Treatment Of Central Precocious Puberty Research Articles

Efficacy of leuprolide acetate versus triptorelin pamoate administered every 3 months for treatment of central precocious puberty.

Central precocious puberty (CPP) is typically treated with gonadotropin-releasing hormone (GnRH) agonists. Although numerous GnRH agonist variants are available, limited research has compared the efficacy of leuprolide acetate and triptorelin pamoate administered at 3-month intervals. This study aimed to assess the efficacy of CPP treatment with triptorelin pamoate and leuprolide acetate administered at 3-month intervals. This retrospective cohort study included 116 girls with CPP: 71 treated with leuprolide acetate every 3 months and 45 treated with triptorelin pamoate every 3 months. Anthropometric measurements were compared before and after therapy. At 6 months after the therapy, luteinizing hormone (LH) suppression was evaluated. When administered every 3 months, leuprolide acetate and triptorelin pamoate significantly suppressed LH. The predicted adult height (PAH) and degree of bone age advancement at the end of treatment were comparable. Treatment with leuprolide acetate and triptorelin pamoate every 3 months did not have significantly different effects on LH suppression or PAH.

7128 Efficacy and Safety of Leuprolide Acetate 3M Depot in Chinese Children with Central Precocious Puberty: Interim Analysis of Multicenter, Single-Arm, Prospective Study

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) due to early activation of the hypothalamic-pituitary-gonadal axis leads to early puberty. CPP has a negative impact on adult height. Leuprolide acetate (LA), a gonadotropin-releasing hormone agonist (GnRHa) is the standard treatment for CPP. As CPP requires prolonged treatment, a 3-month (3M) depot formulation would increase patient compliance and reduce the injection burden. This interim analysis presents the effect of LA 3M depot on the gonadotropic axis and assesses safety in children with CPP. Methods: In this open-label, multicenter, single-arm, and prospective study, 31 children with CPP were included. Key inclusion criteria were the appearance of secondary sexual characteristics below the age of eight years in girls and nine years in boys with a confirmed diagnosis of CPP. Children treated with prior GnRHa and/or having underlying medical conditions were excluded. Eligible children were treated with LA 11.25 mg subcutaneously every 12 weeks. The primary endpoint of this interim analysis was the proportion of children achieving inhibition of peak LH defined as peak LH ≤ 3.0 IU/L in the GnRH stimulation test at weeks 24. The secondary endpoint was safety analysis in the children receiving at least one dose of LA 3M depot. Results: At baseline, 30 girls and one boy were enrolled. The median (95% CI) chronological age (CA) of the girls was 8.0 (7.0, 9.0) years and the boy was 10 years old. Girls had a median height of 136.95 (131.5, 139.7) cm, weight of 30 (27, 34) kg, and BMI of 16.4 (15.1, 17.9) kg/m2. Baseline bone (BA) age was 11 (10, 11) years, and BA/CA was 1.24 (1.2, 1.3). Boy’s characteristics at baseline differed in CA (10 years), height (144 cm), and BMI (17.4 kg/m2) from girls of this cohort. Due to the data collection time points for the interim analysis, 8 out of the 31 enrolled subjects had a visit at week 24, and 30 subjects reached the week 12 visit time point and had a visit at week 12. The percentage of children achieving inhibition of peak LH (≤ 3.0 IU/L) in the GnRH stimulation test at week 12 was 100 (88.4, 100) %. At week 24, all of them achieved inhibition of LH in the GnRH stimulation test 100 (63, 100) %. Decreases in BA/CA from baseline at weeks 12 and 24 are 93 (77.9, 99.2) % and 50 (15.7, 84.3) % respectively. No progression of the Tanner stage was observed in 96.7 (82.8, 99.9) % and 100 (63, 100) % at weeks 12 and 24. At the data cut-off, 4 (13.33%) patients experienced a total of 5 treatment-emergent adverse events (TEAEs) in the safety population of 30 subjects. No grade ≥3 AE or serious AE was reported. The incidence of injection site reaction was 3.33%. Conclusion: LA at 11.25mg/3M depot effectively suppresses the gonadotropic axis at weeks 12 and 24, normalizing growth and reversibly slowing the early onset of puberty in children with CPP. LA in a 3-month injecting frequency is a safe and convenient treatment option to improve patient compliance. Presentation: 6/3/2024

Retrospective evaluation of patients diagnosed with central precocious puberty who reached the final height.

Central precocious puberty (CPP) is the onset of puberty before the age of 8 in girls and 9 in boys. The primary goal of CPP treatment is control and arrest of puberty development. In this study, it was aimed to determine the factors associated with final height in patients who received gonadotropin-releasing hormone analogs (GnRHa) treatment and reached their final height. From the medical records of the patients, age on admission, bone age (BA), weight-standard deviation score (SDS), height-SDS, BMI-SDS, target height-SDS, basal LH, FSH, E2, age at menarche, and pelvic USG findings were obtained. The mean age on admission of the 67 female patients was 7.5 ± 0.60 years. On admission, 4.5 % of the patients were obese and 19.4 % were overweight. There was no difference between BMI-SDS at admission and after treatment. The mean age at menarche was 11.57 ± 0.78 years. About 58.2 % of the patients reached the target height, 35.8 % exceeded the target height, and 6 % were below the target height. The mean height-SDS and predicted adult height (PAH) on admission were better in patients who exceeded the target height. It was determined that target height-SDS had a positive effect on delta height-SDS, while BA/CA ratio had a negative effect. It was found that GnRHa treatment did not have a negative effect on BMI-SDS. It was shown that 94 % of the patients who received GnRHa treatment reached the target height, and in fact, 35.8 % exceeded the target height. A greater final height may be associated with good height-SDS and PAH values on admission.

Kisspeptin and DLK1 levels for monitoring treatment of girls with central precocious puberty.

Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an important role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of ≥6 versus <6 IU/L after a gonadotropin-releasing hormone (GnRH) stimulation test. Serum kisspeptin and DLK1 levels were determined in both groups at baseline and after 6 months of GnRH analog treatment in the CPP group and analyzed by enzyme-linked immunosorbent assay. The study divided a total of 48 girls into CPP (n=24; mean age, 7.7±0.7 years) and PT (n=24; mean age, 7.4±0.8 years) groups. The baseline median serum kisspeptin levels were 50.5 pg/mL (range, 38.2-77 pg/mL) and 49.5 pg/mL (range, 39.7-67.6 pg/mL), respectively (P=0.89), while the baseline median serum DLK1 levels were 6.5 ng/mL (range, 5.9-7.5 ng/mL) and 6 ng/mL (4.4-14.4 ng/mL), respectively (P=0.68). After 6 months of GnRH analog treatment in the CPP group, the median serum kisspeptin level was lower (46.4 ng/mL; range, 37.1-60 ng/mL) than that at baseline (P=0.002), while the median serum DLK1 level was higher (7 ng/mL; range, 6.7-8.9) than that at baseline (P=0.002). Our findings suggest that baseline serum kisspeptin and DLK1 levels are not reliable biomarkers for differentiating between CPP and PT. However, significant changes in serum kisspeptin and DLK1 levels may be used to monitor CPP treatment.

Unstimulated Luteinizing Hormone for Assessment of Suppression during Treatment of Central Precocious Puberty with 6-Month Subcutaneous Leuprolide Acetate: Correlations with Clinical Response

Introduction: Phase 3 trial of 6-month subcutaneous leuprolide acetate (SC-LA) in children with central precocious puberty (CPP) demonstrated efficacy and safety. The aims of this secondary analysis were to evaluate unstimulated luteinizing hormone (LH) as efficacy measure, assess clinical suppression metrics, and present biochemical and clinical data for subgroups not achieving hormone suppression. Methods: Sixty-two children with treatment-naïve CPP received 2 doses of 45 mg SC-LA at 24-week intervals. Unstimulated and GnRH-stimulated LH, E2, and T concentrations were measured. Clinical measures included bone age (BA) and predicted adult height (PAH). Results: Eighty-four percentage and 86% of children achieved unstimulated LH <1 IU/L at weeks 24 and 48, respectively. Of 8 children not achieving unstimulated LH <1 IU/L at week 24 that completed the study, all showed a lack of pubertal stage progression and stable/decreased BA to chronological age ratio (BA/CA). Received operating characteristic (ROC) analyses suggested unstimulated LH is a good diagnostic predictor of GnRH-stimulated LH <4 IU/L at weeks 24 and 48 (AUC = 0.88). Across all children, mean BA/CA improved from 1.4 (screening) to 1.3 (week 48) and mean PAH increased by 3 cm. Of 7 girls not achieving stimulated LH <4 IU/L at week 24, all achieved E2 <10 pg/mL, showed a lack of pubertal stage progression, and had stable or decreased BA/CA by week 48. Additionally, 6/7 had increased PAH by week 48 and 4 had unstimulated LH <1 IU/L. Conclusion: Unstimulated LH has value as an efficacy measure and concentrations <1 IU/L may be an adequate surrogate of treatment response in children with CPP. All children who completed the study had evidence of pubertal suppression.

Effectiveness of leuprolide acetate administered monthly compared to three-monthly in the treatment of central precocious puberty: evaluation at the end of treatment.

Gonadotropin-releasing hormone (GnRH) analogs are the standard treatment for central precocious puberty (CPP). Although there are numerous varieties of GnRH agonists, the effectiveness of 1-monthly compared with 3-monthly Leuprolide acetate is still restricted. The objective of this study was to evaluate the outcomes of CPP treatment with Leuprolide acetate at a 1-monthly dosage of 3.75 mg, in comparison to a dosage of 11.25 mg administered every 3 months. This retrospective cohort study involved 143 girls diagnosed with CPP with 72 of them receiving the monthly treatment regimen and 71 receiving the 3-monthly treatment regimen. Anthropometric measurements were compared at the start and end of the therapy. The rates and level of LH suppression were assessed six months after therapy. The regimen administered every 3 months showed more significant suppression of LH. The 3-monthly group showed lower actual height and degree of bone age advancement at the end of therapy. However, the predicted adult height (PAH) remained comparable in both groups. The 3-monthly treatment showed greater hormonal and growth suppression effects, but there was no significant difference in PAH between the two groups.

Long-Acting Gonadotropin-Releasing Hormone Analogues for Central Precocious Puberty, Including 45-Mg 6-Month Subcutaneous Leuprolide Acetate: Use for Treatment and Treatment Monitoring

Plain Language SummaryThe gonadotropin-releasing hormone analogue (GnRHa) stimulation test has historically been used for diagnosing and monitoring treatment efficacy in children with central precocious puberty (CPP). However, this test is not always practical due to costs related to lengthy hospital or clinical testing, and additional injections that may negatively impact the child’s therapeutic experience. Therefore, alternative methods of assessing therapeutic efficacy would be valuable. This manuscript presents an overview of the studies supporting the suitability of therapeutic dosing of CPP medications (intramuscular [IM] leuprolide acetate [LA], IM triptorelin pamoate, and subcutaneous [SC] LA) for treatment monitoring. Four studies of injectable CPP medications have demonstrated that these therapies achieved similar stimulated luteinizing hormone (LH) levels compared to a traditional GnRHa stimulation test. However, the effect of SC LA (approved by the US FDA for treatment in May 2020) on LH levels has not been directly compared to those measured as part of a traditional stimulation test. As several studies have shown that SC LA has similar efficacy on the physical characteristics of puberty as IM LA, we postulate that therapeutic SC LA may also be used to monitor the response to CPP treatment, in place of a traditional GnRHa stimulation test.

Meta-analysis of machine learning models for the diagnosis of central precocious puberty based on clinical, hormonal (laboratory) and imaging data.

Central precocious puberty (CPP) is a common endocrine disorder in children, and its diagnosis primarily relies on the gonadotropin-releasing hormone (GnRH) stimulation test, which is expensive and time-consuming. With the widespread application of artificial intelligence in medicine, some studies have utilized clinical, hormonal (laboratory) and imaging data-based machine learning (ML) models to identify CPP. However, the results of these studies varied widely and were challenging to directly compare, mainly due to diverse ML methods. Therefore, the diagnostic value of clinical, hormonal (laboratory) and imaging data-based ML models for CPP remains elusive. The aim of this study was to investigate the diagnostic value of ML models based on clinical, hormonal (laboratory) and imaging data for CPP through a meta-analysis of existing studies. We conducted a comprehensive search for relevant English articles on clinical, hormonal (laboratory) and imaging data-based ML models for diagnosing CPP, covering the period from the database creation date to December 2023. Pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), summary receiver operating characteristic (SROC) curve, and area under the curve (AUC) were calculated to assess the diagnostic value of clinical, hormonal (laboratory) and imaging data-based ML models for diagnosing CPP. The I2 test was employed to evaluate heterogeneity, and the source of heterogeneity was investigated through meta-regression analysis. Publication bias was assessed using the Deeks funnel plot asymmetry test. Six studies met the eligibility criteria. The pooled sensitivity and specificity were 0.82 (95% confidence interval (CI) 0.62-0.93) and 0.85 (95% CI 0.80-0.90), respectively. The LR+ was 6.00, and the LR- was 0.21, indicating that clinical, hormonal (laboratory) and imaging data-based ML models exhibited an excellent ability to confirm or exclude CPP. Additionally, the SROC curve showed that the AUC of the clinical, hormonal (laboratory) and imaging data-based ML models in the diagnosis of CPP was 0.90 (95% CI 0.87-0.92), demonstrating good diagnostic value for CPP. Based on the outcomes of our meta-analysis, clinical and imaging data-based ML models are excellent diagnostic tools with high sensitivity, specificity, and AUC in the diagnosis of CPP. Despite the geographical limitations of the study findings, future research endeavors will strive to address these issues to enhance their applicability and reliability, providing more precise guidance for the differentiation and treatment of CPP.

Causal association between mTOR-dependent circulating protein levels and central precocious puberty: a Mendelian randomization study.

The mechanistic target of rapamycin (mTOR) signaling pathway has a significant effect on central precocious puberty (CPP). However, the causality between mTOR-dependent circulating protein levels and CPP is still unclear. Our aim is to assess the effects of seven mTOR-dependent circulating protein levels on CPP using Mendelian randomization (MR). Instrumental variables (IVs) for mTOR-dependent circulating protein levels were retrieved from the proteomics-GWAS INTERVAL study and eQTLGen. The summary-level genetic datasets for CPP outcome were obtained from the FinnGen Consortium. Inverse-variance weighted (IVW) was used as the primary method and the pleiotropy, heterogeneity and robustness of the analyses were detected as sensitivity analysis. Positive exposures in the discovery cohort would be revalidated in the validation cohort. This two-sample MR study revealed a causal association between eIF4G level in plasma and CPP in both discovery cohort (IVW: OR = 0.45, 95% CI = 0.22-0.91, p = 0.026) and validation cohort (IVW: OR = 0.45, 95% CI = 0.24-0.85, p = 0.014). There was a causal association between eIF4G level in plasma and CPP. Whether eIF4G can be used for the prevention or treatment of CPP needs to be explored in further studies.

Network pharmacology combined with lipidomics to reveal the regulatory effects and mechanisms of Kangzao granules in the hypothalamus of rats with central precocious puberty

Central precocious puberty (CPP) is a prevalent endocrine disorder that primarily affects children, specifically females, and is associated with various physical and psychological complications. Although Kangzao granules (KZG) are efficacious in managing CPP, the underlying mechanisms remain unclear. Therefore, this study aimed to elucidate the therapeutic mechanisms of KZG using network pharmacology, molecular docking, pharmacodynamics, and pathway validation. A putative compound–target–pathway network was constructed using Cytoscape, before KEGG and Gene Ontology enrichment analyses were conducted. Moreover, molecular docking was performed using AutoDockTools. Quality control of the 10 key components of KZG was carried out using UHPLC-ESI/LTQ-Orbitrap-MS/MS, and hypothalamic lipids were analyzed using UHPLC-Q-Exactive Orbitrap MS/MS. In total, 87 bioactive compounds that targeting 110 core proteins to alleviate CPP were identified in KZG. Lipidomic analysis revealed 18 differential lipids among the CPP, KZG, and control groups, wherein fatty acids were significantly reduced in the model group; however, these changes were effectively counteracted by KZG treatment. Molecular docking analysis revealed a strong binding affinity between flavonoids and RAC-alpha serine/threonine-protein kinase (AKT) when docked into the crystal structure. Moreover, a substantial disruption in lipid metabolism was observed in the model group; however, treatment with KZG efficiently reversed these alterations. Furthermore, the phosphoinositide 3-kinase/AKT signaling pathway was identified as a pivotal regulator of hypothalamic lipid metabolism regulator. Overall, this study highlights the effectiveness of a multidisciplinary approach that combines network pharmacology, lipidomics, molecular docking, and experimental validation in the elucidation of the therapeutic mechanisms of KZG in CPP treatment.

Long-term efficacy of a triptorelin 3-month depot in girls with central precocious puberty.

Three-month gonadotropin-releasing hormone agonists (GnRHas) are expected to achieve better compliance in patients with central precocious puberty (CPP) compared to the monthly formulation. However, 1-month depot remains the dominant choice for conventional treatment worldwide. Our study aimed to investigate the long-term efficacy of a 3-month GnRHa for CPP treatment. In this retrospective study, 69 Korean girls with CPP were prescribed either triptorelin pamoate (TP) 3-month depot (n=29) or triptorelin acetate (TA) 1-month depot (n=40) and were followed for 1 year after the end of treatment. Auxological, radiological, and biochemical data were collected every 6 months. Baseline characteristics were similar between the 2 groups. In the TP 3-month depot group, 27 of 29 patients (93.1%) exhibited suppressed luteinizing hormone level (below 2.5 IU/L) after 6 months of treatment, and this suppression level was reserved until the final injection. The degree of bone age advancement in the TP 3-month depot group decreased from 1.8±0.4 years at the start of treatment to 0.6±0.5 years at 1-year posttreatment. The gain in predicted adult height (PAH) 1 year after the end of treatment was similar between the TP 3-month and TA 1-month depot groups (5.2±3.1 and 5.3±2.4 cm, respectively; p=0.875). A 3-month depot of triptorelin effectively inhibited gonadal and sex hormones, suppressed bone maturation, and increased PAH. For patient convenience, we suggest a 3-month GnRHa regimen as a promising CPP treatment option.

Precocious Puberty: Etiology and Current Treatment

Precocious puberty also known as premature puberty is an abnormal pubertal development that can affect a child's growth and development. The clinical manifestations of precocious puberty are generally diverse and based on etiology are classified into central precocious puberty (GnRH dependent) and peripheral precocious puberty (GnRH independent). The main concern with precocious puberty is that precocious puberty can be a clinical symptom of an underlying serious disease such as a brain tumor, adrenal or gonadal tumor and others. Early identification of etiology plays an important role in prevention, diagnosis, and treatment of this disease. This literature review aims to determine the etiology and current management of precocious puberty. This literature review uses the keywords "Precocious Puberty AND etiology AND treatment" through the National Center for Biotechnology Information (NCBI) and Google Scholar databases. This article uses 11 articles that were used as references in its preparation. In conclusion, it is necessary to know the etiology of precocious puberty using imaging examinations for optimal management and excluding malignant abnormalities. The current treatment for central precocious puberty is GnRH agonists (gold-standard) and surgery in cases of intracranial lesions and peripheral precocious puberty using a combination of androgen antagonists (spironolactone) and aromatase inhibitors (anastrozole, testolactone) and surgery is indicated for gonadal and adrenal tumors. The role of parents is very important in early detection of precocious puberty, because the earlier the therapy, the better the prognosis.

Clinical Management and Therapy of Precocious Puberty in the Sapienza University Pediatrics Hospital of Rome, Italy.

Puberty identifies the transition from childhood to adulthood. Precocious puberty is the onset of signs of pubertal development before age eight in girls and before age nine in boys, it has an incidence of 1/5000-1/10,000 with an F:M ratio ranging from 3:1 to 20:1. Precocious puberty can be divided into central, also known as gonadotropin-dependent precocious puberty or true precocious puberty, and peripheral, also recognized as gonadotropin-independent precocious puberty or precocious pseudopuberty. Thus, the main aim of this narrative report is to describe the standard clinical management and therapy of precocious puberty according to the experience and expertise of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is important to collect information regarding the age of onset, the speed of maturation of secondary sexual features, exposure to exogenous sex steroids and the presence of neurological symptoms. The objective examination, in addition to the evaluation of secondary sexual characteristics, must also include the evaluation of auxological parameters. Initial laboratory investigations should include serum gonadotropin levels (LH and FSH) and serum levels of the sex steroids. Brain MRI should be performed as indicated by the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs before 6 years of age. The gold standard in the treatment of central precocious puberty is represented by GnRH analogs, whereas, as far as peripheral forms are concerned, the triggering cause must be identified and treated. At the moment there are no reliable data establishing the criteria for discontinuation of GnRH analog therapy. However, numerous pieces of evidence suggest that the therapy should be suspended at the physiological age at which puberty occurs.

Body mass index evolution and ovarian function in adolescent girls who received GnRH agonist treatment for central precocious puberty or early and fast puberty.

Gonadotropin-releasing hormone agonist (GnRHa) has been used for central precocious puberty (CPP) or early and fast puberty. It was aimed to assess changes in body mass index (BMI), polycystic ovary syndrome (PCOS) frequency, and anti-Müllerian hormone (AMH) in girls who had been treated with GnRHa. Fifty-eight adolescent girls treated with GnRHa for CPP or early and fast puberty (3.75 mg/28days), between 2011 and 2015, were re-evaluated in 2020-2022 at least 2 years after menstruation. Hormonal analyses were compared with 51 healthy adolescents. In the GnRHa-treated group, a statistically significant increase was observed when the BMI standard deviation score (SDS) at the beginning of the treatment was compared with the BMI SDS at the end of the treatment (p=0.038). A statistically significant decrease was observed when the BMI SDS at the end of the treatment was compared with the BMI SDS in late adolescence (p=0.012). When the BMI SDS at the beginning of the treatment was compared with the BMI SDS in late adolescence, it was observed that there was no statistically significant difference (p=0.196). Of the 58 girls in the GnRHa-treated group, 8 (14 %) had PCOS. Serum AMH levels did not differ between the GnRHa-treated and the control group. GnRHa treatment causes no adverse effect on BMI, at least in late adolescence. Girls treated with GnRHa were not found to be prone to developing PCOS. AMH levels were similar in the GnRHa-treated group as in the control group.

Efficacy and Safety of Leuprolide Acetate 6-Month Depot for the Treatment of Central Precocious Puberty: A Phase 3 Study.

Treatment options for central precocious puberty (CPP) are important for individualization of therapy. We evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration. LA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (<4 mIU/mL) was the primary outcome. Secondary/other outcomes included basal sex hormone suppression (girls, estradiol <20 pg/mL; boys, testosterone <30 ng/dL), suppression of physical signs, height velocity, bone age, patient/parent-reported outcomes, and adverse events. All patients (age, 7.8 ± 1.27 years) received both scheduled study doses. At 24 weeks, 39/45 patients (86.7%) had LH suppressed. Six were counted as unsuppressed; 2 because of missing data, 3 with LH of 4.35-5.30 mIU/mL and 1 with LH of 21.07 mIU/mL. Through 48 weeks, LH, estradiol, and testosterone suppression was achieved in ≥86.7%, ≥97.4%, and 100%, respectively (as early as week 4 for LH and estradiol and week 12 for testosterone). Physical signs were suppressed at week 48 (girls, 90.2%; boys, 75.0%). Mean height velocity ranged 5.0 to 5.3 cm/year post-baseline in previously treated patients and declined from 10.1 to 6.5 cm/year at week 20 in treatment-naïve patients. Mean bone age advanced slower than chronological age. Patient/parent-reported outcomes remained stable. No new safety signals were identified. No adverse event led to treatment discontinuation. Six-month intramuscular LA depot demonstrated 48-week efficacy with a safety profile consistent with other GnRH agonist formulations.

Precocious Puberty.

Precocious puberty is a common presentation to pediatricians with a significant overlap between physiology and pathology. While most girls with precocious puberty have no identifiable cause, boys are more likely to have a pathological cause. The trend of earlier onset of thelarche with slow pubertal tempo has led to a significant increase in the number of girls presenting with precocious puberty. Advanced growth, bone age, uterine maturation, and elevated LH suggest rapidly progressive puberty. The critical issues in evaluating a child presenting with precocious puberty include its confirmation, exclusion of physiological variants, identification of the cause, and determining the need for treatment. Step-wise evaluation with emphasis on clinical parameters provides cost-effective assessment. Gonadotropin-releasing hormone (GnRH) analogs remain the mainstay of treatment for central precocious puberty but should be restricted to individuals with rapidly progressive puberty and compromised final height. The management of rarer forms of peripheral precocious puberty (McCune Albright syndrome, congenital adrenal hyperplasia, and testotoxicosis) involves using experimental drugs under the guidance of specialists.

Effect of gonadotropin-releasing hormone agonist treatment in Vietnamese children with central precocious puberty

Gonadotropin-releasing hormone agonists (GnRHa) are generally indicated in central precocious puberty (CPP) patients. We aimed to analyze the auxological outcomes of GnRHa treatment on CPP children. A cross-sectional study with observational data were collected from 143 CPP patients who finished GnRHa therapy in Children Hospital 2, Vietnam. Anthropometry and sexual maturity rating were assessed after 6 months and each year of the therapy. The Bayley-Pinneau method was used to estimate the predicted adult height (PAH). The mean calendar age and bone age at the start of the treatment were 8.0 ± 0.7 years and 10.5 ± 0.1 years, respectively. The mean treatment period was 2.4 ± 0.6 years. GnRHa led to the regression of pubertal symptoms after treatment. The pre-treatment PAH was 157.8 ± 0.6 cm (girls) and 172.3 ± 2.4 cm (boys). The PAH at treatment discontinuation (162.0 ± 0.5 cm in girls and 176.7 ± 2.3 cm in boys) was higher than the initial PAH (p&lt;0.05). For girls with treatment before 6 years old, GnRHa results in a predicted average gain in adult height of 10.2 ± 3.2 cm, whereas the predicted height advancement in the 6-8 age group was 5.3 ± 0.7 cm. The predicted average height gain of girls aged over 8 years was 3.2 ± 0.6 cm. GnRHa therapy was effective for CPP treatment with the improvement of predicted final height. Predicted height advancement was still documented in females who started the treatment after 8 years old.

Analysis of the efficacy of Dabuyin pill combined with gonadotropin-releasing hormone analogue in the treatment of central precocious puberty girls based on network pharmacology.

Traditional Chinese medicine (TCM) believes that central precocious puberty (CPP) is affected by the imbalance of kidney Yin and Yang. Dabuyin pill is a recipe for nourishing Yin and lowering fire. The network pharmacology method was used to analyze the active components, action targets, and molecular pathways of Dabuyin pill in the treatment of CPP. The main chemical components of Dabuyin pill were obtained from the Integrative database of Traditional Chinese Medicine enhanced by Symptom Mapping (SymMap) database and Traditional Chinese Medicine Systems Pharmacology (TCMSP), and compound targets were retrieved from SymMap and the Encyclopedia of Traditional Chinese Medicine (ETCM). Disease targets were retrieved from the DisGeNET and Gene Expression Omnibus (GEO) databases, and the intersection of compound targets and disease targets was performed to obtain the prediction targets of Dabuyin pill acting on CPP. The key targets enriched by Database for Annotation, Visualization, and Integrated Discovery (DAVID) were then used for Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. GO analysis showed that the biological functions of Dabuyin pill in the treatment of key targets of CPP mainly involved apoptosis, nitric oxide synthesis, estradiol response, angiogenesis, inflammation, and so on. KEGG pathway analysis was mainly enriched in the tumor necrosis factor (TNF) signaling pathway, phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway, hypoxia-inducible factor-1 (HIF-1) signaling pathway, and apoptosis. Among them, the regulation effect of Dabuyin pill prescription on apoptosis may both act on TP53 and different signaling pathways of apoptosis, thus playing a synergistic role. Dabuyin pill combined with GnRHa for the prevention and treatment of CPP in girls can effectively intervene CPP, and the effect of Dabuyin pill on sex hormones is one of its protective mechanisms against CPP.

Comparison of the effect of gonadotropin-releasing hormone agonist dosage in girls with central precocious puberty.

There are no definite guidelines on the optimal dosage of gonadotropin-releasing hormone (GnRH) agonist for treatment of central precocious puberty (CPP). We compared growth outcomes of GnRH agonist at different dosages in girls with idiopathic CPP to assess the optimal dosage. This retrospective study included 86 girls with idiopathic CPP who had been treated with GnRH agonist for at least one year and had attained their final adult height. Leuprolide was given as fixed dosage (3.75 mg every 4 weeks in body weight >20 kg, n=72) or weight-based dosage (60-85 μg/kg every 4 weeks, n=14). We compared suppression of advanced puberty and treatment response between the 2 groups. Peak estradiol and luteinizing hormone and bone age (BA)/chronological age after injection of GnRH agonist were effectively suppressed in both groups. In both groups, the height standard deviation score (SDS) for BA increased after treatment. Final adult height (FAH) (fixed dosage group,160.8±4.1 cm and weight-based dosage group, 161.2±4.4 cm) was significantly higher than the initial predicted adult height (PAH) (155.5±3.3 and 156.1±3.6 cm, respectively) (both P<0.001) and similar to midparental height (159.8±3.3 and 160.6±3.7 cm, respectively). There were no differences in gain in height SDS for BA and gain in height (FAH-PAH at the start) between the 2 groups. There were no differences in treatment outcome between fixed dosage (3.75 mg/4 wk) and weight-based dosage (60-85 μg/kg/4wk) of GnRH agonist. Therefore, a fixed dosage of GnRH agonist can be used more conveniently for CPP treatment without growth oversuppression.

Serum metabolomic analysis reveals key metabolites in drug treatment of central precocious puberty in female children.

Precocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl-tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid-biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice.