Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children.
Waldhauser F,Boepple P A,Schemper M,Mansfield M J,Crowley W F
The Journal of clinical endocrinology and metabolism
In children a progressive decrease in nocturnal serum melatonin (MT) has been shown with advancing age, suggesting a reduction in the amplitude of the circadian MT curve with maturation. Whether this alteration of MT levels is related to human sexual maturation or occurs independently remains to be elucidated. Also, the impact of gonadal steroids on the MT rhythm remains an open question. We examined 56 patients (51 females and 5 males) with central precocious puberty (52 idiopathic and 4 neurogenic). Patients were studied before and 3, 6, and 12 months after initiation of GnRH analog treatment. Three hundred and thirty-seven endocrinologically normal subjects (190 males and 147 females) served as controls. In all subjects nocturnal serum MT (blood collection between 2300 and 0100 h) was measured with a highly specific RIA. In young patients, aged 1-5 yr, we found significantly lower MT levels than in age-matched controls. Pubertal patients, aged 5-9 yr, displayed nocturnal MT levels in the same range as control subjects approaching normal pubertal age. In contrast to endocrinologically normal children, there was no age-dependent decrease in nocturnal MT in untreated precocious puberty; rather, it appeared that serum MT had already declined in association with the onset of sexual maturation. Although there was a significant difference in weight between patients and age-matched controls, the low MT values in patients 1-5 yr old were only partly explained by the weight difference (P less than 0.0009); their pubertal status also contributed significantly (P less than 0.006). Pituitary-gonadal suppression induced by long term GnRH analog treatment did not result in a return to prepubertal MT levels; rather, nocturnal MT decreased during therapy. The collected data indicate that nocturnal serum MT levels are related to sexual maturation, since serum MT is similar in precocious puberty and normal pubertal children. Since suppression of the pituitary-gonadal axis did not result in increases in nocturnal MT levels in young patients with precocity (i.e. return to age-appropriate levels), the reduction of nocturnal MT with normal puberty is not likely to be dependent on pubertal gonadotropin or sex steroid milieu.
10.1210/jcem-73-4-793
The mystery of puberty initiation: genetics and epigenetics of idiopathic central precocious puberty (ICPP).
Journal of endocrinological investigation
Puberty is a major developmental stage. Damaging mutations, considered as "mistakes of nature", have contributed to the unraveling of the networks implicated in the normal initiation of puberty. Genes involved in the abnormal hypothalamic-pituitary-gonadal (HPG) axis development, in the normosmic idiopathic hypogonadotropic hypogonadism (nIHH), in the X-linked or autosomal forms of Kallmann syndrome and in precocious puberty have been identified (GNRH1, GNRHR, KISS1, GPR54, FGFR1, FGF8, PROK2, PROKR2, TAC3, TACR3, KAL1, PROK2, PROKR2, CHD7, LEP, LEPR, PC1, DAX1, SF-1, HESX-1, LHX3, PROP-1). Most of them were found to play critical roles in HPG axis development and regulation, the embryonic GnRH neuronal migration and secretion, the regulation and action of the hypothalamic GnRH. However, the specific neural and molecular mechanisms triggering GnRH secretion remain one of the scientific enigmas. Although GnRH neurons are probably capable of autonomously generating oscillations, many gonadal steroid-dependent and -independent mechanisms have also been proposed. It is now well proven that the secretion of GnRH is regulated by kisspeptin as well as by permissive or opposing signals mediated by neurokinin B and dynorphin. These three supra-GnRH regulators compose the kisspeptin-neurokinin B-dynorphin neuronal (KNDy) system, a key player in pubertal onset and progression. Moreover, an ongoing increasing number of inhibitory, stimulatory and permissive networks acting upstream on GnRH neurons, such as GABA, NPY, LIN28B, MKRN3 and others integrate diverse hormonal and peripheral signals and have been proposed as the "gate-keepers" of puberty, while epigenetic modifications play also an important role in puberty initiation.
10.1007/s40618-017-0627-9
Difference of Precocious Puberty Between Before and During the COVID-19 Pandemic: A Cross-Sectional Study Among Shanghai School-Aged Girls.
