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Rationale: Childhood precocious puberty (CPP) is a common pediatric endocrine disorder with significant associated risks. Zhibai Dihuang pill (ZBDHP), a classic recipe of the Qing dynasty with its efficacy of nourishing yin and clearing heat, can downregulate the expression of ESR1 in the uterus and ovaries, thereby inhibiting CPP. However, as of now, the main active ingredients and pharmacological mechanisms of ZBDHP remain unclear., Methods: A comprehensive approach was proposed using ultra-high-performance liquid chromatography coupled with quadrupole-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS) and network pharmacology to explore the potentially active constituents of ZBDHP and reveal the underlying mechanisms against CPP. Molecular docking was used to verify the possible mechanisms., Results: A total of 214 constituents derived were identified via UHPLC-Q-Exactive Orbitrap-MS, and 12 of them were definitely characterized using reference standards. Subsequently, compounds tetrahydropalmatine, alisol C, 25-anhydroalisol A 11-acetate, hispidone, cavidine, alisol E, melianone, neogitogenin, denudatin B, and 16β-hydroperoxyalisol B with related targets PIK3CA, HSD11B1, CYP19A1, AR, PTGS2, CDK2, NR3C1, MMP2, MMP1, and MAPK1 were regarded as key components and targets for ZBDHP treating CPP using the compound-target-pathway network. Besides, the results revealed that the pathways conduced obviously to therapeutic efficacy, including pathways in cancer, neuroactive ligand-receptor interaction, and cyclic adenosine monophosphate（cAMP） signaling pathways. Molecular docking indicated that PIK3CA, HSD11B1, and CYP19A1 exhibited high affinities to corresponding compounds. Overall, the study determined the multicomponent, multitarget, and multipathway mechanisms of ZBDHP against CPP., Conclusions: This study provided a new method for exploring the chemical constituents and pharmacology mechanism of traditional Chinese medicine., (© 2024 John Wiley & Sons Ltd.)

Purpose: The study aimed to investigate the correlation between the change of sex hormone levels and ocular surface parameters in girls with idiopathic central precocious puberty(ICPP)., Methods: Eighteen girls with ICPP and 18 age-matched normal girls participated in this study, all of the participants had undergone physical measurements, laboratory tests, imaging examination and ocular surface assessments., Results: The Objective Scatter Index (OSI) in the ICPP group was significantly higher than in the control group ( P = 0.031), girls with ICPP showed slightly lower MNITBUT compared to the normal control group, although this difference was not statistically significant. Bivariate analysis revealed a positive association between estradiol and OSI (r=0.383, P =0.021), Additionally, in the study population, both Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were negatively correlated with Mean noninvasive tear breakup time (MNITBUT) (r=-0.359, P =0.031)(r=-0.357, P =0.032)., Conclusion: In comparison with the normal control group, alterations in the OSI were observed in girls with ICPP. This alteration may be associated with an elevation in estrogen levels. Although there was a slight non-significant decrease in NITBUT in ICPP girls, the negative correlation between LH and FSH with MNITBUT suggests new perspective for further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Yang and Liang.)

In recent years, central precocious puberty (CPP) in children is becoming more common, which seriously affects their physical and psychological health and requires finding a safe and effective treatment method. The aim of this study was to investigate the therapeutic effect of melatonin on CPP. A CPP model was established by subcutaneous injection of 300 micrograms of danazol into 5-day-old female mice, followed by treatment with melatonin and leuprolide. The vaginal opening was checked daily. Mice were weighed, gonads were weighed, gonadal index was calculated, and gonadal development was observed by hematoxylin and eosin (HE) staining. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E 2 ) levels were measured by ELISA. By using RT-PCR and Western blotting, the mRNA and protein expression of the hypothalamus Kiss-1, Kiss-1 receptor (Kiss1R), gonadotropin-releasing hormone (GnRH), and pituitary GnRH receptor (GnRHR) were identified. The results showed that melatonin delayed vaginal opening time and reduced body weight, gonadal weight and indices in female CPP mice. Melatonin treatment prevents uterine wall thickening and ovarian luteinization in female CPP mice. Melatonin treatment reduces serum concentrations of FSH, LH, and E 2 in female CPP mice. Melatonin suppressed the expressions of Kiss-1, Kiss1R and GnRH in the hypothalamus, and the expression of GnRHR in the pituitary of the female CPP mice. Our results suggest that melatonin can inhibit the hypothalamic-pituitary-gonadal (HPG) axis by down-regulating the Kiss-1/Kiss1R system, thereby treating CPP in female mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: This study aimed to determine the effect of body mass index (BMI) on bone turnover markers in girls with idiopathic central precocious puberty (ICPP) according to weight status at diagnosis., Methods: Two hundred and eleven girls with ICPP were divided according to their weight status at diagnosis into three groups: normal weight, overweight, and obese. The serum levels of total procollagen type 1 N-terminal propeptide (P1NP), N-terminal midfragment of osteocalcin, β -C-terminal telopeptide of type 1 collagen, and some biochemical indicators were measured. Associations between variables were evaluated by multiple regression analysis., Results: Serum P1NP concentrations were significantly different among groups ( p < 0.001). No other significant differences were noted in N-terminal midfragment of osteocalcin and β -C-terminal telopeptide of type 1 collagen. BMI was associated with estradiol ( r  = 0.155, p < 0.05) and inversely associated with P1NP ( r  = -0.251, p < 0.01), luteinizing hormone peak ( r  = -0.334, p < 0.01), follicle-stimulating hormone peak ( r  = -0.215, p < 0.01), and luteinizing hormone/follicle-stimulating hormone peak ( r  = -0.284, p < 0.01). Multiple regression analysis of factors associated with BMI showed that it was correlated with P1NP, follicle-stimulating hormone base, and luteinizing hormone peak in the overweight group and the obese group., Conclusions: Our findings showed that BMI was associated with P1NP, revealing the reduction of bone formation in overweight and obese girls with ICPP. During the diagnosis and treatment of girls with ICPP, attention should be paid to body weight and bone metabolism., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Jing Zhang et al.)

Makorin ring finger protein 3 (MKRN3) was identified as an inhibitor of puberty initiation with the report of loss-of-function mutations in association with central precocious puberty. Consistent with this inhibitory role, a prepubertal decrease in Mkrn3 expression was observed in the mouse hypothalamus. Here, we investigated the mechanisms of action of MKRN3 in the central regulation of puberty onset. We showed that MKRN3 deletion in hypothalamic neurons derived from human induced pluripotent stem cells was associated with significant changes in expression of genes controlling hypothalamic development and plasticity. Mkrn3 deletion in a mouse model led to early puberty onset in female mice. We found that Mkrn3 deletion increased the number of dendritic spines in the arcuate nucleus but did not alter the morphology of GnRH neurons during postnatal development. In addition, we identified neurokinin B (NKB) as an Mkrn3 target. Using proteomics, we identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as another target of MKRN3. Interactome analysis revealed that IGF2BP1 interacted with MKRN3, along with several members of the polyadenylate-binding protein family. Our data show that one of the mechanisms by which MKRN3 inhibits pubertal initiation is through regulation of prepubertal hypothalamic development and plasticity, as well as through effects on NKB and IGF2BP1.

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 ( n = 130) and sham group ( n = 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 ( P > 0.05). There were statistically significant differences in bone age, BMI, uterine volume, and ovarian volume between the two groups ( P < 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 ( P < 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 ( P < 0.05), but there were no significant differences in FSH peak value, uterine volume, and ovarian volume among the three groups ( P > 0.05). There was a negative correlation between BMI, LH peak value, and FSH base value ( P < 0.05), but there was no significant correlation between BMI and FSH peak value ( P > 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., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Chunqing Zhao et al.)

The GABA A receptor (GABA A R) plays important roles in the regulation of Mn-induced GnRH secretion in immature female rats. However, the underlying molecular mechanisms remain unknown. Here, we assessed whether FTO and its substrate m 6 A are correlated with GABA A R expression in GnRH neurons after treatment with Mn in vitro and in vivo. Our study indicated that Mn treatment increased the expression of GnRH mRNA and decreased the levels of GABA A R protein but had no effect on GABA A R mRNA. Moreover, Mn upregulated the levels of FTO and inhibited global cellular m 6 A levels and GABA A α2 mRNA m 6 A levels. Knockdown of FTO increased the expression of GABA A R protein and GABA A α2 mRNA m 6 A levels. Data from rat models further demonstrate that inhibition of FTO suppressed GABA A R protein expression in the hypothalamus, causing delayed puberty onset. Collectively, our findings suggest that FTO-dependent m 6 A demethylation plays a critical role in regulating GABA A R mRNA processing in GnRH neurons., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The average age for pubertal onset in girls has declined over recent decades. Epidemiological studies in humans and experimental studies in animals suggest a causal role for endocrine disrupting chemicals (EDCs) that are present in our environment. Of concern, current testing and screening regimens are inadequate in identifying EDCs that may affect pubertal maturation, not least because they do not consider early-life exposure. Also, the causal relationship between EDC exposure and pubertal timing is still a matter of debate. To address this issue, we have used current knowledge to elaborate a network of putative adverse outcome pathways (pAOPs) to identify how chemicals can affect pubertal onset. By using the AOP framework, we highlight current gaps in mechanistic understanding that need to be addressed and simultaneously point towards events causative of pubertal disturbance that could be exploited for alternative test methods. We propose 6 pAOPs that could explain the disruption of pubertal timing by interfering with the central hypothalamic trigger of puberty, GnRH neurons, and by so doing highlight specific modes of action that could be targeted for alternative test method development., (© 2021 S. Karger AG, Basel.)

Though central precocious puberty (CPP) as a disease that seriously affects the development of a child is increasing year by year, treatment options remain limited and is the same as the 1980s' method. These are mainly due to the complex pathogenesis of central precocious puberty. Therefore, systems biology approach to identify and explore the multiple factors related to the pathogenesis of central precocious puberty is necessary. Our data established the first proteome profile of CPP revealed 163 down-regulated and 129 were up-regulated differentially expressed proteins. These altered proteins were primarily enriched in three metabolic process including energy metabolism, amino acid metabolism and nitrogenous base metabolism. The identified altered members of the metabolic signaling are valuable and potential novel therapeutic targets of central precocious puberty.

Recent studies have shown a rise in precocious puberty, especially in girls. At the same time, childhood obesity due to overnutrition and energy imbalance is rising too. Nutrition and fertility are currently facing major challenges in our societies, and are interconnected. Studies have shown that high-fat and/or high-glycaemic-index diet can cause hypothalamic inflammation and microglial activation. Molecular and animal studies reveal that microglial activation seems to produce and activate prostaglandins, neurotrophic factors activating GnRH (gonadotropin-releasing hormone expressing neurons), thus initiating precocious puberty. GnRH neurons' mechanisms of excitability are not well understood. In this review, we study the phenomenon of the rise of precocious puberty, we examine the physiology of GnRH neurons, and we review the recent literature regarding the pathophysiological mechanisms that connect diet-induced hypothalamic inflammation and diet-induced phoenixin regulation with precocious puberty.

Background: Toy slime is popular in Korea, and in parallel, pre-pubertal girls visit hospitals for early pubertal signs. Thus far, numerous studies have investigated the association of endocrine-disrupting chemicals (EDCs) with precocious puberty (PP). However, there is a lack of studies on the clinical manifestations and sex hormones. We aimed to investigate early pubertal development in Korean girls with or without a history of toy slime exposure and determine changes in bone age, Tanner stage, and sex hormones., Methods: In this study, 140 girls underwent stimulation tests at Kyungpook National University Children's Hospital Endocrinology Department, during January 2018 and December 2020. Patients were divided into two groups for gonadotropin-releasing hormone (GnRH) stimulation test and frequency of exposure to toy slime (EDCs). GnRH stimulation test was conducted after an intravenous injection of 100 µg of luteinizing hormone-releasing hormone. Slime exposure was defined as Slime ≥ 3 times/week for ≥ 3 months., Results: History of slime exposure was found in 14 of 58 and 65 of 82 patients in the central PP (CPP) and non-CPP groups, respectively. Slime-exposed patients had advanced bone age, although their Tanner stage was low. Patients with a history of toy slime exposure were 5.5 times more likely to be diagnosed with non-CPP than patients without slime exposure (p < 0.05)., Conclusions: Exposure to toy slime in prepubertal girls may be associated with rapid clinical advancement of pubertal development and bone age, and the patients appear more likely to be diagnosed with non-CPP., (© 2021. The Author(s).)

