RESUMEN
INTRODUCTION: SSRIs have been shown to affect bone health in adults, but this has been poorly studied in children. Given the frequency of SSRI prescription in children and adolescents, it is crucial to evaluate the impact of SSRIs on bone growth because the bone mass attained early in life is the most important predictor of a normal bone constitution. Experimental studies have demonstrated a direct functional role of serotonin in bone metabolism, independently of hyperprolactinemia or growth hormone levels. We have reviewed the literature on serotonin and bone metabolism, including experimental studies, clinical studies in adults as well as in the pediatric population. EXPERIMENTAL STUDIES: Experimental studies have shown that 5-HT transporter (5-HTT) is expressed in all kind of bone cells and is highly specific of the 5-HT recapture. 5-HTT inhibition by the SSRIs in these cells affects their function in vitro. Even though a few studies have suggested exposure to SSRIs could be beneficial by an anabolic effect on the trabecular bone, more concluding studies have demonstrated that SSRIs negatively affect bone growth, resulting in a specific bone phenotype including a reduction in bone mass, an altered bone architecture, and decreased mechanical properties. This phenotype is most probably the consequence of a decrease in bone formation, rather than an increase in bone resorption and is a direct and dose-dependent effect. However, many aspects of this bone effect of 5-HTT inhibition need to be further clarified, including the signal ways for 5-HTT and 5-HT receptors, origins of 5-HT in bone, and methods to isolate the inhibitory effect of 5-HTT specifically on bone. CLINICAL STUDIES: Metabolic and neuroendocrine side effects have been documented in children and adolescents taking SSRIs but the specific and direct effect of these molecules on bone metabolism has been poorly studied in this population. In adults, clinical studies have shown an association between the use of SSRIs and bone demineralization as well as reduction in bone mass, especially in the elderly and post-menopausal women. However, depression itself has been associated with a lower bone mass and increased risk of osteoporosis. In children, case reports show a decrease in growth due to a decreased secretion of growth hormone, but not by a direct effect. One cross-sectional study suggests a decrease in bone mass following SSRI treatment that is independent of variation in prolactin levels, but without elevation of fracture risk. These results, however, need to be replicated in further studies. CONCLUSION: Our review shows that experimental studies have demonstrated the implication of the serotonin system in bone metabolism. Mice with genetic disruption of 5-HTT have a bone phenotype of decreased bone mass, altered architecture, and decreased mechanical properties. Clinical studies exploring the effect of SSRIs on bone metabolism are scarce in children. However, results in adults tend to show a deleterious effect in the elderly. Regarding the frequency of SSRI prescription in the pediatric population, it is becoming urgent to better explore the effect of SSRIs on bone growth of children, as it can have major implications on the ulterior follow-up and on the precautions to take.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Desarrollo Óseo/fisiología , Huesos/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Absorciometría de Fotón , Adolescente , Adulto , Animales , Densidad Ósea/fisiología , Huesos/fisiopatología , Niño , Femenino , Humanos , Masculino , Proteínas de Transporte de Serotonina en la Membrana Plasmática/fisiologíaRESUMEN
AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Proteínas de Transporte de Catión/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos de Linfocito T/inmunología , Antígeno HLA-A2/inmunología , Adolescente , Adulto , Animales , Autoanticuerpos/genética , Linfocitos T CD4-Positivos/inmunología , Proteínas de Transporte de Catión/genética , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Mapeo Epitopo , Epítopos de Linfocito T/genética , Femenino , Antígeno HLA-A2/genética , Humanos , Lactante , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Transportador 8 de ZincRESUMEN
