Efficacy and safety of different doses of gonadotropin-releasing hormone analogues in the treatment of precocious puberty in children: a systematic review and meta-analysis

Introduction

In recent years, shifts in living environments and dietary habits have contributed to a gradual decrease in the age at which puberty begins. However, this earlier onset may result in precocious puberty, a condition characterized by abnormal pubertal development. Precocious puberty primarily manifests as the premature appearance of secondary sexual characteristics in affected individuals (1). Based on the early activation of the hypothalamic-pituitary-gonadal axis (HPGA), precocious puberty can be classified into central precocious puberty, peripheral precocious puberty, and incomplete precocious puberty. Epidemiological studies indicate that the overall incidence of precocious puberty is approximately 1 in 5,000 to 1 in 10,000, with an incidence rate 5 to 10 times higher in girls than in boys (2,3). Children with precocious puberty experience abnormal structural changes due to a mismatch between their biological and chronological ages, impacting their future health. A study indicated that early menarche may result in short stature in adulthood and raise the risk of cardiovascular disease, obesity, type 2 diabetes, and breast cancer (4). In addition, children with precocious puberty may experience psychological challenges, including low self-esteem, social withdrawal, anxiety, depression, and reduced attention span, due to the early development of secondary sexual characteristics, which can make them appear physically different from their peers (5-7). Timely identification and diagnosis of precocious puberty in children, along with appropriate interventions, are essential.

Currently, gonadotropin-releasing hormone analogue (GnRHa) is the standard treatment for precocious puberty in children (1). GnRHa can halt premature sexual development and delay bone age maturation by binding to GnRH receptors and inhibiting the secretion and release of gonadotropins from the pituitary gland, thus helping to preserve growth potential. In North America, Europe, and other regions, treatment protocols typically use higher doses of GnRHa to achieve full HPGA suppression (8,9). The Chinese guidelines for diagnosing and treating precocious puberty recommend a GnRHa dose of 60–80 µg/kg/4 week, which should be individualized, with a maximum dose of 3.75 mg per administration per month (10). In clinical practice, it has been observed that high or low doses of GnRHa can lead to inadequate control of patients’ sex hormone levels or hinder growth, significantly impacting therapeutic outcomes (11).

Therefore, the primary objective of this study was to systematically evaluate and meta-analyze the efficacy and safety of various GnRHa doses in treating precocious puberty in children. This study aims to provide clinicians with evidence-based guidance for the application of GnRHa in managing precocious puberty in pediatric patients. We present this article in accordance with the PRISMA reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-439/rc).

Methods

Literature search strategies

We searched four Chinese medical electronic databases and three English-language databases, including the National Knowledge Infrastructure Database (CNKI), the VIP database, the Wanfang database, the Chinese Biomedical Literature Database (CBM), EMbase, PubMed, and the Cochrane Library. The search covered studies published from the establishment of each database up to September 2024. We used a combination of subject terms and free text to construct the search formula with keywords such as “Puberty, Precocious”, “Pubertas Praecox”, “Central Precocious Puberty”, “Sexual Precocities”, “Gonadotropin-Releasing Hormone”, “Gonadoliberin”, “GnRHa”, among others. Detailed search strategies for each database are provided in Appendix 1. Additionally, we manually reviewed references from the included articles, clinical trial registry platforms, and other sources to ensure a comprehensive search.

Arrangement criteria for documentation

Only clinical studies published in Chinese or English were included, and each study had to report at least one relevant outcome indicator.

The study subjects included were children with a confirmed diagnosis of precocious puberty. The diagnostic criteria were as follows: breast development by age 8 years and first menstruation by age 10 years for girls, and testicular enlargement by age 9 years for boys (3); GnRH stimulation test results showing peak luteinizing hormone (LH) above the critical concentration of 5 IU/L and a peak LH/follicle-stimulating hormone (FSH) ratio above 0.6 (12,13); bone age evaluated of the left wrist, with children whose bone age exceeded their chronological age by 1 year or more classified as having advanced bone age (14); ultrasound imaging indicating an enlarged uterus and ovaries with multiple ovarian follicles over 4 mm in diameter (15). Treatment should involve GnRHa, with the test and control groups comparing different dosage levels.

The primary objective of this study was to evaluate the efficacy and safety of varying doses of GnRHa in treating precocious puberty in children. Thus, the primary outcome indicators included bone age and predicted adult height (PAH), while the secondary outcome indicators were bone metabolism markers (P1NP), sex hormone levels (LH), and the incidence of adverse effects.

Animal studies, systematic reviews, literature reviews, case reports, and grey literature (e.g., conference abstracts) were excluded, as they did not meet the inclusion criteria. Additionally, studies with duplicate publications, interventions using only a single group application of GnRHa, and studies that did not report the required outcome indicators were excluded.

Literature screening and data extraction

The retrieved literature was imported into EndNote to create a screening database, and two independent researchers (Y.Z. and X.Z.) screened the studies according to the predefined inclusion and exclusion criteria. First, duplicate records were removed; second, a primary screening based on titles and abstracts was conducted to identify studies potentially meeting the inclusion criteria. Finally, the full text of each article was downloaded and reviewed to confirm its eligibility for subsequent statistical analysis. In cases of inconsistency or disagreement, a third independent researcher (P.J.) or experts in relevant fields were consulted to make a final judgment.

Data from the included studies were extracted using Excel software. The extracted information included the first author, year of publication, country, general characteristics of the subjects (mean age, mean duration of disease), diagnostic criteria, sample size, names of intervention methods in the test and control groups, dosage used, duration of treatment, frequency, and relevant outcome indicators. Researchers underwent prior training to minimize subjective differences and ensure consistency in data extraction.

Literature quality assessment

The risk of bias in the included studies was assessed using RevMan 5.3 software, following the bias assessment guidelines provided by the Cochrane Handbook. The results were presented in a risk of bias diagram. The assessment included seven criteria: random sequence generation, allocation concealment, blinding of participants and intervention providers, blinding of outcome assessors, completeness of outcome data, selective reporting, and other potential sources of bias. Each criterion was classified into three levels: “high risk”, “unclear”, and “low risk”. Studies were categorized by their overall bias risk based on the number of low-risk items: low risk of bias (>5 low-risk items), moderate risk of bias (4–5 low-risk items), and high risk of bias (≤3 low-risk items).

Statistical analysis

Data were quantitatively analyzed using RevMan 5.3 software. Dichotomous variables were expressed as relative risk ratios (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs), while continuous variables were expressed as mean difference (MD) or standardized mean difference (SMD) with 95% CI. Heterogeneity was assessed using I², with significant heterogeneity indicated by I²≥50% and P≤0.05. If little or no heterogeneity was observed, a fixed-effects model was applied; otherwise, significant heterogeneity was addressed with a random-effects model, with subgroup analysis or individual study characteristics examined to explore the sources of heterogeneity. Sensitivity analyses were conducted to evaluate the stability and reliability of the results, and funnel plots were used to assess publication bias. Additionally, trial sequential analysis (TSA) was performed to assess whether sample sizes met expectations.

Results

Literature search and screening results

A total of 8,553 documents were retrieved through the search, reduced to 7,306 after removing duplicates via EndNote and manual screening. Following an initial screening based on titles and abstracts, 7,239 papers were excluded, leaving 67 for further review. Full-text screening excluded an additional 54 studies that did not meet the inclusion criteria, resulting in the inclusion of 13 studies for quantitative meta-analysis. The screening process is illustrated in Figure 1.

Figure 1 PRISMA flowchart summarizing the screening process for the study of different doses of GnRHa for the treatment of precocious puberty in children. GnRHa, gonadotropin-releasing hormone analog; CNKI, National Knowledge Infrastructure Database; CBM, Chinese Biomedical Literature Database.

General characteristics of the included literature

A total of 686 children, including 19 males and 667 females aged 6.16 to 10.14 years, were included in the 13 clinical studies. The treatment group received low-dose GnRHa, with doses ranging from 40–60, 50, and 60 µg/kg/4 week per dose; 11.25 mg per dose; or a three months dosage form. The control group received high-dose GnRHa, with doses of 80, 90, 100, 80–100, and 120 µg/kg/4 week per dose; 22.5 and 30 mg per dose; or a 1 month dosage form. The treatment duration ranged from 3 months to 3 years, as detailed in Table 1.

Quality assessment of the included studies

Of the 13 studies included, 2 (16,17) did not mention randomization, while the remaining 11 (18-28) applied randomization methods. Of these, eight studies used the random number table method, two studies (18,22) used simple randomization, and one study (20) used complete randomization. Six studies reported allocation concealment, with five (19-21,25,26) using opaque envelopes and one (28) using a computer for allocation concealment. Blinding was applied in six studies (19-21,26-28) for patients or operators and in seven studies (16,20,23,24,26-28) for data collection and enumerators. All studies provided complete reporting with no selective reporting or other risks of bias. In the comprehensive assessment, six studies were rated as low risk of bias (low risk >5), six as moderate risk of bias (low risk 4–5), and one as high risk of bias (low risk ≤3). The overall quality of the studies was moderate, as shown in Figure 2.

Figure 2 Evaluation of risk of bias for the inclusion of 13 literatures.

