3 - Puberty (Part 2): Precocious Puberty

In this next part of the puberty series, Camille Imbo, MD and Susan Kaufman, MD discuss precocious puberty including isolated, peripheral, and central precocious puberty. They also discuss treatment and management goals.

Outline
- Understanding Abnormal Puberty
- Types of precocious puberty
- Peripheral precocious Puberty
- McCune Albright Syndrome
- Central Precocious Puberty
- Treatment
- Case discussion and management

Check out the visual post on YouTube. 
References:

• Essentials of Pediatric and Adolescent Gynecology: Chapter 6

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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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Transcript

Susan K  0:00  
So a six year old girl presents with breast development and body odor. Her parents are concerned, wondering if these changes are normal or if there's an underlying medical issue.

Camille I.  0:11  
Well, hi everyone, and welcome to pack over pastries an educational review podcast where we cover all things Pediatric and Adolescent gynecology. In about 20 minutes, we'll be talking about precocious puberty as a continuation of our last podcast where we talked about normal puberty. Our reference this time is chapter six, abnormal puberty, by Ellen Connor and Lauren canner in essentials of Pediatric and Adolescent gynecology, released by naspag. I'm Camille imbo, a second year pediatric and adolescent gynecology Fellow at Phoenix Children's Hospital. 

Susan K  0:49  
And I'm Susan Kaufman and attending at Virtua Hospital in Cherry Hill, New Jersey, and a pediatric and adolescent gynecologist. 

Camille I.  0:58  
And do you have another favorite pastry, 

Susan K  1:01  
cheesecake. Oh, good. Cheesecake. 

Camille I.  1:04  
Does brownies count as a pastry? 

Susan K  1:07  
Absolutely. 

Camille I.  1:08  
Okay, that's high up there for me. All right, let's get started.

Can you tell us the different ways that puberty can be considered abnormal. 

Susan K  1:23  
Okay, so puberty can be considered abnormal in both the timing that the physical landmarks begin and when periods begin, and the tempo, meaning how long it takes to go through the process. So generally, we think that he lucky begins about age eight, but if it starts earlier than that, it may be abnormal. If periods start before age 10, that may be concerning in terms of the progression or the timeline through this process. If the time between tilaki and then our key is less than two years, meaning that the time is very quick. We want to look into that and see if there's something going on, or if the time between teal, arche and menarche is too long four years or more. We want to find out why this process has appeared to have stalled. Yeah, I think we often think about timing and memorize the ages by when things should happen, but I hadn't considered the importance of the tempo and kind of how things should progress. So that's definitely a good point. Yeah, and that's a question that people ask a lot when they bring their daughters in for evaluation. Well, when is she going to get her period, her you know, she has breast development, she has pubic hair, but when is the period going to start? So that's why these guidelines are helpful. So let's talk about precocious puberty. Yes, so precocious puberty is from the perspective of too early. So things that they may present with is early breast development, torment our key an accelerated linear growth, early signs of adarc development, such as acne, body odor or pubic hair, things that you may notice on testing or advanced bone age and enlarged uterus on their ultrasound. Then we split that up into, is it isolated, where it's just one of these things that they're having, or is it all of puberty that is happening at an early stage, and then, if it is a precocious puberty, is it Central or peripheral? So first, let's go over isolated precocious puberty so you can have early breast development. Premature thelarche is only breast development. This is common in girls under age three. We will see breast budding and perhaps progression to a tanner stage three breast where there is actually palpable breast tissue, but no enlargement in the nipple or the areola. Premature thelarche usually arrests at about stage three and does not progress, and that's one of the factors to help us discern whether this is isolated, precocious thelarche. We can observe these patients for a period of time and or start a workup earlier or later, depending on the concern and anxiety of the family. 

Camille I.  4:24  
And if I remember correctly, stage three is where there's no separation between the aerial and the mount itself, right? So that's kind of as far as we should see. So that's a good call back, correct? 

Susan K  4:37  
Yep, then we can have precocious adrenarche. We see that with early secretion of dheas or androstenedione without any other hormonal changes and without changes in FSH and LH levels, we can see pubic hair growth acne or body hair, but the most common symptom.

