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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 -
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 -
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 -
Archives of Disease in Childhood.... Mar 2024Precocious puberty has traditionally been defined as the onset of secondary sexual characteristics occurring before age 8 years in girls and 9 years in boys. This...
Precocious puberty has traditionally been defined as the onset of secondary sexual characteristics occurring before age 8 years in girls and 9 years in boys. This earlier onset of puberty may have significant physical and psychological consequences if left untreated. Moreover, it should be excluded that pubertal signs are not secondary to malignancies, other organic aetiologies or associated syndromic phenotypes. Initial assessment involves a thorough medical history and physical examination; a hand and wrist X-ray to determine bone age, and hormonal tests might be indicated to confirm the diagnosis and to determine the origin of hormonal production. Treatment options depend on the underlying cause. Given the complexity of the differential diagnosis, this article aims to familiarise clinicians with the different steps that can be taken when precocious puberty is suspected.
PubMed: 38514136
DOI: 10.1136/archdischild-2023-326217 -
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 -
Endocrine Mar 2024To identify cut-off for basal LH levels and for pelvic ultrasound uterine and ovarian parameters indicating an Hypotalamic-Pituitary-Gonadal (HPG) axis activation as...
PURPOSE
To identify cut-off for basal LH levels and for pelvic ultrasound uterine and ovarian parameters indicating an Hypotalamic-Pituitary-Gonadal (HPG) axis activation as diagnostic of Central Precocious Puberty (CPP).
METHODS
248 girls referred for suspected precocious/early puberty who had undergone a GnRH stimulation test were enrolled and divided into three groups: Premature Idiopathic Thelarche (PIT), CPP, and Early Puberty (EA). For every patient basal serum Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH), basal LH/FSH ratio and pelvic ultrasonographic parameters were also collected. Through the use of Receiver Operating Curves (ROCs) the sensitivity (Se) and specificity (Sp) of basal LH, FSH, LH/FSH ratio and ultrasonographic parameters were evaluated at each level and Area Under the Curve (AUC) was measured.
RESULTS
Basal LH model ≥0.14 mIU/mL reached the highest predictability (90.6% and 78.2%, Se and Sp, respectively). Basal LH/FSH ratio ≥0.1 showed a sensitivity of 85.90% and a specificity of 78.14%, while basal FSH cut-off (≥2.36 mIU/mL) had the lowest predictability, with a less favourable sensitivity (71%) and specificity (70.5%). Cut-off point for uterine length as 35 mm, (83.5% and 42.9% of Se and Sp, respectively) was calculated. For ovarian volumes, ROC curves showed very low sensitivity and specificity.
CONCLUSION
A single basal LH measurement under the cut-off limit may be adequate to exclude an HPG axis activation as CPP.
PubMed: 38507183
DOI: 10.1007/s12020-024-03781-9 -
Acta Paediatrica (Oslo, Norway : 1992) Jul 2024To evaluate changes in body mass index (BMI) in girls during and after treatment for idiopathic central precocious puberty (iCPP).
AIM
To evaluate changes in body mass index (BMI) in girls during and after treatment for idiopathic central precocious puberty (iCPP).
METHODS
We studied 123 girls receiving gonadotropin-releasing hormone analogue (GnRHa)treatment for iCPP from 2009 to 2019. Pubertal and anthropometric measurements were monitored at routine clinical visits. BMI standard deviation scores (SDS) were estimated at baseline and followed in two stages from baseline to end of treatment (median 18.9 months) and from end of treatment to end of follow-up (median 18.2 months). The influence of baseline BMI SDS and the frequency and dose of treatment was evaluated using BMI trajectories and latent class mixed models.
RESULTS
The median age at treatment initiation was 8.5 years. The median BMI SDS at baseline was 0.7, corresponding to a median BMI of 17.4 kg/m. Overall, no changes in BMI SDS were observed during treatment. According to baseline BMI subgroups, an increasing trend in BMI trajectories during treatment was observed for girls in the lowest BMI group. After treatment, most girls maintained stable BMI levels.
CONCLUSION
Our retrospective study did not provide evidence that GnRHa treatment for iCPP had a significant impact on BMI trajectories in girls.
Topics: Humans; Female; Puberty, Precocious; Body Mass Index; Child; Gonadotropin-Releasing Hormone; Retrospective Studies
PubMed: 38506052
DOI: 10.1111/apa.17185 -
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