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autoimmune disease causing a wide spectrum of autoimmune dysfunction potentially including diabetes of an autoimmune etiology. We have previously described a pair of discordant APECED siblings and pointed to a possible role of 5'insulin variable number of tandem repeats (VNTR) locus IDDM2 in the appearance of diabetes within this disease. In vitro studies have previously suggested that class I VNTR alleles were associated with decreased fetal thymic insulin expression. We genotyped the 5'INS VNTR locus and several flanking 11p15.5 markers in 50 Finnish APECED subjects and explored the possible contribution of IDDM2 in the development of diabetes. The shorter 5'INS VNTR class I alleles (<35 repeats) were more prevalent in the diabetic Finnish APECED subjects than in non-diabetic APECED subjects. Logistic regression analysis revealed that having 1 short (<35) VNTR allele did not increase the risk of developing diabetes (95% CI 0.6-27.0), whereas having 2 short alleles conferred a 43.5-fold increased risk (95% CI 3.0-634.6). We conclude that short 5'INS VNTR class I alleles play a role in susceptibility to autoimmune diabetes in the context of APECED.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Insulina/genética , Repeticiones de Minisatélite/genética , Poliendocrinopatías Autoinmunes/genética , Adulto , Alelos , Estudios de Cohortes , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 2/genética , Susceptibilidad a Enfermedades , Femenino , Genotipo , Humanos , Insulina/biosíntesis , Insulina/inmunología , Masculino , Estudios Retrospectivos , Riesgo , Población Blanca/genéticaRESUMEN
Measurement of beta-cell function is an important marker of progression to diabetes in individuals at risk for the disease. Although the peak incidence for the disease occurs before 17 years of age, normal values for insulin secretion were not available in this age group. We performed a simplified intravenous glucose tolerance test in 167 normal children, and in 98 islet cell antibody (ICA)-negative and 12 ICA-positive siblings of diabetic patients. Their age range was 1-16 yr. The first phase of insulin secretion, evaluated as the sum of plasma insulin concentrations at 1 and 3 min, increased with age and was significantly lower in ICA-negative siblings (86 +/- 6 microU/ml, P < 0.002) than in normal controls (115 +/- 6 microU/ml). This difference was not apparent before 8 yr of age. None of the ICA-negative siblings developed diabetes after an average of 4.5 yr. ICA-positive siblings at first study had a first phase insulin response similar to that of ICA negative siblings, but significantly lower than that of the normal controls (74 +/- 13 microU/ml, P < 0.02). The reason for the decreased insulin secretion in ICA-negative siblings is unknown, but could involve a defect in the growth of beta-cell mass or insulin secretion that could be part of the multifactorial pathogenesis of type 1 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Glucosa/fisiología , Insulina/metabolismo , Islotes Pancreáticos/inmunología , Adolescente , Autoanticuerpos/inmunología , Niño , Preescolar , Diabetes Mellitus Tipo 1/inmunología , Humanos , Lactante , Secreción de Insulina , LinajeAsunto(s)
Hiperplasia Suprarrenal Congénita/diagnóstico , Tamizaje Masivo , Hiperplasia Suprarrenal Congénita/epidemiología , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/mortalidad , Errores Diagnósticos/estadística & datos numéricos , Reacciones Falso Negativas , Francia/epidemiología , Genética de Población/métodos , Genética de Población/estadística & datos numéricos , Genética de Población/tendencias , Humanos , Mortalidad Infantil/tendencias , Recién Nacido , Enfermedades del Prematuro/diagnóstico , Enfermedades del Prematuro/epidemiología , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Tamizaje Masivo/tendencias , Morbilidad , Tamizaje Neonatal/normas , Tamizaje Neonatal/estadística & datos numéricos , Tamizaje Neonatal/tendencias , Población , Práctica Profesional/normas , Práctica Profesional/estadística & datos numéricos , Evaluación de Programas y Proyectos de SaludRESUMEN
Gender dysphoria, originally called gender identity disorder, is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress and social, academic, and other important forms of isolation. This state is also known as transgender or transsexualism and is recognized as a medical disease. Adults with gender dysphoria can benefit from psychological, medical, and surgical care. However, gender dysphoria rarely occurs in adulthood but rather emerges in childhood or adolescence, generating deep social and academic difficulties, especially at puberty. For the last 10years, the management of gender dysphoria in children and adolescents has developed in several countries, specifically in Europe, but remains under-recognized in France. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients. This article reviews the clinical criteria helping diagnose gender dysphoria and presents the different steps in the assessment and management of these patients in accordance with international guidelines.