Frontiers in endocrinology
Objective:To compared the incidence rates and clinical features of precocious girls before and during the COVID-19 pandemic among Shanghai school-aged girls, and explored the potential mechanisms. Methods:This cross-sectional study collected medical data about precocious girls between 2016 and 2020 from Shanghai Children's Medical Center. Data of inpatient precocious girls from March to August in 2016-2019 (n=246) and 2020 (n=237) were collected. Subjects with abnormal brain and pituitary gland MRI reports, other endocrine diseases or chronic diseases were excluded. Finally, 209 precocious girls were included in the 2016-2019 group and 191 precocious girls were include in the 2020 group. Monthly incidence rates and clinical features were compared between before and during the COVID-19 pandemic. Linear regression models were used to examine the associations between biomarkers to explore the potential mechanisms. Results:Monthly incidence rates of precocious puberty in outpatient girls from March to December 2020 (0.44-1.36%) and in inpatient girls from March to August 2020 (27.04-47.83%) were higher than those in 2016-2019 (0.30-0.52% and 10.53-18.42%, respectively). Serum concentrations of GnRH were higher in the 2020 group than in the 2016-2019 group (2.81 vs 1.99 mg/L). Serum concentrations of MKRN3 (1.02 vs 1.93 ng/ml) and ghrelin (0.38 vs 0.88 ng/ml) were lower in the 2020 group than in the 2016-2019 group. Moreover, the serum concentration of ghrelin was positively associated with the serum concentration of MKRN3 [0.891 (, 0.612, 1.171); 0.001]. Conclusions:These findings suggest an increased incidence of precocious puberty during the COVID-19 pandemic among Shanghai school-aged girls, which may be associated with decreased serum concentrations of MKRN3 and ghrelin, and indicated ghrelin as a potential regulatory mechanism of puberty.
10.3389/fendo.2022.839895
New insights into precocious puberty and ADHD: a nationwide cohort study.
Pediatric research
BACKGROUND:Attention deficit-hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children; however, studies delineating the association between ADHD and central precocious puberty are limited. This study aimed to understand whether children with ADHD are at a higher risk of central precocious puberty. METHODS:This population-based retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan to investigate the association between ADHD and the incidence of central precocious puberty between 2000-2015. We identified ADHD individuals treated with methylphenidate, atomoxetine or not. The control cohort consisted of individuals without ADHD. The outcome measure was central precocious puberty diagnosis. RESULTS:Among 290,148 children (mean age: 5.83 years), central precocious puberty incidence was 4.24 and 1.95 per 10 person-years in the ADHD and control groups, respectively. Children with ADHD treated with medication had a higher risk than those without ADHD. However, medication use did not affect the incidence of central precocious puberty among children with ADHD. CONCLUSION:This study showed an association between ADHD and a higher risk of central precocious puberty. Early referral of children with ADHD to a pediatric endocrinologist for evaluation may facilitate correct diagnoses and early interventions. IMPACT:ADHD is associated with a higher risk of central precocious puberty. This study provides relevant findings, as it is the first nationwide, population-based cohort study to investigate the association between ADHD and the risk of central precocious puberty with a 15-year follow-up. Early referral of children with ADHD to a pediatric endocrinologist for the evaluation of suspected precocious puberty could facilitate correct diagnosis. Early intervention treatment with gonadotropin-releasing hormone agonist might improve final height in children with central precocious puberty.
10.1038/s41390-022-02028-5
Diagnostic Value of LH Peak Value of the GnRH Stimulation Test for Girls with Precocious Puberty and Its Correlation with Body Mass Index.
