RARE DISEASE
Rare central precocious puberty
Rare central precocious puberty
Rare central precocious puberty
Synonyms: Gonadotropin-dependant precocious puberty, Rare CPP
Synonyms: Gonadotropin-dependant precocious puberty, Rare CPP
Synonyms: Gonadotropin-dependant precocious puberty, Rare CPP
Drug discovery
7
drugs
With orphan designations
Overview
Rare Central Precocious Puberty (CPP)
Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis, triggering puberty before age 8 in girls and 9 in boys. Etiology is often idiopathic, but mutations in MKRN3 and other genes, or CNS abnormalities (e.g., tumors, hamartomas), may contribute. Untreated CPP leads to short stature and psychosocial challenges. Diagnosis relies on clinical signs, gonadotropin levels, and imaging. GnRH analogs remain the gold-standard therapy to suppress puberty and preserve growth potential [1][3][7].
Therapies
GnRH analogs (e.g., leuprolide, triptorelin): Administered via monthly injections, 3-/6-month depots, or annual implants to suppress gonadotropin release [3][8][13].
Treatment duration typically spans 1–4 years, discontinued near physiological pubertal age [3][7].
Regular monitoring of growth velocity, bone age, and hormone levels ensures efficacy [7][8].
Categories: rare endocrine diseases
Research Papers
1,013 drug discovery papers about Rare central precocious puberty, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,013 drug discovery papers about Rare central precocious puberty, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-09 | Syndrome differentiation and treatment of pediatric central precocious puberty: role of the spleen-kidney axis.
Pediatric central precocious puberty (CPP) is driven by premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, along with immune-inflammatory imbalance, metabolic dysfunction, obesity, and gut microbiota-derived signals. According to traditional Chinese medicine (TCM) principles, kidney yin deficiency with hyperactive ministerial fire and spleen deficiency with phlegm-dampness form the basis for central pubertal activation and peripheral metabolic-inflammatory burden, thus supporting a combined approach for obesity-related or mixed-pattern CPP. Representative prescriptions include modified Zhibai Dihuang pills with Liujunzi decoction and modified Danzhi Xiaoyao powder with Erchen decoction, which integrate kidney yin-nourishment and ministerial fire-clearance with spleen qi-strengthening and phlegm resolution. Available clinical evidence suggests potential benefits in controlling secondary sexual characteristics, reducing gonadotropin and sex-steroid levels, and slowing bone-age advancement. Mechanistic studies indicate possible regulation of kisspeptin/GPR54/GnRH and LH/FSH-sex-steroid signaling, Th1/Th2/Treg homeostasis, NF-κB/NLRP3 pathways, adipokine imbalance, insulin resistance, hypothalamic inflammation, and gut microbiota-associated metabolism. However, most mechanistic links remain indirect, comparative trials are scarce, and direct correction of pathogenic MKRN3 or DLK1 variants has not been demonstrated. In this review, we have discussed the role of kidney and spleen dysfunction in CPP and explored the underlying mechanisms - particularly in the context of the neuro-endocrine-immune network that links central neuroendocrine activation with peripheral immune-metabolic signals. In addition, the application of TCM in the management of CPP, and the translational challenges of applying TCM as an adjunct to established CPP management have also been explored. Future research should prioritize CPP-specific pathway validation, identification of syndrome biomarkers, multi-omics-based stratification, multicenter trials, and long-term pediatric safety monitoring.
2026-09-03 | Botanical drug preparations and related East Asian medicine interventions for central and idiopathic central precocious puberty: an umbrella review of systematic reviews and meta-analyses.
Central precocious puberty (CPP), particularly idiopathic CPP (ICPP), is characterized by the premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHas) are established biomedical treatments, but treatment burden, cost, and incomplete long-term outcome data have encouraged interest in adjunctive botanical drug preparations used in East Asian medicine. However, these preparations differ substantially in composition, dose, comparator, and reporting quality. The aim of this study is to synthesize systematic reviews (SRs) and meta-analyses (MAs) evaluating botanical drug preparations and related East Asian medicine interventions for CPP/ICPP, appraise methodological quality and certainty, quantify the overlap of primary trials, and identify evidence gaps. Eligible studies included systematic reviews/meta-analyses of randomized trials in children with CPP/ICPP. Databases were searched from inception to September 2025. Evidence was narratively synthesized by formulation family, comparator, and outcome. Review quality was assessed using AMSTAR-2, risk of bias using ROBIS, certainty using GRADE domains where feasible, and primary-trial overlap using the corrected covered area. Four systematic reviews/meta-analyses were included. Favorable signals were reported mainly for Zhibai Dihuang-based preparations, Dabuyin-based preparations, Nourishing Yin-Purging Fire regimens, and botanical drug preparations combined with GnRHas. Outcomes included clinical response, uterine/ovarian volume, gonadotropin levels, estradiol levels, and bone age index. However, interpretation was limited by heterogeneous formulations, variable comparators, an unclear or high risk of bias in the primary trials, incomplete formulation reporting, possible publication/language bias, and overlap of primary studies. Adverse events were incompletely defined and may have been under-reported; long-term pediatric safety was rarely assessed. Current evidence suggests a possible adjunctive benefit of selected botanical drug preparations, particularly in combination with GnRHas, for CPP/ICPP. However, the certainty of the evidence remains low because of methodological weaknesses, heterogeneous interventions, single-country evidence, incomplete safety reporting, and limited long-term outcome data. High-quality multicenter trials with standardized botanical authentication, dosing, outcome definitions, adverse-event surveillance, and long-term follow-up are needed before routine clinical integration can be recommended.
2026-08-13 | Effects of leuprorelin acetate microspheres on sex hormones, secondary sexual characteristics, and predicted adult height in early and fast puberty girls: a real-world, single-arm, retrospective cohort study.
Gonadotropin releasing hormone analogs (GnRHa) are recommended for both central precocious puberty (CPP) and early and fast puberty, but their benefit on final adult height in later onset cases remains controversial. Boennuokang® leuprorelin acetate microspheres, the first domestic generic formulation, have been approved for CPP, but evidence in early and fast puberty girls is still limited. Considering the complexity of clinical management in early and fast puberty, more real-world studies are needed. Therefore, this study aimed to explore the effect of Boennuokang® leuprorelin acetate microspheres on hypothalamic-pituitary-gonadal (HPG) axis and predicted adult height (PAH) in early and fast puberty girls. This real-world, single-arm, retrospective cohort study consecutively enrolled 198 early and fast puberty girls treated with Boennuokang® leuprorelin acetate microspheres at The First Bethune Hospital of Jilin University between January 2022 and November 2023. Early and fast puberty was defined as pubertal onset after the diagnostic age cutoff for CPP, accompanied by progression to the next Tanner stage within 6 months and bone age (BA) advancement exceeding chronological age (CA) progression. Baseline variables were collected from the electronic medical record. Tanner stage was assessed by pediatric endocrinologists, sex hormones were measured using standardized biochemical assays, uterine length was evaluated by pelvic ultrasonography, BA was assessed using the Greulich Pyle method, and PAH was calculated using the Bayley-Pinneau method. Follow-up assessments were performed at baseline (T0) and at 3 (T1), 6 (T2), 12 (T3), and 18 (T4) months. Longitudinal changes were analyzed using repeated measures analysis of variance (ANOVA) or Friedman tests. The mean CA and BA of girls were 9.73±0.99 and 12.08±0.82 years, respectively. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol decreased after 18 months of treatment (all P<0.001). Specifically, the median [quartile 1 (Q1)-quartile 3 (Q3)] LH decreased from 2.7 (2.23-3.51) mIU/mL at T0 to 0.66 (0.48-1.22) mIU/mL at T4; the median (Q1-Q3) FSH decreased from 5.27 (4.82-6.10) mIU/mL at T0 to 2.00 (1.56-2.42) mIU/mL at T4; the median estradiol decreased from 163.50 (129.00-195.00) pmol/L at T0 to 36.70 (36.70-36.70) pmol/L at T4. Of note, the proportions of girls in the Tanner stage B5 exhibited a decreasing trend over time. The length of uterus decreased after 18 months of treatment (P<0.001). BA/CA ratio (P<0.001) and growth velocity (P=0.002) decreased over time. PAH increased, and loss in growth potential [genetic target height (GTH) minus PAH] decreased over time (both P<0.001). Body mass index initially increased after 3 months of treatment, then showed a reducing trend until month 18 (P=0.005). Boennuokang® leuprorelin acetate microspheres are associated with suppression of the HPG axis and increased PAH in early and fast puberty girls.
2026-08-07 | Stigmasterol alleviates central precocious puberty by targeting the IGF-1/PI3K/Akt/mTOR signaling pathway and modulating the Kisspeptin/GnRH axis.
Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis, causing early sexual development and related health risks. Stigmasterol (ST), a natural phytosterol with diverse pharmacological activities, has not been fully evaluated for CPP. This study integrated network pharmacology, molecular docking, and molecular dynamics simulations to identify ST targets in CPP. Experimental validation used an N-Methyl aspartic acid-induced CPP rat model and high-glucose high-fat-stimulated GT1-7 hypothalamic neurons. Techniques included histology, ELISA, qPCR, western blot, and flow cytometry. In silico analyses demonstrated favorable binding of ST to core proteins within the IGF-1/PI3K/Akt/mTOR signaling pathway. In vivo, ST treatment significantly delayed vaginal opening, reduced serum levels of estradiol and testosterone, and ameliorated pathological abnormalities in uterine and ovarian tissues. At the molecular level, ST suppressed the hypothalamic overactivation of the IGF-1/PI3K/Akt/mTOR pathway and attenuated neuronal damage and apoptosis. In vitro, ST inhibited HGHF-induced proliferation, inflammatory cytokine release, and apoptosis in GT1-7 cells, while concurrently modulating the expression of key puberty-related genes and proteins, including those within the Kisspeptin/GnRH axis. Conversely, pharmacological reactivation of PI3K signaling with the agonist 740YP attenuated selected protective effects the protective effects of ST, supporting the functional involvement the PI3K/Akt/mTOR pathway in mediating these benefits. Stigmasterol exhibits significant therapeutic effects against CPP by concurrently targeting the IGF-1/PI3K/Akt/mTOR and Kisspeptin/GnRH signaling pathways. These findings provide robust preclinical evidence supporting ST as a promising multi-targeted natural candidate for CPP management.
