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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 agematched 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. [ABSTRACT FROM AUTHOR]

Precocious puberty is diagnosed when pubertal characteristics appear before the age of 8 years in females. The most common form is gonadotropin-dependent, called axial. The primary method of treatment is administration of gonadotrophin-releasing hormone analogues (GnRHa). The aim of the study was to verify hypothesis that GnRHa therapy in the childhood may be of additive risk factor for polycystic ovary syndrome (PCOS) in adulthood. Material and Methods: The study group consists of 24 women (median age 22 88 years, median BMI 23.5) treated with GnRHa for central precocious puberty in childhood. The control group includes 40 women (median age 23 years, median BMI 25.6) diagnosed with isolated premature thelarche and not using GnRHa in the childhood. Anthropometric measurements, ultrasound examination of minor pelvis and hormonal profile were performed. PCOS diagnosis was based on Rotterdam criteria. Results: The study confirmed a higher prevalence of PCOS in the study group (50%) than in the control group (10%); p=0.0006. Significant, linear correlation between free testosterone levels and ovarian size was found in the study group (R=0.45 p= 0.03). Conclusions: GnRHa therapy during childhood may have a potential influence on incidence of PCOS in the adulthood. Therefore, in this group of patients longterm follow-up focused on screening for PCOS would seem beneficial. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to explore the impact of gonadotropin-releasing hormone agonists (GnRHa) on final adult height (FAH) in girls with early and fast puberty. Methods: A retrospective study was conducted by reviewing data from the medical records of the Pediatric Endocrinology Clinics between January 1, 2010, and December 31, 2020, at MacKay Children's Hospital. The treatment group included 109 patients who received 3.75 mg monthly for at least 1 year, whereas the control group consisted of 95 girls who received no treatment. Results: The treatment group was significantly older at the time of inclusion (chronological age (CA1), treatment vs. control, 8.7 vs. 8.4 years, p < 0.001), had a more advanced bone age (BA) (BA1, 11.5 vs. 10.8 years, p < 0.001), BA1-CA1 (2.7 vs. 2.2 years, p < 0.001), and shorter predicted adult height (PAH1) (153.3 vs. 157.1 cm, p = 0.005) that was significantly lower than their target height (Tht) (PAH1-Tht, -3.9 vs. -1.3 cm, p = 0.039). The FAHs of the GnRHa and the control group were similar (157.0 vs. 156.7 cm, p = 0.357) and were not significantly different from their Tht (FAH vs. Tht in the GnRHa group, 157.0 vs. 157.0 cm; control group, 156.7 vs. 157.0 cm). In the subgroup analysis, FAH was significantly higher after GnRHa treatment in those with PAH1 less than 153 cm and Tht (154.0 vs. 152.0 cm, p = 0.041), and those whose CA1 was between 8 and 9 years (158.0 vs. 155.4 cm, p = 0.004). We defined satisfactory FAH outcome as FAH- PAH1>5 cm and significant factors were GnRHa therapy, PAH1 shorter than their Tht, age younger than 9 years, and faster growth velocity during the first year. Discussion: GnRHa is effective in restoring the Tht in some early and fast pubertal girls, especially in those with poorly PAH (PAH lower than 153 cm and shorter than their target height). A younger age at initiation of treatment and a faster growth velocity during treatment are associated with a better height gain. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to examine the effects of blue light exposure on prepubertal male rats' puberty and testis tissue. Methods: Eighteen 21-day-old male Sprague Dawley rats were divided into three groups consisting of six rats in each group: Control Group (CG), Blue Light-6 hours (BL-6), and Blue Light-12 hours (BL-12). CG rats were maintained with 12/12-hour light-dark cycles. The rats of BL-6 and BL-12 were exposed to blue light (450-470nm/irradiance level 0.03uW/cm2) for 6 hours and 12 hours, respectively. Rats were exposed to blue light until the first signs of puberty. The ELISA method was used to analyze the serum levels of FSH, LH, testosterone, DHEA-S, leptin, ghrelin, melatonin, glutathione, glutathione peroxidase, and malondialdehyde. Testes were dissected for histomorphological examination. Results: The medians of the pubertal entry days of the CG, BL-6, and BL-12 were 38th, 30th, and 28th days, respectively. (p:0.001) The FSH, LH, and testosterone concentrations of all groups were similar. The FSH concentration increased as the LH concentration increased (r: 0.82 p: 0.001). The serum LH concentration increased as serum testosterone, and DHEAS decreased, respectively (r: -0.561, p: 0.01) (r:-0.55 p:0.01). Testicular lengths and weights of the BL groups were smaller compared to CG (p: 0.03), (p: 0.04). GPx was higher for BL-6 and BL-12 than the CG (p:0.021, p:0.024). Testis tissue was compatible with the pubertal period in all groups. As the blue light exposure time increased, spermatogenesis was suppressed, and capillary dilatation and edema in the testis tissue increased. Conclusion: Our study is the first to show the effects of blue light exposure on male rats' puberty process. And we showed that exposure to blue light and the duration of exposure lead to precocious puberty in male rats. The blue light exposure suppressed spermatogenesis, marked vasodilatation in the interstitial area of the testis, and disrupted the integrity of the basement membrane. These findings intensified with increasing exposure time. [ABSTRACT FROM AUTHOR]

