Between the lines: central precocious puberty

The word puberty evokes images of early adolescence and for most children, that is when they transition to this next stage of growth. However, some children who are going through central precocious puberty (CPP) will enter puberty earlier than their peers, in some cases much earlier. In a webinar from the Between the Lines series, 2 experts discussed a variety of subjects on CPP, including findings from a recent study that examined treatment initiation and duration with height, the need to individualize treatment decisions for girls with CPP, and 2 case reports.¹ Karen O. Klein, MD, a pediatric endocrinologist at Rady Children’s Hospital-San Diego in California and an associate clinical professor of pediatrics at the University of California San Diego School of Medicine, led the discussion with Kent L. Reifschneider, MD, a pediatric endocrinologist at Children’s Hospital of The King’s Daughters in Norfolk, Virginia.

Defining CPP

CPP occurs when the hypothalamic-pituitary-gonadal axis is activated early on, which leads to an increase in gonadal steroid hormone secretion. The ages of affected children are less than 8 years for girls and less than 9 years for boys. Children affected by CPP develop secondary characteristics early on; have at least 1 Tanner stage progression per year; and have less than 2 standard deviations in bone age (BA) beyond chronological age (CA). If untreated, CPP can lead to early fusing of growth plates, a reduction in adult stature, atypical pubertal physical development, and premature menarche. Gonadotropin-releasing hormone agonists are the standard-of-care treatment.

Studies on treatment for CPP

Klein discussed her recent study coauthored with Marcela Vargas Trujillo, MD; Sanja Dragnic, MD; and Petra Aldridge, MS. The authors performed the investigation to supply data for an area in which data were scarce: the benefit to height outcomes when treatment with leuprolide was initiated after CA of 7 years and continued after CA of 10 years or BA of 12 years. The study was carried out in 48 treatment-naïve girls who were treated with monthly leuprolide, administered intramuscularly every 28 days at doses based on weight. The investigators only included girls so that the results would have statistical power. The patients had visits at weeks 4, 8, 12, 24, 36, and 48 and then every 6 months until leuprolide was discontinued. They then had annual visits until age 21 years. The average treatment duration was 3.9 plus/minus 2.0 years (range, 1.1-9.8). The average CA at the end of treatment was 11.5 plus/minus 0.97 years (range, 9.8-14.1) whereas the average BA was 12.7 plus/minus 0.94 years (range, 11.5-16.4). Throughout the treatment period, the ratio of BA to CA consistently decreased. Fifteen girls achieved a BA that was less than 1 year above the CA. Longer duration of treatment was associated with increased predicted adult height for nearly all the girls, 45 of 48. Those who saw no improvement were either near midparental height when they started the treatment or showed poor growth velocity. A wide range was found in final heights: 162.54 plus/minus 7.35 cm (range, 146.47-176.11) that was similar to the predicted adult height in treatment (162.39 ± 8.38 cm). Midparental height was not available for all the girls, but of the 29 for whom it was available, 17 either met or surpassed it.

Individualizing treatment

Reifschneider joined Klein to discuss nuances in the treatment of CPP. He noted, “With CPP, I think of the limitations of the disease state, which includes the impact of estrogen on growth velocity and BA and how much that should factor into clinical decisions as well as the variability in interpreting BA.”

Klein added, “When examining a patient, a clinician should balance the need for more data with the fact that early commencement of treatment can lead to better height outcomes.” She also noted that estimating predicted adult height is also mostly based on average-sized children who are having average growth patterns. Another consideration for starting treatment is the predicted adult height of the patient and the height of the child’s parents. For example, if the predicted height for a child is 155 cm and the mother is 157.5 cm, treatment may not be considered necessary by the patient’s family.

Klein added that although treatment will pause the tempo of puberty, once treatment ends, the tempo will resume its speed. However, this does not mean that a pubertal growth spurt will occur, and, in fact, data indicate that this typically doesn’t occur.

Case report #1: When to treat

The first case Reifschneider and Klein examined concerned a girl, with the following details:

• Age: 8 years, 4 months
• Height: 129.5 cm
• Growth: 8.5 cm a year
• BA: 10.5 years
• Tanner stage 3 breast development, starting at age 7 years
• Tanner stage 3 pubic hair

With the girl’s BA and current height, her predicted final height is roughly 147 cm and her midparental height, 168 cm. The BA maturation was noted as significant by Reifschneider and the patient would meet his criteria for treatment. However, Klein emphasized the patient’s age, noting that she had been trained to only treat children when pubertal onset occurred before age 8 years. Countering that assertion, Reifschneider said, “One has to keep in mind the individual and that a lab [finding] or CA is just a piece of the puzzle. In this case, the fact that the girl started developing breast tissue when she was aged 7 years is important, in addition to growth velocity that is greater than prepubertal [velocity] as well as bones that are considerably advanced.”

When discussing treatment with families, a conversation about outcomes can be important. Many girls with CPP can be among the tallest girls in their class but their BA is often much advanced, and when their non-CPP peers reach puberty, many affected girls will be left behind in terms of height. If he were treating this patient, Reifschneider said, he would ideally initiate treatment and then see her every 4 to 6 months to determine how the treatment has changed the tempo of her puberty. Once the tempo became prepubertal, he would transition to twice yearly maintenance screenings.

Case report #2: When to cease treatment

The second case was of a girl with CPP who had undergone treatment, with the following details:

• Leuprolide acetate treatment initiated at age 6 years
• Current age: 10 years
• 1 incidence of vaginal bleeding following treatment initiation
• BA at treatment initiation: 10 years
• Tanner stage 3 breast development at age 6 years
• Predicted adult height: 142 cm

The patient’s breast development has stabilized at Tanner stage 3. Her BA is 12 years and her height is currently predicted to reach 60 cm. She is now asking whether it’s time to stop treatment.

Reifschneider emphasized that this was a very successful case and the patient had responded very well to therapy. “When considering the ceasing of treatment, there are a couple of things that need to be thought through, like the limitation of predicted adult heights and not knowing the tempo that will occur when she ceases treatment. Although she is currently predicted to reach 5 feet, there is a likelihood that she would not achieve that height if she ended treatment.” Klein added that a BA of 12 years has often been considered the end point for treatment because of questions about whether continued growth could be achieved, but her study findings showed that 5 to 10 additional cm can be achieved with continued treatment. Reifschneider confirmed that prior to publication of the study’s results, he would have considered ending treatment at BA 12, although he noted that this patient was an outlier who likely would continue to benefit from treatment.

Reference:

1. Klein KO, Reifschneider K. Between the lines: central precocious puberty. Virtual webinar. Recorded March 4, 2022.