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Clinical Epigenetics Jun 2024Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the...
BACKGROUND
Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the onset of puberty or the susceptibility to a wide range of diseases later in life. The present study aims to investigate changes in genomic DNA methylation profiles associated with pubertal onset analyzing human peripheral blood leukocytes from three different groups of subjects: 19 girls with central precocious puberty (CPP), 14 healthy prepubertal girls matched by age and 13 healthy pubertal girls matched by pubertal stage. For this purpose, the comparisons were performed between pre- and pubertal controls to identify changes in normal pubertal transition and CPP versus pre- and pubertal controls.
RESULTS
Analysis of methylation changes associated with normal pubertal transition identified 1006 differentially methylated CpG sites, 86% of them were found to be hypermethylated in prepubertal controls. Some of these CpG sites reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome profiles in CPP patients showed 65% and 55% hypomethylated CpG sites compared with prepubertal and pubertal controls, respectively. In addition, interestingly, our results revealed the presence of 43 differentially methylated genes coding for zinc finger (ZNF) proteins. Gene ontology and IPA analysis performed in the three groups studied revealed significant enrichment of them in some pathways related to neuronal communication (semaphorin and gustation pathways), estrogens action, some cancers (particularly breast and ovarian) or metabolism (particularly sirtuin).
CONCLUSIONS
The different methylation profiles of girls with normal and precocious puberty indicate that regulation of the pubertal process in humans is associated with specific epigenetic changes. Differentially methylated genes include ZNF genes that may play a role in developmental control. In addition, our data highlight changes in the methylation status of genes involved in signaling pathways that determine the migration and function of GnRH neurons and the onset of metabolic and neoplastic diseases that may be associated with CPP in later life.
Topics: Humans; Puberty, Precocious; Female; DNA Methylation; Child; CpG Islands; Epigenesis, Genetic; Epigenome; Case-Control Studies
PubMed: 38909248
DOI: 10.1186/s13148-024-01683-1 -
Journal of Pediatric Endocrinology &... Jun 2024
PubMed: 38898800
DOI: 10.1515/jpem-2024-0277 -
Journal of Endocrinological... Jun 2024It was aimed to compare circulating levels of ghrelin, leptin, peptide YY (PYY), and neuropeptide (NPY) between girls with idiopathic central precocious puberty (ICPP)...
PURPOSE
It was aimed to compare circulating levels of ghrelin, leptin, peptide YY (PYY), and neuropeptide (NPY) between girls with idiopathic central precocious puberty (ICPP) and prepubertal girls, as well as to evaluate alterations in these hormone levels and body composition during leuprolide acetate treatment in girls with ICPP.
METHODS
This prospective study was conducted on girls with isolated premature thelarche (IPT), girls with ICPP, and age-matched prepubertal controls. Anthropometric measurements, body composition analysis and appetite-regulating hormone level measurements were performed in each group and also at the 6th and 12th months of the leuprolide acetate treatment for the girls with ICPP.
RESULTS
Seventy-three girls participated in the study (24 girls with ICPP, 28 with IPT, and 21 prepubertal controls). No significant differences were observed in ghrelin, leptin, PYY, and NPY levels among the three groups. Leuprolide acetate treatment resulted in increased leptin, decreased PYY and NPY levels, and no significant changes in ghrelin. Despite no significant change in body mass index standard deviation score (BMI SDS), body fat percentage increased during treatment.
CONCLUSION
While appetite-regulating hormones do not seem to directly contribute to precocious puberty pathogenesis, puberty blockade was shown to lead to altered levels of these hormones along with changes in body composition.
PubMed: 38896175
DOI: 10.1007/s40618-024-02413-3 -
Nutrients May 2024The onset of puberty, which is under the control of the hypothalamic-pituitary-gonadal (HPG) axis, is influenced by various factors, including obesity, which has been... (Review)
Review
The onset of puberty, which is under the control of the hypothalamic-pituitary-gonadal (HPG) axis, is influenced by various factors, including obesity, which has been associated with the earlier onset of puberty. Obesity-induced hypothalamic inflammation may cause premature activation of gonadotropin-releasing hormone (GnRH) neurons, resulting in the development of precocious or early puberty. Mechanisms involving phoenixin action and hypothalamic microglial cells are implicated. Furthermore, obesity induces structural and cellular brain alterations, disrupting metabolic regulation. Imaging studies reveal neuroinflammatory changes in obese individuals, impacting pubertal timing. Magnetic resonance spectroscopy enables the assessment of the brain's neurochemical composition by measuring key metabolites, highlighting potential pathways involved in neurological changes associated with obesity. In this article, we present evidence indicating a potential association among obesity, hypothalamic inflammation, and precocious puberty.