Objective: The present study aimed to assess the diagnostic utility of the Luteinizing hormone (LH) levels and single 60-minute post gonadotropin-releasing hormone (GnRH) agonist stimulation test for idiopathic central precocious puberty (CPP) in girls., Methods: Data from 1,492 girls diagnosed with precocious puberty who underwent GnRH agonist stimulation testing between January 1, 2016, and October 8, 2020, were retrospectively reviewed. LH levels and LH/follicle-stimulating hormone (FSH) ratios were measured by immuno-chemiluminescence assay before and at several timepoints after GnRH analogue stimulation testing. Mann-Whitney U test, Spearman's correlation, χ 2 test, and receiver operating characteristic (ROC) analyses were performed to determine the diagnostic utility of these hormone levels., Results: The 1,492 subjects were split into two groups: an idiopathic CPP group ( n = 518) and a non-CPP group ( n = 974). Basal LH levels and LH/FSH ratios were significantly different between the two groups at 30, 60, 90, and 120 minutes after GnRH analogue stimulation testing. Spearman's correlation analysis showed the strongest correlation between peak LH and LH levels at 60 minutes after GnRH agonist stimulation ( r = 0.986, P  < 0.001). ROC curve analysis revealed that the 60-minute LH/FSH ratio yielded the highest consistency, with an area under the ROC curve (AUC) of 0.988 (95% confidence interval [CI], 0.982-0.993) and a cut-off point of 0.603 mIU/L (sensitivity 97.3%, specificity 93.0%). The cut-off points of basal LH and LH/FSH were 0.255 mIU/L (sensitivity 68.9%, specificity 86.0%) and 0.07 (sensitivity 73.2%, specificity 89.5%), respectively, with AUCs of 0.823 (95% CI, 0.799-0.847) and 0.843 (95% CI, 0.819-0.867), respectively., Conclusions: A basal LH value greater than 0.535 mIU/L can be used to diagnose CPP without a GnRH agonist stimulation test. A single 60-minute post-stimulus gonadotropin result of LH and LH/FSH can be used instead of a GnRH agonist stimulation test, or samples can be taken only at 0, 30, and 60 minutes after a GnRH agonist stimulation test. This reduces the number of blood draws required compared with the traditional stimulation test, while still achieving a high level of diagnostic accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cao, Liu, Fu, Zhou, Li and Liu.)

The family of Poly(A)-binding proteins (PABPs) regulates the stability and translation of messenger RNAs (mRNAs). Here we reported that the three members of PABPs, including PABPC1, PABPC3 and PABPC4, were identified as novel substrates for MKRN3, whose deletion or loss-of-function mutations were genetically associated with human central precocious puberty (CPP). MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA, which led to shortened poly(A) tail-length of GNRH1 mRNA and compromised the formation of translation initiation complex (TIC). Recently, we have shown that MKRN3 epigenetically regulates the transcription of GNRH1 through conjugating poly-Ub chains onto methyl-DNA bind protein 3 (MBD3). Therefore, MKRN3-mediated ubiquitin signalling could control both transcriptional and post-transcriptional switches of mammalian puberty initiation. While identifying MKRN3 as a novel tissue-specific translational regulator, our work also provided new mechanistic insights into the etiology of MKRN3 dysfunction-associated human CPP., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: To determine appetite-regulating hormone levels in girls with central precocious puberty (CPP) before and after 20 weeks of gonadotropin-releasing hormone analogue (GnRH-A) treatment., Methods: Eighteen newly diagnosed CPP girls were enrolled. Body composition measured by bioelectrical impedance analysis and GnRH-A test were performed with fasting serum leptin, ghrelin and peptide YY (PYY) measurements at baseline (before) and after 20 weeks of GnRH-A treatment., Results: Following GnRH-A treatment, all patients had prepubertal gonadotropin and estradiol levels. Mean (SD) fat mass index (FMI) was significantly increased from 4.5 (1.7) to 5.0 (1.8) kg/m 2 after treatment. Also, median (IQR) serum leptin level was significantly increased from 6.9 (4.2-8.6) to 7.4 (5.3-13.1) ng/mL. FMI had a positive correlation with serum leptin level (r=0.64, p=0.004). In contrast, no significant changes of serum ghrelin and PYY levels were observed., Conclusions: Decreased estrogen following short-term GnRH-A treatment in CPP girls may cause an increase in appetite and consequently an elevation of FMI. Increased serum leptin may be a result of having increased FMI secondary to an increase in appetite., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: The impact of gonadotropin-releasing-hormone-analogue (GnRHa) treatment on weight and body composition is controversial. Exploring the nutritional, psychological patterns of this population may aid to clarify this propensity to gain weight. This prospective observational study aimed to evaluate longitudinal changes in adiposity, nutrition and quality of life in girls with central precocious/early-fast puberty (CPP/EFP) during GnRHa treatment., Methods: Thirty-two GnRHa-treated girls with CPP/EFP and 27 prepubertal girls (7-10 years) were included in the analysis. Outcome measures assessed at baseline for CPP/EFP and the control groups and during up to two years of GnRHa treatment for the CPP/EFP group, included anthropometrics, body-composition, basal-metabolic-rate (BMR), 3-day food-diaries, child eating-behavior questionnaire, and pediatric quality-of-life questionnaire (PedsQL)., Results: Girls with CPP/EFP had higher pretreatment BMI-SDS, fat percentages, waist circumference and waist-per-height ( p<0.01 for all), and lower psychosocial functioning than controls (p<0.05). Changes in anthropometric and body composition measurements indicated a gradual increase in adiposity and a decrease in muscle mass (p<0.001 for all). Dynamics in body composition could not be explained by the participants' self-reported dietary patterns and physical activity levels or by the measured BMR, which revealed an adequate and relatively low energy intake as compared to energy requirements. A gradual decline in physical functioning (PedsQL) after one and two years of GnRHa treatment was observed (p<0.001)., Conclusions: Our findings highlight the need for comprehensive surveillance in girls with CPP/EFP. Dynamics in weight status and body composition during GnRHa treatment indicate the need for tailored nutritional and physical activity counseling aimed at preventing obesity., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Abstract: This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient's motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.

Kisspeptin is a 54- amino acid peptide that acts as a ligand of a receptor called GPR54 which is basically a transmembrane receptor that spins seven times across the cell membrane and coupled with G-protein. Kisspeptin regulates the development of reproductive functions and the onset of puberty in human and other mammals by acting at the brain, hypothalamus, pituitary and gonad levels of reproductive axis. Kisspeptin is also involved in regulation of trophoblastic invasion during pregnancy, ovulation, and sperm hyperactivation. Inactivating mutations in human kisspeptin gene (KISS1) cause idiopathic hypogonadotropic hypogonadism. Some mutations in human kisspeptin receptor gene (KISS1R) make the receptor inactive which result in idiopathic hypogonadotropic hypogonadism. Some mutations in human KISS1R gene make the receptor prematurely activated and result in the development of central precocious puberty. Central precocious puberty is also caused by some mutations in human KISS1 gene that make the kisspeptin resistant to degradation. This leads to an increased basal kisspeptin level and subsequently the development of central precocious puberty. Higher kisspeptin level has been detected in the serum and plasma of central precocious puberty patients, which suggest that serum or plasma kisspeptin level can be used as a marker for diagnosis of central precocious puberty.

Childhood obesity, especially in girls, is frequently bound to earlier puberty, which is linked to higher disease burden later in life. The mechanisms underlying this association remain elusive. Here we show that brain ceramides participate in the control of female puberty and contribute to its alteration in early-onset obesity in rats. Postnatal overweight caused earlier puberty and increased hypothalamic ceramide content, while pharmacological activation of ceramide synthesis mimicked the pubertal advancement caused by obesity, specifically in females. Conversely, central blockade of de novo ceramide synthesis delayed puberty and prevented the effects of the puberty-activating signal, kisspeptin. This phenomenon seemingly involves a circuit encompassing the paraventricular nucleus (PVN) and ovarian sympathetic innervation. Early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. In turn, obesity-induced pubertal precocity was reversed by virogenetic suppression of SPTLC1 in the PVN. Our data unveil a pathway, linking kisspeptin, PVN ceramides, and sympathetic ovarian innervation, as key for obesity-induced pubertal precocity., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Idiopathic central precocious puberty (iCPP) presents a disproportionate advancement of bone age and maturation, as well as metabolic and endocrinological changes that may be related to effects on telomere biology., Objective: To investigate the telomere length in iCPP girls treated with GnRHa., Study Design: Observational case-control study with 85 girls, including 45 iCPP treated with GnRHa and 40 controls. It was analyzed age, height, weight and body mass index (BMI), insulin, triglycerides, testosterone, insulin resistance by HOMA, and telomere length by real-time PCR. Statistical analyses were determined by Wilcoxon test and Spearman correlation was carried out., Results: Weight, BMI, insulin level and HOMA index were higher in the iCPP than in the control group ( p  < .01); without difference between mean ages. The telomere length did not differ between iCPP and control group. However, a negative correlation was observed between the telomere length and age in iCPP ( p  = .0009) and control group ( p  = .014), and weight in the iCPP ( p  = .017)., Conclusions: We did not observe any difference in the telomere length in the iCPP and control group. Even though, some characteristics of the disease, such as increased weight and body fat, negatively influence the telomere biology.

Context: Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche is unknown and the role of novel biosynthetic pathways remains unclear., Objective: To compare the urinary steroid metabolome and enzyme activities of girls with PA to age-matched control girls and to published steroid values of girls with normal adrenarche and of women with PCOS and their newborn daughters., Design: Prospective observational study from 2009 to 2014., Setting: Academic pediatric endocrinology referral center., Participants: Twenty-three girls with PA and 22 healthy, age-matched girls., Main Outcome Measures: Steroid metabolites in 24-hour urine samples, including 4 progesterones, 5 corticosterones, aldosterone, 13 androgens, 2 estrogens, 14 glucocorticoids, and enzyme activities represented by metabolite ratios., Results: Girls with PA had a higher body mass index (mean standard deviation scores 0.9 vs -0.3, P = 0.013). Androgen excretion was higher in PA girls than in control girls (median 3257 nmol/24 hours vs 1627 nmol/24 hours, P < 0.001), in particular metabolites from alternate androgen pathways. The amount of progesterone, corticosterone, aldosterone, estrogen, and cortisol metabolites were similar between groups. Activities of 17β-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3β-hydroxysteroid-dehydrogenase, 21-hydroxylase, and 5α-reductase activity were not different between groups, in contrast to published results on girls with normal adrenarche or PCOS females., Conclusions: Metabolites and enzymes involved in alternate androgen pathways appear to be markers of PA. Prospective studies should assess whether steroid production in PA also differs from adrenarche at normal timing and persists into adulthood., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood., Objective: Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations., Patients: A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed., Results: Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401&#95;404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels., Conclusion: Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropin-releasing hormone (GnRH) secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, decreases as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and that MKRN3 repressed promoter activity of human KISS1 and TAC3, 2 key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve an MKRN3-directed ubiquitination-mediated mechanism.

Background In 2011, we described 64 girls diagnosed with central precocious puberty (CPP) during 1995-2009. In 2019, the former CPP patients were 16-30 years of age and had been followed-up for 6-20 years after cessation of gonadotropin-releasing hormone analog (GnRHa) treatment. Objectives To determine the menstrual cycle, reproductive function, and long-term sequelae of the former GnRHa-treated and untreated CPP patients. Methods Sixty-seven former CPP women diagnosed during January 1995 to December 2010 were evaluated in 2019 for current menstrual cycle and pregnancy rate and for general health status, weight, height, blood pressure, and metabolic profiles of glucose, lipids, insulin, and testosterone. Results In 2019, the former CPP women averaged 20.7 ± 2.7 years of age (range: 16.5-30). Eighty-three percent had a regular menstrual cycle. Of the 14 married women, six (43%) were fertile with 1-2 children. The untreated women had a significantly higher rate of obesity (BMI >25 kg/m2) than the GnRHa-treated women (72.1% vs. 36.6%, p < 0.01). Two women (3%) had polycystic ovary syndrome (PCOS). Fasting plasma glucose, serum high-density lipoprotein cholesterol (HDL-C), and testosterone levels were normal and similar between the GnRHa-treated and untreated participants. The serum insulin, cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR) levels were higher in the untreated group than the GnRHa-treated group, but without significant differences. Conclusions At a 10-20-year follow-up, our former CPP patients had regular menstruation, normal reproductive function, and normal metabolic outcomes. The low prevalence of PCOS of 3% suggests that CPP is not a risk factor for PCOS, at least during early adulthood.

