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
9 - Primary & Secondary Amenorrhea
Dr. Julie Cron, an OBGYN with PAG certification at Presbytarian and Cornell, joins Dr. Camille Imbo PGY6 to explore amenorrhea - the absence of menstruation - breaking down how to evaluate and diagnose this important vital sign in adolescent patients.
Outline
- Introduction to Amenorrhea Types
- Physical Exam Importance
- Hormonal Evaluation & Causes
- Understanding Lab Results
- Genetics and Structural Causes
- Secondary Amenorrhea & PCOS
- Case Discussion and Conclusion
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.
All right let's get started.
Camille Imbo:So, Julie, let's talk about amenorrhea. What is it and how do we categorize it
Julie Cron:The first thing that I always think about is is it primary or secondary? However, I think importantly, the workup is essentially the same for both of them, for particularly the learners out there know the difference between the two but recognize that the evaluation and workup is the same. Primary, obviously, is the absence of menarche. A patient has never gotten a period in someone that's 15 or older, with or without secondary sexual characteristics.
Camille Imbo:I talked about this in the puberty one, but I always thought about the age that you needed to be to reach a certain milestone, but not the differences between each milestone.
Julie Cron:Yeah, so I usually think of puberty as normal sequence, but also normal tempo, right? So the normal tempo between telarchy and menarche is about two years. Therefore, if you go three years without menses after telarchy, that is not normal Secondary. I like to keep things simple, so thinking of it as no menses for six months.
Camille Imbo:Yeah, I know there's also whether the number of cycles in a whole year, and if you ever spoken to a teenager, they can barely remember three months back, much less the entire year. Right, and so you know why is this even important. Why do we talk about this? So there's a lot of crossovers between all the topics that we record. With this, we're going to bring up a lot of the things we talked about in puberty, but puberty is important. That's how you reach your adult height, your bone strength, your sexual characteristics and reproductive capabilities, or, in other words, fertility. Not having periods is a huge part of that, and what I often tell patients is it's not so much that you're not bleeding I don't care about the blood itself, it's just. That's what tells me. What's going on with your hormones, or your lack of periods, whether for the first time in primary or secondary, is how I know that something's not right.
Julie Cron:It was NASPAG that was instrumental in having us all think about the menstrual cycle as a vital sign, right? The acquisition of menses is a signal that things are proceeding normally, and so the absence of that means we have to investigate because something is not right.
Camille Imbo:Right, yeah, and a little asterisk too, depending on who's listening when we're talking about amenorrhea and not having periods that's not on purpose.
Julie Cron:Correct. I think that's important because I think there's a lot of people out there that think not having their period is really abnormal, even if they're on birth control pills. But I agree we have to qualify this as this is not on hormonal modification.
Camille Imbo:And that kind of leads us into what are the questions that we're asking? And starting with primary amenorrhea how are you evaluating?
Julie Cron:Primary amenorrhea. The physical exam, ie the genital exam, is vitally important.
Camille Imbo:And this comes up with pretty much every topic we've recorded. It's something that can be a little bit scary for our patients and apprehensive, so I'll explain why it needs to be done. And if they're still not convinced or nervous in that first visit where I'm like that's fine, you just met me, then there's some workup we can do. But then it's like the next visit you're aware that it'll need to happen.
Julie Cron:Yeah, and I think important also for patient and the patient's caregiver is that a general exam does not equal a speculum exam. So now you've decided you are going to do the genital exam, what are you looking for?
Camille Imbo:I started with the basics. You know the heart ungs feeling feeling for the thyroid I think sometimes we forget about that as well For breast development, and I talk to the patient about what they prefer, whether they want to keep their own clothes on and just kind of show one breast at a time, because in this situation we're not doing a breast exam like you do on adults, where you're feeling for masses, you're really just Tanner staging. I'll look at their axillary for hair growth. What are you looking at when you do a genital exam?
Julie Cron:First, just the external genitalia. Do you see any evidence of pubic hair? What does the labia look like? Does it look like it's estrogenized Distal to proximal right? So, hymen, transverse septum, absent vagina, essentially and I think it is really important to differentiate between the imperfect hymen and the transverse vaginal septum, because the surgical approach to those is drastically different and recognizing that the transverse vaginal septum repair is a complicated repair that should not be done in practice untrained hand and sometimes it's not so obvious by the physical exam alone. And this is where further imaging, like an MRI, will help you.