Topics: Humans; Pediatric Obesity; Hypothalamus; Child; Puberty, Precocious; Puberty; Inflammation; Female; Gonadotropin-Releasing Hormone; Male; Hypothalamo-Hypophyseal System
PubMed: 38892653
DOI: 10.3390/nu16111720 -
Journal of Pediatric Endocrinology &... Jun 2024Central 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...
OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
PubMed: 38881279
DOI: 10.1515/jpem-2024-0124 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To explore the relationship between puberty timing and cardiovascular metabolic risk factors among primary and secondary students with different genders in Beijing.
OBJECTIVE
To explore the relationship between puberty timing and cardiovascular metabolic risk factors among primary and secondary students with different genders in Beijing.
METHODS
Using the method of stratified cluster sampling by urban and rural areas and school sections, 3 067 students from 16 primary and secondary schools in Fangshan District of Beijing were selected in October 2012, with questionnaire survey, physical examination and serum laboratory testing. In this study, we controlled for confounding factors such as school segments, current residence of the family, birth weight, feeding method, only child, highest educational level of parents, and monthly family income, and then the associations between cardiovascular metabolic risk factors and puberty timing among the primary and secondary students was analyzed by multivariate Logistic analysis. To ensure the reliability of the data, this study adopted strict quality control.
RESULTS
A total of 3 067 primary and middle school students aged 7 to 16 years were included in this study, including 1 575 boys and 1 492 girls. The prevalence of premature puberty was 14.73% among the boys and 12.89% among the girls, respectively. The prevalence of delayed puberty was 9.49% among the boys and 10.99% among the girls, respectively. The detection rates of central obesity, hypertension, hyperglycemia, and dyslipidemia among the primary and secondary students were 35.87%, 19.95%, 2.54% and 26.31%, respectively. The detection rates of 1 risk factor clustering, 2 risk factors clustering and more than 3 risk factors clustering were 29.21%, 16.17% and 9.36%, respectively. The difference in the detection rate of cardiovascular and metabolic risk factors in different youth stages was insignificant (>0.05), the detection rate of risk factor aggregation of 0 was lower than that of the timely group and delayed group, and the detection rate of risk factors aggregation of 2 was higher than that of the timely group ( < 0.05).After adjusting the effects of learning stage, region, birth weight, feeding patterns, one-child, family income and the parents' educational levels, multivariate Logistic regression analysis showed that, compared with the on-time puberty group, the risk of 1 risk factor clustering, 2 risk factors clustering and more than 3 risk factors clustering increased by 1.94 times (95% =1.29-2.91), 2.97 times (95% =1.89-4.67) and 2.02 times (95% = 1.13-3.63) among the girls; It had not been found that the relationship between puberty timing and cardiovascular risk factor clustering among the boys (>0.05).
CONCLUSION
Premature puberty is an independent risk factor for the clustering of cardiometabolic risk factors in girls, and primary prevention strategies should be implemented to reduce the burden of cardiovascular metabolic diseases in the population.
Topics: Humans; Female; Male; Adolescent; Child; China; Students; Puberty; Cardiovascular Diseases; Risk Factors; Surveys and Questionnaires; Heart Disease Risk Factors; Hypertension; Dyslipidemias; Puberty, Precocious; Obesity, Abdominal; Prevalence; Hyperglycemia; Age Factors
PubMed: 38864126
DOI: 10.19723/j.issn.1671-167X.2024.03.007 -
Journal of the ASEAN Federation of... 2024We aimed to study the trend of referrals for precocious puberty during the COVID-19 pandemic compared to pre-COVID years, explore the differences in the demographic and...
OBJECTIVES
We aimed to study the trend of referrals for precocious puberty during the COVID-19 pandemic compared to pre-COVID years, explore the differences in the demographic and clinical features, and evaluate the contributing factors.
METHODOLOGY
The cases referred for assessment of PP from 2018-2021 to our endocrine centre were grouped into pre-COVID (2018-2019) and COVID (2020-2021) years. Cases fulfilling the diagnosis of PP included the onset of thelarche <8 years in females and 4 ml testicular volume <9 years in males. The PP was further differentiated as Isolated Thelarche (IST) and Central Precocious Puberty (CPP). Early menarche was defined as menarche <10 years old.
RESULTS
There were more referrals for PP and more diagnosed as CPP during the COVID-19 pandemic, predominantly among females. There were more endocrine tests done and more cases received treatment. None of the abnormal magnetic resonance imaging (MRI) pituitary findings required surgical intervention. The body mass index (BMI) was found to be positively associated with the risk of getting CPP with a crude-odd ratio (COR) of 1.8, <0.001, and early menarche (COR 2.1, <0.001).
