Long-term outcomes of gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty

Article information

Ann Pediatr Endocrinol Metab. 2025;30(1):31-37

Publication date (electronic) : 2025 February 28

doi : https://doi.org/10.6065/apem.2448038.019

Jung Hwangbo, Eungu Kang, Hyo-Kyoung Nam, Young-Jun Rhie, Kee-Hyoung Lee

Department of Pediatrics, Korea University College of Medicine, Seoul, Korea

Address for correspondence: Young-Jun Rhie Department of Pediatrics, Korea University College of Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea Email: human21@korea.ac.kr

Received 2024 February 21; Revised 2024 April 9; Accepted 2024 April 23.

Abstract

Highlights

· This study highlights the long-term effects of gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty and the factors influencing final height outcomes. Treatment at 8–9 years of age may also be beneficial, and bone age advancement and height standard deviation scores at baseline are important predictors of treatment outcomes.

Introduction

Central precocious puberty (CPP) is the initiation of puberty before age 8 in girls and before age 9 in boys, resulting from early activation of the hypothalamic-pituitary-gonadal axis [1]. Gonadotropin-releasing hormone agonists (GnRHas), which suppress gonadotropin secretion, constitute the standard treatment for idiopathic CPP. By delaying the progression of puberty and bone maturation, this treatment preserves growth potential and can enhance final adult height [1-3].

Several studies have reported that GnRHa treatment increases final adult height by decreasing bone age (BA) advancement [3,4]. Various factors influence final height and height gain, including the initial chronological age (CA), midparental height (MPH), initial predicted adult height (PAH), treatment duration, and the rate of BA advancement [5,6]. In particular, girls with CPP who are treated before the age of 6 years have been reported to exhibit an increase in final height and greater height gain [7-9]. Conversely, other studies have shown that, in girls with onset between 6 and 8 years, GnRHa treatment offered either no benefit in increasing final height or only a moderate height gain of 4.5 to 7.9 cm [7,9-11]. Moreover, some studies have reported height gain even in patients who started treatment after the age of 8 years [9,12]. Mul et al. [9] reported that the final height of all 87 girls with CPP was 7.4 cm greater than their pretreatment PAH. When divided into 3 groups based on age at treatment initiation, the average final height gains were 11.7 cm, 7.9 cm, and 6.1 cm for the age groups of <6 years, 6–8 years, and 8–9.8 years, respectively. In a recent study of 134 Portuguese girls with CPP, the final height gain was similar between those under 8 years of age (5.0±4.3 cm) and those aged 8 years and older (1.1±6.1 cm) [12]. The impact of treatment on final adult height can also depend on the rate of puberty progression; specifically, rapid puberty progression may require treatment up to the age of 9 [2,10,13]. However, in Korea, only a few studies have evaluated the long-term results of GnRHa therapy in girls with CPP and analyzed factors influencing outcomes, such as age at treatment initiation [14-16].

Therefore, the aim of our study was to compare the long-term growth outcomes of girls with idiopathic CPP who received GnRHa treatment according to the age at which treatment was initiated and to analyze factors affecting height gain.

Materials and methods

Results

1. Clinical and auxological characteristics of subjects at treatment initiation, completion, and the last visit after menarche

At treatment initiation, the average CA and BA of the 200 girls with CPP were 8.24±0.73 years and 10.09±0.76 years, respectively. At initiation, BA exceeded CA by 1.85±0.62 years. By the end of treatment, the mean CA was 11.32±0.34 years, and the gap between BA and CA had significantly narrowed to 0.43±0.54 years. At the final postmenarche visit, the mean BA was 13.40±0.76 years, outpacing the CA by 0.43±0.66 years. The discrepancy between BA and CA had significantly diminished by the end of treatment and at the last visit compared to the beginning of treatment. Height SDS for BA increased significantly during treatment and at the last visit postmenarche. BMI SDS rose significantly from baseline to 0.73±1.16 at treatment completion and to 0.60±1.20 at the last visit (all P<0.001). The PAH at the last visit significantly surpassed both the initial PAH (increase of 8.66±5.67 cm, P<0.001) and the MPH (increase of 4.00±4.69 cm, P<0.001) (Table 1). The PAH SDS improved markedly from -1.33±1.46 at treatment onset to 0.12±1.11 at treatment completion (P<0.001) and further to 0.48±0.99 at the last visit postmenarche (P<0.001) (Table 1, Fig. 1). The PAH SDS at the end of treatment and postmenarche were significantly higher than the MPH SDS (-0.32±0.78). The mean duration of GnRHa treatment was 3.12±0.81 years. The average age at menarche was 12.73±0.56 years, 17.15±5.52 months after completing GnRHa treatment.

Table 1.

Clinical and auxological characteristics of 200 girls with central precocious puberty

Fig. 1.

Changes in PAH SDS in all CPP patients (◆), in the early treatment group (■), and in the later treatment group (▲). PAH, predicted adult height; SDS, standard deviation score; CPP, central precocious puberty; GnRHa, gonadotropinreleasing hormone agonist. ***P<0.001, vs. the start of GnRHa treatment.