BACKGROUND This study was designed to investigate the effect of high-glucose and high-fat condition on estrogen receptor- and sexual precocity-related genes in GT1-7 cells. MATERIAL AND METHODS In this study, CCK8 was used to detect cell viability, and TUNEL assay was used to detect apoptosis levels of GT1-7 cells after treatment with glucosamine and palmitate. The expression level of GnRH was measured by ELISA and RT-qPCR. RT-qPCR and Western blot were used to detect the expression of ERß, CD36, and GPR54 in GT1-7 cells, and the expression of ERß was detected using immunohistochemistry analysis. Finally, after adding the intervening drug tamoxifen to GT1-7 cells, the expression level of GnRH was measured by ELISA and Western blot analysis was used to detect the expression of GPR54 and GnRH. RESULTS GnRH secretion in the high-fat and high-glucose group increased continuously over time and peaked at 18 h, and GnRH gene expression peaked at 12 h. High-fat and high-glucose conditions also significantly increased the levels of estrogen receptors ß (ERß), fatty acid translocase protein (CD36), and G Protein-Coupled Receptors 54 (GPR54) in GT1-7 cells. After estrogen receptors ß (ER) was inhibited, GnRH secretion and GPR54 expression were decreased at 12 h and 18 h. CONCLUSIONS Our study demonstrates that high-glucose and high-fat conditions promote the secretion of GnRH and ER and the expression of genes related to sexual precocity in GT1-7 cells.

The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the synthesis of androgens by the adrenal gland has been considered of little physiologic importance. Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the major adrenal androgen precursors, but they are biologically inactive. The second most abundant unconjugated androgen produced by the human adrenals is 11β-hydroxyandrostenedione (11OHA4). 11-Ketotestosterone, a downstream metabolite of 11OHA4 (which is mostly produced in peripheral tissues), and its 5α-reduced product, 11-ketodihydrotestosterone, are bioactive androgens, with potencies equivalent to those of testosterone and dihydrotestosterone. These adrenal-derived androgens all share an oxygen atom on carbon 11, so we have collectively termed them 11-oxyandrogens. Over the past decade, these androgens have emerged as major components of several disorders of androgen excess, such as congenital adrenal hyperplasia, premature adrenarche and polycystic ovary syndrome, as well as in androgen-dependent tumours, such as castration-resistant prostate cancer. Moreover, in contrast to the more extensively studied, traditional androgens, circulating concentrations of 11-oxyandrogens do not demonstrate an age-dependent decline. This Review focuses on the rapidly expanding knowledge regarding the implications of 11-oxyandrogens in human physiology and disease.

Introduction: The pineal gland, an endocrine organ of the posterior cranial fossa famously involved in sleep and wakefulness, has continually been a topic of scientific advancement and curiosity. Methods: We review present an up-to-date review including the anatomy, embryology, and physiology of the pineal gland and its ability to secrete hormones including melatonin, pathophysiology of pineal gland tumors, cysts, and calcifications, their clinical presentation including their association with parkinsonism and precocious puberty, and various treatment approaches. Results: Exploring the biochemistry of melatonin, various calcification morphologies, and pineal tumors may uncover a wider role and the exhaustive case study consolidation allows clinicians to carefully review the literature and aid their treatment approaches. Conclusion: It is imperative that clinicians and diagnosticians are able to distinguish manifestations of an overlooked gland.

Purpose: With the wide implementation of the universal two-child policy in China, the number of pregnant women in advanced maternal age (AMA) will increase gradually. We aimed to assess the association between age at menarche (AAM) and insulin resistance (IR) before delivery in AMA. Methods: A total of 80 pregnant women in AMA were consecutively enrolled before delivery in Zhongda hospital. Pregnant women were stratified into early menarche group and late menarche group according to the age of regular menstruation (about 13 years). At delivery, serum glucose and lipid levels were measured. IR was calculated by the method of homeostasis model assessment 2(HOMA2). Results: The fasting blood insulin (17.68(9.72-36.71) and 10.35(7.76-15.10), respectively; p  = .006) and HOMA-IR (2.08(1.18-4.37) and 1.24(0.89-1.78), respectively; p  = .005) were higher in early menarche group than in late menarche group. AAM was inversely associated with HOMA-IR in AMA ( r = -0.27, p  = .014). In the multivariable analysis, AAM in late menarche group was negatively related to the level of HOMA-IR compared to those in early menarche group ( β = -2.275, p ≤.0001). Conclusions: Taken together, our findings suggest that AAM was inversely associated with HOMA-IR in AMA. Furthermore, pregnant women in AMA with early menarche might have higher HOMA-IR levels than those with late menarche. Clinical trial registration: Chinese Clinical Trial Registry (No. ChiCTR-RRC-16008714), retrospectively registered.

The introduction of nusinersen, the first therapeutic modality for Spinal Muscular Atrophy (SMA) patients has raised hopes and led to construction of a multi-professional medical SMA service, including pediatric endocrinology. Our study aimed to provide a comprehensive description of the endocrine manifestations of SMA patients with variable degree of sarcopenia. Real-life clinical and laboratory data of 62 SMA patients (age range 3 months to 31 years, 24 type 1, 21 type 2, 17 type 3) were collected including: weight-status, self-reported information on puberty, current pubertal stage, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), basal gonadotropin and androgen levels. Precocious pubarche (mean age at onset 3.9 ± 2.8 years) was found in 24% (15/62) of the SMA cohort [45.9%(11/24) type 1 and 19%(4/21) type 2]. A higher HOMA-IR predicted precocious pubarche after adjustment for SMA type and age (OR=1.42; 95% CI, 1.05, 1.93, P = 0.025). Bilateral cryptorchidism was found in 60% of type 1 and 30% of type 2 boys; type 3 young adult males attained full puberty. Most of the young women had normal pubertal development and regular menses, regardless of degree of obesity. Our findings suggest that isolated precocious pubarche is associated with early-onset insulin resistance linked to severity of muscular atrophy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: 5-Hydroxymethylfurfural (HMF) is formed when sugars are heated in the presence of amino acids. HMF is naturally present in many foods. To investigate the toxic effects of HMF on the reproductive system of peripubertal rats., Methods: In the study, 24 immature female Wistar rat were divided into three groups: control (CT) fed with no HMF; low dose fed with 750 mg/kg/day of HMF and high dose (HD) groups fed with 1500 mg/kg/day of HMF. All groups received these diets for three weeks from postnatal day (PND) 21. The vaginal opening (VO) was monitored daily and euthanasia occurred on PND 44. Gonadotropin, estradiol (E2), progesterone and anti-Müllerian hormone (AMH) concentrations were measured. Reproductive organ weights and ovarian follicle counts were compared., Results: The HD HMF group had earlier VO. Higher mean luteinising hormone (2.9±1.2 vs 1.3±0.3 mIU/mL) and mean E2 (34.7±8.8 vs 21.2±3.9 pg/mL) and lower mean AMH (2.7±0.5 vs 4.7±0.7 ng/mL) concentrations were found in the HD compared to the CT group. The HD group also had increased number of secondary atrophic follicles., Conclusion: These results indicate that peripubertal exposure to HMF at HD result in precocious puberty and decreased AMH levels in female Wistar rats.