Julie Cron:You really need to talk to your radiologist and you need to have a radiologist that knows what they're looking for,
Camille Imbo:right, yeah, measuring the thickness of the septum, at what level it is, and again, a lot of this will depend on the comfort of the patient, but using a Q-tip sometimes to make sure, because I've had some where I think there's a hymen abnormality but I really just needed to open a little bit more or use a Q-tip to find my way If really absolutely needed an exam under anesthesia where you're not necessarily moving forward to doing anything, but it gives you more opportunity to really take a deeper look before making a final decision to really take a deeper look before making a final decision.
Julie Cron:I once saw a younger patient. She was around 14, but unquestioning, like when she had breast development. She really was like four years past, but she was 14.
Julie Cron:So no one had worked her up
Camille Imbo:, and this is why this is so multidisciplinary, because our pediatricians are most likely to be the ones to see this first, because they're following them in those early years, and it's not until it's identified as a problem that we may see them.
Julie Cron:The other things that are important, whether there's any physical signs of androgen excess you know, when I'm thinking about amenorrhea. Those are the things I'm thinking about the general exam, the breast exam, and like looking for androgen excess.
Camille Imbo:Yeah, the physical exam tells us about the hormonal status, so androgen and estrogen specifically. So to break that down a little bit more, when thinking about the estrogen aspects of sexual characteristics, what are you looking for?
Julie Cron:Adequate breast development equals adequate estrogen, right. So breasts, equal estrogen. If a patient has breast development appropriate for her age, then we have reason to believe she has appropriate estrogen production. When we think about androgens, we think about basically axillary and pubic hair.
Camille Imbo:And that's something I really actually love about things like primary amenorrhea is, as you're talking to the patient and examining the patient, you're answering your own questions. So if we have a patient who doesn't have any breast development and essentially looks like they're in a hypogonadal, low estrogen state, can you tell us kind of what the different ideologies of that would be and what your thought process about that is?
Julie Cron:Yeah. So number one, you either have no ovaries or your ovaries are not making estrogen, so gonadal dysgenesis, which we think about in Turner's and in Swire's syndrome, so that's like no ovary essentially. Then you think about the ovary is not working correctly, to classify that primary ovarian insufficiency due to either chromosomal things, iatrogenic, such as chemo or radiation. And then the enormous category of we don't really know, which we think is probably autoimmune but we don't know for sure, moving up in the world, we think about hypothalamic causes, so the Kalman syndrome, and then just constitutional delay. And then the category of what we call now REDS, relative Energy Deficiency Syndrome, which I kind of put disordered eating as like a subcategory of that Another we don't really know category, for example the patient that is undergoing significant stress. And I think that's a big category that we see and we can't pinpoint a exact ideology to it.
Camille Imbo:I mentioned in the puberty podcast, but it was shown that after COVID there was a lot of delayed puberty, just kind of that generic stress and anxiety that happened in a lot of kids. When I talk to my residents or med students who are going in to interview a patient, you know when the MA comes in and says, oh, she's here because she doesn't have periods. You should have these differentials in your mind. Yes, we're doing the HPI before the physical exam. But sometimes you know I'll realize, oh, I didn't ask this question. So I do the exam and don't see any breasts and I'm kind of taking a step back of wait. Any history of cancers? Any history of chemo? What's your eating like? How much do you exercise? All those types of things? And then what if they do have breast development?
Julie Cron:Going back to the primary versus secondary. So somebody with normal breast development, you really have to think about those anatomic causes, most notably the imperfect hymen, mrkh and the transverse vaginal septum, and that is why you have to do an exam in these patients. So that's the primary and then the secondary amenorrhea for the normal estrogen. So the breast developed patient, then we think about PCOS and then the other things that cause anovulation. The third category is the androgen insensitivity.
Camille Imbo:Something that we didn't quite talk about too, you know, looking at breast development, which is kind of a more obvious one, but unfortunately childhood obesity is a thing where sometimes I'm like I can't tell is this breast, Is this adipose tissue? So, if they're comfortable, part of the vaginal exam can be looking at their labia minora, looking at the discoloration, if it's more of that red pre-pubertal. So there are other ways to assess for estrogen levels in the physical exam, which is really great.
Julie Cron:That's a great point. So now you've done your history and physical right and so now you start thinking about labs, and my really simple lab workup is FSH, lh, prolactin, tsh plus or minus your androgens, depending on what your physical exam is telling you. Your testosterone, which you're looking for, you know, your kind of classic PCOS. Your 17-hydroxyprogesterone ruling out late-onset congenital adrenal hyperplasia, and then your DHEAS, looking for an adrenal tumor that will essentially result in secondary amenorrhea because of anovulation essentially a hyperandrogen state. Myrminorrhea because of anovulation essentially a hyperandrogen state. I just went to talk about appropriate lab given by a pediatric endocrinologist here at NASPAG. Yeah, talking about normal values, you have to look at it in relation to age.
