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2 April 2025

Effect of GnRH Analog Therapy on Adult Height in Girls with Idiopathic Central Precocious Puberty

and
1
Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan
2
Division of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, Tokyo 183-8561, Japan
3
Department of General Pediatrics, Tokyo Metropolitan Tama Hokubu Medical Center, Tokyo 173-0015, Japan
*
Author to whom correspondence should be addressed.
Endocrines2025, 6(2), 16;https://doi.org/10.3390/endocrines6020016
This article belongs to the Section Pediatric Endocrinology and Growth Disorders
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Abstract

Precocious puberty (PP) is characterized by the early onset of secondary sexual characteristics and accelerated growth, which often result in compromised adult height (AH). Central precocious puberty (CPP), a subset of PP, is treated with gonadotropin-releasing hormone analogs (GnRHa) to suppress premature hormonal activation and delay epiphyseal closure, thereby preserving height potential. The present review examined the effects of GnRHa on AH outcomes in girls with idiopathic CPP. Although AH is greater with GnRHa therapy than without it, the treatment does not consistently restore the patient’s genetic potential. The benefits of the treatment are most evident in girls in whom idiopathic CPP is diagnosed before 6 years of age and they achieve a height gain of 4.5–14.1 cm, which is unattainable without treatment. However, the treatment of older children (ages 6–8) shows conflicting results, with the AH outcome varying among previous reports. In particular, slowly progressive CPP is known to have a favorable height prognosis even without treatment. Another factor influencing the AH prognosis is the timing of GnRHa discontinuation; the best time to discontinue GnRHa therapy for the best AH outcome is reportedly the bone age of approximately 12 years. In conclusion, although GnRHa therapy significantly improves the AH, especially in early-onset CPP, its effectiveness is uncertain in borderline or late-onset cases. Further research is required to formulate more precise criteria for patient selection and treatment discontinuation to optimize height outcome in girls with idiopathic CPP.

1. Introduction

Recent studies have highlighted a global trend toward earlier pubertal onset in girls, as measured by the onset of breast development. Camilla et al. [1] reported in a systematic review and meta-analysis that the age at thelarche decreased by an average of three months per decade from 1977 to 2013. This trend may also have increased the number of patients with precocious puberty (PP), the definition of which has not been revised for several decades.
PP is a condition in which the secretion of sex hormones is enhanced at an early chronological age (CA), resulting in the earlier appearance of physical, pubertal changes, such as breast development. PP is classified into a gonadotropin-dependent form, referred to as central PP (CPP) in this manuscript, and a gonadotropin-independent form. These two types are caused by the central activation of the hypothalamus and pituitary gland and by other mechanisms related to peripheral gonadal and adrenal gland tumors, respectively. CPP is more common in girls, with approximately 80–90% of cases being idiopathic. In boys, approximately 20–30% of cases are idiopathic, with the rest being organic [2,3,4,5,6,7].
CPP can be divided into two clinical types according to progression [2,8,9,10]: slower type and the others. The former is referred to as slowly progressive CPP, where growth velocity remains normal or slightly accelerated, and BA advancement is less pronounced. Patients with this condition generally have a better AH prognosis and may reach their target height (TH) range even without treatment. On the contrary, the latter, here classified as progressive CPP, is characterized by the continuous progression of pubertal symptoms, accelerated growth velocity, and significant bone age advancement, often leading to a reduction in AH.
The clinical problems associated with PP include (1) psychological and social problems due to the early appearance and progression of secondary sexual characteristics; (2) compromised adult height (AH) due to early growth arrest; and (3) serious complications, such as a brain tumor or sex hormone-producing tumor. In PP, excess sex hormones increase the growth rate at the initial presentation but also accelerate bone maturation, causing early growth plate closure.
In children with CPP, gonadotropin-releasing hormone analogs (GnRHa) have been the treatment of choice for nearly 40 years [11]. Although this therapy is beneficial (see below), uncertainty regarding its ability to achieve the desired AH remains [12,13]. For example, randomized controlled trials have not been conducted, and the comparisons of historical controls and treatment groups between 1990 and 2007 included only small numbers of heterogeneous patients [11]. The present review examines the effects of GnRHa therapy on the AH of girls with idiopathic CPP. In this review, the “treated” group consists of patients with idiopathic CPP who received GnRHa therapy, the “untreated” group includes those who did not, and the “control” group comprises individuals without CPP.

