PAG over Pastries
A pediatric and adolescent gynecology review podcast. Started by a fellow for residents, fellows, and others to learn more about PAG topics.
PAG over Pastries
10 - Primary Ovarian Insufficiency & Turner's Syndrome
Dr. Jane Su, a PGY4 OBGYN resident at university of Ottawa, joins Dr. Susan Kaufman to discuss POI with a special emphasis on Turner's syndrome. Both important and life changing diagnoses that cannot be missed!
Outline
- Case Presentation
- Introduction to POI
- Defining POI: Causes and Prevalence
- Clinical Presentation and Diagnostic Approach
- Treatment Strategies for POI
- Turner Syndrome: Characteristics and Management
- Case Conclusion and Key Takeaways
References:
Help us with education research! Please fill out this 4-question survey so we can gather unidentified data on who our podcast is reaching!
What is PAG?
Pediatric and Adolescent Gynecology is a subspecialty of OBGYN (2 year fellowship) focusing on reproductive healthcare for children and young adults. It fills the overlap between general gynecologists and pediatricians. It is a multi-disciplinary field involving work with pediatric endocrinology, dermatology, hematology, surgery, ect. Go to NASPAG.org for more PAG educational resources.
Want to test your knowledge?
PAG WebEd cases are a great way to review our podcast content.
This is a 19-year-old with secondary amenorrhea. She underwent menarche at age 13, and she had regular menses for the first two years. Since then, her period's spaced out and her LMP was eight months ago On exam. Her vital signs are normal. Her height is five foot six inches and her weight is 130 pounds. She has Tanner stage five breasts and pubic hair.
Susan:Hello everyone, Welcome to PAG over pastry, which is a 20 to 30 minute podcast about everything related to pediatric and adolescent gynecology. And I am Susan Kaufman and I'm a pediatric and adolescent gynecology attending at Virtua Health in South Jersey and I am here with
Jane:Hi My name is Jane Su, I'm a fourth year OBGYN resident at the University of Ottawa and I practice at the Ottawa Hospital.
Susan:What Kind of pastry do you like?
Jane:My favorite pastry is a chocolate croissant.
Susan:That happens to be one of my favorites. I'm just going to say chocolate cake with chocolate icing.
Jane:Today we're going to start by talking about primary ovarian insufficiency and then later have a little section about Turner syndrome. We'll discuss how to diagnose these conditions, their prevalence and epidemiology, different etiologies for POI, as well as the evaluation of POI and then treatment for delayed puberty and amenorrhea and special considerations for POI, followed by some specific information about the physical findings of Turner syndrome, associated conditions for those with Turner syndrome and special considerations for that as well.
Jane:So, dr Kaufman, what is the definition of POI?
Susan:So POI refers to a decline in ovarian function prior to the age of 40. We used to call this premature ovarian failure. Even in adolescence we used to use that term, but now, because we know that there can be some resurgence of ovarian function, rather than call it ovarian failure, we call it ovarian insufficiency. Rather than call it ovarian failure, we call it ovarian insufficiency. Another term for this is hypogonadotropic hypogonadism, because it is the ovaries that are not working, whereas the hypothalamus and the pituitary are working, and this can occur in various stages in teenagers, in young women in their 20s and 30s.
Susan:Once somebody hits 40 or over 40, then we're going to call it menopause. When we first begin a workup for this and we're going to go through the testing in a moment we're looking at an FSH that may be greater than 25 milliunits per milliliter and a suppressed estradiol level, and so I don't forget to point it out later I want to say that we have to always get two sets of FSHLH and estradiol when we're doing our testing. We don't rely on just one set of values to make this diagnosis. So what is the incidence of POI?
Jane:So the prevalence of the POI is 0.01% for those under the age of 20, and then 0.1% for those under the age of 30, and then 1% for those under the age of 40. In terms of the epidemiology, we sort of see this higher in Black and Hispanic populations and sort of lower in East Asian ancestry. There are some modifiable risk factors, so, for example, people who are smokers or heavy smokers tend to have earlier age of menopause, and so smoking is a risk factor. What is some of the reasons why people develop POI, dr Kaufman?
