Karen O. Klein, MD

So Charlotte is now 10 years old. She was diagnosed with central precocious puberty and treated with leuprolide acetate since she was 6. So she’s 4 years into treatment. She did have 1 incidence of vaginal bleeding after her first injection. When she started treatment at 6 years old, her bones were 10, so very advanced. This is not a borderline case. This is someone with rapidly progressing precocious puberty. Her predicted adult height was 56 inches. She also has a midparental height of 66 inches. She was in the middle of puberty at 6 years old with stage 3 breasts and she stabilized her physical exam. During these 4 years, her breasts are still stage 3; they’re softer, they’re not stimulated. And now her bone age is 12. She’s predicted now to reach 5 feet, so she’s gained 4 inches of predicted adult height during her treatment. And she’s actually asking you, “Is it time to stop my treatment? I’ve been doing this a long time.” So what things would you look at to decide whether to say yes, you’re ready to stop treatment or no, I would recommend we continue?

This is a great case to talk about the back end. It really highlights some of the key features that we often see every day in our clinics. Really, the crux of the clinical questions that are asked for her, she has been treated for 4 years, which is quite some time. But over that 4 years, she has actually done a really good job. She’s responded quite nicely that over the course of 4 chronological years, her bones have only advanced 2 years.

I think that she has done fabulous. She’s certainly achieved the goals of therapy. Our goal is to slow the maturation of the bones that is noted here that over course of 4 years, the bones only matured 2 years. And of course, this correlates with a considerably improved predicted adult height, so really great response to therapy. But the question is that you proposed is when do we stop? And I think there’s a couple things to think about here is 1, the limitations of the predicted adult heights. So once we stop therapy, what tempos is she going to initiate afterwards.

So excellent question with regards to when to stop therapy especially given the fact that she’s been treated for the last 4 years and is probably has some treatment fatigue. In this regard, she has met all the criteria for treatment, a great response clinically and radiographically. However, the thoughts are, and it’s a judgment by the family and the clinician is the predicted adult height has some limitations. Those limitations consider the tempo in which she was entering puberty at the beginning of therapy, 4 years previous, and 2, the tempo in which she’s going to travel after you stop therapy. So I think those things are that you need to consider when you have this conversation with the family about when to stop therapy, would you agree?

Yes. So the highlights of the benefit to continuing treatment is to continue to improve that predicted adult height. She’s come this far, even though she’s tired, we’ve just shown that more treatment will benefit height further.

And then if some people might ask about the cost-effectiveness of continuing treatment, well, again, we don’t want to make medical decisions just based on cost. Obviously, we spend lots of money to save lives and to improve patient outcomes, and 1 of the benefits I think we’ve just shown is that the difference in growth potential can be many inches. Some people will say how much is 1-inch worth in dollars, but we’ve just shown, again, the importance of individualizing treatment. This child is predicted at 5 feet right now, 60 inches. But if we stop treatment, she probably will not reach that. So we’ll make that point again to the family she’s done so great, you wouldn’t want to go backwards again. And then the parents—the midparental height is 66 inches. And so is it even possible that we could gain 6 more inches by continuing her treatment. Now in general, that sounds like a lot, and probably the family’s going to be happy if we just gain 2 or 3 more. But when we look at the data I just showed you, some of these children with the good genetic potential as long as we keep that process slow, steady growth, they do gain 5 to 10 centimeters, so as many as 4 and a half inches potentially by continuing treatment past a bone age of 12. So that bone age of 12 has sometimes been a stopping point for clinicians around the country and world, but we’ve just shown that at bone age of 12, you can still gain 5 to 10 centimeters in some cases. Now not everyone, so again, we’re looking at each patient and this particular patient is doing extremely well so there’s no reason to suspect she wouldn’t continue that.

 And I think that’s exactly your point. She’s had such a great response just like in other conditions that we treat that are relating to growth, those kids are demonstrating a great response. Why would you want to lose the momentum that you have achieved, right? So I absolutely concur with you, Dr. Klein, is that I would really encourage this family that Charlotte has done such a great job responding and all the momentum that we’ve gained, I wouldn’t want to risk losing it, let alone the fact that I think that she’s probably going to be 1 of those individuals that are going to continue to gain a lot of recovery in height.

So before you saw this data, when you looked at a patient and she got to a point that her bone age was 12 or more, did you use that as 1 of your criteria to consider stopping treatment?

I did to some degree because of the publication in 2018 did talk about that to some degree. So that was brought to my attention, having read that journal, but I think with Charlotte’s case, I think she’s such an outlier that I think she’s pretty easy to distinguish that she’s probably going to continue to benefit. I think that there are some out there that it’s a little bit grayer, a little bit harder to tell because the recovery responsiveness to therapy is not so obvious. And in part, I think with Charlotte, she’s been treated for quite some time, and we know that 1 of the best predictors of outcome with predicted height relative to midparental height is the duration of therapy, right? And I think that’s part of this whole conversation is the duration is the tail end too. That’s part of duration, right? And so she, I think, Charlotte, is an easy case, but there are some that’s not so cut and dry that I really kind of hem and haw on when do we do the call it quits because knowing that duration is such a critical point.

