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Communications Biology Dec 2023N-methyladenosine (mA) plays a crucial role in the development and functional homeostasis of the central nervous system. The fat mass and obesity-associated (FTO) gene,...
N-methyladenosine (mA) plays a crucial role in the development and functional homeostasis of the central nervous system. The fat mass and obesity-associated (FTO) gene, which is highly expressed in the hypothalamus, is closely related to female pubertal development. In this study, we found that mA methylation decreased in the hypothalamus gradually with puberty and decreased in female rats with precocious puberty. FTO expression was increased at the same time. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the mA methylation of PLCβ, a key enzyme of the Ca signalling pathway, was decreased significantly in the hypothalamus in precocious rats. Upregulating FTO increased PLCβ3 expression and activated the Ca signalling pathway, which promoted GnRH expression. Dual-luciferase reporter and MeRIP-qPCR assays confirmed that FTO regulated mA demethylation of PLCβ and promoted PLCβ expression. Upon overexpressing FTO in the hypothalamic arcuate nucleus (ARC) in female rats, we observed advanced puberty onset. Meanwhile, PLCβ and GnRH expression in the hypothalamus increased significantly, and the Ca signalling pathway was activated. Our study demonstrates that FTO enhances GnRH expression, which promotes puberty onset, by regulating mA demethylation of PLCβ3 and activating the Ca signalling pathway.
Topics: Animals; Female; Rats; Demethylation; Gonadotropin-Releasing Hormone; Hypothalamus; Methylation; Signal Transduction
PubMed: 38129517
DOI: 10.1038/s42003-023-05677-2 -
Journal of the Endocrine Society Aug 2023Since the COVID-19 outbreak, the number of girls with suspected precocious puberty has increased.
CONTEXT
Since the COVID-19 outbreak, the number of girls with suspected precocious puberty has increased.
OBJECTIVE
To compare the incidence of idiopathic central precocious puberty (ICPP) during COVID-19 with that of the previous 4 years.
METHODS
Anthropometric, biochemical, and radiological parameters were collected between January 2016 and June 2021 from 133 girls who met the Rapidly Progressive ICPP criteria (RP-ICPP).
RESULTS
We found a higher incidence of RP-ICPP between March 2020 and June 2021 (group 2) compared with January 2016 through March 2020 (group 1) (53.5% vs 41.1%); 2021 showed the highest annual incidence ( < .05). Group 1 and group 2 differed in age at diagnosis (7.96 ± 0.71 vs 7.61 ± 0.94; < .05), mean Tanner stage (2.86 ± 0.51 vs 2.64 ± 0; < .05), and in the time between the appearance of thelarche and diagnosis (0.93 ± 0.75 vs 0.71 ± 0.62 years, < .05). There was an increase in the number of girls aged <8 years in group 2 and a significantly higher number of girls aged >8 years was found in group 1 (42 in group 1 vs 20 in group 2, < 0.05). Overall body mass index SD score showed higher values in group 2 (1.01 ± 1.23 vs 0.69 ± 1.15; = .18), which spent an average of 1.94 ± 1.81 hours per day using electronic devices; 88.5% of this group stopped any physical activity.
CONCLUSIONS
A spike in new diagnoses of idiopathic (1.79-fold higher) and RP-CPP coincided with the COVID-19 pandemic. The incidence of RP-ICPP was 1.3-fold higher during COVID-19 with a trend toward an increase in body mass index SD score. The expanding use of digital devices and the reduction of daily physical activity represent possible risk factors.
PubMed: 37873499
DOI: 10.1210/jendso/bvad094 -
The Lancet. Diabetes & Endocrinology Aug 2023Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene,...
BACKGROUND
Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype.
METHODS
In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation.
FINDINGS
Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice.
INTERPRETATION
We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process.
FUNDING
Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.
Topics: Animals; Child; Female; Humans; Male; Mice; Brazil; Cohort Studies; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Puberty, Precocious; Rett Syndrome
PubMed: 37385287
DOI: 10.1016/S2213-8587(23)00131-6 -
The Journal of Steroid Biochemistry and... Jul 2023The incidence of central precocious puberty (CPP) in boys is rising, but lack of effective molecular biomarkers often leads to delayed treatment and thus the terrible...
The incidence of central precocious puberty (CPP) in boys is rising, but lack of effective molecular biomarkers often leads to delayed treatment and thus the terrible clinical complications in adulthood. This study aims to identify the specific-biomarkers of CPP boys and understand the gender-related differences in metabolic characteristics of CPP. The specific-biomarkers of CPP boys were identified from serum by cross-metabolomics combined with linear discriminant analysis effect size analysis after age correction, and union receiver operating characteristic curve analyses were perform to optimize the combination of specific-biomarkers. The differences in metabolic characteristics between boys and girls with CPP were explored by cross-metabolomics and weighted gene co-expression network analysis. Results show that CPP activated in advance the HPG axis and induced gender-related clinical phenotypes. Seven serum metabolites were identified as specific-biomarkers of CPP boys, including acetoacetate, aspartate, choline, creatinine, myo-inositol, N,N-dimethylglycine and N-Acetyl-glycoprotein. The combination of aspartate, choline, myo-inositol and creatinine achieved an optimized diagnosis, where AUC is 0.949, prediction accuracy for CPP boys is 91.1%, and the average accuracy is 0.865. The metabolic disorders of CPP boys mainly involve in glycerophospholipid metabolism, and synthesis and degradation of ketone bodies. Betaine, glutamine, isoleucine, lactate, leucine, lysine, pyruvate, α-&β-glucose were identified as gender-related biomarkers for CPP, and they are mainly involved in glycolysis/gluconeogenesis, pyruvate metabolism, and alanine, aspartate and glutamate metabolism. Biomarkers combination provides a promising diagnostic potential for CPP boy with a favorite sensitivity and specificity. In addition, the differences of metabolic characteristics between boys and girls with CPP will contribute to the development of individualized clinical treatments in CPP.
Topics: Aspartic Acid; Creatinine; Metabolomics; ROC Curve; Biomarkers; Gonadotropin-Releasing Hormone
PubMed: 36997004
DOI: 10.1016/j.jsbmb.2023.106305 -
Journal of Magnetic Resonance Imaging :... Dec 2023
Editorial for "Development and Validation of a Combined MRI Radiomics, Imaging and Clinical Parameter Based Machine Learning Model for Identifying Idiopathic Central Precocious Puberty in Girls".
Topics: Female; Humans; Puberty, Precocious; Magnetic Resonance Imaging
PubMed: 37036743
DOI: 10.1002/jmri.28728 -
Nutrition Journal Jan 2024The role of dietary intake on precocious puberty remains unclear. This study aimed to investigate the association between the amount and frequency of dietary intake and...
BACKGROUND
The role of dietary intake on precocious puberty remains unclear. This study aimed to investigate the association between the amount and frequency of dietary intake and the risk of precocious puberty in Chinese girls.
METHODS
In this case-control study, we enrolled 185 precocious puberty girls and 185 age-matched controls. Their dietary intake was assessed through a semi-quantitative food frequency questionnaire. Their sociodemographic and lifestyle data were collected. The associations between dietary intake and risk of precocious puberty were assessed by conditional logistic regression models.
RESULTS
After multivariate adjustment, consuming a higher amount of red meat was associated with higher precocious puberty risk (OR = 2.74, 95% CI: 1.25-6.02), while a higher frequency of fruit ( P for trend = 0.024) and amount of vegetable intake was associated with a lower risk of precocious puberty (P for trend = 0.002). The high vegetable and protein dietary pattern was significantly negatively associated with precocious puberty (OR = 0.78, 95% CI: 0.63-0.97), whereas the high animal food and fruits dietary pattern was remarkably positively associated with precocious puberty (OR = 1.36, 95% CI: 1.09-1.69), after adjusting for age and body mass index.
CONCLUSIONS
High vegetable and protein dietary pattern is a protective factor against precocious puberty, while high animal food and fruits dietary pattern is a risk factor for precocious puberty in Chinese girls. Attentions should be paid to a reasonable intake of red meat, eggs, and fruits in children's daily diet, increase their intake of vegetables, in order to reduce the risk of precocious puberty.
Topics: Female; Animals; Child; Humans; Dietary Patterns; Case-Control Studies; Puberty, Precocious; Diet; Risk Factors; Fruit; Vegetables; China
PubMed: 38291391
DOI: 10.1186/s12937-024-00916-6 -
European Journal of Endocrinology Mar 2024Recent studies suggest that boys enter puberty at a younger age, and the incidence of male central precocious puberty (CPP) is increasing. In this study, we explore the...
OBJECTIVE
Recent studies suggest that boys enter puberty at a younger age, and the incidence of male central precocious puberty (CPP) is increasing. In this study, we explore the incidence of male CPP and identify key clinical and auxological indicators for organic CPP (OCPP).
DESIGN
A retrospective registry-based study.
METHODS
The medical records of 43 boys treated with CPP at the Helsinki University Hospital between 1985 and 2014 were reviewed. Clinical, auxological, and endocrine data of the CPP patients were included in the analyses.