Susan:So the most common reason is idiopathic, meaning despite our testing and going through somebody's social history and their developmental history, we cannot find a reason. So about 75 to 90% of cases will be determined to be idiopathic. Sometime later we may find a specific cause. But we also look for autoimmune causes, infectious causes, genetic etiologies and, of course, young ladies that are exposed to radiation and chemotherapy may develop ovarian insufficiency. So what are some of the autoimmune etiologies?
Jane:So some of those are lymphocytic euphoritis, polyglandular syndrome, thyroid disease and an elevated TPO in that case, as well as anti-adrenal antibodies or sort of adrenal and autoimmune causes.
Susan:Right. We used to call this autoimmune euphoritis, where the body is attacking the ovaries and also attacking the thyroid glands and the adrenal glands, so they can be involved in this lymphocytic autoimmune euphoritis as well. What about genetic causes?
Jane:Genetic causes that can cause this include Turner syndrome, which we'll discuss in a bit more detail, both the classic and mosaic type, as well, as you know, fragile X or FMR1 pre-mutation carriers. As well as you know, fragile X or FMR1 pre-mutation carriers. Other ones include Trisomy X, with or without mosaicism, as well as 46XX or 46XY gonadal dysgenesis and some multiple single gene abnormalities, including Sankoni anemia and Werner syndrome, I think. Are there any infections that can cause POI?
Susan:There are, and this list includes mumps, hiv, tuberculosis, varicella, shigella, malaria and CMV virus. And then, without going into detail about specific chemotherapy agents, young ladies who receive chemotherapy for cancer or other disorders and or radiation therapy can end up with premature ovarian insufficiency. So how do these patients present?
Jane:Well, what we're seeing with people who have POI is somebody who has either delayed puberty or primary or secondary amenorrhea. They're going to have that irregular menstrual cycle or irregular menses, and they might also present at the time of infertility workup. Sometimes for these patients they have vasomotor symptoms, so kind of that premature menopause syndrome, and included in that they could also have vaginal dryness, mood changes, sleep disturbance. And in the long term we might see that these people either develop metabolic disorders, osteopenia, osteoporosis, cardiovascular disease and, depending on when they had the POI, they also might lack secondary sexual characteristics as well.
Susan:So if somebody reaches age 13 and they have no breast development and no pubic hair growth, that is a time when we're going to start working them up for lack of appropriate development and one of the things we might find is premature ovarian insufficiency. If a young lady about the age of 15 reaches age 15 and has breast and pubic hair development that's at least 10 or 4, but no onset of menarche, again they may have POI. So what are some of the tests that we want to do when someone comes in either with primary amenorrhea or secondary amenorrhea?
Jane:So I think first and foremost we want to do a beta-HCG just to make sure they're not pregnant if they have, you know, had menstrual cycles in the past and you know, even if they haven't and then we also want to evaluate their thyroid function with the TSH, check their prolactin levels, their FSH, like we discussed earlier, at least with two separate readings at least a month apart, and then the LH and estradiol levels as well, and so those are the main sort of lab tests.
Jane:Obviously we also want to do a physical exam and sort of see their Tanner staging and, of course, vital signs. Then, secondarily, we always usually do order a pelvic ultrasound to assess, just to make sure that we have a uterus, ovaries, and to rule out things like malaria anomalies or any pelvic masses that could be contributing, out things like malaria anomalies or any pelvic masses that could be contributing, and so those are the sort of start line exams. Obviously, down the road, if POI is diagnosed, we want to rule out other sort of etiologies, and so sometimes in those situations we do a chromosome analysis, including a karyotype screening for fragile X or single gene mutations, and then, you know, doing the autoimmune workup that you talked about earlier. So those adrenal, anti-adrenal antibodies, tpo antibodies If we are thinking about something like diabetes, we can also have an HbA1c done just to check for, like sugar or glucose control.
Susan:Right. And also there are times when we want to order free and total testosterone and DHEAS because, again, we need to rule out all other causes for primary and secondary amenorrhea before we diagnose POI, and someone who presents with primary or secondary amenorrhea may or may not have physical stigmata of adrenal hyperplasia or PCOS. So we don't want to forget to do that. And people often ask about why not order ovarian antibodies. Well, they are very difficult to get in the commercial labs, they're often not accurate and should primarily be done under a research protocol. But antithyroid antibodies and antiadrenal antibodies can be markers for autoimmune euphoritis.
