New liquid chromatography tandem mass spectrometry reference data for estradiol show mini-puberty in both sexes and typical pre-pubertal and pubertal patterns.

CONTEXT: Reliable estradiol (E2) reference intervals (RIs) are crucial in pediatric endocrinology. OBJECTIVES: This study aims to develop a sensitive ultra-performance liquid chromatographic tandem mass spectrometry (UPLC-MS/MS) method for E2 in serum, to establish graphically represented RI percentiles and annual RIs for both sexes, and to perform a systematic literature comparison. METHODS: First, a UPLC-MS/MS method for E2 was developed. Second, graphically represented RI percentiles and annual RIs covering 0-18 years were computed (cohort of healthy children [1181 girls and 543 boys]). Subsequently, RIs were compared with published data by systematic searches. RESULTS: Lower limit of quantification was 11 pmol/L, indicating high sensitivity. Estradiol first peaked during mini-puberty in both sexes (girls up to 192 pmol/L; boys up to 225 pmol/L). As could be expected, girls showed higher pubertal E2 (up to 638 pmol/L). However, boys' RIs (up to 259 pmol/L) overlapped considerably. We found 4 studies in the literature that also used LC-MS/MS to determine E2 and published RIs for the complete pediatric age range. Reference intervals varied considerably. Pre-pubertal and pubertal phases were present in all studies. Higher E2 during the time of mini-puberty in both sexes was documented in 3 studies including ours. CONCLUSIONS: Variability of RIs for E2 between studies illustrates the importance of laboratory-specific RIs despite using a LC-MS/MS reference method. In boys, the striking E2 peak during mini-puberty as well as high pubertal E2 without phenotypic estrogenization in regular male puberty indicates that the role of E2 in children and, especially in boys, requires better functional understanding.

Correlation between imaging findings and hormonal markers at the onset of puberty in girls.

INTRODUCTION: This study aimed to determine the diagnostic performance of transabdominal pelvic ultrasonography and bone age in identifying the onset of puberty in girls at the Clínica Las Américas in Medellín, Colombia. METHODS: We included girls aged ≤11 years referred to our clinic between March 2016 and March 2019 for signs of puberty. We compared the findings on pelvic and breast ultrasonography and bone age versus the baseline measurement of luteinizing hormone (LH) in serum, used as the reference standard for identifying the onset of puberty. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios, analyzing subgroups of patients of different ages. RESULTS: We analyzed 43 patients. Ultrasound assessment of breast development had the highest sensitivity (94.1%) of all the imaging parameters evaluated, but its specificity was low. However, characteristics such as the length of the body of the uterus >3.0 cm and the presence of endometrial echoes were highly specific for identifying the onset of puberty, particularly in patients aged ≤8 years. CONCLUSION: Pelvic ultrasonography, ultrasonographic assessment of Tanner stage of breast development, and the evaluation of bone age are useful tools for the imaging confirmation of the onset of puberty. The results of this study support the use of these techniques in clinical practice in the workup for pubertal disorders in girls.

Sexual maturity of children on regular hemodialysis: Role of testosterone and estradiol, a tertiary multicenter experience.

ABSTRACT: A big problem is the delayed growth and sexual maturity in children with chronic kidney disease (CKD) with the consequent reduction in adults' height. Testosterone and estradiol have significant physiologic changes in children suffering from CKD, resulting in delayed puberty. We aim to assess blood levels of these hormones in patients with CKD-5 on regular hemodialysis.One hundred-six participants were enrolled in the current study, 56 of whom had CKD on hemodialysis 3 times a week 4 hours per session, and 60 healthy age- and gender-matched children acted as controls. Full history was taken, and a clinical review was performed on both patients and controls. The pubertal assessment was performed according to Tanner's classification and laboratory investigations of total and free serum (s.) testosterone in boys and s.estradiol in girls.Patients' weight and height were considerably lower than controls. The free and total s.testosterone of patients were significantly reduced. The same applies to s.estradiol levels which were substantially reduced in comparison to controls. In both patients and controls, Tanner staging & male total s.testosterone levels and female s.estradiol levels had significant positive associations. There was a negative association between the sex hormones levels and the disease's and dialysis duration in the patients' group.S.testosterone and s.estradiol levels were significantly low in CKD patients on dialysis and were positively correlated with delayed pubertal growth observed in those patients.