Computational and mathematical methods in medicine
Objective:To analyze the diagnostic value of luteinizing hormone (LH) peak value of the gonadotropin-releasing hormone (GnRH) stimulation test for girls with precocious puberty and its correlation with body mass index (BMI). Methods:A total of 230 girls with precocious puberty who came to our hospital for testing from June 2019 to June 2021 were selected and divided into a true group ( = 130) and sham group ( = 100) according to the results of the GnRH stimulation test. According to the BMI, the true group was further divided into a normal group (48 cases), overweight group (43 cases), and obese group (39 cases). The GnRH stimulation test was performed on all subjects, and the basal value and peak value of LH and the basal value and peak value of follicle-stimulating hormone (FSH) were recorded. The general data and serological indexes of the true group and the sham group were compared. Indicators of the GnRH stimulation test, breast stage, bone age, BMI, uterine volume, ovarian volume, and serological indicators (leptin, sex hormone-binding protein (SHBG), and adiponectin (APN)) were compared among the normal group, the overweight group, and the obese group. Results:There were no significant differences in age and breast stage between the true group and the sham group ( > 0.05). There were statistically significant differences in bone age, BMI, uterine volume, and ovarian volume between the two groups ( < 0.05). The LH base value, LH peak value, FSH base value, and FSH peak value in the true group were higher than those in the sham group, and the differences were statistically significant ( < 0.05). ROC curve analysis showed that the AUC of LH peak value in diagnosing girls with precocious puberty was 0.973, which was higher than 0.895, 0.875, and 0.912 of LH base value, FSH base value, and FSH peak value, respectively. There were statistically significant differences in LH base value, LH peak value, FSH base value, breast development stage, bone age, BMI, SHBG, leptin, and APN among the normal group, overweight group, and obese group ( < 0.05), but there were no significant differences in FSH peak value, uterine volume, and ovarian volume among the three groups ( > 0.05). There was a negative correlation between BMI, LH peak value, and FSH base value ( < 0.05), but there was no significant correlation between BMI and FSH peak value ( > 0.05). Conclusion:The LH peak value of the GnRH stimulation test has high diagnostic value for girls with precocious puberty, and BMI is negatively correlated with the LH peak value of CPP children.
10.1155/2022/4118911
Clinical risk score for central precocious puberty among girls with precocious pubertal development: a cross sectional study.
You Jingyu,Cheng Xianying,Li Xiaojing,Li Mingqing,Yao Li,Luo Feihong,Cheng Ruoqian,Xi Li,Ye Jiangfeng
BMC endocrine disorders
BACKGROUND:The gold standard for the diagnosis of central precocious puberty (CPP) is gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation test. But the stimulation test is time-consuming and costly. Our objective was to develop a risk score model readily adoptable by clinicians and patients. METHODS:A cross-sectional study based on the electronic medical record system was conducted in the Children's Hospital, Fudan University, Shanghai, China from January 2010 to August 2016. Patients with precocious puberty were randomly split into the training (n = 314) and validation (n = 313) sample. In the training sample, variables associated with CPP (P < 0.2) in univariate analyses were introduced in a multivariable logistic regression model. Prediction model was selected using a forward stepwise analysis. A risk score model was built with the scaled coefficients of the model and tested in the validation sample. RESULTS:CPP was diagnosed in 54.8% (172/314) and 55.0% (172/313) of patients in the training and validation sample, respectively. The CPP risk score model included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume. The C-index was 0.85 (95% CI: 0.81-0.89) and 0.86 (95% CI: 0.82-0.90) in the training and the validation sample, respectively. Two cut-off points were selected to delimitate a low- (< 10 points), median- (10-19 points), and high-risk (≥ 20 points) group. CONCLUSIONS:A risk score model for the risk of CPP had a moderate predictive performance, which offers the advantage of helping evaluate the requirement for further diagnostic tests (GnRH or GnRHa stimulation test).
10.1186/s12902-021-00740-7
Obesity is a risk factor for central precocious puberty: a case-control study.
BMC pediatrics
BACKGROUND:Obesity is an important underlying cause of central precocious puberty (CPP), but previous large studies are flawed by using just age and breast examination to diagnose CPP. We aimed to determine whether overweight and obesity in childhood increases hormonally diagnosed CPP. METHODS:Our retrospective, case-control study recruited 846 children diagnosed as having CPP and randomly sampled 1650 healthy control subjects in Xingtai Third Hospital in China between November 2018 and March 2021. Information was obtained from an electronic medical record and questionnaire investigated in the outpatient visit. Observations were made before the a priori hypothesis. Unconditional logistic regression for analysis was used to determine whether overweight and obesity status and duration of overweight/obesity were associated with CPP. RESULTS:Overweight and obesity were significantly associated with increased odds of CPP among girls, even after adjusting for birth weight, exclusive breastfeeding for 6 month, household income, maternal overweight, paternal overweight, and maternal menarche age (overweight: the adjusted odds ratio (aOR) (95%CI): 1.92 (1.16, 3.24), p = 0.02; obesity: aOR (95%CI): 1.78 (1.13, 3.48), p = 0.03). Furthermore, the effects of overweight and obesity were significant when ongoing for 1 to 2 years, 2 to 3 years, and greater than 3 years, but not at less than 1 year. For boys, association between obesity and increased odds of CPP was observed (aOR (95%CI): 1.68 (1.09, 3.75), p = 0.03). The effects of overweight and/or obesity were only significant when ongoing for greater than 2 years. CONCLUSIONS:Prolonged overweight and obesity in early childhood may be risk factors for CPP, especially in girls. Weight loss might be an important approach for the prevention of precocious puberty in children.
10.1186/s12887-021-02936-1
Green tea catechin EGCG could prevent obesity-related precocious puberty through NKB/NK3R signaling pathway.
The Journal of nutritional biochemistry
This study aimed to explore the potential regulatory pathways of (-)-epigallocatechin-3-gallate (EGCG) in preventing obesity-related precocious puberty. A retrospective analysis on the impact of EGCG on puberty onset in obese girls was conducted on plasma samples collected from a human randomized controlled trial. In the trial, participants consumed EGCG capsules for 12 weeks. In the animal experiment, rats were divided into four groups: normal diet control (NC) group, high-fat diet (HFD) group, NC+EGCG group, and HFD+EGCG group. Blood samples were collected on postnatal days 27, 33, and 36 to detect sexual development indicators. The hypothalamic expressions of kisspeptin/Kiss1R and neurokinin B (NKB)/NK3R signaling were measured by RT-qPCR and Western blot assay. The ovary NKB protein expression was assessed by immunohistochemical assays. Serum NKB level in the EGCG group was lower than the placebo group by 0.599 ng/mL [β=-0.599, 95% CI: (-1.005, -0.193)], at the end of intervention and after adjusting for confounders (clinical study). In the animal experiment, EGCG intervention could significantly delay the vaginal opening (VO) time of rats fed with HFD. On day 33, EGCG intervention could significantly reduce serum NKB, luteinizing hormone (LH) levels, ovarian NKB protein expression, and endometrial thickness of HFD-fed rats, while EGCG intervention could remarkably increase mRNA and protein expression of NKB/NK3R. EGCG could prevent obesity-related precocious puberty through NKB/NK3R signaling pathway, which may provide a novel insight into the role of EGCG in preventing precocious puberty in obese girls.
10.1016/j.jnutbio.2022.109085
The interference of DEHP in precocious puberty of females mediated by the hypothalamic IGF-1/PI3K/Akt/mTOR signaling pathway.
Shao Pu,Wang Yuzhuo,Zhang Meng,Wen Xinggui,Zhang Jun,Xu Zhonghang,Hu Min,Jiang Jinlan,Liu Te
Ecotoxicology and environmental safety
DEHP is reported to cause precocious puberty of females in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of sexual precocity. Prepubertal female rats were treated with DEHP for 4 weeks. Key organs were analyzed in control conditions and after exposure to 0.2, 1, and 5 mg/kg/day DEHP in pubertal female rats. To determine the role of the IGF-1/PI3K/Akt/mTOR signaling pathway in DEHP-induced female precocious puberty, 36 rats were treated with 5 mg/kg/day DEHP to establish a model of female precocious puberty. And we investigated the expression of genes and proteins related to IGF-1 pathway in rat hypothalamus after treatment with inhibitors. In the present study, we observed that DEHP treatment resulted in earlier vaginal opening time, higher number of Nissl bodies in the hypothalamus neurons, lower apoptosis of hypothalamic cells, higher IGF-1 and GnRH levels in the serum and hypothalamus. DEHP could also upregulated the expression of IGF-1/PI3K/Akt/mTOR pathway and GnRH in the hypothalamus of adolescent female rats, and inhibition of IGF-1R and mTOR in hypothalamus could block the activation of Kiss-1, GPR54, and GnRH by DEHP. In summary, our study suggested that DEHP might activate the hypothalamic GnRH neurons prematurely through the IGF-1 signaling pathway and promote GnRH release, leading to the initiation of female sexual development. Our results provide a new molecular mechanism underlying reproductive and developmental toxicity in pubertal female rats induced by DEHP.