2. Adult Height of Patients with Idiopathic Central Precocious Puberty Receiving GnRHa

Table 1 shows 24 reports of AH outcomes in female patients with idiopathic CPP receiving GnRHa therapy [9,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. The age range at puberty onset was 3–8 years. Young children in past studies were diagnosed with a severe form of CPP whereas older patients in more recent studies who began therapy at the age of 5.4–8.9 years had a milder form. The mean bone age (BA) of patients with idiopathic CPP (Table 1) at the start of treatment was approximately 10 years (range: 8.2–11.1 years), and the mean duration of treatment was approximately 3.0 years. In all but two reports [26,29], AH was 1.1–10.5 cm greater than the predicted adult height (PAH). However, AH was 0.1–7.1 cm below the TH in 16 reports [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,21,22,25,26,27,31,32,33,36] but was 0.4–3.6 cm above the TH in the remaining eight studies [20,23,24,28,29,30,34,35], indicating that GnRHa therapy may not be sufficient for patients to attain their genetic height potential.
Table 1. Adult height of girls with idiopathic central precocious puberty receiving GnRHa therapy.
Table 2 shows that AH differed by age at treatment initiation. Several studies demonstrated that GnRHa therapy significantly improved AH in girls diagnosed before the age of 6 years. As summarized in Table 2, these patients have been reported to achieve an AH increase of 9 to 10 cm, which is substantially greater than their predicted adult height without treatment. These findings support early intervention in younger patients to maximize height potential.
Table 2. Adult height by age at treatment initiation in girls with idiopathic central precocious puberty.
In contrast, girls with idiopathic CPP who were 6 years or more achieved less favorable results. For example, Carel et al. [20] reported that AH increased 4.5–5.3 cm above the pretreatment PAH in 42 treated girls who had puberty onset at the age of 6–8 years. Lazer et al. also demonstrated that AH increased 7.2 ± 5.3 cm in girls who were aged ≥6 years old and had already begun puberty [37]. Additionally, Klein et al. [9] reported the best treatment outcome in those aged 6–8 years; the mean AH of the girls who began treatment at these ages was significantly greater (6.8 ± 6.9 cm) than their pretreatment PAH.
In contrast, Kletter et al. [25]. reviewed the AH of 131 girls treated in ten different clinical study groups and concluded that the treatment did not improve AH in girls aged > 6 years at diagnosis. This conclusion was based on the finding that the AH of 114 girls aged ≥ 6 years did not differ from that of 54 controls. The reason for the difference in growth outcomes in these patients may be explained by the lack of homogeneity in the sample population. These findings suggest that the benefits of treatment in girls diagnosed after the age of 6 years remain uncertain and should be carefully evaluated on a case-by-case basis.
Several studies [5,20,24,39,40,41,42] have compared treated and untreated patients with idiopathic CPP. Table 3 summarizes the comparative data on treated and untreated groups published thus far. The untreated groups mostly comprised patients who came to the hospital at more advanced pubertal stages and did not receive treatment; they were not enrolled in a randomized trial. Paul et al.’s [42] comparison of three sets of data on treated and untreated girls with idiopathic CPP [43,44,45] found that the median age at treatment initiation was 4.7 years and that the average AH was 7.8 cm greater for treated (160.5 ± 6.6 cm) than for untreated (152.7 ± 8.6 cm) patients. Although the mean AH of the treated patients was one standard deviation (SD) less than the TH, this outcome was superior to the mean AH of the untreated patients, which was −2.4 SD below the TH.
Table 3. Adult height of treated and untreated girls with idiopathic central precocious puberty.
Kauli et al. [24], Carel et al. [20] and Antoniazzi et al. [39] reported that AH was greater than the TH in treated patients; the mean AH of the untreated patients fell short of the TH. Magiakou et al. [40] compared girls who reached puberty at the age of 7.9 years with untreated patients, both of whom achieved an AH close to the TH. A recently published retrospective study [46] of girls with idiopathic CPP onset at the age of 6, 7, or 8 years revealed that GnRHa therapy improved adult height (AH) as compared to the TH, although this data may have included those of slowly progressive PP (see below). Their next analysis in the same paper has overcome this issue by including a pair of patients matched for age at onset in the treated and untreated groups [46]. Future comparisons should be made within a group that excludes patients with slowly progressive PP.