Yes. Thank you. So, and now that you’ve seen some data to support the growth continuing after bone age of 12, will that change your sort of general thinking of the bone age of 12 isn’t as hard of a line?

Yes, yes. And I think that this is a question that we’ve always had as pediatric endocrinologists, and again, their publication is helping to answer that question. And I think that people need to be mindful that there is not a hard stop, a hard start, or line in the sand that you start or stop for therapy because it has to be individualized. And I think that us as clinicians who are helping the child and the family in front of us, we need to take them into consideration and not just data, absolutely.

And now we—yeah. And now we have data to support that thought that we’ve been having, and I think it is important. So having, you know, listened to everything and looked carefully at this new paper, do you have any questions for me for our discussion today?

No. I think that your paper has really been long overdue, and I love the fact that you guys try to tackle the 2 really hard questions. When is it too late to start therapy? And when is it the benefits versus the risk to stop therapy? And I think this publication really starts to help bring some clarity to those questions and help us all to remember that there is not a line in the sand on either end, and then that there are some kids who definitely continue to benefit from ongoing therapy, absolutely.

Well, it was so nice talking to you today and going back and forth on our thoughts about these patients and look forward to seeing you in person sometime.

Videos

Karen O. Klein, MD, and Kent L. Reifschneider, MD, discuss a central precocious puberty (CPP) patient case regarding factors that would lead a physician to either stop treating a patient or continue with treatment.

CPP Patient Case: When to Stop Treatment

So let’s look at Sophia. She’s 8 years, 4 months, currently 51 inches, which is 50th percentile for her age. She’s growing at 8.5 centimeters a year, which is greater than the 99th percentile for her current age. And her bone age is 10 and half. She’s Tanner stage 3 for breasts. When you go back in the history, the family thinks probably her breast started around 7. She also has Tanner stage 3 pubic hair. Right now, with her bone age of 10 and a half and her current height, she predicts to reach a final height about 58 inches. Her midparental height based on mom and dad and correcting for gender is 66 inches. All of her lab testing imaging confirms central precocious puberty, idiopathic central precocious puberty. No other etiology or pathologies are found. And so what things would you highlight as you look at this description to decide whether to treat her or not?

 Well, I think the points that you made in your presentation in the article are dead-on that you can get a little bit of insight here. One is the degree of bone age maturation already noted at this point in time is pretty significant. And of course, that’s correlating with a compromise in adult—predicted adult height. So you have a sense of the tempo here. Number 2, 1 of the things that I think that people might forget to think about is that bone age, there’s still a little bit of delay between what’s really going on in the body and its impact on the bone maturation. So although at this point in time, it’s 10 and a half, reality is that momentum is still ongoing. So even if I was able to wave or initiate therapy immediately right now, there’s still going to be some lingering acceleration before it slows down. And so this person clearly meets the criteria in my mind to treat therapy, to initiate therapy. I think the challenges is the back end. What are you going to say to the families? Well, how long do you think we’re going to treat her? And for me, my personal impressions, I want to say this person’s going to be treated for some time because of the reasons I just mentioned, but I love your insight.

So let’s come back to the how long part of the discussion in a few minutes, but let’s make a couple other points. One of which, as we talk to our colleagues around the country and the world, let me just pretend I’m someone else for a minute and get your response. But Dr. Reifschneider, this patient’s already 8 and a half, basically. I was trained to treat children if they have pubertal onset before age 8. Why do you even want me to think about treating her just based on that age question?

That’s a great question, and I think this is where we talk about the uniqueness in individual medicine. We are treating an individual. We’re not treating a lab or chronological age. And so 1 of the things here that helps you to kind of get a sense of the tempo is that the parents report the onset of breast tissue at 7 years of age. And so if we were going to use the classic definition, then just history itself helps you to kind of say yes, they meet that criteria, right? And then that’s further validated by 2 other important what I call objective data. The growth velocity is greater than prepubertal, and the bones at this 1 point in time are quite considerably advanced.

That’s great. I think it’s so important to make the point that just because you meet them after age 8, you need to look back in history. Thank you. And then what would the benefits be to treatment? What are you going to tell the parent why we’re even considering treating?