Camille Imbo:I feel like if I asked 100 people they have different answers that all the labs and all the ultrasounds, everything all at once or order as you go, depending on what you find?
Julie Cron:Yeah, I mean, I feel like getting multiple lab draws is not ideal, particularly in young people, and it's like logistically challenging and also some labs have a cost associated with going to the lab, right, so I am an do all, but do you do your androgens at that same time? And I usually base that on the physical exam and then the history. I usually don't do the ultrasound right off the bat.
Camille Imbo:Okay, Ultrasound I'll throw in. Part of that is also institution dependent of do you have an ultrasound in your office? Does it need to be scheduled? Sometimes I'll order it and be like hold on to this, to like call you back with the lab results and I'll tell you if you need to go and do it. The one that I definitely hold off on but even that I've seen people are different is chromosome analysis, and while we tell people not to pigeonhole into a diagnosis, sometimes you're fairly sure you're leaning towards one thing, so there's not necessity to order everything else. But I agree with your baseline.
Julie Cron:And I think also we have to also caveat of pregnancy tests, Like let's we're just going to put that out there that everybody that walks in the door is getting a pregnancy test, whether it's primary or secondary.
Camille Imbo:Yes, so starting with LH/FSH. So if we kind of break down the results that we would get, so if you get a low FSH and LH, what are you thinking?
Julie Cron:Yeah, so then you're thinking about hypo, hypo, right? So remember, we went back to the hypo. Hypo is Kalman syndrome and for those of you that are out there studying for exams, that is the one where you have the lack of smell, because development of your olfactory neurons and your GNRH are in the same pathway.
Camille Imbo:And then we've briefly kind of talked about this of constitutional delay of puberty. It's a diagnosis of exclusion, right? There's not necessarily a lab or anything that'll tell us. It's probably one of the more frustrating ones to tell a patient of like, oh, you've just been really stressed. Or also thinking about their family members, right, is everyone delayed? And so if mom didn't get her period until 17 and was told that was normal and sisters are the same, then that's probably true as well. But I would advise to probably follow them closely.
Julie Cron:Yeah, and this is where family history is really important, absolutely. What are your thoughts on when to do a head MRI?
Camille Imbo:I think if you're not finding an answer before just saying oh, it's quote, unquote, just constitutional delay, you can't say you've done a thorough exam without doing the brain MRI.
Camille Imbo:And then, of course, if there's certain things like an elevated prolactin or
Julie Cron:Right, and going back to our like functional hypothalamic hypogonadism, the stressed out kid probably at some point deserves an MRI of their head.
Camille Imbo:The way I break down to patients is something can be wrong at one of three levels either your brain not releasing the hormones, your ovaries not slash, uterus not responding to the hormones to do their part, or anatomically, things just aren't working and exiting like they should. So this would be that first level where it's like GnRH is not LH and and FSH appropriately, for whatever reason. Now what if our FSH came back elevated?
Julie Cron:Interestingly, we haven't talked about checking in estradiol this is where in general. I don't. I don't put that in the initial workup but, for example, if you are looking for primary ovarian insufficiency, it can be helpful and throwing along that in
Camille Imbo:AMH as well.
Camille Imbo:It can be helpful to know just how detrimental the function of their ovaries is, because the question about reproduction always comes up.
Julie Cron:If you have an elevated FSH. Basically your brain is trying to turn on your ovaries so you can have your iatrogenic chemo radiation, you can have your chromosomal. So your Turner syndrome or the giant, giant category of we don't know why, we think it's autoimmune, everything else right. To me, gonadal dysgenesis kind of fits into two categories Turner's is XO, right, and so they generally are not having estrogen production. It's not always complete expression, but in general when we think about Turner's we think about gonadal dysgenesis, lack of pubertal development, ie amenorrhea, and so I remember, you know, learning about androgen insensitivity syndrome, what we used to call I don't know if you even know this we used to call it testicular feminization. Oh no, yeah, you know the phenotype is somebody that is very well estrogenized. Usually they have very developed breasts and they have the typical body habitus suggestive of female, estrogenized female, but absolutely no axillary or pubic hair.