3. Adult Height in Patients with Slowly Progressive Central Precocious Puberty

Table 4 shows the definition of slowly progressive CPP in girls used in this review. These criteria, which aim to distinguish (idiopathic) progressive CPP from slowly progressive CPP, were formulated using data from past cross-sectional and small longitudinal studies [2,8,9,10].
Table 4. Comparison of girls with progressive and slowly progressive idiopathic central precocious puberty.
Patients with slowly progressive CPP do not necessarily have a poor AH outcome even without treatment. The progression of hormonal activation in this type of CPP is somewhat slower in girls, as the luteinizing hormone concentration falls within the prepubertal or early puberty range at the initial presentation, indicating that the hypothalamic-pituitary-gonadal axis is not fully active. Some studies of GnRH stimulation in this population have found a predominantly follicle-stimulating hormone response [10,17,24]. The BA of these patients is not very advanced at the initial diagnosis, which probably accounts for the good AH (as discussed below) despite the early onset of secondary sexual characteristics.
Table 5 summarizes the previous studies, which reported a difference ranging from −2.8 cm to 1.5 cm between AH and the TH in girls with slowly progressive idiopathic CPP. On average, AH was 0.65 cm lower than the TH [10,25,26,28,40,47,48,49]. While BA-CA < one year has been the main criterion for defining a slowly progressing CPP, some studies have incorporated other criteria. The difference in AH-TH may be due to variations in research methods and classification criteria in different reports. Carel et al. recommended a follow-up examination every three to six months without therapy to assess the rate of progression if the clinical course suggests slowly progressive PP [2]. In short, this normal variant appears similar to, but actually differs from, progressive CPP, which is treatable.
Table 5. Adult height in untreated girls with slowly progressive idiopathic central precocious puberty.
In Japan, Tanaka et al. [50] reported in their longitudinal study that approximately 1~10% of girls (8.1~10.8%, 4.0~7.2%, 2.8~7.9%, and 1.4~4.7% at the age of 6, 7, 8, and 9 years, respectively) in one elementary school demonstrated transient breast development (n = 894 in total). Their follow-up evaluations confirmed the transient nature of breast pubertal development. Many pediatric endocrinologists in Japan, including the authors of the present review, encounter similar patients in their clinical practice, suggesting that this type of transient breast development may merely be another, normal, variation in pubertal development. Although the long-term prognosis of this variant has not been studied yet, clinical experience would suggest that it has several favorable aspects compared to the other types, including its relatively light impact on the social and psychological dimensions of the patients’ life as well as its superior AH outcomes.

4. Optimal Age at Which to Discontinue GnRHa Therapy for Central Precocious Puberty

Some studies have examined the timing at which treatment discontinuation is most likely to achieve the optimal AH [15,17,20,51]. Ohyama et al. reported changes in BA and the height standard deviation score (Ht-SDS) in 35 girls with idiopathic and organic CPP receiving GnRHa therapy [51]. Their results demonstrated that the Ht-SDS BA gradually increased from 10 years (−1.55 ± 1.07) to 11.5 years (−0.47 ± 0.84) and significantly decreased at 12 years (−1.06 ± 0.84). During treatment, advancement of bone maturation was noticeably suppressed during the period between BA of 11.0 and 11.9 years of age. The annual increments in height SDS relative to BA were higher when BA was younger than 12 years, but they subsequently declined to lower values when BA was 12 years or older. Taken together, these data suggested that extending the treatment beyond BA 12 years would not improve AH. The study concluded that therapy should be discontinued around BA 12 years on the Japanese version of the standardized RUS method (13 years on the TW-2 method). Prolonging treatment may increase the risk of psychosocial problems related to the suppression of sexual characteristics and induce future osteoporosis. Table 6 summarizes some previous reports, including the study by Ohyama et al., examining the best timing at which to discontinue therapy to achieve optimal AH. Most studies [2,15,17,32,49,51] found that discontinuing therapy at BA 12–12.5 years resulted in the greatest AH.
Table 6. Optimal age at which to discontinue GnRHa therapy for central precocious puberty.

5. Conclusions

GnRHa therapy can halt the progression of idiopathic CPP in girls and contribute to improving their AH, even if it cannot achieve the patient’s full genetic potential for AH. The increase in height is more pronounced if therapy begins at age < 6 years. However, several studies have also reported height benefits in patients diagnosed at ages 6–8 years, although the degree of improvement varies. Additionally, factors such as the latency from pubertal onset to treatment initiation may influence final height outcomes. Because RCTs are difficult to conduct for ethical reasons, the efficacy of treatments needs to be examined in observational studies and case studies, which may help formulate new guidelines for treating girls with idiopathic CPP. Regarding the optimal timing of GnRHa discontinuation, a BA of 12 years is likely to produce the best AH outcome.

Author Contributions

Conceptualization: R.S. and Y.H. Methodology: R.S. and Y.H. Resources: R.S. and Y.H. Original draft preparation: R.S. Final editing: R.S and Y.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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