Central Precocious Puberty Research Articles

Clinical and Analytical Presentation of Central Precocious Puberty: A 20-Year Cross-Sectional Study

Objectives − This study aims to compare the clinical and analytical presentation of Central precocious puberty (CPP), considering age.Methods − An observational, cross-sectional study was conducted on children diagnosed with CPP at a level III hospital, between January 2002 and April 2022. Clinical, auxological, sociodemographic, laboratory, and imaging parameters were analyzed.Results − Out of the 52 children studied, the majority were girls (N=44). The median age of puberty onset in girls was 6.79 years and the mean age at first consultation of 8.13 years, with a significantly lower age at hospital referral (7.65 years; P=0.045) compared to boys. Idiopathic etiology was predominant in both. In girls, breast development appeared at older mean ages (P=0.009), while pubic hair growth and accelerated growth were associated with younger ages at puberty onset (P=0.021; P=0.018, respectively). Basal and peak levels of gonadotropin hormones were higher in girls, although not statistically significant. In girls, age at puberty onset correlated negatively with standard deviation of body mass index (P=0.023), while age at first consultation correlated positively with bone age (P<0.001), and was associated with younger ages at Gonadotropin-Releasing Hormone stimulation test (P=0.020).Conclusion − This study provides innovative and relevant findings that enhance understanding of CPP presentation according to age, thereby improving clinical management of this condition.

Efficacy of leuprolide acetate versus triptorelin pamoate administered every 3 months for treatment of central precocious puberty.

Central precocious puberty (CPP) is typically treated with gonadotropin-releasing hormone (GnRH) agonists. Although numerous GnRH agonist variants are available, limited research has compared the efficacy of leuprolide acetate and triptorelin pamoate administered at 3-month intervals. This study aimed to assess the efficacy of CPP treatment with triptorelin pamoate and leuprolide acetate administered at 3-month intervals. This retrospective cohort study included 116 girls with CPP: 71 treated with leuprolide acetate every 3 months and 45 treated with triptorelin pamoate every 3 months. Anthropometric measurements were compared before and after therapy. At 6 months after the therapy, luteinizing hormone (LH) suppression was evaluated. When administered every 3 months, leuprolide acetate and triptorelin pamoate significantly suppressed LH. The predicted adult height (PAH) and degree of bone age advancement at the end of treatment were comparable. Treatment with leuprolide acetate and triptorelin pamoate every 3 months did not have significantly different effects on LH suppression or PAH.

Premature Thelarche: An Updated Review.

Premature thelarche is the most common pubertal disorder in girls. The condition should be differentiated from central precocious puberty which may result in early epiphyseal fusion and reduced adult height, necessitating treatment. The purpose of this article is to familiarize physicians with the clinical manifestations of premature thelarche and laboratory tests that may help distinguish premature thelarche from central precocious puberty. A search was conducted in September 2022 in PubMed Clinical Queries using the key term "Premature thelarche". The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used to compile the present article. Premature thelarche denotes isolated breast development before the age of 8 years in girls who do not manifest other signs of pubertal development. The condition is especially prevalent during the first two years of life. The majority of cases of premature thelarche are idiopathic. The condition may result from an unsuppressed hypothalamic-pituitary-gonadal axis in the early years of life, an "overactivation" of the hypothalamic-pituitary axis in early childhood secondary to altered sensitivity to steroids of the hypothalamic receptors controlling sexual maturation, increased circulating free estradiol, increased sensitivity of breast tissue to estrogens, and exposure to exogenous estrogens. The cardinal feature of premature thelarche is breast development which occurs without additional signs of pubertal development in girls under 8 years of age. The enlargement may involve only one breast, both breasts asymmetrically, or both breasts symmetrically. The breast size may fluctuate cyclically. The enlarged breast tissue may be transiently tender. There should be no significant changes in the nipples or areolae and no pubic or axillary hair. The vulva, labia majora, labia minora, and vagina remain prepubertal. Affected girls have a childlike body habitus and do not have mature contours. They are of average height and weight. Growth and osseous maturation, the onset of puberty and menarche, and the pattern of adolescent sexual development remain normal. Most cases of premature thelarche can be diagnosed on clinical grounds. Laboratory tests are seldom indicated. No single test can reliably differentiate premature thelarche from precocious puberty. Premature thelarche is benign, and no therapy is necessary apart from parental reassurance. As enlargement of breasts may be the first sign of central precocious puberty, a prolonged follow- up period every 3 to 6 months with close monitoring of other pubertal events and linear growth is indicated in all instances.

Buserelin Promotes the Differentiation and Function of Macrophage-Colony-Stimulating Factor-Producing T Helper Cells

ABSTRACT Background Buserelin has been used to treat central precocious puberty (CPP). However, it could potentially result in immune dysregulation to undermine patients’ health. Therefore, it is necessary to elucidate the effects of buserelin on immune cells. Here we explored buserelin-induced impacts on the differentiation and function of macrophage-colony-stimulating factor-producing T helper (ThGM) cells to uncover the immunoregulatory role of buserelin. Methods Rat CPP was induced by danazol injection followed by buserelin treatment. The frequencies of ThGM cells in the spleen and lymph nodes were evaluated by flow cytometry. ThGM cell generation and function were analyzed in cell culture assays. Cell signaling was measured by Immunoblotting. Results Buserelin increased the frequencies of splenic and lymph node ThGM cells. Buserelin promoted the in vitro differentiation and proliferation of ThGM cells. Buserelin-treated ThGM cells showed stronger supportive effects on other effector T helper cells. Buserelin induced the activation of the nuclear factor of activated T cells and extracellular signal-regulated kinase 1/2 in ThGM cells. Conclusion Buserelin enhances the differentiation and function of pro-inflammatory ThGM cells, thus increasing the risk of autoimmune or inflammatory disorders. Therefore, it is necessary to monitor ThGM cells in buserelin-treated children to prevent latent immune dysregulation.

