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Hepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and ß-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype-phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.
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Diabetes Mellitus Tipo 2 , Fator 4 Nuclear de Hepatócito , Regiões Promotoras Genéticas , Ativação Transcricional , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Ativação Transcricional/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Hep G2 , Variação Genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Linhagem CelularRESUMO
BACKGROUND: This multicenter study examines the contemporary management of penetrating carotid artery injury (PCAI) to identify trends in management, outcomes, and to determine prognostic factors for stroke and death. METHODS: Data from three large urban trauma centers in South Africa were retrospectively reviewed for patients who presented with PCAI from 2012 to 2020. RESULTS: Of 149 identified patients, 137 actively managed patients were included. Twenty-four patients (17.9%) presented in coma and 12 (9.0%) with localizing signs (LS). CT angiography was performed on admission for 120 (87.6%) patients. Thirty patients (21.9%) underwent nonoperative management, 87 (63.5%) open surgery, and 20 (14.6%) endovascular stenting. Eighteen patients (13.1%) died, and 15 (12.6%) surviving patients had strokes. Ligation was significantly related to death and reperfusion to survival. A mechanism of gunshot wound, occlusive injuries, a threatened airway, a systolic blood pressure <90 mmHg, hard signs of vascular injury, a low GCS, coma, a CT brain demonstrating infarct, a high injury severity score and shock index, a low pH or HCO3, and an elevated lactate were significant independent prognostic factors for death. Ligation was unsurvivable in all patients with severe neurological deficits, whereas reperfusion procedures resulted in survival in 63% (12/19) patients with coma and 78% (7/9) with LS although with high stroke rates (coma: 25.0%, LS: 85.7%). CONCLUSIONS: Outcomes in PCAI, including patients with severe neurological deficit and stroke, are better when reperfused. Reperfusion holds the best promise of survival and ligation should be reserved for technically inaccessible bleeding injuries.
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Lesões das Artérias Carótidas , Humanos , África do Sul/epidemiologia , Masculino , Adulto , Feminino , Estudos Retrospectivos , Lesões das Artérias Carótidas/cirurgia , Lesões das Artérias Carótidas/mortalidade , Lesões das Artérias Carótidas/terapia , Lesões das Artérias Carótidas/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto Jovem , Angiografia por Tomografia Computadorizada , Ferimentos Penetrantes/mortalidade , Ferimentos Penetrantes/cirurgia , Ferimentos Penetrantes/terapia , Ferimentos Penetrantes/diagnóstico por imagem , Prognóstico , Resultado do Tratamento , Ligadura/métodos , Escala de Gravidade do Ferimento , Centros de Traumatologia , Acidente Vascular Cerebral/etiologia , Procedimentos Endovasculares/métodosRESUMO
OBJECTIVES: Marked physiological changes in growth and development present challenges in defining pediatric reference intervals for biomarkers of health and disease. Lambda, Mu, and Sigma (LMS)-based statistical modeling provides a continuous normal distribution by negating skewness and variation, and is commonly used to establish growth charts. Such LMS reference curves are suggested to enhance laboratory test result interpretation. The current study establishes LMS-based continuous reference percentiles for 14 biomarkers in the CALIPER cohort of healthy children and adolescents. METHODS: Data from healthy children and adolescents aged 1-<19 years were used to establish continuous reference percentiles using a novel LMS-based statistical method, including 2.5th, 25th, 50th, 75th, and 97.5th percentiles. The LMS approach applies a Box-Cox data transformation and summarizes continuous distributions by age via three curves: skewness (Lambda), median (Mu), and coefficient of variation (Sigma). RESULTS: LMS-based percentiles and z-scores were generated for 14 common pediatric biomarkers that demonstrate dynamic concentration patterns with age (e.g., alkaline phosphatase) and/or wherein the magnitude of difference from the population mean may be clinically relevant (e.g., triglycerides). The LMS model captured age- and sex-specific distributions accurately and was not substantially influenced by outlying points. CONCLUSIONS: This is the first study to establish LMS-based continuous reference percentiles for biochemical markers in a healthy Canadian pediatric population. The current LMS-based approach builds upon previous continuous reference interval models by providing graded percentiles to improve test result interpretation, particularly with repeated measures over time. This method may assist in facilitating a patient-centered approach to laboratory medicine.