Is pubic hair growth, if this occurs before age eight, without any other changes, so no breast development, no accelerated growth, then it may be isolated adrenarchy. Isolated adrenarchy may be associated with conditions that we see occur later, such as polycystic ovarian syndrome, late onset congenital adrenal hyperplasia or insulin resistance. Besides the two I just mentioned, we can have precocious menarche, but we can also have precocious menarche, which is actually uterine bleeding, which occurs before the pubertal stages are complete, so before somebody reaches Tanner stage four or five, breast development tanner stage four or five, pubic hair growth. Now, while this can be related to trauma, infections, foreign bodies, ovarian cysts, urethral prolapse, rectal bleeding, it can also be related to what we call peripheral precocious puberty, such as McCunne Albright syndrome. Can you tell us a little bit more about that? 

Camille I.  6:06  
Sure, yeah, McCune Albright syndrome is definitely high on the differential when someone is coming in with precocious puberty, especially if they have multiple symptoms. So as you talk about if they have the premature men are key, but then also the accelerated growth. Two of the other big things that is, kind of be on every test question, and also part of what you should look out for is if they have the skin findings, so the cafe ole macules, and then on X ray, they'll have the fibrous dysplasia, which there's a really good picture of that in the book as well that we'll put up on the website, of what that looks like. But then they can have a lot of other different things. So they can have a unilateral ovarian cyst, which is important to note that if you see that and they have McCune Albright syndrome, that it's not like other cysts, where you do a cystectomy, this is one that resolves based on how you treat the syndrome. And then they can have things like thyrotoxicosis, giganticism, Cushing syndromes, rickets, cholestasis, hepatitis polyps, cardiac arrhythmias, malignancies, so a whole lot of things that can be associated with it. So it's very important that if that is in any shape or form, in a potential differential that you work it up. And just as far as kind of the background of why it occurs, it's a post psychotic gnas mutation that creates G protein activation in multiple tissues and creates that active change leading to early puberty and active growth in a lot of different tissue. And we'll talk a little bit more about the full treatment process for it later in this podcast.

Susan K  7:45  
 I think there's some controversy about how early we can diagnose this as well. I had a three year old who presented with precocious puberty, breast development, she had an ovarian cyst, she had some genital bleeding, for which I ruled out other causes, and I really thought that she had McCain Albright syndrome. And there was some controversy about whether that was the diagnosis or not, and how early it could be diagnosed.

Camille I.  8:14  
 Is there any consensus of how long to wait? 

Susan K  8:18  
Not in that No. In that particular case, because I referred her to endocrinology as well, was to wait and not treat 

Camille I.  8:26  
gotcha

Susan K  8:27  
 to see if these symptoms stabilized or regressed or progressed. So it's an interesting syndrome that there's still a lot we don't know about, 

Camille I.  8:36  
right, like most hormonal syndrome related things. So we talked a little bit about Mccune Albright, which is a form of peripheral precocious puberty. But going into it a little bit more specifically, it's essentially where you have low gonadotropin so low GnRH, but the sex steroid themselves are in pubertal range. And so essentially, there's some outside cause outside of the brain that may be causing puberty. So it could be genetic, which we already covered with the Mccune Albright or late onset CAH. But there could be a tumor, whether from the ovaries or the adrenal glands. It could be another hormonal disease. So if they have severe hypothyroidism, we know the thyroid messes with everything. I always emphasize to patients how important it is to keep up with their thyroid medications, because that will healthily impact their periods and development, right if they're taking anything. So if they picked up steroids laying around someone's birth control pill and then an interesting one as well, are things like lavender or tea tree oil. I actually read an article about a family, I guess they were obsessed with lavender. And every their shampoo, soaps, you name it, were lavender based, and their sons were developing gynecomastia, and once they figured out that was the cause that was able to be reversed. And then lastly, obesity.

So we know that fat cells get converted to estrone, which then gets essentially becomes estrogen in the system. And that's why we often see people with higher BMI have irregular periods or heavier periods, because of those higher levels of estrogens and eventually testosterones as well. 

