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Zhongguo Dang Dai Er Ke Za Zhi =... Mar 2024Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly... (Review)
Review
Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the and genes and loss-of-function mutations in the , , and genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.
Topics: Humans; Puberty, Precocious; Gonadotropin-Releasing Hormone; Mutation; MicroRNAs; Puberty; Ubiquitin-Protein Ligases
PubMed: 38557384
DOI: 10.7499/j.issn.1008-8830.2309098 -
Frontiers in Pediatrics 2024We previously published the increased frequency of new CPP cases during the Covid-19 pandemic in our pediatric endocrinology clinic at Rady Children's Hospital in San...
BACKGROUND AND AIM OF THE STUDY
We previously published the increased frequency of new CPP cases during the Covid-19 pandemic in our pediatric endocrinology clinic at Rady Children's Hospital in San Diego, CA, US. We conducted this follow-up study to examine the incidence of new CPP cases requiring treatment with GnRH agonist (GnRHa) in our clinic during 2 years post-pandemic.
METHODS
We performed a retrospective comparison of the number of visits of children newly diagnosed with CPP treated with GnRHa during the 2 years following the first year of Covid-19 pandemic (5/2021-7/2023). We evaluated clinical and bone maturation data as well as differences in timing from diagnosis to onset of treatment.
RESULTS
We previously reported in the pre-Covid year, 28 children (1 boy, 27 girls) treated with GnRHa for CPP out of 2,340 new endocrinology visits (1.2% of patients seen). During Covid-19 year, 64 children (7 boys, 57 girls) were treated out of 2,261 new visits (2.8%). The incidence of new CPP cases requiring GnRHa during the pandemic more than doubled compared to pre-pandemic. In the first year post-year 1 of the pandemic (5/2021-4/2022), 46 children (3 boys, 40 girls) started treatment with GnRHa for CPP out of 2,595 new endocrinology visits (1.6% of patients seen). During the second follow-up year (5/2022-4/2023), 22 children (4 boys, 18 girls) started treatment with GnRHa for CPP out of 2,676 new endocrinology visits (0.8% of patients seen). Age at onset of treatment, degree of bone age (BA) advancement, time from diagnosis to onset of treatment, and changes in BMI during the pandemic were not different from pre-pandemic or post-pandemic.
CONCLUSIONS
CPP cases requiring GnRHa treatment significantly increased during the first year of the Covid-19 pandemic and then decreased each year post-pandemic. This was not related to BMI, age at diagnosis, degree of bone age advancement, or time from diagnosis to onset of treatment as all these factors have been similar during pre-pandemic, pandemic, and post-pandemic years. It is reasonable that the postulated hypotheses published regarding the increase during the pandemic would resolve post-pandemic.
PubMed: 38545431
DOI: 10.3389/fped.2024.1352295 -
International Journal of Reproductive... Jan 2024Precocious puberty (PP) involves early activation of the hypothalamic gonadotropin-releasing hormone (GnRH) generator. The RFamide-related peptide/G protein-coupled...
Modulating the RFamide-related peptide-3/G protein-coupled receptor 147 signaling pathway with nourishing Yin-removing fire herbal mixture to alleviate precocious puberty in female rats: An experimental study.
BACKGROUND
Precocious puberty (PP) involves early activation of the hypothalamic gonadotropin-releasing hormone (GnRH) generator. The RFamide-related peptide/G protein-coupled receptor 147 () signaling pathway is vital in inhibiting GnRH and delaying puberty onset. The nourishing Yin-removing fire (NYRF) herbal mixture has shown promising results in treating PP.
OBJECTIVE
This study aimed to assess the impact of the NYRF herbal mixture on the signaling pathway in the hypothalamus and its potential in alleviating PP in female rats.
MATERIALS AND METHODS
In a controlled experiment, 24 female Sprague-Dawley rats (11.20 0.69 gr, postnatal day [PD5]) were divided into normal, model, normal saline, and NYRF groups (n = 6/each). PP was induced in the model, normal saline, and NYRF groups by subcutaneous injection of danazol at PD5. The NYRF herbal mixture or normal saline was administered from PD15. Serum sex hormone levels and hypothalamic samples were collected for mRNA and protein expression at PD30.
