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

Disclosures

Clin Endocrinol. 2021;94(5):786-796. 

In This Article

Results

Search Results

A total of 3515 hits were identified from searching the electronic databases. After assessing their eligibility, 98 studies with 105 references were included in this systematic review. The detailed reasons for exclusion are illustrated in the PRISMA study selection flow diagram (Figure 1).

Figure 1.

PRISMA study selection flow diagram

Included Studies

The 98 included studies enrolled a total of 5475 participants (98.5% were girls). All references for the included studies are presented in the Supplementary Material. The sample size of the included studies ranged from 6 to 333. No RCTs were identified. Among the 98 included studies, 18 were randomized comparative studies (n = 1303) and the remaining 81 (n = 4172) were single-arm studies. Antoniazzi 2000 employed both comparative and single-arm study designs, thereby accounting for both non-randomized comparative and single-arm studies. The average age of CPP onset ranged from 4.5 to 8 years, and the average age of GnRHa treatment initiation ranged from 5 to 9.31 years. Various formulations of GnRHa were used in the included studies such as leuprorelin, triptorelin, buserelin, goserelin, deslorelin and histrelin. Thirteen studies (n = 1047) compared GnRHa treatment with no treatment, and six studies (n = 310) compared GnRHa treatment with GnRHa plus GH. The treatment duration ranged from 3 months to 5 years for all included studies. Additional study details are presented in Table S1.

Quality Assessment of Included Studies

Among the 18 comparative studies, none received low risk of bias scores across all domains. Based on ROBINS-I, 10 (55.6%) studies (Liang 2015, Poomthavorn 2011, Antoniazzi 2000, Shiasi Arani 2015, Colmenares 2014, Gyon 2015, Lanes 2004, Léger 2000, Magiakou 2010, and Pucarelli 2003) were judged to have an overall moderate risk of bias. Six (33.3%) studies (Faienza 2017, Swaiss 2017, Antoniazzi 2000, Bridges 1995, Jung 2014, and Yuan 2011) were judged to have a critical risk of bias because they selected participants based on either the intervention they received or the prediction of FAH. Two (11.1%) studies (Lazar 2014 and Lazar 2015) were judged to have a critical risk of bias with regards to the selection of participant domains as well as an overall critical risk of bias. Following our protocol that was established a priori, the 81 single-arm studies were regarded to have a high risk of bias. The summary of our assessment of risk of bias for comparative studies is presented in Table S2. Following the consideration of inconsistency and indirectness, the overall quality of evidence for each outcome ranged from very low to moderate.

Results of Single-arm Studies

Among the 81 single-arm studies (n = 5316), 47 included non-specified CPP patients (n = 2527) and 34 included ICPP patients (n = 2789). A total of 130 males and 5903 females were included in 80 studies, and one study (Comite 1986) did not report information on sex. The age of onset of ICPP ranged from 4.5 to 8 years, and the age at which the patients first received treatment ranged from 5 to 9.31 years. The included participants were treated with leuprolide in 26 studies, buserelin in one study, decapeptyl (including triptorelin) in 34 studies, histrelin in two studies, nafarelin in one study, non-specific GnRHa treatment in 10 studies, and a combination of these drugs in the remaining seven studies. The duration of treatment ranged from 3 months to 5 years (Table S1).

Among the 81 studies, 12 (Nabhan 2007, Borges 2015, Lin 2017, Lazar 2007, Antoniazzi 2000, Antoniazzi 2003, Baumann 2001, Carel 1999, Chen 2009, Gillis 2013, Kempers 2002, and Ying 2017) (n = 485) reported the average TH and FAH of girls (Table S4). In six studies (Borges 2015, Lin 2017, Lazar 2007, Carel 1999, Chen 2009, and Gillis 2013), the mean FAH of girls exceeded their TH (Table 1). One retrospective study (Lazar 2007) investigated the posttreatment height gain against the age of onset.

Four studies reported average BMI (n = 72), and eight studies reported average BMI-SDS (n = 300) in girls with ICPP after GnRHa treatment (Table S4).

The age at menarche was reported in 11 studies (n = 615), and all 11 studies reported the time to menarche after discontinuation of treatment. Further, 26 studies reported GV, 8 reported IGF-1 level, five reported BMD, 6 reported glucose and lipid indices, and three reported insulin resistance parameters. There were no remarkable findings in relation to the secondary outcomes (including GV, IGF-1 level, BMD, glucose and lipid indices, and insulin resistance parameters; Table S4, S6 and S7).

Five studies reported psychological outcomes, including cognitive functioning and emotional reactivity (Baumann 2001, Menk 2017, Schoelwer 2017, Wojniusz 2016, and Zheng 2008). Meta-analysis was not performed because the included studies used different scales. In general, GnRHa-treated CPP girls did not significantly differ in their cognitive or psychosocial functioning from age-matched controls.

Five single-arm studies evaluated boys with ICPP, and the descriptive results regarding FAH, BMI, GV and IGF-1 based on single-arm studies are presented in Table S5. The results were similar to those of girls, although the sample size of each study was very small (n = 8–13).

Meta-analysis of Comparative Studies

All comparative studies included girls with ICPP (Table 2; Table S3).

Adult Height Improvement

Five studies compared GnRHa treatment with no treatment (Faienza 2017, Swaiss 2017, Poomthavorn 2011, Antoniazzi 2000, and Lanes 2004). The results of these studies demonstrated that girls treated with GnRHa reached their TH, whereas most girls without treatment did not reach their TH. In addition, FAH (cm) was greater in girls treated with GnRHa than in those who were not treated (studies = 4, n = 242; MD = 4.83; 95% CI, 2.32 to 7.34; I 2 = 49%; Figure 2A). The participants of the study by Lanes 2004 (not included in the meta-analysis) were assigned to the intervention group based on their predicted height, and the girls with a predicted height of <155 cm received GnRHa treatment. The average FAH of the participants in the intervention group was not significantly different from that of the participants in the no-treatment group.

The difference between FAH and TH (FAH minus TH, cm) was larger in the GnRHa group than in the no-treatment group (studies = 3, n = 148; MD = 5.78; 95% CI, 2.33 to 9.23; I 2 = 59%; Figure 2B).

Figure 2.

Forest plots of gonadotropin-releasing hormone analog treatment compared with no treatment for height outcomes [Colour figure can be viewed at wileyonlinelibrary.com]

Five studies (Liang 2015, Gyon 2015, Bridges 1995, Jung 2014, and Pasquino 1996) were included in this comparison (Table S3). All girls in both GnRHa and GnRHa plus GH groups (Liang 2015, Gyon 2015, Jung 2014, and Pasquino 1996; n = 168) reached their TH. No significant difference was found in FAH or FAH minus TH after treatment between the groups.

BMI

Six studies compared GnRHa treatment with no treatment and reported relevant outcomes on weight (Poomthavorn 2011, Shiasi Arani 2015, Colmenares 2014, Yuan 2011, Lazar 2015, and Arcari 2016). When participants reached their FAH, the pooled BMI level was lower in the GnRHa group treatment than in the no-treatment group (BMI (kg/m2): studies = 3, n = 334; MD = −1.01; 95% CI, −1.64 to −0.37; I 2 = 0%; Figure 3A and BMI-SDS: studies = 3, n = 285; MD = −0.51; 95% CI, −0.75 to −0.28; I 2 = 13%; Figure 3B). The proportion of girls who were overweight or obese was similar between the two groups (studies = 3, n = 289; RR = 0.95; 95% CI, 0.66 to 1.38; I 2 = 58%; Figure 3C).

Figure 3.

Forest plots of gonadotropin-releasing hormone analog treatment compared with no treatment for body mass index [Colour figure can be viewed at wileyonlinelibrary.com]

Menarche and Menstrual Irregularity

Four studies (Faienza 2017, Lazar 2014, Léger 2000, and Lazar 2015) reported that girls who received GnRHa treatment did not experience early menarche, and the average age at menarche ranged from 12 to 13 years. Results showed that girls who received GnRHa treatment experienced menarche later than those who did not (studies = 4, n = 458; MD = 1.18; 95% CI, 0.77 to 1.58; I 2 = 94%; Figure 4B). Two studies (Liang 2015 and Gyon 2015) (n = 125) showed that the GnRHa group experienced menarche at a younger age than the GnRHa plus GH group (MD = −0.35; 95% CI, −0.62 to −0.09; I 2 = 0%).

Figure 4.

Forest plots of gonadotropin-releasing hormone analog treatment compared with no treatment for reproductive issues [Colour figure can be viewed at wileyonlinelibrary.com]

Fertility and PCOS

Only one study (Lazar 2014) reported that the proportion of pregnancies was lower in the GnRHa (triptorelin) group than in the no-treatment group (n = 235; RR = 0.63; 95% CI, 0.50 to 0.80). However, among pregnant women (n = 108), the proportion requiring ovulation induction and/or in vitro fertilization was significantly lower in the GnRHa (triptorelin) group than in the no-treatment group (RR = 0.33; 95% CI, 0.15 to 0.75). There was no clear difference in the incidence of early miscarriages or preeclampsia between the two groups (RR = 1.07; 95% CI, 0.32 to 3.58).

Individual studies showed more oligomenorrhoea and higher adrenal androgen levels (Faienza 2017) and reduced ovarian volume, LH:FSH ratio and Ferriman-Gallwey score (Magiakou 2010) in GnRHa-treated girls. However, overall the meta-analysis showed there was no significant difference between the GnRHa and no-treatment groups (studies = 3, n = 179; RR = 1.21; 95% CI, 0.46 to 3.15; I 2 = 48%) (Figure 4A). Bridges 1995 (n = 29) showed that there was no significant difference in the incidence of PCOS between GnRHa and GnRHa plus GH groups.

Malignant Diseases

Only one study (Lazar 2015; n = 142) reported only one patient had acute lymphoblastic leukaemia in the GnRHa group. No significant difference in the incidence of malignant diseases during young adulthood (around 30 years) between GnRHa and no GnRHa groups.

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