Susan K  10:18  
When we talk about exogenous steroids, and we shouldn't forget about testosterone. You know, a lot of folks may be using testosterone gel for a variety of reasons, and this can easily be passed to somebody else if they've just put it on and it hasn't dried and they haven't covered up their arms and they're hugging a child. So so if we're seeing a signs of androgen activity, we need to think about that, and also soy. I had a young child, less than two years old, but started with breast budding and went through the whole assessment that we're talking about, and it turns out that she was eating a lot of soy every single day in her diet. And so when we stopped that, then we saw a regression of the breast growth. 

Camille I.  11:08  
Wow. I wonder just how much of it you'd have to consume to get to that point. 

Susan K  11:12  
It's a good question. I researched that and couldn't find any way of quantifying it. Yeah, but she was eating tofu every single day. 

Camille I.  11:21  
Oh, my goodness. That makes me wonder if there's higher levels noted in vegans and vegetarians or anything that often consume tofu. But, but as far as treatment, it's going to depend on what the etiology is. So of course, if there's a tumor that needs to be removed, if their thyroid needs to be treated, if there's anything exogenous, like they need to stop eating so much tofu that all will depend but as far as other treatments, there are things like aromatase inhibitors or serums selective estrogen receptor modulators. Both of these help decrease the amount of estrogen in the system. For CAH you want to use corticosteroids, and as I mentioned already, otherwise, it's more about removing whatever the specific source is. So that's peripheral precocious puberty. What about central precocious puberty?

Susan K  12:10  
 So central precocious puberty is GnRH dependent, and it is always isosexual precocious puberty, and it is premature activation of the hypothalamic pituitary axis. So it again, is a change in secretion of GnRH, from a constant secretion to a pulsatile secretion, which then stimulates the pituitary to produce SSH and LH, which then stimulates the ovaries to produce estrogen and testosterone. There are multiple causes of central precocious isosexual precocious puberty. One of the genetic causes is mKRn3, which is a genetic mutation. And this is the most common genetic mutation causing this. There are also other CNS abnormalities, which can be congenital or acquired. So an example of a couple of congenital anomalies would include hydrocephalus. One of the examples of acquired central precocious puberty would be cerebral palsy tumors that may be genetically related or related to other genetic syndromes, trauma, encephalitis, endocrine disruptors. The most common cause, however, is idiopathic central precocious puberty, and we did see a rise in central precocious puberty in up and coming nations during the pandemic. I'm not sure why. Do you know what it was? There a reason postulated for that ?

Camille I.  13:48  
 Post edit Camille here, according to  Chiarelli and Frontiers in Endocrinology, they say stress and sedentary lifestyles increasing during the pandemic may be what led to more precocious puberty. Back to our podcast, 

Susan K  14:02  
So there's a good figure that details the workup about this in our textbook. Figure 6.1, we're always going to start with family history of pubertal landmarks and menarche. We're going to do a physical exam to look for other pubertal signs, breast development, pubic hair, acne, body odor. We're going to obtain a bone age and ultra sensitive FSH and LH and estradiol level, other hormonal levels, including testosterone, DHEAs, prolactin, if the LH level is greater than 0.3 it is suggestive of central precocious puberty. When we're doing our physical exam, we're going to do our Tanner staging, or sexual maturation index in children under the age of six. We may need to do a brain MRI. In the past, we used to do GnRH Stimulation test looking for a rise in the LH level. But it's not as common to do this anymore because of all the other testing that we have. So if we make a diagnosis of central isosexual precocious puberty, what are our treatment goals?

Camille I.  15:17  
 One big goal is we want the patients to reach their genetic potential height, as we talked about in the last podcast, the mid parental height. This is something that I brought up to some of my attendings of oh, why does this particularly matter? Right? Everyone is a different height, but there is the heights that are important to be able to function in society, be able to drive a car and all of those kinds of things. And of course, we want to try to decrease the psychological impact of having a shorter stature than expected for their age and their family. So our goal is to delay with GnRH agonists such as leuprolide injections, which are every three to six months. There's also triptolin injections. Something that we use here often is the histrelin implant. And there's another table in the book that goes into more details about how often and the doses for each of these. But the idea overall is to stop that GnRH pulsatile release, and kind of go back to that continuous release, which stops the LH and FSH. 

