Network pharmacology combined with lipidomics to reveal the regulatory effects and mechanisms of Kangzao granules in the hypothalamus of rats with central precocious puberty.

Central precocious puberty (CPP) is a prevalent endocrine disorder that primarily affects children, specifically females, and is associated with various physical and psychological complications. Although Kangzao granules (KZG) are efficacious in managing CPP, the underlying mechanisms remain unclear. Therefore, this study aimed to elucidate the therapeutic mechanisms of KZG using network pharmacology, molecular docking, pharmacodynamics, and pathway validation. A putative compound-target-pathway network was constructed using Cytoscape, before KEGG and Gene Ontology enrichment analyses were conducted. Moreover, molecular docking was performed using AutoDockTools. Quality control of the 10 key components of KZG was carried out using UHPLC-ESI/LTQ-Orbitrap-MS/MS, and hypothalamic lipids were analyzed using UHPLC-Q-Exactive Orbitrap MS/MS. In total, 87 bioactive compounds that targeting 110 core proteins to alleviate CPP were identified in KZG. Lipidomic analysis revealed 18 differential lipids among the CPP, KZG, and control groups, wherein fatty acids were significantly reduced in the model group; however, these changes were effectively counteracted by KZG treatment. Molecular docking analysis revealed a strong binding affinity between flavonoids and RAC-alpha serine/threonine-protein kinase (AKT) when docked into the crystal structure. Moreover, a substantial disruption in lipid metabolism was observed in the model group; however, treatment with KZG efficiently reversed these alterations. Furthermore, the phosphoinositide 3-kinase/AKT signaling pathway was identified as a pivotal regulator of hypothalamic lipid metabolism regulator. Overall, this study highlights the effectiveness of a multidisciplinary approach that combines network pharmacology, lipidomics, molecular docking, and experimental validation in the elucidation of the therapeutic mechanisms of KZG in CPP treatment.

Therapeutic effects of melatonin in female mice with central precocious puberty by regulating the hypothalamic Kiss-1/Kiss1R system.

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 (E2) 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 E2 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.

Efficacy and mechanism of nourishing yin and purging fire therapy for central precocious puberty based on meta-analysis and network pharmacology.

BACKGROUND: Central precocious puberty (CPP) is due to the early activation of the hypothalamus-pituitary-gonadal axis, and its incidence is on the rise. A number of studies have shown that nourishing yin and purging fire (NYPF) therapy can be beneficial for CPP. Therefore, we conducted this review to investigate the efficacy, safety, and mechanism of NYPF therapy for CPP. METHODS: Electronic databases including PubMed, the Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wan-fang Database, and China Scientific Technical Journals Database and 2 platforms including Clinical Trials and Chinese Clinical Trial Registry were searched for randomized controlled trials of NYPF therapy for CPP. A meta-analysis was conducted using RevMan 5.3 and Stata 17.0 software. The core herb pair of NYPF was identified by data mining using IBM SPSS Modeler 18.0 software. The active ingredients and targets of the core herb pair were obtained through the TCMSP database. The main targets of CPP were acquired form the GeneCards, Disgenet and TTD databases. A protein-protein interaction network was carried out to select the core genes by using STRING platform and Cytoscape 3.7.2 software. Metascape platform was used to conduct gene ontology (GO) and KEGG enrichment analysis. The results were verified utilizing molecular docking. RESULTS: A total of 23 studies were included. Meta-analysis shows the NYPF therapy could significantly improve the clinical efficacy rate and secondary sexual indicators (uterine volume, ovarian volume, breast nucleus diameter, follicular diameter), reduce TCM syndrome scores and serum sex hormone (FSH, LH, E2), and slow down bone age maturation compared to GnRHa therapy group. In addition, NYPF therapy was safe and has no obvious adverse events. Data mining revealed that the core herb pair of NYPF was "Anemarrhenae Rhizoma (Zhimu) - Phellodendri Chinensis Cortex (Huangbai)." Network pharmacology predicted that quercetin, kaempferol, beta-sitosterol, etc were the key components of Zhimu-Huangbai for treating CPP. The core targets were TP53, JUN, AKT1, ESR1, TNF, IL6, CCND1, MAPK1, BCL2, EGFR, IL1B, and PTGS2. They played a pivotal role in modulating multiple signaling pathways, such as Endocrine resistance, MAPK signaling pathway, and PI3K-Akt signaling pathway. CONCLUSION: This article revealed that NYPF therapy is effective and safe against CPP. The mechanism of the core herb pair of NYPF therapy for CPP through muti-components, muti-targets and muti-pathways.

