal. Our patient was hypogonadal, so you do gonadotropins. And if they're elevated, they have gonadal failure and you do a karyotype. If gonadotropins are low or normal, which is inappropriate given hypogonadism, then it's hypothalamic pituitary and you do an MRI. There's also a eugonadal group that's more relevant usually in females. And you examine for outflow obstruction. So in an adolescent, it's not easy to do a pelvic exam, but if they permit a Q-tip, you know that there's a vagina. If you look at the perineum and there's no vagina, then it's, you know, normally either malaria apalasia, MRKH, which are 46 XX, or complete androgen insensitivity, which are individuals are 46 XY. If she has a vagina and is eugonadal, it's most likely PCOS if you've excluded thyroid disease and hyperprolectinemia. So remember in hypogonadism, you have low levels of sex steroids and gametes. So the normal feedback is not happening to the brain and pituitary. And so we get gonadotropins, and if they're elevated, the defect is gonadal. So that's, in this case, our patient. So when do you evaluate? I mentioned 13 or 14 with no breasts, no menarche by 15. Usually three to six months of amenorrhea if they've already started menses. And you want to assess pubertal milestones, as this audience is well aware of. The other thing is associated thyroid or adrenal disease and autoimmunity. It's important, of course, to get a history of malignancy, chemotherapy, or radiation. And a family history, especially a pedigree, is very useful because there could be other relatives with associated anomalies that might point you in the proper direction and or POI in the family. So this is an overview of gonadotropins throughout life. And remember in utero, gonadotropins can be detected at the end of the first trimester, and they peak at about 30 weeks, and then they drop. And then after, and this is presumably from placental steroid feedback on the gonadotropins, but after the delivery, the gonadotropins go up. They become quiescent and then later become reawakened. But the reason I show this is you can, in the little mini puberty that occurs in children, boys maybe up to six months, and then girls up to one to two years. We heard a nice talk on transient theolarchy here, which happens in up to 25% of boys and girls, which I didn't realize until I heard that talk. But gonadotropins are elevated and you can detect hypogonadism. It's really tough if you're not thinking about it, because we don't normally draw gonadotropins in babies. But if there's a family history and you're worried, you can measure gonadotropins. And remember in the quiescent period, childhood, ages two to eight before the pulse generator gets going again, you can't determine if they have gonadal failure. On physical exam, you're going to do all of the things we mentioned, height, weight, thyroid in particular. You're paying attention to tanner staging, breast and pubic hair. So a pelvic exam is probably best avoided in somebody who's hypogonadal. Certainly not a speculum exam. But if they'll permit, at least to look externally and have them valsalva and see if there's a vagina. And if they permit it, you can place a q-tip into the vagina. And you would expect, you know, a patient with POI should have a patent outflow tract if you don't find a vagina then other etiologies other than POI need to be considered So this this overview of the evaluation, I think works pretty well So if gonadotropins are elevated It's gonadal failure, do a karyotype and if they're low or normal, it's hypothalamic pituitary So how do you tell about hypoestrogenism? Well, the obvious way is to draw an estradiol level, but that's not always helpful First of all breast development. Is there breast development? If the answer is no, then it's highly likely they're hypoestrogenic There have been several cases. We described one Where patients have variants pathogenic variants in the estrogen receptor alpha gene ESR1 Where you can have very high levels of estradiol and no breast development, but that's incredibly uncommon If they have estrogen exposure and they have breasts that tells you they've had it at some time It doesn't mean it's occurring right now So certainly doing an estradiol is very helpful if it's really low if it's a very sensitive assay If it comes back 10 picograms per ml, you feel pretty good. It's 25 or 30 It's a little less clear and sometimes we do a progestin withdrawal test Will you give something like medroxyprogesterone for seven days and if they have a decent period then that indicates Estrogen stimulation of the endometrium if you're spotting or there's just very light flow or no flow Then that more suggests hypogonadism We don't do this as much anymore But if you put a q-tip in the vagina to document patency you can roll it on to a slide Stain it with a urine stain that stains the nuclei and look at it under a microscope So, I mean I'm not a pathologist, but you know to tell a superficial cell which indicates estrogen status You can tell versus a parabasal cell the small cell on the left with a huge nuclear cytoplasmic ratio The thing is they're not always very black and white But when there's a predominance of superficial or a predominant pair of basal cells, that's helpful So the patient We did a karyotype on the patient and you have to think about Turner syndrome Which is from the Medical College of Georgia series It was 25% of primary amenorrhea and a little and about a half a percent was secondary amenorrhea short stature is the most common feature and If you look in the literature about 