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


In this systematic review, we aimed to determine the long-term efficacy and safety of GnRHa treatment in children with ICPP. Current evidence is mainly focused on girls with ICPP, and the overall quality of evidence for each studied outcome was found to range from very low to moderate. The main findings of our meta-analyses showed that compared with no treatment, GnRHa treatment improved the FAH of girls by increasing FAH by ≥2.32 cm. The average FAH of girls after GnRHa treatment was closer to their TH, if not more than their TH. The impact of GnRHa treatment on girls with different ages of CPP onset remains unclear due to insufficient evidence. In addition, the follow-up results (average follow-up: 3 years, range: 6 months to >20 years) revealed that GnRHa treatment might not lead to strong side effects such as risk of overweight/obesity and of PCOS, other malignancies, and metabolic syndromes. Although BMI levels were shown to increase slightly at the start of GnRHa treatment (particularly in girls with a normal baseline BMI status), girls who received treatment had lower BMI levels (reduced by ≥0.28 kg/m2) than those who did not in adulthood. Furthermore, BMI levels did not significantly exceed the normal range, which indicated that GnRHa treatment is less likely to increase the risk of overweight/obesity. GnRHa treatment may reduce the risk of early menstruation, and the average age at menarche was 1 year older than that in girls who did not receive treatment. There was no significant difference in the incidence of PCOS between the GnRHa and no-treatment groups. In addition, the prevalence of malignant diseases was low among women with former ICPP and in healthy controls. The evidence regarding fertility was obtained from only one study (Lazar 2014; n = 235); among the pregnant women with former ICPP, more women experienced spontaneous pregnancy in the GnRHa group than in the no-treatment group. Furthermore, GnRHa did not increase the risk of early miscarriage. Bone densitometric parameters were within the normal range for the respective sex and age groups before and after GnRHa treatment, and GnRHa treatment did not increase the risk of metabolic diseases such as diabetes and hyperlipidemia.

Early evidence has indicated that precocious puberty may lead to certain psychological or social problems, which are considered to bother parents and may affect the clinical treatment of CPP.[40] However, according to the results of the included studies, GnRHa treatment did not worsen the cognitive, psychological and social problems of children with ICPP and has the potential to reduce problems in some children, which was consistent with recent evidence.[41,42]

Several of the outcomes in the present review showed substantial heterogeneity (I 2 > 50%) and one possible source may be the use of different drugs of GnRHa treatment. In addition, the small sample size may have contributed to the heterogeneity.

Our findings are somewhat consistent with those of a previous systematic review[3] that explored the long-term outcomes of GnRHa treatment in children with CPP. Guaraldi 2016[3] reported that GnRHa treatment appeared to improve FAH in girls with CPP and had no clear negative impact on BMI, risk of PCOS, or BMD. However, only the PubMed database was searched in this review. Another network meta-analysis is currently assessing the efficacy and safety of GnRHa treatment.[43] Although the present review did not predefine the exact population as Gu 2019,[43] a similar conclusion was reached.

Strengths and Limitations

The strengths of this systematic review include the creation of comprehensive search strategies to identify all relevant published studies and the use of sound methodology, which involved use of two reviewers to independently select studies and extract data. The latter strength minimizes the risk of performance bias in conducting the systematic review. However, our work also has some limitations. The results generated from pooling data of single-arm studies had a high level of statistical heterogeneity; thus, it was not possible to infer and draw meaningful conclusions from these meta-analyses. Furthermore, bias in the selection of participants is a major concern in several of the included comparative studies. The treatment regimen of GnRHa and the dropout rates were not well described in most of the comparative studies, which may exaggerate the magnitude of the estimated effects of meta-analysis. Treatment duration has been suggested as a contributing factor to improved FAH in the literature. However, all of the included comparative studies reported treatment duration of 2–5 years, which limited the conduction of subgroup analysis. Furthermore, a substantial level of statistical heterogeneity was evident for some outcomes such as the differences between FAH and TH and age at menarche. Therefore, our results should be interpreted with caution. Moreover, the current evidence cannot be directly applied to boys with CPP due to the lack of data on this population. Further research, particularly large-scale RCTs (multicenter) or high-quality comparative studies with an adequate sample size, follow-up rate and duration, including both girls and boys, are required before firm conclusions can be drawn. In addition, it will be important to explore the main influencing factors on the long-term effects of GnRHa treatment.[44]