Asunto(s)
Disforia de Género/diagnóstico , Disforia de Género/psicología , Adolescente , Niño , Humanos , Entrevista Psicológica , Encuestas y CuestionariosRESUMEN
CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Enfermedades de la Mama/inmunología , Mastitis/inmunología , Adolescente , Adulto , Autoanticuerpos/análisis , Mama/patología , Enfermedades de la Mama/diagnóstico , Enfermedades de la Mama/metabolismo , Enfermedades de la Mama/patología , Niño , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Hormonas/sangre , Humanos , Hipertrofia , Imagen por Resonancia Magnética , Mamografía , Mastitis/diagnóstico , Mastitis/metabolismo , Mastitis/patología , Embarazo , Complicaciones del Embarazo , Pubertad/inmunología , Ultrasonografía MamariaRESUMEN
In juvenile IDDM patients, immunosuppression with cyclosporin A allows partial beta-cell function recovery and transient remissions of insulin dependency. The effects of this therapeutic approach, however, have not been evaluated in the long-term, since no reported trial exceeded 1 year. Here we analyze 130 diabetic children followed at our institution during the first years of their disease. Cyclosporin was given to 83 of them at an initial dose of 7.2 +/- 0.1 mg.kg-1.day-1, which was decreased stepwise then interrupted after 6-62 months, depending on the response to therapy. A total of 47 diabetic children, who served as control subjects in two trials, were pooled for comparison. Over 4 years, the cyclosporin-treated group kept plasma C-peptide approximately twice as high as the control group (P < 0.02). It took 5.8 +/- 0.6 years for C-peptide secretion stimulated by glucagon to become undetectable in the cyclosporin group versus 3.2 +/- 0.6 years in the control group (P < 0.02). Average insulin dose remained lower by 0.2-0.4 U.kg-1.day-1 and glycated hemoglobin by approximately 1% in cyclosporin-treated patients (P < 0.02), who also had less hypoglycemia than the diabetic control subjects (P < 0.05). After 4 years, differences between the groups became nonsignificant. We observed no significant secondary effects of cyclosporin. In conclusion, positive effects of low-dose cyclosporin in recently diagnosed clinical IDDM patients are prolonged beyond interruption of the drug. The magnitude and duration of the benefit, however, do not appear sufficient to justify this immunosuppressive treatment in clinical practice.
Asunto(s)
Ciclosporina/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Autoanticuerpos/análisis , Péptido C/sangre , Niño , Ciclosporina/administración & dosificación , Diabetes Mellitus Tipo 1/sangre , Método Doble Ciego , Quimioterapia Combinada , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Insulina/inmunología , Insulina/uso terapéutico , Islotes Pancreáticos/inmunología , Estudios Longitudinales , PronósticoRESUMEN
To study the effect of expression of a single foreign antigen on the outcome of otherwise compatible mouse islet grafts, we have used transgenic mice expressing the human complement receptor 2 (CR2, CD21, C3d/EBV receptor) on their pancreatic beta-cells (RIP-CR2 mice). Donors were RIP-CR2 mice, typed at the major histocompatibility complex (MHC) as H-2(k), H-2(b), or H-2(bxk), and recipients were streptozotocin-treated nontransgenic B6 x CBA F1 mice (H-2(bxk)). H-2(b) or H-2(bxk) CR2-expressing islets were not rejected (mean survival time [MST] >100 days) but induced a peri-insulitis and an antibody response to CR2. In contrast, H-2(k) CR2-expressing islets were rejected in 80% of the cases with a MST of 65 +/- 23 days and were massively infiltrated by a destructive insulitis. In both cases, the infiltrate was mainly made of CD4+ cells, with few CD8+ cells. The isotype of IgG antibody response to CR2 was studied: recipients of H-2(k) grafts had a predominantly IgG1 response, while recipients of H-2(b) grafts had a balanced IgG2a and IgG1 response. To further evaluate the mechanism of differential rejection of the two types of grafts, recipients were immunized with CR2-expressing rat insulinoma cells before transplantation. Preimmunization with CR2 did not affect the outcome of H-2(b) grafts but greatly accelerated the rejection of H-2(k) grafts. These experiments indicate that expression of a single foreign antigen on beta-cells triggers an immune response leading to rejection or to peri-insulitis, depending on the MHC of donor islets.