10% of 45x and about 50% of 45x mosaics have puberty But there's usually not long-term follow-up and menses are usually short-lived You definitely want to exclude a 46xy cell line because of dysgenetic gonads I didn't put the other Turner stigmata up here, but you know, there's shield chest and wide-space nipples and Madelung Deformities and all the other things that can happen when we see them at least as a reproductive endocrinologist Most of those kids have been identified. So the ones we tend to see are ones that have none of those They have short stature, but we know that cardiac anomalies are in about half of these kids. So Coarctation dilated aortic root and valvular anomalies and you can also have renal anomalies as well Pregnancy is realistically Best handled with donor egg IVF and we'll talk about that briefly, but there are aortic rupture concerns So in the laboratory diagnosis of POI, you know doing an estradiol Gonadotropin, thyroids with or without free T4 prolactin are reasonable to do And you diagnose it if you have low estradiol and two sets of gonadotropins that are elevated in the US Usually 40 miu's per ml is the cutoff in Europe It tends to be 25, but the reality is if it's elevated in their amenorrheic and hypoestrogenic Doesn't matter the exact value And remember accounting The number of chromosomes in 50 cells is reasonable when you suspect a Turner Mosaicism. So really in all patients with primary amenorrhea Because it's incredibly common to have It's more than half of them have in our series had Turner's syndrome. Short stature If they're under 5'3 with secondary amenorrhea We also would karyotype them because we occasionally see the patients with recurrent pregnancy loss and we're looking for a translocation And we realize it comes back 45 X 47 XXX and you realize oh, she's 4'11 We've missed that so regardless of the presence or absence of Turner's stigmata. It's good to have chromosomes Okay, so here's our next Question her karyotype is reported as 46 XX with 50 cells counted More detailed family history is obtained and she states that her mother had menopause at age 33 Her maternal aunt without children had some type of tremor and she has a first cousin with autism So which of these genes would you consider it given this? phenotype and this family history So FMR1, FOXL2, FSHR or SHOX So allow a little time for people to vote Okay Okay, so 75% said FMR1 and we have FSHR and FOXL2 and maybe one vote for SHOX So, let's look at this So the correct answer is FMR1 It's the gene involved in Fragile X syndrome It's an X-linked dominant disorder with reduced penetrance due to a full expansion of a triplet repeat CGG in the 5' untranslated region of the FMR1 gene Normally, we have 5 to 50 repeats and if you have an expansion of that It's called a pre mutation and that's 50 to 200 repeats And if you have the full mutation That's more than 200 repeats and when that happens you get methylation of the promoter the gene is inactivated So so that's with a full mutation with the pre mutation. It's an RNA overexpression mechanism So it's different so the phenotypes can be different with the full mutation Males have variable degrees of intellectual disability or autism that can have facial abnormalities and macro-organism Females can have intellectual disability with the full mutation, which is usually less severe But they don't have POI. So the full mutation is not a risk for that. The pre mutation is and It depends how you look at this if you look at females and known Fragile X syndrome families And the risk of POI is 15 to 20 percent However, if you ascertain a woman with POI and there's you don't get a family history of Fragile X if there's no one else affected the chance of her being a carrier is about 3 to 4 percent However, if she has a sister or an aunt that also have POI it goes up to 10 or 15 percent because now it's more likely to be a Fragile X family So these patients have an increased risk of tremor and ataxia when they get older both males and females it's a little bit higher in males, but that's significant and that was recognized in the last decade or so So Answer B is not correct here FOXL2 is an important gene in the ovary and certainly variants do cause POI But it causes an interesting I always thought this was really interesting that you can have eyelid abnormalities with POI blepharophymosis ptosis epicanthus syndrome In which you have eyelid abnormalities and POI and this is autosomal dominant Answer C FSHR is incorrect because these are associated with resistant ovary syndrome They were identified in Finland all the patients have the same pathogenic variant It's incredibly uncommon outside of Finland that variant especially And this is an autosomal recessive disorder SHOX variants may cause short stature Or they can cause Larry wheel dyschondrostiosis or Langer Mesomelic dysplasia both of these have skeletal anomalies among others and they're X-linked None of these disorders Answers B C or D or is associated with intellectual disability or tremor ataxia Like fmr1 and and all of them are actually pretty uncommon So in 46 XX POI we have to worry about autoimmune thyroiditis TPO antibodies have been suggested to be obtained Addison disease. We have to be Cognizant of that 21 hydroxylase antibodies or am cortisol is reasonable and type 1 diabetes Should be followed in these patients genetic testing usually fragile X is definitely worth considering a Targeted POI gene panel can also be considered and remember a targeted panel if it's next-generation Sequencing may not pick up fragile