Long-Term Efficacy and Safety of Gonadotropin-Releasing Hormone Analog Treatment in Children With Idiopathic Central Precocious Puberty

A Systematic Review and Meta-Analysis

Xiaoping Luo; Yan Liang; Ling Hou; Wei Wu; Yanqin Ying; Feng Ye


Clin Endocrinol. 2021;94(5):786-796. 

In This Article



The protocol for this review was registered with the International Prospective Register of Systematic Reviews (CRD42018102792). This article has been prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.[36]

Literature Search and Study Selection

We searched PubMed, EMBASE and the Cochrane Library in November 2019, without placing any limitations on language or publication year. The detailed search strategies were developed by an information specialist and are presented in the Online Supplementary Materials. Two reviewers (LH and WW) independently screened the search results based on the following inclusion criteria: (a) prospective or retrospective comparative studies and single-arm studies; (b) participants with ICPP (as defined in the original study) with the onset of secondary sex characteristics before 8 years of age in girls and before 9 years of age in boys; and (c) studies that reported long-term (defined as a duration of ≥6 months) outcomes in participants who received GnRHa (any type of dosage regimen) compared with participants who received no treatment/placebo or GnRHa plus growth hormone (GH; any type of dosage regimen). We excluded studies that enrolled participants with negative results in the GnRH stimulation test and those with non-idiopathic CPP (such as isosexual precocious puberty, familial male-limited precocious puberty, or familial precocious puberty). Studies in which the participants were diagnosed with a brain tumour, trauma, infection, macrophage activation syndrome, congenital adrenal hyperplasia or GH deficiency were also excluded. Any disagreement during screening was resolved by discussion and, when necessary, with assistance from a third reviewer (YL).

Outcome Measures

The primary outcomes were as follows: FAH, which is considered the final adult stature of an individual when the bone age is ≥15 years and/or the rate of growth in height is <1 cm/year in the past year (or within ≥2 years after a girl has experienced menarche); target height (TH), which is calculated using the height of the individual's parents (as defined in the original study); BMI and risk of being overweight/obese (being overweight is defined as a BMI above the 85th percentile or 25–29.9 kg/m2 and obesity as a BMI above the 95th percentile or >30 kg/m2); and the incidence of PCOS among girls and androgen excess among boys. PCOS is defined as a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. The secondary outcomes included menstrual parameters (such as age at menarche and regularity of menstruation), growth velocity (GV), insulin-like growth factor 1 (IGF-1) level, BMD, glucose and lipid metabolism, insulin resistance parameters and psychological state.

Data Extraction and Risk of Bias Assessment

Two reviewers (LH and WW) independently extracted qualitative and quantitative data using a standard data collection form. The risk of bias of the included studies was assessed according to the study design. Randomized controlled trials (RCTs) were assessed using the risk of bias tool from the Cochrane Handbook for Systematic Reviews of Interventions.[37] Non-randomized comparative studies were assessed using the 'Risk Of Bias In Non-randomized Studies - of Interventions' (ROBINS-I) tool.[38] Single-arm studies were rated as having a high risk of bias. Disagreements were resolved by discussion or by consulting with the third reviewer (XPL) when necessary.

Statistical Analysis

Separate analyses were performed based on single-arm studies and comparative studies. Regarding single-arm studies, qualitative and quantitative data are summarized to provide a comprehensive description of the phenotype of the participants and the primary reasons for treatment. Meta-analyses were performed for comparative studies. We estimated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) with 95% CIs for continuous outcomes. We employed a random-effects model for all meta-analyses using the R software,[39] and we performed separate analyses based on sex. The outcome data derived from comparative studies and single-arm studies were combined if there was no clinical and methodological heterogeneity present. To explore clinical heterogeneity, we planned to perform a priori subgroup analysis on primary outcomes based on the age of onset (<6 vs ≥6 years of age) as well as the type of GnRHa used. However, due to insufficient data and wide CIs for most treatment estimates, we did not perform additional sensitivity analyses. Statistical heterogeneity was estimated by I 2 and χ 2 statistics (substantial statistical heterogeneity was defined as I 2 ≥ 50% with a p-value of <.1 in the χ 2 test).