Precocious Puberty: To Treat or Not to Treat?

Jessica Sparks Lilley, MD; Maria G. Vogiatzi, MD


July 13, 2022

This transcript has been edited for clarity.

Jessica Sparks Lilley, MD: Hi. I'm Dr Jessica Lilley. I'm a pediatric endocrinologist at the Mississippi Center for Advanced Medicine in Tupelo, Mississippi. Today, I'm interviewing Dr Maria Vogiatzi from the Adrenal and Puberty Center at The Children's Hospital of Philadelphia (CHOP).

Maria G. Vogiatzi, MD: Good morning. So glad to be with you.

Lilley: You’re the director of the Puberty Center. What's the full name of that center?

Vogiatzi: It is called the Adrenal and Puberty Center, and it is a subspecialty center that focuses on helping children with gonadal problems. Within the center, we have a program for children with precocious puberty and also a program for congenital adrenal hyperplasia (CAH), Klinefelter syndrome, and other gonadal concerns.

Lilley: I have really enjoyed going through your summary of research on PubMed. It is voluminous. I definitely have many articles that I want to go back and see, such as some of the work that you've been doing on puberty suppression with children with CAH — for example, height outcomes, and other things that we all wonder about and haven't had much guidance to help us. You're getting ready to do a talk here at the Endocrine Society ENDO 2022 Annual Conference on evidence-based guidelines for treating central precocious puberty.

I know for many of us in private practice who do not have access to a wonderful multidisciplinary center like you have at CHOP or are getting a little bit lost, especially as the latest research emerges. During the pandemic, we haven't had national meetings in the same way that we have in the last few years.

For a private practice endocrinologist like me, what are some of the considerations that we should take into the exam room when we see a child who presents to us with central precocious puberty?

Vogiatzi: One area I would like to emphasize is the management of girls with breast development between the ages of 6 and 8 years. There is great and growing evidence from the US, but also globally, that thelarche is happening at a younger and younger age. This is more frequently seen in certain ethnicities, like African American and Hispanic children, and it also is seen in children with higher BMI.

However, there is a very interesting finding that the age of menarche has not shifted at the same rate or as people would have expected. There is some kind of disconnect between thelarche that happens at the younger age and menarche that hasn't changed significantly in timing.

People are thinking that the tempo of puberty may be longer in some of those children who present with early thelarche, and I think for the practicing physician, taking this into account will be important. Many people advocate observing these girls for a period of time before making a decision about putting them on a gonadotropin releasing hormone (GnRH) analog to suppress puberty.

Lilley: The kind of thoughts that I was trained with — and I've been in practice about 10 years — were learning about the different considerations about height outcomes, for instance. The dogma was that if you saw, say, a girl who was older than 6, she wouldn't get much height benefit from suppression. We're seeing now from more longitudinal studies that that's not necessarily the case.

Vogiatzi: It is an area where people are still looking at this age group. Definitely, the literature is clear for kids younger than 6 that by stopping puberty, the adult height improves. What is happening at a range between 6 and 8 years is a little bit in a gray area. There are some data to support that there is not much of a change, and there are also some data to say that even untreated girls in the range of 6-8 years can reach an adult height very close to their mid-parental height.

As always in endocrinology and pediatric endocrinology, we don't have very robust randomized controlled trials and much of our treatment is a little bit empirical. I think the challenge for the clinical practitioner is to pick up the girls who will definitely benefit from some treatment.

This is highlighted by a recent paper by Klein and colleagues, who said that, yes, there are selected cases that will definitely have a benefit. Dr Klein's paper was not a randomized controlled trial, which is very typical in our field. That's why the practice of pediatric endocrinology is sometimes art, because you have to pick out the correct candidate for therapy.

Lilley: These children don't always read the book.

Vogiatzi: That's right.

Lilley: As a specialty I think we have seen more precocious puberty during the pandemic. I think these girls are coming to our practices more and they're coming in with these early findings. We're all wondering, what do we need to do?

A couple of years ago, there was an analysis that looked at cost-effectiveness of treatment. I thought, my goodness, I didn't know that cost was the primary outcome that we're looking at. I've got three little girls, and they're all right in that window of the kind of patient who would come in. I often ask myself the question that parents ask us: What would you do if this was your child?

It was very theoretical, but now that I have girls in this age window, I think, oh, goodness, suppression sounds really good. It sounds like something that we would like to do. You see psychosocially what 7- to 9-year-old girls are capable of. It's been really informative to me to have these conversations with families and see what matters to them.

Vogiatzi: Absolutely. Developing a very trusting relationship with families is very important because it will benefit the family and help the physician make the appropriate recommendation for this specific child who is under his or her care.

Lilley: I think there's so much importance of that frequent follow-up because the tempo matters. This is a condition that can change over time, and our initial assessment and treatment plan may change as we notice how the child progresses through puberty.

What are some pitfalls that you see in practicing medicine in this arena? What are some things that we need to avoid in treating these patients?

Vogiatzi: I think we covered the issue about assessing who is the appropriate candidate. Another challenge is to pick the right formulation for them. At this particular point, we have two recent long-acting GnRH analogs that can be administered every 6 months. We also have the option of the histrelin implant, which according to the guidelines is annually, but its implantation can be delayed even for a little longer.

One of the challenges is to see what is the best fit for the families. I have to say that all formulations are pretty effective in clinically controlling puberty. There are no good data to compare which one, let's say, will have a stronger effect on bone age or on adult height. When it comes to suppression of puberty, they are all effective. At the end of the day, the physician needs to have a conversation to see what is the best fit for this particular child.

Lilley: It's been very interesting to me because I make assumptions sometimes and think, goodness, I would want to avoid the shot. To some parents, the thought of having an implant in their child is distressing. Some people want to have the latest and greatest or the tried and true, so we have to try to weigh what matters to the family and then see what insurance will cover. That always seems to be one of the biggest barriers.

Any other parting thoughts today?

Vogiatzi: Another area that I would like to bring to the attention of people is that we understand a little bit better the regulation behind the onset of puberty. The onset of puberty is characterized by this awakening of the GnRH pulse generator that triggers the awakening and activation of the gonadal axis. We now know that there are many neuropeptides that are involved in this process. One name that people may recognize is kisspeptin. There are some other regulators that are critical as well. People now identify mutations in these neurotransmitters in children with central precocity.

What is also interesting is that this GnRH pulse generator that generates neurons is in crosstalk with so many other neurons that bring all kind of signals from the body. For example, we all know that people with chronic illness or malnutrition have a delay in their onset of puberty. All the signaling happens through this neuronal system that eventually either stimulates or inhibits this GnRH pulse generation.

We have learned a lot about this. Perhaps down the line there will be some alternative options out of the box. I will be interested to see how this area evolves and how we will find its applications, maybe in future treatments.

Lilley: Maybe I'm a little biased, but I think we have the very most fascinating field of study. I really appreciate you sitting down with me to chat and to share your expertise for those who weren't able to join us in Atlanta. I'm looking forward to hearing your talk.

Vogiatzi: Thank you.

Lilley: Thank you.

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