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Frontiers in Endocrinology 2021Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final...
BACKGROUND
Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in , , , and genes were investigated in patients with CPP.
METHODS
Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the gene. All children found negative ( = 44) for the gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the gene, mimicking a holistic regulatory depiction of the crosstalk between and other genes was designed.
RESULTS
Three previously described pathogenic variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the Among the 44 CPP patients submitted to WES, nine rare variants were identified in 11 girls, two rare variants in six girls, and two rare variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the gene appeared to be less frequent in the cohort of patients with CPP.
CONCLUSION
The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.
Topics: Brain Diseases; Calcium-Binding Proteins; Child; Child, Preschool; Cohort Studies; Cyprus; DNA Mutational Analysis; Female; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Kisspeptins; Male; Membrane Proteins; Mutation; Puberty, Precocious; Receptors, Kisspeptin-1; Ubiquitin-Protein Ligases; Exome Sequencing
PubMed: 34630334
DOI: 10.3389/fendo.2021.745048 -
Frontiers in Endocrinology 2023(-)-Epigallocatechin-3-gallate (EGCG) has preventive effects on obesity-related precocious puberty, but its underlying mechanism remains unclear. The aim of this study... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Humans; Female; Network Pharmacology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Puberty, Precocious; Tandem Mass Spectrometry; Metabolomics; Estrogens; ErbB Receptors
PubMed: 37334310
DOI: 10.3389/fendo.2023.1159657 -
Journal of Pediatric and Adolescent... Oct 2022Given the global secular declining trends of the age at puberty and its relevant mechanisms, as illustrated in the first part of this series, the present part will... (Review)
Review
Given the global secular declining trends of the age at puberty and its relevant mechanisms, as illustrated in the first part of this series, the present part will discuss the public health implications of early puberty and potential clinical and public health measures. Although the major effect of earlier maturation impacts adolescents' mental health and likelihood of engaging in risky behaviors, there are also effects in adulthood on cardiometabolic health, especially type 2 diabetes, and an increased risk of certain cancers, especially hormone-related cancers such as breast cancer. The paper ends with recommendations for clinical management, especially for girls who should receive further evaluation, as well as recommendations for the patient and her family and public health considerations.
Topics: Adolescent; Adult; Diabetes Mellitus, Type 2; Female; Hormones; Humans; Iatrogenic Disease; Puberty; Puberty, Precocious
PubMed: 35644513
DOI: 10.1016/j.jpag.2022.05.005 -
Current Opinion in Pediatrics Aug 2021In this review, we outline the usage and formulations of gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP), short stature, and gender... (Review)
Review
PURPOSE OF REVIEW
In this review, we outline the usage and formulations of gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP), short stature, and gender diverse individuals, as well as adverse effects, long-term outcomes, and monitoring of therapy. There is a particular focus on citing references published within the last 24 months.
RECENT FINDINGS
Long-acting formulations of GnRHa now include Federal Drug Administration approval for subcutaneous injections. Significant adverse events continue to be rarely reported; extremely rare events include arterial hypertension and pseudotumor cerebri. There continue to be no significant long-term consequences including the impact upon body mass index and bone mineral density, which appear to be transient. GnRHas have been used in differences of sexual development (DSD) and increasingly in the treatment of adolescent transgender individuals.
SUMMARY
GnRHas remain as the only fully efficacious therapy for CPP and effectively suppress pubertal hormones in other situations. The use of GnRHa therapy in gender incongruent individuals has proven beneficial and has become a standard of care, whereas use in those with DSDs should still be considered experimental.
VIDEO ABSTRACT
http://links.lww.com/MOP/A62.
Topics: Adolescent; Body Height; Bone Density; Child; Dwarfism; Gonadotropin-Releasing Hormone; Humans; Puberty, Precocious
PubMed: 34001716
DOI: 10.1097/MOP.0000000000001026 -
Hormones (Athens, Greece) Mar 2023Central precocious puberty (CPP) in neurofibromatosis type 1 (NF1) occurs mainly in association with optic pathway glioma (OPG), but it can also develop in the absence...
PURPOSE
Central precocious puberty (CPP) in neurofibromatosis type 1 (NF1) occurs mainly in association with optic pathway glioma (OPG), but it can also develop in the absence of OPG. The aim of this study was to analyze the prevalence of puberty disorders in children with NF1 and its association with OPG and its location.
METHODS
A retrospective study of 45 children with NF1 (68.9% boys) followed at our center between 2008 and 2020 was conducted. A cerebral MRI scan was performed in all children. We analyzed auxological, laboratory, and imaging data of children with CPP or accelerated puberty (AP). Treatments used for CPP/AP and their effect on height were also evaluated.
