RESUMO
Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 µg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 µg/dL] and High DHEAS (HD) [≥42 µg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.
Assuntos
Adrenarca , Feminino , Humanos , Criança , Adrenarca/genética , Androgênios , Projetos Piloto , Metilação de DNA , Sulfato de Desidroepiandrosterona , ObesidadeRESUMO
CONTEXT: An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight. DESIGN: Prospective observational. PATIENTS: Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (>75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups. MEASUREMENTS: Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders. RESULTS: Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI > 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI. CONCLUSIONS: Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.
Assuntos
Adrenarca , Síndrome Metabólica , Adolescente , Índice de Massa Corporal , Criança , Estudos de Coortes , Desidroepiandrosterona , Sulfato de Desidroepiandrosterona , Feminino , Humanos , Masculino , Obesidade , PuberdadeRESUMO
CONTEXT: Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 15 years. OBJECTIVE: We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. METHODS: Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (nâ =â 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort. RESULTS: We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (Pâ =â 3.81â ×â 10-8). In addition, variants suggestive of association (Pâ <â 1â ×â 10-5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher PRS for greater DHEAS based on these newly identified variants. CONCLUSION: Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche.
Assuntos
Estudo de Associação Genômica Ampla , Sulfatos , Adolescente , Criança , Pré-Escolar , Chile/epidemiologia , Estudos de Coortes , Sulfato de Desidroepiandrosterona , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
OBJECTIVE: To determine whether multiple daily injections of parathyroid hormone (PTH) 1-34 are safe and effective as long-term therapy for children with hypoparathyroidism. STUDY DESIGN: Linear growth, bone accrual, renal function, and mineral homeostasis were studied in a long-term observational study of PTH 1-34 injection therapy in 14 children. METHODS: Subjects were 14 children with hypoparathyroidism attributable to autoimmune polyglandular syndrome type 1 (N = 5, ages 7-12 years) or calcium receptor mutation (N = 9, ages 7-16 years). Mean daily PTH 1-34 dose was 0.75 ± 0.15 µg/kg/day. Treatment duration was 6.9 ± 3.1 years (range 1.5-10 years). Patients were evaluated semiannually at the National Institutes of Health Clinical Center. RESULTS: Mean height velocity and lumbar spine, whole body, and femoral neck bone accretion velocities were normal throughout the study. In the first 2 years, distal one-third radius bone accrual velocity was reduced compared with normal children (P < .003). Serum alkaline phosphatase correlated with PTH 1-34 dose (P < .006) and remained normal (235.3 ± 104.8 [SD] U/L, N: 51-332 U/L). Mean serum and 24-hour urine calcium levels were 2.05 ± 0.11 mmol/L (N: 2.05-2.5 mmol/L) and 6.93 ± 1.3 mmol/24 hour (N: 1.25-7.5 mmol/24 hour), respectively-with fewer high urine calcium levels vs baseline during calcitriol and calcium treatment (P < .001). Nephrocalcinosis progressed in 5 of 12 subjects who had repeated renal imaging although renal function remained normal. CONCLUSIONS: Twice-daily or thrice-daily subcutaneous PTH 1-34 injections provided safe and effective replacement therapy for up to 10 years in children with hypoparathyroidism because of autoimmune polyglandular syndrome type 1 or calcium receptor mutation.