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Modelos Estatísticos , Adolescente , Criança , Feminino , Humanos , Masculino , Biomarcadores , Canadá , Valores de Referência , Lactente , Pré-Escolar , Adulto JovemRESUMO
BACKGROUND: The Bergen Growth Study 2 (BGS2) aims to characterise somatic and endocrine changes in healthy Norwegian children using a novel methodology. SUBJECTS AND METHODS: A cross-sectional sample of 1285 children aged 6-16 years was examined in 2016 using novel objective ultrasound assessments of breast developmental stages and testicular volume in addition to the traditional Tanner pubertal stages. Blood samples allowed for measurements of pubertal hormones, endocrine disruptive chemicals, and genetic analyses. RESULTS: Ultrasound staging of breast development in girls showed a high degree of agreement within and between observers, and ultrasound measurement of testicular volume in boys also showed small intra- and interobserver differences. The median age was 10.4 years for Tanner B2 (pubertal onset) and 12.7 years for menarche. Norwegian boys reached a pubertal testicular volume at a mean age of 11.7 years. Continuous reference curves for testicular volume and sex hormones were constructed using the LMS method. CONCLUSIONS: Ultrasound-based assessments of puberty provided novel references for breast developmental stages and enabled the measurement of testicular volume on a continuous scale. Endocrine z-scores allowed for an intuitive interpretation of changing hormonal levels during puberty on a quantitative scale, which, in turn, provides opportunities for further analysis of pubertal development using machine-learning approaches.
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Puberdade , Maturidade Sexual , Masculino , Feminino , Humanos , Criança , Estudos Transversais , Menarca , MamaRESUMO
AIM: To estimate references for testicular volume measured with ultrasound and Tanner stages of pubic hair in Norwegian boys, and to compare the timing of puberty with data from similar populations. METHODS: Testicular volume was derived from ultrasound measurements of testicular volume in a cross-sectional study of 514 healthy boys. A continuous testicular volume for age reference curve was estimated with the LMS method. Tanner stages for pubic hair were clinically assessed in 452 boys. Age references for pubertal milestones were estimated with probit regression. RESULTS: Puberty onset, defined by an ultrasound testicular volume of 2.7 mL, equivalent to an orchidometer volume of 4 mL, occurred at a mean (SD) age of 11.7 (1.1) years. The reference range was 9.7 (3rd) to 13.7 years (97th percentile). Pubic hair (Tanner stage 2) appeared on average at 11.8 (1.2) years with a corresponding reference range of 9.5-14.1 years. CONCLUSION: The references for testicular volume measured with ultrasound are continuous in age and allow for the quantification of pubertal development. The age distribution of reaching pubertal milestones was comparable with data from other Northern European countries.
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Cabelo , Puberdade , Testículo , Criança , Estudos Transversais , Humanos , Masculino , Valores de Referência , Testículo/diagnóstico por imagem , Testículo/crescimento & desenvolvimento , UltrassonografiaRESUMO
BACKGROUND: This paper reviews our experience with penetrating cervical venous trauma and aims to validate the selective non-operative management (SNOM) of these injuries. METHODS: This was a retrospective review of a prospectively maintained registry. All patients presenting alive with an injury to the internal jugular vein, subclavian vein or innominate vein following a PNI were reviewed for a 6-year period. RESULTS: Among 817 patients admitted for the management of PNI, 76 (9.3%) had a venous injury. Of these, 37 (48.7%) patients were managed non-surgically, 20 (26.3%) required immediate surgical exploration, seven of whom had an associated arterial injury, and 19 (25%) underwent surgery following a diagnostic CTA, 16 of whom had an associated arterial or aero-digestive injury. In total, only 16 (21.1%) of the 76 patients required exploration for venous injury alone. The majority (63.2%) of patients had a history of severe bleeding or hemodynamic instability prior to arrival, but only 20 (26.3%) required immediate exploration. Two (2.6%) patients died as a result of venous injury. No patients developed complications related to the venous injury. CONCLUSIONS: SNOM is applicable to a well-defined subset of patients with isolated penetrating cervical venous trauma to the IJV and SCV identified on CTA.