Camille Imbo:Yeah, it's an interesting one, and I think of all the different types of hormonal abnormalities or DSDs that can be hard to get a conclusion to, especially because there's not always a full AIS Exactly, so they'll have a little bit, and so that's where the combination of labs and what you have in physical exams and then, as we talked about, chromosome analysis then comes into that and if you get XY or any variation of that, that kind of answers your question too.
Julie Cron:Yeah, in terms of management, whether they want a vagina, what are their goals? And the difference here is we have to think about what to do with those gonads, right, so in the MRKH patient they're gonads are completely normal, but here there is a risk of malignancy. The general thought is that it can be monitored, but at some point those gonads need to come out.
Camille Imbo:The NASPAG conference, I think two years ago there was a conversation about gonadectomy and when that is necessary and up to a certain point, ais was always thought I think it was like two years old, you remove the gonads. But then there's been a lot of conversations of is that necessary? Can you wait until the patient's older and gives consent
Julie Cron:. Yeah, I would say that's kind of like an emerging topic, right? And then there's always Swyer syndrome, which is inactivation of the SRY gene or the sex determining region on the Y chromosome. I like to simplify it as, like, the female pathway is the default, right? So if your genetics don't say go to the male pathway, you, by definition, the default is to go the mullerian development to uterus and tubes. But remember, embryologically uterus and tubes. But remember, embryologically your gonads are different than your Eulerian structures. So you have female uterus tubes but you are XY and basically your gonads do not develop. In the Swire syndrome they present with absent puberty, essentially an external female phenotype. Those gonads are non-functional and should come out as soon as the diagnosis is made.
Camille Imbo:Yeah, and a lot of these get kind of muddy. We talked about XY when we mentioned AIS, and then again with SWYERS. And a big difference is with SWYERS, right at the beginning, basically the Y chromosome didn't do its job. It didn't tell the body to not be female, while AIS it did. And so everything is developed, but the receptors aren't working. So they have the testosterone, but just not expressing it. And then the other part of it is with AIS. When you look at it from a structural standpoint, you are missing the malarian anatomy, which now looks like MRKH. So how do you differentiate those two
Julie Cron:Right, essentially with your karyotype, right, because remember AIS is XY and MRKH is XX, right?
Camille Imbo:So pretty much end of story. That's the answer.
Julie Cron:Yeah, we pass, or test right?
Camille Imbo:Talking about MRKH a little bit more, it's more common than AIS about one in 5,000 patients. It's the failure of malaria and duct formation. So what they'll have and this was another go-to test question of the uterus and the upper two thirds of the vagina don't develop as well as the fallopian tubes. So they'll have that blind vaginal pouch because the lower third of the vagina is formed separately and that's the only part that's abnormal. So they still have ovaries. Therefore they still have estrogen, still have breasts. Your labs should look completely normal, still XX.
Camille Imbo:So treatment has nothing to do with hormones. Treatment is up to the patient, right? Do they want a vagina? Do they want to be sexually active? What does that come down to? And it's actually a lot simpler than one would imagine. For most of patients it's vaginal dilation and whether that's something that they can do and are comfortable doing and are mentally ready for before even thinking about any surgeries. And so that covers our primary amenorrhea, I think, pretty thoroughly. So kind of a real quick touch on secondary amenorrhea, where we talked about PCOS a little bit. Do you want to dive into that?
Julie Cron:Yeah, this, you know, is a category of hyperandrogenism. Obviously, pcos is very common, so I'm sure you have a podcast just about PCOS.
Camille Imbo:I was going to say we'll dive way more into it.
Julie Cron:Yeah, and I think the important thing here is many of the things about PCOS are common in adolescents, so I generally favor the terminology of like at risk for PCOS. We have to be cautious about giving that diagnosis too early, because there are a lot of 16-year-olds out there that think they can't get pregnant because they have PCOS and they read that it's associated with infertility and either they are maybe thinking they don't need contraception or B most likely it's their parent is worried that they're never going to have grandchildren. So just talking about elevated testosterone causing anovulation instead of labeling it PCOS, but recognizing that there is a time to intervene, particularly for the patient that has obesity, and it might be an opportunity to talk about the benefits of proper diet and exercise and physical activity.
Camille Imbo:Yeah, it's important to know that it's not diagnosed by ultrasound, like it can be an adult, the amount of patients that I come in. I went to the ER, I was told I have multiple cysts in my ovaries and I have PCOS. Whoa, slow down back up.
Julie Cron:Yeah, If I could like have a dollar for every one of those people. Yeah, this like polycystic morphology, is very normal in teens, so I don't usually get hung up on that, but I do always think about all right in the elevated testosterone. I don't want to miss that androgen secreting tumor, the sertolidic cell right Like. I've seen it a couple of times. So your ultrasound might be helpful in those cases.
