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Change in height velocity and body mass index during gonadotropin-releasing hormone agonist therapy in girls with central precocious puberty
*Corresponding author: Anjana Hulse, Department of Pediatrics, Apollo Hospital, Bengaluru, Karnataka, India. anmhulse@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Hulse A, Rai S. Change in height velocity and body mass index during gonadotropin-releasing hormone agonist therapy in girls with central precocious puberty. J Pediatr Endocrinol Diabetes. 2025;5:22-7. doi: 10.25259/JPED_8_2025
Abstract
Objectives:
Precocious puberty is increasingly being recognized in children. Since decades, gonadotropin-releasing hormone analogs (GnRHa) have been used to treat precocious puberty. Effect of GnRHa on height velocity (HV) and body mass index (BMI) during the treatment of precocious puberty is not well documented in the literature.
Material and Methods:
The study involved retrospective analysis of electronic medical records of 80 girls with central precocious puberty (CPP), who were treated with GnRHa, at least for 1 year. HV, height standard deviation score (SDS), weight SDS, and BMI SDS, at baseline and annually for 3 subsequent years, were analyzed.
Results:
Mean age at the start of treatment was 8.1 ± 1 year. The duration of treatment was 2.56 ± 0.9 years in those girls who completed treatment (n = 34). HV was 5.08 ± 1.41, 4.35 ± 1.56, 4.09 ± 1.44 cm, respectively, at the end of 1, 2, and 3 years from the start of treatment. The reduction in HV was statistically significant. At the time of diagnosis, the incidence of overweight and obesity was 61.25 % in girls with CPP. In overall study population, BMI SDS increased from 0.85 ± 0.9 at baseline to 1.3 ± 0.67 at the completion of treatment. Final height (FH) for 17 of the 18 girls who completed their growth was observed to be in the target height range.
Conclusion:
Observations from this study indicate that there is decline in HV during GnRHa treatment, but it does not seem to affect FH. BMI SDS is noted to increase during GnRHa treatment.
Keywords
Body mass index
Gonadotropin-releasing hormone analogs treatment
Height velocity
Precocious puberty in girls
INTRODUCTION
Precocious puberty in girls is defined as breast development before the age of 8 years or menarche before the age of 9½ years because of premature activation of hypothalamic-pituitary-gonadal axis.[1] The reason for central precocious puberty (CPP) is idiopathic in 95% of the girls with precocity.[1]
Precocious puberty is generally treated for two reasons: For improving the final height (FH) and for psychosocial reasons. Gonadotropin-releasing hormone analogs (GnRHa) are used to treat CPP. GnRHa in high doses will bind to gonadotropin-releasing hormone receptors on the gonadotropic cells of pituitary gland, leading to desensitization of these receptors, eventually leading to gonadal suppression for the duration of treatment.[2] This leads to reduction in height velocity (HV) to pre-pubertal growth rate, but provides more time for growth before epiphyseal fusion, leading to a better FH outcome. However, some studies have demonstrated reduction in HV that is lower than the normal pre-pubertal HV during GnRHa treatment for CPP.[3,4]
The prevalence of obesity is high in CPP.[5,6] There are conflicting data about changes in body mass index (BMI) during GnRHa therapy. While some studies demonstrated increase in BMI during and after GnRHa therapy, others have reported no correlation between BMI changes and GnRHa therapy.[5-10]
While there are many studies looking at the FH outcome in girls with CPP, the data on changes in HV and BMI changes during GnRHa therapy are scanty. The aim of this study is to observe the changes in HV and BMI during GnRHa treatment in girls with CPP.
MATERIAL AND METHODS
Eighty girls with idiopathic CPP, who were treated with GnRHa, at least for 1 year in three urban pediatric endocrine out-patient clinics in South India were retrospectively recruited. The study involved retrospective analysis of case records. A formal consent waiver from the institutional review board was sought and it was waived off. Confidentiality of the patients was maintained using password protected software and designated users.
All the subjects were diagnosed with CPP based on the following criteria: (1) chronological age (CA) of <8 years at the start of breast development or menarche before 9½ years, (2) basal luteinizing hormone (LH) level more than 0.6 IU/L or stimulated (2 h post GnRHa stimulation) LH level more than 5 IU/L (in response to subcutaneous injection of leuprorelin 20 μg/kg), (3) 1 or more year advancement of bone age (BA), and (4) longitudinal measurement of uterus more than 3.5 cm and ovarian volume more than 1.5 cm3 on uterine ultrasound scan.[11,12] BA was assessed using Greulich and Pyle method by one of the two observers. Target height (TH) range was calculated by adding and subtracting 5 cm to TH or mid-parental height (MPH). Magnetic resonance imaging of brain and pituitary was performed for all subjects below 7 years of age and for some children (depending on affordability and clinical symptoms) between 7 and 8 years of age.
The subjects were treated with leuprorelin acetate 12 weekly depot intramuscular injection. The children were followed up every 12 weeks. Auxological parameters and Tanner staging were documented at every visit. We compared their HV and BMI standard deviation score (SDS) at baseline and annually for 3 successive years, post GnRHa treatment. BA was assessed at 6–12 monthly intervals. Determination of LH levels was done once in 6–12 months, 2 h after administration of leuprorelin injection. Serum LH, follicle-stimulating hormone, and estradiol were measured using chemiluminescent detection method (Beckman Coulter UniCel Dxl 600 Access Immunoassay System).
The treatment was discontinued at a CA of 11 years or at a CA of 10.5–11.5 years in conjunction with a BA of 12 years. After stopping GnRHa treatment, patients were followed up every 6 months until they attained menarche and then annually. Auxological parameters were recorded at every visit. The patients were considered to have reached FH, if their HV was ≤2 cm/year. FH was compared with TH range in those girls who completed growth.
Exclusion criteria included those subjects who discontinued follow-up within 1 year of starting treatment, those who had additional diagnosis affecting growth, and those with suboptimal pubertal suppression. Adequacy of treatment was assessed based on clinical parameters and assessment of BA.[13]
Statistical analysis
The data retrieved from electronic medical records was entered into Microsoft Excel. The data were analyzed using Microsoft Excel Macros. Quantitative data are presented as mean ± standard deviation (SD) and discrete data as numbers and percentages. For comparison, paired t-test (unequal variance t-test) was used where P < 0.05 was considered statistically significant.
RESULTS
The study included 80 subjects. The data on 12 weekly out-patient clinic visits of these patients were evaluated. At the start of GnRHa treatment, CA was 8.1 ± 1 years and BA was 10.9 ± 1.39 years. The duration of treatment was 2.56 ± 0.9 years in those girls who had completed treatment. GnRHa treatment was stopped at CA of 10.84 ± 0.63 years, in conjunction with a BA of 12.10 ± 0.77 years. Auxological and clinical characteristics of the subjects are listed in Table 1.
| Characteristic | Start of treatment Mean±SD n=80 | Completion of treatment Mean±SD n=34 |
|---|---|---|
| CA (year) | 8.1±1 | 10.84±0.63 |
| BA (year) | 10.9±1.39 | 12±0.8 |
| TH and range (cm) | 157±5 | |
| Tanner stage B2 | 13 | |
| B3 | 40 | |
| B4 | 10 | |
| B5 | 17 | |
| M1 | 16 | |
| Overweight/Obese | 49/80 (61.25%) | 26/34 (76.47%) |
SD: Standard deviation, CA: Chronological age, BA: Bone age, TH: Target height, M1: Menarche
We analyzed the auxological parameters at 1, 2, and 3 years as well as at the completion of GnRHa treatment [Table 2]. HV, height SDS, weight SDS, and BMI SDS, at baseline and annually for 3 subsequent years and at the completion of treatment, were analyzed and are listed in Table 2.
| Characteristic | Start of treatment Mean±SD n=80 | Year 1 Mean±SD n=72 | Year 2 Mean±SD n=53 | Year 3 Mean±SD n=23 | Completion of treatment Mean±SD n=34 |
|---|---|---|---|---|---|
| HV (cm) | 5.08±1.41 | 4.35±1.56 | 4.09±1.44 | ||
| Height SDS | 1.47±1.18 | 1.26±1.10 | 1.04±1.11 | 0.52±1.69 | 0.79±1.13 |
| Weight SDS | 1.22±0.84 | 1.20±0.90 | 1.09±0.97 | 0.93±1.12 | 1.28±0.74 |
| BMI SDS | 0.85±0.9 | 0.94±0.93 | 0.9±1 | 1.08±0.93 | 1.3±0.67 |
HV: Height velocity, BMI: Body mass index, SDS: Standard deviation score, SD: Standard deviation
Height SDS was 1.47 ± 1.18 at the start of treatment and gradually reduced to 0.79 ± 1.13 at the completion of treatment. HV was 5.08 ± 1.41, 4.35 ± 1.56, and 4.09 ± 1.44 cm, respectively, at the end of 1, 2, and 3 years from the start of treatment. Reduction in HV after GnRHa treatment is illustrated in Figure 1 and Table 3. The reduction in HV was statistically significant with a P < 0.001 (t value 3.941) and 0.006 (t value 3.069) between 1st and 2nd year and 2nd and 3rd year of treatment, respectively.
- Reduction in height velocity (HV) after gonadotropin-releasing hormone analog (GnRHa) treatment (n = 80), Each subject is represented by a colored line.
| HV | Min-Max | Mean±SD | Difference | 95% confidence interval of the difference | t-value | P-Value | |
|---|---|---|---|---|---|---|---|
| Lower | Upper | ||||||
| HV at 1 year | 1.5–8.5 | 5.08±1.41 | − | − | − | − | − |
| HV at 2 years | 0.5–8.9 | 4.35±1.56 | 0.926 | 0.455 | 1.398 | 3.941 | <0.001** |
| HV at 3 years | 0.9–7.5 | 4.09±1.44 | 1.335 | 0.433 | 2.237 | 3.069 | 0.006** |
The data for subgroup of 35 girls with HV of <4 cm at least once during the study period were further studied. The factors associated with subnormal HV were (a) later age of presentation (33 of the 35 girls were started on treatment after 7 years of age), (b) advanced skeletal age (more than 9 years in 34 girls), and (c) Tanner stage III or higher at presentation.
The incidence of overweight and obesity was 61.25% in girls with CPP. In overall study population, BMI SDS increased from 0.85 ± 0.9 at baseline to 1.3 ± 0.67 at the completion of treatment. The change in BMI SDS [Table 4] at the end of treatment was significant with a P = 0.005. The change in BMI SDS at 1 year after the start of treatment was also significant with the P = of 0.022. However, change in BMI SDS after 2 and 3 years after starting treatment was not significant (P = 0.204 and 0.174 at 2 and 3 years, respectively). Majority of those who were in the normal BMI range at the start of treatment continued to maintain normal BMI whereas those who were overweight or obese continued to be in the same category.
| BMI-SDS values | Min-Max | Mean±SD | Difference | 95% Confidence Interval of the Difference | t-value | P-value | |
|---|---|---|---|---|---|---|---|
| Lower | Upper | ||||||
| BMI (SDS) at start | −1.9–2.73 | 0.85±0.9 | − | − | − | − | − |
| BMI (SDS) at 1 year | −2.12–2.56 | 0.94±0.93 | 0.103 | −0.190 | −0.015 | 2.346 | 0.022** |
| BMI (SDS) at 2 years | −1.88–2.7 | 0.9±1 | 0.082 | −0.209 | 0.046 | 1.288 | 0.204 |
| BMI (SDS) at 3 years | −1.2–2.93 | 1.08±0.93 | 0.145 | −0.359 | 0.069 | 1.406 | 0.174 |
| BMI (SDS) at stop | 0.03–2.57 | 1.3±0.67 | 0.249 | −0.417 | −0.082 | 3.025 | 0.005** |
Among the cohort, 16 girls were started on treatment after menarche. Thirty-four girls from the entire cohort had completed treatment; at the time, this study was undertaken. Among these 34 girls who completed treatment, 25 girls had attained menarche and 18 had reached FH at the time of this study. FH for all the girls, except one, who was treated after the onset of menarche, was observed to be in the TH range (MPH ± 5 cm).
DISCUSSION
The present study evaluated the changes in HV and BMI during treatment in 80 girls with CPP treated with GnRHa. In our cohort, HV significantly decreased at 2 and 3 years and BMI SDS significantly increased at 1 year and at the end of GnRHa treatment.
Changes in HV
In this cohort of 80 girls, HV reduced during the 2nd and 3rd year of treatment, compared to the 1st year. Şahin et al. investigated the frequency, time of occurrence, and factors associated with subnormal HV and its effect on FH during GnRHa treatment in patients with idiopathic CPP.[3] They concluded that, in girls with idiopathic CPP, the risk of subnormal HV appears highest at the 3rd year of GnRHa treatment, particularly in those patients who were older age (above 7 years), had pubic hair in conjunction with high baseline and peak LH and advanced BA at diagnosis and excessive LH suppression on follow-up.[3] We too observed that the HV was lowest in the 3rd year after starting GnRHa treatment. We too observed that those who were noted to have HV of <4 cm at least once during the study period were started on treatment after the age of 7 years, had advanced skeletal age (more than 9 years), and were at Tanner stage III or higher.
In our study, 34 girls had completed treatment at the time when this study was undertaken and among them, 18 girls had reached near FH. FH was within the MPH range in all except for one girl. The effect of reduced HV on FH during treatment is not conclusive in the existing literature. Some studies have indicated that the reduction in HV during GnRHa treatment is so significant that they fail to reach predicted height.[14,15] However, in our cohort reduced HV during treatment did not affect the FH, similar to what was observed by Şahin et al.[3]
The reason for the decline in HV during GnRHa treatment is not clearly known. Studies have reported conflicting findings about suppression of growth hormone axis and HV during GnRHa treatment.[3,16-20] Moreover, growth hormone deficiency or decreased insulin-like growth factor-I levels have not been demonstrated in studies that looked at subnormal HV during GnRHa treatment.[14,20] Weise et al., based on their study including 100 girls with precocious puberty, concluded that premature growth plate senescence induced by the prior estrogen exposure leads to decline in HV during GnRHa treatment.[21] In the present study, 16 (20%) girls were started on GnRHa after menarche, which also could have resulted in decline in HV in these subjects.
Changes in BMI
In the past few decades, a remarkable increase in the prevalence of obesity in children has been observed all over the world.[22,23] According to a recent two-decade meta-analysis, the pooled prevalence of childhood obesity and overweight in India was estimated to be 8.4% and 12.4%, respectively.[24] Occurrence of obesity in CPP is higher than in general population. In our study, more than 60% were overweight or obese at the time of diagnosis. Earlier studies have confirmed that obesity is a risk factor for onset of precocious puberty.[25]
In our study, 61.25% (49/80) were overweight or obese at the start of treatment in contrast to 76.47% (26/34) at the end of treatment. BMI SDS increased from 0.85 ± 0.9 at the start of treatment to 1.3 ± 0.67 at the completion of treatment. However, the change in BMI SDS during 2nd and 3rd years after starting GnRHa treatment was not significant. We observed that the children who were in the normal BMI category mostly remained in the same category at the end of treatment. Those who were overweight continued to be overweight. This is in contrast to observations made by Yang et al.[26] Yang et al. demonstrated a significant difference in the patterns of the changes in BMI between the normal-weight and overweight CPP patients. In their study, the girls who were overweight at the start of treatment maintained their BMI, whereas those who had normal BMI showed an increase in their BMI.[26] Several previous studies have evaluated changes in BMI after GnRHa treatment in CPP.[9,26-28] However, whether GnRHa treatment directly increases, BMI remains controversial.
Delayed presentation
The present study indicates that in our region, many parents seek medical intervention for precocious puberty at later stages of puberty. This is obvious from the fact that 16 (20%) of the girls in the cohort sought medical attention after menarche. Similar observations are documented from other parts of India.[29] This may be due to the lack of awareness about timing and progression of puberty among public. The exact reasons for delayed presentation are out of the scope of the present study. However, this could be a subject for further investigation.
What this study adds?
The data on growth velocity and BMI changes during the treatment of precocious puberty are scanty in the existing literature. The present study throws some light on this information. It is reassuring to see that the FH (in 22% of the cohort who completed growth) is not compromised despite fall in HV during GnRHa treatment.
Limitations of the study
The present study examined the data retrospectively. Because of the retrospective nature of the study and non-uniform sample size at different intervals during the study, factors associated with subnormal HV and changes in BMI in subgroups of normal and overweight subjects could not be formally investigated. In the present study, majority of our study participants have neither completed treatment nor have attained FH. It would be interesting to see further work in this area with larger cohort.
CONCLUSION
The present study evaluates the effect of GnRHa therapy on HV and BMI in our cohort of 80 girls with CPP. Observations from this study indicate that there is a decline in HV during GnRHa treatment, but it does not seem to affect FH. BMI SDS is noted to increase during GnRHa treatment. In our country, clinical presentation of precocious puberty among girls at advanced stages of puberty is very common. Increasing awareness about normal timing of puberty and information about precocious puberty among public may help in early identification of precocious puberty cases.
Acknowledgment:
We would like to thank Dr. Vaman Khadilkar for providing growth standards data for calculation of height and body mass index standard deviation scores for Indian children.
Ethical approval:
The study involved retrospective analysis of deidentified data. Hence, the authors had sought formal consent waiver from their IEC, which was waived off.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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