RESULTS
In the model group, hypothalamic GnRH and kisspeptin levels increased, while RFRP3 and GPR147 levels decreased, luteinizing hormone levels elevated, reproductive organ coefficients increased, and the vagina opened earlier compared to the normal group. Conversely, the NYRF group exhibited lower GnRH and kisspeptin levels but higher RFRP3 levels in the hypothalamus. Serum luteinizing hormone levels were reduced, reproductive organ coefficients were reduced, and the vaginal opening was delayed compared to the model and normal saline groups.
CONCLUSION
The NYRF herbal mixture delayed sexual development in rats with PP by hypothalamic upregulating RFRP3 and downregulating GnRH and kisspeptin.
PubMed: 38544669
DOI: 10.18502/ijrm.v22i1.15240 -
Medicina (Kaunas, Lithuania) Mar 2024: bLH is considered an excellent biochemical predictor of CPP. However, its utilization in clinical practice shows some uncertainties. This study aims to evaluate the...
: bLH is considered an excellent biochemical predictor of CPP. However, its utilization in clinical practice shows some uncertainties. This study aims to evaluate the diagnostic power of bLH and propose a diagnostic algorithm for CPP. : We conducted a monocentric cohort retrospective study evaluating all females referred for suspicion of CPP between 1 January 2017 and 31 December 2020 who underwent a GnRH test. Auxological, hormonal, and instrumental data were collected, including pelvic ultrasonography and bone age (BA) assessment. Simple linear regression, -test, and ROC tests were utilized to study the diagnostic value of basal hormone levels. Two hundred thirteen girls were included in the study. They were subdivided into two groups according to the results of the GnRH test: Group 1, with LH peak > 5 IU/L (pubertal) and 79 patients (37%), and Group 2, with an LH peak ≤ 5 IU/L (prepubertal) and 134 patients (63%). : The ROC curve showed that bLH level > 1.5 Ul/L best predicts a pubertal response to the GnRH test (AUC 0.8821, accuracy 82%), with low sensitivity (34%). The multivariate analysis found that bLH > 0.5 IU/L, basal FSH (bFSH) > 3.5 IU/L, bLH/bFSH ratio > 0.16, BA advancement > 1.7 years, uterine volume > 3.6 mL, longitudinal uterine diameter > 41 mm, and the presence of endometrial rhyme were significantly associated with a pubertal response at the GnRH test. An algorithm based on these features was created, and its application would reduce the number of GnRH tests by 34%. Overall, 96.2% of Group 1 patients reached the LH peak at the 30th minute of the GnRH test, supporting the hypothesis that the GnRH test duration could be reduced to 30 min. : Morning bLH > 1.5 IU/L could be carefully used as a diagnostic predictor of CPP. The GnRH test, even reduced to 30 min, could be reserved for girls who show low intermediate morning bLH and specific clinical signs of pubertal development.
Topics: Female; Humans; Luteinizing Hormone; Follicle Stimulating Hormone; Puberty, Precocious; Retrospective Studies; Gonadotropin-Releasing Hormone
PubMed: 38541222
DOI: 10.3390/medicina60030497 -
Frontiers in Endocrinology 2024The mechanistic target of rapamycin (mTOR) signaling pathway has a significant effect on central precocious puberty (CPP). However, the causality between mTOR-dependent...
BACKGROUND
The mechanistic target of rapamycin (mTOR) signaling pathway has a significant effect on central precocious puberty (CPP). However, the causality between mTOR-dependent circulating protein levels and CPP is still unclear. Our aim is to assess the effects of seven mTOR-dependent circulating protein levels on CPP using Mendelian randomization (MR).
METHODS
Instrumental variables (IVs) for mTOR-dependent circulating protein levels were retrieved from the proteomics-GWAS INTERVAL study and eQTLGen. The summary-level genetic datasets for CPP outcome were obtained from the FinnGen Consortium. Inverse-variance weighted (IVW) was used as the primary method and the pleiotropy, heterogeneity and robustness of the analyses were detected as sensitivity analysis. Positive exposures in the discovery cohort would be revalidated in the validation cohort.
RESULTS
This two-sample MR study revealed a causal association between eIF4G level in plasma and CPP in both discovery cohort (IVW: OR = 0.45, 95% CI = 0.22-0.91, = 0.026) and validation cohort (IVW: OR = 0.45, 95% CI = 0.24-0.85, = 0.014).
CONCLUSIONS
There was a causal association between eIF4G level in plasma and CPP. Whether eIF4G can be used for the prevention or treatment of CPP needs to be explored in further studies.
Topics: Humans; TOR Serine-Threonine Kinases; Eukaryotic Initiation Factor-4G; Mendelian Randomization Analysis; Puberty, Precocious; Causality
PubMed: 38516410
DOI: 10.3389/fendo.2024.1360043 -
Human Reproduction (Oxford, England) May 2024Is the 24-h urinary gonadotropin assay an effective diagnostic tool in central precocious puberty (CPP) in girls?
STUDY QUESTION
Is the 24-h urinary gonadotropin assay an effective diagnostic tool in central precocious puberty (CPP) in girls?
SUMMARY ANSWER
This study is the first to provide 24-h urinary gonadotropin assay data, using an electrochemiluminescent immunoassay (CMIA), and to report its usefulness as a tool for the diagnosis of CPP.
WHAT IS KNOWN ALREADY
Data about the GnRH test in the diagnosis of CPP are variable and there is no consensus regarding its interpretation. The measurement of FSH and LH in urines was previously reported to be an alternative biological tool.
STUDY DESIGN, SIZE, DURATION
This is a retrospective two-cohort study, involving a setting and a validation cohort. A total of 516 girls, included between October 2012 and July 2015, and 632 urinary collections were analyzed in the setting cohort. In the validation cohort, 39 girls were included between January 2021 and May 2023, and 49 urinary collections were analyzed.
PARTICIPANTS/MATERIALS, SETTING, METHODS
This study included girls who consulted for an investigation of disturbed growth rate or a clinical suspicion of puberty onset in different medical centres across France (setting cohort). Girls with a suspicion of precocious puberty onset were addressed at the expert centre of paediatric endocrinology of the Groupement Hospitalier Lyon Est (validation cohort). Pelvic ultrasonography was performed and enabled their classification according to clinical and morphologic changes criteria (prepubertal or pubertal groups). The parents collected 24-h urine samples (u24) according to standardized instructions. FSH and LH (urinary or plasmatic) were measured using a current and automated CMIA.
MAIN RESULTS AND THE ROLE OF CHANCE
The area under the ROC curves for CPP prediction was 0.709 for u24FSH (P < 0.001), 0.767 for u24LH (P < 0.001), and 0.753 for the u24LH/u24FSH ratio (P < 0.001). We retained all possible combinations of the four thresholds in the validation cohort (u24FSH = 1.1 or 2.0 IU/24 h; u24LH = 0.035 or 0.08 IU/24 h). The combination of u24FSH > 1.1 IU/24 h and u24LH > 0.08 IU/24 h had a positive PV of 85.7% and a negative PV of 94.3%, a sensitivity of 85.7% and a specificity of 94.3%, for classifying prepubertal and pubertal girls in this cohort.
LIMITATIONS, REASONS FOR CAUTION
This is a retrospective study, in which a margin of error remains due to the inherent uncertainty regarding the clinical assessment of pubertal onset. It must be considered that the thresholds can only apply to the used reagents; measurements without extractions using other reagents are likely to show important heterogeneity.
WIDER IMPLICATIONS OF THE FINDINGS
The assay performed herein is a simple, non-invasive, and analytically robust technique meeting the criteria for an alternative to the GnRH test which could be used to supplement its lack of sensitivity.
STUDY FUNDING/COMPETING INTEREST(S)
No specific funding was used. All authors declared no conflict of interest.
TRIAL REGISTRATION NUMBER
In-house #23-5214 registered study.
Topics: Humans; Female; Puberty, Precocious; Retrospective Studies; Child; Luteinizing Hormone; Follicle Stimulating Hormone; Immunoassay; Predictive Value of Tests
PubMed: 38514451
DOI: 10.1093/humrep/deae055 -
International Journal of Surgery Case... Apr 2024Although female victims of sexual child abuse present with symptoms such as local pain and vaginal bleeding, however, before any definitive diagnosis a comprehensive...
INTRODUCTION
Although female victims of sexual child abuse present with symptoms such as local pain and vaginal bleeding, however, before any definitive diagnosis a comprehensive physical examination along with a detailed history related to vaginal bleeding should be taken from the patient. Undoubtedly, we must not forget that only one of the causes of vaginal bleeding is rape. Therefore, before making a final diagnosis, other causes of this symptom must be carefully examined.
CASE PRESENTATION
The patient was a 6-years-old female who was hospitalized for notable generalized abdominal distention, acute lower abdomen pain associated with nausea and mild fever lasting 5 days progressively worsening, thelarche and vaginal bleeding. Ultrasound examination showed that multilocular-solid masses located in right side of abdomen which led to surgery and mass excision. Histopathology diagnosis was a juvenile granulosa cell tumor of the ovary.
DISCUSSION
Among the various causes of peripheral premature puberty, granulosa cell tumor (GCT) is rare but very important. Since in the two age groups - prepuberty and menopause - we don't expect to see vaginal bleeding, the occurrence of this disorder especially in association with breast enlargement in prepubertal group, need to appropriate imaging including pelvic ultrasound and bone age determination also laboratory data such as level of sex hormones and tumor markers to avoid misdiagnosis.
CONCLUSION
We report the case of a granulosa cell tumor patient with vaginal bleeding that a complete history and examination provides the right path to a diagnosis.
PubMed: 38513413
DOI: 10.1016/j.ijscr.2024.109546 -
JCEM Case Reports Mar 2024Hypothalamic hamartomas (HHs) are rare, benign brain tumors or lesions of the hypothalamus that are predominantly identified in cases of epilepsy and central precocious...
Hypothalamic hamartomas (HHs) are rare, benign brain tumors or lesions of the hypothalamus that are predominantly identified in cases of epilepsy and central precocious puberty (CPP), whereas isolated manifestations of infantile obesity are atypical. We herein report an 8-month-old boy with severe obesity (Kaup index 26.4 [>100th percentile]) and uncontrollable hyperphagia. His growth chart demonstrated remarkable weight gain that exceeded the length gain in magnitude. Brain magnetic resonance imaging identified a lesion consistent with HH. There were no episodes or clinical findings of epilepsy, CPP, or Cushing disease. Hypothalamic obesity should be considered in the diagnosis even in infants with excessive weight gain due to overeating.
PubMed: 38505090
DOI: 10.1210/jcemcr/luae033 -
Frontiers in Endocrinology 2024Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a...
OBJECTIVE
Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP.
MATERIAL AND METHODS
First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP.
RESULTS
A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM-DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats.
CONCLUSION
This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.
Topics: Humans; Child; Female; Rats; Animals; Puberty, Precocious; Gonadotropin-Releasing Hormone; Multiomics
PubMed: 38487340
DOI: 10.3389/fendo.2024.1285666 -
Cureus Feb 2024Hemispherectomy is a neurosurgical procedure that is frequently performed in pediatric patients diagnosed with Rasmussen's encephalitis. Postoperative complications...
Hemispherectomy is a neurosurgical procedure that is frequently performed in pediatric patients diagnosed with Rasmussen's encephalitis. Postoperative complications include immediate complications such as hydrocephalus and hemorrhage and behavioral complications such as language impairments and contralateral weakness. However, there are limited studies or case reports that address the potential endocrinopathies associated with this and other pediatric epileptic surgeries. This case report describes the endocrinopathies following an anatomical hemispherectomy procedure. A four-year-old African-American female had a right anatomical hemispherectomy for the treatment of Rasmussen's encephalitis in 2020. The postoperative course was immediately complicated by central diabetes insipidus which was stabilized with desmopressin. The patient's labs in 2021 were consistent with central precocious puberty with elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Additionally, the patient was found to have secondary adrenal insufficiency in which she failed a low-dose adrenocorticotropic hormone (ACTH) stimulation test. Oral hydrocortisone therapy was initiated for secondary adrenal insufficiency in addition to initiating leuprolide injections for central precocious puberty. Furthermore, at the age of seven years, the patient had her first menarche. This case report emphasizes the need for closer and long-term surveillance for endocrine issues in postepileptic surgical pediatric patients as well as a surveillance plan for the development of other potential endocrine abnormalities throughout the patient's life.
PubMed: 38465024
DOI: 10.7759/cureus.53894