Camille Imbo:Secondary amenorrhea in general, the one thing that differentiates it from primary and I think is the definition can be a little bit harder, because it's kind of that irregular periods and, as you talked about, there's a lot of things that are normally abnormal in teenagers. Right, we expect some irregularities in those first two years, so I'm less likely to jump into this full workup, especially if everything else looks stone cold and then sometimes it's something that kind of comes and goes.
Camille Imbo:If it's related to life circumstances, something people don't realize. Weight on either direction, whether it's too much weight gain or weight loss, can affect your periods. Your history can tell you a lot about the kind of lifestyle changes that they've made.
Julie Cron:That can affect that the 16, 17 year old that's having two periods a year really does need to be worked out.
Camille Imbo:I actually looked into this because there's a lot of different opinions about this, and it's 60% of girls will have their normal periods within those first two years, and then 90% in that four to five year range. But there's also the thought of well, if they've had a normal regular period from 12 to 16, and all of a sudden it's irregular, that's also something to talk about Important question. Yeah, great point. And lastly, we talked about we order prolactin but not really why we forgot about prolactin.
Julie Cron:Yeah, so prolactin is a quote stress hormone. The most common cause is medication Like psych medications.
Camille Imbo:Yeah.
Julie Cron:If it's mildly elevated, do a fasting first thing in the morning.
Camille Imbo:Something I was taught by an endocrinologist was yeah, fasting first thing in the morning, no exercise or showering beforehand, because you don't want any nipple stimulation.
Julie Cron:But if it is persistently elevated and usually we think about 50 to 70, then you should image your head for a prolactinoma.
Camille Imbo:I think of prolactin the same way I think of thyroid, where it's unrelated, where any treatment I do is not what's going to fix it. So if you have a patient where they're terrible about taking their Synthroid, then that goes back to the endocrinologist and really their period itself is not the issue. And also knowing that after that's resolved it can take a little while before we see their periods come back to normal, A thyroid abnormality can influence your prolactin, so make sure that you check those two together.
Julie Cron:Either hyper or hypo can cause menstrual irregularities. We are not going to get into the basic science,
Camille Imbo:I just tell people a thyroid is the most needy of hormones. If anything's wrong with it, everything else will be wrong. But I think we've dove into quite a few of them and, like you mentioned, there's a lot of these topics that will get their own time, but this is just a good way to go over that differential and what questions we ask our patients.
Julie Cron:My advice to the listeners is like keep it simple. In other words, your history, physical, those three labs, lh/fsh, which I'm going to group together, prolactin, thyroid, plus or minus androgens, you will get to the right answer.
Camille Imbo:And this is one where history is huge. You could practically get a diagnosis just from your history and physical, if you're very thorough.
Julie Cron:And don't forget your pregnancy test
Camille Imbo:Do not forget - that would be a faux pas as a gynecologist, 100% yeah. So going back to our patient case, so we had a 15-year-old who presented with primary amenorrhea. She underwent therapy at age 12 and a half. She's 5'5", 130 pounds. She has Tanner stage five breasts, and we got a little bit more information. She has a normal external genitalia with a one centimeter blind vaginal pouch with normal hymenal tissue. So what would you do next? What do you think she has
Julie Cron:Amazing right that we could actually come to a diagnosis with a physical exam alone. Right? This patient has mullerian agenesis, mrkh. The recommendation would be to image her right. So pelvic ultrasound, normal ovaries with no uterine tissue. And here do your chromosomes to confirm your diagnosis and talk to her about her options.
Camille Imbo:I just went to a talk about uterine transplantation. So our counseling might just change in the near future, but that's a talk for a very different time. But thank you, julie for joining us today.
Julie Cron:This was really wonderful.
Julie Cron:It's so fun to do it live here at NASPAG.
Camille Imbo:Thank you everyone for listening to PAG Over Pastries. You can go to our NASPAG website, where we'll have full transcripts of the podcast as well as links to the books and references that we mentioned. If you have any questions for us today or feedback about the podcast in general, feel free to email us at pagoverpastries@ gmail. com. We're also doing a survey to learn a little bit more about who our audience is. So if you go on the website, you'll see a short four-question survey that you can answer to help us out. But thank you again for listening to Pag over Pastries. Feel free to explore some of our other topics and look forward to our next podcast in a month. Look forward to our next podcast in a month. Bye.