Serum DLK1 During Minipuberty and Pubertal Transition in Healthy Girls and in Girls with Precocious Puberty.

Delta-like non-canonical notch ligand 1 (DLK1) is negatively associated with bodyweight. DLK1 pathogenic variants cause central precocious puberty (CPP) and obesity, suggesting that DLK1 link the well-established association between higher BMI and earlier pubertal onset. However, little is known about the trajectories of circulating DKL1 in healthy girls as well as in girls with precocious puberty. To evaluate longitudinal changes in circulating DLK1 concentrations in 1) full-term, singleton healthy infant girls 2) healthy girls during pubertal transition 3) girls with CPP during treatment with gonadotropin-releasing hormone agonist (GnRHa). Three longitudinal studies of 1) healthy, infant girls (n=85), 2) healthy, peripubertal girls (n=15), 3) girls with CPP before and after GnRHa treatment (n=15).Body fat percentage (BF%) by Slaughter equation. Serum concentrations of DLK1 by ELISA. Serum concentration of DLK1 in healthy infant girls declined significantly through the first year of life (17.6 ng/mL to 9.9 nh/mL, p=0.020). DLK1 was inversely correlated with birth weight and BF%: r=-0.220, p=0.044 and r=-0.503, p<0.001, respectively. DLK1 declined from one year prior to pubertal onset to time of first examination after pubertal onset (10.4 ng/mL to 9.2 n/mL, p=0.004) as well as to time at the last pubertal evaluation (10.4 ng/mL to 9.8 ng/mL, p=0.006). DLK1 levels were not affected by GnRHa treatment. Circulating DLK1 levels declined steeply during infancy and less pronounced through pubertal development. Due to considerable inter-individual variation, DLK1 is not useful as a diagnostic marker of pubertal onset. Importantly, DLK1 was negatively associated with birth weight and body fat percentage.

Serum phoenixin levels in girls with central precocious puberty and premature thelarche.

Phoenixin (PNX), a newly discovered neuropeptide associated with reproduction, has been speculated to be involved in precocious puberty. Therefore, we assessed serum PNX levels in girls with precocious puberty. Serum phoenixin-14 (PNX-14) and phoenixin-20 (PNX-20) levels were determined in girls with central precocious puberty (CPP) and premature thelarche (PT) and in healthy controls (n = 58 per group). Spearman's correlation was used to analyze the correlations between variables. Receiver operating characteristic curves were used to evaluate the performance of PNX for the diagnosis of CPP. Significant predictors of serum PNX levels were determined using least absolute shrinkage and selection operator regression and multiple linear regression analyses. Serum PNX-14 and PNX-20 levels were significantly higher in girls with CPP than in the controls; however, no significant differences in serum PNX-14 and PNX-20 levels were observed between girls with PT and the controls. PNX-20 levels were positively correlated with basal luteinizing hormone (LH) levels, peak LH levels, the peak LH to follicle-stimulating hormone (FSH) ratio, and estradiol levels. No significant correlation was observed between PNX-14 levels and any of these parameters. Multivariate linear regression analysis revealed that PNX-20 levels exhibited the strongest correlation with peak LH/FSH values. The areas under the curve (AUCs) of PNX-14 and PNX-20 for predicting CPP were 0.628 (cut-off value, 100.12 pg/mL; sensitivity, 44.6%; specificity, 77.6%) and 0.775 (cut-off value, 360.03 pg/mL; sensitivity, 66.5%; specificity, 79.3%), respectively. When these two indicators were combined, the AUC was 0.785. Serum PNX levels may be associated with precocious puberty in girls and can be used as an auxiliary CPP indicator. However, given the low sensitivity and specificity of PNX, it should not be used as a single diagnostic indicator of CPP.

Three Therapy Regimens and Their Cost-effectiveness for Girls With Central Precocious Puberty: A Real-World Clinical Study.

The objective of this study was to evaluate the effectiveness and cost-effectiveness of different therapy regimens for girls with central precocious puberty (CPP). This study retrospectively analyzed CPP girls from 2013 to 2021 and grouped them into GnRHa, Mixed, and GnRHa+GH based on therapy regimen. While comparing the differences among these groups, initial age and bone age of GnRHa group girls were significantly lower than Mixed and GnRHa+GH groups, but their growth level was significantly higher (P < .05). In the Mixed group, starting with GnRHa alone, the predicted adult height improvement (ΔPAH) decreased to -1.0 cm in the second year, prompting addition of growth hormone (GH) therapy in the third year, resulting in a ΔPAH increase to 3.0 cm. At therapy completion, final predicted adult heights (PAHs) were similar among the groups at 155.6 to 156.7 cm, with ΔPAH between 5.8 and 6.5 cm and no significant intergroup differences (P > .05). Younger CPP girls with greater height can begin therapy with GnRHa alone. Consideration of combining GH therapy depends on growth velocity and PAH during treatment.

Comparison of central precocious puberty frequency before and during COVID-19: a systematic review and meta-analysis

ObjectiveThe current systematic review and meta-analysis assessed the prevalence of central precocious puberty (CPP) throughout the novel coronavirus disease 2019 (COVID-19) pandemic.DesignA systematic review and meta-analysis were carried out following the principles outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA, 2020).Data sourcesPubMed, Embase, Web of Science, and WANFANG databases were searched from January 1, 2019, to March 30, 2023.Eligibility criteria for selecting studies(1) children and adolescents ≤ 15 years; (2) studies with the outcome of frequency of central precocious puberty, measured prior to and throughout the COVID-19 pandemic; (3) a novel CPP diagnosis was created depending on all of the following criteria: girls with a chronological age < 8 years and boys with a chronological age < 9 years at the onset of symptoms, basal luteinizing hormone (LH) levels > 0.3 UI/L, and/or GnRH-stimulated peak LH levels > 5 IU/L.Data extraction and synthesisThe process of extracting data and evaluating the likelihood of bias was carried out by two independent reviewers. The data were pooled employing the generic inverse-variance method and presented as mean differences (MDs) with 95% CIs. The evaluation of heterogeneity was conducted employing the Cochran Q statistic, and the degree of heterogeneity was measured employing the I2 statistic.ResultsThis meta-analysis included 17 studies. In contrast to the same period prior to the COVID-19 pandemic, the occurrence of CPP elevated (OR = 2.57; 95% CI, 1.85–3.56). Moreover, body mass index standard deviation score (BMI SDS) differences between CPP patients prior to COVID-19 and throughout the pandemic follow-up was 0.12 (95% CI − 0.01 to 0.25 P = 0.06).ConclusionOverall, CPP frequency significantly elevated throughout the COVID-19 pandemic. Given the restricted number of cohort investigations in this meta-analysis, additional research may be conducted on larger groups of children in order to establish a correlation between the observed rise in precocious puberty and specific pathogenic factors.

A Phase3, Open-Label, Single-Arm Trial of the Efficacy and Safety of Triptorelin 6-Month Formulation in Chinese Children with Central Precocious Puberty.

This phase3 study assessed the efficacy, safety, and pharmacokinetics of the 6-month prolonged release (PR) formulation in Chinese children with central precocious puberty (CPP). In this open-label study (NCT05029622), Chinese children (girls < 9years, boys < 10years) received two doses of triptorelin pamoate 22.5mg (day1 and month6). Primary endpoint was the proportion at month6 with luteinizing hormone (LH) suppression (stimulated peak LH ≤ 5IU/L after gonadotropin-releasing hormone stimulation). Secondary endpoints included safety assessments, hormone level changes, and clinical parameters from baseline. Overall, 66 children completed the study (93.9% girls; median age 8.0 [range 5-9] years). At month6, all patients had LH suppression; this was maintained at month12 in 98.5% of patients. Mean basal and peak LH and follicle-stimulating hormone levels were suppressed throughout follow-up. All patients at months3 to 12had sex hormone suppression to prepubertal levels. Stable or reduced breast development was seen for 98.4% and 93.5% of girls at month6 and 12, respectively; all boys had regression or stable genital development until month12. Compared with baseline (9.82cm/year), mean growth velocity was 5.88cm/year at month6 and 5.17cm/year at month12. Mean bone age/chronological age ratio decreased from 1.27 at baseline to 1.23 and 1.21 at month6 and 12, respectively. In girls, 64.5% showed decreased uterine length at month6 and 12 versus baseline, while 75.0% of boys showed stable testicular volume versus baseline. Thirteen patients (19.7%) had 22 drug-related treatment emergent adverse events (TEAEs); no grade ≥ 3 TEAEs were reported. The efficacy and safety profile of triptorelin 6-month PR in Chinese children with CPP was consistent with data previously reported in non-Chinese children with CPP, supporting this as a viable treatment option for Chinese children with CPP. Trial registration:ClinicalTrials.gov identifier, NCT05029622.

Osteocalcin: may be a useful biomarker for early identification of rapidly progressive central precocious puberty in girls.