Assuntos
Estatura/efeitos dos fármacos , Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Adolescente , Calcinose , Cálcio/sangue , Cálcio/urina , Criança , Creatinina/urina , Análise Mutacional de DNA , Feminino , Homeostase , Terapia de Reposição Hormonal , Humanos , Testes de Função Renal , Modelos Lineares , Masculino , Nefrocalcinose/metabolismo , Hormônio Paratireóideo/administração & dosagem , Fósforo/sangue , Fósforo/urina , Poliendocrinopatias Autoimunes/genética , Receptores de Detecção de Cálcio/genética , Resultado do Tratamento , Vitamina D/sangueRESUMO
OBJECTIVE: Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult height (AH) in boys with familial male-limited precocious puberty (FMPP). To evaluate the effect of long-term antiandrogen, aromatase inhibitor, and GnRHa on AH, boys with FMPP who were treated were followed to AH. STUDY DESIGN: Twenty-eight boys with FMPP, referred to the National Institutes of Health, were started on antiandrogen and aromatase inhibitor at 4.9 ± 1.5 years of age; GnRHa was added at 6.9 ± 1.5 years of age. Treatment was discontinued at 12.2 ± 0.5 years of age (bone age, 14.4 ± 1.3). AH was assessed at 16.4 ± 1.3 years of age (bone age, 18.5 ± 0.6). RESULTS: AH (mean ± SD) for all treated subjects was 173.6 ± 6.8 cm (-0.4 ± 1.0 SD relative to adult US males). For 25 subjects with pretreatment predicted AH, AH significantly exceeded predicted AH at treatment onset (173.8 ± 6.9 vs 164.9 ± 10.7 cm; P < .001), but fell short of predicted AH at treatment discontinuation (177.3 ± 9.0 cm; P < .001). For 11 subjects with maternal or sporadic inheritance, the mean AH was 3.1 cm (0.4 SD score) below sex-adjusted midparental height (175.4 ± 5.8 vs 178.5 ± 3.1 cm [midparental height]; P = .10). For 16 subjects with affected and untreated fathers, AH was significantly greater than fathers' AH (172.8 ± 7.4 vs 168.8 ± 7.2 cm; P < .05). CONCLUSIONS: Long-term treatment with antiandrogen, aromatase inhibitor, and GnRHa in boys with FMPP results in AH modestly below sex-adjusted midparental height and within the range for adult males in the general population.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Estatura/efeitos dos fármacos , Leuprolida/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Pamoato de Triptorrelina/análogos & derivados , Adulto , Anastrozol , Criança , Pré-Escolar , Esquema de Medicação , Quimioterapia Combinada , Seguimentos , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Masculino , Nitrilas/uso terapêutico , Puberdade Precoce/fisiopatologia , Espironolactona/uso terapêutico , Testolactona/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêutico , Pamoato de Triptorrelina/uso terapêuticoRESUMO
OBJECTIVE: To compare the response with synthetic human parathyroid hormone (PTH) 1-34 delivered by twice-daily injection vs insulin pump in children with severe congenital hypoparathyroidism due to calcium receptor mutation or autoimmune polyglandular syndrome type 1. STUDY DESIGN: Children and young adults aged 7-20 years with congenital hypoparathyroidism (N = 12) were randomized to receive PTH 1-34, delivered either by twice-daily subcutaneous injection or insulin pump for 13 weeks, followed by crossover to the opposite delivery method. The principal outcome measures were serum and urine calcium levels. Secondary outcomes included serum and urine magnesium and phosphate levels and bone turnover markers. RESULTS: PTH 1-34 delivered via pump produced near normalization of mean serum calcium (2.02 ± 0.05 [pump] vs 1.88 ± 0.03 [injection] mmol/L, P < .05, normal 2.05-2.5 mmol/L), normalized mean urine calcium excretion (5.17 ± 1.10 [pump] vs 6.67 ± 0.76 mmol/24 h/1.73 m(2), P = .3), and significantly reduced markers of bone turnover (P < .02). Serum and urine calcium and magnesium showed a biphasic pattern during twice-daily injection vs minimal fluctuation during pump delivery. The PTH 1-34 dosage was markedly reduced during pump delivery (0.32 ± 0.04 vs 0.85 ± 0.11 µg/kg/d, P < .001), and magnesium supplements were also reduced (P < .001). CONCLUSION: Compared with twice-daily delivery, pump delivery of PTH 1-34 provides more physiologic calcium homeostasis and bone turnover in children with severe congenital hypoparathyroidism.