Analysis of risk factors of precocious puberty in children.

BACKGROUND: The purpose of this study is to explore the related factors of precocious puberty in children. METHODS: 1239 children who underwent physical examination in our hospital from January 2020 to December 2022 were analyzed, including 198 precocious children and 1041 normal children. According to the age of 198 precocious children and 1041 normal children, 205 normal children were selected, and the remaining 836 normal children were excluded. They were divided into precocious group and normal group. The general data of the two groups were recorded. Logistic regression was used to analyze the influencing factors of precocious puberty in children. RESULTS: There were statistically significant differences (P < 0.05) between the two groups in sex, bone age, daily exercise time, E2, FSH, LH, leptin, mother's menarche time, living environment, consumption of nutritional supplements, consumption of foods containing pigments and preservatives, consumption of high-protein foods, and sleeping time. The multifactor logistic regression analysis shows that the risk factors of children's precocious puberty included gender (female), bone age (> 10 years old), and daily exercise time (< 0.9 h), E2 (≥ 66.00pmol/L), FSH (≥ 6.00U/L), LH (≥ 3.50U/L), leptin (≥ 8.00 µ G/L), mother's menarche time (< 12 years old), living environment (chemical industry zone), consumption of nutritional supplements (often), consumption of high-protein food (often), and sleep time (< 10 h). CONCLUSION: In conclusion, children's gender, bone age, exercise habits, E2, FSH, LH, leptin, mother's menarche time, living environment, eating habits, sleep time and other factors are closely related to precocious puberty in children. Reminding parents to actively prevent related factors in clinical work is helpful to prevent the occurrence of precocious puberty in children.

[Acupuncture combined with auricular point sticking for girls aged 3-8 years with incomplete precocious puberty: a randomized controlled trial].

OBJECTIVE: To observe the efficacy and safety of acupuncture combined with auricular point sticking for girls aged 3-8 years with incomplete precocious puberty (IPP). METHODS: Sixty girls with IPP were randomly divided into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 2 cases were eliminated). The girls in the control group were treated with healthy diet and proper exercise for 12 weeks. On the basis of the treatment in the control group, the girls in the observation group were treated with acupuncture combined with auricular point sticking. The acupuncture was applied at Sanyinjiao (SP 6), Guanyuan (CV 4), Guilai (ST 29), etc., the needles were retained for 20 min, acupuncture was given twice a week (once every 3 days). The auricular point sticking was applied at Luanchao (TF2), Neishengzhiqi (TF2), Neifenmi (CO18), Yuanzhong (AT2,3,4i), etc., twice a week. The treatment was given for 12 weeks. Before treatment, after treatment and in follow-up after 12 weeks of treatment completion, the Tanner stage of breast, serum contents of sex hormone (luteinizing hormone [LH], follicle-stimulating hormone [FSH], estradiol [E2]) were observed. The ovarian volume, the number of follicles with diameter>4 mm, and the uterine volume were measured by abdominal color Doppler ultrasound. In addition, the safety of the observation group was evaluated. RESULTS: Compared with before treatment, the Tanner stage of breast in the observation group was improved after treatment and in follow-up (P<0.05); after treatment and in follow-up, the Tanner stage of breast in the observation group was better than that in the control group (P<0.05). Compared with before treatment, the serum levels of LH and E2 in the observation group were increased (P<0.05), and the volume of bilateral ovaries was larger (P<0.05) in follow-up. Compared with before treatment, the serum contents of LH, FSH and E2 in the control group were increased (P<0.05), the volume of bilateral ovaries was larger (P<0.05), and the number of follicles was increased (P<0.05) after treatment and in follow-up. The serum levels of LH, FSH and E2 in the observation group were lower than those in the control group (P<0.05), the volume of bilateral ovaries was smaller than that in the control group (P<0.05), and the number of follicles was lower than that in the control group (P<0.05). Compared with before treatment, the uterine volume in the two groups was larger in follow-up (P<0.05). There was no statistically significant difference between the two groups after treatment and in follow-up (P>0.05). During the treatment, 3 cases in the observation group had slight abdominal pain and subcutaneous blood stasis, without serious adverse reactions. CONCLUSION: Acupuncture combined with auricular point sticking could improve the Tanner stage of breast, reduce the level of sex hormone, slow down the development and maturation of ovary and follicle, and control the degree and speed of sexual development in girls aged 3-8 years with IPP.