Context: The clinical effects of classical 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency are insufficiently defined due to a limited number of published cases., Objective: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3βHSD2 deficiency., Design: Multicenter, cross-sectional study., Setting: Nine tertiary pediatric endocrinology clinics across Turkey., Patients: Children with clinical diagnosis of 3βHSD2 deficiency., Main Outcome Measures: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3βHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS., Results: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ± 5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3βHSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed., Conclusions: Genetically-documented 3βHSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3βHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3βHSD2 deficiency., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background The use of gonadotropin-releasing hormone agonists (GnRHa) for pubertal suppression has been associated with increased body mass index (BMI) in female subjects with central precocious puberty (CPP), although results have been so far conflicting. This study examined the effects of GnRHa therapy in both genders and in subjects treated for CPP, early puberty or short stature. Methods This was a longitudinal retrospective study of subjects followed at outpatient pediatric endocrinology clinics of an academic medical center from 2005 to 2014 receiving GnRHa therapy. Results At 12 months, subjects on depot GnRHa had a statistically significant increase in BMI standard deviation score (SDS) from baseline (0.13 ± 0.35, p < 0.02). Subjects with short stature (0.17 ± 0.34, p < 0.02) but not early or precocious puberty, and subjects with normal baseline BMI (0.18 ± 0.38, p < 0.02) had significant increases in BMI SDS; no significance was noted at 24 months. Male subjects did not have a significant increase in BMI SDS, whereas female subjects did (0.11 ± 0.36, p < 0.01). Conclusions Subjects with short stature, normal BMI at baseline and female sex had significant increases in BMI SDS at 12 months. This is the first study to show an increase in BMI SDS in children treated with GnRHa for short stature, and is one of the few studies to assess BMI changes in males.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is widely acknowledged that kisspeptin and its receptor Kiss1R play central regulatory roles in the hypothalamus-pituitary-gonad (HPG) axis and reproduction. Mutations of KISS1 and KISS1R lead to disorders associated with pubertal development, such as central precocious puberty (CPP) and idiopathic hypogonadotropic hypogonadism (IHH). This review focuses on KISS1 and KISS1R mutations found in CPP and IHH and its purposes are twofold: Firstly, based on the mutations found in KISS1 and KISS1R, this review provides insights into the precise mechanism of kisspeptin and the kisspeptin/Kiss1R pathway in the reproductive axis and in puberty. Secondly, G protein-coupled receptors (GPCRs) are known to share highly conserved structural motifs; therefore, knowledge of mutations found at different structural domains of Kiss1R in the diseased state, and how they affect Kiss1R function can be used to decipher GPCR domain function., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Central precocious puberty (CPP) is defined as an early pubertal development that occurs before the age of 9 years in boys and 8 years in girls. It results from premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHa) have been the gold standard therapy for CPP for more than 30 years. These compounds have a high affinity for the pituitary LHRH receptor and are resistant to enzymatic degradation. Through continuous stimulation, GnRHa inhibit the pulsatile secretion of gonadotropin, resulting in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. The goal of therapy is to halt pubertal progression and delay epiphyseal maturation that leads to improvement of final adult height. There are no widely accepted guidelines for how long to continue treatment with a GnRHa for CPP, and individual practice varies widely. Furthermore, conflicting results have been published on the long-term effects of GnRHa therapy in patients with CPP. Therefore, we reviewed the current literature focusing our attention on the long-term effects and the significant adverse drug reactions (ADRs) observed during treatment with GnRHa in patients with CPP. Our review may provide the necessary data to enable clinicians to administer GnRHa in the safest and most appropriate way. Further studies are necessary to identify the mechanisms of development of potential adverse drug reactions related to GnRHa therapy in CPP.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population., (Published by Elsevier Inc.)

Context: Central precocious puberty (CPP) may be the first presentation of nonclassical congenital adrenal hyperplasia (NCCAH) in girls. Data on the prevalence and the clinical phenotype of CPP associated with NCCAH are sparse., Objectives: To study the clinical and laboratory characteristics that could differentiate idiopathic CPP from CPP associated with NCCAH and to determine the prevalence of NCCAH among girls with CPP., Design: Case-control study., Setting: Tertiary pediatric endocrinology institute., Participants and Methods: From 2008 to 2017, 147 girls who had undergone stimulation tests with gonadotropin-releasing hormone and ACTH were diagnosed with CPP; of these, seven (4.8%) were eventually diagnosed with NCCAH. These seven patients together with 30 girls who presented with CPP during 1984 to 2008 and were later diagnosed with NCCAH comprised the NCCAH group. Demographic, anthropometric, clinical, and laboratory data were compared between the NCCAH group and the 140 girls with idiopathic CPP (ICPP group)., Results: No between-group differences were found in height, weight, body mass index, bone age, and Tanner stage. Mean basal levels of androstenedione, dehydroepiandrosterone-sulphate, and 17-hydroxyprogesterone were significantly higher in the NCCAH group, although ranges overlapped between the groups, and stimulated cortisol level was higher in the ICPP group., Conclusion: NCCAH was found in 4.8% of girls presenting with true CPP over 10 years, and no single parameter could differentiate between the diagnoses. Thus, in girls with true CPP from populations in which NCCAH is prevalent, assessment of adrenal androgens is required, and ACTH test should be considered., (Copyright © 2019 Endocrine Society.)