RESULTS
The prevalence of puberty disorders in our cohort was 17.8% (male to female ratio of 7:1). CPP and AP were diagnosed in 8/45 (17.8%) NF1 children. Among children with puberty disorders, 5/8 (62.5%) had an OPG with chiasm involvement, 1/8 (12.5%) had an isolated optic nerve tumor, and 2/8 (25%) did not have any evidence of OPG on MRI. Fisher's exact test showed an association between CPP/AP and chiasm OPG (p = 0.025). Treatment with triptorrelin was initiated in 5/8 children, of whom four attained final predicted height.
CONCLUSION
Our study confirms the higher prevalence of CPP/AP in NF1 patients, as well as an association between chiasm OPG and puberty disorders. However, CPP/AP also occurred in the absence of OPG with an incidence of 9.1%. Comprehensive evaluation of every child with NF1 regardless of the presence of OPG is therefore essential.
Topics: Humans; Child; Male; Female; Neurofibromatosis 1; Follow-Up Studies; Retrospective Studies; Optic Nerve Glioma; Optic Nerve Neoplasms; Puberty, Precocious; Gonadotropin-Releasing Hormone
PubMed: 36269545
DOI: 10.1007/s42000-022-00411-9 -
Hormone Research in Paediatrics 2020Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty... (Meta-Analysis)
Meta-Analysis
BACKGROUND/AIMS
Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. Premature activation of GnRH secretion leads to idiopathic/central gonadotropin-dependent precocious puberty (CPP). We aimed to compare the blood KP concentrations in girls with CPP and healthy controls.
METHODS
A systematic review and meta-analysis was performed. We searched MEDLINE, EMBASE, The Cochrane Library, and SciELO. Random-effects model and standardized mean difference (SMD) were used. Heterogeneity was assessed through I2. Meta-regression considered patient age, KP fraction, and analytical method for KP measurement.
RESULTS
The 11 studies included comprised 316 CPP patients and 251 controls. Higher KP levels in the CPP group were found (SMD 1.53; CI 95% = 0.56-2.51). Subgroup analysis revealed association with patient age (p = 0.048), indicating a positive correlation between elevation in KP concentration and age in CPP group. A group of patients with precocious thelarche (PT) from 5 of the included studies comprising 121 patients showed higher levels of KP (1.10; -0.25-2.45: CI 95%) and high heterogeneity (I2 = 91%). The CPP/PT ratio for KP level indicates KP 36% higher on CPP than PT patients.
CONCLUSIONS
A consistent difference in KP levels between girls with CPP and controls was identified. While there are important limitations in KP assays which argue against its use as a diagnostic tool, the KP levels in CPP versus control and PT children are consistent with the predicted mechanisms and pathophysiology of CPP.
Topics: Case-Control Studies; Child; Female; Humans; Kisspeptins; Puberty, Precocious
PubMed: 33887744
DOI: 10.1159/000515660 -
Frontiers in Endocrinology 2022Puberty is a critical process characterized by several physical and psychological changes that culminate in the achievement of sexual maturation and fertility. The onset... (Review)
Review
Puberty is a critical process characterized by several physical and psychological changes that culminate in the achievement of sexual maturation and fertility. The onset of puberty depends on several incompletely understood mechanisms that certainly involve gonadotropin-releasing hormone (GnRH) and its effects on the pituitary gland. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP), which to date, represent the most commonly known genetic cause of this condition. The gene showed ubiquitous expression in tissues from a broad spectrum of species, suggesting an important cellular role. Its involvement in the initiation of puberty and endocrine functions has just begun to be studied. This review discusses some of the recent approaches developed to predict MKRN3 functions and its involvement in pubertal development.
Topics: Gonadotropin-Releasing Hormone; Humans; Puberty; Puberty, Precocious; Ribonucleoproteins; Ubiquitin-Protein Ligases
PubMed: 36187104
DOI: 10.3389/fendo.2022.991322 -
Frontiers in Endocrinology 2022Central precocious puberty (CPP) is a multifactorial and complex condition. Traditional studies focusing on a single indicator cannot always elucidate this panoramic...
BACKGROUND
Central precocious puberty (CPP) is a multifactorial and complex condition. Traditional studies focusing on a single indicator cannot always elucidate this panoramic condition but these may be revealed by using omics techniques.
OBJECTIVE
Proteomics and metabolomics analysis of girls with CPP were compared to normal controls and the potential biomarkers and pathways involved were explored.
METHODS
Serum proteins and metabolites from normal girls and those with CPP were compared by LC-MS/MS. Multivariate and univariate statistical analysis were used to identify the differentially expressed proteins (DEPs) and differentially expressed metabolites (DEMs). Functional annotation and pathway enrichment analysis were performed by using GO and KEGG databases, and candidate markers were screened. Finally, bioinformatic analysis was used to integrate the results of proteomics and metabolomics to find the key differential proteins, metabolites and potential biomarkers of CPP.