High-fructose diet during puberty alters the sperm parameters, testosterone concentration, and histopathology of testes and epididymis in adult Wistar rats.

The consumption of fructose has increased in children and adolescents and is partially responsible for the high incidence of metabolic diseases. The lifestyle during postnatal development can result in altered metabolic programming, thereby impairing the reproductive system and fertility during adulthood. Therefore, the aim of this study was to evaluate the effect of a high-fructose diet in the male reproductive system of pubertal and adult rats. Male Wistar rats (30 d old) were assigned to four different groups: Fr30, which received fructose (20%) in water for 30 d and were euthanized at postnatal day (PND) 60; Re-Fr30, which received fructose (20%) for 30 d and were euthanized at PND 120; and two control groups C30 and Re-C30, which received water ad libitum and were euthanized at PND 60 and 120, respectively. Fructose induced an increase in abnormal seminiferous tubules with epithelial vacuoles, degeneration, and immature cells in the lumen. Moreover, Fr30 rats showed altered spermatogenesis and daily sperm production (DSP), as well as increased serum testosterone concentrations. After discontinuing high-fructose consumption, DSP and sperm number decreased significantly. We observed tissue remodeling in the epididymis, with a reduction in stromal and epithelial compartments that might have influenced sperm motility. Therefore, we concluded that fructose intake in peripubertal rats led to changes in the reproductive system observed both during puberty and adulthood.

Low Serum 25-hydroxyvitamin D Level Does Not Adversely Affect Bone Turnover in Prepubertal Children.

Both vitamin D and insulin-like growth factor 1 (IGF-1) play essential roles in bone metabolism and may interact during prepubertal bone accrual. We investigated the association of low serum 25-hydroxyvitamin D (25(OH)D) (<20 ng/mL) with the circulating bone turnover markers, when compared to their interaction with IGF-1. SUBJECTS AND METHODS: Serum 25(OH)D, IGF-I, P1NP (N-terminal propeptide of type I procollagen), and CTX-1 (C-terminal telopeptide of type I collagen) were measured, and the bone turnover index (BTI) was calculated in 128 healthy children, aged 9-11 years. RESULTS: Mean 25(OH)D concentration was 21.9 ± 4.9 ng/mL, but in 30.5% of participants it was <20 ng/mL (<50 nmol/L). We observed a trend for higher P1NP (p < 0.05) and IGF-1 (p = 0.08), towards lower 25(OH)D in tertiles. Levels of P1NP in the lowest 25(OH)D tertile (<20 ng/mL) were the highest, while CTX and BTI remained unchanged. Additionally, 25(OH)D negatively correlated with IGF-1, while the correlation with P1NP was not significant. A strong positive correlation of IGF-1 with P1NP and BTI but weak with CTX was observed. Low 25(OH)D (<20 ng/mL) explained 15% of the IGF-1 variance and 6% of the P1NP variance. CONCLUSIONS: Low levels of 25(OH)D do not unfavorably alter bone turnover. It seems that serum 25(OH)D level may not be an adequate predictor of bone turnover in children.

Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood.

BACKGROUND: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. METHODS: In this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). FINDINGS: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. INTERPRETATION: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. FUNDING: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyv€askyl€a, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001), the Food and Health Bureau of Hong Kong SAR's Health and Medical Research Fund (HMRF grants 15162161 and 07181036) and the CUHK Direct Grants for Research (2016¢033 and 2018¢034), and a postdoctoral fellowship from K. Carole Ellison (to T.W.). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. This work was supported by European Union's Horizon 2020 research and innovation programme LongITools 874739.

Reduced Insulin-Like Growth Factor 1 Is Associated with Insulin Resistance in Obese Prepubertal Boys.

