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
4 - Puberty (Part 3): Delayed Puberty
Camille Imbo, MD PGY6 and Susan Kaufman, MD discuss delayed puberty, the last in their series on puberty. The episode provides an in-depth exploration of delayed puberty, discussing key signs and the clinical evaluation process for young teens facing this challenge. It addresses common causes, the importance of physical exams, and appropriate treatments while offering reassurance and guidance for families.
Check out the video on YouTube.
Outline
• Defining delayed puberty by breast development and menstruation standards
• Importance of comprehensive medical and family history in evaluations
• Role of growth charts in monitoring physical development
• Value of physical exams in diagnosing anatomical issues
• Differentiating between hypogonadotropic and hypergonadotropic hypogonadism
• Exploring hormonal treatments and lifestyle changes
• Addressing oncofertility considerations for young patients
• Understanding eugonadotropic amenorrhea and its anatomical causes
• Concluding reassurance and guidance for families on managing delayed puberty
References:
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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.
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PAG WebEd cases are a great way to review our podcast content.
A 14-year-old girl comes to your clinic with her mom, who's concerned because her daughter hasn't had her period yet. She's noticed that all of her friends have started developing breasts and growing taller, but her daughter still looks the same as she did a couple of years ago. She denies any other symptoms but feels like her growth seems to have slowed down and she's feeling self-conscious. So what would be your differential and how would you evaluate this patient?
Susan:Hi everyone, I'm Susan Kaufman. I'm an attending at Virtua Health and a pediatric and adolescent gynecologist.
Camille:And I'm Camille Imbo, a second year fellow in pediatric and adolescent gynecology at Phoenix Children's Hospital, and welcome to Pagover Pastries. Today we'll be covering part three of our puberty series and talking about the late puberty.
Susan:What's your favorite pastry this session?
Camille:Oh I like eclairs.
Susan:Well, I have to go with chocolate, chocolate cake.
Camille:Oh, let's get started. So now, looking on the other side of things what is considered delayed puberty?
Susan:So one of the landmarks that we keep talking about is breast development. So if a teenager has no breast development by age 13, that we definitely want to evaluate that, and then by age 15, if somebody does not have on set of their periods, we absolutely want to evaluate them, and that's actually been moved back. The previous guideline was age 16. And now it's been moved back to 15. And some people even talk about using 14. Only because we see so many young ladies getting periods at nine or 10, do we want to wait as long as age 15 to start evaluating folks that don't have their periods? So when someone comes in with either no breast development or no periods, what are we going to do? Well, we want to look at their growth charts and see whether their growth charts have continued to go up or whether they've suddenly plateaued.
Susan:We want to look at their medical history. Chronic diseases will certainly delay puberty or the onset of menses. We want to look at their nutrition. Examples are girls that are malnourished because of lack of accessibility to food, girls with eating disorders, athletes who are not eating properly and have energy deficit. We want to think about genetic causes for lack of pubertal development or onset of menarche and family history, which we keep stressing.
Susan:We're going to go through their physical exam and their Tanner staging For skeletal abnormalities. We may need to do an external genital exam to rule out anatomic causes. We're going to do a pelvic ultrasound, a bone age and, of course, lab tests, including the ultrasensitive FSH, lh, estradiol, thyroid hormones, tsh and either a free T4 or a total T4, depending on your philosophy 17-hydroxyprogesterone if we're thinking about a late-onset or non-classic congenital adrenal hyperplasia, free and total testosterone and a prolactin level. We may then need to do pituitary or adrenal imaging, depending on what all these other tests show us, and ultimately we might need a karyotype again based on what the these other tests show us, and ultimately we might need a karyotype again based on what the other tests have shown us.
Camille:Important part about the physical exam, as we've discussed, I think, in all of the podcasts now, how it can be uncomfortable for patients to want a physical exam. But I had a patient who had an imperfect hymen, which is something I feel like everyone knows about and talks about, but for several years I had a huge amount of colposts because she was getting all of this workup for primary amenorrhea but no one had done a pelvic exam. So while it can be uncomfortable, at some point it is important to discuss with patients that it is a very important part of their workup and could make the rest of the workup very unnecessary if we're able to just take a quick look.
Susan:And then we went over. You know some causes already. The most common cause in the United States is constitutional delay, but this is a rule out cause, rule out cause. So after we have done the evaluation that I just listed, if everything comes back normal, then we're going to say that this is constitutional delay, especially if we get a family history of other women not starting periods until 16 or 17. And then we can reassure this young lady and her family that you will go through this process, you will get your periods and we'll follow you to make sure that that happens. Can you describe the breakdown of delayed puberty?
Camille:Yeah, so taking a step back, really the way to think about this and how I explain this to patients is your brain releases hormones that then communicate with your ovaries, that then tell your uterus what to do. It's really like the exact sentence. Baseline works for both the five-year-old and the 15-year-old and, honestly, sometimes there are parents even who don't realize how this functions, and so sometimes when you hear things like hypogonadotropic hypogonadism can sound like mumble jumbo, but really what each word is telling you is is the brain releasing hormones or is it the gonads or ovaries in this case, releasing hormones and how they're communicating with each other? So hypogonadotropic hypogonadism is telling you the brain is not releasing the hormones and the ovaries are not responding Well in this situation, that means there's lack of signaling from the pituitary gland and hypothalamus, so all of your labs should be low GNRH, lh and FSH.
Camille:This can be due to chronic illnesses, malnutrition, constitutional delay as well, tumors, genetic syndrome. So thinking of it from a global perspective affecting their brain and that down the line, therefore, is affecting their ovaries. So there's nothing wrong with their ovaries, they just don't have anything to respond to. There's some different genetic syndromes, so common is the most common genetic cause. I always automatically think of that as associated with the hearing impairment and lack of smell, but there's also things like CHARGE syndrome, optic nerve hypoplasia. So these are things to potentially look into, depending on what other symptoms someone is presenting with.
Susan:I think it's important to stress that the ovaries in hypogonadotropic hypogonadism the ovaries are actually normal and have the potential to function, and this is a question that we often get asked when we make this diagnosis. What about fertility? And that's something we'll cover in the future but the important point to remember here is that the ovaries are actually normal. There's just nothing stimulating them to work
Camille:Right. Let's see. So then treatment and kind of the answer to this always comes back treat the underlying disease. So if it's malnutrition, getting appropriate nutrition, if it's a chronic illness, a brain tumor, whether they need surgery, but GnRH replacement, so kind of mimicking that pulsatile GnRH that the hypothalamus is supposed to be performing. And then if it's something long term, while you're treating the underlying cause, we also want to make sure that we don't develop new problems from the lack of estrogen. So if the bone age is under 10, you want to do estrogen replacement, which we'll talk about later. But this is important because we want to protect our bones. But also estrogen is important for heart, brain memory formation, learning, all of those things Right.
Camille:So that's hypo hypo. What about hypergonadotropic hypogonadism?
Susan:this is differentiated from hypo hypo, because in this case the hypothalamus and the pituitary are working, but the ovaries are not, and it's what we commonly refer to as premature ovarian insufficiency. We used to call this premature ovarian failure, but changed the terminology, because sometimes this is not permanent and sometimes the ovaries can be stimulated to work. So what we essentially have is unresponsive gonads, and this has a variety of causes. It may be generic, such as Turner syndrome. There may be gonadal dysgenesis, where the ovaries just don't develop normally. It can be due to a chromosomal issue, such as galactosemia, or where somebody is XY instead of XX. Someone may have ovarian insufficiency due to one or more oophorectomies, due to torsion, ovarian cysts or ovarian cancer. There certainly can be autoimmune causes, infectious causes, or it may be related to cancer therapies unrelated to ovarian cancer, but radiation or chemotherapy from some other type of cancer.
Camille:And I'm glad the field of oncofertility is growing and developing. Now, when patients are unfortunately diagnosed with a malignancy, they are also immediately having a discussion about fertility and ovarian preservation, and there were patients who had childhood cancers 10, 15, 20 years ago and now they're not having their periods and wondering about fertility and I'm unfortunately having to tell them it's potentially too late.
Susan:Yeah, and I think it's on everybody's radar now where it's. Like you said, even seven years ago it was not, and we know that it doesn't have to interfere with the onset of their cancer treatment. And we'll talk about oncofertility in another session. What about treatment for premature ovarian insufficiency?
Camille:It comes down to replacing estrogen, which is what they're missing. It's a stepwise process. I tell patients at whatever age that they're being diagnosed. We're taking them through the process of puberty from the beginning right. So it's not like an overnight thing where we want them to develop breasts and have their periods right away. We want a slow increase in estrogen. There are two main ways to do this either with oral estrogen via pills, or transdermal via patches. Patches are preferred. It's been shown that transdermal absorption is better and is more physiological, and so with patches you start as low as 0.025 micrograms or a quarter of a patch, and then usually we do it where we follow that for about three months. Then you go to half a patch, three quarters and then a full patch, with the goal of seeing how their development is being affected breast development and the assumption is that their uterus is growing at the same time as this. And then eventually we add progesterone there, two years into the estrogen treatment or once you start noticing bleeding. This is really important because if you start progesterone too early, you can develop what's called tubular breasts, which is really unfortunate because it can't be undone. And then another thing to consider is when counseling about this. This is not like hormone replacement therapy from a form of birth control or menopausal. This is just putting them at physiological range. So when thinking about, like VTE risks, it doesn't count in this situation, because we're giving them amount of estrogen that any other woman their age makes, and so we're bringing their VTE risk to what they would be at if they didn't have POI. So that's not something that should change your management.