2026-07-17 | Mental Health of Youths Who Use Puberty Blockers.
Puberty blockers are an established, reversible intervention for central precocious puberty in children and gender dysphoria in adolescents. Despite broad clinical support, these treatments are currently politically contested. To characterize the mental health of transgender youths prescribed puberty blockers compared with cisgender peers who received these medications for treatment of precocious puberty and with transgender and cisgender youths who did not receive these medications. This retrospective cohort study used data from a US nationwide, multipayer claims database from January 2016 to January 2025. Youths aged 10 to 17 years were categorized into 4 cohorts based on gender modality (transgender or cisgender) and prescription of a puberty blocker (yes or no). Primary outcomes were International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnoses of mood disorders and suicidal thoughts and behaviors. Inverse probability-weighted generalized estimating equation models were fit to obtain adjusted odds ratios (aORs) and 95% CIs, adjusting for demographics, payer type, region, year, socioeconomic disadvantage, and policy environment indices. In demographics, female gender marker is used to indicate that an F (female) has been applied as a marker for the individual by some entity (eg, a medical professional or government body). Among 231 783 youths in the analytical sample, 41 472 youths (17.89%) were transgender (median [IQR] age at baseline, 9.00 [7.00-11.00] years; 31 246 with female gender marker [75.34%]) and 190 311 youths (82.11%) were cisgender (median [IQR] age at baseline, 8.00 [6.00-10.00] years; 128 942 with female gender marker [67.75%]). Being transgender was associated with higher odds of mood disorder diagnosis (aOR, 4.42 [95% CI, 4.24-4.60]) and suicidal thoughts and behaviors (aOR, 12.21 [95% CI, 10.69-13.95]) compared with being cisgender. Being prescribed a puberty blocker was associated with higher odds of mood disorder diagnosis (aOR, 2.11 [95% CI, 2.02-2.19]) and suicidal thoughts and behaviors (aOR, 3.04 [95% CI, 2.65-3.49]) compared with no prescription. However, among transgender youths, prescription of a puberty blocker was associated with decreased adjusted odds of mood disorder diagnosis (aOR, 0.52 [95% CI, 0.45-0.60]) and suicidal thoughts and behaviors (aOR, 0.20 [95% CI, 0.14-0.29]). In this study, transgender youths overall had substantially higher rates of diagnosed mood disorder and suicidal thoughts and behaviors than their cisgender peers, highlighting the need for population-specific interventions. Prescription of a puberty blocker was associated with partial attenuation of this disparity, suggesting mental health benefits associated with this treatment for transgender youth.
proteins
2026-09-03 | Rising incidence of central precocious puberty in Thailand: a nationwide population-based study before, during, and after the COVID-19 pandemic (2018-2024).
Nationwide data on the incidence of central precocious puberty (CPP) and premature thelarche (PT), a benign variant of pubertal development, are limited. To evaluate trends in CPP and PT incidence among Thai children before, during, and after the COVID-19 pandemic. This cross-sectional population-based study used National Health Security Office (NHSO) claims data from 2018 to 2024. CPP and PT were identified using ICD-10-TM (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Thai Modification) codes. Annual incidence rates (AIRs) were calculated for each NHSO-insured population, while incidence rate ratios (IRRs) were estimated using quasi-Poisson regression. A total of 6,782 girls and 189 boys with CPP, and 1,594 girls with PT, were included. Among girls, the CPP AIR increased from 15.0 per 100,000 person-years in 2018 to 51.7 in 2021 and remained elevated during 2022-2024 (44.1-47.7). The IRR was 2.27 (95% confidence interval [CI], 1.82-2.83) for pandemic versus prepandemic, and 1.06 (95% CI, 0.89-1.26) for postpandemic versus pandemic period. An age-stratified analysis showed the greatest increase among girls aged 8 to <9 years. Among boys, the CPP AIR remained low and stable (0.6-1.0 per 100,000 person-years). The female-to-male IRR was 43.0 (95% CI, 33.5-55.3). The incidence of PT in girls increased from 7.2 in 2018 to 14.6 per 100,000 person-years in 2024, with the largest increase observed among those aged 7 to <8 years. The incidence of CPP among Thai girls increased during the COVID-19 pandemic and remained elevated thereafter, whereas the incidence of PT increased gradually. Both trends were most pronounced in peripubertal age groups. Further studies are required to determine whether these patterns reflect pandemic-related factors or an earlier onset of puberty.
2026-05-28 | The central precocious puberty-associated gene MKRN3 is a tumor suppressor regulating CSDE1 ubiquitination in ovarian cancer.
Earlier age at menarche has long been known to be associated with an increased risk of ovarian cancer (OC). However, the underlying mechanisms are not completely understood. Here, we report a paternally inherited imprinted gene, MKRN3, that is associated with central precocious puberty (CPP) and that plays a tumor suppressive role in OC. We found that genomic MKRN3 mutations are significantly more common in OC patients. Genomic mutations in MKRN3 and low MKRN3 expression levels are correlated with poor patient survival. The restoration of MKRN3 in MKRN3-inactivated OC cells significantly suppresses tumor growth and proliferation in vitro and in vivo. Ovary-specific knockout of endogenous MKRN3 accelerates P53 inactivation-induced tumorigenesis in mice. Mechanistically, CSDE1 was identified as a major substrate for MKRN3 in OC via mass spectrometry-based proteomics screens. MKRN3 regulates OC cell proliferation through proteolytic ubiquitination of CSDE1. Our comprehensive data reveal that the CPP-associated gene MKRN3 is a tumor suppressor in human OC. We propose that germline mutations in the MKRN3 gene might partially explain the association between precocious puberty and the risk of OC.
2026-03-12 | Hypothalamic endoplasmic reticulum stress drives pubertal precocity due to early-onset obesity in female rodents.
Early-onset obesity, especially in girls, is frequently associated with advanced puberty; a phenomenon bound to increased risk of long-term complications. Hypothalamic endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of obesity and its comorbidities. However, its contribution to pubertal disorders associated with obesity remains unexplored. We report herein that central ER stress drives obesity-induced precocious female puberty. Hypothalamic expression of key ER stress markers was blunted during normal pubertal transition and altered in female rats with early-onset obesity and advanced puberty, which displayed increased levels of p-PERK and p-eIF2α, and reduced ATF6α content. Central stimulation of hypothalamic ER stress with Thapsigargin in prepuberal lean female rats mimicked advanced puberty onset caused by obesity, without changes in body weight. This phenomenon seemingly involves a circuit including the hypothalamic arcuate nucleus (ARC), since obesity-induced precocious puberty was largely prevented by alleviation of ER stress via virogenetic overexpression of the ER chaperone, GRP78, in the ARC, but not in the paraventricular nucleus, in female rats. In addition, expression analyses of ER stress markers in mouse Kiss1 neurons isolated from juvenile and pubertal female mice revealed increased expression of Perk and Ire1α mRNAs in Kiss1ARC neurons in early-overfed mice at the juvenile stage, while Xbp1s/u expression ratio was significantly increased during juvenile-pubertal transition in overweighed mice. Collectively, our data uncover a relevant role of hypothalamic ER stress in the control of female puberty and the pathogenesis of obesity-induced pubertal alterations.
2026-02-27 | Differential microRNA Expression Profiles in Girls with Idiopathic Central Precocious Puberty and Premature Thelarche.
Idiopathic central precocious puberty (CPP) is increasingly observed in girls. Premature thelarche (PT) and exaggerated thelarche (ET) are early pubertal variants that can be challenging to distinguish from CPP in clinical practice. Exosomal microRNAs are stable biomarkers capable of crossing the blood-brain barrier. Although miR-30b-5p has been reported to increase in pubertal boys and girls, human studies investigating microRNAs in CPP and puberty remain limited. To investigate exosomal microRNA expression profiles and associated pathways in early pubertal development, we conducted a cross-sectional study of 28 girls aged 6-8 years. Serum exosomal microRNA expression was analyzed using next-generation sequencing. Differentially expressed microRNAs (DEmiRNAs) between groups were identified, followed by pathway enrichment analysis. Distinct exosomal miRNA expression patterns were observed among the CPP, ET, and control groups, with 307 DEmiRNAs identified. The CPP, PT, and ET groups exhibited distinct miRNA expression profiles compared with the control group. miR-30b-5p was upregulated in the CPP, ET, and PT groups compared with the control group. Pathway enrichment analysis revealed the involvement of various signaling pathways including AGE-RAGE, MAPK, and mTOR signaling pathways. Serum exosomal microRNAs may serve as biomarkers for early puberty and provide insight into metabolic influences on pubertal development.
2025-12-08 | High-fat diet-induced obesity accelerates puberty in male rats through SMIM20/phoenixin upregulation.