X because it's an expanded repeat. So you need a specific test for that So the the main thing to remember with fragile X the full full mutation more than 200 repeats It's a null mutation where the promoter is methylated not associated with POI Whereas the pre mutation which is probably the most significant cause Is associated with POI and it's an RNA overexpression Mechanism and then these are the both males and females are at risk for tremor ataxia There are a lot of genes have been studied and there are a lot of papers in the last few years and It's not clear We know that probably at least 25 or 30 percent of patients with POI may have pathogenic variants and diseases These are the ones Categorized in OMIM online Mendelian inheritance in man and They call them POF1 to 19 and ovarian dysgenesis These genes have been have been reported to have pathogenic variants more than once or twice There are a lot of new ones that have been Identified and I think time will tell I mean I think most of these are pretty uncommon But by the time we get more of the genes known Well, it'll be very useful But I think to say that there are 50 to 70 that are causative is a little premature I mean they certainly may affect function, but they need to be studied and within family studies and in vitro analyses So, how do we treat this patient? We're going to give her estrogen treatment that will help complete her breast development You're trying to prevent osteoporosis down the road cardiovascular disease and you can use oral or transdermal Once breast development is completed or you get vaginal bleeding We usually add a progestin to protect the endometrium and it's also reasonable to consider oral contraceptives As an acceptable alternative You don't really need the estrogen free days, though So usually you're going to treat people till their you know normal menopause age this Estrogen treatment does not give the same risks as menopausal hormone replacement Certainly when they get 50, then you have to readdress things Estradiol of course is important for protecting against bone loss that could lead to osteoporosis preventing urogenital atrophy and pain with intercourse and preventing cardiovascular disease So I have another question here this patient now we've counseled her She has questions about infertility because they're usually pretty concerned with this She should be counseled that her chances for for getting pregnant are A 5% B 25% C 50% D 75% Okay Okay, so we have 73% Say A and we have some that answer each of the others. So let's go through that the correct answer is A Expected management and ovulation induction or even IVF with her own eggs offer very low pregnancy rates The thing to keep in mind is patients with POI and a normal karyotype The ovarian function can wax and wane and you never want to tell them they'll never conceive You don't look good when that's the case, but I usually tell them it's less than 5% per cycle Because I've had a couple I mean I've had a patient who early 20s. We did that a month or two later She was spontaneously pregnant, but she had clearly elevated gonadotropins and was amenorrheic and had normal chromosomes Only egg donation right now has the potential to result in pregnancy rates of about 50% So depending of course upon sperm and uterine factors so The pregnancy rates are low even with expected management or oral medications like clomiphene injectable gonadotropins or IVF and the pregnancy rates are particularly closer to zero for Turner's syndrome if you don't If you don't treat them there are some other methods people have talked about of giving estrogen first and trying it or using steroids and then inducing ovulation and the pregnancy rates we can talk about that if there's a question, but it's maybe in certain circumstances So if the patient has Turner syndrome We need to do an echocardiogram To rule out you know to look at whether there's a dilated aorta a bicuspid aortic valve or coarctation, and regular follow-up is suggested to reduce aortic dissection. I was having trouble finding specific guidelines, but at least every few years. And where we really try to dissuade people from egg donation and the patient with Turner syndrome carrying it, because of the risk of aortic dissection, which people liken this to similar to Marfan syndrome, where you have instability in the vessel. And even in patients that have no risk factors and have normal echoes, can still rupture the aorta or dissect postpartum. Baseline kidney ultrasound is also good to make sure there's not a horseshoe kidney or missing a kidney on one side. If patients are 46XX, then pregnancy with egg donation is safe. In pre-mutation carriers, you wanna counsel them, because there's a 50% risk of her son being affected, so 50% of boys will be affected, since she has one X with the variant one wild type. And 50% of her daughters will be carriers. The FMR1 status is useful, even if pregnancy isn't possible. So in our patient, she's probably not gonna get pregnant, but if she has a sister or an aunt, they could be at risk for having a child with intellectual disability. Most of the disorders that are on that panel I showed you and that have been reported are autosomal recessive. So even if she has bi-allelic variants and she does get pregnant, it's uncommon that the partner would have to be a carrier as well. And we definitely wanna consider thyroid, adrenal, and diabetes yearly assessments. I wanna mention a little about the polyglandular autoimmune syndromes. Those are generally diagnosed when there are at least two endocrinopathies, and