Context Germ cell tumours (GCTs) secreting β-human chorionic gonadotropin (β-HCG) are a rare cause of gonadotropin-independent precocious puberty (GIPP). Case description A 5.7-year-old boy presented with GIPP. Investigations to elucidate the underlying cause revealed elevated serum β-HCG. Ultrasound of the abdomen and testes, urine steroid profile, bone isotope scan, and sequencing of the luteinizing hormone receptor gene (LHCGR) were normal. Despite paired serum and cerebrospinal fluid β-HCG measurement suggesting local (brain) β-HCG production, repeated magnetic resonance imaging (MRI) of the brain as well as MRI of the mediastinum did not identify a tumour source of persistently elevated serum β-HCG. Treatment with cyproterone acetate and spironolactone was unsuccessful. Increase in testicular volumes prompted the addition of a gonadotropin releasing hormone (GnRH) analogue. Due to progressing virilisation and skeletal maturation, treatment was changed to a combination of anastrozole and bicalutamide at the age of 7 years. One year later, serum β-HCG and testosterone concentrations spontaneously normalised followed by reductions in the height velocity, skeletal maturation and virilisation. The proband achieved his genetic height potential. No medication side effects were observed. The patient subsequently presented with non-secreting pineal GCT at 14 years, 8½ years after his initial presentation with GIPP. Conclusions Our case highlights that GIPP with no definite underlying aetiology at diagnosis should be considered as a prodrome for GCTs, and regular radiological surveillance for earlier tumour identification is warranted. To the best of our knowledge, our case is the first reported case of the use of anastrozole and bicalutamide in the setting of idiopathic GIPP. The good height outcome in our case warrants the trial of anastrozole and bicalutamide in similar cases.

Background: Luteinizing hormone (LH) is a useful parameter in diagnosing precocious puberty. The pubertal response of serum LH to a GnRH stimulation test is varied, and clinical symptoms of precocious puberty are sometimes disproportionate with serum LH concentrations. Many patients present in a state of precocious puberty that advances rapidly, but the post-GnRH peak LH remains prepubertal. LH receptor mutations are suspected of involvement in the non-classic type of central precocious puberty (CPP)., Objective: To examine the association between LHCGR polymorphism and non-classic CPP in subjects exhibiting a peak LH<5 IU/L on a GnRH stimulation test., Methods: In total, 102 girls with non-classic CPP and 100 normal adult women were enrolled. All subjects underwent LHCGR gene analysis by the Sanger method, and patients and controls were compared. Auxological data and gonadotropin concentrations were analyzed in the 102 patients. Of these patients, 75 completed GnRH agonist treatment, and the treatment outcomes were analyzed., Results: A total of seven variants were identified, including two missense mutations (g.48698754 G/A and g.48688613 G/A) that were found in the patient group (no patients contained both mutations). In silico analysis of these missense mutations suggested the possibility of damaging the LHCGR. However, no significant association was found between the identified LHCGR variants and non-classic CPP. GnRH agonist treatment decreased bone age advancement and increased predicted adult height., Conclusions: LHCGR gene polymorphisms do not appear to be a major causative factor for the relatively low concentration of LH in patients with non-classic CPP. GnRH agonist treatment improved clinical parameters in these patients., Competing Interests: No conflict of interest has been declared by the authors., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background Puberty is associated with a physiological decline in insulin sensitivity (IS). Overweight (OW) and obesity (OB) are common among girls with central precocious puberty (CPP). CPP is considered a risk factor for metabolic diseases. The aim of this study was to assess surrogate measures of IS, body mass index (BMI) and other metabolic parameters in CPP girls at diagnosis and during treatment with gonadotropin-releasing hormone analogues (GnRHa). Methods We present a prospective longitudinal study of CPP girls. The standard oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), whole-body IS index (ISI) and fasting lipid profiles were evaluated at diagnosis, and at 6 and 12 months of treatment. Results Nineteen CPP girls were included; 17 were evaluable. At baseline, seven patients had normal weight (NW), five were OW and five were OB. During GnRHa treatment no significant changes were observed in BMI, HOMA-IR or ISI when considering the whole group. Whereas, when we analyzed patients according to BMI status, in NW patients, BMI increased significantly with no changes in HOMA-IR or ISI along treatment. In the OW/OB group, no significant differences were observed in BMI, HOMA-IR or ISI. Conclusions Girls with CPP showed a high frequency of OW/OB and a high prevalence of IR. GnRHa did not affect BMI, IS or the lipid profile when considering the whole cohort of patients. However, there was an increase in BMI in NW girls but not in OW/OB patients.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Follow-up studies of girls with premature adrenarche have reported the development of polycystic ovary syndrome, insulin resistance, and dyslipidemia and a propensity to cardiovascular disease. The aim of this study was to analyze the presence of these conditions in patients previously treated at the Universidade Federal do Triângulo Mineiro., Methods: A total of 130 medical records reported premature adrenarche. One hundred and twenty-two patients were invited to participate, of whom 54 accepted; 34 patients were selected, as they had reached their final height. Anthropometric, blood glucose, insulin, and lipid and hormonal profile (LH, FSH, estradiol, 17α-OH-progesterone, androstenedione, dehydroepiandrosterone sulfate, testosterone) data were obtained, the HOMA-IR index was calculated, and pelvic ultrasonography was performed. To characterize polycystic ovary syndrome and metabolic syndrome, the Rotterdam and International Diabetes Federation criteria, respectively, were used. Data were analyzed according to measures of dispersion, frequency and correlations of interest., Results: The age of the participants ranged from 15.2 to 28.2 years/months; 23.5% of the patients were overweight, 11.8% were obese, 29.4% had a large waist circumference, and 8.8% were hypertensive. None of the patients had altered glucose levels, and insulin levels and HOMA-IR were elevated in 29.4% and 38.2% of the participants, respectively; 14.7% of the patients exhibited acanthosis nigricans. The lipid profiles of the participants were variable, and one patient (2.9%) had metabolic syndrome. Polycystic ovary syndrome was found in 41.2% of patients., Conclusion: The percentage of patients with polycystic ovary syndrome who also had overweight, obesity and insulin resistance corroborates the literature data about the need for follow-up aiming at interventions, especially for conditions associated with cardiometabolic risk.

Concerns over anxiety and depressive symptoms in children with premature adrenarche (PA) have been recently raised. However, to date, most relevant studies are on a small number of girls. In this cross-sectional study, 82 pre-pubertal children (66 girls and 16 boys) diagnosed with PA, were compared to 63 control children regarding their psychological characteristics and hypothalamic-pituitary-adrenal (HPA) axis function, as assessed by salivary cortisol measurement. Symptoms of anxiety and depression were assessed by child self-report (Spence Children's Anxiety Scale (SCAS) and Depression self-rating scale for Children (DSRS)) and parent-report (Child Behaviour Checklist (CBCL)) tests validated for the Greek population. Salivary cortisol levels were determined directly after awakening (approximately 7am) and evening (8pm) of the same day. Morning serum DHEAS levels were assessed in PA children. Girls with PA scored significantly higher on anxiety (p = .016) and depression (p =.039) scales than controls. No group differences were noted for parent reports and children's salivary cortisol concentrations. Boys with PA did not demonstrate significant differences in any of the aforementioned parameters. Our findings suggest that girls with PA may be at higher risk for reporting symptoms of anxiety and depression than their non-PA peers. HPA axis dysregulation in this population was not documented.