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Lesões do Pescoço/terapia , Lesões do Sistema Vascular/terapia , Ferimentos Penetrantes/terapia , Adolescente , Adulto , Veias Braquiocefálicas/lesões , Tratamento Conservador , Feminino , Hemorragia/terapia , Humanos , Veias Jugulares/lesões , Masculino , Pessoa de Meia-Idade , Pescoço/irrigação sanguínea , Lesões do Pescoço/cirurgia , Seleção de Pacientes , Sistema de Registros , Estudos Retrospectivos , Veia Subclávia/lesões , Ferimentos Penetrantes/cirurgia , Adulto JovemRESUMO
BACKGROUND: The purpose of this study was to audit our experience with computed tomography angiography (CTA) for the detection of aerodigestive tract injury (ADTI) following penetrating neck injury (PNI) and to assess the significance of deep surgical emphysema on CTA. METHODS: A prospectively maintained trauma registry at the Pietermaritzburg Metropolitan Trauma Service, Pietermaritzburg, South Africa was retrospectively interrogated. The data of all patients with PNI investigated with CTA over a 4-y period were reviewed. All findings of deep surgical emphysema were correlated to an aggregate standard of reference for ADTI as demonstrated by results from clinical examination, surgical neck exploration, endoscopy or contrasted swallow to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this finding. RESULTS: A total of 383 patients underwent a CTA for PNI. A total of 94 vascular injuries were identified on 78 positive CTA studies. The sensitivity and specificity of CTA in detecting a vascular injury were 94.4% and 96.7%. Of the 383 patients investigated a total of 38 patients were diagnosed with digestive tract injury (DTI), and all of these patients were found to have deep surgical emphysema on CTA, except for one patient with a clinically insignificant oral cavity injury. Another 126 patients also had deep surgical emphysema on CTA but no DTI. The sensitivity, specificity, PPV, and NPV of deep surgical emphysema for the diagnosis of confirmed DTI in PNI were therefore 97.4%, 63.5%, 22.7%, and 99.5%, respectively. The sensitivity and NPV were, however, 100% when clinically insignificant injuries were excluded. Including patients with confirmed airway injuries and excluding all patients with pneumothoraces yielded a sensitivity, specificity, PPV, and NPV of 94.1%, 71.9%, 30.0%, and 98.9%, respectively, for the identification of ADTI. When excluding surgically irrelevant injuries, the sensitivity and NPV were again both 100%. CONCLUSIONS: CTA for PNI has a high sensitivity and specificity for demonstrating vascular injury. The absence of deep surgical emphysema in the deep cervical fascial planes virtually excludes surgically significant ADTI. The presence of deep surgical emphysema is nonspecific but warrants further investigation.
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Angiografia por Tomografia Computadorizada , Esôfago/lesões , Lesões do Pescoço/diagnóstico por imagem , Faringe/lesões , Traqueia/lesões , Lesões do Sistema Vascular/diagnóstico por imagem , Ferimentos Penetrantes/diagnóstico por imagem , Adolescente , Adulto , Idoso , Criança , Auditoria Clínica , Esôfago/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Faringe/diagnóstico por imagem , Sistema de Registros , Estudos Retrospectivos , Sensibilidade e Especificidade , África do Sul , Traqueia/diagnóstico por imagem , Adulto JovemRESUMO
Entering puberty early or late can have long-term effects on health. We do not know enough about what induces puberty and what factors contribute to its onset.
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Puberdade , Fatores Etários , Índice de Massa Corporal , HumanosRESUMO
CONTEXT: Nonprogressive premature thelarche (PT) is a self-limiting variant of early puberty, while idiopathic central precocious puberty (ICPP) is a disorder that causes progressive development of secondary sexual characteristics and often requires treatment. The diagnostic differentiation between these conditions is important but can be challenging since they often both initially present clinically with isolated breast development. OBJECTIVE: To describe relevant clinical variables in a large cohort of girls referred for early puberty, and to evaluate clinical and biochemical parameters to distinguish between girls with ICPP and PT. METHODS: This retrospective study included 1361 girls referred with signs of early puberty to a single, tertiary center from 2009 to 2019. We evaluated clinical presentation, medical history, growth velocity, bone age, hormonal serum concentrations, and gonadotropin-releasing hormone (GnRH) test results. RESULTS: Central precocious puberty was diagnosed in 11% (ICPP: n = 143, organic CPP: n = 11) girls, whereas 8% (n = 91 girls) presented with PT. Receiver operating characteristic (ROC) analysis showed several biochemical and anthropometric markers as potential parameters to differentiate between ICPP and PT; however, none were individually adequate. Principal component analysis (PCA)-derived clinical and hormone profiles could predict girls with ICPP from girls with PT with a specificity of 90% and sensitivity of 84%, outperforming any single marker. CONCLUSION: Differentiation of girls with ICPP and PT can be supported by individual clinical and biochemical parameters. However, dimension reduction of clinical and hormonal profiles by PCA improved the diagnostic value, which in the future may support the diagnostic process as a supplement to the GnRH test in evaluation of pubertal disorders.