RESULTS
Based on brain MRI, 26% of patients had OCPP. Between 2010 and 2014, the CPP incidence in boys was 0.34 per 10 000 (95% CI 0.20-0.60). Between 1990 and 2014, the male CPP incidence increased (incidence rate ratio [IRR] 1.10, P = .001). This increase was driven by rising idiopathic CPP (ICPP) incidence (IRR 1.11, 95% CI 1.05-1.19, P < .001), while OCPP incidence remained stable (P = .41). Compared with the patients with ICPP, the patients with OCPP were younger (P = .006), were shorter (P = .003), and had higher basal serum testosterone levels (P = .038). Combining 2 to 4 of these readily available clinical cues resulted in good to excellent (all, area under the curve 0.84-0.97, P < .001) overall performance, differentiating organic etiology from idiopathic.
CONCLUSIONS
The estimated incidence of CPP in boys was 0.34 per 10 000, with 26% of cases associated with intracranial pathology. The increase in CPP incidence was driven by rising ICPP rates. Patients with OCPP were characterized by shorter stature, younger age, and higher basal testosterone levels, providing valuable cues for differentiation in addition to brain MRI. Utilizing multiple cues could guide diagnostic decision-making.
Topics: Humans; Male; Luteinizing Hormone; Puberty, Precocious; Follicle Stimulating Hormone; Retrospective Studies; Testosterone; Gonadotropin-Releasing Hormone
PubMed: 38523472
DOI: 10.1093/ejendo/lvae021 -
Journal of Personalized Medicine Jun 2024Limited knowledge is available about the association between autistic spectrum disorder (ASD) and precocious puberty. Our study examined the association between the two...
Limited knowledge is available about the association between autistic spectrum disorder (ASD) and precocious puberty. Our study examined the association between the two medical conditions and effect modification by sex and neuropsychiatric comorbidities in a nationwide population. To compare the risk of precocious puberty between ASD and non-ASD cases, we conducted a Cox regression analysis using ASD as the exposure and time to precocious puberty as the outcome. We adjusted for sex, attention-deficit/hyperactivity disorder (ADHD), tic disorder, obsessive-compulsive disorder (OCD), anxiety disorder, intellectual disability, and epilepsy. We performed a moderation analysis to examine the potential moderating effects of sex and comorbidities. Patients with ASD were prone to have precocious puberty, with an adjusted hazard ratio (aHR) of 1.80 (95% CI: 1.61-2.01). For effect modification, sex, specifically females, moderated the association between ASD and precocious puberty, with a relative excess risk due to interaction (RERI) of 7.35 (95% CI 4.90-9.80). No significant effect modification was found for any of the comorbidities within the scope of additive effect modification. We found that patients with ASD were prone to precocious puberty, regardless of sex or comorbid neuropsychiatric disorders. Girls with ASD are at a particularly higher risk of developing precocious puberty.
PubMed: 38929853
DOI: 10.3390/jpm14060632 -
Frontiers in Endocrinology 2023
PubMed: 37654564
DOI: 10.3389/fendo.2023.1266239 -
International Journal of Pediatric... May 2024In this prospective study, we aimed to investigate the difference in voice acoustic parameters between girls with idiopathic central precocious puberty (ICPP) and those...
PURPOSE
In this prospective study, we aimed to investigate the difference in voice acoustic parameters between girls with idiopathic central precocious puberty (ICPP) and those who developed normally during prepuberty.
MATERIALS AND METHODS
Our study recruited 54 girls diagnosed with ICPP and randomly sampled 51 healthy prepubertal girls as the control. Tanner stages, circulating hormone levels and bone ages of the girls with ICPP and the age and body mass index (BMI) of all participants were recorded. Acoustic analyses were performed using PRAAT computer-based voice analysis software and the mean pitch (F0), jitter, shimmer, noise-to harmonic-ratio (NHR) and harmonic-to-noise ratio (HNR) values were compared in the patient and control groups.
RESULTS
The two groups did not significantly differ in age or BMI. In the evaluation of the F0 and jitter values, we were found to be lower in the control group than in the patient group. However, we did not find a statistical significance. The mean shimmer values of the patient group were significantly higher than those of the control group. In addition, a statistically significant difference was noted for the mean HNR and NHR values (P < 0.001). A moderate negative correlation was found between shimmer and hormone levels in the patient group.
CONCLUSIONS
Voice acoustic parameters one of the defining features of girls with ICPP. Voice changes in acoustic parameters could reflect hormonal changes during puberty. Clinicians should suspect ICPP when there is a change in the voice.
Topics: Humans; Puberty, Precocious; Female; Child; Prospective Studies; Voice Quality; Speech Acoustics; Case-Control Studies; Voice; Body Mass Index
PubMed: 38657429
DOI: 10.1016/j.ijporl.2024.111962