they may be associated with non-endocrine autoimmunity, pernicious anemia, lupus, gastritis, myasthenia gravis, rheumatoid arthritis, and autoimmune hepatitis. There's a juvenile form, type one, and then the adult forms are two, three, and four. All of these are more common in females. And PAS1 is monogenic, it's autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome, and it's very uncommon. I've not had a patient with it. Autosomal recessive disorder due to pathogenic variants in the AIR gene, which was the first gene that was identified that was a genetic cause of an autoimmune disorder. It's a transcription factor expressed in the thymus and protects against disease by eliminating autoreactive T cells. And the phenotype is pretty unusual. Most children have chronic mucocutaneous candidiasis, covering up to 5% of their body surface before age five. Then they get hypoparathyroidism, which is the first endocrine disease, and they get hypocalcemic tetany in 75% of patients. By age 15, they get Addison disease usually. And they can get these other disorders as well, diabetes, autoimmune thyroiditis, but you can see hypogonadism is very common in this entity. It's 60 to 65% and also is present in males. You can also have other non-endocrine autoimmune conditions. For the adult forms, PAS2 and 4, they're more common as a group. The genetics is not as well characterized. They're probably polygenic multifactorial. There's some evidence that some are autosomal dominant, so you would want to counsel on error on the side of safety and maybe counsel that it could be a 50-50 chance of passing it on. PAS2 is Addison disease with one other endocrinopathy. PAS3 is type 1 diabetes and autoimmune thyroiditis. PAS4 is heterogeneous with two endocrinopathies that don't fit into either category. And these are nicely summarized in this paper by Kahali and Fromer. PAS involves both cellular and serologic immunity with breakdown of self-tolerance. Immunogenetic markers can distinguish the different adult types. Affected patients usually have high titers of gamma isotope antibodies that correlate with the severity of tissue destruction. In these adult forms, hypergonadotropic hypogonadism is less common than with PAS1. So in conclusion, the diagnosis of POI in adolescents really consists of amenorrhea, estrogen deficiency, and elevated gonadotropins. It's important to exclude chromosomal anomalies in all adolescents with primary amenorrhea who have gonadotropins that are elevated. And consider those with secondary amenorrhea and elevated gonadotropins based on stature. Don't forget about Turner's syndrome in the absence of somatic anomalies. And then we always have to keep in mind autoimmune disorders and pathogenic variants and POI genes probably is gonna be very useful coming up in the next decade, I imagine. It'll be fairly standard. And of course, knowing a history of chemotherapy and radiation should be considered. Estrogen treatment may alleviate the vasomotor and neurogenital symptoms. And estrogen, of course, is important. We know it decreases the risk of osteoporosis and probably cardiovascular disease in these individuals as well. And practically speaking, fertility is extremely unlikely without egg donation, even though there are a lot of methods that people are looking at right now, still egg donation is probably the best. So I think I'll stop there. And if anybody has questions, I gotta see. Thank you. Go ahead, sure. Thank you for a wonderful talk. Is there any commercially available ovarian antibody assay that we can order? I think there are some. I mean even Nelson's group from the NIH didn't think they were always terribly accurate. But yeah, I think there are. We don't usually order them. And the next question was, could you elaborate a couple minutes on the estrogen replacement protocol for this patient, knowing that she's already 18? I mean, we tend to give her either transdermal estrogen or a pill. Most of my patients have wanted a pill. So I mean I usually just use 0.5 milligrams of estradiol and we reassess them in a few months. They tolerate it well, go up to 1 milligram, and then base it on the breast development. And then when it's adequate breast development, then adding a progestin. And then we talk about oral contraceptives if they want to do it. And we don't measure any levels at all? I don't usually. You can. I mean if you're worried they're taking too much, like if you end up raising their dose and the levels, then it's helpful, I think, to do. But we've usually used the bioassay of the breast. I mean, but if you give increasing doses and you're getting no breast development, then I would definitely check an estradiol level. It's very reasonable. And the progesterone, would you give like 12 days in a month? Yeah, I mean there's been argument, debate of that over the many years. You can use 7 to 10 days. I mean as long as you're following the patient and they have regular bleeding. We used to use 14 days, and then the WHI study came out in the early 2000s because some of the, especially the progestin, was more worrisome for breast cancer. So you're weighing against protecting the endometrium with potentially increasing the risk of breast cancer. So I think you can do 7 to 10 days is fine. Thank you. So is this, Corey, this is not on? I can't tell. Oh, there it came. Okay, let's see. Does anybody else have any questions? Let me see if any have showed up here. I had a question about bone health monitoring and how you ensure that they're taking enough estrogen to maintain bone density. I'm sorry, can you repeat that again? Sorry, how do you make sure they're taking enough estrogen to maintain bone density long term? How often are you kind of monitoring that? Yeah, I mean I don't usually do it right away. I mean I think once they've become, once you've gotten breast development and they're menstruating, then I think it's reasonable to do a DEXA scan and follow it periodically. I mean I think a lot of this is unknown right now. So I think if, you know, we talk about exercise and everything as well. But I think you can, you know, repeat a DEXA periodically, maybe 3 to 5 years. But I think most of the time if they're taking things, taking their medicines and they're bleeding and they're progressing, I think you're okay. Let me just see if anything else came up here. What's the role of AMH for fertility prediction? Pardon, oh another, okay, sorry, go ahead. Hello, Christa from Switzerland. Do you have any experience putting them on a long term cycle? Like most of the youth like that, that you give them two packages of pills in a row and then they bleed less? Yeah, that's true. And then long term outcome? Do you have any experience? Yeah, we use that too. I think people, at least in our experience, tend to have more irregular bleeding if you use the three month packs. So usually I put them on a regular one. And then after they've become, they're used to the OCPs where they bleed every month, then they can switch to every two or three months. But I think that's very reasonable. I mean, you know, your pills are progestin dominant, you're protecting the endometrium, so you're okay. And also bone should be an issue, right? It shouldn't be an issue. I mean, you know, when you look in the literature, some people say maybe pills aren't as good. Others say it's fine. So I think as long as they're getting estrogen, they're okay. And maybe a second question. Do you have any new data comparing transdermal over oral? No. I mean, in the one review I looked at, they were both acceptable in some cases. I mean, certainly if the patient has more metabolic problems, they're obese, you know, you would try to encourage transdermal. But I usually leave it up to what they prefer. Okay. If there's nobody, a third question. Sorry. Because I'm a pediatric endocrinologist. If you start early, because you diagnose them early, is there a preference of preparation? Or do you do also the same scheme like in Turner's? That slowly do you... Yeah, I just usually slowly go up. I make sure they can tolerate it and then follow breast development. Yeah, because then you attain the final height, right? Yes. Thank you. Yeah. So there are a few other questions here. The role of serum AMH for fertility prediction. I didn't see anything in these patients, but their AMHs are likely to be low. You know, that's not always the case, especially if FSHR variants. There is at least one case published. And as we know from the Finnish group that a lot of those patients, they had primary amenorrhea, but also had a bunch of follicles. And that's where the term resistant ovary syndrome seemed like a genetic reason for that. There have been... There was a case that I reviewed in the last year or two where the woman had ovarian insufficiency. Her AMH was 4.3, and she had a lot of follicles. So usually an AMH we think of as 1 to 1.5 nanograms per ml is reasonably good. Hers was 4, and she elevated gonadotropins, and they presumed an anti-FSH antibody, which they didn't study, but they treated her with prednisone for several weeks and then stimulated her with gonadotropins, and they got... And IVF got 30-some eggs, whereas they had already tried gonadotropins and GnRH agonists prior to that and didn't get any at all. So I think, you know, if you do have a high AMH, you know, it's probably worth looking at. Most of them you would expect would be low. But if you have somebody who has an AMH of 2 or 3 or 4 nanograms per ml, then that person may have a chance at stimulating down the road. So the other one is the usefulness of ovarian cryopreservation. There are some other methods that people are looking at now. They're looking at activation, you know, follicle activation. I heard some talks at this meeting on using, like, P10 inhibitors or PK3 agonists, and so to try to do that, but it's still kind of experimental. It's not clear whether that will help. Using steroids on everybody, to me, seems a little premature. But, you know, if you had a patient who had one of the polyendocrinopathy syndromes and they had follicles, they might respond, you know, for fertility to giving steroids. I think that should probably be looked at, but probably not blanket giving it to everybody. Freezing eggs can be done. You'd have to biopsy the ovary. That's not terribly easy to do in a hypogonadal ovary. People have also started trying to use plasma-rich proteins and inject it into the ovary and to use stem cells, mesenchymal stem cells, and also, you know, induce pluripotent stem cells. But that's still a little bit early. I know in mice the fertility has been obtained, and in humans, at least what I can find, is they've generated oogonium, but it didn't progress beyond that unless somebody knows anything more recent than that. But I think those down the road may be useful, but they're still experimental right now. So I think I've hit everything here. Anybody else have any questions? All right. Well, thanks for staying from the last day. Thank you.

POI

adolescents

management strategies

long-term health

etiologies of POI

chromosomal abnormalities

interactive discussions

infertility