Effect of gonadotropin-releasing hormone agonist monotherapy and combination therapy with growth hormone on final adult height in girls with central precocious puberty

DOI: https://doi.org/10.21203/rs.3.rs-1485883/v1

Abstract

Objective: This study aimed to compare clinical parameters, including final adult height (FAH), in girls with central precocious puberty treated with gonadotropin-releasing hormone agonists (GnRHa) with and without growth hormone (GH).

Methods: This retrospective study reviewed data of 210 girls with precocious puberty who had reached FAH in a long-term trial of GnRHa treatment. The subjects were divided into the GnRHa treatment group (n=188), and the combined GnRHa+GH treatment group (n=22). Chronological age, bone age, height, height standard deviation score (SDS), predicted adult height (PAH), FAH, Tanner stage, and hormone levels were assessed during the treatment period.

Results: At the start of treatment, PAH was 156.35 ± 6.34 cm in the GnRHa monotherapy group and 150.41 ± 5.32 cm in the GnRHa+GH group (P<0.001). At the end of treatment, PAH was 166.25 ± 5.26 cm in the GnRHa group and 164.07 ± 4.99 cm in the combined GnRHa+GH treatment group, which had increased compared to the start of treatment. The FAH in the GnRHa group and GnRHa+GH combination group were 161.07 ± 4.78 cm and 159.63 ± 3.8 6 cm, respectively, without significant difference. In addition, the height gain (FAH−PAH) was significantly higher in the GnRHa+GH group than the GnRHa group (9.22 ± 6.03 cm vs. 4.72 ± 5.01 cm, P<0.001).

Conclusion: In girls with central precocious puberty, the height gain in the FAH compared to PAH at the start of treatment was significantly higher with the GnRHa+GH combination treatment.

Introduction

Central precocious puberty refers to conditions in which secondary sexual characteristics develop before the age of 8 years in girls and before the age of 9 years in boys due to activation of the hypothalamic-pituitary-gonadal axis [1, 2]. Early puberty accelerates growth and promotes bone maturation, resulting in early fusion that causes a decrease in final adult height (FAH) [3–5]. Gonadotropin-releasing hormone agonists (GnRHa) have been used as a standard treatment for central precocious puberty for decades to suppress the secretion of sex hormones, inhibit rapid bone maturation, and extend the growth period, thereby improving FAH [5–8]. However, several reports suggest that GnRHa treatment can reduce the growth rate below the age-appropriate normal range, and that this phenomenon may be associated with a decrease in the biological activity of insulin-like growth factor-1 (IGF-1) levels [9–11]. Therefore, in recent clinical trials, if the predicted adult height (PAH) is small or the height velocity is decreased among the children who have been treated with GnRHa, growth hormone (GH) is added to GnRHa to compensate for the decreased IGF-1.

In this study, we aimed to analyze the effect on FAH and the change in PAH in girls diagnosed with central precocious puberty by classifying them into two groups; those that received GnRHa monotherapy and those that received combined GnRHa + GH treatment.

Materials And Methods

Study design and patients

This was a retrospective study of 210 girls diagnosed with and treated for central precocious puberty at the Department of Pediatrics of Ajou University Hospital, whose FAH could be assessed in a long- term trial of GnRHa treatment. The subjects were divided into the GnRHa monotreatment group (n = 188), and the combined GnRHa + GH treatment group (n = 22). Chronological age (CA), bone age (BA), BA standard deviation score (SDS), BA-CA, height, height SDS, weight, weight SDS, body mass index (BMI), BMI SDS, PAH, PAH SDS, luteinizing hormone (LH) level, and follicle-stimulating hormone (FSH) level were measured at three time points: the start of GnRHa treatment, after 1 year of treatment, and at the end of treatment.

The diagnostic criteria for idiopathic central precocious puberty are 1) breast enlargement before 8 years of age, and 2) LH levels (cutoff: ≥5 IU/L) in response to the GnRH stimulation test. We excluded girls with brain tumors or ovarian or adrenal lesions. In addition, thyroxine and thyroid stimulating hormone (TSH) levels were measured in all patients to exclude hyperthyroidism.

Leuprolide acetate was administered every 28 days at a dose of 3.75 mg in girls weighing more than 30 kg, 2.5 mg in girls weighing between 20 and 30 kg, and 1.87 mg in girls weighing less than 20 kg.