As one of the most common features of obesity, insulin resistance is central to the pathogenesis of the metabolic syndrome. Low insulin-like growth factor 1 (IGF-1) levels have been proven to be associated with many traditional cardiovascular risk factors, but it still remains controversial with the relationship between IGF-1 and insulin resistance. Accordingly, the main purpose of this study is to investigate the relationship between IGF-1 and insulin resistance in obese prepubertal boys. We used the whole-body insulin sensitivity index (WBISI) to represent insulin resistance. 70 obese prepubertal boys were included in the study, and the obese subjects were divided into two groups by using 1.285 as a threshold value for WBISI. Clinical examination and laboratory examinations were assessed for all participants. Among obese boys, the group of children with WBISI ≤ 1.285 had lower IGF-1 standard deviation scores (SDS) (p = 0.021) than the WBISI > 1.285 group. The results of multiple linear analyses show that lg WBISI was positively correlated with IGF-1 SDS (p = 0.031) after adjusting for traditional cardiovascular risk factors. IGF-1 SDS was negatively associated with insulin resistance in obese prepubertal boys, independent of other traditional cardiovascular disease risk markers.

PRO-C3, a Serological Marker of Fibrosis, During Childhood and Correlations With Fibrosis in Pediatric NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and may lead to cirrhosis requiring liver transplant. Thus, prompt diagnosis of advanced fibrosis is essential. Our objectives were to examine PRO-C3 (a neo-epitope pro-peptide of type III collagen formation) levels across childhood/adolescence and associations with advanced fibrosis in pediatric NAFLD. This cross-sectional study included 88 children and adolescents with biopsy-proven NAFLD (mean age: 13.9 ± 2.9 years, 71% male) and 65 healthy participants (11.8 ± 4.5 years, 38% male). PRO-C3, and the bone remodeling biomarkers C-terminal telopeptide of type I collagen (CTX-I; bone resorption) and osteocalcin (N-MID; bone formation), were measured in serum by enzyme-linked immunosorbent assay. Fibrosis was assessed by liver biopsy in participants with NAFLD, who were categorized as having advanced (Ishak score ≥ 3) or none/mild fibrosis (Ishak score ≤ 2). Overall, PRO-C3 was similar in participants with NAFLD (median [interquartile range]: 20.6 [15.8, 25.9] ng/mL) versus healthy participants (19.0 [13.8, 26.0] ng/mL), but was significantly lower in older adolescents ≥ 15 years old (16.4 [13.0, 21.2] ng/mL) compared with children ≤ 10 years old (22.9 [18.1, 28.4] ng/mL; P < 0.001) or 11-14 years old (22.4 [18.3, 31.2] ng/mL; P < 0.001). PRO-C3 was also directly correlated with levels of CTX-I and N-MID (r = 0.64 and r = 0.62, respectively; both P < 0.001). Among participants with NAFLD, PRO-C3 was higher in those with advanced fibrosis (median [IQR]: 28.5 [21.6, 37.6]) compared with none/mild fibrosis (20.3 [18.2, 22.8]; P = 0.020) in models adjusted for age, sex, and body mass index z-score. However, associations were attenuated after additionally adjusting for bone-remodeling CTX-I (P = 0.09) or N-MID (P = 0.08). Conclusion: Collectively, these findings show that PRO-C3 levels are higher in children with advanced fibrosis in NAFLD, but are also influenced by age and pubertal growth spurt, assessed by bone remodeling biomarkers, and therefore may not be a reliable biomarker for liver fibrosis in pediatric NAFLD until late adolescence.

Vitamin D status in pubertal children.

BACKGROUND: Optimal vitamin D status has a great importance in puberty, which is a period of peak bone mineral acquisition. In this study, we aimed to assess the effect of pubertal period on vitamin D status. METHODS: The study included totally 200 healthy children, aged between 4 and 14 years. Group 1 included 100 prepubertal, children, aged between 4 and 8 years. Group 2 included 100 pubertal children, aged between 9 and 14 years. They had no chronic illnesses. Ages, heights, weights, genders, Body Mass Indexes (BMIs), socioeconomic and educational status of families were established. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured by high performance liquid chromatography (HPLC). Serum parathyroid hormone (PTH) was evaluated using an immunoradiometric assay kit. Serum calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) levels were measured. RESULTS: We determined that 25(OH)D levels were lower with higher PTH levels in the group aged 9 to 14 years (pubertal children), compared to the group aged 4 to 8 (prepubertal children). Gender, weight, height or BMI, family socioeconomic and education status did not affect serum 25(OH)D levels of children in each group. CONCLUSIONS: We demonstrated that vitamin D deficiency was more commonly seen in the pubertal children, compared to pre pubertal period. Children should be supported with vitamin D supplements during the puberty, which has a great importance for rapid increase in bone mass.

Pediatric Reference Intervals for Thyrotropin, Free Triiodothyronine, and Free Thyroxine and the Relevance of Body Mass Index and Puberty in Measurement Interpretation.

Background: The present study aimed to establish age- and sex-specific reference intervals for serum concentrations of thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) in healthy children and adolescents. Additionally, we investigated the association of TSH, fT3, and fT4 with putative influencing factors, such as sex, body mass index (BMI), and puberty. Methods: A total of 9404 blood serum samples from 3140 children and adolescents without thyroid affecting diseases were included in determining TSH, fT3, and fT4 levels and age- and sex-specific reference ranges. To investigate the association of TSH, fT3, and fT4 with age, sex, weight status, and the role of puberty-based changes, the hormone levels and BMI values were converted to standard deviation scores (SDS). Results: In general, TSH, fT3, and fT4 were found to be age- and sex-dependent. Puberty was accompanied by decreased TSH, decreased fT3 with a temporary peak in males, and a temporary nadir of fT4 in Tanner stage 3 for both sexes. BMI-SDS was positively associated with TSH-SDS (ß = 0.081, p < 0.001); the effect was more pronounced in overweight subjects (ß = 0.142, p < 0.01) and insignificantly negative in underweight subjects (ß = -0.047, p > 0.05). BMI-SDS was positively associated with fT3-SDS (ß = 0.066, p < 0.001) and negatively associated with fT4-SDS (ß = -0.135, p < 0.001), with the effect insignificantly less negative in overweight children (ß = -0.055, p > 0.05). Conclusions: Age- and sex-specific reference intervals are important for the interpretation of measurements of TSH, fT3, and fT4 in children and adolescents. Influencing factors such as BMI and puberty should be taken into consideration when using measurements of TSH and thyroid hormones in the diagnosis, treatment, and monitoring of thyroid diseases. Clinical Trial Registration number: NCT02550236.

Circulating miR-30b levels increase during male puberty.

OBJECTIVE: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. DESIGN AND METHODS: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. RESULTS: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05). CONCLUSIONS: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.

The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

The gap between overweight and obesity status in children - (STROBE-compliant article).

ABSTRACT: Overweight might represent only the early stage of obesity or it might act as a trigger of self-awareness turning into an ideal chance for preventing further obesity development.The aim of this study was to assess the differences between overweight and obese children in terms of anthropometric, low-grade systemic inflammation, liver impairment and atherosclerotic risk.We performed a study on 132 children aged between 5 and 18 years, divided according to the BMI into 2 groups: group 1 to 76 obese children, and group 2 to 56 overweight children, assessing anthropometric, laboratory and elastography parameters.We obtained significantly higher values of anthropometric parameters in obese children versus overweight ones. We found higher levels of leukocytes, lymphocytes, AST, ALT, and E median (P = .0345, P = .0103, P < .0001, P = .0008 and P < .0001) in the obese group as compared to the overweight one. BMI was positively correlated with neutrophils, NLR, ESR, glycemia, anthropometric parameters, and E median (P = .0007/<.0001/.0018/.0044/<.0001/<.0001/<.0001/<.0001/<.0001/.0204); and negatively with lymphocytes and HDL-cholesterol (r = -0.2747/-0.2181, P = .0116/.0120).Our study underlined significant differences between overweight and obese children in terms of inflammatory status and liver impairment suggesting that the risk is directly related to the increase in BMI.

Recovery of hypothalamus-pituitary-gonadal dysfunction after the treatment of suprasellar germ cell tumors.

OBJECTIVE: To investigate the incidence of hypothalamus-pituitary-gonadal (HPG) axis initiation/recovery after treatment and to identify predictive risk factors for noninitiation/recovery. METHODS: A total of 127 consecutive suprasellar germ cell tumor (GCT) patients managed at Peking Union Medical College Hospital (2006-2019) were retrospectively analyzed. Prepubertal patients (followed up until 13 years of age for girls and 14 years of age for boys) and patients with HPG dysfunction (followed up for 2 years) were divided into the initiation/recovery and noninitiation/recovery groups. RESULTS: Of the 127 suprasellar GCT patients, 75 met the follow-up criteria, 28 (37.3%) of whom experienced HPG axis initiation/recovery. Compared to the noninitiation/recovery group, the initiation/recovery group included more males and had shorter delayed diagnosis times, smaller tumor sizes, lower panhypopituitarism rates, thinner pituitary stalk widths, lower visual deficit rates, and higher serum testosterone and estradiol levels. The cutoff values of pituitary stalk width, tumor size, and delayed diagnosis time used to predict noninitiation/recovery were 6.9 mm, 6.9 mm and 1.7 years, respectively. Tumor size ≥6.9 mm (odds ratio (OR) = 7.5, 95% CI: 2.2-25.8, P = 0.001), panhypopituitarism (OR = 5.0, 95% CI: 1.4-17.6, P = 0.013), and delayed diagnosis time ≥1.7 years (OR = 5.7, 95% CI: 1.5-20.7, P = 0.009) were risk factors for noninitiation/recovery. CONCLUSIONS: Among suprasellar GCT patients, nearly one-third of prepubertal patients and patients with HPG dysfunction experience HPG axis initiation/recovery after treatment. Tumor size ≥6.9 mm, panhypopituitarism, and delayed diagnosis time ≥1.7 years were identified as predictive risk factors for noninitiation/recovery.

Pubertal Testosterone and the Structure of the Cerebral Cortex in Young Men.

Adolescence is a period of brain maturation that may involve a second wave of organizational effects of sex steroids on the brain. Rodent studies suggest that, overall, organizational effects of gonadal steroid hormones decrease from the prenatal/perinatal period to adulthood. Here we used multimodal magnetic resonance imaging to investigate whether 1) testosterone exposure during adolescence (9-17 years) correlates with the structure of cerebral cortex in young men (n = 216, 19 years of age); 2) this relationship is modulated by the timing of testosterone surge during puberty. Our results showed that pubertal testosterone correlates with structural properties of the cerebral cortex, as captured by principal component analysis of T1 and T2 relaxation times, myelin water fraction, magnetization transfer ratio, fractional anisotropy and mean diffusivity. Many of the correlations between pubertal testosterone and the cortical structure were stronger in individuals with earlier (vs. later) testosterone surge. We also demonstrated that the strength of the relationship between pubertal testosterone and cortical structure across the cerebral cortex varies as a function of inter-regional profiles of gene expression specific to dendrites, axonal cytoskeleton, and myelin. This finding suggests that the cellular substrate underlying the relationships between pubertal testosterone and cerebral cortex involves both dendritic arbor and axon.

Relationship of age at menarche and serum leptin with the metabolically unhealthy phenotype in adolescents.

INTRODUCTION: Objective: to analyze the relationship of age at menarche and leptin with the metabolically healthy (MH) and metabolically unhealthy (MUH) phenotypes in adolescent girls in different body mass index (BMI) categories. Method: an observational and cross-sectional study consisting of 139 female adolescents attended to at the Adolescent Reference Center in Macaé, Rio de Janeiro. Menarche was classified as early (EM) when the first menstruation occurred at or before 11 years of age; normal menarche (NM) was categorized at ages 12 to 14; menarche was considered late (LM) when it occurred at age 15 or older. The factors required to ascertain the subjects' phenotype, as well as their leptin levels, weight, and height, were measured and their BMIs were calculated. The girls were classified as MH or MUH based on the NCEP-ATP III criteria as adapted for children and adolescents. Results: 82 % (n = 114) of the girls were classified as MH and 18 % (n = 25) as MUH. Mean age at menarche was 11.79 ± 1.39 years. There was a higher prevalence of MUH amongst the girls who had EM (p = 0.04). A higher inadequacy of serum leptin concentrations was found in girls who had EM (p = 0.05) and in those classified as MUH (p = 0.01). The adolescents who were severely obese exhibited inadequate leptin levels (p < 0.01) and had gone through EM (p = 0.02). A total of 8.1 % (n = 7) of the normal-weight girls were classified as MUH, and 29.4 % (n = 5) of those who were severely obese were classified as MH (p < 0.01). Conclusion: early menarche and high serum leptin concentrations are related with the MUH phenotype in adolescent girls in different BMI categories.

