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

Abstract and Introduction


Objective: To investigate the long-term efficacy and safety of gonadotropin-releasing hormone analog (GnRHa) treatment in children with idiopathic central precocious puberty (CPP).

Method: The protocol was registered with International Prospective Register of Systematic Reviews (CRD42018102792). PubMed, EMBASE and the Cochrane Library were searched for eligible comparative and single-arm studies.

Results: We identified a total of 98 studies that included 5475 individuals. The overall risk of bias of the eligible studies ranged from critical to moderate. The overall quality of evidence for each outcome ranged from very low to moderate. Evidence-based comparative studies showed that GnRHa treatment increase final adult height (FAH, cm; studies = 4, n = 242; mean difference [MD] = 4.83; 95% confidence interval [CI], 2.32 to 7.34; I 2 = 49%) and decrease body mass index (BMI, kg/m2; studies = 3, n = 334; MD = −1.01; 95% CI, −1.64 to −0.37; I 2 = 0%) in girls with idiopathic CPP compared with no treatment. The incidence of polycystic ovary syndrome (PCOS) did not significantly differ with and without GnRHa treatment (studies = 3, n = 179; risk ratio = 1.21; 95% CI, 0.46 to 3.15; I 2 = 48%). The evidence for other long-term outcomes was very weak to deduce the effects of GnRHa treatment. Further, limited evidence is available on its effects in boys.

Conclusion: Compared with no treatment, evidence indicates that GnRHa treatment increase FAH and decrease BMI in girls with idiopathic CPP. GnRHa treatment did not evidently increase the risk of PCOS. However, evidence regarding other key long-term outcomes (such as infertility and malignant or metabolic diseases) was considered very weak to suggest the benefits or side effects of GnRHa treatment. Additional high-quality evidence is needed before firm conclusions can be drawn.


Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal axis (HPGA) and is commonly characterized by the early development of pubertal biochemical and physical features before 8 years of age for girls and 9 years of age for boys.[1,2] CPP is a rare condition and has an estimated overall prevalence of approximately 1 per 5000–10,000 children, with a five- to 10-fold higher incidence in girls than in boys.[3–6] CPP can be classified into idiopathic CPP (ICPP) and secondary CPP; the latter is including genetic causes(familial CPP, chromosomal abmormalities), central nervous system abnormalities (hypothalamic hamartomas, cysts, central nervous system granulomas, hydrocephalus, septo-optic hypoplasia), secondary to chronic exposure to sex steroid hormones (late treatment of simple virilizing congenital adrenal hyperplasia, following resection of tumours secreting sex steroid hormones, testotoxicosis, McCune-Albright syndrome) or endocrine disruptors..[7] ICPP is the most frequent form of CPP, accounting for approximately 90% cases of CPP in girls and 25%–60% in boys.[8–10] Although the exact mechanism underlying the development of ICPP is not well understood, several potential metabolic, genetic and epigenetic explanations have been considered.[11–15] CPP is associated with a lower final adult height (FAH), potential sexual abuse, increased risk of psychological disturbances and increased risk of developing cardiovascular diseases and reproductive tract cancers.[16,17]

Gonadotrophin-releasing hormone analog (GnRHa) is a synthetic peptide drug that is modelled based on human hypothalamic gonadotropin-releasing hormone (GnRH), which is designed to act on the anterior pituitary.[7] GnRHa interacts with the GnRH receptor and stimulates the synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the initial phase of administration ('flare up'). Sustained release of GnRHa suppresses the production of FSH and LH, which in turn suppress the production of sex hormones by the gonads.[7] Several pharmaceutical formulations of GnRHa, such as buserelin, histrelin, leuprorelin, triptorelin and goserelin, are available and used clinically.[18,19] The choice of drug and duration of treatment depend on the unique growth and development needs.[19,20] GnRHa has been a treatment choice for CPP since the mid-1980s, and its effects on HPGA suppression has been generally recognized.[19,21,22] However, the long-term efficacy and safety of GnRHa treatment remain unclear, and some studies have reported contradictory findings.[3]

Several studies have reported that GnRHa may improve FAH in girls with CPP;[3,23–26] this is particularly true if they were diagnosed before the age of 6 years and treated with GnRHa from Tanner stage 2–3 to chronological age 11–12 years and bone age 12–12.5 years.[27] However, the effects of GnRHa treatment are unknown in girls diagnosed between 6 and 8 years of age.[3] Regarding body mass index (BMI), several studies have found that GnRHa treatment did not lead to an increased risk of weight gain.[28–30] Among these studies, Corripio et al[30] reported an increase in weight based on BMI standard deviation score (SDS). In terms of its effect on the reproductive system, GnRHa treatment was not confirmed to be harmful to ovarian function or fertility.[31] There was no clear difference in the incidence of androgen excess or polycystic ovary syndrome (PCOS) between children with CPP treated with GnRHa and those in the healthy comparison group.[31–33] However, the effects of GnRHa treatment on bone mineral density (BMD), glucose and lipid metabolism, and psychological status remain unclear.[19,20,34,35] Therefore, we conducted this systematic review and meta-analysis to evaluate the long-term efficacy and safety of GnRHa treatment in children with ICPP.