Meta-analysis

Primary outcome indicators

A total of eight studies (16-20,23,27,28) reported on the improvement of bone age in children with precocious puberty treated with different doses of GnRHa, with no significant heterogeneity among studies (P=0.32, I²=14%), allowing for the use of a fixed-effects model. The results indicated no significant difference in bone age improvement between the low- and high-dose groups (MD =0.10, 95% CI: 0.00 to 0.21, P=0.06), as shown in Figure 3.

Figure 3 Forest plot of improvement in bone age in children with precocious puberty with different doses of GnRHa. The study marked ② is identical to the previously included study with the same name. As the study involved more than 2 groups that could be included in the analysis, it has been divided into 2 studies for entry into the analysis. GnRHa, gonadotropin-releasing hormone analog; SD, standard deviation; CI, confidence interval.

Seven studies (16-19,26-28) reported on the improvement in PAH in children with precocious puberty treated with different doses of GnRHa. Significant heterogeneity was observed across these studies (P=0.01, I²=59%), leading to the use of a random-effects model. The results showed no significant difference in PAH improvement between the low- and high-dose groups (MD =−0.14, 95% CI: −1.23 to 0.96, P=0.81). Analysis of the sources of heterogeneity indicated that the primary contributor was the study by Zhang F (2023) (19). As shown in Figure 4.

Figure 4 Forest plot of improvement in predicted adult height in children with precocious puberty at different doses of GnRHa. The study marked ② is identical to the previously included study with the same name. As the study involved more than 2 groups that could be included in the analysis, it has been divided into 2 studies for entry into the analysis. GnRHa, gonadotropin-releasing hormone analog; CI, confidence interval; SD, standard deviation.

Secondary outcome indicators

Three studies (19,20,28) examined the effects of different doses of GnRHa on the bone metabolism marker P1NP in children with precocious puberty. Significant heterogeneity was observed among these studies (P=0.08, I²=56%), leading to the use of a random-effects model. The results indicated that the high-dose group had a more pronounced effect on P1NP than the low-dose group (MD =−36.03, 95% CI: −57.63 to −14.43, P=0.001). Analysis of heterogeneity sources suggested that the primary contributor was the study by Li JY (2023) (28). As shown in Figure 5.

Figure 5 Forest plot of the effect of different doses of GnRHa on P1NP, an indicator of bone metabolism in children with precocious puberty. The study marked ② is identical to the previously included study with the same name. As the study involved more than 2 groups that could be included in the analysis, it has been divided into 2 studies for entry into the analysis. GnRHa, gonadotropin-releasing hormone analog; CI, confidence interval; SD, standard deviation.

Eight studies (16,17,19,20,25-28) reported the effect of different doses of GnRHa on the sex hormone LH in children with precocious puberty, showing no significant heterogeneity between studies (P=0.18, I²=29%), and thus a fixed-effects model was used. The results indicated a more pronounced effect on LH in the low-dose group compared to the high-dose group (MD =0.10, 95% CI: 0.03 to 0.18, P=0.009), as shown in Figure 6.

Figure 6 Forest plot of the effect of different doses of GnRHa on LH in children with precocious puberty. The study marked ② is identical to the previously included study with the same name. As the study involved more than 2 groups that could be included in the analysis, it has been divided into 2 studies for entry into the analysis. GnRHa, gonadotropin-releasing hormone analog; LH, luteinizing hormone; SD, standard deviation; CI, confidence interval.

Eleven studies (16,17,19-22,24-28) reported the incidence of adverse reactions at different doses of GnRHa, showing no significant heterogeneity among studies (P=0.96, I²=0%), allowing for the use of a fixed-effects model. The results indicated that the incidence of adverse reactions was significantly higher in the high-dose group compared to the low-dose group (OR =0.21, 95% CI: 0.13 to 0.33, P<0.001). See Figure 7.

Figure 7 Forest plot of the incidence of adverse reactions to different doses of GnRHa. The study marked ② is identical to the previously included study with the same name. As the study involved more than 2 groups that could be included in the analysis, it has been divided into 2 studies for entry into the analysis. GnRHa, gonadotropin-releasing hormone analog; CI, confidence interval.

Funnel plot and sensitivity analysis

The publication bias test for bone age, PAH, bone metabolism marker P1NP, sex hormone markers LH, and the incidence of adverse reactions in studies evaluating different doses of GnRHa for treating precocious puberty in children suggests minimal publication bias among the included studies. See Figure 8. Sensitivity analysis using the one-by-one exclusion method showed no significant changes in the combined results, indicating that the findings of this study are robust.

