Anastrozole monotherapy further improves near-adult height after the initial combined treatment with leuprorelin and anastrozole in early-maturing girls with compromised growth prediction: results from the second phase of the GAIL study.

Background: The first phase of the GAIL study ("Girls treated with an Aromatase Inhibitor and Leuprorelin," ISRCTN11469487) has shown that the combination of anastrozole and leuprorelin for 24 months is safe and effective in improving the predicted adult height (PAH) in girls with early puberty and compromised growth prediction by +1.21 standard deviation score (SDS; +7.51 cm) compared to inhibition of puberty alone, +0.31 SDS (+1.92 cm). Objectives and hypotheses: In the second phase of the GAIL study, we assessed the adult height (AH)/near-adult height (NAH) at the end of the first phase and, in addition, the efficacy of anastrozole monotherapy thereafter in further improving NAH. Methods: We measured the AH (age 16.5 years)/NAH [bone age (BA), 15 years] of the 40 girls included, divided into two matched groups: group A (20 girls on anastrozole + leuprorelin) and group B (20 girls on leuprorelin alone). Group A was further randomized into two subgroups: A1 and A2. Group A1 (n = 10), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until BA 14 years, with a 6-month follow-up. Group A2 (n = 10) and group B (n = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH. Results: AH or NAH exceeded the PAH at the completion of the 2-year initial phase of the GAIL study in all groups, but the results were statistically significant only in group A1: NAH-PAH group A1, +3.85 cm (+0.62 SDS, p = 0.01); group A2, +1.6 cm (+0.26 SDS, p = 0.26); and group B, +1.7 cm (+0.3 SDS, p = 0.08). The gain in group A1 was significantly greater than that in group A2 (p = 0.04) and in group B (p = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1. Conclusions: In early-maturing girls with compromised growth potential, the combined treatment with leuprorelin and anastrozole for 2 years or until the age of 11 years resulted in a total gain in height of +9.7 cm when continuing anastrozole monotherapy until the attainment of NAH, as opposed to +7.4 cm if they do not continue with the anastrozole monotherapy and +3.6 cm when treated with leuprorelin alone. Thus, the combined intervention ends at the shortest distance from the target height if continued with anastrozole monotherapy until BA 14 years.

Congenital adrenal hyperplasia complicated by gonadotropin-dependent precocious puberty.

Precocious puberty, characterised by the early appearance of secondary sexual characteristics, poses challenges in diagnosis and management. Here, we describe a case of precocious puberty diagnosed in a boy in middle childhood, who presented with progressive phallus enlargement, pubic hair development and increased aggressive behaviour. Hormonal evaluation confirmed the diagnosis of congenital adrenal hyperplasia (CAH), complicated by gonadotropin-dependent precocious puberty. The case highlights the importance of assessment of testicular volume in a patient presenting with precocious puberty. Symmetrical testicular enlargement in a patient with CAH suggests premature activation of the hypothalamic-pituitary-gonadal axis. The patient received glucocorticoid therapy to suppress androgen production related to CAH and gonadotropin-releasing hormone analogue therapy to control premature activation of the hypothalamic-pituitary-gonadal axis. Follow-up visits showed regression of secondary sexual characteristics and improved growth velocity.

The effect of gonadoliberin analog treatment in precocious puberty on polycystic ovarian syndrome prevalence in adulthood.

Precocious puberty is diagnosed when pubertal characteristics appear before the age of 8 years in females. The most common form is gonadotropin-dependent, called axial. The primary method of treatment is administration of gonadotrophin-releasing hormone analogues (GnRHa). The aim of the study was to verify hypothesis that GnRHa therapy in the childhood may be of additive risk factor for polycystic ovary syndrome (PCOS) in adulthood. Material and Methods: The study group consists of 24 women (median age 22 88 years, median BMI 23.5) treated with GnRHa for central precocious puberty in childhood. The control group includes 40 women (median age 23 years, median BMI 25.6) diagnosed with isolated premature thelarche and not using GnRHa in the childhood. Anthropometric measurements, ultrasound examination of minor pelvis and hormonal profile were performed. PCOS diagnosis was based on Rotterdam criteria. Results: The study confirmed a higher prevalence of PCOS in the study group (50%) than in the control group (10%); p=0.0006. Significant, linear correlation between free testosterone levels and ovarian size was found in the study group (R=0.45 p= 0.03). Conclusions: GnRHa therapy during childhood may have a potential influence on incidence of PCOS in the adulthood. Therefore, in this group of patients long-term follow-up focused on screening for PCOS would seem beneficial.

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.

The effect of GnRH analog treatment on BMI in children treated for precocious puberty: a systematic review and meta-analysis.

INTRODUCTION: The purpose of the present meta-analysis was to systematically evaluate the effect of GnRHa treatment on the BMI of children with precocious puberty after GnRHa treatment as compared to before, and to analyze the effect of GnRHa treatment on the body composition of children with precocious puberty at different BMIs by classifying into normal body mass, overweight, and obese groups according to BMI at the time of initial diagnosis. CONTENT: A meta-analysis was performed using Stata 12.0 software by searching PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP database), and Wan fang database for relevant literature on standard deviation score of body mass index (BMI-SDS) after GnRHa treatment as compared to before in children with precocious puberty. SUMMARY: A total of eight studies were included with a total sample size of 715 cases, and the results of meta-analysis showed that BMI-SDS increased in children with precocious puberty after GnRHa treatment as compared to before starting [(weighted mean difference (WMD)=0.23, 95 % CI: 0.14-0.33, p=0.000)] and also increased in children with normal body mass [(WMD=0.37, 95 % CI: 0.28-0.46, p=0.000)], and there was no significant change in BMI-SDS in children in the overweight or obese group [(WMD=0.01, 95 % CI: -0.08-0.10, p=0.775)]. OUTLOOK: Overall, there was an observed increase in BMI-SDS at the conclusion of GnRHa treatment in children with precocious puberty. Additionally, it was found that the effect of GnRHa treatment on body composition varied among children with different BMI status. Clinicians should emphasize the promotion of a healthy lifestyle and personalized dietary management for children.

The effect of gonadotropin-releasing hormone analog treatment on the endocrine system in central precocious puberty patients: a meta-analysis.

OBJECTIVES: Gonadotropin-releasing hormone (GnRHa) is the first choice for the treatment of patients with central precocious puberty (CPP). However, the effects of GnRHa on the endocrine system of CPP patients, including insulin sensitivity, lipid level, thyroid function, bone mineral density (BMD), and testosterone (T) level, are currently contradictory. Therefore, the long-term safety of GnRHa therapy remains controversial. CONTENT: A systematic literature search was performed using PubMed, Embase, Cochrane Library, and CNKI databases. The changes in HOMA-IR, TG, LDL-C, HDL-C, TSH, FT3, FT4, T, and BMD in CPP patients before and after GnRHa treatment were compared by meta-analysis. As the heterogeneity between studies, we estimated standard deviation mean differences (SMDs) and 95 % confidence intervals (CIs) using a random-effects model. Egger's test was used to assess publication bias. SUMMARY: A total of 22 studies were included in our meta-analysis. Compared with before GnRHa treatment, there were no statistically significant differences in endocrine indicators including HOMA-IR, TG, LDL-C, HDL-C, TSH, FT4, FT3, T, and BMD of CPP patients treated with GnRHa. OUTLOOK: Treatment with GnRHa for central precocious puberty will not increase the adverse effect on the endocrine system.

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With the changes in various factors such as genetics and the environment, the incidence of childhood precocious puberty has been gradually increasing. Improving height is one of the key issues in the clinical management of precocious puberty. Currently, gonadotropin-releasing hormone analogs (GnRHa) remain the preferred treatment for precocious puberty, but their effect on height improvement is influenced by multiple factors, which may result in lower-than-expected height benefits. Combining recombinant human growth hormone (rhGH) therapy with GnRHa treatment is an alternative strategy to enhance the efficacy of GnRHa, but there is still no clear recommendation regarding the timing of their combination. Considering the current status of precocious puberty treatment, it is crucial to reevaluate the effects of GnRHa monotherapy and combination therapy with rhGH on height improvement. This article discusses strategies such as combination therapy indications to guide clinical medication and help children with precocious puberty achieve optimal height benefits.

Efficacy and safety of leuprorelin 3-month depot (11.25 mg) for idiopathic central precocious puberty treatment of Chinese girls: a single-center retrospective study.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of 3-month leuprorelin acetate (3-month LA, 11.25 mg) for the treatment of idiopathic central precocious puberty (ICPP) in Chinese girls. METHODS: We conducted a single-center retrospective study in China on 28 girls with ICPP who received at least one year of 3-month LA treatment. Data from anthropometry, biochemistry, bone age (BA), and pelvic ultrasonography were assessed before and every 6 months during medication. RESULTS: At CPP diagnosis, the mean chronological age (CA) was 7.8±0.8 years, with bone age advancement (BA-CA) of 1.5±0.8 years. After treatment initiation, growth velocity decreased significantly from 8.5±1.6 cm/year to 5.8±1.1 cm/year at month 12 (p<0.001). GnRH-stimulated peak LH ≤3IU/L, the primary efficacy criterion, was observed in 27 out of 28 (96.4 %) children at month 3. Basal estradiol <20 pg/mL was achieved by all 28 girls (100 %) at month 6 and remained stable at month 12. Basal follicle-stimulating hormone (FSH) decreased from 4.1±3.5 to 1.7±0.9 (p<0.001), and basal LH was also significantly reduced from 3.3±6.5 to 0.7±0.8 (p=0.035) at month 12. The mean predicted adult height (PAH) at treatment initiation was 152.7±5.8 cm, it increased significantly to 157.5±5.5 cm (p=0.007) after one-year treatment. Pubertal development was slowed in most patients, and in some cases, it was even reversed. Only one patient (3.6 %) reported local intolerance. CONCLUSIONS: Three-month leuprorelin acetate is a safe and effective treatment for suppressing the pituitary-gonadal axis and restoring impaired adult height in Chinese girls.

Therapeutic effects of melatonin in female mice with central precocious puberty by regulating the hypothalamic Kiss-1/Kiss1R system.

In recent years, central precocious puberty (CPP) in children is becoming more common, which seriously affects their physical and psychological health and requires finding a safe and effective treatment method. The aim of this study was to investigate the therapeutic effect of melatonin on CPP. A CPP model was established by subcutaneous injection of 300 micrograms of danazol into 5-day-old female mice, followed by treatment with melatonin and leuprolide. The vaginal opening was checked daily. Mice were weighed, gonads were weighed, gonadal index was calculated, and gonadal development was observed by hematoxylin and eosin (HE) staining. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) levels were measured by ELISA. By using RT-PCR and Western blotting, the mRNA and protein expression of the hypothalamus Kiss-1, Kiss-1 receptor (Kiss1R), gonadotropin-releasing hormone (GnRH), and pituitary GnRH receptor (GnRHR) were identified. The results showed that melatonin delayed vaginal opening time and reduced body weight, gonadal weight and indices in female CPP mice. Melatonin treatment prevents uterine wall thickening and ovarian luteinization in female CPP mice. Melatonin treatment reduces serum concentrations of FSH, LH, and E2 in female CPP mice. Melatonin suppressed the expressions of Kiss-1, Kiss1R and GnRH in the hypothalamus, and the expression of GnRHR in the pituitary of the female CPP mice. Our results suggest that melatonin can inhibit the hypothalamic-pituitary-gonadal (HPG) axis by down-regulating the Kiss-1/Kiss1R system, thereby treating CPP in female mice.

Longitudinal assessment of auxological parameters, adult height outcome and its determinants in leuprolide-treated Indian girls with idiopathic central precocious puberty.

OBJECTIVES: To assess auxological parameters, adult height outcome and its determinants in Indian girls with idiopathic central precocious puberty (iCPP) treated with gonadotropin-releasing hormone analogues (GnRHa). METHODS: Retrospective study. Inclusion: data on girls with iCPP from initiation to stopping GnRHa (n=179). Exclusion: boys, peripheral, organic central precocity. RESULTS: Mean age of starting GnRHa: 8.2± 1.1 years, duration: 2.8± 1.2 years. 11.7 % had attained menarche at first presentation. The difference between bone (BA) and chronological (CA) ages reduced significantly from 2.6± 0.9 years (onset) to 1.6± 0.8 years (cessation). Weight, BMI Z-scores increased (p<0.01), height Z-scores decreased (0.8 vs. 0.6; p<0.01), predicted adult height (PAH) and Z-scores improved by 3.5 cm, 0.5 SDS following treatment (p<0.01). Overweight/obese girls (vs. normal BMI) were taller, with more advanced BA at starting (height Z-score: 0.7 vs. 1.0, BA-CA: 2.2 vs. 2.9 years), stopping (height Z-score: 0.5 vs. 0.9, BA-CA: 1.4 vs. 1.9 years) treatment, but showed no difference in PAH at starting, stopping treatment. Adult height data (n=58) revealed 1.9 cm gain above target height. Adult height Z-scores significantly exceeded target height Z-scores (p<0.01). Mean adult height (157.1± 5.8 cm) crossed PAH at starting treatment (155.9± 6.4 cm) but remained 1.6 cm lesser than PAH at cessation. Adult weight, BMI Z-scores (-0.2± 1.3, -0.1± 1.2) were significantly lower (p<0.01) than those at stopping GnRHa. Height gain adjusted for age at starting GnRHa correlated negatively with height, weight, BMI, Tanner-staging, BA, FSH, Estradiol at treatment onset, BA at cessation, and correlated positively with treatment duration. CONCLUSIONS: GnRHa treatment in Indian girls with iCPP resulted in improved PAH, decelerated bone age advancement and growth velocity. Most girls achieved adult height within target range, surpassing PAH at treatment initiation. Lesser anthropometric, sexual, skeletal maturity, lower baseline FSH, estradiol, longer treatment duration, less advanced BA at stopping GnRHa may translate into better adult height outcomes.

Correlation between serum vitamin D level and uterine volume in girls with idiopathic central precocious puberty.

OBJECTIVES: Investigate serum vitamin D (vit D) levels' relation to uterine volume in idiopathic central precocious puberty (ICPP) girls and compare findings with normal peers. METHODS: Analyzed 278 ICPP cases from January 2017 to September 2022 alongside 239 normally developing girls. Collected clinical data and lab markers and performed subgroup analysis based on vit D levels. Correlation and regression analyses were conducted. RESULTS: The ICPP group exhibited elevated uterine volume and lower serum vit D compared to controls (p<0.05). A weak negative correlation was noted between vit D and uterine volume in ICPP (r=-0.193, p=0.004), and no such correlation in controls (r=-0.073, p=0.319). The ICPP vit D deficiency subgroup displayed higher uterine volume than the insufficiency and sufficiency subgroups (p<0.05). Uterine volume in the insufficiency subgroup exceeded the sufficiency subgroup (p<0.05). After adjusting for confounders, lower vit D is linked to increased ICPP uterine volume (non-standardized regression coefficient ß=-25.55, 95 % CI= -46.23, -4.87, p=0.016). A Limited correlation between vit D and uterine volume was seen in girls with normal pubertal timing. CONCLUSIONS: We demonstrated a correlation between vit D and uterine volume in ICPP girls, absent in normal peers. ICPP girls often exhibit lower vit D levels and increased uterine volume. Further research is vital for understanding vit D's role in ICPP pathogenesis and guiding prevention and treatment strategies.

Long-term health consequences of central precocious/early puberty (CPP) and treatment with Gn-RH analogue: a short update.

BACKGROUND: The relationship between precocious or early puberty and its treatment has received significant research attention, yielding diverse outcomes. This short review aims to comprehensively analyze and summarize research articles to elucidate the potential link between precocious or early pubertal onset (CPP) and crucial health factors. METHODS: We conducted a systematic review of studies published from -January 2000 to March 2023, sourced from databases of Medline, PubMed, Google Scholar and Web of Science. We assessed the relationship between CPP and final adult height (FHt), bone health, reproductive function, body mass index, metabolic and cardiovascular abnormalities, and increased cancer risk. RESULTS: Upon reviewing and analyzing selected studies, the following key findings emerged: (a) treating CPP in girls before age 6-7 and in boys before age 9 improves FHt; (b) bone mineral density (BMD) decreases during GnRHa treatment but normalizes afterward, with no lasting effects on peak bone mass during puberty; (c) GnRH treatment does not negatively affect menstrual cycles; however, untreated CPP increases the risk of premature or early-onset menopause; (d) the incidence of PCOS/hyperandrogenemia may be slightly elevated in women with a history of CPP, but overall reproductive function remains largely unaffected; (e) earlier thelarche and menarche may enhance susceptibility to breast carcinogenesis; (f) CPP contributes to an increased risk of obesity and type 2 diabetes in both genders; (g) early menarche may slightly increase the risk of coronary heart disease and ischemic strokes and (h) early pubertal timing increases the risk of depression and anxiety disorders. CONCLUSION: Monitoring and early diagnosis of these conditions are of paramount importance for successful management.

Efficacy and mechanism of nourishing yin and purging fire therapy for central precocious puberty based on meta-analysis and network pharmacology.

BACKGROUND: Central precocious puberty (CPP) is due to the early activation of the hypothalamus-pituitary-gonadal axis, and its incidence is on the rise. A number of studies have shown that nourishing yin and purging fire (NYPF) therapy can be beneficial for CPP. Therefore, we conducted this review to investigate the efficacy, safety, and mechanism of NYPF therapy for CPP. METHODS: Electronic databases including PubMed, the Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wan-fang Database, and China Scientific Technical Journals Database and 2 platforms including Clinical Trials and Chinese Clinical Trial Registry were searched for randomized controlled trials of NYPF therapy for CPP. A meta-analysis was conducted using RevMan 5.3 and Stata 17.0 software. The core herb pair of NYPF was identified by data mining using IBM SPSS Modeler 18.0 software. The active ingredients and targets of the core herb pair were obtained through the TCMSP database. The main targets of CPP were acquired form the GeneCards, Disgenet and TTD databases. A protein-protein interaction network was carried out to select the core genes by using STRING platform and Cytoscape 3.7.2 software. Metascape platform was used to conduct gene ontology (GO) and KEGG enrichment analysis. The results were verified utilizing molecular docking. RESULTS: A total of 23 studies were included. Meta-analysis shows the NYPF therapy could significantly improve the clinical efficacy rate and secondary sexual indicators (uterine volume, ovarian volume, breast nucleus diameter, follicular diameter), reduce TCM syndrome scores and serum sex hormone (FSH, LH, E2), and slow down bone age maturation compared to GnRHa therapy group. In addition, NYPF therapy was safe and has no obvious adverse events. Data mining revealed that the core herb pair of NYPF was "Anemarrhenae Rhizoma (Zhimu) - Phellodendri Chinensis Cortex (Huangbai)." Network pharmacology predicted that quercetin, kaempferol, beta-sitosterol, etc were the key components of Zhimu-Huangbai for treating CPP. The core targets were TP53, JUN, AKT1, ESR1, TNF, IL6, CCND1, MAPK1, BCL2, EGFR, IL1B, and PTGS2. They played a pivotal role in modulating multiple signaling pathways, such as Endocrine resistance, MAPK signaling pathway, and PI3K-Akt signaling pathway. CONCLUSION: This article revealed that NYPF therapy is effective and safe against CPP. The mechanism of the core herb pair of NYPF therapy for CPP through muti-components, muti-targets and muti-pathways.

Central precocious puberty: a review of diagnosis, treatment, and outcomes.

Central precocious puberty (CPP) refers to early activation of the hypothalamic-pituitary-gonadal (HPG) axis and is manifested by breast development in girls or testicular enlargement in boys before the normal physiological age ranges. CPP can be precipitated by intracranial pathology, exposure to high levels of sex steroids, or environmental risk factors, but most cases are idiopathic. Monogenic causes have also been identified. In this Review, we summarise pathophysiology, risk factors, diagnosis, and management of CPP. Concern for CPP should prompt referral to paediatric endocrinology where diagnosis is confirmed by clinical, biochemical, radiological, and genetic testing. CPP is treated with a gonadotropin-releasing hormone analogue, the primary aims of which are to increase adult height and postpone development of secondary sexual characteristics to an age that is more commensurate with peers. Although long-term outcomes of treatment with gonadotropin-releasing hormone analogues are reassuring, additional research on the psychological effect of CPP is needed.

The effects of gonadotropin-releasing hormone agonist on final adult height among girls with early and fast puberty.

Introduction: This study aimed to explore the impact of gonadotropin-releasing hormone agonists (GnRHa) on final adult height (FAH) in girls with early and fast puberty. Methods: A retrospective study was conducted by reviewing data from the medical records of the Pediatric Endocrinology Clinics between January 1, 2010, and December 31, 2020, at MacKay Children's Hospital. The treatment group included 109 patients who received 3.75 mg monthly for at least 1 year, whereas the control group consisted of 95 girls who received no treatment. Results: The treatment group was significantly older at the time of inclusion(chronological age (CA1), treatment vs. control, 8.7 vs. 8.4 years, p < 0.001), had a more advanced bone age (BA) (BA1, 11.5 vs. 10.8 years, p < 0.001), BA1-CA1 (2.7 vs. 2.2 years, p < 0.001), and shorter predicted adult height (PAH1) (153.3 vs. 157.1 cm, p = 0.005) that was significantly lower than their target height (Tht)(PAH1-Tht, -3.9 vs. -1.3 cm, p = 0.039). The FAHs of the GnRHa and the control group were similar (157.0 vs. 156.7 cm, p = 0.357) and were not significantly different from their Tht (FAH vs. Tht in the GnRHa group, 157.0 vs. 157.0 cm; control group, 156.7 vs. 157.0 cm). In the subgroup analysis, FAH was significantly higher after GnRHa treatment in those with PAH1 less than 153 cm and Tht (154.0 vs. 152.0 cm, p = 0.041), and those whose CA1 was between 8 and 9 years (158.0 vs. 155.4 cm, p = 0.004). We defined satisfactory FAH outcome as FAH-PAH1≥5 cm and significant factors were GnRHa therapy, PAH1 shorter than their Tht, age younger than 9 years, and faster growth velocity during the first year. Discussion: GnRHa is effective in restoring the Tht in some early and fast pubertal girls, especially in those with poorly PAH (PAH lower than 153 cm and shorter than their target height). A younger age at initiation of treatment and a faster growth velocity during treatment are associated with a better height gain.

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

OBJECTIVES: 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. METHODS: Fifty-eight adolescent girls treated with GnRHa for CPP or early and fast puberty (3.75 mg/28 days), between 2011 and 2015, were re-evaluated in 2020-2022 at least 2 years after menstruation. Hormonal analyses were compared with 51 healthy adolescents. RESULTS: 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. CONCLUSIONS: 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 Triptorelin 3-Month Formulation in Chinese Children with Central Precocious Puberty: A Phase 3, Open-Label, Single-Arm Study.

INTRODUCTION: Triptorelin is available as 1- and 3-month prolonged-release (PR) formulations; at the time of the study, only the former was approved for central precocious puberty (CPP) in China. This study assessed the efficacy and safety of the triptorelin 3-month PR formulation in Chinese children with CPP. METHODS: In this 12-month, prospective, open-label, multicentre, single-arm study (NCT04736602), Chinese children (mean age [standard deviation (SD)], 7.6 ± 0.8 years) with CPP received triptorelin pamoate 15 mg on day 1 and at months 3, 6 and 9. The primary endpoint was the proportion with luteinizing hormone (LH) suppression (stimulated peak LH ≤ 3 IU/L after gonadotropin-releasing hormone [GnRH] stimulation) at month 3. Secondary endpoints included changes from baseline in hormone levels and clinical parameters, as well as safety assessments. RESULTS: Overall, 32 children were enrolled, including three boys. LH suppression to prepubertal levels (≤ 3 IU/L) after GnRH stimulation was observed in 100%, 93.5% and 93.5% of participants at months 3, 6 and 12, respectively. Basal and peak LH and follicle-stimulating hormone levels were substantially suppressed at months 3, 6 and 12, and most participants showed sex hormone suppression. At months 6 and 12 respectively 92.9% and 89.3% of girls had stable breast development, and all boys had stable genital development. There was a decrease in mean growth velocity from baseline (8.96 cm/year) to months 3, 6 and 12 (8.07, 5.24 and 6.94 cm/year, respectively). The mean difference between bone and chronological age decreased from baseline (2.85 years) to month 12 (2.39 years). In girls, uterine length was stable or reduced at month 12; in boys, testicular volume was reduced. Triptorelin was well tolerated. CONCLUSION: The triptorelin 3-month PR formulation demonstrated similar efficacy to that previously reported in non-Chinese patients with CPP and had an acceptable safety profile. This supports triptorelin 3-month PR as a viable option for Chinese children with CPP.

Central precocious puberty (CPP) occurs when the reproductive organs and secondary sexual characteristics develop too early in children (before 8 years old in girls or 9 years old in boys). It can cause significant psychological harm and may lead to health problems later in life. Triptorelin is a type of treatment designed to suppress the hormonal activity responsible for CPP and therefore slow down early pubertal development. Triptorelin can be given as an injection into muscle every month or every 3 months; the 3-monthly formulation is commonly used in many countries but at the time of this study it was not licensed for patients with CPP in China. Our trial assessed the effect of triptorelin treatment every 3 months for 1 year in 32 Chinese children with CPP. For all patients who had measurements available, 3-monthly triptorelin suppressed luteinizing hormone­a key hormone involved in CPP­to below typical prepubertal levels. Other hormones involved in puberty were also suppressed. Children experienced a slowing down of the development of secondary sexual characteristics (breasts, genitals and pubic hair), and stabilization or reduction in the size of internal sexual organs (uterine length in girls and testicular volume in boys). Their height also increased less rapidly than previously. There were no concerning side effects of triptorelin treatment, and the safety profile matched that seen in other countries where triptorelin is widely used for CPP. Overall, our study findings suggest that the 3-monthly triptorelin formulation may be a good option for Chinese children with CPP.

Role of luteinizing hormone urinary levels in the diagnostic and therapeutic management of female central precocious puberty.

BACKGROUND: Diagnosing central precocious puberty (CPP) requires an integrated approach based on clinical, biochemical and instrumental data. The diagnostic gold standard is represented by GnRH (gonadotropin-releasing hormone) stimulation test. Some undoubted limitations of this procedure led the international scientific community to look for cheaper and less invasive alternative diagnostic methods, such as luteinizing hormone urinary levels (uLH) measurement. This study aims to define the reliability of urinary LH levels as a biomarker of pubertal development, both concerning the initial diagnostic management and the monitoring of patients with central precocious puberty undergoing therapy with GnRH analogues. Furthermore, the study plans to detect the potential association between LH peak serum (pLH) and urinary LH in patients undergoing diagnostic tests with GnRH and to identify a possible cut-off of uLH that may be suggestive of ensued successful hormonal stimulation. METHODS: The study includes 130 female patients with suspected precocious puberty or in follow-up during suppressive therapy. After the collection of the informed consent, the patients underwent clinical evaluation, auxological assessment, and hormone assays (basal levels of LH, FSH, and oestradiol; GnRH stimulating test in patients with suspected precocious puberty; urinary LH assay on the first-morning urine sample, collected after waking up). RESULTS: Two uLH cut-off values have been identified: the first of 0.25 UI/L [C.I. 95% 0.23-0.27], able to distinguish between pubertal and pre-pubertal patients, the second of 0.45 UI/L [C.I. 95% 0,20 - 0,70] suggestive of occurred hormonal stimulation in patients with diagnosis of CPP at GnRH test. All 30 patients with CPP in follow-up during suppressive therapy presented uLH values ≤ 0.45 IU/L (pU < 0.05), and uLH collected in prepubertal group control. CONCLUSIONS: uLH assays on the first morning urine specimen could be considered a low-cost and minimally invasive tool for precocious puberty diagnosing and monitoring, making possible to be easily performed even by a general pediatrician. Thus, this could help referring only selected patients to pediatric endocrinologists. After an appropriate validation, this approach could reasonably reduce hospital attendance and costs of performing more invasive procedures, with a more significant emotional impact on the pediatric patient.

Which method is more effective in predicting adult height in pubertal girls treated with gonadotropin-releasing hormone agonist?

PURPOSE: The aim of the present study was to determine the efficiency of three different predictive models [Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner-Whitehouse 2 (TW2)] by comparing their predictions with near-adult height data of girls receiving gonadotropin-releasing hormone agonist (GnRHa) therapy. METHODS: Clinical findings were retrospectively analyzed. Bone ages obtained before treatment were evaluated from left hand and wrist radiographs by three researchers. Predicted adult height (PAH) was calculated using the BP, RWT, and TW2 methods for each patient at the beginning of therapy. RESULTS: The median age at diagnosis of the 48 patients included in the study was 8.8 (8.9-9.3) years. There was no significant difference between the mean bone ages evaluated separately with the Greulich-Pyle atlas and the TW3-RUS method (p=0.34). Among the PAH methods, only PAH measured by the BP method was very close to and no different from near adult height (NAH) [159.8±6.3 vs. 158.8±9.3 cm. p=0.3; (-0.5±1.1) vs. (-0.7±1.6) standard deviation score, p=0.1]. Accordingly, the BP method was found to be the most accurate prediction tool in girls with puberty treated with GnRHa. CONCLUSION: The BP method is more effective at predicting adult height than the RWT and TW2 methods in female patients who will receive GnRHa treatment.

The therapeutic role and potential mechanism of EGCG in obesity-related precocious puberty as determined by integrated metabolomics and network pharmacology.

Objective: (-)-Epigallocatechin-3-gallate (EGCG) has preventive effects on obesity-related precocious puberty, but its underlying mechanism remains unclear. The aim of this study was to integrate metabolomics and network pharmacology to reveal the mechanism of EGCG in the prevention of obesity-related precocious puberty. Materials and methods: A high-performance liquid chromatography-electrospray ionization ion-trap tandem mass spectrometry (LC-ESI-MS/MS) was used to analyze the impact of EGCG on serum metabolomics and associated metabolic pathways in a randomized controlled trial. Twelve weeks of EGCG capsules were given to obese girls in this trail. Additionally, the targets and pathways of EGCG in preventing obesity-related precocious puberty network pharmacology were predicted using network pharmacology. Finally, the mechanism of EGCG prevention of obesity-related precocious puberty was elucidated through integrated metabolomics and network pharmacology. Results: Serum metabolomics screened 234 endogenous differential metabolites, and network pharmacology identified a total of 153 common targets. These metabolites and targets mainly enrichment pathways involving endocrine-related pathways (estrogen signaling pathway, insulin resistance, and insulin secretion), and signal transduction (PI3K-Akt, MAPK, and Jak-STAT signaling pathways). The integrated metabolomics and network pharmacology indicated that AKT1, EGFR, ESR1, STAT3, IGF1, and MAPK1 may be key targets for EGCG in preventing obesity-related precocious puberty. Conclusion: EGCG may contribute to preventing obesity-related precocious puberty through targets such as AKT1, EGFR, ESR1, STAT3, IGF1, and MAPK1 and multiple signaling pathways, including the estrogen, PI3K-Akt, MAPK, and Jak-STAT pathways. This study provided a theoretical foundation for future research.