The initial dose of GH treatment in all patients was 0.6 IU/kg/wk. The GH dose was divided and administered subcutaneously 6 times a week.

This study was approved by the Institutional Review Board of the Ajou University Hospital (AJIRB-MED-MDB-19-538). The need for obtaining informed consent from the participants was waived due to the retrospective nature of the study; all measurements were performed as part of routine practice. The study adhered to the tenets of the Declaration of Helsinki.

Measurements

BA was measured using the by taking Greulich–Pyle method simple radiographs of the left hand and wrist [12]. Target height (TH) was defined as the midparental height, which was calculated by subtracting 6.5 cm to the average parental height. The Bayley-Pinneau (BP) advanced table was used to measure PAH [13]. The FAH was defined as the height measured when BA reached 15 years or growth rate was < 1 cm/year. The standard growth chart for children and adolescents published by the Korean Pediatrics Association in 2017 was used [14]. Serum LH and FSH levels were measured by IRMA (BioSource, Nivelles, Belgium). The detection limits for the LH and FSH assays were 0.1 IU/L and 0.2 IU/L, the intra-assay coefficients of variation (CV) were 1.4–3.9% and 1.1–2.0%, and the interassay CVs were 3.4–8.0% and 2.4–4.4%, respectively.

Statistical analysis

All statistical analysis were performed using SPSS version 24 (SPSS Inc. Chicago, USA) and the results were expressed as the mean value ± standard deviation. An independent t-test was performed to evaluate the significance of the difference in auxological and biochemical factors between the GnRHa group (n = 188) and the GnRHa + GH group (n = 22). For factors that can affect the height gain (FAH − initial PAH), simple linear regression and multiple linear regression with stepwise variable selection were used.

Results

Auxological and clinical characteristics of girls with idiopathic central precocious puberty according to type of treatment at the start of treatment

Clinical factors according to the type of treatment in a total of 210 girls are shown in Table 1.

Table 1

Auxological and clinical characteristics of the patients by type of treatment

Variable

GnRHa

(n = 188)

GnRH + GH

(n = 22)

P-value

CA (yr)

8.20 ± 0.62

8.34 ± 0.44

0.298

BA (yr)

10.30 ± 0.77

10.51 ± 0.61

0.198

BA (SDS)

3.59 ± 1.12

4.20 ± 1.21

0.020

BA-CA

2.10 ± 0.72

2.18 ± 0.73

0.634

Tanner stage (breast)

    

0.550

II

130 (69.1%)

16 (72.7%)

  

III

31 (58.5%)

88 (65.7%)

  

IV

7 (2.1%)

0

  

Tanner stage (pubic hair)

    

0.552

I

184(97.9%)

22(100.00%)

  

II

4(2.1%)

    

Height

132.24 ± 5.17

128.52 ± 3.84

< 0.001

Height SDS

1.10 ± 0.79

0.32 ± 0.73

< 0.001

Weight (Kg)

30.94 ± 5.34

28.55 ± 4.00

0.043

Weight SDS

0.65 ± 3.25

0.37 ± 0.73

0.693

BMI (kg/m2)

17.64 ± 2.50

17.25 ± 1.73

0.479

BMI SDS

-0.28 ± 10.63

0.29 ± 0.81

0.479

PAH (cm)

156.35 ± 6.34

150.41 ± 5.32

< 0.001

PAH SDS

-0.92 ± 1.31

-2.17 ± 1.17

< 0.001

TH (cm)

159.01 ± 3.69

158.93 ± 4.01

0.923

Basal LH (mIU/mL)

1.07 ± 0.86

1.15 ± 1.41

0.787

Basal FSH (mIU/mL)

2.50 ± 1.74

2.60 ± 1.29

0.796

Peak LH (mIU/mL)

11.89 ± 11.14

11.78 ± 9.57

0.964

Peak FSH (mIU/mL)

12.96 ± 4.39

13.46 ± 4.21

0.615

Duration of GnRHa treatment(yr)

3.21 ± 0.73

3.00 ± 0.58

0.184

Time of menarch after GnRHa treatment (yr)

1.34 ± 0.51

1.17 ± 0.53

0.145

Menarche age(yr)

