RESUMO
Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.
Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Síndrome de Noonan/tratamento farmacológico , Animais , Modelos Animais de Doenças , Transtornos do Crescimento/etiologia , Humanos , Camundongos , Síndrome de Noonan/complicações , Resultado do TratamentoRESUMO
BACKGROUND: Recent studies have suggested that there is an earlier age of onset of puberty in healthy boys. However, no study has determined the age of pubertal development in boys with type 1 diabetes (T1D) and compared the results with a simultaneously recruited group of healthy children. OBJECTIVE: The aim of this study was to evaluate the age of pubertal events in boys with TD1 and determine whether the duration of diabetes, metabolic control or insulin dose are associated with the age of puberty in boys with T1D. METHODS: Boys aged 7 to 19 years with T1D (n = 148, age 12.9 ± 3.0 years) and healthy boys recruited from schools (n = 388 controls, age 12.8 ± 2.2 years) were studied. A pediatric endocrinologist evaluated pubertal development. RESULTS: Boys at genital Tanner stage 2 and the final stages of puberty (genital Tanner 4 and 5) were younger than the control group (P = 0.005, P = 0.003, and P = 0.015, respectively). Both groups of boys had a similar age of pubic Tanner stage development. There were no cases of pubertal delay observed in the T1D cohort. There was no association observed between metabolic control with pubertal timing. T1D adolescents had lower height-SDS than the C group at the final stages of puberty. CONCLUSIONS: Boys with T1D who are treated with modern insulin therapy appear to have an earlier age of onset and an earlier age of final pubertal events than a simultaneously studied group of healthy children. These data suggest that pubertal delay is not a frequent problem for male T1D patients.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/fisiopatologia , Puberdade Precoce/epidemiologia , Puberdade/fisiologia , Adolescente , Desenvolvimento do Adolescente/fisiologia , Idade de Início , Estatura/fisiologia , Estudos de Casos e Controles , Criança , Chile/epidemiologia , Estudos Transversais , Humanos , Masculino , Puberdade Precoce/etiologia , Maturidade Sexual/fisiologia , Adulto JovemRESUMO
Noonan syndrome (NS) is a genetic disorder, which can present clinically with a variable phenotype. Proportional post natal short stature is a common manifestation of NS, with the majority of affected patients having an adult height below the third percentile. Some investigators have reported minor abnormalities in GH secretion and/or action, suggesting that recombinant growth hormone (rhGH) therapy may be useful for the treatment of their short stature. Our review of the literature regarding rhGH therapy in children with NS indicates that this therapy improves height velocity, but relatively few controlled clinical trials reporting adult height are available. rhGH treatment does not appear to be associated with adverse effects in these patients, but data on the possible development of malignancy during treatment are somewhat limited. Therefore, we believe that there is a need for large controlled clinical trials in patients with this condition, in order to accurately assess the effects of rhGH therapy over adult height.
Assuntos
Hormônio do Crescimento/uso terapêutico , Síndrome de Noonan , Estatura , Transtornos do Crescimento , Hormônio do Crescimento Humano , Humanos , Síndrome de Noonan/tratamento farmacológicoRESUMO
BACKGROUND: Menarche is the last stage of pubertal development, which coincides, with the completion of longitudinal growth. Our aim was to evaluate, post-menarcheal growth and clinical variables proposed to be associated with this growth. METHODS: In a prospective fashion, 106 healthy girls attending five different socioeconomic status (SES) schools of Santiago were randomly recruited. A pediatric endocrinologist obtained anthropometrics and registration of date at menarche every 6 months. The evolution of the girls' heights was assessed through mixed models adjusted to the SESes, parental height and body mass index (BMI). RESULTS: Sixty-three girls from a high socioeconomic status (HSS) and 50 from a low socioeconomic status (LSS) were followed. Four years post menarche, the girls reached a growth plateau and the average height gain was 5.2±2.5 cm. This gain was not associated with SES, BMI, nor with parental height (p=0.744). The only variable that modulated this gain was age at menarche (r=-0.1997, p=0.0332). There was an inverse correlation between height at the moment of menarche and the height reached after 4 years of follow-up adjusted to parental height (r=-0302, p=0.0011). CONCLUSIONS: Post-menarcheal growth ends 4 years post-event and is inversely correlated with the age at menarche and with the height at the moment of menarche independent of BMI, parental height and SES.
