Abstract
Objective
We aimed to examine the auxological findings of girls diagnosed with idiopathic central precocious puberty (CPP) at the end of the GnRHa treatment and to investigate the effect of related factors on the height gain of those patients.
Design
Single-center, descriptive, cross-sectional retrospective study.
Method
A total of 43 patients who were diagnosed with idiopathic CPP and treated with GnRHa between 2012 - 2021 were included in to the study.
Results
A decline in height standard deviation score (SDS) from 1.20 ± 0.14 to 1.02 ± 0.06 during the therapy was observed (P<0.001). The bone age/chronological age ratio was decreased and predictive adult height was increased at the end of the therapy (P<0.001; P=0.001). Both the rates of being overweight and obesity were increased (38.6% to 50% and 9% to 15.9%) when the treatment onset compared to the end of therapy. At the end of the treatment, the mean body mass index (BMI) SDS of the overweight patients was still higher compared to the normal-weight group (P<0.001).
Conclusion
We observed a positive effect of GnRHa therapy on height potential. An increase in BMI during the therapy has been also demonstrated especially in subjects who were overweight before treatment.
Keywords: Central precocious puberty, GnRH analog therapy, Growth, Obesity
Introduction
Puberty is a complex period from childhood to adulthood in which sexual maturation and reproductive ability are acquired. The major findings of puberty are the development of secondary sex characteristics, acceleration in skeletal maturation and change in body fat distribution (1). In precocious puberty, secondary sexual characteristics maturate before 8 years in girls and before 9 years in boys (2). Central precocious puberty (CPP) occurs with the early activation of the hypothalamus-pituitary-gonadal axis due to an organic or a functional reason (2). The diagnosis of idiopathic CPP is made after all organic causes have been ruled out. Gonadotropin-releasing hormone analogs (GnRHa) have been used in the treatment of CPP since the 1980s (3). The aim of GnRHa therapy in CPP is to promote normal growth and provide a normal adult height as well as to reduce psychosocial stress associated with early puberty (2).
There are many studies on CPP which is a constantly up-to-date subject. In this study, we aimed to examine the auxological findings of the girls who were diagnosed with CPP and treated in our pediatric endocrine outpatient clinic and to investigate the effect of related factors on the height gain at the end of the treatment.
Material and Method
Study design
This study was designed as a single-center, descriptive, cross-sectional retrospective study. A total of 43 girls who were diagnosed with idiopathic CPP and treated with GnRHa in pediatric endocrinology clinic of our hospital between 2012 and 2021 were included into the study. We have investigated the clinical and laboratory findings of those patients through the electronic medical records of the hospital at initiation (< 8 years) and at the end (11 years) of the treatment and compared them with each other. Patients diagnosed with peripheral precocious puberty or had any other chronic illness as well as using medication that may affect puberty and growth were excluded from the study. Boys diagnosed with CPP were also excluded from the study because of different growth patterns.
Two subgroup analyses were performed on the study group. The patients whose treatment was started before the age of 7 were compared with the patients whose treatment was started between the ages of 7 - 8 years. In addition, patients who were overweight (including overt obese patients) at the treatment initiation were compared with the patients who were not.
Diagnosis of idiopathic CPP and treatment procedure
Diagnosis of patients with idiopathic CPP was made according to the following criteria (2):
Having breast buds under 8 years of age;
Basal luteinizing hormone (LH) level >1.0 IU/L or peak LH level > 5 IU/L as a response to LH releasing hormone stimulation test;
Presence of accelerated growth and bone age (BA) advancement [BA at least 1 year ahead of the chronological age (CA)];
Absence of hypothalamus-pituitary lesions at magnetic resonance imaging (MRI) scan.
All subjects diagnosed with idiopathic CPP were treated with 3.75 mg (starting dose) GnRHa (Leuprolide acetate, Lucrin depot ®) subcutaneously, every 28 days. At follow-up, the treatment interval was reduced to 21 days in case of progression of pubertal symptoms.
Clinical and laboratory investigations
The standard deviation scores (SDS) of height, weight, and body mass index (BMI) were measured according to Turkish children’s reference values (4). The value of weight divided by the value of height squared (kg/m2) was used to calculate the BMI. Being overweight was defined as having BMI above the 85th percentile for age and sex, according to Turkish children’s references and the cases who have a BMI above the 95th percentile were defined as obese (4). The pubertal stage was evaluated in accordance with Marshall and Tanner (5). Bone age was determined according to the Greulich and Pyle method (6). The predicted adult height (PAH) was calculated by the Bayley-Pinneau method for the subjects who have BA > 6 years (7). The PAH was calculated by the Roche-Wainer-Thissen (RWT) method for the subjects who have BA < 6 years (8). The mid-parenteral height (MPH) was calculated according to the following formula: (height of mother + height of father – 13)/2. Height velocity (HV) was expressed as cm/year at the end of the 1st year of the treatment. Total change in height (Δheight) was also measured at the end of the treatment. Average HV was calculated by dividing the Δheight (cm) by the follow-up time (year).
Follicle-stimulating hormone (FSH), luteinizing hormone (LH) were measured by chemiluminescence immunoassay, and estradiol (E2) were measured by electrochemiluminescence immunoassay method (Roche, Mannheim, Germany). Pelvic ultrasonography (USG) was performed on all subjects by a radiologist. Ovarian volume was calculated using the following formula: (D1xD2xD3/1000) x 0.523 where D1 is the longest longitudinal, D2 is the largest anteroposterior, and D3 is the largest transverse diameters in centimeter (cm) for each ovary and the total volume was calculated as the sum of two ovaries in milliliter (mL). Uterus volume was also calculated with the same formula.
Ethics
Ethics Committee permission was obtained (Number:70904504/870). The study was managed in accordance with the Declaration of Helsinki and ethical guidelines.
Statistical analysis
Statistical analysis was made by using The Statistical Package for the Social Sciences (SPPS for Windows, Version 23.0, Chicago, IL, USA). Continuous measurements were given as median [Interquartile range (IQR)] or mean ± SD while categorical measurements were expressed as numbers and percentages. Categorical variables were compared with Pearson chi-square and Fisher’s exact tests. Normal distribution was checked by the Shapiro–Wilk test. The distribution was also controlled when the continuous measurements were compared. Normally distributed parameters were compared with t-Test and the parameters that did not show normal distribution were compared by the Mann–Whitney U test. Spearman correlation test was used to investigate the relationship between the parameters. A p-value of <0.05 was considered statistically significant.
Results
A total of 43 CPP patients who completed the GnRHa therapy were included into the study. The mean chronological age (CA) of the subjects was 7.39 ± 0.76 years at the treatment initiation and 10.93 ± 0.21 at the end of the therapy. The mean treatment duration was 3.96 ± 1.37 years. Changes in anthropometric measures, BA, and PAH are summarized in Table 1. A decline in height SDS from 1.20 ± 0.14 to 1.02 ± 0.06 during the treatment was observed (P<0.001). The BA/CA ratio was also decreased and PAH was increased at the end of the treatment (P<0.001; P=0.001). Before the treatment, 17 (39.6 %) of the patients were overweight and 4 (9 %) of the patients were obese. At the end of the therapy, both the proportion of being overweight (+10.4 %) and obesity (+6 %) were increased.
Table 1.
Changes in antropometric measures, BA and PAH during the treatment
| Variable | Before treatment | At the end of the treatment | P |
|---|---|---|---|
| CA (years) | 7.39 ± 0.76 | 10.93 ± 0.21 | - |
| BA (years) | 9.06 ± 1.33 | 11.2 ± 0.71 | - |
| BA/CA | 1.20 ± 0.14 | 1.02 ± 0.06 | <0.001 |
| Statural age (years) | 8.45 ± 1.49 | 11.55 ± 1.05 | - |
| Weight SDS | 1.33 (1.56) | 1.1 (1.21) | 0.928 |
| Height SDS | 1.19 (1.97) | 0.59 (1.03) | <0.001 |
| BMI (kg/m2) | 18.3 ± 2.59 | 21.1 ± 3.74 | <0.001 |
| BMI SDS | 0.68 (1.4) | 0.92 (1.68) | 0.007 |
| Overweight prevalance (%) | 17/44 (39.6%) | 22/44 (50%) | - |
| Overt obesity prevalance (%) | 4/44 (9%) | 7/44 (15.9%) | - |
| MPH | 158.7 ± 5.08 | - | - |
| MPH SDS | -0.75 (1.01) | - | - |
| PAH | 157 ± 6.64 | 163.04 ± 5.95 | 0.001 |
| PAH SDS | -1.18 (1.79) | 0.07 (1.07) | 0.001 |
Data are expressed as mean ± SD or median (IQR) or as number (percent). CA: Chronological age; BA: Bone age; SDS: Standart deviation score; BMI: Body mass index; MPH: Midparenteral height; PAH: Predicted adult height.
Hormonal parameters and pelvic ultrasonographic characteristics of the patients are shown in Table 2.
Table 2.
Hormonal parameters and pelvic ultrasonographic characteristics of the patients
| Variable | Before treatment | At the end of the treatment |
|---|---|---|
| Tanner Stage | ||
| 2 | 28 (63.6%) | 12 (27.2%) |
| 3 | 14 (31.8%) | 18 (40.9%) |
| 4 | 2 (4.6%) | 14 (31.9%) |
| Basal LH (mIU/mL) | 0.27 (0.48) | 0.29 (0.72) |
| Basal FSH (mIU/mL) | 2.75 (3.2) | 1.85 (1.79) |
| Basal E2 (pg/mL) | 13.3 (24) | 11.8 (8.78) |
| Peak LH on LHRH test (mIU/mL) | 10.37 ± 7.41 | - |
| Peak FSH on LHRH test (mIU/mL) | 12.86 ± 7.06 | - |
| Total ovarian volume (mL) | 7.85 ± 4.31 | 7.06 ± 5.00 |
| Uterus (Long axis, mm) | 32.5 ± 7.79 | 34.6 ± 7.73 |
| Uterus (Volume, mL) | 3.31 (1.65) | 3.1 (2.93) |
Data are expressed as mean ± SD or median (IQR) or as number (percent). FSH: Follicle stimulating hormone; LH: Luteinizing hormone; E2: Estradiol.
Correlations of pre- and after-treatment height SDS and PAH SDS with each other and with BMI SDS, BA/CA ratio, MPH SDS, HV are shown in Table 3. After-treatment height SDS was positively correlated with pre-treatment height SDS, MPH SDS, pre- and after-treatment PAH SDS, and HV. There were no significant correlations between pre-treatment BMI and height parameters (pre- and after-treatment height SDS as well as pre- and after-treatment PAH SDS).
Table 3.
Corelations of pre- and after-treatment height SDS and PAH SDS with eachother and with BMI SDS, BA/CA ratio, MPH SDS, HV
| Height SDS (pre-treatment) | PAH SDS (pre-treatment) | Height SDS (after-treatment) | PAH SDS (after-treatment) | |
|---|---|---|---|---|
| Height SDS (pre-treatment) |
- |
P=0.002*
R=0.473 |
P<0.001*
R=0.805 |
P<0.001*
R=0.660 |
| BMI SDS (pre-treatment) |
P=0.011 R=0.388 |
P=0.869 R=0.027 |
P=0.232 R=0.232 |
P=0.238 R=0.208 |
| BA/CA (pre-treatment) |
P=0.001*
R=0.496 |
P=0.694 R=-0.064 |
P=0.284 R=0.178 |
P=0.370 R=0.156 |
| PAH SDS (pre-treatment) |
P=0.002*
R=0.473 |
- |
P=0.003*
R=0.489 |
P=0.055 R=0.338 |
| MPH SDS |
P=0.024*
R=0.365 |
P<0.001*
R=0.609 |
P=0.003*
R=0.491 |
P=0.032*
R=0.381 |
| Height SDS (after-treatment) |
P<0.001*
R=0.805 |
P=0.003*
R=0.489 |
- |
P<0.001*
R=0.828 |
| BA/CA (after-treatment) |
P=0.064 R=0.317 |
P=0.922 R=-0.017 |
P=0.520 R=0.327 |
P=0.474 R=0.123 |
| PAH SDS (after-treatment) |
P<0.001*
R=0.660 |
P=0.055 R=0.338 |
P<0.001*
R=0.828 |
- |
| HV |
P=0.011*
R=-0.412 |
P=0.002*
R=0.510 |
P=0.01*
R=0.416 |
P=0.002*
R=0.510 |
Statistically significant correlation. BA: Bone age; CA: Chronological age; SDS: Standart deviation score; BMI: Body mass index; MPH: Midparenteral height; PAH: Predicted adult height; HV: Height velocity.
Subgroup analyzes of normal-weight and overweight subjects are summarized in Table 4. The BA/CA ratio was higher in the overweight group at the beginning of the treatment when compared to the normal-weight group (P=0.039). At the end of the therapy, the mean BMI SDS of the overweight subjects was still higher compared to the normal-weight group (P<0.001).
Table 4.
Subgroup analyzes of normal weight and overweight/obese subjects
| Variable | Normal Weight N=26 | Overweight/obese N=17 | P |
|---|---|---|---|
| Duration of treatment (year) | 4.01 ± 1.49 | 3.48 ± 0.78 | 0.289 |
| Δheight (cm, total) | 24.17 ± 11.54 20.88 (6.22) | 19.3 ± 6.02 18.38 (6.95) | 0.124 |
| HV at the 1st year (cm/year) | 7.34 ± 2.23 | 6.34 ± 1.89 | 0.106 |
| Height SDS (before) | 1.06 (1.45) | 1.5 (1.15) | 0.055 |
| Height SDS (end) | 0.63 (0.80) | 0.87 (1.11) | 0.329 |
| BMI SDS (before) | 0.32 (1.44) | 1.39 (0.99) | <0.001 |
| BMI SDS (end) | 0.46 (1.77) | 1.81 (1.97) | <0.001 |
| BA/CA (before) | 1.16 ± 0.19 | 1.23 ± 0.09 | 0.039 |
| BA/CA (end) | 1.02 ± 0.06 | 1.04 ± 0.07 | 0.290 |
| PAH SDS (before) | -0.66 (1.88) | -1.0 (1.35) | 0.518 |
| PAH SDS (end) | 0.07 (0.75) | 0.66 (1.15) | 0.644 |
Data are expressed as mean ± SD or median (IQR). Δ: delta; BMI: Body mass index; SDS: Standart deviation score; BA: Bone age; CA: Chronological age; PAH: Predicted adult height.
Table 5.
Subgroup analyzes of subjects according to age at the treatment initiation
| Variable | < 7 years N=11 | 7- 8 years N=32 | P |
|---|---|---|---|
| Duration of treatment (year) | 5.42 ± 1.38 | 3.20 ± 0.30 | <0.001 |
| Δheight (cm, total) | 33.42 ± 12.33 30.76 (20.1) | 18.4 ± 5.13 18.09 (5.70) | <0.001 |
| HV at the 1st year (cm/year) | 8.04 ± 2.74 | 6.86 ± 1.36 | 0.032 |
| Height SDS (before) | 1.21 (1.41) | 1.24 (1.83) | 0.528 |
| Height SDS (end) | 0.59 (0.69) | 0.91 (0.90) | 0.767 |
| BMI SDS (before) | 0.46 (1.41) | 0.82 (1.75) | 0.083 |
| BMI SDS (end) | 1.41 (2.06) | 0.81 (1.84) | 0.638 |
| BA/CA (before) | 1.25 ± 0.26 | 1.16 ± 0.11 | 0.788 |
| BA/CA (end) | 1.02 ± 0.05 | 1.03 ± 0.06 | 0.436 |
| PAH SDS (before) | -0.92 (1.8) | -0.68 (1.35) | 0.928 |
| PAH SDS (end) | -0.02 (1.56) | 0.27 (0.81) | 0.858 |
Data are expressed as mean ± SD or median (IQR) or as number (percent). Δ: delta; BMI: Body mass index; SDS: Standart deviation score; BA: Bone age; CA: Chronological age; PAH: Predicted adult height.
Subgroup analyzes of subjects according to age at the treatment initiation are shown in Table 4. While Δheight and HV at the 1st year were higher in the patients whose treatment was initiated before the age of 7 years; both pre- and after-treatment height and PAH SDS were similar in two groups (P<0.001; P<0.032; P=0.528; P=0.768; P=0.928; P=0.858).
Discussion
Central precocious puberty is characterized by the development of secondary sex characteristics, acceleration in skeletal maturation and change in body fat distribution. Early menarche and impaired adult height can be seen in untreated CPP patients. GnRHa have been widely used in the treatment of CPP (3). It has been proven in many studies that GnRHa treatment has positive effects on height in the literature (9, 10). Klein et al. (11) reported that the final height of 80 girls with idiopathic CPP averaged 159.8 ± 7.6 cm (−0.6 ± 1.3 SDS), which was greater than the pre-treatment PAH of 149.3 ± 9.6 cm (−2.4 ± 1.6 SDS). In our study, we observed a decrease in height SDS during the therapy similar to many other studies (12, 13). Although linear growth decreased during GnRHa administration, the growth potential seems to improve due to a decrease in bone maturation rate. Weise et al. (14) reported that the height SDS for CA tended to decrease after GnRHa treatment and the reason for this situation is excessive advancement in growth plate senescence which induced priorly exposure to high estrogen levels. By the administration of GnRHa, BA maturation slows down and height SDS for BA tends to increase which resulted in a greater PAH. When height was adjusted for BA, an increase in PAH was observed at the end of the treatment compared to the beginning of the treatment, which was consistent with the literature. It is difficult to evaluate the growth with the GnRHa treatment since the subjects diagnosed with CPP create a heterogeneous group in terms of age of onset and rate of progression of puberty symptoms, age of treatment initiation, and other factors affecting height. In our study, when the subjects were grouped to evaluate the effect of the treatment initiation age on growth, we observed that the HV at the 1st year and Δheight at the end of the therapy were higher in patients whose treatment was started under the age of 7, compared to patients whose treatment was initiated older than the 7 years of age. There was no difference in height SDS and PAH SDS in both groups at the beginning and end of the treatment which may be a result of the small sample size. In a study evaluating 40 girls diagnosed with CPP, when the subjects were similarly compared according to the age of onset of treatment, it has been reported that PAH SDS was similar in both groups at the end of the treatment although it was worse at the treatment initiation in the group under 7 years of age (12). The authors supported that, earlier introduction of GnRHa therapy (under the age of 7), results in a better height prognosis in girls with CPP with these findings. In some studies, it has been shown that the significant contribution of GnRHa treatment to adult height is only observed in subjects whose treatment is started under the age of 6 years (2, 15). In our study, we could not investigate the exact height gain because the final height of the cases was not known.
The effect of GnRHa therapy on body weight is controversial. Some studies have reported that BMI SDS did not change during GnRHa treatment in idiopathic CPP patients and obesity was not related to GnRHa administration (16, 17). On the other hand, some studies have shown that the rates of being overweight/obese are already high in girls with CPP at the time of diagnosis and these rates remained constant at the end of the treatment (18, 19). In our study, the risk of being overweight was already high at the treatment initiation and continued to increase until treatment discontinuation (38.6% to 50%). The rate of obesity was also increased (9% to 15.9%). The BMI was also significantly changed when the treatment onset compared to the end of therapy (18.3 ± 2.59 to 21.1 ± 3.74, P=<0.001). Traggiagi et al. (20) reported that they also observed increasing BMI during the therapy (median 18.5 to 21.3, P=0.001). There are several other studies that report an increase in BMI during the treatment (13, 21). The changes in BMI SDS during GnRHa treatment also showed a significant difference according to baseline BMI status. The change in BMI SDS during the treatment in the overweight group (BMI median: 1.39 to 1.81; ΔBMI: 0.42) was higher than the change in the BMI SDS in the subjects with normal weight during the treatment (BMI median: 0.32 to 0.46; ΔBMI: 0.14). Palmert et al. (22) also reported that an increase in BMI SDS was mostly observed in overweight idiopathic CPP patients during the therapy. Contradictory, Wolters et al. (23) found that BMI SDS increased during GnRHa treatment only in normal-weight children but not in overweight children. Three other studies that demonstrated an increase in BMI SDS in both groups showed that the change in BMI SDS was significantly greater in normal-weight patients than in overweight patients (13, 24, 25). Additional data acquisition and long-term, case-control follow-up studies are needed to prove the effects of GnRHa on body weight in this field.
Study Limitations
The most important limitation of our study, the number of cases is relatively low and we could not assess the final height of the subjects.
In conclusion, a decrease in bone maturation rate and an increase in PAH were observed with GnRHa treatment which had a positive effect on height potential. The HV at the 1st year and Δheight were higher when the treatment was initiated under the age of 7. An increase in BMI during the therapy has been also demonstrated especially in subjects who were overweight before treatment. The weight gain during the GnRHa treatment may contribute to BA acceleration which results in a lower PAH. Therefore, it is important to discuss with the family the importance of diet and exercise during and after treatment for optimizing adult height.
Conflict of interest
The authors declare that they have no conflict of interest.
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