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Puberdade Precoce , Feminino , Humanos , Puberdade Precoce/diagnóstico , Estudos Retrospectivos , Análise de Componente Principal , Curva ROC , Hormônio Liberador de GonadotropinaRESUMO
Objective: Klinefelter syndrome (KS) is the most common sex chromosome disorder and genetic cause of infertility in males. A highly variable phenotype contributes to the fact that a large proportion of cases are never diagnosed. Typical hallmarks in adults include small testes and azoospermia which may prompt biochemical evaluation that typically shows extremely high follicle-stimulating hormone and low/undetectable inhibin B serum concentrations. However, in prepubertal KS individuals, biochemical parameters are largely overlapping those of prepubertal controls. We aimed to characterize clinical profiles of prepubertal boys with KS in relation to controls and to develop a novel biochemical classification model to identify KS before puberty. Methods: Retrospective, longitudinal data from 15 prepubertal boys with KS and data from 1475 controls were used to calculate age- and sex-adjusted standard deviation scores (SDS) for height and serum concentrations of reproductive hormones and used to infer a decision tree classification model for KS. Results: Individual reproductive hormones were low but within reference ranges and did not discriminate KS from controls. Clinical and biochemical profiles including age- and sex-adjusted SDS from multiple reference curves provided input data to train a 'random forest' machine learning (ML) model for the detection of KS. Applied to unseen data, the ML model achieved a classification accuracy of 78% (95% CI, 61-94%). Conclusions: Supervised ML applied to clinically relevant variables enabled computational classification of control and KS profiles. The application of age- and sex-adjusted SDS provided robust predictions irrespective of age. Specialized ML models applied to combined reproductive hormone concentrations may be useful diagnostic tools to improve the identification of prepubertal boys with KS.
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BACKGROUND: Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. METHODS: Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. RESULTS: Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). CONCLUSIONS: The expression of SRCs and HER-2 and -3 is stimulated by tamoxifen treatment in DMBA-induced breast cancer. Stimulation and positive correlation of coactivators and HERs may represent an early response to endocrine treatment. The role of SRCs and HER-2 and -3 should be further studied in order to evaluate their effects on response to long-term tamoxifen treatment.
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Antineoplásicos Hormonais/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Mamárias Experimentais/genética , Coativadores de Receptor Nuclear/genética , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Tamoxifeno/farmacologia , 9,10-Dimetil-1,2-benzantraceno/efeitos adversos , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/metabolismo , Peso Corporal/efeitos dos fármacos , Feminino , Humanos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/tratamento farmacológico , Coativadores de Receptor Nuclear/metabolismo , Proteína Proto-Oncogênica c-ets-2/genética , Proteína Proto-Oncogênica c-ets-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Tamoxifeno/administração & dosagem , Tamoxifeno/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
Introduction: Breast tissue in infancy is a rather undescribed phenomenon. We aimed to describe the prevalence and progression of palpable breast tissue in healthy boys and girls aged 0-1 years and to evaluate clinical markers, individual serum hormone concentrations as well as combined hormone profiles as determinants of the persistence of breast tissue. Methods: In total, 233 term infants (119 boys, 114 girls) were included and followed from birth until 1 year of age in The COPENHAGEN Minipuberty Study (ClinicalTrials.gov #NTC02784184). Infants were followed up to six times with a clinical examination and serum sampling. Principal component analyses (PCAs) produced combined hormone profiles. Results: A total of 98% of all infants aged 0-1 year exhibited breast tissue at some point. 50% still had breast tissue present at 0.5-0.6 years in girls and 0.3-0.4 years in boys ('persistent'). At one year, more girls than boys had breast tissue present (p=0.010). Most clinical and hormonal markers did not differ in infants with/without persistent breast tissue. However, in those with persistent breast tissue, estradiol (first visit, girls, p=0.034), androstenedione, corticosterone, cortisol (first visit, boys, all p<0.050), length (first visit, boys, p=0.030), and testicular volume (0.3-0.4 years, p=0.040) were higher, while IGF-I (0.3-0.4, boys, p=0.033) was lower. In boys, a combined, PCA-derived hormone profile (first visit) was able to predict the persistence of breast tissue (area under the curve=83%) better than any single marker. Discussion: Palpable breast tissue in infancy is common in both sexes although it persists in significantly more girls than boys at one year of age. Data supports both the early origin of breast tissue (in utero- and early postnatal) as well as a role of endogenous hormone production in later development and maintenance.