Introduction: Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats. Design: Female rats were exposed to KTZ or DES during perinatal (DES 3-6-12mg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48mg/kg.d; KTZ 3-12-48mg/kg.d). Results: Ex vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with IngenuityPathwayAnalysis predicted "CrebsignalinginNeurons" and "IGF-1 signaling" among the most downregulated pathways by all doses of KTZ and DES before puberty, and "PPARg" as a common upstream regulator driving gene expression changes. Deeper screening of RNAseq datasets indicated that a highnumber of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood. Conclusion: nRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation. [ABSTRACT FROM AUTHOR]

Objective: To determine if the leptin, adiponectin, and leptin/adiponectin ratio (LAR) can predict weight gain at the end of GnRH analogs (GnRHa) treatment in girls with central precocious puberty (CPP). Material and methods: Study design: prospective cohort. Serum levels of leptin and adiponectin were determined at diagnosis of CPP. Anthropometry was performed at diagnosis of CPP and every six-months, until treatment with GnRHa was discontinued and they presented menarche. Patients were divided according to BMI<94 and BMI>95 percentile at diagnosis of CPP. The outcome was the increased in weight gain (e.g., from normal weight to overweight) at the end of follow-up. Statistical analysis: repeated measures ANOVA test and Student's t-test were used to compare groups. Logistic regression analysis was used to evaluate the association of leptin and adiponectin levels, as well as LAR values with increased weight gain. Results: Fifty-six CPP patients were studied, 18 had BMI >95 percentile and 38 BMI <94 percentile. Of the 18 patients who initially had BMI >95th, two patients went from obesity to overweight, while among the 38 patients who started with BMI <94th, 21 (55.2%) increased their weight gain at the end of follow-up. This last group had higher leptin levels (8.99 ± 0.6 vs 6.14 ± 0.8, p=0.005) and higher LAR values compared to those who remained in the same weight (1.3 ± 0.5 vs 0.96 ± 0.56, p=0.01). In the logistic regression analysis, it was found that higher leptin levels and higher LAR values were associated with increased weight gain (RR 1.31, 95%CI 1.03-1.66, RR 4.86, 95%CI 1.10-21.51, respectively), regardless of birth weight, pubertal stage, age, and bone/chronological age ratio. Conclusions: In patients with CPP, leptin levels and higher LAR values appear to be associated with significantly greater weight gain during GhRHa treatment, particularly in girls starting with BMI < 94 percentile. [ABSTRACT FROM AUTHOR]

Background: Triptorelin, a long-acting gonadotropin-releasing hormone (GnRH) agonist, is available in 1-, 3-, and 6-month formulations to treat central precocious puberty (CPP). The triptorelin pamoate 22.5-mg 6-month formulation recently approved for CPP offers greater convenience to children by reducing the injection frequency. However, worldwide research on using the 6-month formulation to treat CPP is scarce. This study aimed to determine the impact of the 6-month formulation on predicted adult height (PAH), changes in gonadotropin levels, and related variables. Methods: We included 42 patients (33 girls and nine boys) with idiopathic CPP treated with a 6-month triptorelin (6-mo TP) formulation for over 12 months. Auxological parameters, including chronological age, bone age, height (cm and standard deviation score [SDS]), weight (kg and SDS), target height (TH), and Tanner stage, were evaluated at baseline, and after 6, 12, and 18 months of treatment. Hormonal parameters, including serum luteinizing hormone (LH), folliclestimulating hormone (FSH), and estradiol for girls or testosterone for boys, were analyzed concurrently. Results: The mean age at treatment initiation was 8.6 ± 0.83 (8.3 ± 0.62 for girls, 9.6 ± 0.68 for boys). The peak LH level following intravenous GnRH stimulation at diagnosis was 15.47 ± 9.94 IU/L. No progression of the modified Tanner stage was observed during treatment. Compared to baseline, LH, FSH, estradiol, and testosterone were significantly reduced. In particular, the basal LH levels were well suppressed to less than l.0 IU/L, and the LH/FSH ratio was less than 0.66. The bone age/chronological age ratio remained stable with a decreasing trend (1.15 at the start of treatment, 1.13 at 12 months, 1.11 at 18 months). PAH SDS increased during treatment (0.77 ± 0.79 at baseline, 0.87 ± 0.84 at the start of treatment, 1.01 ± 0.93 at six months, and 0.91 ± 0.79 at 12 months). No adverse effects were observed during treatment. Conclusion: The 6-mo TP suppressed the pituitary-gonadal axis stably and improved the PAH during treatment. Considering its convenience and effectiveness, a significant shift to long-acting formulations can be expected. [ABSTRACT FROM AUTHOR]

During the year 2020, the COVID-19 pandemic rapidly became a severe health emergency worldwide. In order to contrast the spread of the novel SARS-CoV2, many countries implemented extraordinary restrictive measures, such as a strict lockdown and school closures. The pandemic had a great impact on children and adolescents’ daily life, leading to a much more sedentary lifestyle, to larger use of electronic devices and to an increase in stress-related symptoms. These conspicuous changes acted as disruptors of children’s normal development. Since the beginning of the pandemic, many studies reported an increase in the number of precocious puberty cases as well as a faster progression rate of puberty itself, if compared to the pre-pandemic years. In this review, our aim was to evaluate the incidence of new cases of early and precocious puberty during the COVID-19 pandemic, analyzing variations in the timing of puberty and in pubertal progression rate, and to investigate the role of environmental and lifestyle factors during the pandemic in modulating the physiopathology of pubertal development. While a direct effect of SARSCoV-2 infection remains, at the moment, a remote hypothesis, both physical and psychological factors related to the pandemic seem to have a role in triggering GnRH pulsatile secretion leading to earlier pubertal onset. It is indeed important to stress the need to clarify the exact role of COVID-19 in early pubertal onset comparing data from all over the world; long-term comprehensive studies are also pivotal to explain whether this phenomenon will continue while we resume pre-pandemic habits. [ABSTRACT FROM AUTHOR]

Objective: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder in reproductive-age women, characterized by the accretion of small cystic follicles in the ovary associated with chronic anovulation and overproduction of androgens. Ovarian function in all mammals is controlled by gonadotropin-releasing hormone (GnRH) neurons, which are the central regulator of the hypothalamic-pituitary-gonadal (HPG) axis. However, the impact on the neurotransmitter system regulating GnRH neuronal function in the letrozole-induced PCOS mouse model remains unclear. Methods: In this study, we compared the response of various neurotransmitters and neurosteroids regulating GnRH neuronal activities between letrozoleinduced PCOS and normal mice via electrophysiological techniques. Results: Response to neurotransmitter systems like GABAergic, glutamatergic and kisspeptinergic were suppressed in letrozole-fed compared to normal mice. In addition, neurosteroids tetrahydrodeoxycorticosterone (THDOC) and 4,5,6,7- tetrahydroisoxazolo[5,4-c] pyridine-3-ol (THIP) mediated response on GnRH neurons were significantly smaller on letrozole-fed mice compared to normal mice. Furthermore, we also found that letrozole-fed mice showed irregularity in the estrous cycle, increased body weight, and anovulation in female mice. Conclusion: These findings suggest that PCOS is an endocrine disorder that may directly affect the neurotransmitter system regulating GnRH neuronal activity at the hypothalamic level and impact reproductive physiology. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic premature adrenarche (IPA) is considered a normal variant of puberty, presenting more commonly in female patients. There are concerns as to whether IPA alters the final height of these girls. Our main objectives were to (a) compare the adult height of girls with IPA against their target height and (b) design a mathematical model to predict adult height at diagnosis in female patients with IPA. Materials and Methods: A cohort study of girls with IPA was conducted from the time of IPA diagnosis until adult height. The following data were collected: target height, perinatal history, anthropometric and biochemical variables and bone age at diagnosis, age at Tanner stage 2 and menarcheal age, and adult height. First, we performed a univariate statistical analysis after which we carried out a multiple linear regression analysis using adult height as the dependent variable. Results: We obtained data from 79 female patients diagnosed with IPA with a mean adult height of 164.6 cm (95% CI: 163.36–165.85 cm). The mean follow-up time was 6.60 years. Average age at Tanner stage 2 was 9.71 years. Mean menarcheal age was 11.64 years. There were no significant differences between target height and adult height. Of the several predictive models designed for these patients, one of them, which included bone age, obtained an R 2 value of 71%. Conclusions: Although slightly advanced puberty was observed among the girls with IPA, their adult height was preserved. The use of predictive models of adult height on diagnosis of IPA could facilitate closer follow-up of girls at risk of reduced adult height. [ABSTRACT FROM AUTHOR]

Idiopathic central precocious puberty (ICPP) is a relatively common condition in preadolescent girls, and its pathogenesis remains to be uncovered. A variety of studies have highlighted the association of gut microbiota (GM) with endocrine diseases, such as obesity, which is commonly associated with ICPP. However, the relationship between GM and ICPP remains unexplored. Feces samples were collected from 25 girls with ICPP (ICPP group) and 23 healthy girls (Control group). We applied 16S rDNA sequencing to compare the GM between two groups. The ICPP group had higher GM diversity and was enriched for several GM species, including Ruminococcus gnavus, Ruminococcus callidus, Ruminococcus bromii, Roseburia inulinivorans, Coprococcus eutactus, Clostridium leptum , and Clostridium lactatifermentans , which are known to be associated with obesity and are related to the production of short-chain fatty acids. Additionally, 36 candidate GM biomarkers for patients with ICPP screening were identified with high accuracy (AUC = 0.95, 95% CI 0.88 to 1). We observed that the GM of the ICPP group was enriched for the microbial functions of cell motility, signal transduction, and environmental adaptation. Positive correlations were also detected between Fusobacterium and follicle-stimulating hormone, and Gemmiger and luteinizing hormone. This study documents relationships between GM and ICPP, and the implication of these findings remains to be determined. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the effect of the traditional Chinese medicine Fuyou formula on precocious puberty (PP). The Fy formula may exert an effect in female rats with PP and GT-7 cells through the GPR54/GnRH signaling pathway. To confirm the effect of the Fy formula on PP through the GPR54/GnRH signaling pathway, we first treated GT1-7 cells with the Fy formula and observed changes in the expression of related genes and proteins and in GnRH secretion. Then, we randomly divided young female Sprague-Dawley rats into the control group, model group, leuprorelin group and the Fy formula group. A PP model was established by injection of danazol on postnatal day 5, and the Fy formula was administered on PND15. The time of vaginal opening, the wet weights of the ovary and uterus, serum hormone levels and the expression of hypothalamic-related genes were observed. We found that the Fy formula delayed vaginal opening, decreased the wet weights and coefficients of the ovary and uterus, decreased the levels of serum hormones (E2, follicle-stimulating hormone and luteinizing hormone) and the cellular GnRH level, and downregulated the gene expression of Kiss1, GPR54 and GnRH in the hypothalamus and the gene and protein expression of GPR54 and GnRH in GT1-7 cells. In conclusion, the Fy formula may alleviate PP via the GPR54/GnRH signaling pathway. [ABSTRACT FROM AUTHOR]