Does vitamin D have a potential role in precocious puberty? A meta-analysis.

Background: Precocious puberty, one of the common pediatric endocrine system diseases, has been related to reduced adult height, adverse psychological outcomes and long-term health consequences. Previous findings have found that low levels of vitamin D appear to be associated with the characteristics of precocious puberty such as early menarche. However, the effect of vitamin D on precocious puberty remains controversial. Methods: The published literature was searched from PubMed, Web of Science, Cochrane Library, MEDLINE, EMBASE, CNKI, Wan Fang and VIP databases up to October 2022. A randomized effect model was used to perform a meta-analysis to evaluate differences in vitamin D concentration between precocious puberty subjects and normal subjects, the risk of precocious puberty in subjects with low vitamin D levels, and the effect of supplementation of vitamin D on subjects with precocious puberty on medication. Results: Our study found that precocious puberty subjects had lower serum vitamin D levels than the normal population (standardized mean difference (SMD) = -1.16 ng ml-1 and 95% confidence interval (CI) = -1.41 and -0.91 ng ml-1). Meanwhile, the lower level of vitamin D was associated with the risk of precocious puberty (odd ratio (OR) = 2.25 and 95% CI = 1.66 and 3.04). Moreover, compared with gonadotropin-releasing hormone analogue (GnRHa) intervention alone, subjects receiving GnRHa + vitamin D intervention had significantly lower luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels and bone age, and higher predicted adult height (PAH). Conclusions: Vitamin D may have a potential role in precocious puberty and more data from large clinical trials are needed to confirm the findings.

MKRN3 inhibits puberty onset via interaction with IGF2BP1 and regulation of hypothalamic plasticity.

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.

[Effect of transcutaneous electrical acupoint stimulation combined with auricular acupressure on sexual hormone level and gonadal development in girls with precocious puberty].

OBJECTIVE: To explore the effect of transcutaneous electrical acupoint stimulation (TEAS) combined with auricular acupressure on serum sexual hormone level, and the ovarian, follicular and uterine development in the girls with precocious puberty. METHODS: Sixty girls with precocious puberty were randomly divided into a control group (30 cases, 2 cases dropped off) and a treatment group (30 cases, 3 cases dropped off). In both the control group and the treatment group, the healthy life-style intervention was provided for 12 weeks. Besides, in the treatment group, TEAS was delivered for 20 minutes each time, twice a week; and bilateral auricular acupressure was combined. The duration of treatment was 12 weeks. The levels of serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol (E2), as well as ovarian volume, maximum follicular diameter and uterine volume before and after treatment were detected, and the safety was evaluated separately. RESULTS: Compared with before treatment, the contents of serum LH and FSH were increased (P<0.05), and the ovarian volume and the maximum follicle diameter were increased (P<0.05) in the control group after treatment; the contents of serum FSH and E2 were decresed (P<0.05), and the maximum follicular diameter was reduced significantly (P<0.05) in the treatment group after treatment. Compared with the control group, the contents of serum LH, FSH and E2 were decreased (P<0.05), while the ovarian volume and the maximum follicle diameter were decreased (P<0.05) in the treatment group after treatment. CONCLUSION: TEAS combined with auricular acupressure can effectively decrease the level of sex hormone, improve the ovarian and uterine development and retard the gonadal development. Such combined therapy is of high safety and conductive to regulating the development for the girls with precocious puberty.

The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty.

The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.

Acupuncture combined with auricular point sticking for girls aged 3-8 years with incomplete precocious puberty: a randomized controlled trial / 中国针灸

OBJECTIVE@#To observe the efficacy and safety of acupuncture combined with auricular point sticking for girls aged 3-8 years with incomplete precocious puberty (IPP).@*METHODS@#Sixty girls with IPP were randomly divided into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 2 cases were eliminated). The girls in the control group were treated with healthy diet and proper exercise for 12 weeks. On the basis of the treatment in the control group, the girls in the observation group were treated with acupuncture combined with auricular point sticking. The acupuncture was applied at Sanyinjiao (SP 6), Guanyuan (CV 4), Guilai (ST 29), etc., the needles were retained for 20 min, acupuncture was given twice a week (once every 3 days). The auricular point sticking was applied at Luanchao (TF2), Neishengzhiqi (TF2), Neifenmi (CO18), Yuanzhong (AT2,3,4i), etc., twice a week. The treatment was given for 12 weeks. Before treatment, after treatment and in follow-up after 12 weeks of treatment completion, the Tanner stage of breast, serum contents of sex hormone (luteinizing hormone [LH], follicle-stimulating hormone [FSH], estradiol [E2]) were observed. The ovarian volume, the number of follicles with diameter>4 mm, and the uterine volume were measured by abdominal color Doppler ultrasound. In addition, the safety of the observation group was evaluated.@*RESULTS@#Compared with before treatment, the Tanner stage of breast in the observation group was improved after treatment and in follow-up (P<0.05); after treatment and in follow-up, the Tanner stage of breast in the observation group was better than that in the control group (P<0.05). Compared with before treatment, the serum levels of LH and E2 in the observation group were increased (P<0.05), and the volume of bilateral ovaries was larger (P<0.05) in follow-up. Compared with before treatment, the serum contents of LH, FSH and E2 in the control group were increased (P<0.05), the volume of bilateral ovaries was larger (P<0.05), and the number of follicles was increased (P<0.05) after treatment and in follow-up. The serum levels of LH, FSH and E2 in the observation group were lower than those in the control group (P<0.05), the volume of bilateral ovaries was smaller than that in the control group (P<0.05), and the number of follicles was lower than that in the control group (P<0.05). Compared with before treatment, the uterine volume in the two groups was larger in follow-up (P<0.05). There was no statistically significant difference between the two groups after treatment and in follow-up (P>0.05). During the treatment, 3 cases in the observation group had slight abdominal pain and subcutaneous blood stasis, without serious adverse reactions.@*CONCLUSION@#Acupuncture combined with auricular point sticking could improve the Tanner stage of breast, reduce the level of sex hormone, slow down the development and maturation of ovary and follicle, and control the degree and speed of sexual development in girls aged 3-8 years with IPP.

Development of precocious puberty in children: Surmised medicinal plant treatment.

Precocious puberty in children is one of the common endocrine diseases in paediatrics. Epidemiological surveys have shown that the number of children with precocious puberty has significantly increased globally. Precocious puberty negatively affects the physical and mental health of children and may increase the risk of hypertension, diabetes, obesity and infertility in adulthood. Therefore, the initiating factors of adolescence have become core issues in the study of sexual development in children. Owing to developments in molecular genetics, many studies have been able to show that precocious puberty is mostly resulted in autosomal inheritance. For instance, makorin ring finger protein 3 gene (MKRN3) may be implicated in familial CPP. Gonadotropin-releasing hormone agonist (GnRHa) is the gold standard for treatment, but its safety still requires long-term evaluation and management. Traditional medicinal plants have been used in clinical treatments and in exploring novel treatment methods. From the collected datas, in Asia, traditional Chinese medicine treatment is based on the principles of nourishing Yin, lowering fire and draining fire from the liver to help precocious children and alleviate or delay the onset of precocious puberty by medicinal plants such as Anemarrhena asphodeloides Bge., Phellodendron amurense Rupr., Rehmannia glutinosa and Poria cocos Wolf. They play an important role in exploring the pharmacological mechanisms of precocious puberty treatment effects and drug development. Therefore, by elucidating the occurrence and development of precocious puberty, this review provides novel and valuable insights of paediatric endocrine therapy accessing the published researches on the effectiveness of traditional herbal medicine in the treatment of precocious puberty and its therapeutic mechanisms.

Perceptions and use of complementary and alternative medicine in patients with precocious puberty.

OBJECTIVES: Use of complementary and alternative medicine (CAM) is widespread. This study aimed to investigate the use of CAM in children with central precocious puberty (PP) who used gonadotropin-releasing hormone analog (GnRHa) treatment. METHODS: Parents of 108 patients who were diagnosed as having PP were involved in the study. A questionnaire was administered to the parents during follow-ups. The patients were divided into two groups according to the use of CAM. RESULTS: Forty (37%) patients had used CAM. Parents who graduated from primary school tended not to use CAM (χ 2 =10.463; p=0.015). There was no other statistically significant difference between the sociodemographic features (p>0.05). The most common information source was physicians (40%). Seventy-five percentage of CAM users and 44.1% of non-CAM users knew/heard about herbal medicine (χ 2 =8.517; p=0.004) and herbal medicine was the most common type of CAM used. 80% of parents in the CAM group and 54.4% of parents in the non-CAM group knew at least one biologically based therapy that had estrogenic activity (χ 2 =6.082; p=0.014). Seventy-one percentage of parents in the CAM group and 29% of parents in the non-CAM group stated that they would consider using CAM in the future (χ 2 =16.979; p<0.001). CONCLUSIONS: The use of CAM among patients with PP is high. Although most CAM therapies are harmless, there may be adverse effects or drug interactions with current conventional treatment in children. Health professionals should be aware and inquire about the use and type of CAM, considering the medical history at every patient encounter.

Green tea catechin EGCG could prevent obesity-related precocious puberty through NKB/NK3R signaling pathway.

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 [ß=-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.

Vitamin D status and parathyroid hormone assessment in girls with central precocious puberty.

PURPOSE: The objective of this study was to analyze vitamin D status and PTH concentrations in 6- to 8-year-old girls with central precocious puberty. METHODS: A cross-sectional clinical and blood testing study (calcium, phosphorus, 25(OH)D and PTH) was carried out in 78 girls with central precocious puberty (CPP group), aged 6.1-7.9 years. A control group was recruited (137 prepubertal girls, aged 6.1-8.2 years). The criteria of the US Endocrine Society were used for the definition of hypovitaminosis D. RESULTS: There were no significant differences in vitamin D status between both groups. There were no significant differences in 25(OH)D concentrations between CPP (25.4 ± 8.6 ng/mL) and control groups (28.2 ± 7.4 ng/mL). In contrast, PHT concentrations in CPP group (44.8 ± 16.3 pg/mL) were higher (p < 0.05) with respect to control group (31.0 ± 11.9 ng/mL). In CPP group, there was a positive correlation (p < 0.05) between PTH concentrations and growth rate, bone age, and basal estradiol, basal FSH, basal LH and LH peak concentrations. CONCLUSION: Vitamin D status in 6- to 8-year-old girls with CPP is similar to that in prepubertal girls. PTH concentrations were significantly higher in girls with CPP, and this could be considered as a physiological characteristic of puberty and, in this case, of pubertal precocity.

Association of Early Pubertal Onset in Female Rats With Inhalation of Lavender Oil.

BACKGROUND: Central precocious puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis but its major cause remains unclear. Studies have indicated an association between chronic environmental exposure to endocrine-disrupting chemicals and pubertal onset. Essential oil is widely used in homes worldwide for relief of respiratory symptoms, stress, and/or sleep disturbance. METHODS: To evaluate this association, we compared the hormone levels and timing of vaginal opening (VO) in female rats exposed to lavender oil (LO) through different routes (study groups: control, LO nasal spray [LS], and indoor exposure to LO [LE]) during the prepubertal period. The body weights of the animals were also compared every 3 days until the day of VO, at which time gonadotropin levels and internal organ weights were assessed. RESULTS: The LS group showed early VO at 33.8 ± 1.8 days compared with the control (38.4 ± 2.9 days) and LE (36.6 ± 1.5 days) groups. Additionally, luteinizing hormone levels were significantly higher in the LE and LS groups than those in the control group. Body weights did not differ significantly among the groups. CONCLUSION: Inhalation exposure to an exogenic simulant during the prepubertal period might trigger early pubertal onset in female rats. Further evaluation of exposure to other endocrine-disrupting chemicals capable of inducing CPP through the skin, orally, and/or nasally is warranted.

The m6A mRNA demethylase FTO regulates GnRH secretion in Mn-induced precocious puberty.

The GABAA receptor (GABAAR) 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 m6A are correlated with GABAAR 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 GABAAR protein but had no effect on GABAAR mRNA. Moreover, Mn upregulated the levels of FTO and inhibited global cellular m6A levels and GABAAα2 mRNA m6A levels. Knockdown of FTO increased the expression of GABAAR protein and GABAAα2 mRNA m6A levels. Data from rat models further demonstrate that inhibition of FTO suppressed GABAAR protein expression in the hypothalamus, causing delayed puberty onset. Collectively, our findings suggest that FTO-dependent m6A demethylation plays a critical role in regulating GABAAR mRNA processing in GnRH neurons.

Diet-Induced Hypothalamic Inflammation, Phoenixin, and Subsequent 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.

Effect of Decaffeinated Green Tea Polyphenols on Body Fat and Precocious Puberty in Obese Girls: A Randomized Controlled Trial.

Background: Obesity has been reported to be an important contributing factor for precocious puberty, especially in girls. The effect of green tea polyphenols on weight reduction in adult population has been shown, but few related studies have been conducted in children. This study was performed to examine the effectiveness and safety of decaffeinated green tea polyphenols (DGTP) on ameliorating obesity and early sexual development in girls with obesity. Design: This is a double-blinded randomized controlled trial. Girls with obesity aged 6-10 years old were randomly assigned to receive 400 mg/day DGTP or isodose placebo orally for 12 weeks. During this period, all participants received the same instruction on diet and exercise from trained dietitians. Anthropometric measurements, secondary sexual characteristics, B-scan ultrasonography of uterus, ovaries and breast tissues, and related biochemical parameters were examined and assessed pre- and post-treatment. Results: Between August 2018 and January 2020, 62 girls with obesity (DGTP group n = 31, control group n = 31) completed the intervention and were included in analysis. After the intervention, body mass index, waist circumference, and waist-to-hip ratio significantly decreased in both groups, but the percentage of body fat (PBF), serum uric acid (UA), and the volumes of ovaries decreased significantly only within the DGTP group. After controlling confounders, DGTP showed a significantly decreased effect on the change of PBF (ß = 2.932, 95% CI: 0.214 to 5.650), serum UA (ß = 52.601, 95% CI: 2.520 to 102.681), and ovarian volumes (right: ß = 1.881, 95% CI: 0.062 to 3.699, left: ß = 0.971, 95% CI: 0.019 to 1.923) in girls with obesity. No side effect was reported in both groups during the whole period. Conclusion: DGTP have shown beneficial effects of ameliorated obesity and postponed early sexual development in girls with obesity without any adverse effects. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT03628937], identifier [NCT03628937].

Case Report: Lipoma of the Tuber Cinereum Mimicking a Pituitary Gland Abnormality in a Girl With Central Precocious Puberty.

Introduction: Magnetic Resonance Imaging (MRI) is the best approach to investigate the hypothalamic-pituitary region in children with central precocious puberty (CPP). Routine scanning is controversial in girls aged 6-8 year, due to the overwhelming prevalence of idiopathic forms and unrelated incidentalomas. Cerebral lipomas are rare and accidental findings, not usually expected in CPP. We report a girl with CPP and an unusually shaped posterior pituitary gland on SE-T1w sequences. Case Description: A 7.3-year-old female was referred for breast development started at age 7. Her past medical history and physical examination were unremarkable, apart from the Tanner stage 2 breast. X-ray of the left-hand revealed a bone age 2-years ahead of her chronological age, projecting her adult height prognosis below the mid parental height. LHRH test and pelvic ultrasound were suggestive for CPP. Routine brain MRI sequences, SE T1w and TSE T2w, showed the posterior pituitary bright spot increased in size and stretched upward. The finding was considered as an anatomical variant, in an otherwise normal brain imaging. Patient was started on treatment with GnRH analogue. At a thorough revaluation, imaging overlap with adipose tissue was suspected and a new MRI scan with 3D-fat-suppression T1w-VIBE sequences demonstrated a lipoma of the tuber cinereum, bordering a perfectly normal neurohypophysis. 3D-T2w-SPACE sequences, acquired at first MRI scan, would have provided a more correct interpretation if rightly considered. Conclusion: This is the first evidence, to our knowledge, of a cerebral lipoma mimicking pituitary gland abnormalities. Our experience highlights the importance of considering suprasellar lipomas in the MRI investigation of children with CPP, despite their rarity, should the T1w sequences show an unexpected pituitary shape. 3D-T2w SPACE sequences could be integrated into standard ones, especially when performing MRI routinely, to avoid potential misinterpretations.

Transient central precocious puberty: a new entity among the spectrum of precocious puberty?

OBJECTIVE: Recently, we observed some cases of Precocious Puberty (PP) with a partial central activation of hypothalamic-pituitary-gonadal (HPG) axis that tended to normalized in 6-12 months. To evaluate the frequency of this form within the spectrum of forms of PP, we retrospectively assessed the clinical, hormonal and ultrasound characteristics of patients attending to our Center for signs of PP, between 2007 and 2017. To hypothesize some causes of this "pubertal poussée" a questionnaire about environmental data was provided to patients. METHODS: 96 girls were recruited for the study and divided into three Groups. Group 1: 56 subjects with Central PP (CPP) requiring treatment with GnRH analogue; Group 2: 22 subjects with transient activation of pubertal axis, that tended to normalize, "Transient CPP"(T-CPP); Group 3: 18 subjects with Isolated Thelarche (IT). RESULTS: Mean age at diagnosis was 6.8 ± 1.0 years in Group 1, 5.9 ± 1.3 years in Group 2 and 5.6 ± 1.5 years in Group 3. A significant increase of diagnosis of T-CPP was observed over the study period. Significantly higher use of some homeopathic medicines and potential exposure to pesticides was reported in Group 2 vs Group 1. CONCLUSIONS: To our knowledge, we first reported a form defined as T-CPP, characterized by partial activation in the HPG axis normalizing over time. An increased use of homeopathic medicines and exposure to environmental pollutants in these patients was evidenced.