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Mama , Estradiol , Feminino , Humanos , Lactente , Masculino , Prevalência , Puberdade , Hormônios Esteroides GonadaisRESUMO
CONTEXT: Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age. OBJECTIVE: We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI). METHODS: Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established "LMS" growth chart algorithm in R. RESULTS: Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (ßâ =â 0.5, Pâ <â 0.001) and leptin (ßâ =â 0.6, Pâ <â 0.001), and inversely correlated with serum levels of sex hormone-binding globulin (SHBG) (ßâ =â -0.4, Pâ <â 0.001). Biomarker z-score profiles differed significantly between cohort subgroups stratified by puberty phenotype and BMI weight class. CONCLUSION: Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients.
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Gráficos de Crescimento , Puberdade , Adolescente , Biomarcadores , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Humanos , Valores de ReferênciaRESUMO
Purpose: Principal component analysis (PCA) is a mathematical model which simplifies data into new, combined variables. Optimal treatment of pediatric congenital adrenal hyperplasia (CAH) remains a challenge and requires evaluation of all biochemical and clinical markers. The aim of this study was to introduce PCA methodology as a tool to optimize management in a cohort of pediatric and adolescent patients with CAH by including adrenal steroid measurements and clinical parameters. Methods: This retrospective, longitudinal cohort of 33 children and adolescents with CAH due to 21-hydroxylase deficiency included 406 follow-up observations. PCAs were applied to serum hormone concentrations and compared to treatment efficacy evaluated by clinical parameters. Results: We provide and describe the first PCA models with hormone parameters denoted in sex- and age-adjusted standard deviation (SD) scores to comprehensibly describe the combined 'endocrine profiles' of patients with classical and non-classical CAH, respectively. Endocrine profile scores were predictive markers of treatment efficacy for classical (AUC=92%; accuracy 95%; p=1.8e-06) and non-classical CAH (AUC=80%; accuracy 91%; p=0.004). A combined PCA demonstrated clustering of patients with classical and non-classical CAH by serum 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone-sulphate (DHEAS) concentrations. Conclusion: As an example of the possibilities of PCA, endocrine profiles were successfully able to distinguish between patients with CAH according to treatment efficacy and to elucidate biochemical differences between classical and non-classical CAH.
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17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/patologia , Biomarcadores/sangue , Sulfato de Desidroepiandrosterona/sangue , Análise de Componente Principal/métodos , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Previous studies investigating the association between weight status and onset of puberty in boys have been equivocal. It is currently unclear to what extent weight class influences puberty onset and progression. OBJECTIVES: To explore the relationship between degree of sexual maturation and anthropometric measures in Norwegian boys. METHODS: The following endpoints were collected in a Norwegian cross-sectional study of 324 healthy boys aged 9-16: ultrasound-determined testicular volume (USTV), total serum testosterone, Tanner pubic hair stage, height, weight, waist circumference (WC), subscapular skinfolds (SSF), and body fat percentage (%BF). Testicular volume-for-age z-scores were used to classify "early," "average," or "late" maturing boys. Ordinal logistic regression analyses with a proportional odds model were applied to analyze the association between anthropometric variables and age-adjusted degree of pubertal development, with results expressed as age-adjusted odds ratios (AOR). Cumulative incidence curves for reaching pubertal milestones were stratified by BMI. RESULTS: Boys with a low BMI for age (BMIz < -1) were less likely to have reached a pubertal testicular volume (USTV ≥ 2.7 mL) or a pubertal serum level of testosterone (≥0.5 nmol/L) compared to normal weight boys (AOR 0.3, p = 0.038, AOR 0.3, p = 0.026, respectively), and entered puberty on average with a delay of approximately eight months. Boys with high BMI for age (BMIz > 1) exhibited a comparable timing as normal weight boys. The same was found for WC. Pubertal markers were not associated with SSF or %BF. CONCLUSION: By examining the association between puberty and weight status classified as low, average, or high, we found that a low BMI or WC for age were associated with a less advanced pubertal development and delayed timing of puberty in boys. No significant association was observed for a high BMI or WC. Moreover, no significant effects of SSF or %BF were observed. A low weight status should also be considered when assessing pubertal development in boys.
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Índice de Massa Corporal , Obesidade/fisiopatologia , Puberdade/fisiologia , Maturidade Sexual/fisiologia , Adolescente , Criança , Estudos Transversais , Humanos , Masculino , Testículo/diagnóstico por imagem , UltrassonografiaRESUMO
OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. DESIGN: This is a follow-up study of 5-10 years old children from the PregMet-study-a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. METHODS: There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. RESULTS: Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14-1.17), p = 0.014). CONCLUSION: Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.
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Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Esteroides/metabolismo , Criança , Feminino , Glucose/metabolismo , Homeostase , Humanos , Masculino , Gravidez , PuberdadeRESUMO
Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
Assuntos
Adipócitos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Células 3T3-L1 , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Western Blotting , Diabetes Mellitus Tipo 2/metabolismo , Genótipo , Glutationa/metabolismo , Humanos , Resistência à Insulina/fisiologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA , Peixe-ZebraRESUMO
CONTEXT: Discriminating adipose and glandular tissue is challenging when clinically assessing breast development. Ultrasound facilitates staging of pubertal breast maturation (US B), but has not been systematically compared to Tanner breast (Tanner B) staging, and no normative data have been reported. OBJECTIVE: To present normative references for US B along with references for Tanner B, pubic hair (PH), and menarche. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional sample of 703 healthy girls aged 6 to 16 years were examined. MAIN OUTCOME MEASURES: Breast development was determined with US B and Tanner B staging. Tanner PH and menarcheal status were recorded. The age distributions of entry in US B, Tanner B, and PH stages and menarche were estimated with generalized linear and generalized additive models with a probit link. Method agreement was tested with weighted Cohen's kappa. RESULTS: The median (±2SD) ages for thelarche, US B2 and Tanner B2, were 10.2 (7.7, 12.8) and 10.4 (8.0, 12.7) years. The median (±2SD) ages at Tanner PH2 and menarche were 10.9 (8.5, 13.3) and 12.7 (11.0, 16.2) years. Cohen's kappa of agreement (95% confidence interval) between US B and Tanner B was 0.87 (0.85-0.88). When the methods disagreed, US B was usually more advanced. CONCLUSION: Thelarche occurred at a slightly younger age when assessed with ultrasound compared to clinical Tanner staging, although the 2 methods had a very good agreement when determining pubertal breast maturation. A significant decrease of 2.8 months in age at menarche was observed during the past decade in Norwegian girls.
Assuntos
Mama/diagnóstico por imagem , Cabelo/crescimento & desenvolvimento , Menarca/fisiologia , Ultrassonografia/normas , Adolescente , Desenvolvimento do Adolescente/fisiologia , Mama/crescimento & desenvolvimento , Criança , Estudos Transversais , Técnicas de Diagnóstico Endócrino/normas , Feminino , Humanos , Noruega , Puberdade/fisiologia , Osso Púbico , Valores de Referência , Maturidade Sexual/fisiologiaRESUMO
CONTEXT: Testicular growth represents the best clinical variable to evaluate male puberty, but current pediatric hormone references are based on chronological age and subjective assessments of discrete puberty development stages. Determination of testicular volume (TV) by ultrasound provides a novel approach to assess puberty progression and stratify hormone reference intervals. OBJECTIVE: The objective of this article is to establish references for serum testosterone and key hormones of the male pituitary-gonadal signaling pathway in relation to TV determined by ultrasound. DESIGN, SETTING, AND PARTICIPANTS: Blood samples from 414 healthy Norwegian boys between ages 6 and 16 years were included from the cross-sectional "Bergen Growth Study 2." Participants underwent testicular ultrasound and clinical assessments, and serum samples were analyzed by liquid chromatography tandem-mass spectrometry and immunoassays. MAIN OUTCOME MEASURES: We present references for circulating levels of total testosterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin in relation to TV, chronological age, and Tanner pubic hair stages. RESULTS: In pubertal boys, TV accounted for more variance in serum testosterone levels than chronological age (Spearman râ =â 0.753, Pâ <â .001 vs râ =â 0.692, Pâ <â .001, respectively). Continuous centile references demonstrate the association between TV and hormone levels during puberty. Hormone reference intervals were stratified by TV during the pubertal transition. CONCLUSIONS: Objective ultrasound assessments of TV and stratification of hormone references increase the diagnostic value of traditional references based on chronological age or subjective staging of male puberty.