Well, that’s a great question because sometimes these individuals are like—are often elite athletes in elementary school or middle school in basketball specifically because they’re tall, right? But then when we have the conversation of the outcomes, it should not intervene. That, “Hey look, although she stands out at this point in time, the repercussions on the backend are pretty profound because she is really 10 and a half, at least on the inside, probably 11 plus that she’s going to stop growing if we assume normal speed within the next few years.” And then what’s going to happen is all of her peers are going to wind up growing right past her. She’ll wind up actually way below where we’d expect her to be based on her family as well as her peers. And we can demonstrate that to some degree based on the predicted or calculated adult height.

That is so great and makes such a good point that’s so confusing to families when their child is so tall, and we’re saying we’re worried about them being too short. So thank you for walking us through that carefully. And of course, we also want to emphasize that, you know, she’s in the middle of puberty, so menarche is around the corner. And if she’s only 8 years old, that would be very early for menarche to start in the next 6 months, potentially. We can’t know for sure. So let’s get back now to your question of how long should we anticipate with the family that she’s going to need treatment. And, you know, 1 of the ways I like to think about it to make it a visual for the family, you very nicely just said really we can think of her body like a 10 and a half or 11-year-old, so we can think of her growth that way as well. As we start treatment, we’re going to slow down the rate of progression of those bones. Now they’re not going to just stop, but our goal is if we start treatment now, her bones are 2 years ahead. A year from now, her bones won’t still be 2 years ahead. We’ll have denarrowed that gap some between her chronological age and her bone age. So you can sort of think of it as to grow typically you would need to catch up to your bone age, right?

And like how you mentioned, we want to treat her past when her peers have caught up to her because she’s going to accelerate as soon as we stop treatment. And so if we think of, like, ideally, we catch up to her bone age, now the bone age, since it’s not going to hold still and is going to continue to advance, we already know that’s at least 2 years in her.

It’s going to be more than 2 years. And we’re going to talk about another case in a minute when we look at that other end of the spectrum that will help us tease out some of those factors. But just looking at her, you would say she needs 2 to 3 years of treatment.

 I’m in agreement absolutely. And again, that article that you guys presented is it did as good a job as you possibly can to try to clarify the gray zone on the front end and the back end. And I think this case study does a great job of kind of helping to depict the gray zone on the front end as to when to treat versus not. Just because she’s almost 8 and a half chronologically she clearly meets the criteria for central precocious puberty, uh, based on history and bone advancement. But the other thing is we have a little bit of an insight and tempo, but my suspicion is tempo is also perhaps accelerated so that further compromises the predicted adult height. And so I think that your article did a great job highlighting these points, and I look forward to discussing the back end with—I think you have another case where we can talk about when do we stop therapy?

Yes. One more question about Sophia and then we’ll go to the next case. What considerations should be made regarding monitoring during treatments so that Sophia has the optimal results from this treatment?

 So I think that’s an excellent question. And I often ask my colleagues how often you see your growth-related kids? Do you see them every 4 months? Do you see them 6 months? And knowing that we’re all so very, very busy, it’s often, well, ideally, I’d like to see them 4 months, 3 or 4 months, but the reality is probably 50/50, 4 months versus 6 months, depending on your backlog on new patient referrals. But for her, I’d like to see the initiation of therapy. I’d certainly like to follow every 4 months until I get a better appreciation of the tempo, and then once I see the tempo has declined into more of a pre-pubertal, then I kind of go into conceptually a maintenance biannual screening with once a year bone age, watching that predicted height improve and get closer and closer to the midparental height, which is really our goal here. It’s to help with the psychological kind of disparities, but also to help get them closer to where they were supposed to be. Is that your approach as well?

Yes. So I think the general things are we need to continue to watch the physical exam, exactly what you said that the rate of clinical progression of puberty is slowing down. We want to do some hormonal measurements early on to make sure that we can show some hormonal suppression. And then yes, once a year bone age just to show that the rate of bone maturation has decreased and that we are improving predicted adult height. And we can use that to help decide the end of treatment, which leads us to our next case.

Karen O. Klein, MD, and Kent L. Reifschneider, MD, discuss a central precocious puberty (CPP) patient case regarding factors that would lead a physician to treat a patient.

CPP Patient Case: When to Treat 

Nice to be with everyone today, virtually. Just a reminder, I'm Karen Klein from the University of California, San Diego and Rady Children's Hospital, Division of Pediatric Endocrinology, and I'm very much looking forward to a discussion about precocious puberty treatment nuances, with Dr. Kent Reifschneider and I will let him introduce himself.

Fabulous. Thank you Dr. Klein. My name is Kent Reifschneider. I'm a Pediatric Endocrinologist at the Children's Hospital, the King's Daughters in Norfolk, Virginia. I trained at Cincinnati, and I've been here for about 13 years and I've enjoyed the opportunity to take care of kids and be involved in growth and precocious puberty related topics.