Camille:And then, once you have progesterone added, how you go about it. What's wonderful is that there's a lot of different ways. So you can use progesterone pills like medroxyprogesterone acetate. You can do it cyclically, either 10 days, 14 days, 21 days, where they have a period. You can do it continuously, even with an IUD, where they don't have a period. At a certain point. You can even switch to birth control if they are sexually active. So, like I mentioned, the IUD or a combined oral contraceptive. So there's a lot of different ways to go about it. The true summary here is to start slow, but if you look into the book, which will post these details online, we can break down a little bit more of the exact doses and when to increase.
Susan:And we primarily use estradiol. In the past, we used to use conjugated estrogens, but we don't use that anymore. We feel that estradiol has a better impact on the bones and breast development, which is also a reason why we got away from using birth control pills.
Susan:We used to use birth control pills standardly in patients with POI, but the synthetic estrogen was found not to be as good for bone density development. But, as you said, if we have taken somebody through puberty and now they're older and they're sexually active because they have insufficiency and not failure, we may switch them to a birth control pill. The patch, the ring for both their estrogen and their birth control.
Camille:And lastly, the other question I get is how long do they need to be on this treatment? And so I explained we're mimicking physiological female development, so it's like women produce normal amounts of estrogen until they reach menopause. It is in the same way where, while I personally technically haven't treated anyone that long, my assumption is around the average age of menopause is when we stop.
Susan:Right, and I have had the privilege of treating people as teenagers all the way through into their 20s, 30s, 40s, just because I do some adult gynecology, and so I have continued therapy in them, and occasionally we will check estradiol levels as well, aiming for about 100 pipe grams of estrogen in their bloodstream After we go through hypo, hypo and hyper hypo. The last category is eugonatotropic amenorrhea. So what are some of the causes for that? Because that's completely different than what we've been talking about.
Camille:Yes. So that's essentially non-hormonal and kind of what I hinted about earlier where it's important to do an exam, an ultrasound. It's some structural abnormality, so it could be an imperfect hymen. With that you probably see a normal breast development, normal pubic hair development, because it's not a hormonal issue, or a vaginal septum, which is the same idea, but higher up in the vagina, which of course would be a transverse vaginal septum. These two are very important because the longer that it persists, the more blood builds up and eventually can start to present as pelvic pain. And then you have symptoms like MRKH or Mayer-Rokitansky-Kusterhauser syndrome, which is essentially a malarian or vaginal agenesis or cervical agenesis, and again this would be diagnosed via ultrasound or MRI.
Camille:Lastly, the one that is hormonal of sorts but different than what we've been talking about, is AIS androgen insufficiency syndrome, which is where they're missing the SRY genes. So while they are making testosterone they don't have the receptors to respond to that testosterone. So they are technically XY chromosome, as you mentioned earlier, and they'll present as female. But oftentimes the first way that it's diagnosed is because they don't have their periods or aren't developing breasts appropriately and through the workup you would know very high testosterone levels that they don't have a uterus ovaries, and then, eventually, that they have an XY chromosome.
Camille:All right, we've reached the end of our puberty series, finally. And so going back to our case, we had a 14-year-old girl who came in concerned because she hadn't started her period yet. She was noticing her friends were developing breasts and growing taller, but she was looking about the same. She had no other symptoms but was starting to feel self-conscious. So what do we do?
Susan:Okay. So the first thing to do is think about the two cutoffs that we have. If somebody reaches age 13 without breast development or pubic hair growth, we should absolutely be evaluating that patient and that's the category this young lady falls into. On the other hand, if somebody reaches age 15 and has appropriate breast development and pubic hair, then she should be evaluated also. Development and pubic hair then she should be evaluated also. So when somebody does not have any pubertal development, we're going to, of course, do our comprehensive history and family history, our physical exam. Sometimes we need to do an external genital exam, sometimes not on that first visit. We're going to order hormone studies in this case and an ultrasound to make sure that she has a uterus and tubes and ovaries. Depending on what the hormone studies show, it will generally point us in the direction of ovarian insufficiency or a hormonal problem that is causing the delayed puberty. And then from there we may need to order chromosome tests but treat the underlying cause and provide estrogen therapy if it turns out to be premature ovarian insufficiency.
Camille:Absolutely Wonderful. Well, thank you for listening and we'll see you on our next podcast.