Susan K  16:25  
And also, I think the histrelin implants are more commonly used now than the leuprolide injections, just because of convenience and not having to give somebody a shot every few months

Camille I.  16:38  
 you stop treatment, that's another important part to know, either when they reach their expected final adult height or within 12 to 18 months of their average pubertal onset. So the goal is to kind of get them to a point where they're psychologically ready to deal with puberty and, quote, unquote, feel and look the way that they expect to at their age. And then the other part to know, though, is that there's some times where there's only so much that we can do. So if they're presenting after age six, the recovery in height may be very limited. How much of puberty that's already happened that we can undo is also limited. So this is another reason why it's so important to be aware of these kinds of things, because if care is delayed, it may not be able to be undone afterwards, right? 

Susan K  17:28  
And I think this is something that the pediatricians assess at annual visits, and it's something that parents are certainly very aware of when they're, you know, taking care of their children, and they see what's happening to them physically. It's amazing how important height is to a family. And if the parents are particularly tall, they don't want their children to be shorter than them. And if somebody's very engaged in sports and sports focused, they are looking at their children being a certain height as well

Camille I.  18:00  
And it's funny, what you say about height, my middle sister, out of three of us, is the shortest one of our family, but she's like 5'5" which is average everywhere else, we're just a very tall family. So yeah, that that's very true. 

Susan K  18:15  
Okay, so circling back to our case, our six year old, who presented with breast development and body odor. So is this normal, or is this not normal, and what do we do about it? 

Camille I.  18:29  
It's definitely early, as we've talked about, we don't expect any form of puberty before age eight. So it's important to as we talked about, getting history, developmental history, when all of these presented, were they on any medications during pregnancy? When family members developed through puberty? It's important to get an exam, so getting Tanner staging of the breast and pubic hair, looking at their growth chart, and essentially to be able to assess, is this something isolated, or is it an actual precocious puberty. And then we go down the road of, is it central versus peripheral? And through the history, would get a lot of that information as well. But then we do labs, as we talked about, looking at all our hormones, LH, FSH, estradiol. Always want to check the thyroid, dhes, testosterone and 17 ohp, due to the adrenarcal development, and then also doing an ultrasound to tell is everything in the pre pubertal range, and this is maybe some an isolated thing that'll self resolve, or Are any of these abnormal and then kind of going down that road 

Susan K  19:34  
ultimately, if we get a history that mom started her period at age nine, and maybe a sibling started her period at age nine, and we're not finding any overt abnormalities in our testing, but the testing is consistent with the early onset of puberty, then this might be normal for this young lady, because we also said that it's about a four year time span between. The onset of breast development, pubic hair growth and menarche. So if she's going to get her period at nine or even 10, we might see some development beginning at age six. And then what factors into our decision making for management is what's her emotional state. Is she able to handle the breast development? Is she being teased? Is she being looked at as though she's older, and that's affecting how people are reacting to her, and what about her height? So those factors then come into play when we're talking about management options, right?

Camille I.  20:39  
 And depending on those situations, maybe someone that gets placed on a GnRH agonist until they're a little bit older, 

Susan K  20:47  
right to maximize their growth and their emotional development. 

Camille I.  20:52  
Well, that was a great review on precocious puberty. Follow us in our last podcast of the series where we discuss the late puberty highly, highly recommend reviewing both of these normal and abnormal puberty chapters for more information or references to the tables that we discuss, visit the PAG over pastries page on the naspad website. It will include a transcript of all the podcasts, links to references and any helpful pictures or tables we mentioned. If you have any questions for us for feedback, email pagverpastries@gmail.com. otherwise, thank you for listening to pag over pastries. Check out some of the other topics available anywhere you can list on the podcast.

transcribed by otter.ai