12.74 ± 0.60

12.50 ± 0.60

0.085

Duration of GH treatment after GnRHa treatment (months)

  

6.59 ± 7.77

  

Duration of total GH treatment (years)

  

2.99 ± 1.25

  
GnRH, gonadotropin-releasing hormone agonist; GH, growth hormone; CA, chronological age; BA, bone age; SDS; standard deviation score, BMI, body mass index; PAH, predicted adult height-calculated with advanced table of baley-Pinneau(BP)method; TH, target height; LH. luthenizing hormone; FSH, follicular stimulating hormone


In the GnRHa group, the CA and BA at the start of treatment were 8.20 ± 0.62 years and 10.30 ± 0.77 years, respectively. In the GnRH + GH group, the CA and BA at the start of treatment were 8.34 ± 0.44 years and 10.51 ± 0.61 years, respectively. There was no significant difference in BA and CA in both groups, but BA SDS was significantly higher in the GnRHa + GH group than in the GnRHa group (4.20 ± 1.21 vs. 3.59 ± 1.21, P < 0.05). The height and height SDS at start of treatment was significantly higher in the monotherapy group (132.24 ± 5.17 cm vs. 128.52 ± 3.84 cm, 1.10 ± 0.79 vs. 0.32 ± 0.79, respectively, P < 0.001).

At start of treatment, the PAH was 156.35 ± 6.34 cm in the monotherapy group and 150.41 ± 5.32 cm in the combination treatment group; PAH was significantly lower in the combination group (P < 0.001). The TH was 158.93 ± 4.01 cm in the GnRHa + GH group, which was smaller than in the GnRHa group (159.0.1 ± 3.69 cm), but the was not significant.

The mean duration of GnRHa treatment in both groups was 3.21 ± 0.73 years and 3.00 ± 0.58 years, respectively, with no significant difference.

In the GnRHa + GH group, the mean duration of initial GnRHa treatment was 6.59 ± 7.78 months before GH treatment was started. In addition, the mean duration of total GH treatment was 2.99 ± 1.25 years and that of the combined treatment was 2.04 ± 0.90 years.

Changes in auxological parameters after GnRHa treatment and GnRHa+GH treatment

We compared the results of auxological data between two groups during the treatment period (Table 2). In both groups, it was confirmed that PAH and PAH SDS increased after 1 year of treatment and at the end of treatment compared to at the start of treatment, indicating that growth potential was restored. After 1 year of treatment, the PAH and PAH SDS were significantly higher in GnRHa monotherapy group than the GnRH + GH combination group (158.76 ± 5.29 cm vs. 154.52 ± 4.73 cm, -0.42 ± 1.06 vs. -1.29 ± 0.99, respectively P < 0.001). At the end of treatment, the PAH and PAH SDS were 166.25 ± 5.26 cm and 1.01 ± 1.00 in the monotherapy group and 164.07 ± 4.99 cm and 0.63 ± 0.95 in the combination group, respectively, with no significant difference. This indicates a large progression in PAH in the combination treatment group and improvement of height potential in the GnRHa + GH treatment group.

Table 2

Changes in auxological parameter after GnRHa treatment or GnRHa + GH combination treatment

Variable

GnRHa

(n = 188)

GnRHa + GH

(n = 22)

P-value

1 year after treatment

Height(cm)

138.84 ± 5.00

136.29 ± 4.27

0.023

Height SDS

1.06 ± 0.72

0.60 ± 0.83

0.006

Weight(kg)

35.95 ± 5.89

32.81 ± 4.35

0.016

Weight SDS

0.88 ± 0.68

0.42 ± 0.69

0.003

BMI (kg/m2)

18.59 ± 2.37

17.63 ± 1.76

0.067

BMI SDS

0.55 ± 0.83

0.21 ± 0.70

0.027

PAH (cm)

158.76 ± 5.29

154.52 ± 4.73

< 0.001

PAH SDS

-0.42 ± 1.06

-1.29 ± 0.99

< 0.001

At end of treatment

Height (cm)

149.28 ± 5.02

147.89 ± 4.83

0.346

Height SDS

0.50 ± 0.77

0.37 ± 0.73

0.278

Weight (kg)

45.20 ± 7.10

42.58 ± 5.42

0.046

Weight SDS

0.70 ± 0.78

0.48 ± 0.64

0.047

BMI (kg/m2)

20.23 ± 2.70

19.41 ± 1.78

0.007

BMI SDS

0.59 ± 0.84

0.40 ± 0.59

0.017

PAH (cm)

166.25 ± 5.26

164.07 ± 4.99

0.067

PAH SDS

1.04 ± 1.00

0.63 ± 0.95

0.068

At final adult height

FAH (cm)

161.07 ± 4.78

159.63 ± 3.86

0.174

Height SDS

-0.09 ± 0.94

-0.23 ± 0.77

0.530

Weight(kg)

55.82 ± 8.39

53.50 ± 0.77

0.209

Weight SDS

0.18 ± 1.01

0.02 ± 0.77

0.500

BMI (kg/m2)

21.51 ± 3.09

20.99 ± 1.94

0.437

BMI SDS

0.17 ± 1.03

0.07 ± 0.68

0.547
GnRH, gonadotropin-releasing hormone agonist; GH, growth hormone; CA, chronological age; BA, bone age; SDS; standard deviation score, BMI, body mass index; PAH, predicted adult height-calculated with advanced table of baley-Pinneau (BP) method; FAH., final adult height

 

Height outcome in central precocious puberty with GnRHa treatment or GnRHa+GH treatment

The height gain (FAH − initial PAH) in the GnRHa + GH group was 9.22 ± 6.03 cm, which was significantly higher than in the GnRHa group (4.72 ± 5.01 cm, p < 0.001) (Table 3). In addition, in the treatment period, ΔPAH was significant higher in the GnRHa + GH group than in the GnRHa group (13.66 ± 6.39 cm vs. 9.90 ± 5.86 cm, p = 0.005). The total growth from the end of GnRHa therapy to FAH in GnRHa and GnRH + GH group was 11.79 ± 5.86 cm and 11.74 ± 2.70 cm, respectively, but there was no significant difference.

Table 3

Height outcome in subjects with GnRHa treatment or GnRHa + GH treatment

Variable

GnRHa

(n = 188)

GnRH + GH

(n = 22)

P-value

During GnRHa treatment

Δ PAH *

9.90 ± 5.86

13.66 ± 6.39

0.005

From end of GnRHa to final adult height

Total growth (cm)

11.79 ± 5.86

11.74 ± 2.70

0.937

Final adult height

Height gain (FAH- initial PAH) cm

4.72 ± 5.01

9.22 ± 6.03

< 0.001

Genetic height gain (FAH-TH) cm

2.04 ± 4.75

0.69 ± 3.53

0.199
* Δ PAH: the difference between PAH at the end of treatment and initial PAH
GnRH, gonadotropin-releasing hormone agonist; GH, growth hormone; PAH, predicted adult height-calculated with advanced table of baley-Pinneau(BP)method; FAH, final adult height, TH, target height

 

Clinical factors influencing height gain (FAH − initial PAH)

We performed a simple linear regression analysis on the factors that influence the height gain (FAH − initial PAH) in subjects receiving GnRHa + GH treatment (Table 4). At the start of treatment, BA, BA SDS, PAH, and PAH SDS were correlated with height gain (ß=0.693, 0.600, -0.775, -0.769, respectively, all p < 0.05). After 1 year of treatment, BA, BA − CA, LH, and FSH had significant correlations with height gain (ß=0.632, 0.484, -0.533, -0.485, respectively, all p < 0.05). At the end of treatment, there was no significant variable affecting the height gain. Furthermore, the duration and dose of GH treatment had no significant correlation with height gain. In the multiple linear regression analysis using stepwise variable selection based on factors that were significantly correlated with the height gain, the PAH and BA at start of treatment were found to be significantly correlated with FAH (Table 5).

Table 4

Factors influencing height gain in GnRHa + GH treated girls at GnRHa treatment.
 

At GnRHa treatment

At 1 year after treatment

At end of treatment

coefficient(β)

Ρ

coefficient(β)

Ρ

coefficient(β)

Ρ

TH (cm)

0.361

0.099

        

CA (yr)

-0.128

0.571

-0.125

0.581

0.264

0.235

BA (yr)

0.693

< 0.001

0.632

0.002

0.155

0.539

BA-CA

0.600

< 0.001

0.484

0.023

0.141

0.576

Height

-0.121

0.590

0.006

0.979

0.386

0.076

Height SDS

-0.181

0.858

0.061

0.786

0.197

0.381

Weight

0.060

0.792

0.112

0.619

0.407

0.060

Weight SDS

0.121

0.592

0.157

0.485

0.304

0.169

BMI (kg/m2)

0.154

0.495

0.152

0.501

0.315

0.153

BMI SDS

0.168

0.456

0.172

0.445

0.274

0.216

PAH (cm)

-0.775

< 0.001

-0.295

0.183

0.325

0.140

PAH SDS

-0.769

< 0.001

-0.302

0.172

0.333

0.130

LH (mIU/mL)

-0.375

0.085

-0.533

0.023

-0.029

0.911

FSH (mIU/mL)

-0.128

0.571

-0.485

0.041

-0.397

0.114

E2 (pg/mL)

0.216

0.373

0.123

0.627

0.277

0.299

Dose of GH

        

-0.338

0.124

Duration of GH treatment

        

0.371

0.090
GnRH, gonadotropin-releasing hormone agonist; GH, growth hormone; TH, target height, CA, chronological age; BA, bone age; SDS; standard deviation score, BMI, body mass index; PAH, predicted adult height-calculated with advanced table of baley-Pinneau (BP) method; luthenizing hormone; FSH, follicular stimulating hormone; E2, estrogen

 

Table 5

Multiple regression analysis of factors influencing height gain (FAH-initial PAH) in treated girls. (n = 22, R2 = 0.764)

Variable

B

SE

P

PAH at start of treatment(cm)

-0.593

0.153

0.001

BA at start of treatment

0.394

1.344

0.019
Stepwise regression linear regression of the following independent variable: BA, BA -CA, PAH, PAH SDS, 1 year BA, 1 year BA-CA ,1 year LH, 1 year FSH

Discussion

In this study, the height gain, which is the difference between FAH and PAH at the start of treatment, was significantly higher in the GnRHa + GH group compared to the GnRHa group in girls with central precocious puberty.

GnRHa is a standard treatment for central precocious puberty in both boys and girls. It is known to suppress the secretion of sex hormones to slow puberty and suppress rapid bone fusion to achieve FAH within the TH range [15, 16]. However, several studies have reported that GnRHa can reduce the growth velocity below the normal range suitable for age [7, 17, 18]. Studies on changes in the GH-IGF-1 axis during GnRHa treatment have been conducted; although no consensus has been reached, some studies have reported that a decrease in the biologically active IGF-1 level contributes to the subnormal growth velocity [8, 10, 19, 20]. Therefore, in the current clinical trial, if the PAH was small or the growth rate showed a noticeable reduction during GnRHa treatment, GH combination treatment was used to improve FAH.

In a previous study that analyzed factors affecting the subnormal growth velocity during GnRHa treatment in 50 girls with idiopathic central precocious puberty [21], the average age when subnormal growth velocity appeared was 9.9 years. In addition, the third year of GnRHa treatment carried the highest risk of subnormal growth velocity. There was a significant negative correlation with growth velocity SDS in the third and fourth years of treatment with BA at diagnosis. In our study, CA and BA at the start of GnRHa + GH treatment were 8.34 ± 0.44 years and 10.51 ± 0.91 years, respectively, which were older than those in the GnRHa group; however, there was no significant difference. Furthermore, the Tanner stage of the breast and pubic hair at the beginning of treatment showed no significant difference between the groups.

A study on 448 Chinese children with central precocious puberty and early puberty divided participants into a control group (n = 118), GnRHa monotherapy group (n = 276), and combination therapy group (n = 54). In the combination therapy group, the height gain (FAH − initial PAH) and genetic height gain were 9.51 ± 0.53 cm and 4.00 ± 0.05 cm, respectively, which were significantly higher than those in the other groups [22]. In addition, when compared according to the GH treatment period in the combination therapy group, the height gain was significantly higher in the group starting after 6–12 months than in the group starting GH therapy at the same time as GnRHa treatment. Furthermore, in a meta-analysis published in China, the GH combination treatment significantly improved the height, PAH, and height SDS − BA. In addition, when the starting age of GH treatment was less than 10 years and the GH treatment period was 12 months or more, a significant improvement was confirmed in height, PAH, and height SDS − BA [11].

In a previous study conducted of 20 girls with idiopathic central precocious puberty who received GnRHa monotherapy and GnRHa + GH treatment, pretreatment PAH and FAH were 155.5 ± 1.7 cm and 157.1 ± 2.5 cm, respectively, in patients treated with GnRHa alone. In the GnRHa + GH treatment group, pretreatment PAH was 152.7 ± 1.7 cm and FAH was 160.6 ± 1.3 cm. The height gain in the two groups was different, at 7.9 ± 1.1 cm and 1.6 ± 1.2 cm, respectively, which was significantly higher in combination treatment groups (P < 0.001) [23]. In a study of 35 girls with central precocious puberty published in Italy, the pretreatment PAH and FAH were 153.2 ± 5.0 cm and 161.2 ± 4.8 cm, respectively, in those treated with GnRHa + GH. In the groups treated with GnRHa alone, pretreatment PAH and FAH were 153.9 ± 3.8 cm and 156.6 ± 5.7 cm, respectively. The height gain when treated with GnRHa + GH was 12.7 ± 4.8 cm, which was higher than that in the GnRHa group, 2.3 ± 2.9 cm [24]. In the current study, the duration of GH treatment was 2.04 ± 0.90 years and the period between GnRHa and GH treatment was 6.59 ± 7.77 months. The height gain (FAH − initial PAH) was 9.22 ± 6.03 cm in patients treated with GnRHa + GH, which was significantly higher than the 4.72 ± 5.01 cm in those treated with GnRHa alone (P < 0.001). The ΔPAH in the GnRHa + GH group was 13.66 ± 6.39 cm, which was significantly higher than the GnRHa group (P = 0.005). This indicates a large progression in PAH in the combination treatment group and an improvement of height potential with GnRHa + GH treatment.

Previous studies showed that young CA at the time of diagnosis, height, height SDS, and PAH at the start and end treatment influence FAH after GnRHa monotherapy in girls with central precocious puberty [6, 25–27]. However, studies on factors affecting FAH in GnRHa + GH treatment in central precocious puberty are scarce. Moreover, there is no study reported in Korea. GH itself can certainly be a variable contributing to height gain, but in order to analyze the effect on gain in FAH according to GH dose and duration of treatment, we conducted this analysis. As a result, in this study, the factors influencing height gain in girls treated with GnRHa + GH were the PAH and BA at start of treatment. Contrary to expectations, GH treatment periods and dose were not identified as factors affecting gain in FAH; however, there is the limitation of a small sample size in this study.

The current study had several limitations. First, this study was a retrospective single-center study; therefore, further large prospective studies are required. Second, the sample size was relatively small. Thus, our findings are limited to this study population.

In conclusion, this study demonstrated the GnRHa + GH treatment is effective for girls with central precocious puberty. The gain in the FAH compared to PAH at the start of treatment was significantly higher with GnRHa + GH treatment when compared with GnRHa monotherapy.

Declarations

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

References

  1. A. Bajpai, P.N. Menon, Contemporary issues in precocious puberty. Indian J. Endocrinol. Metabol. 15, S172 (2011)
  2. J.H. Kim, C.H. Shin, S.Y. Lee, Observed trends for an earlier onset of puberty: When is the need for treatment indicated? J. Korean Med. Association 52, 1189–1200 (2009)
  3. S. Bertelloni, G. Baroncelli, M. Sorrentino et al., Effect of central precocious puberty and gonadotropin-releasing hormone analogue treatment on peak bone mass and final height in females. Eur. J. Pediatrics 157, 363–367 (1998)
  4. J.S. Fuqua, Treatment and outcomes of precocious puberty: an update. J. Clin. Endocrinol. Metabolism 98, 2198–2207 (2013)
  5. N. Lahlou, J.-C. Carel, J.-L. Chaussain et al., Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics. J. Pediatr. Endocrinol. Metab. 13, 723–738 (2000)
  6. A.Y. Cho, S.Y. Ko, J.H. Lee et al., Relationship between final adult height and birth weight after gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty. Annals of pediatric endocrinology & metabolism 25, 24 (2020)
  7. R.D. Clemons, M.S. Kappy, T.E. Stuart et al., Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty. Am. J. Dis. Child. 147, 653–657 (1993)
  8. J. DiMartino-Nardi, R. Wu, R. Varner et al., The effect of luteinizing hormone-releasing hormone analog for central precocious puberty on growth hormone (GH) and GH-binding protein. J. Clin. Endocrinol. Metabolism 78, 664–668 (1994)
  9. M.S. Kim, H.J. Koh, G.Y. Lee et al., Comparing adult height gain and menarcheal age between girls with central precocious puberty treated with gonadotropin-releasing hormone agonist alone and those treated with combined growth hormone therapy. Annals of pediatric endocrinology & metabolism 24, 116 (2019)
  10. J. Müller, A. Juul, A.-M. Andersson et al., Hormonal changes during GnRH analogue therapy in children with central precocious puberty. J. Pediatr. Endocrinol. Metab. 13, 739–746 (2000)
  11. M. Wang, Y. Zhang, D. Lan et al., The efficacy of GnRHa alone or in combination with rhGH for the treatment of Chinese children with central precocious puberty. Sci. Rep. 6, 1–10 (2016)
  12. W.W. Greulich, S.I. Pyle, Radiographic atlas of skeletal development of the hand and wrist (Stanford university press, 1959)
  13. N. Bayley, S.R. Pinneau, Tables for predicting adult height from skeletal age. Revised for use with the Greulich-Pyle hand standards. The Journal of pediatrics 1952
  14. J.H. Kim, S. Yun, S. Hwang et al., The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects. Korean J. Pediatr. 61, 135 (2018)
  15. D. Mul, W. Oostdijk, B. Otten et al., Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty: the Dutch experience. J. Pediatr. Endocrinol. Metab. 13, 765–772 (2000)
  16. Y.-J. Rhie, K.-H. Lee, Overview and treatment of precocious puberty. J. Korean Med. Association 58, 1138–1144 (2015)
  17. W. OOSTDUK, S. Drop, R. Odink et al., Long-term results with a slow‐release gonadotrophin‐releasing hormone agonist in central precocious puberty. Acta Pædiatrica 80, 39–45 (1991)
  18. G. Saggese, S. Bertelloni, G. Baroncelli et al., Growth velocity and serum aminoterminal propeptide of type III procollagen in precocious puberty during gonadotropin-releasing hormone analogue treatment. Acta Paediatr. 82, 261–266 (1993)
  19. J. DIMARTINO-NARDI, R. WU, K. FISHMAN et al., The effect of long-acting analog of luteinizing hormone-releasing hormone on growth hormone secretory dynamics in children with precocious puberty. J. Clin. Endocrinol. Metabolism 73, 902–906 (1991)
  20. J.F. Cara, S. Burstein, L. Cuttler et al., Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty. J. Pediatr. 115, 64–68 (1989)
  21. N.M. Şahin, A.U. Dikmen, S. Çetinkaya et al., Subnormal growth velocity and related factors during GnRH analog therapy for idiopathic central precocious puberty. J. Clin. Res. Pediatr. Endocrinol. 10, 239 (2018)
  22. J. Fu, J. Zhang, R. Chen et al., Long-term outcomes of treatments for central precocious puberty or early and fast puberty in Chinese girls. J. Clin. Endocrinol. Metabolism 105, 705–715 (2020)
  23. A.M. Pasquino, I. Pucarelli, M. Segni et al., Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone. J. Clin. Endocrinol. Metabolism 84, 449–452 (1999)
  24. I. Pucarelli, M. Segni, M. Ortore et al., Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J. Pediatr. Endocrinol. Metab. 16, 1005–1010 (2003)
  25. F. Guaraldi, G. Beccuti, D. Gori et al., Management of endocrine disease: long-term outcomes of the treatment of central precocious puberty. Eur. J. Endocrinol. 174, R79–R87 (2016)
  26. S. Heger, C.-J. Partsch, W.G. Sippell, Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. J. Clin. Endocrinol. Metabolism 84, 4583–4590 (1999)
  27. H.S. Lee, J.S. Yoon, K.J. Park et al., Increased final adult height by gonadotropin-releasing hormone agonist in girls with idiopathic central precocious puberty. PLoS One 13, e0201906 (2018)