Dr. Klein, I had a chance to review your presentations and I think you did an excellent job introducing and trying to answer questions that are very challenging for us clinical providers. The question as to when to start therapy, when is it too late to start therapy, and equally, on the back end, when do you stop therapy? These are critical questions that myself as a provider, and even the families often ask, and it's always a very difficult question to answer. And so, I think this publication and your presentation did a great job highlighting the importance that, it's really an individual decision. Data is just that. It's averages, it's means, it's statistics, but at the end of the day, we're here to help take care of the patients in front of us so I think you did an excellent job and I look forward to this discussion.

Thank you, so let's just start with your response to, you know, what you read, what you've heard and jump into talking about it.

Yeah. So I, you know, I always like to think at the very beginning of things. When I think about central precocious puberty, the first thing is, what are the limitations of just the disease state to begin with? Some of things I've always had thoughts about, is, you know, this is all driven by the hypothalamic ovarian estrogen production axis, that's starting prematurely before the age of 8 in girls and before the age 9 in boys. However, the impact of estrogen on growth velocity and bone age, there's a little bit of a delay there. So, I always wonder, how much to factor that in your decision when you're seeing the person in front of you with regards to the exam, growth velocity, and how advanced the bone age is. So, that's1limitation that I always wonder. Number 2, I'll completely admit that sometimes when I even review my own, my own bone ages, that sometimes there's a little bit of variability in interpretations. So, I know that's a limitation and so I think that's something for everybody to consider, and I suspect many of us interpret our own bone ages, at least that would be my impression. And then, lastly, what's your thoughts about the accuracy of predicted adult heights relative to the actual outcomes because this presentation or this article actually has some of that data, which is very, very reassuring and great news to show that up to 58% actually achieved midparental height. I thought that was fantastic.

Those are great questions, and it's really, basically, all relate to each other, right? So, if I'm understanding your first and second1together well, is when we look at that bone age, it's our interpretation, and you're right, I think most pediatric endocrinologists interpret our own bone ages, so we can at least compare our own interpretation to our own interpretation. It is not precise, that's a very important point to make. We can't know exactly what the bone age is, and, you know, as they say, 2 points makes a better line, right? It's the only way to make a line. So, to have 2 bone ages, if you have time, tells you a lot more because you can see the rate of progression. So, you're exactly right. When you first meet that patient and the estrogen has been maturing the bones but we don't see that right away when we looking at the bone age, and I think that's what you were getting at, is, that's 1 point in time and really doesn't tell you too much about where you're going to be in 4 months. And, that's so important to either take the time to know because not every 7-year-old who's started puberty, is going to rapidly progress through puberty and need treatment. Yet, some 7-year-olds who have started puberty, are rapidly progressing and very much would benefit from treatment. So, when you have that first point in time, I think you're exactly right, you do think about estrogen as having an effect and some of that I'm not going to see till later. So, I need to look at my best estimate of where we are right now, do I have time to get another point or is this bone age so much ahead, that I probably should consider starting treatment sooner because we know from other people's data, that the sooner we start treatment, the longer the duration, the better the outcomes. So, was that sort of the first point you were making?

 Absolutely, and I think you nailed it. For me it's time and tempo that you have to take into consideration and if you don't think about tempo, then I think sometimes what we miss the boat or lose the efficacy of the treatment if we should choose to intervene.

Yes. Totally agree. So, let's tie that predicted adult height in because we get that predicted adult height by looking at the child's height and the bone age at the time. So, it's very—it’s completely dependent on our interpretation of the bone age. So, again, it cannot be very precise because the bone age is not very precise. And then the other limitation is that the data we have for estimating what the predicted adult height is going to be, based on 1 point in time, comes from mostly average size, average growing children. There's a little bit of data on extremes. So, you're right that we don't know what that really means, and we definitely don't know with 1 point in time what that really means. But, as we look at data over time, what's really important is are we changing that predicted adult height. So, if our first estimate is this child's headed toward 4ft 8 inches, we can't really say if that child's going to be 4ft 8 inches, but the next time we look at it, if our estimate done is calculated the same way with us reading the bone age again is 4ft 10 inches, there's a difference, right? So, in the early stages of treatment, we're looking for improvement. Does that make sense, and do you agree that that's what we can look at?

 Yeah, I absolutely agree, and I think for me, that’s why that helps me to kind of determine what's the likelihood because part of the question I have when I'm first meeting these families is not only, "What we can do about it?" Well, first and foremost I want to make sure there's not an organic problem, right? Once I've eliminated organic problem, then we're dealing with idiopathic or central precocious puberty, which is the most common in females. Then, it's the benefit of therapy, and if we're going to initiate therapy, then the appropriate follow up question is, "Well, how long, right?" And it's an appropriate question to ask, and it's often asked upfront because it's kind of like, "How long are we committing?" by the families toto this treatment. And, for me, acknowledging that the limitations of the delay between estrogen and its impact on the maturation of bones and the tempo helps me to say, "Okay, well I think we're going to be treating for 3 years here," as opposed to 2 years or even 4 years. And so because I'm committed to try and educate them as much as possible, maybe too much, and that gets me in trouble in the beginning, but at least they know that, you know, we're in this for the long haul. To help them both psychologically and from a height recovery perspective, right? And so, with that in mind, 1 of the other things that helps me to think about, I'd love your thoughts about this, is after you've finished treating, what's your take on the pubertal growth velocity after therapy relative to those that are not treated? We know that normal pubertal growth velocity is 9 plus centimeters in females and 10 centimeters per year in males. But those that are treated and then discontinuation GnRH agonist therapy, do they resume that at exact same speed? Is it greater or is it less? Because I think you need to think about that as it relates to when you stop therapy.

