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Initiation of the Hypothalamic-Pituitary-Gonadal Axis in Young Girls Undergoing Central Precocious Puberty Exerts Remodeling Effects on the Prefrontal Cortex.

ABSTRACT: Central precocious puberty (CPP) has been shown to exert significant effects on psychosocial development. These early puberty-related hormones and psychosocial functional changes are considered to be associated with specific brain development. However, the biological mechanisms underlying the sculpting of human brain architecture and modulation of psychosocial transformation by puberty-related hormonal maturation remain elusive, especially during the early phase of CPP. The current investigation aims to specify the brain regions in which early hormone-related maturation effects occur during CPP and their relationships with psychological functions. 65 young girls (aged 4.3-8.0 years) underwent structural imaging on a 3T MR system, completed psychological tests and performed the gonadotropin-releasing hormone (GnRH) stimulation test to identify hormonal manifestations of hypothalamic-pituitary-gonadal axis (HPG axis) activation. Based on the GnRH test, 28 young girls were identified with CPP, whereas the other 37 girls were identified with non-central precocious puberty (NCPP). Cortical parameters were calculated and compared between the two groups after adjusting for age, weight, and height. Brain regions showing group differences were extracted and correlated with serum hormone levels and psychological parameters. The CPP girls showed thinner cortices primarily in the right rostral middle frontal cortex. This morphological difference was positively correlated with stimulated estradiol (E2) levels. Further, higher E2 levels were significantly associated with higher hyperactivity scores. Premature HPG axis activation in CPP girls at an early stage appears to exert remodeling effects on brain anatomy, primarily in the prefrontal cortex, which may affect psychological development following the emergence of robust changes in sex hormones.

SUBMITTER: Yang D

PROVIDER: S-EPMC6524415 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Initiation of the Hypothalamic-Pituitary-Gonadal Axis in Young Girls Undergoing Central Precocious Puberty Exerts Remodeling Effects on the Prefrontal Cortex.

Yang Di D Zhang Wenjing W Zhu Yaxin Y Liu Peining P Tao Bo B Fu Yuchuan Y Chen Yu Y Zhou Lu L Liu Lu L Gao Xin X Liu Xiaozheng X Rubin Leah H LH Sweeney John A JA Yan Zhihan Z

Frontiers in psychiatry 20190510

Central precocious puberty (CPP) has been shown to exert significant effects on psychosocial development. These early puberty-related hormones and psychosocial functional changes are considered to be associated with specific brain development. However, the biological mechanisms underlying the sculpting of human brain architecture and modulation of psychosocial transformation by puberty-related hormonal maturation remain elusive, especially during the early phase of CPP. The current investigation ...[more]

PMID: 31133903

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Project description:BackgroundRecent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal.ResultsAnalyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP.ConclusionMethylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty.

Project description:BackgroundCentral 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.ObjectiveProteomics and metabolomics analysis of girls with CPP were compared to normal controls and the potential biomarkers and pathways involved were explored.MethodsSerum 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.Results134 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.ConclusionsOur 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.

Dataset Information

Initiation of the Hypothalamic-Pituitary-Gonadal Axis in Young Girls Undergoing Central Precocious Puberty Exerts Remodeling Effects on the Prefrontal Cortex.

Publications

Initiation of the Hypothalamic-Pituitary-Gonadal Axis in Young Girls Undergoing Central Precocious Puberty Exerts Remodeling Effects on the Prefrontal Cortex.

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