Assuntos
Estatura/fisiologia , Menarca/fisiologia , Maturidade Sexual/fisiologia , Adolescente , Desenvolvimento do Adolescente , Fatores Etários , Índice de Massa Corporal , Criança , Chile , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Classe SocialRESUMO
BACKGROUND: A secular trend towards a younger age of puberty onset has been reported in Chilean girls. AIM: To evaluate the age of onset of puberty and prevalence of early puberty in Chilean boys. MATERIAL AND METHODS: A pediatric endocrinologist examined 319 children attending schools in central Santiago. Pubertal development was assessed by testicular volume (TV) and genital inspection (GI) using Tanner graduation. Precocious and early puberty development was diagnosed if TV ≥ 4 ml or GI > stage 2 occurred in boys younger than 9 years and at 9-10 years of age, respectively. RESULTS: Pubertal onset occurred at 10.2 ± 1.5 years according to TV and at 11.1 ± 1.6 years according to GI (p < 0.01). Before the age of nine, 15.2% of children had a VT ≥ 4 ml, 3% had genital changes in GI and only 3% had both changes simultaneously. Early puberty was observed in 23.8% of children according to TV and 9.5% according to GI. However, no child of less than 11 years old had a TV ≥ 4 ml, genital changes and pubic hair simultaneously. Late pubertal stages occurred at the same age according to both criteria used. Body mass index z score was not associated with the age of pubertal onset. CONCLUSIONS: Testicular enlargement occurs one year earlier than changes in genitalia according to inspection. Testicular growth, but not late stages of puberty, are occurring one year earlier than previously reported in Chile 10 years ago.
Assuntos
Idade de Início , Genitália Masculina/crescimento & desenvolvimento , Puberdade/fisiologia , Maturidade Sexual/fisiologia , Testículo/crescimento & desenvolvimento , Adolescente , Distribuição por Idade , Índice de Massa Corporal , Criança , Chile , Genitália Masculina/anatomia & histologia , Humanos , Masculino , Puberdade Precoce/diagnóstico , Valores de Referência , Testículo/anatomia & histologia , Adulto JovemRESUMO
Background: A secular trend towards a younger age of puberty onset has been reported in Chilean girls. Aim: To evaluate the age of onset of puberty and prevalence of early puberty in Chilean boys. Material and Methods: A pediatric endocrinologist examined 319 children attending schools in central Santiago. Pubertal development was assessed by testicular volume (TV) and genital inspection (GI) using Tanner graduation. Precocious and early puberty development was diagnosed if TV ≥ 4 ml or GI > stage 2 occurred in boys younger than 9 years and at 9-10 years of age, respectively. Results: Pubertal onset occurred at 10.2 ± 1.5 years according to TV and at 11.1 ± 1.6 years according to GI (p < 0.01). Before the age of nine, 15.2% of children had a VT ≥ 4 ml, 3% had genital changes in GI and only 3% had both changes simultaneously. Early puberty was observed in 23.8% of children according to TV and 9.5% according to GI. However, no child of less than 11 years old had a TV ≥ 4 ml, genital changes and pubic hair simultaneously. Late pubertal stages occurred at the same age according to both criteria used. Body mass index z score was not associated with the age of pubertal onset. Conclusions: Testicular enlargement occurs one year earlier than changes in genitalia according to inspection. Testicular growth, but not late stages of puberty, are occurring one year earlier than previously reported in Chile 10 years ago.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apresentação de Antígeno , /imunologia , /imunologia , Diferenciação Celular/imunologia , Apresentação Cruzada , Bactérias Gram-Negativas/imunologia , Bactérias Gram-Positivas/imunologia , Imunidade Adaptativa , /patologia , /patologia , Imunidade Inata , Neutrófilos , Receptores de Antígenos de Linfócitos T gama-delta/imunologiaRESUMO
BACKGROUND: The possible relationship between the circulating concentrations of T4 and GH sensitivity has not been elucidated. OBJECTIVE: The aim of this study is to evaluate the effect of levothyroxine supplementation on GH sensitivity in prepubertal boys with idiopathic short stature (ISS). METHODS: We selected 28 prepubertal boys with ISS (mean age 8.2±0.5years) and free T4 (Ft4) concentrations between the 3rd and the 25th percentiles (Ft4: 0.8-1.5ng/dl). They were randomly divided into two groups: Group A received thyroid supplementation (1-3µg/kg/day) for 120days, and Group B received placebo for the same period. To evaluate GH sensitivity, an IGF-I generation test (GH: 33µg/kg/day sc for 3days) was performed in both groups: under basal conditions, and after 120days of levothyroxine supplementation (or placebo). RESULTS: After thyroid supplementation, Group A had higher Ft4 concentrations compared with Group B (2.14±0.06 vs 1.48±0.06ng/dl, p=0.01), their growth velocity was significantly higher (2.3±0.1 vs 1.5±0.2cm/4months), and they exhibited a greater increase in IGF-I after GH administration (Group A: 32.5±3.8% vs Group B 17.3±2.6%). CONCLUSION: Supplementation with levothyroxine for 120days promotes an increase in growth velocity, and a greater IGF-I response to short-term GH administration in prepubertal boys with ISS and low-normal thyroid hormone concentrations.
Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Tiroxina/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Tiroxina/sangue , Tiroxina/farmacologia , Resultado do TratamentoRESUMO
AIM: Conflicting results regarding testicular function in adults with type 1 diabetes (T1D) have been reported, but little is known about Leydig and Sertoli cell function during puberty in boys treated with multiple daily insulin doses. Our aim was to assess testicular function in boys with T1D. METHODS: Pubertal boys with T1D (n = 71) and healthy control boys (Control group; n = 104) who were 10-18 years were studied. Both groups were matched by pubertal stage, age, and BMI. Total testosterone (TT), calculated free testosterone (cfT), SHBG, inhibin B, AMH, and gonadotropin levels were determined. RESULTS: At the beginning of puberty, the T1D group had higher levels of SHBG (p = 0.003) and similar androgen levels than the Control group. At the end of puberty, higher TT, and cfT were observed in T1D compared to the Control group (p < 0.01 and p < 0.001, respectively). Gonadotropins and AMH were similar in both groups. Regression analysis showed that T1D was a significant factor, even after adjusting for Tanner stage and BMI-SDS, affecting TT, cFT, and SHBG levels. BMI-SDS was a significant factor affecting TT and SHBG levels. Higher HbA1c had a negative effect on total testosterone and cFT and a positive effect on SHBG levels in T1D boys. CONCLUSION: Adolescents with T1D do not exhibit hypogonadism, as shown by normal gonadotropin, testosterone, inhibin B, and AMH levels. However, in T1D boys, HbA1c and BMI-SDS had a negative association with testosterone levels. Elevated testosterone levels are observed during late puberty, which were not present earlier.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Glândulas Endócrinas/fisiopatologia , Doenças do Sistema Endócrino/complicações , Hipogonadismo/complicações , Modelos Biológicos , Puberdade , Testículo/fisiopatologia , Adolescente , Biomarcadores/sangue , Criança , Chile , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/fisiopatologia , Glândulas Endócrinas/efeitos dos fármacos , Glândulas Endócrinas/metabolismo , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/prevenção & controle , Hemoglobinas Glicadas/análise , Hospitais Públicos , Hospitais Urbanos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Hipogonadismo/induzido quimicamente , Hipogonadismo/prevenção & controle , Insulina/efeitos adversos , Insulina/uso terapêutico , Masculino , Puberdade/efeitos dos fármacos , Análise de Regressão , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/análise , Testosterona/metabolismoRESUMO
OBJECTIVE: To evaluate the prevalence and risk factors of menstrual cycle irregularities in adolescents with type 1 diabetes mellitus. DESIGN: Prospective diary of menstrual cycle. SETTING: Pediatric diabetes clinics and nearby schools. PATIENT(S): Adolescents with type 1 diabetes mellitus treated with multiple daily insulin doses (n = 56) and 56 healthy adolescents. MAIN OUTCOME MEASURE(S): Duration and variability of menstrual cycle. RESULT(S): Duration of the menstrual cycle was 48 ± 39 and 32 ± 7 days in girls with type 1 diabetes mellitus and controls, respectively. Oligomenorrhea (58.9% vs. 19.6%) and amenorrhea (10.7% vs. 1.8%) were more prevalent in girls with type 1 diabetes mellitus than in controls. Oligomenorrhea was observed in 53.3% of the girls with type 1 diabetes mellitus with optimal metabolic control. Girls with an HbA1c level of 7.6% to 8.9% exhibited increased cycle duration, menstrual cycle variability, and prevalence of oligomenorrhea compared with controls. Regression analysis showed that, for each point of increase in HbA1c, the menstrual cycle duration increased by 5.1 days. Cycle variability was associated with a higher daily insulin dose. CONCLUSION(S): Despite optimal metabolic control, a higher prevalence of oligomenorrhea was observed in girls with type 1 diabetes mellitus compared with controls. This is the first report to describe the high variability of the menstrual cycle in type 1 diabetes mellitus. HbA1c and insulin dose are important factors related to menstrual irregularities in type 1 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Distúrbios Menstruais/epidemiologia , Adolescente , Amenorreia/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/complicações , Relação Dose-Resposta a Droga , Feminino , Humanos , Ciclo Menstrual/fisiologia , Oligomenorreia/epidemiologia , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Fatores de Risco , Fatores de TempoRESUMO
Background: A decline in the age of menarche was observed from early 1900s to the 1970s. However, it is not known if a further decline ocurred thereafter. Aim: To evaluate the age of menarche in girls from Santiago, Chile and its relationship with body mass index (BMI) and socioeconomic status. Material and Methods: We studied 1302 healthy girls aged 7 to 19 years. Age of menarche was evaluated through a questionnaire to the patient and her parents. Kaplan-Meier curves were used to determine age of menarche and Cox regression analysis was employed to evaluate the effect of the type of school and BMI on the age of menarche. Results: The mean age at menarche was 12.7±0.04 years. Girls from public and private schools had their period at 12.5±0.1 and 13.05±0.05 years respectively. A negative correlation between z scores for BMIand age of menarche was observed (r-0.3: p =0.001). Girls whose menarche occurred before 11.5 years had higher z scores for BMI and a larger proportion were overweight, compared to girls who had menarche later. Cox regression analysis showed that after adjusment for BMI, age of menarche was similar in both types of schools. Conclusions: Age of menarche is ocurring three months earlier in girls from public schools, which is associated with higher z scores for BMI. Type of school, a marker of socio-economic status in Chile, affects timing of menarche due to differences in body mass index.