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.

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.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty.

The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.

Vitamin D status and parathyroid hormone assessment in girls with central precocious puberty.

PURPOSE: The objective of this study was to analyze vitamin D status and PTH concentrations in 6- to 8-year-old girls with central precocious puberty. METHODS: A cross-sectional clinical and blood testing study (calcium, phosphorus, 25(OH)D and PTH) was carried out in 78 girls with central precocious puberty (CPP group), aged 6.1-7.9 years. A control group was recruited (137 prepubertal girls, aged 6.1-8.2 years). The criteria of the US Endocrine Society were used for the definition of hypovitaminosis D. RESULTS: There were no significant differences in vitamin D status between both groups. There were no significant differences in 25(OH)D concentrations between CPP (25.4 ± 8.6 ng/mL) and control groups (28.2 ± 7.4 ng/mL). In contrast, PHT concentrations in CPP group (44.8 ± 16.3 pg/mL) were higher (p < 0.05) with respect to control group (31.0 ± 11.9 ng/mL). In CPP group, there was a positive correlation (p < 0.05) between PTH concentrations and growth rate, bone age, and basal estradiol, basal FSH, basal LH and LH peak concentrations. CONCLUSION: Vitamin D status in 6- to 8-year-old girls with CPP is similar to that in prepubertal girls. PTH concentrations were significantly higher in girls with CPP, and this could be considered as a physiological characteristic of puberty and, in this case, of pubertal precocity.

Transient central precocious puberty: a new entity among the spectrum of precocious puberty?

OBJECTIVE: Recently, we observed some cases of Precocious Puberty (PP) with a partial central activation of hypothalamic-pituitary-gonadal (HPG) axis that tended to normalized in 6-12 months. To evaluate the frequency of this form within the spectrum of forms of PP, we retrospectively assessed the clinical, hormonal and ultrasound characteristics of patients attending to our Center for signs of PP, between 2007 and 2017. To hypothesize some causes of this "pubertal poussée" a questionnaire about environmental data was provided to patients. METHODS: 96 girls were recruited for the study and divided into three Groups. Group 1: 56 subjects with Central PP (CPP) requiring treatment with GnRH analogue; Group 2: 22 subjects with transient activation of pubertal axis, that tended to normalize, "Transient CPP"(T-CPP); Group 3: 18 subjects with Isolated Thelarche (IT). RESULTS: Mean age at diagnosis was 6.8 ± 1.0 years in Group 1, 5.9 ± 1.3 years in Group 2 and 5.6 ± 1.5 years in Group 3. A significant increase of diagnosis of T-CPP was observed over the study period. Significantly higher use of some homeopathic medicines and potential exposure to pesticides was reported in Group 2 vs Group 1. CONCLUSIONS: To our knowledge, we first reported a form defined as T-CPP, characterized by partial activation in the HPG axis normalizing over time. An increased use of homeopathic medicines and exposure to environmental pollutants in these patients was evidenced.

Overexpression of p53 accelerates puberty in high-fat diet-fed mice through Lin28/let-7 system.

IMPACT STATEMENT: High-fat intake and subsequent obesity are associated with premature onset of puberty, but the exact neuroendocrine mechanisms are still unclear. The transcriptional factor p53 has been predicted to be a central hub of the gene networks controlling the pubertal onset. Besides, p53 also plays crucial roles in metabolism. Here, we explored p53 in the hypothalami of mice fed a high-fat diet (HFD), which showed an up-regulated expression. Besides, we also revealed that overexpressed p53 may accelerate hypothalamo-pituitary-gonadal (HPG) axis activation partially through the c-Myc/Lin28/let-7 system. These results can deepen our understanding of the interaction between metabolic regulation and puberty onset control, and may shed light on the neuroendocrine mechanisms of obesity-related central precocious puberty.

Clinical Efficacy of Modified Huqianwan Combined with Auricular Acupressure with Seeds on Central Precocious Puberty due to Yin Deficiency and Fire Hyperactivity / 中国实验方剂学杂志

Objective:To observe the clinical efficacy of modified Huqianwan combined with auricular acupressure with seeds on girls with central precocious puberty （CPP） due to Yin deficiency and fire hyperactivity. Method:A total of 150 cases were randomly divided into three groups （A group，B group， and C group），with 50 cases in each group. The cases received modified Huqianwan，Zhibo Dihuangwan，and modified Huqianwan combined with auricular acupressure with seeds， respectively， for 12 weeks. The traditional Chinese medicine （TCM） symptoms，bone age difference/chronological age difference （ΔBA/ΔCA）， predicted adult height （PAH），ovarian volume，uterine volume，breast nodule index，serum sex hormones ［follicle-stimulating hormone （FSH），luteinizing hormone （LH），and estradiol （E₂）］，and serum kisspeptin-1 （KISS-1）/G protein-coupled receptor 54 （GPR54）/hypothalamic gonadotropin-releasing hormone （GnRH） signaling pathway of the three groups were observed before and after treatment. The clinical efficacy and safety of the three groups were evaluated. Result:The total effective rate was 97.9% in the C group， which was higher than 81.3% in the A group （<italic>χ</italic>²=4.516，<italic>P</italic><0.05） and 71.4% in the B group （<italic>χ</italic>²=5.162，<italic>P</italic><0.05）. Compared with the results in the A group after treatment，TCM syndrome，ΔBA/ΔCA，E₂，LH，KISS-1，GPR54，and GnRH decreased（<italic>P</italic><0.05），and ovarian volume，uterine volume，and breast nodule index were reduced （<italic>P</italic><0.05），but PAH increased in the C group （<italic>P</italic><0.05）. Compared with the B group after treatment，the C group showed decreased TCM syndrome，ΔBA/ΔCA， FSH，E₂，LH，KISS-1，GPR54，and GnRH （<italic>P</italic><0.05），reduced ovarian volume，uterine volume，and breast nodule index （<italic>P</italic><0.05），and increased PAH（<italic>P</italic><0.05）. During the study，there was one case of anorexia in the A group，and no obvious adverse reactions were found in the B group and the C group. Conclusion:Modified Huqianwan combined with auricular acupressure with seeds can significantly increase the PAH of girls with CPP due to Yin deficiency and fire hyperactivity and improve the serum sex hormones and the KISS-1/GPR54/GnRH signaling pathway.

Herbal Medicine for Idiopathic Central Precocious Puberty: A Systematic Review and Meta-Analysis.

Introduction: Herbal medicine (HM) is widely used in East Asia to treat idiopathic central precocious puberty (ICPP). However, no systematic reviews of the efficacy and safety of HM for treatment of ICPP have been reported. Thus, this systematic review assessed the efficacy and safety of HM for ICPP. Most available clinical trials that investigated HM for ICPP were included in this review. Methods and analysis: Eleven databases, including Asian databases, were searched from the date of inception until June 2018. We included randomized controlled trials (RCTs) that assessed HM for ICPP. Results: Nine RCTs including 650 participants with ICPP, were included in this review. As a result of meta-analysis, response rate of HM group was 1.14 times higher compared with control group, with moderate level of evidence. Also, serum estradiol (E2) level was significantly lower in HM group compared to control group with moderate level of evidence. Notably, serum luteinizing hormone (LH) level (IU/L) and E2 level were significantly lower in HM group than triptorelin injection group with moderate level of evidence. Bone age index and uterine volume were also significantly lower in HM group than control group with very low level of evidence. The incidence of adverse events was lower in the HM group than control group, but it was not statistically significant. Conclusions: According to the results of the meta-analysis, it seems that HM treatment has a significant effect on the treatment of ICPP and can effectively reduce serum LH, E2 level, and bone age. In particular, as gonadotropin-releasing hormone analog therapy has a negative effect on the growth rate and final height if bone age ≥13 years, this study suggests that HM treatment may be helpful. Additional higher quality RCTs are needed to demonstrate the efficacy and safety of HM for treatment of ICPP.

Hamartomas hipotalámicos: distintas formas de debut. Casos clínicos / Hypothalamyc hamartomas: different ways of clinical debut. Cases report

Los hamartomas hipotalámicos son malformaciones no neoplásicas de sustancia gris compuestas por neuronas hiperplásicas. Suelen ser lesiones pequenas localizadas en la base del cerebro, en el piso del tercer ventrículo y, generalmente, asintomáticas. Sin embargo, pueden ocurrir con alteraciones conductuales-cognitivas, crisis epilépticas y/o signos de pubertad precoz central en función de la localización en la que se encuentren. Se presentan dos pacientes de 2 años 8 meses y 7 años, con presencia de hamartomas hipotalámicos diagnosticados tras el estudio de pubertad precoz central. La paciente de menor edad presenta, además, crisis gelásticas, típicamente asociadas a hamartomas hipotalámicos. Tras los hallazgos clínicos y radiológicos, se trataron con análogos de gonadotropinas, y se observó una regresión de los signos puberales y una no progresión del tamano de los hamartomas.

Hypothalamic hamartomas are benign tumors of gray substance composed by hyperplasic neurons. They are usually asymptomatic small masses with extensions into the third ventricular cavity. In some instances they can cause cognitive behavioral alterations, seizures and/or central precocious puberty depending on the location. Here we present two cases of central precocious puberty due to hypothalamic hamartomas at 2(8/12) and 7 years of age. The younger patient also presents gelastic seizures, typically associated with hypothalamic hamartomas. After the clinical and radiological findings, they started treatment with GnRH analogues and a regression of the puberty signs without progression in the hamartomas size was observed.

Bone density in children treated with gonadotropin-releasing hormone analogs for central precocious puberty.

Estrogens, growth hormones and IGFs are essential in the development and growth of the skeleton and for the maintenance of bone mass and density. Treatment of precocious puberty with gonadotropin-releasing hormone analogs (GnRHa), leads to a situation of hypoestrogenism by reducing sex-steroid levels, which, theoretically, may have a detrimental effect on bone mass during pubertal development. A reduction in bone mineral density during GnRHa treatment has been shown, but GnRHa treatment in patients with central precocious puberty does not seem to impair the achievement of normal peak bone mass at adult height. However, calcium supplementation is effective in improving bone densitometric levels and may promote better peak bone mass achievement.