CONCLUSION
We found a significant increase in the referrals of PP and diagnosis of CPP during the COVID-19 pandemic. Higher BMI was found to be associated with CPP and early menarche.
Topics: Humans; COVID-19; Puberty, Precocious; Female; Retrospective Studies; Male; Child; Singapore; Tertiary Care Centers; Menarche; SARS-CoV-2; Body Mass Index; Referral and Consultation
PubMed: 38863916
DOI: 10.15605/jafes.039.01.12 -
European Journal of Endocrinology Jun 2024The etiology of central precocious puberty (CPP) has expanded with identification of new genetic causes, including the monogenic deficiency of MKRN3. We aimed to assess...
OBJECTIVES
The etiology of central precocious puberty (CPP) has expanded with identification of new genetic causes, including the monogenic deficiency of MKRN3. We aimed to assess the prevalence of CPP causes and the predictors of genetic involvement in this phenotype.
DESIGN
A retrospective cohort study for an etiological survey of patients with CPP from a single academic center.
METHODS
All patients with CPP had detailed medical history, phenotyping, and brain MRI; those with negative brain MRI (apparently idiopathic) were submitted to genetic studies, mainly DNA sequencing studies, genomic microarray, and methylation analysis.
RESULTS
We assessed 270 patients with CPP; 50 (18.5%) had CPP-related brain lesions [34 (68%) congenital lesions]; whereas 220 had negative brain MRI. Of the latter, 174 (165 girls) were included for genetic studies. Genetic etiologies were identified in 22 patients (20 girls), indicating an overall frequency of genetic CPP of 12.6% (22.2% in boys and 12.1% in girls). The most common genetic defects were MKRN3, DLK1, and MECP2 loss-of-function mutations, followed by 14q32.2 defects (Temple syndrome). Univariate logistic regression identified family history (OR 3.3; 95%CI 1.3-8.3; p = 0.01) and neurodevelopmental disorders (OR 4.1; 95%CI 1.3-13.5; p = 0.02) as potential clinical predictors of genetic CPP.
CONCLUSIONS
Distinct genetic causes were identified in 12.6% patients with apparently idiopathic CPP, revealing the genetic etiology as a relevant cause of CPP in both sexes. Family history and neurodevelopmental disorders were suggested as predictors of genetic CPP. We originally proposed an algorithm to investigate the etiology of CPP including genetic studies.
PubMed: 38857188
DOI: 10.1093/ejendo/lvae063 -
Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome.Life Sciences Aug 2024Precocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut-brain disease. On the other hand, the use of glycyrrhizin, a natural...
AIMS
Precocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut-brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional).
MATERIALS AND METHODS
In the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk.
KEY FINDINGS
Glycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39-0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic-pituitary-gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations.
SIGNIFICANCE
Our findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.
Topics: Gastrointestinal Microbiome; Glycyrrhizic Acid; Animals; Rats; Male; Female; Puberty, Precocious; Sweetening Agents; Humans; Child; Rats, Sprague-Dawley; Fecal Microbiota Transplantation
PubMed: 38848942
DOI: 10.1016/j.lfs.2024.122789 -
Molecular Syndromology Jun 2024Focal dermal hypoplasia (FDH) is a genodermatosis also known as Goltz-Gorlin syndrome caused by pathogenic variants in the gene and inherited in an X-linked dominant...
INTRODUCTION
Focal dermal hypoplasia (FDH) is a genodermatosis also known as Goltz-Gorlin syndrome caused by pathogenic variants in the gene and inherited in an X-linked dominant manner. Given the course of X-linked dominant inheritance, affected males can only survive in the state of mosaicism for a pathogenic variant or in the presence of XXY karyotype. FDH is a multisystemic disorder in which cutaneous, ocular, and skeletal systems are primarily affected. Patients also may display intellectual disability and central nervous system abnormalities, yet most may have normal mental development.
CASE PRESENTATION
We report on a currently 11-year-old female patient with a novel missense heterozygous variant who exhibited classical ectodermal, skeletal, and ocular findings in addition to mild intellectual disability, left-side diaphragm eventration, and puberty precox, a finding yet unreported in the literature.
CONCLUSION
With this report, we aimed to expand the mutational spectrum and give insight into the importance of neurologic and skeletal system evaluation among other clinical features of FDH. Although gastrointestinal and genitourinary problems can occur during the course of the disease, to our knowledge, left-side diaphragm eventration and puberty precox are new features that have not been reported previously.
PubMed: 38841326
DOI: 10.1159/000535681