INTRODUCCIÓN: Objetivo: analizar la relación de la edad de la menarquia y los niveles de leptina con los fenotipos metabólicamente saludables (MS) y metabólicamente no saludables (MNS) en adolescentes de diferentes categorías de índice de masa corporal (IMC). Método: estudio observacional y transversal compuesto por 139 adolescentes de sexo feminino, atendidas en el Centro de Referencia para Adolescentes de Macaé, Río de Janeiro. La menarquia se clasificó como precoz (MP) cuando se produjo la primera menstruación a o antes de los 11 años de edad; la menarquia normal (MN) se clasificó como aquella sucedida a la edad de 12 a 14 años; la menarquia se consideró tardía (MT) cuando ocurrió a los 15 años o más. Se midieron los factores necesarios para determinar el fenotipo de los sujetos, y se midieron sus niveles de leptina, peso y altura, y se calculó su IMC. Las adolescentes se clasificaron como MS y MNS según los criterios de NCEP-ATP III, adaptados para niños y adolescentes. Resultados: el 82 % (n = 114) de las adolescentes se clasificaron como MH y el 18 % (n = 25) como MUH. La edad media de la menarquia fue de 11,79 ± 1,39 años. Hubo una mayor prevalencia de MUH entre las adolescentes que tenían MP (p = 0,04). Se encontró una mayor insuficiencia de las concentraciones séricas de leptina en las adolescentes que tenían MP (p = 0,05) y en aquellas clasificadas como MNS (p = 0,01). Las adolescentes que eran severamente obesas exhibieron niveles inadecuados de leptina (p < 0,01) y habían pasado por una MP (p = 0,02). El 8,1 % (n = 7) de las adolescentes de peso normal se clasificaron como MNS y el 29,4 % (n = 5) de las que eran severamente obesas se clasificaron como MS (p < 0,01). Conclusión: la menarquia temprana y las altas concentraciones séricas de leptina están relacionadas con el fenotipo MNS en las adolescentes de diferentes categorías de IMC.

Circulating LEAP-2 is associated with puberty in girls.

BACKGROUND/OBJECTIVES: Liver-expressed antimicrobial peptide 2 (LEAP-2) was recently identified as an endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status in humans. Despite the relevant role of ghrelin in childhood, puberty, and childhood obesity, the potential implication of LEAP-2 in these aspects remains totally unknown. We aimed to investigate the regulation of circulating plasma LEAP-2 in childhood and adolescent either lean or obese. METHODS AND RESULTS: Plasma levels of LEAP-2 were analyzed in a cross-sectional study with lean and obese children and adolescents (n = 150). Circulating LEAP-2 levels were significantly higher in girls than in boys independently of whether they were obese or lean. In addition, LEAP-2 was significantly increased (p < 0.001) in pubertal than in prepubertal girls, while no changes were found in boys between both developmental stages. Moreover, in girls LEAP-2 was positively correlated with insulin, IGF-1, HOMA-IR and triglycerides and negatively with ghrelin. In boys, LEAP-2 was positively correlated with leptin and negatively with vitamin D levels. CONCLUSION: This study reveals a sexual dimorphism in LEAP-2 levels in children and adolescents. These changes and the higher levels during puberty imply that LEAP-2 may contribute to some of the biological adaptations occurring during pubertal development in terms of food intake, energy balance, growth rate, and puberty onset. Future studies assessing LEAP-2 levels in longitudinal studies and its implications in growth rate, puberty onset, and reproductive hormones will help to understand the relevance of this hormone in this stage of life.

Puberty Is Associated with a Rising Hemoglobin A1c, Even in Youth with Normal Weight.

Our objective was to explore the longitudinal trajectory of hemoglobin A1c (HbA1c) in well-characterized youth (n = 84) with normal weight and obesity during puberty. HbA1c rose from early puberty to Tanner stage 5, even in healthy, normal weight youth, revealing important implications for defining normal glycemia and prediabetes in adolescents.

ENDOCRINE REGULATION OF ERYTHROID LINEAGE OF HEMATOPOIESIS IN CHILDREN LIVING UNDER A LOW-DOSE RADIATION EXPOSURE AFTER THE CHORNOBYL NPP ACCIDENT. / ENDOKRYNNA REGULIaTsIIa ERYTROTsYTARNOÏ LANKY GEMOPOEZU V DITEI, IaKI ZhYVUT' NA RADIOAKTYVNO ZABRUDNENYKh TERYTORIIaKh PISLIa AVARIÏ NA ChAES.