10.1016/j.ecoenv.2019.06.017
Dynamic Changes of RFRP3/GPR147 in the Precocious Puberty Model Female Rats.
Sun Wen,Li Suhuan,Tian Zhanzhuang,Shi Yumin,Yu Jian,Sun Yanyan,Wang Yonghong
Current molecular medicine
BACKGROUND:Pubertal development is a complex physiological process regulated by the neuroendocrine system and hypothalamic-pituitary-gonadal axis. Sexual precocity is a common childhood endocrine disease.The pathogenesis of sexual precocity has not been fully elucidated. RFRP3/GPRl47 signal pathway is able to inhibit the reproductive capability in avians and mammals, probably by acting on the GnRH neuron and pituitary to regulate gonadotrophin synthesis and release. However, little is known about the role of RFRP3 in puberty development and sexual precocity. OBJECTIVE:To observe the dynamic changes of RFamide related peptide 3/G proteincoupled receptor 147 (RFRP3/GPR147) in hypothalamic during puberty development and explore their role in precocious puberty based on a female rat model. METHODS:The Sprague-Dawley female rats were randomly divided into three groups, normal, vehicle, and precocious puberty model. At 5 days old, the rat model with precocious puberty was prepared by subcutaneously injecting a mixture of danazoldissolved ethanol and glycol. At different day-age (15, 25, 30, 35, and 40 days), the levels of estradiol(E2), follicle-stimulating hormone(FSH), and luteinizing hormone (LH) in the peripheral blood were detected by the enzyme-linked immunosorbent assay, the messenger ribonucleic acid (mRNA) expressions of RFRP3, gonadotropin releasing hormone and GPR147 were examined by real-time polymerase chain reaction(R-T PCR). RFRP3 positive cells were observed using Immunofluorescence confocal microscopy. RESULTS:At 25 and 30 days, the levels of sex hormones and the uterus coefficients were significantly higher in the precocious puberty model group than those in the normal and vehicle groups. The ovarian morphological development in the precocious puberty model rats was significantly earlier than those in the normal and vehicle groups. The mRNA expressions of RFRP3/GPR147 and GnRH in the precocious puberty model group gradually increased and peaked at 25 days. The different day-age and the interaction have significant statistical significance on the expression of RFRP3 mRNA, while the levels of RFRP3 mRNA in the model group and vehicle groups have no significant statistical significance. There was statistical significance between the model group and vehicle groups in different day-age on the expression of GPR147 mRNA.The expression of hypothalamic RFRP3/GPR147 mRNA and RFRP3 positive cells gradually decreased with puberty onset. At 35 days, the levels of RFRP3 mRNA and GPR147 mRNA were significantly lower in the precocious puberty model group than those in the vehicle groups. Meanwhile, the levels of LH in the precocious puberty model rats reached its peak at this age. In the vehicle group, the levels of RFRP3 mRNA and serum LH were gradually increased and LH nearly peaked at 35 day-age. Subsequently, it gradually decreased and reached the lowest level at 35 day-age. The expression of RFRP3 mRNA and LH were positively correlated. CONCLUSION:The findings suggested that RFRP3/GPR147 signaling pathway may be involved in the pathogenesis of sexual precocity by regulating puberty development and sexual maturity in rats.
10.2174/1566524019666190906142445