Jane:For patients who have POI and they might have risk factors, do we need to screen them for bone density?
Susan:Absolutely so. Once we find out that somebody has ovarian insufficiency and they're not making adequate estrogen, we become concerned about their bone density, because more than 85 to 90 percent of bone density is built during the teenage years into the early 20s. That's one of the complications of premature ovarian insufficiency is not building adequate bone strength. So we do want to get a baseline bone density study, and sometimes that's also a helpful argument when we are counseling parents and patients about POI and making a case for treatment, and then we'll talk about treatment in a moment. But a lot of families are resistant to starting hormone therapy because of all the bad things that they heard about hormone therapy just in general, which is not at all applicable to a teenager with POI. So we get our bone density, we have our lab work, we have a diagnosis of ovarian insufficiency. Let's say that it's idiopathic, so we're not finding a specific genetic cause or autoimmune cause. How do we treat that?
Jane:Well, the mainstay of treatment for anybody with POI is going to be some sort of hormone treatment, and in those with no secondary sexual characteristics then we sort of do a three-phase approach. The first phase is to induce breast development and puberty. So that would start with like a low-dose transdermal patch or oral 17-beta estradiol, beginning at age 11 or 12, with a gradual increase in the estradiol level every six months. We're trying to use that transdermal approach to bypass the first pass effect in the liver use that transdermal approach to bypass the first pass effect in the liver.
Susan:Well, just to add a couple of comments on the estrogen therapy. You're absolutely right, we want to get them to adult levels. We want to get them to what their estrogen levels would be at their age, and the patch gives them a sustained level of estrogen which gives a better therapeutic effect, particularly in terms of bone density. But also want to add that we're using the estrogen to accomplish all the other positive impact in the body that estrogen does to help our brain, our heart, our skin, our bladder and so forth. And again, these can be talking points when we're counseling the family about estrogen therapy.
Jane:Phase two, we want to establish normal menses and achieve bone mineralization. We know that, you know, adding progesterone a bit early might lead to development of more tubular breasts or sort of an undesirable breast shape.
Susan:You're right. We tend to start that once we start to see some spotting. So we know their uterus is responding to the estrogen therapy. Or 18 to 24 months after starting estrogen, and there are a number of different progestins we can use and there's a number of different ways of administering it. We generally like to at least give them one cyclic period so we can be sure that the uterine lining is growing appropriately.
Susan:And some young ladies want to have their period, so they want to feel normal, they want to be like their friends and they want to have a period each month. So we'll give them cyclic progestin and we can use medroxyprogesterone, we can use micronized progesterone or we can use northendrone acetate, and these medications are usually given for about 12 to 14 days each month and then they'll have a withdrawal bleed and then we start them again the beginning of the month. But for young ladies who really do not want to have a period, then once we know we have adequate estrogen and we have adequate response to the estrogen, then we can use continuous progestin and we can use the same medications that I just mentioned, or we could use a progesterone containing IUD if they want to go that route. Contrary to previous beliefs. They don't need to continue to have monthly withdrawal bleeds if they don't want to, as long as we are protecting their uterus.
Jane:And then phase three. We know for long-term maintenance. This is sort of when breast development is complete. We will continue on with adult doses of estrogen and progesterone for a lifetime until sort of average age of menopause around 51 years old.
Susan:Are there any other considerations in patients with POI?
Jane:I think it's important that we counsel these patients that even though they might have ovarian insufficiency, it doesn't mean that they will never ovulate. So about 5 to 10% of these patients can ovulate and conceive spontaneously. So we do want to provide birth control for those who don't want an unplanned pregnancy or counsel them to use barrier protection as well, and obviously barrier protection would be important to also prevent STIs. We also want to discuss the early referral to an REI or fertility specialist because you know, in certain cases these patients might be eligible for reproductive-assisted technologies and the earlier we refer them, the more promising their potential future fertility can be as well as we can offer sort of donor eggs and sort of reassure them that even if there is no way for them to conceive with their own eggs, there is a possibility of donor egg and still sort of carrying a pregnancy down the road. But ultimately these patients need ongoing counseling. It can be a pretty devastating diagnosis.