To assess serum osteocalcin (OC) as a potential biomarker for the early detection of rapidly progressive central precocious puberty (RP-CPP) in girls. Serum OC levels were quantified using enzyme-linked immunosorbent assays (ELISAs). In the retrospective analysis, receiver operating characteristic (ROC) curve analysis was employed to evaluate the ability of OC to identify RP-CPP. A prospective study and screening tests were utilized to assess the potential of OC for use in the early prediction of RP-CPP. Variable selection in the multivariate analysis was conducted using the Bayesian Information Criterion (BIC) and binary logistic regression was employed to construct the diagnostic prediction model. Girls with RP-CPP had significantly higher serum OC levels compared to girls with non-rapidly progressive central precocious puberty (NRP-CPP) (149.04±40.50 vs. 89.10±31.83 ng/mL, P < 0.001). The optimal OC cut-off point for differentiating RP-CPP from NRP-CPP was 107.05 ng/mL, the area under the ROC curve (AUC) was 0.90 (95%CI: 0.851-0.949; P < 0.001), with a sensitivity of 91.1% and specificity of 70.7%. The results of the prospective study indicated that changes in OC precede alterations in estradiol (E2) and bone age (BA). A diagnostic prediction model that includes duration of breast development, BA, OC, high-density lipoprotein cholesterol (HDL-C), and uterine length achieved an AUC of 0.961, with a sensitivity of 94.1% and specificity of 91.5% for the detection of RP-CPP. If OC is excluded from the model, the AUC decreases to 0.894, with sensitivity and specificity declining to 80.5% and 83.1%, respectively. Serum OC levels may serve as a promising biomarker for the early differentiation between RP-CPP and NRP-CPP in girls. The diagnostic prediction model that incorporates duration of breast development, BA, OC, HDL-C, and uterine length effectively identifies girls with RP-CPP.

Revising LH cut-off for the diagnosis of central precocious puberty via triptorelin stimulation assay.

Precocious puberty (PP) in girls is defined by thelarche before age 8. The diagnostic gold standard is an increased LH level following gonadotropin-releasing hormone (GnRH) stimulation. Alternatively, GnRH analogues like triptorelin can be used, though their interpretation varies. Since 2000, we have used a triptorelin-induced LH cut-off of 15 IU/L, 4 h post-stimulus. However, many girls showed LH values below this threshold despite evident pubertal progression. To establish a new LH threshold post-triptorelin stimulation for earlier diagnosis of central precocious puberty (CPP) in girls showing pubertal progression and to evaluate additional parameters for diagnostic accuracy. We enrolled 186 girls with thelarche onset between ages 1-8 and a GnRH analogue assay performed between 2015-2019 without signs of axis activation. Within this cohort, 62 patients repeated the triptorelin test due to rapid pubertal progression. The assay involved administering 100 mcg/m² of triptorelin and measuring LH, FSH, and estradiol levels before and four hours post-injection. Patients with axis activation at the second test had significantly higher post-stimulus LH levels at the first test compared to those below 15 IU/L. They also had higher basal LH levels, elevated LH/FSH ratio, and increased growth velocity. Statistical analysis identified a new post-stimulus LH threshold of 5 IU/L. We propose a LH value of 5 IU/L after triptorelin administration as a new threshold for early CPP diagnosis. While the LH/FSH ratio and growth velocity are associated with axis activation, they did not significantly enhance diagnostic accuracy when combined with the LH value.

Central Precocious Puberty During the COVID-19 Pandemic Period: A Systematic Review of Literature.

Central precocious puberty (CPP) is a condition where the hypothalamus-pituitary-gonadal axis is activated earlier than normal, leading to premature development of secondary sexual characteristics before eight years of age in girls and nine years of age in boys. The purpose of this study was to critically and systematically evaluate the literature regarding CPP rise during the COVID-19 pandemic. We searched PubMed and Google Scholar for relevant articles using the following MeSH terms: "COVID-19, "precocious puberty," "early puberty," "pediatric endocrinology," and "pandemic effects." We included studies calculating the risk of CPP before and during the COVID-19 pandemic. We excluded studies looking at patients with an identifiable cause for CPP or with peripheral precocious puberty. The primary outcome was the prevalence of central precocious puberty during the pandemic compared to the pre-pandemic period. We analyzed data regarding anthropometric, biochemical, and pelvic ultrasound data between the two groups. Overall, 16 studies with 2.175 subjects were included, of which 1.818 were diagnosed with CPP. There was a rise in the number of new diagnoses of CPP during the COVID-19 pandemic (985 subjects) compared with the pre-pandemic period (833 subjects). The mean age of diagnosis in the first group was 7.42 years versus 7.54 years in the second group. Notably, CPPduring the pandemic was associated with a higher body mass index (BMI) compared with the group of the pre-pandemic period (17.50 versus 17.08). The pandemic and lockdowns led to changes in lifestyle habits, social isolation, sleep disturbance, excess screen time, and increased stress levels. We hypothesize that these alterations influenced the increase in CPP frequency.

6825 α-Klotho Levels in Girls with Central Precocious Puberty

Abstract Disclosure: I. Hwang: None. E. Kim: None. Background: The exact mechanisms that trigger the onset of puberty are not fully understood. While it is known that elevated estradiol during puberty induces an increase in IGF-1, which subsequently promotes a rise in α-klotho levels, the relevance of these elevated α-klotho levels in children with Central Precocious Puberty (CPP) remains to be established. Given the potential significance of α-klotho in pubertal development, we initiated this study to determine whether increased α-klotho levels in CPP children are meaningfully pronounced and if these levels could serve as a reliable marker for CPP diagnosis and monitoring. Methods: A total of 139 girls were enrolled in the study, comprised of 82 diagnosed with CPP and 57 who were healthy prepubertal controls. From March 2020 to May 2023, we assessed both α-klotho levels and clinical parameters. α-klotho concentrations were measured using an α-klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Result: α-Klotho levels were higher in the CPP group compared with the controls (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P &amp;lt; 0.001). α-Klotho significantly decreased after 6 months on GnRH agonist treatment.(2147± 789 pg/mL) (P &amp;lt; 0.001). α-Klotho levels were positively correlated with height-SDS, weight-SDS, bone age, ALP, IGF-1 SDS, baseline FSH and LH. α-Klotho relationship with IGF-1 SDS, baseline LH studied by partial correlation with adjustment for age, height and weight SDS (r= 0.275, p= 0.003; r= -0.229, p= 0.014). A ROC curve analysis identified an α-klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing CPP girls from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: Our study indicates a notable association between elevated α-klotho levels and CPP, especially as these levels adjust following GnRH agonist treatment. Based on our findings, considering α-klotho concentrations might offer a way to distinguish CPP from controls. Further studies could elucidate the potential of α-klotho as a biomarker for CPP diagnosis and monitoring. Presentation: 6/1/2024

7269 Interim Analysis of Gonadotropin-Releasing Hormone Agonist (GnRHa) Treatment in Children with Central Precocious Puberty: Focus on FMV Urinary LH Levels and Clinical Outcomes

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) refers to early activation of the hypothalamic–pituitary–gonadal (HPG) axis in children. There is an urgent need to understand the treatment pattern and clinical outcomes among children suffering from CPP. Studies have reported that first morning voided (FMV) urinary Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) have substantial association with CPP tested in GnRH stimulation test and can be useful in diagnosis and management of CPP in children. Gonadotropin-releasing hormone agonists (GnRHa) such as Leuprolide acetate (LA) are the recommended treatment for children suffering from CPP. The current study aimed to provide the information on level of LH and FSH in FMV urine when CPP diagnosis at baseline and the present results may also revealed trend of FMV-LH and FMV-FSH change during LA intervention in children with CPP. Here we present interim results from this study. Methods: This is an open-label, multicentre, single arm, prospective study that enrolled 31 subjects with CPP. Individuals were administered LA depot 11.25 mg, subcutaneously every 12 weeks. The study comprises a screening period; a 6-month treatment period: 24 weeks; and a post-treatment follow-up period: 12 weeks. The FMV urinary LH and FSH were diagnosed by Clopper-Pearson method with a 95% confidence interval. Results: Due to the data collection time point for the interim analysis, only 8 female subjects reached the 12-week visit time point and had a 12-week visit for FMV urinary Gn testing. Therefore, for this interim analysis, only FMV Gn decline at week 12 of the 8 subjects who had a 12-week visit will be presented. At baseline, the mean value of FMV urinary LH and FSH is 0.58 IU/L and 2.27 IU/L respectively. The FMV Gn urinary LH was demonstrated a decrease in 87.5% (95% CI: 47.35,99.68) of the children after LA intervention. Additionally, urinary FSH value of FMV urinary Gn was found to decrease in 75.00% of the children (95% CI: 34.91,96.81) compared to baseline FSH value. Conclusion: The present study reveals a decreasing trend in FMV Gn urinary LH and FSH levels in CPP children treated with LA during interim analysis. LA was shown to be safe and effective in ameliorating the level of LH and FSH in children suffering from CPP. From the study, it can be concluded that urinary LH and FSH may act as a potential biomarker for diagnosis and management of CPP. Presentation: 6/3/2024

6669 Association Between Serum Levels of Thyroid Function and Per- and Polyfluoroalkyl Compounds Concentrations in Central Precocious Puberty in Girls

Abstract Disclosure: Y. Li: None. Y. Xing: None. X. Yin: None. J. Yang: None. S. Zang: None. T. Dong: None. Y. Pan: None. J. Dai: None. P. Li: None. Background: Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with thyroid function in the general population and disturb the timing of puberty onset. Objectives: We investigated the possible relationship between PFASs and thyroid hormone (THs) exposure in girls with central precocious puberty (CPP). Methods: In a prospective study initially established for assessing CPP, 627 serum samples were collected with (n = 226) and without (n = 401) CPP. The concentrations of 25 PFASs, thyroxin (T4), 3,5,3’-triiodothyronine (T3), and 3,3’,5’-triiodothyronine (rT3) were measured. We used logistic regression to examine the association of THs with the odds of having CPP and multiple linear regression to analyze the associations between THs and various PFASs in the CPP and control groups. Results: The levels of T4 in the CPP group were significantly lower than those in the control group, and the levels of T3 and rT3 were significantly higher than those in the control group. After adjusting for confounders, T3 concentrations were associated with 1.526-fold increased odds of having CPP [odds ratio (OR) = 1.526, 95% confidence interval (CI):1.216-1.914]. In the CPP cohort, perfluoroheptanoic acid (PFHpA), perfluoro (2-ethoxyethane) sulphonic acid (PFEESA), and fluorotelomer phosphate diester (6:2/8:2 diPAP) were inversely associated with T3; perfluorobutanoic acid (PFBA) was inversely associated with T4, and PFEESA and 6:2/8:2 diPAP positively associated with T4; PFBA was positively associated with rT3, and perfluorooctane sulfonic acid (PFOS) was inversely associated with rT. In the control cohort, perfluorobutanesulfonic acid (PFBS) was positively associated with T3, and PFEESA and 6:2/8:2 diPAP were inversely associated with T3, and these PFASs had an adverse association with T4. Perfluorohexanoic acid (PFHxA) was positively associated with rT3, and 6:2/8:2 diPAP was negatively associated with rT3. Conclusion: In this study, different measurements of PFASs and THs were observed in the CPP and control groups. Discrepancies in exposure to PFASs were associated with THs in the CPP cohort and healthy girls. Further research is necessary to investigate the mechanism by which PFASs affect the timing of puberty onset and thyroid function. Presentation: 6/1/2024

7128 Efficacy and Safety of Leuprolide Acetate 3M Depot in Chinese Children with Central Precocious Puberty: Interim Analysis of Multicenter, Single-Arm, Prospective Study

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) due to early activation of the hypothalamic-pituitary-gonadal axis leads to early puberty. CPP has a negative impact on adult height. Leuprolide acetate (LA), a gonadotropin-releasing hormone agonist (GnRHa) is the standard treatment for CPP. As CPP requires prolonged treatment, a 3-month (3M) depot formulation would increase patient compliance and reduce the injection burden. This interim analysis presents the effect of LA 3M depot on the gonadotropic axis and assesses safety in children with CPP. Methods: In this open-label, multicenter, single-arm, and prospective study, 31 children with CPP were included. Key inclusion criteria were the appearance of secondary sexual characteristics below the age of eight years in girls and nine years in boys with a confirmed diagnosis of CPP. Children treated with prior GnRHa and/or having underlying medical conditions were excluded. Eligible children were treated with LA 11.25 mg subcutaneously every 12 weeks. The primary endpoint of this interim analysis was the proportion of children achieving inhibition of peak LH defined as peak LH ≤ 3.0 IU/L in the GnRH stimulation test at weeks 24. The secondary endpoint was safety analysis in the children receiving at least one dose of LA 3M depot. Results: At baseline, 30 girls and one boy were enrolled. The median (95% CI) chronological age (CA) of the girls was 8.0 (7.0, 9.0) years and the boy was 10 years old. Girls had a median height of 136.95 (131.5, 139.7) cm, weight of 30 (27, 34) kg, and BMI of 16.4 (15.1, 17.9) kg/m2. Baseline bone (BA) age was 11 (10, 11) years, and BA/CA was 1.24 (1.2, 1.3). Boy’s characteristics at baseline differed in CA (10 years), height (144 cm), and BMI (17.4 kg/m2) from girls of this cohort. Due to the data collection time points for the interim analysis, 8 out of the 31 enrolled subjects had a visit at week 24, and 30 subjects reached the week 12 visit time point and had a visit at week 12. The percentage of children achieving inhibition of peak LH (≤ 3.0 IU/L) in the GnRH stimulation test at week 12 was 100 (88.4, 100) %. At week 24, all of them achieved inhibition of LH in the GnRH stimulation test 100 (63, 100) %. Decreases in BA/CA from baseline at weeks 12 and 24 are 93 (77.9, 99.2) % and 50 (15.7, 84.3) % respectively. No progression of the Tanner stage was observed in 96.7 (82.8, 99.9) % and 100 (63, 100) % at weeks 12 and 24. At the data cut-off, 4 (13.33%) patients experienced a total of 5 treatment-emergent adverse events (TEAEs) in the safety population of 30 subjects. No grade ≥3 AE or serious AE was reported. The incidence of injection site reaction was 3.33%. Conclusion: LA at 11.25mg/3M depot effectively suppresses the gonadotropic axis at weeks 12 and 24, normalizing growth and reversibly slowing the early onset of puberty in children with CPP. LA in a 3-month injecting frequency is a safe and convenient treatment option to improve patient compliance. Presentation: 6/3/2024

12427 MKRN3 Methylation Abnormalities In Patients With Pubertal Disorders

Abstract Disclosure: N.C. Grosek: None. T. Silva: None. J.C. Magnotto: None. A. Latronico: None. A.P. Canton: None. Y. Chan: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objectives: Central Precocious Puberty (CPP) is caused by early reactivation of pulsatile GnRH secretion before age 8 years in girls and 9 years in boys. Delayed puberty (DP) is defined by the absence or incomplete development of sexual characteristics by age 13 years in girls and 14 years in boys. Environmental cues affect the HPG axis and timing of puberty via epigenetic mechanisms such as DNA methylation (DNAm). Inactivating mutations in the maternally imprinted Makorin Ring Finger 3 (MKRN3) gene are the most common genetic defect associated with CPP, representing ∼9% of patients with sporadic and familial CPP. Genomic imprinting occurs through differential methylation of CpG islands at a gene promoter or enhancer region. Differentially methylated regions (DMRs) regulate genetic imprinting. We hypothesized that transcription factor binding sites (TFBS) for ZFP57 (CpG57) andNRF1 (CpGs54+55) within the islet 3.7kb upstream of MKRN3 (MRKN3 islet) may impact expression. This study aimed to analyze if aberrant MKRN3 islet DNAm changes are associated with disorders of pubertal timing. Methods and Results: Germline DNA from 2 control patients was used to analyze the MKRN3 promoter region and islet DNAm profile. Bisulfite-treated DNA was amplified by PCR with primers targeting MKRN3 promoter and islet and submitted to Sanger sequencing. All CpG islands in the promoter region were 100% methylated, but those in the MKRN3 islet were differentially methylated with ∼50-60% methylated. DNA from our CPP cohort (n=71) underwent Next-Generation Sequencing analysis of bisulfite-treated DNA of these regions to identify the DMR potentially associated with MKRN3 imprinting. The MKRN3 islet covered CpG59-CpG49. Next, samples from our CPP cohort and patients with DP (n=44) and normal pubertal timing (n=33; 45% prepubertal, 55% pubertal) underwent pyrosequencing analyses of MKRN3islet. To compare DNAm levels between controls and our cohorts at each CpG island, T-tests were used: reported as mean±SEM. In the CPP cohort, 4/11 CpGs were significantly hypomethylated compared to controls (CpGs 54, 53, 51, 50). Specifically, the NRF1 TFBS was hypomethylated compared to controls (37.8 vs 41.6 ± 1.1, p&amp;lt;0.001) and DP (41.4 vs 43.8 ± 0.83, p=0.044). In the DP group, we found no significant difference in DNAm compared to controls. But they had hypermethylation of 4/11 CpGs compared to the CPP group, including the NRF1 TFBS (CpGs 55, 53, 51,50). Neither the CPP nor DP cohorts had significant DNAm differences at the ZFP57 TFBS compared to controls. Conclusion: Our study showed hypomethylation of 4 out of 11 CpGs in MKRN3 islet, including the NRF1 TFBS, in CPP compared to control and DP groups. On the other hand, NRF1 TFBS was hypermethylated in DPP compared to CPP. Further studies are needed to determine if these alternations in methylation are associated with MKRN3 expression levels and pubertal initiation. Presentation: 6/1/2024

8428 Rare Variants in the MECP2 Gene in Two Boys with Central Precocious Puberty

Abstract Disclosure: A.P. Canton: None. J.B. Mebarak: None. M. Magnuson: None. S. Roberts: None. N. Mauras: None. M. Benson: None. S. Witchel: None. R.S. Carroll: None. A. Latronico: None. U.B. Kaiser: None. A. Abreu: None. Introduction: Central precocious puberty (CPP) occurs more frequently in girls and is usually labelled as idiopathic; however, in boys organic causes are more frequent. Identification of imprinted genes causing CPP have revealed epigenetic mechanisms underlying puberty. MECP2, an X-linked gene, encodes a methylated DNA reader protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder that may be associated with early pubertal development. Recently, rare variants in MECP2 have been recognized in girls with sporadic CPP with or without mild neurodevelopmental disorders. In our cohort of 78 patients with idiopathic CPP, no MECP2 mutations were identified in 73 girls. In this study, five boys with CPP were evaluated for potential MECP2 sequence variants. Methods and Results: Five boys with CPP were screened for MECP2 sequence variants using Sanger sequencing. At the time of CPP diagnosis, they had median (interquartile range) chronological age 9.2 yr (4.3), bone age advancement 2.1 yr (3.5), height SDS 2.3 (1.5), basal LH levels 1.6 IU/L (0.9), and testosterone levels 370 ng/dL (570). Organic causes of CPP were excluded. No MKRN3 or DLK1 mutations were identified. Familial segregation analysis was performed when appropriate. We identified a hemizygous MECP2 variant in a boy (Patient 1) who presented at age 2.7 yr with sporadic CPP. In addition, he had speech delay and behavioral changes, defined as autism spectrum disorder by neuropsychological assessment. He harbored an extremely rare (gnomAD AF=0.000004956) missense variant (p.Val312Ile) in exon 3 of MECP2, encoding the transcriptional repression domain, critical for protein function. The p.Val312Ile mutation was classified as likely pathogenic (ACMG criteria) with a potential association with the phenotype. Another hemizygous MECP2 variant was identified in a boy (Patient 2) who presented at age 8.0 yr with sporadic CPP; he had no neurodevelopmental conditions. He harbored a rare (gnomAD AF=0.00008) missense variant (p.Arg366Cys) in exon 3, encoding the C-terminal domain, classified as a variant of uncertain significance (ACMG criteria). Familial segregation analysis revealed that both boys inherited the MECP2 variants from their unaffected mothers, consistent with a pattern of clinical variability described in women with defects in X-linked genes.Conclusions: We identified rare MECP2 variants in two boys with sporadic CPP without classic features of Rett syndrome, expanding the phenotype of patients with MECP2 mutations, as described in girls. The MECP2 p.Val312Ile variant was likely pathogenic, whereas the functional significance of the p.Arg366Cys variant in still indeterminate. These findings provide additional evidence for a role of MECP2, an epigenetic factor, in the hypothalamic control of pubertal timing. Presentation: 6/1/2024

12672 MKRN3 Methylation Abnormalities In Patients With Pubertal Disorders

Abstract Disclosure: N.C. Grosek: None. T. Silva: None. J.C. Magnotto: None. A. Latronico: None. A.P. Canton: None. Y. Chan: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objectives: Central Precocious Puberty (CPP) is caused by early reactivation of pulsatile GnRH secretion before age 8 years in girls and 9 years in boys. Delayed puberty (DP) is defined by the absence or incomplete development of sexual characteristics by age 13 years in girls and 14 years in boys. Environmental cues affect the HPG axis and timing of puberty via epigenetic mechanisms such as DNA methylation (DNAm). Inactivating mutations in the maternally imprinted Makorin Ring Finger 3 (MKRN3) gene are the most common genetic defect associated with CPP, representing ∼9% of patients with sporadic and familial CPP. Genomic imprinting occurs through differential methylation of CpG islands at a gene promoter or enhancer region. Differentially methylated regions (DMRs) regulate genetic imprinting. We hypothesized that transcription factor binding sites (TFBS) for ZFP57 (CpG57) andNRF1 (CpGs54+55) within the islet 3.7kb upstream of MKRN3 (MRKN3 islet) may impact expression. This study aimed to analyze if aberrant MKRN3 islet DNAm changes are associated with disorders of pubertal timing. Methods and Results: Germline DNA from 2 control patients was used to analyze the MKRN3 promoter region and islet DNAm profile. Bisulfite-treated DNA was amplified by PCR with primers targeting MKRN3 promoter and islet and submitted to Sanger sequencing. All CpG islands in the promoter region were 100% methylated, but those in the MKRN3 islet were differentially methylated with ∼50-60% methylated. DNA from our CPP cohort (n=71) underwent Next-Generation Sequencing analysis of bisulfite-treated DNA of these regions to identify the DMR potentially associated with MKRN3 imprinting. The MKRN3 islet covered CpG59-CpG49. Next, samples from our CPP cohort and patients with DP (n=44) and normal pubertal timing (n=33; 45% prepubertal, 55% pubertal) underwent pyrosequencing analyses of MKRN3islet. To compare DNAm levels between controls and our cohorts at each CpG island, T-tests were used: reported as mean±SEM. In the CPP cohort, 4/11 CpGs were significantly hypomethylated compared to controls (CpGs 54, 53, 51, 50). Specifically, the NRF1 TFBS was hypomethylated compared to controls (37.8 vs 41.6 ± 1.1, p&amp;lt;0.001) and DP (41.4 vs 43.8 ± 0.83, p=0.044). In the DP group, we found no significant difference in DNAm compared to controls. But they had hypermethylation of 4/11 CpGs compared to the CPP group, including the NRF1 TFBS (CpGs 55, 53, 51,50). Neither the CPP nor DP cohorts had significant DNAm differences at the ZFP57 TFBS compared to controls. Conclusion: Our study showed hypomethylation of 4 out of 11 CpGs in MKRN3 islet, including the NRF1 TFBS, in CPP compared to control and DP groups. On the other hand, NRF1 TFBS was hypermethylated in DPP compared to CPP. Further studies are needed to determine if these alternations in methylation are associated with MKRN3 expression levels and pubertal initiation. Presentation: 6/1/2024

7202 CPP with Rapid Pubertal Progression in a 9-Year-Old Boy with Hypothalamic Teratoma

Abstract Disclosure: R. Robilliard: None. G. Tung: None. K. Svokos: None. R. Lulla: None. J.Q. Quintos: None. Background: Central Precocious Puberty (CPP) in males is rare, with incidence of 0.01-2/10,000. The most common identifiable cause of CPP in young children is hypothalamic hamartoma. No case hypothalamic teratoma has been reported to cause CPP in males. Clinical Case: At the age of 10-years and 5-months, a boy presented to the pediatric endocrinology with signs of precocious puberty including facial hair development, voice deepening, and increased growth velocity that began at 9 years old. There was no significant past medical history and he denied headache, blurry vision, or diplopia. Physical examination showed height of 140.4 cm (47%), Tanner 4 genitalia, Tanner 3 pubic hair, and testicular volumes of 15 cc (left) and 12-15cc (right). Bone age (BA) determined by radiography was 13.5 years with a predicted adult height (PAH) of 63 inches. The mid-parental target height was 67 +/- 4 inches. Evaluation including TSH, glucose, serum and CSF β-HCG, DHEA, CSF AFP was normal. Serum LH was 2.9 IU/L and testosterone level was 109 ng/dl, consistent with CPP. MRI of the pituitary showed a small, heterogeneous and fat-containing lesion extending inferiorly from the tuber cinereum consistent with teratoma. Treatment included GnRH agonist Lupron (30mg) every 3 months. Laboratory evaluation 8 months after initial presentation showed suppressed LH of 0.9 IU/L and FSH 0.5 mIU/mL, and testosterone of 57 ng/dL. Repeat radiography for BA one year after GnRHa suppression showed BA of 14 years at CA of 11 years 6 months and PAH of 64.4 inches. Growth velocity slowed to 5.3 cm/year. At the most recent follow-up visit at CA of 12 years, height was 151.5 cm (61%), growth velocity 6.3 cm/year (74% for age), Tanner 5 penis and pubic hair, left testicular volume of 15-20cc and right testicular volume of 15 cc. Most recent radiographic BA is14 years, and PAH is 65.9 inches. Given response to GnRH agonist injections every 3 months, the absence of CNS symptoms referable to the teratoma and no change in MR imaging, no surgical intervention is recommended. Conclusion: This is the first case of a hypothalamic teratoma reported in a male associated with CPP. Despite this rare cause, the patient has responded to standard treatment with GnRH agonist therapy alone. Presentation: 6/1/2024