OBJECTIVE: Elucidation of relationship between the levels of thyroid-stimulating hormone (TSH), free serum thyroxine, serum and urine cortisol and parameters of erythroid lineage of hematopoiesis to estimate the thyroid functionin children of prepubertal, pubertal, and postpubertal age permanently residing under a low-dose radiation exposureto determine the premorbid state of thyroid function. MATERIALS AND METHODS: Children aged 3 to 18 years old (n = 203) living in the most intensively radionuclide-contaminated regions of Kyiv, Zhytomyr and Chornihiv oblasts of Ukraine after the Chornobyl NPP accident wereenrolled. Complaints of ossalgia, arthralgia, fatigue, bone fractures in the history, bone dysembryogenetic stigmata,hypermobility syndrome degree, and types of somatic diseases were taken into account. Peripheral blood countparameters, biochemical indices of blood serum were studied, namely the levels of total protein, cholesterol, creatinine and alkaline phosphatase activity. Levels of the free thyroxine, pituitary TSH, serum and daily urine cortisol, anddoses of radiation exposure were determined. RESULTS: The radiation dose values in children ranged from (0.35 ± 0.09) mSv to (0.54 ± 0.12) mSv. There was nodifference between the parameters of erythroid lineage of hematopoiesis depending on radiation dose. At the levels of serum TSH up to 1.0 µIU/ml no correlation was found with cortisol levels; at TSH levels of 1.0-3.0 µIU/ml thecorrelation coefficient was r = 0.31; at TSH levels higher than 3.0 µIU/ml the correlation coefficient was r = 0.61probably indicating a compensatory role of adrenal cortex in children at risk of thyroid disease development. In children with joint hypermobility grade II there was a higher incidence of dentofacial anomalies (χ2 = 6.9), deformitiesof lower extremities (χ2 = 6.9), and dental caries (χ2 = 4.3) (p < 0.05). There was a direct correlation between theserum TSH level (over 3 µIU/ml) and micrognathia (brachygnathia) (r = 0.62) indicating the impact of thyroid disease on dentofacial development. The TSH at a level of upper limit of the reference range values may contribute toa decreased RBC count in peripheral blood, increased average volume and hemoglobin content in erythrocyte beingassociated with the initial manifestations of thyroid dysfunction. CONCLUSIONS: Abnormal endocrine regulation of hematopoiesis affects the connective tissue, stromal microenvironment of bone marrow, and accordingly the erythroid branch of hematopoiesis in children, which may be relevant inthe development and course of oncohematological diseases.

Determination of estrone sulfate, testosterone, androstenedione, DHEAS, cortisol, cortisone, and 17α-hydroxyprogesterone by LC-MS/MS in children and adolescents.

Quantitation of endogenous steroids and their precursors is essential for diagnosis of a wide range of endocrine disorders. Usually, these analyses have been carried out using immunoassays. However, immunoassays often overestimate concentrations due to assay interference by other endogenous steroids, especially for low concentrations. Mass spectrometry based methods offer superior specificity, accuracy, and sensitivity. We therefore present a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with automated sample preparation for determination of 17α-hydroxyprogesterone (17OHP), cortisol, cortisone, dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), testosterone (T), and estrone sulfate (E1S). Samples were prepared using protein precipitation and 96-well filter plates, fully automated in a pipetting robot and analyzed by LC-MS/MS. Serum samples from 187 healthy children and adolescents aged 5-18 years were used to study hormone changes in relation to sex and pubertal stage. Lower limit of quantification for 17OHP was 0.7 nmol/L, for cortisol 11 nmol/L, for cortisone 2 nmol/L, for DHEAS 0.1 µmol/L, and for A4, T, and E1S, 0.2 nmol/L. This study showed a general increase in 17OHP, DHEAS, A4, T and E1S in both genders during puberty. In boys, A4 and T increased significantly throughout pubertal development. Girls had significantly higher A4 and E1S concentrations, while boys had higher T concentrations. No sex- or puberty-specific differences were seen in cortisol or cortisone concentrations. To the best of our knowledge, this is the first presentation of changes in serum E1S concentrations during pubertal development in healthy children.