Susan:Absolutely. It's very difficult to tell a 15-year-old or a 19-year-old that her ovaries are not working and we don't know if they're ever going to work again. So it's really a challenging situation for the patients and the parents. We do want to continue to monitor their bone density, monitor them for any other inadequate estrogen effects on their body. One of the more common genetic causes for POI is Turner syndrome.
Susan:We already mentioned that Turner syndrome is an XO or XY condition. It involves gonadal dysgenesis. So in this case these young ladies are never going to have ovarian function. But having said that, I need to back up a bit because mosaic turners folks may have some early ovarian function early on and they may go into puberty and have breast development and have pubic hair growth and then the ovaries stop working. That can sometimes delay the diagnosis. What are some of the physical findings in Turner syndrome?
Jane:These patients tend to have a short stature. Sometimes they have a webbed neck and more widely spaced nipples and a high arched palate or a low hairline, but overall they can sort of look and appear generally normal. The median age of these patients for their diagnosis is around 15.1 years.
Susan:Some of the other comorbidities that can occur with Turner syndrome include congenital cardiac anomalies, hypertension, thyroid dysfunction, impaired glucose intolerance, hyperlipidemia, celiac disease, hearing loss, strabismus and other ocular problems, dental complications, renal anomalies, neuropsychological behavioral issues and skeletal abnormalities.
Jane:Is there anything differently that we do for these patients with Turner syndrome in terms of their workup?
Susan:Well, we're going to get the same battery of lab tests, because we're not going to know initially, that they have Turners until we rule out other causes, and then we're going to end up doing genetic testing, and that's when we're going to find it. We're going to get a renal ultrasound, we're going to get an echocardiogram, we're going to get a thoracic aortic ultrasound, because many of them can have thoracic aortic aneurysms. We're going to do celiac screening, hearing tests and eye exams. What else do we have to rule out when we're doing their genetic testing?
Jane:I think we need to rule out the Y cell line, but I don't know if there's anything else we need to rule out
Susan:that would be it, so that, you know, should show up when we're doing our genetic testing.
Susan:Okay, so how do we counsel people with Turner syndrome?
Jane:So I would say treatment is very similar to the one we discussed earlier about the transdermal estrogen and progesterone therapy. We also need to sort of inform them about keeping an eye on their bone mineral density with DEXA scans every five years. And then, finally, we also discuss with them their risk in pregnancy in terms of their risk of spontaneous abortion, risk of hypertension due to any cardiovascular complications such as aortic dissection, and this can be more of a high-risk pregnancy. Additionally, we do want to rule out those cardiovascular abnormalities. So an echocardiogram, a cardiac, an MRI are recommended within two years before that planned pregnancy or before any assistive reproductive technology is undertaken, just to make sure that we're ruling out aortic enlargement that might be devastating or life-threatening to the patient.
Susan:This is another group of young ladies that can be sent for fertility preservation counseling With ovarian stimulation.
Susan:It's possible to harvest some eggs for them very early on, especially in the mosaic turners, particularly the ones that undergo some natural pubertal development.
Jane:I'll just go back to the case so that we can finish up. So back to our patient. She has never been sexually active and her beta-HCG was negative. Her labs show a normal prolactin and TSH. Her FSH was 33, LH was 30. Repeat lab work a month later showed an FSH of 45. Her AMH was 0.5 and her TPO was elevated, though her TSH remained normal. Her anti-adrenal antibodies were negative and her karyotype was 46XX and fragile X permutation was normal or negative. So we end up discussing the diagnosis of POI with her and recommend hormone treatment. We also refer her to an REI to review any assisted reproductive technology that might be available to her.
Susan:And, as you mentioned before, we will follow her with DEXA scans, counseling, to help her and her family accept her diagnosis. Well, I think that wraps up our conversation about POI. We hope that our listeners have enjoyed this and picked up some good takeaway points. You can find PAGOver Pastries on the NASBAC website. You can also find us on Spotify, apple and anywhere else that you listen to your podcasts.
Jane:Hi, Camille here with a quick reminder to take our survey on our website so we can get to know who our listeners are for research purposes. Otherwise, thank you for listening to Pag Over Pastries.
Susan:So thank you for joining us and we will see you in our next podcast.
Jane:Thank you so much.