Controversy exists regarding the relationship between obesity and pubertal onset in boys, and the underlying mechanisms remain unclear. To establish a high-fat diet (HFD)-induced obesity model in juvenile male Sprague-Dawley (SD) rats, and to investigate the relationship between obesity and pubertal advancement as well as the role of Smim20/phoenixin (PNX) in male pubertal development. A HFD (45% fat) was administered to male SD rats to induce obesity, while control rats were maintained on a normal diet (ND) from birth. Body weight and preputial separation were monitored as markers of obesity and pubertal onset. At prepubertal (postnatal day 30, PND30) and early pubertal (PND40) stages, serum, hypothalamus, pituitary, testes, and adipose tissue were collected. RT-qPCR was performed to measure the mRNA expression levels of key genes in the hypothalamic-pituitary-gonadal axis (HPGA), including gonadotropin-releasing hormone (GnRH), Kiss1, G protein-coupled receptor 54 (GPR54), GnRH receptor (GnRHr), and Smim20. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and PNX protein were measured by ELISA. Associations among obesity (body mass index, BMI), PNX, and pubertal timing were evaluated using Spearman's correlation. HFD-fed rats exhibited significantly greater body weight and fat mass than ND-fed rats at both time points. (P<0.001), with earlier preputial separation (P<0.001). Testicular weight and expression of GnRH, Kiss1, GPR54, and GnRHr were increased, alongside higher serum LH, FSH, and testosterone (all P<0.05). PNX expression in hypothalamus, pituitary, testes, and subcutaneous fat, as well as serum PNX-14 and PNX-20 levels, were significantly elevated in HFD rats compared with controls (P<0.05). After adjusting for BMI, serum PNX-20 and PNX-14 (P<0.001) remained higher in the HFD group. Body weight was negatively correlated with age at preputial separation and positively correlated with serum LH, testosterone, abdominal circumference, PNX. To our knowledge, this study established a novel HFD-induced model of prepubertal obesity and central precocious puberty (CPP) in male rats. The findings suggest that obesity may accelerate pubertal onset, and that Smim20/PNX may participate in regulating pubertal development in males.
gene therapies
2025-11-17 | Hypothalamic FTO upregulates BDNF to promote GnRH expression through the PI3K/Akt pathway, leading to precocious puberty.
Puberty is among the most important stages in human development. Timely activation of hypothalamic gonadotropin-releasing hormone (GnRH) neurons underlies the initiation of pubertal development. The fat mass and obesity-associated (FTO), which is expressed in the hypothalamus, may regulate the m6A methylation of its target genes, influencing GnRH expression in the hypothalamus during puberty onset. This study aimed to explore the mechanism by which FTO regulates the function of its target neurotrophins within the hypothalamus and to clarify the molecular pathway underlying precocious puberty. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to assess m6A methylation in the hypothalamus of female rats. Serum brain-derived neurotrophic factor (BDNF) levels were measured in girls with central precocious puberty (CPP) and matched controls. BDNF was applied to GnRH neurons in vitro. The functions of FTO were assessed through overexpression and knockdown in animal models, with downstream signaling evaluated via BDNF/PI3K/Akt pathway analysis. Intracerebroventricular (ICV) injections of a BDNF-overexpressing lentiviral vector or a negative control (NC) were used to investigate the role of central BDNF in regulating puberty onset and reproductive function. Hypothalamic GnRH and FTO expression progressively increased whereas m6A methylation decreased during puberty. MeRIP-seq revealed significantly reduced m6A methylation of Bdnf mRNA in the arcuate nucleus (ARC) of female rats during early puberty. In the ARC, BDNF was expressed adjacent to GnRH-positive fibers and terminals. In addition, serum BDNF levels were higher in girls with CPP girls than in the control group. In vitro, BDNF treatment stimulated GnRH expression in GT1-7 cells. FTO positively regulated BDNF expression in an m6A methylation-dependent manner. FTO overexpression activated BDNF/PI3K/Akt signaling in the ARC and accelerated puberty onset. Conversely, FTO knockdown delayed vaginal opening and suppressed BDNF/PI3K/Akt signaling. ICV delivery of a BDNF-overexpressing lentivirus increased hypothalamic BDNF and GnRH expression, leading to a distinct endocrine profile. These findings suggest that FTO regulates the m6A demethylation of BDNF and promotes GnRH expression through the BDNF/PI3K/Akt signaling pathway. This study improves our understanding of the function of BDNF, which is critical for the development of therapeutic strategies for preventing and treating of precocious puberty.
2025-09-15 | Case Report: A case of complex cortical dysplasia with central precocious puberty onset.
A mutation rendering microtubulin and microtubule-associated proteins ineffective leads to a tubulinopathy known as complex cortical dysplasia (CCD), characterized by clinical heterogeneity and a variety of cortical brain developmental abnormalities. These often commence with intellectual disability, epileptic seizures, and motor disorders. In this case, we present a 6-year-old child with CCD whose symptoms began with central precocious puberty. Whole-exome sequencing uncovered a TUBB2B gene heterozygous mutation, NM_178012.5:c.74G > A (p.Ser25Asn). To our knowledge, this mutation has not been previously documented. Computational structural analysis indicated that this variant alters the hydrogen bonding between Ser25 and Trp21, Gly29, and Ile30, thus modifying the secondary structure and function of the protein, contributing to the child's unique clinical presentation. These findings expand the range of TUBB2B gene variants and offer a direction for the precise treatment of this child, underscoring the importance of brain magnetic resonance imaging in children with central precocious puberty.
2025-06-16 | Overexpression of Rap1B alleviate central precocious puberty and neurodevelopmental damage.
The central precocious puberty (CPP) in children and adolescents can adversely impact their overall well-being, affecting both their physical and psychological health. Whether Rap1B can mitigate the development of CPP remains unknown. The expression of Rap1B was investigated through a comprehensive bioinformatics analysis. Precocious puberty model in rats was established through high-fat feeding (HFD), and further injected AAV-Rap1B. Then, HE staining, vaginal exfoliated cell smear and other methods were used to explore the incidence of precocious puberty in rats in each group. In addition, Western blot, RT-qPCR, and IHC was used to detect the expression of GnRH, GnRHR, Kiss1, Kiss1R, NeuN, BDNF, TH, AVP. The contents of LH, FSH, E2, T, and AMH in serum of rats were detected by ELISA. The Rap1B cell line was constructed at the cellular level to explore the effects of FFA(OA + PA) induction on cell proliferation, apoptosis and inflammation. The expression of Rap1B was significantly up-regulated in overexpressing MKRN3 cells, where overexpressing MKRN3 can alleviate the occurrence of CPP. Overexpression of Rap1B alleviates HFD-induced CPP models, including reduce the content of LH, FSH, E2, T, and AMH in serum, and inhibit the expression of GnRH, Kiss1 and Kiss1R in hypothalamus, and alleviates hypothalamus injury. Furthermore, overexpression of Rap1B in the GT1-7 cell. Overexpression of Rap1B can significantly reverse FFA damage to GT1-7 cells and reduce FFA-induced increase of inflammatory factors (IL-6, IL-1β and TNF-α) in GT1-7 cells. This study indicated that overexpression of Rap1B alleviate CPP and neurodevelopmental damage. Our study offers a new approach for the treatment of CPP.
2025-03-13 | Shared Pathophysiological Mechanisms and Genetic Factors in Early Menarche and Polycystic Ovary Syndrome.
Early age at menarche (early AAM) and polycystic ovary syndrome (PCOS) are reproductive and metabolic disorders with overlapping pathophysiological and genetic features. Epidemiological studies suggest a link between these two conditions, both of which are characterized by dysregulation of the neuroendocrine pathways that control pulsatile gonadotropin-releasing hormone secretion, thus affecting gonadotropin release, particularly luteinizing hormone secretion. A common pathophysiology involving positive energy balance and abnormal metabolic status is evident in both disorders. Genetic and epigenetic factors influence the onset of puberty and reproductive outcomes. Genome-wide association studies have identified common genetic variants associated with AAM and PCOS, particularly in genes related to the neuroendocrine axis (e.g., FSHB) and obesity (e.g., FTO). In addition, high-throughput sequencing has revealed rare loss-of-function variants in the DLK1 gene in women with central precocious puberty (CPP), early menarche, and PCOS, who experienced adverse metabolic outcomes in adulthood. This review explores the shared pathophysiological mechanisms between CPP/early AAM and PCOS, examines potential genetic and epigenetic factors that may link these neuroendocrine reproductive conditions, and offers insights into future research and treatment strategies. Understanding these connections may provide new targets for therapeutic interventions and improve outcomes for individuals with these reproductive disorders.
2023-05-17 | A new DLK1 defect in a family with idiopathic central precocious puberty: elucidation of the male phenotype.
We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.
oligonucleotides
2024-03-11 | The functional study of a novel MKRN3 missense mutation associated with familial central precocious puberty.
Central precocious puberty (CPP) refers to a syndrome of early puberty initiation with a characteristic increase in the release of gonadotropin-releasing hormone (GnRH); therefore, it is also called GnRH-related precocious puberty. About a quarter of idiopathic central precocious puberty (ICPP) may be familial. Studies suggest that mutations of makorin ring finger protein 3 (MKRN3) can cause familial central precocious puberty (FCPP). In this report, we describe a Chinese female patient carrying a novel MKRN3 variant (c.980G>A/p.Arg327His) and presenting the CPP phenotype. This novel variant attenuated its own ubiquitination, degradation, and inhibition on the transcriptional and translational activity of GNRH1, which was verified through functional tests. We can consider this variant as a loss-of-function mutation, which subsides the inhibition of GnRH1-related signaling and gives rise to GnRH-related precocious puberty.
2023-09-01 | Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG.