Figure 8 Funnel plot of different doses of GnRHa for the treatment of precocious puberty in children included in the study. (A) Bone age; (B) PAH; (C) LH; (D) FSH; (E) incidence of adverse reactions. SE, standard error; MD, mean difference; GnRHa, gonadotropin-releasing hormone analog; PAH, predicted adult height; LH, luteinizing hormone; FSH, follicle-stimulating hormone; OR, odds ratio.

TSA test sequential analysis

In this study, a TSA was conducted on bone age outcome indicators, allowing for a 20% probability of type I error, with an information axis based on cumulative sample size and a target statistical power of 80%, with sample size as the desired information value (TSA). The resulting cumulative Z-curve did not cross the traditional boundaries, indicating no significant difference between the high- and low-dose groups. Additionally, the cumulative Z-curve did not cross the TSA boundaries, and the cumulative information value did not reach the desired sample size. See Figure 9.

Figure 9 Sequential analysis of TSA trials with different doses of GnRHa for the treatment of precocious bone age in children. The study marked ② is identical to the previously included study with the same name. As the study involved more than 2 groups that could be included in the analysis, it has been divided into 2 studies for entry into the analysis. GnRHa, gonadotropin-releasing hormone analog; TSA, trial sequential analysis.

Discussion

The pathogenesis of precocious puberty is complex. Various factors can trigger the premature activation of the HPGA, leading to the early release and increase of GnRH. This, in turn, raises serum levels of gonadotropins and steroid hormones to pubertal levels prematurely, resulting in the early onset of secondary sexual characteristics (29). Over the past two decades, GnRHa extended-release agents have become a common treatment for precocious puberty in children, both domestically and internationally. After injection, these drugs are released gradually and continuously, binding to GnRH receptors on anterior pituitary gonadotropic cells. This action inhibits the pituitary-gonadal axis, reducing the secretion of LH, FSH, and other gonadotropins, thereby controlling sexual development and delaying skeletal maturation, ultimately contributing to improved adult height as a therapeutic outcome (1,30). Appropriate dosing during extended cycles of GnRHa therapy is crucial to achieving optimal outcomes in treating childhood precocious puberty. Insufficient doses of GnRHa may fail to adequately suppress the HPGA, merely inhibiting gonadal hormone release and thereby impacting the child’s growth and development. Conversely, the high cost of continued high-dose GnRHa use increases the financial burden on the child’s family. Currently, available evidence-based studies focus primarily on the efficacy of GnRHa in treating precocious puberty in children and its effects on body mass index (BMI) and the endocrine system (31-33). Currently, no studies have analyzed the efficacy and safety of different doses of GnRHa for treating precocious puberty in children. Therefore, while the effectiveness of GnRHa in managing precocious puberty is well-established, the optimal dosage remains a topic of ongoing debate.

Thirteen clinical studies were included in this analysis. Meta-analysis was used to compare the effects of low- and high-dose GnRHa on bone age, PAH, bone metabolism markers, and sex hormone levels in children with precocious puberty, as well as evaluating the incidence of adverse reactions. The findings indicated no significant difference between low- and high-dose GnRHa treatments in their effects on bone age, PAH in children with precocious puberty. However, high-dose GnRHa had a more pronounced effect on P1NP, while low-dose GnRHa had a greater impact on LH. Additionally, the incidence of adverse reactions was significantly lower in the low-dose GnRHa group compared to the high-dose group. Overall, the therapeutic effect of low-dose GnRHa is comparable to that of high-dose GnRHa, but its long-term use appears to be safer. For families with high safety requirements, we recommend the low-dose group; for families who expect to see faster results or for patients who prefer the high-dose group, we recommend the high-dose group.

There are some limitations in this study: (I) most of the included studies did not specify the method of random sequence allocation concealment or provide relevant clinical registration information, underscoring the need for additional high-quality evidence. (II) Of the 13 literatures included, eight were in Chinese. Therefore, the included population was also mainly limited to the Chinese region, which may affect the generalisability of the findings, introduce potential bias and affect the reliability of the conclusions. (III) Differences in study locations led to variations in GnRHa dosage conversions, potentially contributing to bias. (IV) TSA analysis indicated that, although no significant difference was found between low- and high-dose GnRHa treatment effects, the desired sample size was not reached, highlighting the need for further studies on varying doses of GnRHa for the prevention and treatment of precocious puberty in children for future reanalysis.

Conclusions

In conclusion, this systematic review and meta-analysis compared the efficacy and safety of different doses of GnRHa for the prevention and treatment of precocious puberty in children. The findings indicate that low-dose GnRHa treatment is both effective and safer, providing evidence to guide dose selection for GnRHa in clinical applications for treating precocious puberty in children.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-439/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-439/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-439/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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