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- [00:01]
A
Hello, I'm aaron lohr and this is the endocrine news podcast. The Endocrine Society regularly develops new guidelines to reflect evolving clinical science and give timely evidence based recommendations for clinical care and practice. The Endocrine Society's newest clinical practice guideline provides recommendations on the diagnosis and treatment of central precocious puberty to help us understand what's in the new guideline. Joining Me today are two of the guideline authors, Dr. Anna Latronica, professor of Endocrinology and Metabolism at Sao Paulo University, and Dr. Stephanie Roberts, pediatric Endocrinologist and Assistant professor of Pediatrics at Boston Children's Hospital. Thank you both for being here.
- [00:45]
B
Thank you very much Harold for this opportunity. It's very nice to participate of this podcast.
- [00:53]
A
How is precocious puberty defined and what do we know about its causation and incidence?
- [01:00]
B
Yes, precocious puberty is defined as the development of secondary sexual features before age 80 years in girls and 9 years in boys. When precautious puberty results from the premature activation of the hypothalamic pituitary gonadal axis. It's called central precautious puberty. It mimics physiological pubertal development, although at inappropriated age. Central precautious puberty is typically characterized by progressive sexual development associated with accelerated growth velocity and and also advanced bone age. It's important to say that final high prediction can be impaired in these patients before treatment and to date, several congenital and acquired causes are associated with this pediatric disease, including brain tumors, congenital malformations, genetic conditions such as monogenic and syndromic cases, and we have many cases. However, the vast majority of the central precocious puberty is still unknown. The cause is idiopathic and another point that I wanted to emphasize today is the incidence of this condition. The incidence is variable among different population registries and it's much more frequent in girls 10 times higher and the incidence can range from 2 to 20 in 10,000 females is very rare in boys
- [03:12]
A
and what are the future health risks associated with central precocious puberty?
- [03:19]
B
As I said one the major concern is the short adult stature in children who had precautious puberty. Other potential health risks are adverse psychosocial outcomes, increase cardiometabolic risk and also cancer risk in adulthood.
- [03:49]
A
And how is central precocious puberty typically treated?
- [03:55]
B
De NRA agonists are typically the first line of treatment of this condition. These drugs, the gonadotropin releasing hormone agonist scan, effectively suppress the premature activation of the hypothalamic pituitary, gonadal eggs and have the potential to increase adult height as well improve psychosocial and long term health outcomes among patients with central precocious puberty. To date we have several preparations of long acting generated agonists including one month duration, three months, six months injectable injectable formulations and also 12 month subcutaneous implant.
- [04:53]
A
Now why did the Endocrine Society decide to develop a clinical practice guideline on central precocious puberty? Now?
- [05:01]
C
It's an important area of clinical practice that's evolving especially as we expand our understanding of the secular trends in pubertal timing as well as the role of genetic etiologies. In fact, this guideline has been needed for some time as the way many endocrinologists historically have been trained in encourages a high level of expensive diagnostic evaluation and expensive treatment in children with central precocious puberty. But the panel suspected that this level of evaluation of treatment is in fact not indicated in all patients.
- [05:34]
A
And can you tell us a little bit about the methodology of this guideline, how it's structured?
- [05:39]
C
The guideline was created by a guideline development panel which referred to in the in the publication as the GDP and that consisted of experts in pediatric endocrinology, pharmacy as well as general pediatrics. We were also fortunate to have a parent representative of a child with central precocious puberty from the United States. In addition, our panel included a clinical practice guideline methodologist from the Mayo Evidence Based Practice center who led the team that conducted the systematic reviews and the meta analyses. And we also had a methodologist, Dr. Christopher McCartney from from the Endocrine Society. The primary goal of the panel was to provide recommendations for the care of children with central precocious puberty. There were many important clinical questions as a panel that we identified related to the identification, diagnosis and treatment of central precocious puberty and we had to prioritize 10 of these and the way we did that was as a panel coming up with the 10 clinical questions that we felt to be most critical. The Endocrine Society follows the GRADE methodology and that stands for grading of recommendations, assessment, development and evaluation. And this includes evidence to decision framework, what's referred to as ETDs to help ensure that all of the different important outcomes and factors are considered when the panel makes its recommendations. And we relied on our methodologist to guide us as a panel with regards to our clinical questions for the development, how to prioritize outcomes, develop and apply these ETD frameworks and then ultimately develop these recommendations. So for each of the clinical questions, the Mayo Evidence Based Practice center conducted systematic reviews of the available evidence and they produce great evidence profiles that not only summarize the body of evidence and the certainty of the evidence for us, but subsequently we then use these as a panel to balance things such as the benefits and harms. In addition to other criteria that were included in those ETD documents, documents and ultimately as a panel, we determined the direction and strength for each recommendation. Subsequently, then the drafted recommendations underwent a number of peer reviews, they underwent public comment as well as review by our co sponsoring organizations. And so the final version of our guideline incorporates all of this feedback by the panel from these various processes.
- [08:04]
A
So clearly there is a lot of information in this guideline and we're not going to be able to cover everything in this podcast episode. So listeners, if you want to know it all, we'll provide a link to the guideline in the episode description and you can find it there. But for now, can you walk us through some of those key questions that the guideline sought to answer?
- [08:25]
B
Sure. I think we started with the diagnosis of central precocious puberty. Our expert panel suggested that all girls with breast initial breast development, it means ternary stage two before age seven should first be observed for four to six months to differentiate non sustained or slowly progressively puberty versus rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. Another aspect that we discussed was the hormone evaluation, the first hormonal evaluation. When hormonal evaluation is performed to confirm central precautious puberty, it means the activation of the APG X as the cause of precautious puberty. Our panel suggests starting the evaluation with ultrasensitive basal luteinizing hormone LH concentration rather the routine GNRH and generate agonist estimation test for all patients. Regarding the etiology of central precocious puberty, one important discussion involved the brain MRI and the importance to establish the ideal age for this. While brain MRI has been a traditional part of the central precautious puberty evaluation, our panel suggests that should not be routinely performed in girls ages 6 to 8 and in boys ages 8 and 9 years without central nervous system symptoms, largely based on the low prevalence of pathological intracranial finds in these age groups. In addition, the panel suggests against routine genetic testing for patients with central precocious puberty. Although people they judged that genetic tests, especially the evaluation of MEK RNA 3 gene should be considered in families with temporal precocious puberty through a shared decision making process.
- [11:30]
C
Thank you, Dr. Letronico. The other half of our clinical Questions, clinical questions 6 through 10, focused more on treatment of central precocious puberty. And that includes different formulations for treatment, duration of treatment, as well as the possibility of using adjunctive recombinant growth hormone therapy. Just to summarize some of the key recommendations from those key clinical questions, the first question we asked related to treatment was whether treatment with GNRH agonist therapy, which is the gold standard as Dr. Letronico has mentioned, should be used for the management of central precocious puberty. And the panel judged that yes, this is indicated as part of the management of children with central precocious puberty. However, we noted importantly in the recommendation that certain patient subgroups may not achieve net benefit with such treatment. An example of this would be girls who have slowly progressive puberty who central who have slowly progressed with central precocious puberty who present between the ages of 7 to 8 years. Additionally, we also judge that other important patient subgroups may be girls and boys who are in fact seeking clinical care and are already in their peak pubertal growth spurt in which there's concern that in fact intervening with treatment at that point could in fact lead to more harm than benefits. We also looked at the panel at the short versus long acting formulations of junior age agnus therapy that Dr. Letronico has introduced. We are aware, the panel was aware that in some clinical practice there may be some preference to start, for example, with a short acting, which is the monthly injectable formulation, with this thought that this may reduce the gonadotropins and quiet the reproductive axis more quickly. But in fact, on the panel's review of all of the factors, including the available evidence, we found no evidence to support using one strategy versus the other. And so ultimately the panel concluded that ultimately you should initiate treatment with whichever the formulation is going to be preferred long term. So what I mean by that is if you think you're going to continue without, quote, long acting formulation, whether that's an injectable or the subcutaneous implant, then it's perfectly acceptable to initiate treatment with such a formulation. Additionally, we looked at monitoring. So again, historically there's been a lot of thought that rigorous biochemical evaluation once you're on therapy is indicated. And so we compared this to just doing clinical assessment alone through one of our clinical questions. And the evidence support that clinical assessment alone, as opposed to routine biochemical testing is again recommended by the panel. Finally, we looked at adjunctive recombinant growth hormone therapy. The panel did not recommend this. There may be certain exceptions to this. So you know, individual clinical situations where this may be beneficial. But in terms of kind of routine recombinant growth hormone therapy, this was not recommended by the panel. And finally we looked at when do we actually stop therapy. So criteria for discontinuation, and the panel concluded that this would be most appropriate when girls are at a chronological age of 10 years or they have a bone age, which is a X ray of the left hand, a tool that we use as endocrinologists. So a bone Age of 11 years in girls or conversely in boys at a chronologic age of 11 years or a bone age of 12 years in boys.
- [15:16]
A
So I'm going to pause here. Real quick note to the editor. I think we just answered 6 and 7 it sounds like to me. So I'm going to skip over seven because I think we just did it.
- [15:24]
C
Great.
- [15:27]
A
So the guideline highlights important knowledge gaps and the need for additional research. Please tell us more about those identified gaps and why they're important.
- [15:36]
B
Yes, it's true. Our clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with temporal precocious puberty and they are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and their families. However, we missed studies randomized control trials in our systematic review comparing interval height gains and adult height outcomes based on different ages are needed in future for patients with central precautious puberty treated with gene. We also have missed four studies in boys. We have very few studies in boys. Additionally, randomized control trials based on discontinuation of generate agonist therapy determined by chronological age and bono age would be very valuable too.
- [17:00]
A
Well, we're about out of time for this episode. I just want to say thank you to my guests and thank you for sharing this guideline with us. Thanks so much.
- [17:08]
B
It was a pleasure to be with you.
- [17:11]
C
Thank you.
- [17:12]
A
And that's all for this episode. I hope you enjoyed hearing about the Endocrine Society's new clinical practice guideline on central precocious puberty. Like I mentioned earlier, there's a lot more in this guideline and what we could discuss in today's episode. If you'd like to learn more, check out the link in this episode description. We'll be back soon with another fascinating dive into the world of endocrinology. Until then, thanks for listening.