Studies in humans and mice support a role for Makorin RING finger protein 3 (MKRN3) as an inhibitor of gonadotropin-releasing hormone (GnRH) secretion prepubertally, and its loss of function is the most common genetic cause of central precocious puberty in humans. Studies have shown that the gonads can synthesize neuropeptides and express MKRN3/Mkrn3 mRNA. Therefore, we aimed to investigate the spatiotemporal expression pattern of Mkrn3 in gonads during sexual development, and its potential regulation in the functional testicular compartments by gonadotropins. Mkrn3 mRNA was detected in testes and ovaries of wild-type mice at all ages evaluated, with a sexually dimorphic expression pattern between male and female gonads. Mkrn3 expression was highest peripubertally in the testes, whereas it was lower peripubertally than prepubertally in the ovaries. Mkrn3 is expressed primarily in the interstitial compartment of the testes but was also detected at low levels in the seminiferous tubules. In vitro studies demonstrated that Mkrn3 mRNA levels increased in human chorionic gonadotropin (hCG)-treated Leydig cell primary cultures. Acute administration of a GnRH agonist in adult mice increased Mkrn3 expression in testes, whereas inhibition of the hypothalamic-pituitary-gonadal axis by chronic administration of GnRH agonist had the opposite effect. Finally, we found that hCG increased Mkrn3 mRNA levels in a dose-dependent manner. Taken together, our developmental expression analyses, in vitro and in vivo studies show that Mkrn3 is expressed in the testes, predominantly in the interstitial compartment, and that Mkrn3 expression increases after puberty and is responsive to luteinizing hormone/hCG stimulation.
2023-06-19 | Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination.
Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.
2023-04-25 | 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.
2022-12-11 | History of Puberty: Normal and Precocious.
Spanning from bench to bedside, the history of normal and precocious puberty is characterized by a series of remarkable advances that have illuminated reproductive physiology and profoundly impacted clinical care. Early recognition of the hypothalamic and pituitary control of ovarian and testicular function led to the identification of GnRH as the key driver of pubertal onset. Decades later, discovery of the kisspeptin system further refined our understanding of human reproductive neuroendocrinology. Development of long-acting analogs of GnRH revolutionized the treatment of precocious puberty worldwide and ushered in the current era of an ever-expanding therapeutic armamentarium. Identification of monogenic etiologies of precocious puberty has further illustrated the exquisite complexity that comprises neurosecretory modulation of the hypothalamic GnRH neuron and may well lead to exciting novel targeted therapies.
other
2026-09-09 | Hypothalamic neuroimmune remodeling as an immunometabolic bridge between childhood obesity and earlier pubertal onset.
While the link between childhood obesity and central precocious puberty (CPP) is well documented, the immune-mediated mechanisms that may precipitate earlier pubertal onset remain incompletely understood. This review proposes hypothalamic neuroimmune remodeling as a candidate immunometabolic bridge through which chronic low-grade peripheral inflammation may influence the timing of hypothalamic-pituitary-gonadal (HPG) axis activation. In obesity, systemic immune activation is primarily by adipose tissue macrophage infiltration, lipotoxic signaling, and gut dysbiosis. Peripheral inflammatory signals may reach the central nervous system through the arcuate nucleus-median eminence complex, disruption of the blood-brain barrier, and immune-mediated gut-brain pathways. Within the hypothalamus, these signals may elicit local neuroimmune responses. Glial cells, particularly microglia, astrocytes, and tanycytes, undergo inflammatory activation and release cytokines and lipid mediators, including IL-1β, TNF-α, and prostaglandin E2. This localized neuroimmune response may alter the excitatory milieu and synaptic connectivity of the kisspeptin-GnRH network, thereby lowering the threshold for HPG axis activation. This review systematically synthesizes current evidence on this immune-endocrine crosstalk and describes how peripheral immune signals may remodel the hypothalamic microenvironment and alter pubertal timing. We further discuss the translational potential of targeting specific neuroimmune pathways for biomarker discovery and the development of novel immunomodulatory interventions for CPP. Although neuroimmune remodeling represents a plausible mechanism underlying obesity-associated pubertal advancement, its causal role requires further validation through targeted mechanistic studies and longitudinal immunophenotyping.
2026-06-22 | Serum inflammatory and metabolic signatures accelerate precocious puberty in obese children.
This study aimed to characterize the interplay of metabolic, hormonal, and inflammatory factors in precocious puberty and obesity. This cross-sectional study enrolled 417 children were included Control (n = 97), Obesity (n = 102), Central Precocious Puberty (CPP, n = 103), and obesity with precocious puberty group (OPP, n = 115) groups. Basic anthropometric, hormonal, metabolic, and inflammatory indicators were analyzed. Group comparisons were performed using ANOVA/Kruskal-Wallis tests. Receiver operating characteristic (ROC) curve was applied to assess biomarkers for predicting precocious puberty in obese children, and Spearman correlation evaluated biomarker relationships. Bone age advancement and elevated levels of LH, FSH, and IGF-1 were observed in both the CPP and OPP group compared to the Controls. ROC curve indicated that IGF-1 had high predictive value (AUC = 0.810) for precocious puberty in obese children. The Obesity and OPP groups exhibited significantly elevated triglycerides, liver enzymes (GGT, ALT), and inflammatory indices (NLR, WBC) relative to the CPP group. OPP correlated positively with LH, FSH, TC, NLR, and IGF-1. Obesity-associated precocious puberty involves concurrent elevations in hormonal, metabolic, and inflammatory biomarkers. Clinical management of pubertal disorders in children with obesity should incorporate integrated assessment of inflammatory and metabolic dysregulation alongside endocrine markers. It provides comparative evidence that the obesity-associated precocious puberty exhibits a more severe metabolic and inflammatory profile than the Central Precocious Puberty without obesity, suggesting obesity exacerbates these dysregulations alongside puberty timing. The findings strongly argue that clinical management of precocious puberty in obese children requires an integrated approach, assessing not just hormonal markers but also metabolic health and inflammation for comprehensive evaluation. It underscores the complex interplay and potential shared mechanisms between metabolic dysfunction, inflammation, and the hormonal activation of puberty, emphasizing the need for future research to investigate these interconnected pathways in pediatric endocrine disorders.
2025-03-20 | Bioinformatics analysis explores key pathways and hub genes in central precocious puberty.
Central precocious puberty (CPP) is one of the common endocrine diseases in pediatrics. However, the molecular mechanisms regulating development of CPP have remained unclear. The purpose of this study was to discover the key pathways and hub genes related to CPP. We analyzed two public datasets (GSE7142 and GSE8310) to identify differentially expressed genes in the progression of CPP. Then, we screened out overlapping differential genes from these two datasets and performed a series of bioinformatics analyses to explore promising targets and molecule mechanism of CPP. We identified 30 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (EP/JUV) datasets and 17 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (LP/JUV) datasets. KEGG signaling pathway shows that calcium signaling pathway is suppressed continuously in early and late pubertal of CPP patients. MAPK signaling pathway also plays an important role in the occurrence and development of CPP. Eventually, we screened out 2 hub genes (FGFR2 and FLT1) highly related to CPP, which may provide a new directions for the diagnosis and treatment of CPP. While further validation is needed, we provide useful and novel information to explore potential signaling pathways and candidate genes for CPP diagnosis and treatment options.
2012-12-31 | The antibodies against the computationally designed mimic of the glycoprotein hormone receptor transmembrane domain provide insights into receptor activation and suppress the constitutively activated receptor mutants.
The exoloops of glycoprotein hormone receptors (GpHRs) transduce the signal generated by the ligand-ectodomain interactions to the transmembrane helices either through direct hormonal contact and/or by modulating the interdomain interactions between the hinge region (HinR) and the transmembrane domain (TMD). The ligand-induced conformational alterations in the HinRs and the interhelical loops of luteinizing hormone receptor/follicle stimulating hormone receptor/thyroid stimulating hormone receptor were mapped using exoloop-specific antibodies generated against a mini-TMD protein designed to mimic the native exoloop conformations that were created by joining the thyroid stimulating hormone receptor exoloops constrained through helical tethers and library-derived linkers. The antibody against the mini-TMD specifically recognized all three GpHRs and inhibited the basal and hormone-stimulated cAMP production without affecting hormone binding. Interestingly, binding of the antibody to all three receptors was abolished by prior incubation of the receptors with the respective hormones, suggesting that the exoloops are buried in the hormone-receptor complexes. The antibody also suppressed the high basal activities of gain-of-function mutations in the HinRs, exoloops, and TMDs such as those involved in precocious puberty and thyroid toxic adenomas. Using the antibody and point/deletion/chimeric receptor mutants, we demonstrate that changes in the HinR-exoloop interactions play an important role in receptor activation. Computational analysis suggests that the mini-TMD antibodies act by conformationally locking the transmembrane helices by means of restraining the exoloops and the juxta-membrane regions. Using GpHRs as a model, we describe a novel computational approach of generating soluble TMD mimics that can be used to explain the role of exoloops during receptor activation and their interplay with TMDs.
1990-02-21 | Luteinizing-hormone-mediated precocious puberty induced in female rats by a prepuberal pituitary graft.
The present study analyzes the mechanism of precocious puberty induced in female rats after a 'young' pituitary graft (obtained from 21-day-old animals). For this purpose, the following experiments have been performed: (1) female rats were grafted or sham-operated on day 21 with a littermate's pituitary the follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol plasma levels as well as the ovarian, uterine and adrenal weights were determined at different times after the graft; (2) female rats grafted or sham-operated on day 21 were treated with 0.2 ml of LH antiserum (LHAS) or the same volume of a normal horse serum (NHS); (3) female rats were injected on day 1 of life with 0.1 mg of estradiol benzoate or olive oil. Groups of these animals were decapitated daily between days 6 and 21 in order to measure gonadotropins and prolactin (PRL) pituitary content. Since on day 21 estrogenized females showed decreased gonadotropin content and normal PRL content, females in experiment 4 were grafted on day 21 with pituitaries obtained from control or neonatally estrogenized female rats. The results obtained showed that FSH, LH and estradiol plasma levels as well as ovarian and uterine weights increased after pituitary grafts. LHAS blocked the precocious puberty induced by the pituitary graft, and pituitaries obtained from neonatally estrogenized female rats were unable to modify the occurrence of puberty when grafted. In conclusion, this work evidences that precocious puberty induced by 'young' pituitary grafts was mediated by the increase in LH secretion from the graft.
small molecules
2026-09-09 | Syndrome differentiation and treatment of pediatric central precocious puberty: role of the spleen-kidney axis.
Pediatric central precocious puberty (CPP) is driven by premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, along with immune-inflammatory imbalance, metabolic dysfunction, obesity, and gut microbiota-derived signals. According to traditional Chinese medicine (TCM) principles, kidney yin deficiency with hyperactive ministerial fire and spleen deficiency with phlegm-dampness form the basis for central pubertal activation and peripheral metabolic-inflammatory burden, thus supporting a combined approach for obesity-related or mixed-pattern CPP. Representative prescriptions include modified Zhibai Dihuang pills with Liujunzi decoction and modified Danzhi Xiaoyao powder with Erchen decoction, which integrate kidney yin-nourishment and ministerial fire-clearance with spleen qi-strengthening and phlegm resolution. Available clinical evidence suggests potential benefits in controlling secondary sexual characteristics, reducing gonadotropin and sex-steroid levels, and slowing bone-age advancement. Mechanistic studies indicate possible regulation of kisspeptin/GPR54/GnRH and LH/FSH-sex-steroid signaling, Th1/Th2/Treg homeostasis, NF-κB/NLRP3 pathways, adipokine imbalance, insulin resistance, hypothalamic inflammation, and gut microbiota-associated metabolism. However, most mechanistic links remain indirect, comparative trials are scarce, and direct correction of pathogenic MKRN3 or DLK1 variants has not been demonstrated. In this review, we have discussed the role of kidney and spleen dysfunction in CPP and explored the underlying mechanisms - particularly in the context of the neuro-endocrine-immune network that links central neuroendocrine activation with peripheral immune-metabolic signals. In addition, the application of TCM in the management of CPP, and the translational challenges of applying TCM as an adjunct to established CPP management have also been explored. Future research should prioritize CPP-specific pathway validation, identification of syndrome biomarkers, multi-omics-based stratification, multicenter trials, and long-term pediatric safety monitoring.
2026-09-03 | Botanical drug preparations and related East Asian medicine interventions for central and idiopathic central precocious puberty: an umbrella review of systematic reviews and meta-analyses.
Central precocious puberty (CPP), particularly idiopathic CPP (ICPP), is characterized by the premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHas) are established biomedical treatments, but treatment burden, cost, and incomplete long-term outcome data have encouraged interest in adjunctive botanical drug preparations used in East Asian medicine. However, these preparations differ substantially in composition, dose, comparator, and reporting quality. The aim of this study is to synthesize systematic reviews (SRs) and meta-analyses (MAs) evaluating botanical drug preparations and related East Asian medicine interventions for CPP/ICPP, appraise methodological quality and certainty, quantify the overlap of primary trials, and identify evidence gaps. Eligible studies included systematic reviews/meta-analyses of randomized trials in children with CPP/ICPP. Databases were searched from inception to September 2025. Evidence was narratively synthesized by formulation family, comparator, and outcome. Review quality was assessed using AMSTAR-2, risk of bias using ROBIS, certainty using GRADE domains where feasible, and primary-trial overlap using the corrected covered area. Four systematic reviews/meta-analyses were included. Favorable signals were reported mainly for Zhibai Dihuang-based preparations, Dabuyin-based preparations, Nourishing Yin-Purging Fire regimens, and botanical drug preparations combined with GnRHas. Outcomes included clinical response, uterine/ovarian volume, gonadotropin levels, estradiol levels, and bone age index. However, interpretation was limited by heterogeneous formulations, variable comparators, an unclear or high risk of bias in the primary trials, incomplete formulation reporting, possible publication/language bias, and overlap of primary studies. Adverse events were incompletely defined and may have been under-reported; long-term pediatric safety was rarely assessed. Current evidence suggests a possible adjunctive benefit of selected botanical drug preparations, particularly in combination with GnRHas, for CPP/ICPP. However, the certainty of the evidence remains low because of methodological weaknesses, heterogeneous interventions, single-country evidence, incomplete safety reporting, and limited long-term outcome data. High-quality multicenter trials with standardized botanical authentication, dosing, outcome definitions, adverse-event surveillance, and long-term follow-up are needed before routine clinical integration can be recommended.
2026-08-13 | Effects of leuprorelin acetate microspheres on sex hormones, secondary sexual characteristics, and predicted adult height in early and fast puberty girls: a real-world, single-arm, retrospective cohort study.
Gonadotropin releasing hormone analogs (GnRHa) are recommended for both central precocious puberty (CPP) and early and fast puberty, but their benefit on final adult height in later onset cases remains controversial. Boennuokang® leuprorelin acetate microspheres, the first domestic generic formulation, have been approved for CPP, but evidence in early and fast puberty girls is still limited. Considering the complexity of clinical management in early and fast puberty, more real-world studies are needed. Therefore, this study aimed to explore the effect of Boennuokang® leuprorelin acetate microspheres on hypothalamic-pituitary-gonadal (HPG) axis and predicted adult height (PAH) in early and fast puberty girls. This real-world, single-arm, retrospective cohort study consecutively enrolled 198 early and fast puberty girls treated with Boennuokang® leuprorelin acetate microspheres at The First Bethune Hospital of Jilin University between January 2022 and November 2023. Early and fast puberty was defined as pubertal onset after the diagnostic age cutoff for CPP, accompanied by progression to the next Tanner stage within 6 months and bone age (BA) advancement exceeding chronological age (CA) progression. Baseline variables were collected from the electronic medical record. Tanner stage was assessed by pediatric endocrinologists, sex hormones were measured using standardized biochemical assays, uterine length was evaluated by pelvic ultrasonography, BA was assessed using the Greulich Pyle method, and PAH was calculated using the Bayley-Pinneau method. Follow-up assessments were performed at baseline (T0) and at 3 (T1), 6 (T2), 12 (T3), and 18 (T4) months. Longitudinal changes were analyzed using repeated measures analysis of variance (ANOVA) or Friedman tests. The mean CA and BA of girls were 9.73±0.99 and 12.08±0.82 years, respectively. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol decreased after 18 months of treatment (all P<0.001). Specifically, the median [quartile 1 (Q1)-quartile 3 (Q3)] LH decreased from 2.7 (2.23-3.51) mIU/mL at T0 to 0.66 (0.48-1.22) mIU/mL at T4; the median (Q1-Q3) FSH decreased from 5.27 (4.82-6.10) mIU/mL at T0 to 2.00 (1.56-2.42) mIU/mL at T4; the median estradiol decreased from 163.50 (129.00-195.00) pmol/L at T0 to 36.70 (36.70-36.70) pmol/L at T4. Of note, the proportions of girls in the Tanner stage B5 exhibited a decreasing trend over time. The length of uterus decreased after 18 months of treatment (P<0.001). BA/CA ratio (P<0.001) and growth velocity (P=0.002) decreased over time. PAH increased, and loss in growth potential [genetic target height (GTH) minus PAH] decreased over time (both P<0.001). Body mass index initially increased after 3 months of treatment, then showed a reducing trend until month 18 (P=0.005). Boennuokang® leuprorelin acetate microspheres are associated with suppression of the HPG axis and increased PAH in early and fast puberty girls.
2026-08-07 | Stigmasterol alleviates central precocious puberty by targeting the IGF-1/PI3K/Akt/mTOR signaling pathway and modulating the Kisspeptin/GnRH axis.
Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis, causing early sexual development and related health risks. Stigmasterol (ST), a natural phytosterol with diverse pharmacological activities, has not been fully evaluated for CPP. This study integrated network pharmacology, molecular docking, and molecular dynamics simulations to identify ST targets in CPP. Experimental validation used an N-Methyl aspartic acid-induced CPP rat model and high-glucose high-fat-stimulated GT1-7 hypothalamic neurons. Techniques included histology, ELISA, qPCR, western blot, and flow cytometry. In silico analyses demonstrated favorable binding of ST to core proteins within the IGF-1/PI3K/Akt/mTOR signaling pathway. In vivo, ST treatment significantly delayed vaginal opening, reduced serum levels of estradiol and testosterone, and ameliorated pathological abnormalities in uterine and ovarian tissues. At the molecular level, ST suppressed the hypothalamic overactivation of the IGF-1/PI3K/Akt/mTOR pathway and attenuated neuronal damage and apoptosis. In vitro, ST inhibited HGHF-induced proliferation, inflammatory cytokine release, and apoptosis in GT1-7 cells, while concurrently modulating the expression of key puberty-related genes and proteins, including those within the Kisspeptin/GnRH axis. Conversely, pharmacological reactivation of PI3K signaling with the agonist 740YP attenuated selected protective effects the protective effects of ST, supporting the functional involvement the PI3K/Akt/mTOR pathway in mediating these benefits. Stigmasterol exhibits significant therapeutic effects against CPP by concurrently targeting the IGF-1/PI3K/Akt/mTOR and Kisspeptin/GnRH signaling pathways. These findings provide robust preclinical evidence supporting ST as a promising multi-targeted natural candidate for CPP management.
2026-07-17 | Mental Health of Youths Who Use Puberty Blockers.
Puberty blockers are an established, reversible intervention for central precocious puberty in children and gender dysphoria in adolescents. Despite broad clinical support, these treatments are currently politically contested. To characterize the mental health of transgender youths prescribed puberty blockers compared with cisgender peers who received these medications for treatment of precocious puberty and with transgender and cisgender youths who did not receive these medications. This retrospective cohort study used data from a US nationwide, multipayer claims database from January 2016 to January 2025. Youths aged 10 to 17 years were categorized into 4 cohorts based on gender modality (transgender or cisgender) and prescription of a puberty blocker (yes or no). Primary outcomes were International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnoses of mood disorders and suicidal thoughts and behaviors. Inverse probability-weighted generalized estimating equation models were fit to obtain adjusted odds ratios (aORs) and 95% CIs, adjusting for demographics, payer type, region, year, socioeconomic disadvantage, and policy environment indices. In demographics, female gender marker is used to indicate that an F (female) has been applied as a marker for the individual by some entity (eg, a medical professional or government body). Among 231 783 youths in the analytical sample, 41 472 youths (17.89%) were transgender (median [IQR] age at baseline, 9.00 [7.00-11.00] years; 31 246 with female gender marker [75.34%]) and 190 311 youths (82.11%) were cisgender (median [IQR] age at baseline, 8.00 [6.00-10.00] years; 128 942 with female gender marker [67.75%]). Being transgender was associated with higher odds of mood disorder diagnosis (aOR, 4.42 [95% CI, 4.24-4.60]) and suicidal thoughts and behaviors (aOR, 12.21 [95% CI, 10.69-13.95]) compared with being cisgender. Being prescribed a puberty blocker was associated with higher odds of mood disorder diagnosis (aOR, 2.11 [95% CI, 2.02-2.19]) and suicidal thoughts and behaviors (aOR, 3.04 [95% CI, 2.65-3.49]) compared with no prescription. However, among transgender youths, prescription of a puberty blocker was associated with decreased adjusted odds of mood disorder diagnosis (aOR, 0.52 [95% CI, 0.45-0.60]) and suicidal thoughts and behaviors (aOR, 0.20 [95% CI, 0.14-0.29]). In this study, transgender youths overall had substantially higher rates of diagnosed mood disorder and suicidal thoughts and behaviors than their cisgender peers, highlighting the need for population-specific interventions. Prescription of a puberty blocker was associated with partial attenuation of this disparity, suggesting mental health benefits associated with this treatment for transgender youth.
proteins
2026-09-03 | Rising incidence of central precocious puberty in Thailand: a nationwide population-based study before, during, and after the COVID-19 pandemic (2018-2024).
Nationwide data on the incidence of central precocious puberty (CPP) and premature thelarche (PT), a benign variant of pubertal development, are limited. To evaluate trends in CPP and PT incidence among Thai children before, during, and after the COVID-19 pandemic. This cross-sectional population-based study used National Health Security Office (NHSO) claims data from 2018 to 2024. CPP and PT were identified using ICD-10-TM (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Thai Modification) codes. Annual incidence rates (AIRs) were calculated for each NHSO-insured population, while incidence rate ratios (IRRs) were estimated using quasi-Poisson regression. A total of 6,782 girls and 189 boys with CPP, and 1,594 girls with PT, were included. Among girls, the CPP AIR increased from 15.0 per 100,000 person-years in 2018 to 51.7 in 2021 and remained elevated during 2022-2024 (44.1-47.7). The IRR was 2.27 (95% confidence interval [CI], 1.82-2.83) for pandemic versus prepandemic, and 1.06 (95% CI, 0.89-1.26) for postpandemic versus pandemic period. An age-stratified analysis showed the greatest increase among girls aged 8 to <9 years. Among boys, the CPP AIR remained low and stable (0.6-1.0 per 100,000 person-years). The female-to-male IRR was 43.0 (95% CI, 33.5-55.3). The incidence of PT in girls increased from 7.2 in 2018 to 14.6 per 100,000 person-years in 2024, with the largest increase observed among those aged 7 to <8 years. The incidence of CPP among Thai girls increased during the COVID-19 pandemic and remained elevated thereafter, whereas the incidence of PT increased gradually. Both trends were most pronounced in peripubertal age groups. Further studies are required to determine whether these patterns reflect pandemic-related factors or an earlier onset of puberty.
2026-05-28 | The central precocious puberty-associated gene MKRN3 is a tumor suppressor regulating CSDE1 ubiquitination in ovarian cancer.
Earlier age at menarche has long been known to be associated with an increased risk of ovarian cancer (OC). However, the underlying mechanisms are not completely understood. Here, we report a paternally inherited imprinted gene, MKRN3, that is associated with central precocious puberty (CPP) and that plays a tumor suppressive role in OC. We found that genomic MKRN3 mutations are significantly more common in OC patients. Genomic mutations in MKRN3 and low MKRN3 expression levels are correlated with poor patient survival. The restoration of MKRN3 in MKRN3-inactivated OC cells significantly suppresses tumor growth and proliferation in vitro and in vivo. Ovary-specific knockout of endogenous MKRN3 accelerates P53 inactivation-induced tumorigenesis in mice. Mechanistically, CSDE1 was identified as a major substrate for MKRN3 in OC via mass spectrometry-based proteomics screens. MKRN3 regulates OC cell proliferation through proteolytic ubiquitination of CSDE1. Our comprehensive data reveal that the CPP-associated gene MKRN3 is a tumor suppressor in human OC. We propose that germline mutations in the MKRN3 gene might partially explain the association between precocious puberty and the risk of OC.
2026-03-12 | Hypothalamic endoplasmic reticulum stress drives pubertal precocity due to early-onset obesity in female rodents.
Early-onset obesity, especially in girls, is frequently associated with advanced puberty; a phenomenon bound to increased risk of long-term complications. Hypothalamic endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of obesity and its comorbidities. However, its contribution to pubertal disorders associated with obesity remains unexplored. We report herein that central ER stress drives obesity-induced precocious female puberty. Hypothalamic expression of key ER stress markers was blunted during normal pubertal transition and altered in female rats with early-onset obesity and advanced puberty, which displayed increased levels of p-PERK and p-eIF2α, and reduced ATF6α content. Central stimulation of hypothalamic ER stress with Thapsigargin in prepuberal lean female rats mimicked advanced puberty onset caused by obesity, without changes in body weight. This phenomenon seemingly involves a circuit including the hypothalamic arcuate nucleus (ARC), since obesity-induced precocious puberty was largely prevented by alleviation of ER stress via virogenetic overexpression of the ER chaperone, GRP78, in the ARC, but not in the paraventricular nucleus, in female rats. In addition, expression analyses of ER stress markers in mouse Kiss1 neurons isolated from juvenile and pubertal female mice revealed increased expression of Perk and Ire1α mRNAs in Kiss1ARC neurons in early-overfed mice at the juvenile stage, while Xbp1s/u expression ratio was significantly increased during juvenile-pubertal transition in overweighed mice. Collectively, our data uncover a relevant role of hypothalamic ER stress in the control of female puberty and the pathogenesis of obesity-induced pubertal alterations.
2026-02-27 | Differential microRNA Expression Profiles in Girls with Idiopathic Central Precocious Puberty and Premature Thelarche.
Idiopathic central precocious puberty (CPP) is increasingly observed in girls. Premature thelarche (PT) and exaggerated thelarche (ET) are early pubertal variants that can be challenging to distinguish from CPP in clinical practice. Exosomal microRNAs are stable biomarkers capable of crossing the blood-brain barrier. Although miR-30b-5p has been reported to increase in pubertal boys and girls, human studies investigating microRNAs in CPP and puberty remain limited. To investigate exosomal microRNA expression profiles and associated pathways in early pubertal development, we conducted a cross-sectional study of 28 girls aged 6-8 years. Serum exosomal microRNA expression was analyzed using next-generation sequencing. Differentially expressed microRNAs (DEmiRNAs) between groups were identified, followed by pathway enrichment analysis. Distinct exosomal miRNA expression patterns were observed among the CPP, ET, and control groups, with 307 DEmiRNAs identified. The CPP, PT, and ET groups exhibited distinct miRNA expression profiles compared with the control group. miR-30b-5p was upregulated in the CPP, ET, and PT groups compared with the control group. Pathway enrichment analysis revealed the involvement of various signaling pathways including AGE-RAGE, MAPK, and mTOR signaling pathways. Serum exosomal microRNAs may serve as biomarkers for early puberty and provide insight into metabolic influences on pubertal development.
2025-12-08 | High-fat diet-induced obesity accelerates puberty in male rats through SMIM20/phoenixin upregulation.
Controversy exists regarding the relationship between obesity and pubertal onset in boys, and the underlying mechanisms remain unclear. To establish a high-fat diet (HFD)-induced obesity model in juvenile male Sprague-Dawley (SD) rats, and to investigate the relationship between obesity and pubertal advancement as well as the role of Smim20/phoenixin (PNX) in male pubertal development. A HFD (45% fat) was administered to male SD rats to induce obesity, while control rats were maintained on a normal diet (ND) from birth. Body weight and preputial separation were monitored as markers of obesity and pubertal onset. At prepubertal (postnatal day 30, PND30) and early pubertal (PND40) stages, serum, hypothalamus, pituitary, testes, and adipose tissue were collected. RT-qPCR was performed to measure the mRNA expression levels of key genes in the hypothalamic-pituitary-gonadal axis (HPGA), including gonadotropin-releasing hormone (GnRH), Kiss1, G protein-coupled receptor 54 (GPR54), GnRH receptor (GnRHr), and Smim20. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and PNX protein were measured by ELISA. Associations among obesity (body mass index, BMI), PNX, and pubertal timing were evaluated using Spearman's correlation. HFD-fed rats exhibited significantly greater body weight and fat mass than ND-fed rats at both time points. (P<0.001), with earlier preputial separation (P<0.001). Testicular weight and expression of GnRH, Kiss1, GPR54, and GnRHr were increased, alongside higher serum LH, FSH, and testosterone (all P<0.05). PNX expression in hypothalamus, pituitary, testes, and subcutaneous fat, as well as serum PNX-14 and PNX-20 levels, were significantly elevated in HFD rats compared with controls (P<0.05). After adjusting for BMI, serum PNX-20 and PNX-14 (P<0.001) remained higher in the HFD group. Body weight was negatively correlated with age at preputial separation and positively correlated with serum LH, testosterone, abdominal circumference, PNX. To our knowledge, this study established a novel HFD-induced model of prepubertal obesity and central precocious puberty (CPP) in male rats. The findings suggest that obesity may accelerate pubertal onset, and that Smim20/PNX may participate in regulating pubertal development in males.
gene therapies
2025-11-17 | Hypothalamic FTO upregulates BDNF to promote GnRH expression through the PI3K/Akt pathway, leading to precocious puberty.
Puberty is among the most important stages in human development. Timely activation of hypothalamic gonadotropin-releasing hormone (GnRH) neurons underlies the initiation of pubertal development. The fat mass and obesity-associated (FTO), which is expressed in the hypothalamus, may regulate the m6A methylation of its target genes, influencing GnRH expression in the hypothalamus during puberty onset. This study aimed to explore the mechanism by which FTO regulates the function of its target neurotrophins within the hypothalamus and to clarify the molecular pathway underlying precocious puberty. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to assess m6A methylation in the hypothalamus of female rats. Serum brain-derived neurotrophic factor (BDNF) levels were measured in girls with central precocious puberty (CPP) and matched controls. BDNF was applied to GnRH neurons in vitro. The functions of FTO were assessed through overexpression and knockdown in animal models, with downstream signaling evaluated via BDNF/PI3K/Akt pathway analysis. Intracerebroventricular (ICV) injections of a BDNF-overexpressing lentiviral vector or a negative control (NC) were used to investigate the role of central BDNF in regulating puberty onset and reproductive function. Hypothalamic GnRH and FTO expression progressively increased whereas m6A methylation decreased during puberty. MeRIP-seq revealed significantly reduced m6A methylation of Bdnf mRNA in the arcuate nucleus (ARC) of female rats during early puberty. In the ARC, BDNF was expressed adjacent to GnRH-positive fibers and terminals. In addition, serum BDNF levels were higher in girls with CPP girls than in the control group. In vitro, BDNF treatment stimulated GnRH expression in GT1-7 cells. FTO positively regulated BDNF expression in an m6A methylation-dependent manner. FTO overexpression activated BDNF/PI3K/Akt signaling in the ARC and accelerated puberty onset. Conversely, FTO knockdown delayed vaginal opening and suppressed BDNF/PI3K/Akt signaling. ICV delivery of a BDNF-overexpressing lentivirus increased hypothalamic BDNF and GnRH expression, leading to a distinct endocrine profile. These findings suggest that FTO regulates the m6A demethylation of BDNF and promotes GnRH expression through the BDNF/PI3K/Akt signaling pathway. This study improves our understanding of the function of BDNF, which is critical for the development of therapeutic strategies for preventing and treating of precocious puberty.
2025-09-15 | Case Report: A case of complex cortical dysplasia with central precocious puberty onset.
A mutation rendering microtubulin and microtubule-associated proteins ineffective leads to a tubulinopathy known as complex cortical dysplasia (CCD), characterized by clinical heterogeneity and a variety of cortical brain developmental abnormalities. These often commence with intellectual disability, epileptic seizures, and motor disorders. In this case, we present a 6-year-old child with CCD whose symptoms began with central precocious puberty. Whole-exome sequencing uncovered a TUBB2B gene heterozygous mutation, NM_178012.5:c.74G > A (p.Ser25Asn). To our knowledge, this mutation has not been previously documented. Computational structural analysis indicated that this variant alters the hydrogen bonding between Ser25 and Trp21, Gly29, and Ile30, thus modifying the secondary structure and function of the protein, contributing to the child's unique clinical presentation. These findings expand the range of TUBB2B gene variants and offer a direction for the precise treatment of this child, underscoring the importance of brain magnetic resonance imaging in children with central precocious puberty.
2025-06-16 | Overexpression of Rap1B alleviate central precocious puberty and neurodevelopmental damage.
The central precocious puberty (CPP) in children and adolescents can adversely impact their overall well-being, affecting both their physical and psychological health. Whether Rap1B can mitigate the development of CPP remains unknown. The expression of Rap1B was investigated through a comprehensive bioinformatics analysis. Precocious puberty model in rats was established through high-fat feeding (HFD), and further injected AAV-Rap1B. Then, HE staining, vaginal exfoliated cell smear and other methods were used to explore the incidence of precocious puberty in rats in each group. In addition, Western blot, RT-qPCR, and IHC was used to detect the expression of GnRH, GnRHR, Kiss1, Kiss1R, NeuN, BDNF, TH, AVP. The contents of LH, FSH, E2, T, and AMH in serum of rats were detected by ELISA. The Rap1B cell line was constructed at the cellular level to explore the effects of FFA(OA + PA) induction on cell proliferation, apoptosis and inflammation. The expression of Rap1B was significantly up-regulated in overexpressing MKRN3 cells, where overexpressing MKRN3 can alleviate the occurrence of CPP. Overexpression of Rap1B alleviates HFD-induced CPP models, including reduce the content of LH, FSH, E2, T, and AMH in serum, and inhibit the expression of GnRH, Kiss1 and Kiss1R in hypothalamus, and alleviates hypothalamus injury. Furthermore, overexpression of Rap1B in the GT1-7 cell. Overexpression of Rap1B can significantly reverse FFA damage to GT1-7 cells and reduce FFA-induced increase of inflammatory factors (IL-6, IL-1β and TNF-α) in GT1-7 cells. This study indicated that overexpression of Rap1B alleviate CPP and neurodevelopmental damage. Our study offers a new approach for the treatment of CPP.
2025-03-13 | Shared Pathophysiological Mechanisms and Genetic Factors in Early Menarche and Polycystic Ovary Syndrome.
Early age at menarche (early AAM) and polycystic ovary syndrome (PCOS) are reproductive and metabolic disorders with overlapping pathophysiological and genetic features. Epidemiological studies suggest a link between these two conditions, both of which are characterized by dysregulation of the neuroendocrine pathways that control pulsatile gonadotropin-releasing hormone secretion, thus affecting gonadotropin release, particularly luteinizing hormone secretion. A common pathophysiology involving positive energy balance and abnormal metabolic status is evident in both disorders. Genetic and epigenetic factors influence the onset of puberty and reproductive outcomes. Genome-wide association studies have identified common genetic variants associated with AAM and PCOS, particularly in genes related to the neuroendocrine axis (e.g., FSHB) and obesity (e.g., FTO). In addition, high-throughput sequencing has revealed rare loss-of-function variants in the DLK1 gene in women with central precocious puberty (CPP), early menarche, and PCOS, who experienced adverse metabolic outcomes in adulthood. This review explores the shared pathophysiological mechanisms between CPP/early AAM and PCOS, examines potential genetic and epigenetic factors that may link these neuroendocrine reproductive conditions, and offers insights into future research and treatment strategies. Understanding these connections may provide new targets for therapeutic interventions and improve outcomes for individuals with these reproductive disorders.
2023-05-17 | A new DLK1 defect in a family with idiopathic central precocious puberty: elucidation of the male phenotype.
We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.
oligonucleotides
2024-03-11 | The functional study of a novel MKRN3 missense mutation associated with familial central precocious puberty.
Central precocious puberty (CPP) refers to a syndrome of early puberty initiation with a characteristic increase in the release of gonadotropin-releasing hormone (GnRH); therefore, it is also called GnRH-related precocious puberty. About a quarter of idiopathic central precocious puberty (ICPP) may be familial. Studies suggest that mutations of makorin ring finger protein 3 (MKRN3) can cause familial central precocious puberty (FCPP). In this report, we describe a Chinese female patient carrying a novel MKRN3 variant (c.980G>A/p.Arg327His) and presenting the CPP phenotype. This novel variant attenuated its own ubiquitination, degradation, and inhibition on the transcriptional and translational activity of GNRH1, which was verified through functional tests. We can consider this variant as a loss-of-function mutation, which subsides the inhibition of GnRH1-related signaling and gives rise to GnRH-related precocious puberty.
2023-09-01 | Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG.
Studies in humans and mice support a role for Makorin RING finger protein 3 (MKRN3) as an inhibitor of gonadotropin-releasing hormone (GnRH) secretion prepubertally, and its loss of function is the most common genetic cause of central precocious puberty in humans. Studies have shown that the gonads can synthesize neuropeptides and express MKRN3/Mkrn3 mRNA. Therefore, we aimed to investigate the spatiotemporal expression pattern of Mkrn3 in gonads during sexual development, and its potential regulation in the functional testicular compartments by gonadotropins. Mkrn3 mRNA was detected in testes and ovaries of wild-type mice at all ages evaluated, with a sexually dimorphic expression pattern between male and female gonads. Mkrn3 expression was highest peripubertally in the testes, whereas it was lower peripubertally than prepubertally in the ovaries. Mkrn3 is expressed primarily in the interstitial compartment of the testes but was also detected at low levels in the seminiferous tubules. In vitro studies demonstrated that Mkrn3 mRNA levels increased in human chorionic gonadotropin (hCG)-treated Leydig cell primary cultures. Acute administration of a GnRH agonist in adult mice increased Mkrn3 expression in testes, whereas inhibition of the hypothalamic-pituitary-gonadal axis by chronic administration of GnRH agonist had the opposite effect. Finally, we found that hCG increased Mkrn3 mRNA levels in a dose-dependent manner. Taken together, our developmental expression analyses, in vitro and in vivo studies show that Mkrn3 is expressed in the testes, predominantly in the interstitial compartment, and that Mkrn3 expression increases after puberty and is responsive to luteinizing hormone/hCG stimulation.
2023-06-19 | Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination.
Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.
2023-04-25 | 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.
2022-12-11 | History of Puberty: Normal and Precocious.
Spanning from bench to bedside, the history of normal and precocious puberty is characterized by a series of remarkable advances that have illuminated reproductive physiology and profoundly impacted clinical care. Early recognition of the hypothalamic and pituitary control of ovarian and testicular function led to the identification of GnRH as the key driver of pubertal onset. Decades later, discovery of the kisspeptin system further refined our understanding of human reproductive neuroendocrinology. Development of long-acting analogs of GnRH revolutionized the treatment of precocious puberty worldwide and ushered in the current era of an ever-expanding therapeutic armamentarium. Identification of monogenic etiologies of precocious puberty has further illustrated the exquisite complexity that comprises neurosecretory modulation of the hypothalamic GnRH neuron and may well lead to exciting novel targeted therapies.
other
2026-09-09 | Hypothalamic neuroimmune remodeling as an immunometabolic bridge between childhood obesity and earlier pubertal onset.
While the link between childhood obesity and central precocious puberty (CPP) is well documented, the immune-mediated mechanisms that may precipitate earlier pubertal onset remain incompletely understood. This review proposes hypothalamic neuroimmune remodeling as a candidate immunometabolic bridge through which chronic low-grade peripheral inflammation may influence the timing of hypothalamic-pituitary-gonadal (HPG) axis activation. In obesity, systemic immune activation is primarily by adipose tissue macrophage infiltration, lipotoxic signaling, and gut dysbiosis. Peripheral inflammatory signals may reach the central nervous system through the arcuate nucleus-median eminence complex, disruption of the blood-brain barrier, and immune-mediated gut-brain pathways. Within the hypothalamus, these signals may elicit local neuroimmune responses. Glial cells, particularly microglia, astrocytes, and tanycytes, undergo inflammatory activation and release cytokines and lipid mediators, including IL-1β, TNF-α, and prostaglandin E2. This localized neuroimmune response may alter the excitatory milieu and synaptic connectivity of the kisspeptin-GnRH network, thereby lowering the threshold for HPG axis activation. This review systematically synthesizes current evidence on this immune-endocrine crosstalk and describes how peripheral immune signals may remodel the hypothalamic microenvironment and alter pubertal timing. We further discuss the translational potential of targeting specific neuroimmune pathways for biomarker discovery and the development of novel immunomodulatory interventions for CPP. Although neuroimmune remodeling represents a plausible mechanism underlying obesity-associated pubertal advancement, its causal role requires further validation through targeted mechanistic studies and longitudinal immunophenotyping.
2026-06-22 | Serum inflammatory and metabolic signatures accelerate precocious puberty in obese children.
This study aimed to characterize the interplay of metabolic, hormonal, and inflammatory factors in precocious puberty and obesity. This cross-sectional study enrolled 417 children were included Control (n = 97), Obesity (n = 102), Central Precocious Puberty (CPP, n = 103), and obesity with precocious puberty group (OPP, n = 115) groups. Basic anthropometric, hormonal, metabolic, and inflammatory indicators were analyzed. Group comparisons were performed using ANOVA/Kruskal-Wallis tests. Receiver operating characteristic (ROC) curve was applied to assess biomarkers for predicting precocious puberty in obese children, and Spearman correlation evaluated biomarker relationships. Bone age advancement and elevated levels of LH, FSH, and IGF-1 were observed in both the CPP and OPP group compared to the Controls. ROC curve indicated that IGF-1 had high predictive value (AUC = 0.810) for precocious puberty in obese children. The Obesity and OPP groups exhibited significantly elevated triglycerides, liver enzymes (GGT, ALT), and inflammatory indices (NLR, WBC) relative to the CPP group. OPP correlated positively with LH, FSH, TC, NLR, and IGF-1. Obesity-associated precocious puberty involves concurrent elevations in hormonal, metabolic, and inflammatory biomarkers. Clinical management of pubertal disorders in children with obesity should incorporate integrated assessment of inflammatory and metabolic dysregulation alongside endocrine markers. It provides comparative evidence that the obesity-associated precocious puberty exhibits a more severe metabolic and inflammatory profile than the Central Precocious Puberty without obesity, suggesting obesity exacerbates these dysregulations alongside puberty timing. The findings strongly argue that clinical management of precocious puberty in obese children requires an integrated approach, assessing not just hormonal markers but also metabolic health and inflammation for comprehensive evaluation. It underscores the complex interplay and potential shared mechanisms between metabolic dysfunction, inflammation, and the hormonal activation of puberty, emphasizing the need for future research to investigate these interconnected pathways in pediatric endocrine disorders.
2025-03-20 | Bioinformatics analysis explores key pathways and hub genes in central precocious puberty.
Central precocious puberty (CPP) is one of the common endocrine diseases in pediatrics. However, the molecular mechanisms regulating development of CPP have remained unclear. The purpose of this study was to discover the key pathways and hub genes related to CPP. We analyzed two public datasets (GSE7142 and GSE8310) to identify differentially expressed genes in the progression of CPP. Then, we screened out overlapping differential genes from these two datasets and performed a series of bioinformatics analyses to explore promising targets and molecule mechanism of CPP. We identified 30 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (EP/JUV) datasets and 17 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (LP/JUV) datasets. KEGG signaling pathway shows that calcium signaling pathway is suppressed continuously in early and late pubertal of CPP patients. MAPK signaling pathway also plays an important role in the occurrence and development of CPP. Eventually, we screened out 2 hub genes (FGFR2 and FLT1) highly related to CPP, which may provide a new directions for the diagnosis and treatment of CPP. While further validation is needed, we provide useful and novel information to explore potential signaling pathways and candidate genes for CPP diagnosis and treatment options.
2012-12-31 | The antibodies against the computationally designed mimic of the glycoprotein hormone receptor transmembrane domain provide insights into receptor activation and suppress the constitutively activated receptor mutants.
The exoloops of glycoprotein hormone receptors (GpHRs) transduce the signal generated by the ligand-ectodomain interactions to the transmembrane helices either through direct hormonal contact and/or by modulating the interdomain interactions between the hinge region (HinR) and the transmembrane domain (TMD). The ligand-induced conformational alterations in the HinRs and the interhelical loops of luteinizing hormone receptor/follicle stimulating hormone receptor/thyroid stimulating hormone receptor were mapped using exoloop-specific antibodies generated against a mini-TMD protein designed to mimic the native exoloop conformations that were created by joining the thyroid stimulating hormone receptor exoloops constrained through helical tethers and library-derived linkers. The antibody against the mini-TMD specifically recognized all three GpHRs and inhibited the basal and hormone-stimulated cAMP production without affecting hormone binding. Interestingly, binding of the antibody to all three receptors was abolished by prior incubation of the receptors with the respective hormones, suggesting that the exoloops are buried in the hormone-receptor complexes. The antibody also suppressed the high basal activities of gain-of-function mutations in the HinRs, exoloops, and TMDs such as those involved in precocious puberty and thyroid toxic adenomas. Using the antibody and point/deletion/chimeric receptor mutants, we demonstrate that changes in the HinR-exoloop interactions play an important role in receptor activation. Computational analysis suggests that the mini-TMD antibodies act by conformationally locking the transmembrane helices by means of restraining the exoloops and the juxta-membrane regions. Using GpHRs as a model, we describe a novel computational approach of generating soluble TMD mimics that can be used to explain the role of exoloops during receptor activation and their interplay with TMDs.
1990-02-21 | Luteinizing-hormone-mediated precocious puberty induced in female rats by a prepuberal pituitary graft.
The present study analyzes the mechanism of precocious puberty induced in female rats after a 'young' pituitary graft (obtained from 21-day-old animals). For this purpose, the following experiments have been performed: (1) female rats were grafted or sham-operated on day 21 with a littermate's pituitary the follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol plasma levels as well as the ovarian, uterine and adrenal weights were determined at different times after the graft; (2) female rats grafted or sham-operated on day 21 were treated with 0.2 ml of LH antiserum (LHAS) or the same volume of a normal horse serum (NHS); (3) female rats were injected on day 1 of life with 0.1 mg of estradiol benzoate or olive oil. Groups of these animals were decapitated daily between days 6 and 21 in order to measure gonadotropins and prolactin (PRL) pituitary content. Since on day 21 estrogenized females showed decreased gonadotropin content and normal PRL content, females in experiment 4 were grafted on day 21 with pituitaries obtained from control or neonatally estrogenized female rats. The results obtained showed that FSH, LH and estradiol plasma levels as well as ovarian and uterine weights increased after pituitary grafts. LHAS blocked the precocious puberty induced by the pituitary graft, and pituitaries obtained from neonatally estrogenized female rats were unable to modify the occurrence of puberty when grafted. In conclusion, this work evidences that precocious puberty induced by 'young' pituitary grafts was mediated by the increase in LH secretion from the graft.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
7 orphan drug designations for Rare central precocious puberty, including 6 approved therapies.
7 orphan drug designations for Rare central precocious puberty, including 6 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
triptorelin pamoate [Triptodur] | peptides | FDA | Approved | Arbor Pharmaceuticals, LLC |
Histrelin [Supprelin LA] | peptides | FDA | Approved | Endo Pharmaceuticals Solutions, Inc. |
Histrelin acetate [Supprelin Injection] | peptides | FDA | Approved | Roberts Pharmaceutical Corp. |
Leuprolide acetate [Lupron Depot-Ped] | peptides | FDA | Approved | AbbVie Endocrine Inc. |
Leuprolide acetate [Lupron Injection] | small molecules | FDA | Approved | AbbVie Endocrine Inc. |
Nafarelin acetate [Synarel Nasal Solution] | small molecules | FDA | Approved | Syntex (USA), Inc. |
Deslorelin | peptides | FDA | Roberts Pharmaceutical Corp. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.