Objective: To evaluate the effect of ZiYin Xiehuo granules (ZYXH) and Zishen Qinggan granules (ZSQG) on partial precocious puberty (PPP)., Methods: This was a multicenter, randomized, single-blind, positive-controlled trial. A total of 143 patients were assigned to either the ZYXH group or the ZSQG group using a random number table. The ZYXH group received ZYXH three times daily for 6 months and the ZSQG group received ZSQG three times daily for 6 months. Mammary nucleus diameter; the results of uterus, ovarian, and maximum follicle measures; and Chinese medicine symptom pattern scores were compared at baseline and after 3 months and 6 months of treatment., Results: After 3 months' treatment, there were no significant differences between the two groups in mammary nucleus index changes (left 3.4 ± 3.1 vs 3.5 ± 3.1, P = 0.790; right 3.0 ± 2.9 vs 3.6 ± 3.0, P = 0.719). The uterine volume in the ZYXH group was smaller than that in the ZSQG group (2.1 ± 1.6 vs 2.6 ± 2.2, P = 0.006). There were no significant between-group differences in ovarian volume and maximum follicular diameter on either side (ovarian volume: left 1.2 ± 0.7 vs 1.3 ± 0.6, P = 0.8; right 1.2 ± 0.7 vs 1.4 ± 1.1, P = 0.984; maximum follicular diameter: left 3.9 ± 1.7 vs 3.5 ± 2.2, P = 0.158; right 3.5 ± 1.7 vs 3.9 ± 2.1, P = 0.314)., Conclusion: ZYXH granules and ZSQG granules both affected the size of the mammary nucleus in girls with PPP, and improved Chinese medicine symptom patterns. ZYXH granules showed slight advantages over ZSQG granules in terms of the decrease in the size of the uterus, ovaries, and ovarian follicles.

Tay-Sachs disease is an autosomal recessive type of lysosomal storage disorder. The disease is very rare in Turkey, with an incidence of 0.54/100,000. The clinical manifestations of Tay-Sachs disease include progressive developmental delay, seizures, deafness, blindness, spasticity, and dystonia, which are caused by the accumulation of gangliosides in the central nervous system. To date, only one case indicating the association between Tay-Sachs disease and central precocious puberty has been reported. Although the mechanism of this association is not clear, it is thought to be due to ganglioside accumulation in the central nervous system or the inhibition of the hypothalamic inhibiting pathway. Herein, we report two patients with genetically proven Tay-Sachs disease who developed central precocious puberty during follow-up. Pubertal development in patients affected by Tay-Sachs disease should be carefully assessed.

The human genome encodes ~750 G-protein-coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain-of-function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain-of-function effects when co-transfected with wild-type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5-year-old girl with central precocious puberty. The mutant mRNA escaped nonsense-mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl-terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co-expressing the mutant and wild-type PROKR2 exhibited markedly exaggerated ligand-induced Ca 2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild-type proteins. Considering the structural similarity among GPCRs, this paradoxical gain-of-function mechanism may underlie various human disorders., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: We and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty., Methods: We conducted a prospective cohort study between 2007 and 2015 with 4-6 years of follow-up in an academic institution research center. We compared 8 daughters and sisters of PCOS women (PCOSr) to 8 age-matched girls unrelated to PCOS (±1.5 years). Girls were assessed initially at 8-14 years old and re-assessed after a median follow-up of 5.4 years, at 13-21 years old. Our main measures were a frequently sampled intravenous glucose tolerance test (FSivGTT)-derived insulin sensitivity (IS) and beta-cell function (disposition index, DI FSivGTT ); and indices of NEFA suppression during FSivGTT (log n -linear slope of NEFA and T 50 of NEFA suppression)., Results: At follow-up, both PCOSr and controls had similar results: IS = 3.2 vs 3.4 (p = 0.88), DI FSivGTT  = 1926 vs 1380 (p = 0.44), log n -linear slope = -0.032 vs -0.032 (p = 0.88) and T 50 NEFA = 18.1 vs 20.8 min (p = 0.57). IS, DI FSivGTT and NEFA suppressibility were stable in PCOSr after 5 years, but decreased significantly in controls (all p < 0.05)., Conclusions: Impaired metabolism observed during early puberty in girls predisposed to PCOS remains stable after 5 years whereas control girls deteriorated their metabolic parameters. Therefore, both groups become comparable in late/post-puberty. Early puberty may thus represent a window during which metabolic alterations are transiently apparent in girls at risk of PCOS.

Objective: Premature thelarche and precocious puberty are frequently diagnosed in girls even below 6 years of age and may be difficult to differentiate in the early stages. A GnRH test is often included in the diagnostic work-up, although interpretation of the GnRH test in girls below 6 years of age is challenging, as no reference interval exists for this age group. The objective is to determine the normal FSH and LH response to a GnRH test in healthy prepubertal girls below 6 years of age., Design and Methods: A standardized GnRH test, baseline reproductive hormones, clinical evaluation and bone age were determined in all participants. Forty-eight healthy normal-weight girls aged 3.5 ± 0.2 years (range: 0.8-5.9 years) were included. Serum concentrations of LH and FSH were measured before and 30 min after the gonadorelin injection., Results: The 30-min LH responses (mean ± 2 s.d.) were 5.2 ± 4.0 and 2.9 ± 2.5 IU/L and the FSH responses were 23.3 ± 16.2 and 14.5 ± 10.3 IU/L in girls aged 0.8-3.0 years and 3.0-5.9 years respectively. This corresponds to upper cut-off limits for LH of 9.2 IU/L (<3 years) and 5.3 IU/L (3-6 years). The stimulated LH/FSH ratio was 0.23 ± 0.19 (range 0.06-0.43) and did not correlate with age., Conclusions: We found that LH increases up to 9.2 IU/L during GnRH test in healthy normal-weight girls below 3 years of age and that the stimulated LH/FSH ratio did not exceed 0.43. Our findings have important implications for appropriate diagnosis of central precocious puberty in girls below 6 years of age., (© 2017 European Society of Endocrinology.)