So these are great questions. I want to add 1 more thing about this predicted adult height and what you're getting at when you're making that decision at the initiation of treatment first. And that is, I use the example, if we estimate 4 ft 8 inches, obviously we think the child needs treatment, and then we watch for that to improve. What if you're seeing that child and the predicted adult height is 5 ft and maybe the mom's 5 ft 1 or 5 ft 2 inches? And so, you say, they're predicted to be close to the mom's height, maybe this child doesn't need treatment? Part of what you're getting at with your question is, if the estrogen is rapidly increasing and affecting those bones, and we don't see that yet, we pretty much know that that estimate of 5 ft at this point in time is not going to happen. That child is not going to reach the predicted adult height. So, here we have a predicted adult height, but they're not going to reach it without treatment. I think that's a really important point for clinicians to hear because they often look at the predicted adult height and say, "Oh, it's good, so I don't need to treat." But that tempo point you made is so important. If the tempo is really rapid, that predicted adult height is going to decrease.

Now, that also relates to your question of, what happens when we stop treatment, and I think you and I will have a nice discussion in a minute about a particular case and whether to stop treatment or not. And so, we can talk more about growth after treatment as we look at a case example. But, in general, the same thing is happening right? We are starting treatment because the tempo is rapid and we are slowing down that process. As soon as we stop treatment, we haven't cured whatever caused the rapid puberty, we've just put it on pause. When we stop treatment, the tempo of puberty is going to continue more rapidly. Now, in general, like you mentioned, we think of a pubertal growth spurt as part of that, but very interestingly, in general, the data we have so far in the literature, we do not see that pubertal growth spurt post treatment. And I think that's a very important point for making these decisions because a lot of clinicians talk about, "Well, it's probably time to just let them finish their spurt." Well, because of the complicated process of growth plates in essence and all those things we're trying to understand of what determines how long the pubertal growth spurt goes, how much growth you get during that spurt? That is all changed with our treatment so we've basically now said we're going to suppress that rapid process, take people back to normal pre-pubertal growth rates, and now we need to treat long enough to project a final height based on prepubertal growth rates because the data on the average, and again, it'll be fun to look at some more individualized data, but on the average, growth velocity decreases posttreatment. We do not see an acceleration of growth, so we cannot factor that in.

 Yeah, that's a great—that’s been my impression clinically. Again, I've been out and practicing for about 15 years and that has been my impression. It's good to hear that other clinicians such as yourself are kind of validating my personal experience is that post-completion of therapy, the resumption, I often use the movie analogy. That they are way into this movie, and all we're doing is pausing the movie, but we need to be conscious of tempo, the speed in which the movie or this puberty is going, and I think that's 1 of the things that a lot of people forget to consider is not where are you in the movie, and are you simply pausing, allowing everyone to get caught up to that point in the movie? But the speed in which you're traveling through the movie is critical as well. So, my appreciation is that this individual is going through at 1.5 speed of the movie right, then I really want their peers to be a little farther ahead of them before I hit play again. If that makes sense, conceptually.

MD: So now that we talked about some of the limitations in treating children with precocious puberty, what are your takeaways from this particular paper?

 Well, I think this paper is critical because it’s really answering the gray zone, right? Because everything in medicine is never crystal clear or white or black. The majority of medicine is gray. And so that gray zone is, you know, when is it too late to benefit from treating therapy? And the back end of the gray zone is when is the right time, the optimal time. to stop therapy? And so, I think these articles really, really did a great job, as best as you could, to try to help clarify some of those questions. And as it’s indicated here in the summary statement, slide, it really shows a couple things that for me kind of validated my approach. One, that’s using a definitive line in the sand for when I start therapy or not start therapy really is not appropriate. Again, we are treating patients, not numbers or statistics. Number 2, likewise, on the back end, we’re treating people and not statistics. Some of the things to think about is the time in which you initiate therapy and the tempo. And then relative to following those points from point A to B to C to D and the delta that you’ve referenced that helps us to acknowledge how well we’re improving that tempo, ie, the predicted adult heights relative to the midparental height. And then lastly, the fact that those on the back end, so many of them benefited from a little bit of “beyond normal treatment,” I think speaks to the point that you need to pay attention to tempo and that there’s benefit there on the tail end.