2. Comparison of clinical and auxological characteristics according to age at GnRHa treatment initiation

The study population was divided into 2 groups based on the age at the initiation of GnRHa treatment: an early treatment group (<8 years, n=56) and a later treatment group (8–9 years, n=144) (Table 2). At treatment initiation, the early treatment group had a mean CA of 7.32±0.69 years, while the later treatment group had a mean CA of 8.58±0.30 years. The early treatment group had a significantly larger difference between BA and CA at the start of treatment (2.15±0.59 vs. 1.73±0.59, P<0.001). Initially, the later treatment group had significantly higher MPH SDS and PAH SDS, but the height SDS for CA and BA were comparable between the groups. At treatment completion and at the last visit, there were no significant differences between the groups in terms of height, BA advancement, PAH SDS, and height SDS for BA and CA. BA advancement decreased significantly from baseline to treatment completion and the last visit in both groups. The early treatment group underwent GnRHa treatment for a longer duration (4.05±0.78 years) than the later treatment group (2.76±0.45 years, P<0.001). The age at menarche and the interval from treatment completion to menarche were similar between the groups (Table 2). PAH SDS increased significantly during treatment and continued to rise after treatment until the last visit postmenarche in both groups (Table 2, Fig. 1). Additionally, there was no significant difference between the groups in the change in PAH SDS from initial to last visit or in comparison to MPH SDS.

Table 2.

Clinical and auxological characteristics of groups according to the age of initiation of GnRHa treatment

3. Correlations between changes in PAH SDS after menarche and other auxological factors

Simple regression analysis was performed to identify factors influencing the increase in PAH SDS at the last visit postmenarche (Table 3). The change in PAH SDS at the last visit was significantly correlated with the CA at treatment initiation, the initial difference between BA and CA, the height SDS for CA at the onset of treatment, and the duration of treatment. However, there were no significant associations with the baseline BMI SDS, posttreatment CA and BA, MPH SDS, menarche age, or interval between treatment completion and menarche. Multiple regression analysis after identifying multicollinearity among clinically relevant parameters revealed that an increase in PAH SDS at the last visit was significantly associated with greater BA advancement at baseline (P<0.001), lower initial height SDS for CA (P<0.001), and a higher MPH SDS (P=0.001) (Table 4). BA advancement at treatment initiation was the most significant predictor of an increase in PAH SDS. However, the CA at treatment initiation, baseline BMI SDS, BA after treatment, menarche age, and time to menarche after treatment were not significantly associated with the change in PAH SDS at the last visit.

Table 3.

Simple regression analysis on change in PAH SDS (PAH SDS at the last visit - PAH SDS at the start)

Table 4.

Multiple regression analysis on change in PAH SDS (PAH SDS at the last visit - PAH SDS at the start)

Discussion

In our study of 200 girls with CPP treated with GnRHa, the PAH SDS at the last visit after menarche significantly surpassed both the initial PAH SDS and MPH SDS. The results demonstrated the efficacy of GnRHa in improving final height. We found that CA at the start of treatment, BA advancement at treatment initiation, and height SDS for CA at the onset of treatment were important factors for height gain. However, the PAH SDS at the last visit was higher than the initial PAH SDS and the MPH SDS in both the early treatment group (under 8 years) and the later treatment group (8–9 years). Furthermore, we found no significant differences in PAH SDS gain (PAH SDS at the last visit minus initial PAH SDS) or near-final height SDS (PAH SDS at the last visit) between these groups. This suggests that GnRHa is effective in improving final height even in patients who initiated treatment after 8 years of age.

Previous studies have reported various outcomes of final height and height gain (final height minus pretreatment PAH) in girls with CPP treated with GnRHa. Some studies have reported that the final height in girls treated with GnRHa was between 3.6 and 9.8 cm higher than the pretreatment predicted height [3,6,18]. Heger et al. [18] found in 50 girls with CPP who received GnRHa treatment that the final height was 5.9±8.5 cm greater than pretreatment PAH, and 78% of the patients reached their individual target height range. Pasquino et al. [4] reported that the treated group showed a 5.4 cm increase in adult height compared to the untreated group. The height gain and the genetic height gain (final height minus MPH) in the 87 treated girls were 9.5±4.6 cm and 2.4±5.2 cm, respectively. In 244 Chinese girls with CPP and early puberty between 8 and 9 years, height gain and genetic height gain were 8.07 ± 0.37 cm and 2.0 ± 0.27 cm, respectively [19]. Kwon et al. [14] reported that the change in PAH was 6-7 cm after 3 years of treatment in both groups of girls treated before 8 years and between 8 and 9 years. Similar to these studies, our study confirmed that GnRHa treatment reduced BA progression compared to CA, resulting in an 8.9 cm increase in PAH from treatment initiation to the last visit and a 4.4 cm increase compared to MPH.