Assuntos
Hipoparatireoidismo/congênito , Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo/administração & dosagem , Adolescente , Criança , Feminino , Humanos , Bombas de Infusão , Injeções Subcutâneas , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVES: To study androgen treatment effects on arithmetic performance in girls with Turner syndrome. STUDY DESIGN: Forty-four girls, ages 10 to 14 years at baseline, completed 4 years of treatment with oxandrolone (Ox) or placebo (Pl). All received growth hormone and estrogen replacement therapy. We assessed the number of girls with severe learning disability (LD, standard score Assuntos
Androgênios/uso terapêutico
, Deficiências da Aprendizagem/tratamento farmacológico
, Matemática
, Oxandrolona/uso terapêutico
, Síndrome de Turner/tratamento farmacológico
, Adolescente
, Criança
, Relação Dose-Resposta a Droga
, Método Duplo-Cego
, Esquema de Medicação
, Avaliação Educacional
, Feminino
, Humanos
, Deficiências da Aprendizagem/diagnóstico
, Deficiências da Aprendizagem/etiologia
, Probabilidade
, Leitura
, Valores de Referência
, Medição de Risco
, Índice de Gravidade de Doença
, Fatores de Tempo
, Resultado do Tratamento
, Síndrome de Turner/complicações
, Síndrome de Turner/diagnóstico
RESUMO
OBJECTIVE: To evaluate the growth disorder and phenotype in prepubertal children with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia, and to compare the findings from girls with Turner syndrome (TS). STUDY DESIGN: We studied the auxologic and phenotypic characteristics in 34 prepubertal LWD subjects (ages 1 to 10 years; 20 girls, 14 boys) with confirmed short stature homeobox-containing gene (SHOX) abnormalities. For comparative purposes, we evaluated similar physical and growth parameters in 76 girls with TS (ages 1 to 19 years) and 24 girls with LWD (ages 1 to 15 years) by using data collected from the postmarketing observational study, GeNeSIS. RESULTS: In the clinic sample LWD subjects, height standard deviation score ranged from -5.5 to +0.1 (-2.3 +/- 1.3, girls and -1.8 +/- 0.6, boys). Wrist changes related to Madelung deformity were present in 18 of 34 (53%) LWD subjects. In comparing the LWD and TS populations in the GeNeSIS sample, Madelung deformity, increased carrying angle, and scoliosis were more prevalent in the LWD population, whereas high arched palate was similarly prevalent in the two populations. CONCLUSIONS: Short stature is common in both LWD (girls and boys) and TS (girls). Clinical clues to the diagnosis of SHOX haploinsufficiency in childhood include short stature, short limbs, wrist changes, and tibial bowing.
Assuntos
Estatura/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Osteocondrodisplasias/genética , Fenótipo , Fatores de Transcrição/genética , Síndrome de Turner/genética , Adolescente , Desenvolvimento Ósseo/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Radiografia , Proteína de Homoeobox de Baixa Estatura , Síndrome , Síndrome de Turner/diagnóstico por imagem , Síndrome de Turner/patologiaRESUMO
OBJECTIVES: To investigate in an open-label randomized study, the effect of two doses of growth hormone (GH) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature (mean baseline height standard deviation score [SDS] -3.2). STUDY DESIGN: Patients were treated with GH at 0.24 mg/kg/week, 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter (0.24-->0.37), or 0.37 mg/kg/week. Final height was evaluated in 50 patients at study completion (mean treatment duration, 6.5 years). RESULTS: Patients who received 0.37 mg/kg/week (n = 72) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week (n = 70) (treatment difference = 0.8 cm/year; P = .003) or 0.24-->0.37 mg/kg/week (n = 67) (treatment difference = 0.9 cm/year; P = .001). For the 50 patients for whom final height measurements were available, mean height SDS increased by 1.55, 1.52, and 1.85 SDS, respectively, for the three dose groups. For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, the mean treatment difference (adjusted for differences in baseline predicted height SDS) was 0.57 SDS (3.6 cm; P = .025). Mean overall height gains (final height minus baseline predicted height) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, respectively, without dose effects on safety parameters. Final height measurements were within the normal adult height range for 94% of patients randomized to 0.37 mg/kg/week who continued to final height. CONCLUSION: GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature.