Individualizing Treatment Decisions in Girls With Central Precocious Puberty

Karen O. Klein, MD: 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.

Kent L. Reifschneider, MD: 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.

Karen O. Klein, MD: 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.

Kent L. Reifschneider, MD: 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.

Karen O. Klein, MD: 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?

Kent L. Reifschneider, MD: 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.

Karen O. Klein, MD: 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?

Kent L. Reifschneider, MD: 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.

Karen O. Klein, MD: 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.

Kent L. Reifschneider, MD: 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.

Karen O. Klein, 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?

Kent L. Reifschneider, MD: 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.

Karen O. Klein, MD: 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?

Kent L. Reifschneider, MD: That sounds fabulous.