Several studies have shown that final height outcomes vary according to the age at treatment initiation. Younger age at the initiation of treatment, especially before 6 years, is associated with greater final height or height gain (final height minus initial PAH) [6-9,20]. Lazar et al. [7] reported that only girls treated before age 6 reached their PAH after treatment, while those treated after 6 years showed less height gain from the end of treatment to final adult height. Partsch et al. [8] showed that girls with CPP who experienced puberty onset before 6 years of age had greater height gain than older patients. However, Carel et al. [11] reported that girls with puberty onset after 6 years achieved a significantly greater final height than their pretreatment PAH. Mul et al. [9] and Arrigo et al. [20] reported that girls treated after 8 years also showed improvement in their final height compared to initial PAH, although those treated before 6 years had greater height gains. In contrast, some studies have reported that adult height showed comparable improvements after GnRHa treatment regardless of the age at pubertal onset [4,11,12,21]. Micillo et al. [21] reported that final height in girls treated between 6 and 8 years and after 8 years old was not impaired compared to both target height and pretreatment PAH. Previous studies have stated that the height benefit of starting treatment after 8 years remains debatable. Bouvattier et al. [22] showed that the final height in the treatment group did not differ from the untreated group of patients who experienced puberty onset between 8.5 and 10 years of age. Vuralli et al. [23] found no significant height gain (final height SDS minus PAH SDS ≥1 SDS) in girls treated after 8.3 years. In contrast, Léger et al. [13] concluded that even slowly progressive precocious puberty requires careful follow-up until the age of 9 years because GnRHa treatment is necessary if the predicted height deteriorates due to acceleration in the advancement of BA. Castro et al. [12] also reported significant improvement in PAH during treatment in both early treatment (before 8 years of age) and late treatment (after 8 years of age) groups. Our study found that near-final height and height gain were similar regardless of whether treatment was started before or after 8 years of age. These inconsistencies in reported findings may be influenced by various factors, such as study population size, race, BA assessments, height differences, duration of treatment, and type of medication.

Several studies have investigated the factors that influence adult height and height gain in girls with CPP. Factors reported to be associated with height gain included CA and BA advancement treatment initiation, pretreatment PAH, and duration of treatment [8,9,18]. Meanwhile, factors associated with final height included pretreatment PAH, height at the start and end of treatment, CA at the start of treatment, MPH, and treatment duration [3,6,8,20]. Klein et al. [6] reported that final height SDS was positively correlated with treatment duration, MPH, and pretreatment PAH, whereas it was negatively correlated with delayed treatment initiation, CA, and BA both at the start and end of treatment. Similarly, in our study, multiple regression analysis demonstrated that a lower height SDS for CA, greater advancement of BA at the start of GnRHa treatment, and a higher MPH SDS were associated with greater PAH SDS gains. Moreover, BA advancement (BA minus CA) at treatment initiation was identified as a more important predictor of PAH SDS increase than other factors, including CA at baseline, according to the multiple regression analysis. Yang et al. [24] reported that GnRHa treatment achieved comparable height gains by reducing BA progression compared to CA both in girls treated before 8 years of age and those treated between 8 and 9 years of age. Their correlation analysis of girls treated between 8 and 9 years indicated that a larger difference between BA and CA was associated with greater height gain at completion of the treatment. In our study, the early treatment group with greater BA progression at baseline had a greater PAH SDS gain than the later treatment group, but the difference was not significant (P=0.232). We also found that GnRH agonist treatment, whether initiated before or after the age of 8 years, led to an increase in PAH SDS at the last visit by delaying BA maturation and prolonging the growth span during treatment. Various factors such as individual growth potential, differences in growth plate maturity, and height SDS for CA at baseline may be more important contributors to treatment effectiveness than age at treatment onset.

Our study has several limitations. For instance, using the Bayley-Pinneau method for PAH, rather than observed adult height, may not be accurate, especially in patients younger than 9 years. This method may overestimate final height up to the BA of 12 or if the BA is advanced by more than 2 years [25,26]. Furthermore, our comparisons of treatment effects might have been less accurate due to variations in sample size, BA advancement, and MPH between the 2 age groups at baseline. Since most patients received leuprolide acetate depot injections, we did not compare the effects of leuprolide with those of triptorelin. Consequently, additional studies are needed to track actual final heights and to adjust for variations in medication types and sample sizes. Despite these limitations, the strength of our study lies in its larger sample size and the analysis of long-term outcomes extending to postmenarche, which is an aspect seldom examined in previous Korean studies.

In conclusion, GnRHa therapy in girls with CPP led to better final adult height results. Our study demonstrated that both girls who received early treatment (<8 years) and those who received later treatment (8-9 years) showed significantly higher PAH SDS at the last compared to the initial PAH SDS. The 2 groups showed similar height gain. Our study suggests that GnRHa treatment may be beneficial for girls diagnosed with CPP at 8–9 years of age, with the height SDS for CA and BA advancement serving as important predictors of height gain.

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