That’s great. So what if we talk about a couple of cases because I think as clinicians think this through, they’re always picturing a case and maybe we’ll have a fun discussion with some actual numbers in front of us. Does that sound good?

Karen O. Klein, MD, and Kent L. Reifschneider, MD, discuss individualizing treatment decisions in girls with central precocious puberty (CPP).

Individualizing Treatment Decisions in Girls With Central Precocious Puberty

: Hello. My name’s Dr Karen Klein from the University of California San Diego in San Diego, California. And I will be discussing a 

article today. The title is “Importance of individualizing treatment decisions in girls with central precocious puberty when initiating treatment after age 7 years or continuing beyond a chronological age of 10 years or a bone age of 12 years.” The first author is Dr Marcela Vargas Trujillo, one of my colleagues at the University of California San Diego. This program is sponsored by AbbVie. I need to disclose that the contents are consistent with all applicable FDA guidelines. I’ve been selected by AbbVie, and I’m presenting on their behalf.

In the discussion of the paper, we talk about the rate of bone maturation slowing throughout treatment, which is known from other studies; the increase in predicted adult height continuing with longer duration. And then the key new findings are the predicted adult height increase in 91% of those who started treatment after a chronological age of 7 years. The girls who initiated treatment who were greater than 7 years of age had comparable predicted adult height increases, as well, and almost 85% of the girls who continued treatment after a bone age of 12 continued to have further increases in predicted adult height. Girls in this study reached a final height similar to the predicted adult height achieved during treatment. And all of this led to our conclusion that treatment decisions should be individualized. Initiation and cessation of treatment should not be based solely on bone age or chronological age alone. In our discussion, we included a few factors that influence that decision, if it’s an individualized decision. What are we thinking about when we’re deciding whether to start treatment? Well, girls with rapid progression of puberty have lower height outcomes than those with slow progression. Those with slow progression may not need treatment. Again, individualized. Further decrease in predicted adult height is due to the rapid bone maturation. If the bones are advanced, they’re going to continue to advance. The predicted adult height at the start of treatment, or when you’re considering treatment, is going to decrease from there, again, if they’re rapidly advancing.

Don’t base your decision on that one predicted adult height alone. And then predicted adult height compared to midparental height, of course, is important because genetics also plays a role in the growth potential of our children. The impending onset of menarche, of course, is a separate discussion not related to growth. But it’s a very important reason to start treatment in girls who might have their menarche at very young ages.

What about the other end of the spectrum, the factors influencing the decision to stop treatment? We want pubertal progression concurrent with peers once we’ve started treatment. We want to remember that bone maturation is going to accelerate post-treatment. If there was rapid acceleration of bones prior to treatment, whatever is causing that is going to resume once we stop treatment. Treatment pauses it, and then bone age accelerates again. And calculating predicted adult height has to consider that. We’ve already talked about, of course, that it matters how tall your family is. We’ve already talked about losing predicted adult height based on these factors. In general, it’s reasonable to continue treatment until predicted adult height is close to midparental height and growth is still reasonable. If growth velocity continues to slow down and chronological age is nearing bone age, and predicted adult height is not improving any further, then discontinuation of treatment is reasonable. If bone age indicates growth potential and predicted adult height is still improving, then even growth velocity alone might not dictate the cessation of treatment. Again, it’s important to individualize the decision with all these factors. A major part of the discussion in this publication is regarding the discussion of the Kaplowitz paper from 2018, which raised the issue of, in general, discontinuing treatment no later than a chronological age of 10 years. And many people have started to use that as sort of a guideline. They do talk in that paper about the rare cases of severe psychosocial stress, and very low predicted adult height. In the present study, the mean chronological age at the end of treatment was 11 and a half years of age, and predicted adult height had continued to improve a year prior to that. Stressing that there are some examples of when just basing discontinuation of treatment on chronological age alone maybe is not a good idea, once they’ve already had many years of treatment. For example, a girl with a chronological age of 10 years and a bone age of 10 has more growth potential than a girl with a chronological age of 10 years and a bone age of 12. This latter child might need to remain on treatment longer to continue to slow the rate of bone maturation and make up for the loss in predicted adult height—again, based partly on how tall they are and where we’re expecting them to be compared with their family. Two children, each age 10 but with different heights, might have different treatment plans, or different bone ages might have different treatment plans. Menses onset is also very important. 

The Kaplowitz paper suggests that since menses occurs an average of 18 months after cessation of treatment, the girl who stops treatment at 10 years of age would have menses at an average of 11 and a half years, consistent with the general population. However, we raised the caution that this reasoning is based on the average of when menses occur, but we know that the range is from 3 months to 3 years. If someone is 10 years of age and had more rapid progression or later onset of treatment and is more likely to start menses sooner—maybe within 3 months—consider in the decision-making…whether that’s reasonable. Based on how she’s doing psychosocially, where she is with her peers, our goals that we want to reach, and her height. The Kaplowitz paper also discussed cost-effectiveness. Again, that needs to be individualized based on all these other factors, and this is not a major topic of the current paper. There’s the presentation of the 

 discussion, we always like to review the strengths and limitations—even if I wasn’t one of the authors. The strengths are that it’s actually a relatively large study for central precocious puberty. It’s not easy to do these studies, and it’s a very long-term follow-up in which we had lots of data and final height in many girls. The diversity of age at initiation of treatment helps us try to address some of these issues. And the rigorous criteria to define central precocious puberty meant that we had rapidly-progressing girls. When we look at some of the other studies in the literature, there’s a wide range of how many girls with slowly-progressing puberty, but their bone age wasn’t that advanced. They weren’t accelerating that rapidly. That affects how much benefit treatment has. And some studies are difficult to interpret, based on the diversity of patients. Limitations: There weren’t enough subjects for a prediction model of who benefits from continued treatment and who doesn’t. We still must put all those factors together. But it gives data to consider all those factors. And then the subgroup analyses that we did were too small for statistical testing. Again, they are just descriptive and are not definitive. And then we didn’t have parental heights in all the patients. Of course, that’s a limitation.

In conclusion, the variability in change of predicted adult height emphasizes the multifactorial influences on height and the importance of individualizing treatment decisions. The girls who initiated treatment after a chronological age of 7 years had improvements in predicted adult height similar to the younger girls. The continuation of treatment after a chronological age of 10 years or a bone age of 12 led to continued increase in predicted adult height in almost all girls. The initiation of treatment despite the chronological age greater than 7 years, and continuation of treatment after a bone age of 12 should be considered in some girls, with the aim of attaining optimal growth. Treatment decisions should be individualized, and initiation or cessation of treatment should not be based on bone age or chronological age alone. Thank you very much for your attention to the discussion of this publication.

Karen O. Klein, MD, leads a discussion of the Vargas Trujillo et al study on the importance of individualizing treatment decisions in girls with CPP, including factors that influence the decision to begin and cease treatment.

Vargas Trujillo CPP Study Review: Conclusion

The first figure in the paper looks at the change in bone age to chronological age ratio over time. As I mentioned, at baseline, it’s about 1.5—very advanced bone age ratio. And then it steadily decreases throughout treatment to about 1.2, and 1.1 by the end of treatment. Also importantly, 31% of the girls reached a point with a bone age less than a year beyond their chronological age. Growth velocity declined. I’m not showing that data. But it also declined appropriately from pubertal rates prior to treatment to prepubertal rates during treatment. Figure 2A is the change in predicted adult height during treatment, which continued to increase with longer duration of treatment. That’s also been previously shown. And then Figure 2B shows this unique distribution. But the change of predicted adult height during treatment was not based on the age that they started treatment. Now, we didn’t have as many that were younger, and you can see the younger girls had a great improvement in predicted adult height over baseline. But when we look at the girls who started at 7 and 8 years old, they also had many girls—and we’ll go through those details—who had significant changes in predicted adult height. Forty-five of the 48 girls has some increase. The line is drawn at 0. There’s a couple that didn’t increase in their predicted adult height during treatment. Figure 2C again shows us that change in predicted adult height, but with the solid dots representing the girls who were less than 7 years of age doing very well. And more than half of the girls who were greater than 7 years of age doing just as well with continued predicted adult height, irrespective of their chronological age at the start of treatment. Another way to summarize it is that predicted adult height increased in 91% of the girls who started treatment at a chronological age greater than or equal to 7 years of age. Forty-six percent of those who initiated greater than or equal to 7 years had at least a 5-centimeter cm increase in predicted adult height. And 16%, 6 of 37 girls, had greater than 10 cm increase in predicted adult height. The sample size was too small to reach statistical significance but makes the point that many girls continue to benefit. And not just 2- to 4-cm benefit, but greater than 5 or even 10 cm in some of the girls. Figure 2D again shows the change in predicted adult height, but by bone age. And you can see, even beyond a bone age of 12, there continues to be increases in predicted adult height. This table separates the girls who were less than 7 years of age at the start of treatment with those who were greater than or equal to 7 years of age at the start of treatment. The numbers are too small to reach statistical significance. But you can see similar numbers, proportionately, of those who achieved at least 5 cm of improvement or greater than 10 cm of improvement. Girls who initiated treatment at a chronological age less than 7 years and girls who initiated treatment at a chronological age greater than or equal to 7 years had comparable increases in predicted adult height during treatment and comparable final height. Table 3 compares those with a bone age less than 12 years to those with a bone age greater than or equal to 12. Eighty-four percent of our population in this study who continued treatment beyond a bone age of 12 continued to increase their predicted adult height. Not all, but most. The 3 girls who did not show improvement were either already at or near their midparental height, shown on the right side, and continued improvement of predicted adult height 1 year prior to near the end of treatment, at and then final height. Interestingly, in this study with girls who were treated longer, final height was close to that last assessment of predicted adult height. There are other studies published that show the risk of final height decreasing after the end of treatment, and our data suggests that might be based on stopping treatment too soon. Although we can’t directly conclude that from this study, I want you to notice that, in this study, where children were treated longer, they did reach those heights, on average. Thirty girls were followed to final height. I’ve already mentioned the key points of this figure. Sixteen girls had a decrease from their greatest predicted adult height. There is some loss of predicted adult height, but 58% reached or surpassed their midparental height.

Karen O. Klein, MD, reviews data and study results from the Vargas Trujillo et al study on the importance of individualizing treatment decisions in girls with CPP.

Vargas Trujillo CPP Study Review: Study Results

We will do a quick overview of central precocious puberty, [CPP] as background to the 

discussion. Central precocious puberty occurs when the hypothalamic-pituitary-gonadal axis is activated prematurely, which leads to increased gonadal steroid hormone secretion, which leads to the physical and hormonal changes seen in children with precocious puberty. We’re going to use the classic definition of onset of puberty as less than 8 years of age in girls, and less than 9 years of age in boys. The signs, as I’ve mentioned, include the physical secondary characteristics, and accelerated bone maturation and growth. We usually define this as at least progression of 1 pubertal stage or Tanner stage per year and a bone age that’s at least 2 standard deviations beyond the chronological age—it’s out of the normal range—and a growth rate consistent with the stage of puberty. The consequences, if left untreated, of central precocious puberty can lead to the changes of physical development that aren’t consistent with peers, and the problems that come with that; the risk of premature menarche, and then the long-term consequences: premature fusion of the growth plates and reduction of adult short stature. Early diagnosis and prompt referral help ensure the best possible treatment outcomes.

Gonadotropin releasing hormone agonists are the standard of care for treating central precocious puberty. With that background, looking at the paper, which is a new retrospective analysis of leuprolide depot data…we can look at these 2 main points. We don’t have a lot of published data. Looking at when treatment is started—before a chronological age of 7, or continued past a chronological age of 10, or a bone age of 12—we wanted to examine the height outcomes in girls with central precocious puberty, when treatment is initiated at a chronological age greater than 7, as well as continued past a bone age of 12.There are 2 knowledge gaps on the spectrum of treating children with central precocious puberty. The study design was based on a large study with 1 monthly injection of depot leuprolide. We have 48 treatment-naïve girls from that study. We only included girls, so that the numbers could have statistical power, since not as many boys were in the study. We took the 48 girls. They had to have breast onset before 8 years of age, a peak stimulated LH [luteinizing hormone] to define central puberty greater than 10 years of age. It was a very robust definition to make sure these were true rapidly-progressing girls with central puberty. All the girls had a chronological age of less than 9 years of age at the beginning of the study, and a bone age of at least 1 year advanced. They were screened and then started on treatment, where they received monthly doses based on their weight at that time, and had monthly examinations, a physical exam and laboratory testing, bone age measurement, and safety measures were applied. And then after the end of treatment, they had a long follow-up period, where they had a visit every 6 months until they reached pubertal levels and then annual visits or questionnaires until the age of 21. We also have long-term outcome published data from this population. But for the purposes of this paper, we wanted to look back at this robust data source and look at the changes in predicted adult height and growth rate between the girls who started treatment at less than age 7 and greater than 7 years of age, and between the girls with bone ages greater than 12 or less than 12. The statistical analyses were straightforward, with correlations between the variables assessed by linear regression, and then changes over time, from baseline, using paired t-tests. All the values are presented as mean plus standard deviations unless otherwise noted. And the software was SAS [statistical analysis system] version 9.4. Table 1 shows the baseline characteristics of race, ethnicity, mean chronological age, which—you can see the mean age was 6.8, but the range was from a girl that was 1 year old to a girl who was 9 years old, the upper limit of our inclusion criteria. The breast stages are shown here, so that you can see most of them. Fifty percent were stage 3—in the middle of puberty. And then the other important thing on this table is how advanced the bone age actually was. There are a couple of ways to look at it. The bone age to chronological age ratio, average 1.5. The difference in bone age and chronological age averaged 3 years. Significantly advanced bone age predicted adult height and midparental height are shown here—obviously with great discrepancy.

Karen O. Klein, MD, provides an overview of CPP (central precocious puberty) as well as a review of the study design and baseline characteristics from the Vargas Trujillo et al study on the importance of individualizing treatment decisions in girls with CPP.