RESULTS
134 DEPs were identified in girls with CPP with 71 up- and 63 down-regulated, respectively. Up-regulated proteins were enriched mainly in the extracellular matrix, cell adhesion and cellular protein metabolic processes, platelet degranulation and skeletal system development. The down-regulated proteins were mainly enriched in the immune response. Candidate proteins including MMP9, TIMP1, SPP1, CDC42, POSTN, COL1A1, COL6A1, COL2A1 and BMP1, were found that may be related to pubertal development. 103 DEMs were identified, including 42 up-regulated and 61 down-regulated metabolites which were mainly enriched in lipid and taurine metabolic pathways. KGML network analysis showed that phosphocholine (16:1(9Z)/16:1(9Z)) was involved in arachidonic acid, glycerophospholipid, linoleic acid and α-linolenic acid metabolism and it may be used as a biomarker of CPP.
CONCLUSIONS
Our study is the first to integrate proteomics and metabolomics to analyze the serum of girls with CPP and we found some key differential proteins and metabolites as well as a potential biomarker for this condition. Lipid metabolism pathways are involved and these may provide a key direction to further explore the molecular mechanisms and pathogenesis of CPP.
Topics: Biomarkers; Chromatography, Liquid; Female; Humans; Proteomics; Puberty, Precocious; Tandem Mass Spectrometry
PubMed: 35966072
DOI: 10.3389/fendo.2022.951552 -
Clinical Obstetrics and Gynecology Sep 2020Onset of puberty, as defined by breast stage 2, appears to be starting at younger ages since the 1940s. There is an ongoing controversy regarding what is normative, as... (Review)
Review
Onset of puberty, as defined by breast stage 2, appears to be starting at younger ages since the 1940s. There is an ongoing controversy regarding what is normative, as well as what is normal, and the evaluation that is deemed necessary for girls maturing before 8 years of age. There are potential implications of earlier pubertal timing, including psychosocial consequences during adolescence, as well as longer term risks, such as breast cancer and cardiometabolic risks. There are additional consequences derived from slower pubertal tempo, for age of menarche has not decreased as much as age of breast development; these include longer interval between sexual initiation and intentional childbearing, as well as a broadened window of susceptibility to endocrine-related cancers.
Topics: Adolescent; Adolescent Development; Body Mass Index; Breast; Breast Neoplasms; Cardiometabolic Risk Factors; Child; Female; Humans; Menarche; Psychology; Puberty; Puberty, Precocious; Sexual Maturation
PubMed: 32482957
DOI: 10.1097/GRF.0000000000000537 -
Food & Function Jun 2023: Precocious puberty, one of the common pediatric endocrine system diseases, has been related to reduced adult height, adverse psychological outcomes and long-term... (Meta-Analysis)
Meta-Analysis
: Precocious puberty, one of the common pediatric endocrine system diseases, has been related to reduced adult height, adverse psychological outcomes and long-term health consequences. Previous findings have found that low levels of vitamin D appear to be associated with the characteristics of precocious puberty such as early menarche. However, the effect of vitamin D on precocious puberty remains controversial. : The published literature was searched from PubMed, Web of Science, Cochrane Library, MEDLINE, EMBASE, CNKI, Wan Fang and VIP databases up to October 2022. A randomized effect model was used to perform a meta-analysis to evaluate differences in vitamin D concentration between precocious puberty subjects and normal subjects, the risk of precocious puberty in subjects with low vitamin D levels, and the effect of supplementation of vitamin D on subjects with precocious puberty on medication. : Our study found that precocious puberty subjects had lower serum vitamin D levels than the normal population (standardized mean difference (SMD) = -1.16 ng ml and 95% confidence interval (CI) = -1.41 and -0.91 ng ml). Meanwhile, the lower level of vitamin D was associated with the risk of precocious puberty (odd ratio (OR) = 2.25 and 95% CI = 1.66 and 3.04). Moreover, compared with gonadotropin-releasing hormone analogue (GnRHa) intervention alone, subjects receiving GnRHa + vitamin D intervention had significantly lower luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels and bone age, and higher predicted adult height (PAH). : Vitamin D may have a potential role in precocious puberty and more data from large clinical trials are needed to confirm the findings.
Topics: Female; Adult; Child; Humans; Puberty, Precocious; Luteinizing Hormone; Vitamin D; Follicle Stimulating Hormone; Vitamins; Gonadotropin-Releasing Hormone
PubMed: 37203349
DOI: 10.1039/d3fo00665d