Asunto(s)
Trasplante de Islotes Pancreáticos/inmunología , Complejo Mayor de Histocompatibilidad/fisiología , Donantes de Tejidos , Animales , Formación de Anticuerpos , Antígenos/análisis , Diabetes Mellitus Tipo 1/cirugía , Ensayo de Inmunoadsorción Enzimática , Rechazo de Injerto/inmunología , Islotes Pancreáticos/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Receptores de Complemento 3d/análisis , Receptores de Complemento 3d/inmunología , Proteínas Recombinantes/análisis , Proteínas Recombinantes/inmunologíaRESUMEN
We stably expressed human complement receptor 2 ([CR2] CD21 C3d/Epstein-Barr virus [EBV] receptor) on the rat insulinoma cell line RINm5F with a recombinant retroviral vector. CR2-expressing RINm5F cells secreted 78-33% less insulin than parental cells or cells transduced with an antisense vector and could be infected with high-titer EBV. We tested whether human CR2 expression on RINm5F cells would affect tumorigenesis after transplantation to syngeneic New England Deaconess Hospital rats. Non-CR2-expressing antisense-transduced RINm5F cells rapidly grew tumors and caused hypoglycemia, hyperinsulinemia, and the death of the animals after 15.7 +/- 0.7 days. CR2-expressing RINm5F cells were infiltrated by mononuclear cells at an early stage and eventually caused noninfiltrated tumors and the death of the animals after 33.0 +/- 0.4 days. These tumors were CR2- and are believed to have arisen from a minor CR2- population of tumor cells. The pancreatic islets were histologically normal at all time points. We conclude that expression of a xenoantigen on a rat insulinoma cell line induces an immune response in syngeneic rats but does not result in breakage of tolerance to parental or revertant cells.
Asunto(s)
Antígenos CD/fisiología , Diabetes Mellitus Experimental/fisiopatología , Herpesvirus Humano 4/crecimiento & desarrollo , Insulinoma/patología , Neoplasias Pancreáticas/patología , Receptores de Complemento/fisiología , Animales , Antígenos de Diferenciación de Linfocitos B/genética , Antígenos de Diferenciación de Linfocitos B/fisiología , Glucemia/metabolismo , Línea Celular , Vectores Genéticos , Rechazo de Injerto , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Insulinoma/inmunología , Masculino , Trasplante de Neoplasias , Neoplasias Pancreáticas/inmunología , Ratas , Ratas Endogámicas , Receptores de Complemento/genética , Receptores de Complemento 3d , Transfección , Trasplante IsogénicoRESUMEN
Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity.
Asunto(s)
Tejido Adiposo/anatomía & histología , Proteínas Portadoras/sangre , Proteínas Portadoras/genética , Resistencia a Medicamentos , Leptina/farmacología , Obesidad/sangre , Receptores de Superficie Celular , Adolescente , Adulto , Biomarcadores/sangre , Niño , Cromatografía en Gel , Consanguinidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , Mutación , Obesidad/genética , Receptores de Leptina , Valores de Referencia , Análisis de RegresiónRESUMEN
Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before, a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms, less severe hyperglycemia, lower incidence of ketoacidosis, and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean +/- SE duration of 316 +/- 21 days (range 31-850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen, titer of autoantibodies, or progression of beta-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo, the patients who had a remission of insulin dependency had better glycemic control, lower insulin dosages, and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically, serum creatinine remained unchanged, and kidney biopsies performed at 18-24 mo of treatment were within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ciclosporinas/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina/uso terapéutico , Adolescente , Autoanticuerpos/análisis , Péptido C/sangre , Niño , Ciclosporinas/efectos adversos , Diabetes Mellitus Tipo 1/sangre , Femenino , Estudios de Seguimiento , Glucagón , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/inmunología , MasculinoRESUMEN
OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.
Asunto(s)
Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Adolescente , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Niño , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/epidemiología , Cetoacidosis Diabética/etiología , Familia , Femenino , Francia/epidemiología , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/sangre , Hiperglucemia/etiología , Hipoglucemia/sangre , Hipoglucemia/etiología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Prevalencia , Calidad de Vida , Análisis de Regresión , Factores de Riesgo , Apoyo Social , Encuestas y CuestionariosRESUMEN
An adapted GH dose regimen was evaluated in 14 untreated patients with Turner's syndrome. The initial GH dose (0.7 U/kg.BW) was increased by 0.7 U/kg.BW, up to a maximum of 2.1 U/kg.BW, when growth velocity (GV) declined to less than 200% of the pretreatment level. These patients were compared to a group of 17 patients with similar initial characteristics, who received a fixed dose of 0.9 U/kg.BW GH. Tolerance to both GH regimens was excellent. The adapted GH doses only partially prevented the waning effect observed with conventional doses of GH, and the initial goal of doubling GV was only achieved in 42% of the 112 patient-semesters. Doubling the GH dose from 0.7 to 1.4 U/kg.BW increased the GV by 1.6 +/- 1.8 cm/yr (P < 0.006); increasing the GH dose from 1.4 to 2.1 U/kg.BW increased GV by 0.8 +/- 1.3 cm/yr (P = NS). The overall height gain during the 4-yr trial was 25.6 +/- 3.9 cm in the adapted dose group and 21.8 +/- 3.9 cm in the conventional group (P < 0.02). Final height (FH) results were obtained in 12 of 14 patients in the adapted dose group and all 17 patients in the conventional group and compared to the predicted FH using Lyon's method. The estimated height benefit was 10.6 +/- 3.8 cm in the adapted dose group compared to 5.2 +/- 3.7 cm in the conventional group (P < 0.01). Eighty-three percent of the patients in the adapted dose group had an FH superior or equal to -2 SD score for the general population compared to 29% in the conventional group. In conclusion, a marked increment in the GH dose in girls with Turner's syndrome associated with a relatively late age at introduction of estrogen therapy brought 83% of the patients into the lower range of the normal height distribution of the general population.
Asunto(s)
Estatura , Hormona de Crecimiento Humana/administración & dosificación , Síndrome de Turner/tratamiento farmacológico , Adolescente , Determinación de la Edad por el Esqueleto , Niño , Estrógenos/administración & dosificación , Estrógenos/uso terapéutico , Femenino , Hormona de Crecimiento Humana/uso terapéutico , HumanosRESUMEN
Short term studies have demonstrated the acceleration of growth velocity after the administration of GH in short children born with intrauterine growth retardation (IUGR). We report the final heights of 70 IUGR children whose short stature was attributed to idiopathic GH deficiency (peak plasma GH <10 ng/mL at 2 provocative tests) and treated with GH at a mean dosage of 0.4 +/- 0.1 U/kg x week during an average of 4.6 +/- 2.5 yr. They were compared to a control group of 40 untreated short children born with IUGR, without GH deficiency. At the time of evaluation, age, auxological data, and pubertal status were similar in the 2 groups (height, -2.9 +/- 0.8 and -2.8 +/- 0.7 SD score). Final heights were comparable in both groups of children (-2 +/- 0.7 and -2.2 +/- 1.1 SD score). A multivariate analysis identified 4 independent predictors of final height, namely target height, age and body mass index at evaluation, and GH treatment. Treatment was associated with a gain of 0.6 SD score, suggesting a final height gain of about 3.4 cm. Fifty-three of 70 treated children were reevaluated after completion of growth, and 43 of 53 had a peak plasma GH level of 10 ng/mL or more. Auxological characteristics of these 53 patients were not different from those of nonreevaluated patients. We believe that the transient character of the GH deficiency in most patients and the nonstringent initial criteria used for the diagnosis of GH deficiency render the spontaneous growth potentials identical in the 2 groups of patients. Our data, therefore, suggest that GH treatment at this dosage has a limited effect on the final height of short children born with IUGR.
Asunto(s)
Estatura , Retardo del Crecimiento Fetal/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Preescolar , Femenino , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/metabolismo , Humanos , Recién Nacido , Masculino , Pronóstico , PubertadRESUMEN
GnRH agonists have been proposed to improve final height in patients with constitutional short stature. We treated 31 girls, aged 11.9 +/- 1 yr (mean +/- SD), with short stature, recent pubertal onset and predicted final height of 155 cm or less with depot triptorelin. During the 23 +/- 4 months of treatment, bone age progression was 0.6 +/- 0.3 bone age yr/yr, and growth velocity declined from 7 +/- 2 to 4 +/- 0.8 cm/yr (P < 0.0001). Height prognosis, calculated by the Bayley-Pinneau method, progressed from 149.6 +/- 3.4 to 151.8 +/- 4 cm at the end of treatment (+2.2 +/- 2.6 cm; P < 0.0001). When treatment was interrupted, growth velocity slightly increased to 4.6 +/- 1.6 cm/yr, and bone age maturation was accelerated: 1.3 +/- 0.4 bone age yr/yr during the first posttreatment year. At the last visit, 26 +/- 9 months after interruption of treatment, bone age was 14.9 +/- 1.3 yr (> or = 13.5 yr in all patients), height was 149.1 +/- 4 cm, and final height prognosis was 150.6 +/- 3.6 cm. Final height prognosis was 1 +/- 2.3 cm greater than pretreatment height prognosis (P < 0.02) and 1.2 +/- 2.2 cm below the height predicted at the end of the treatment (P < 0.01). No major side-effect was observed. Height SD score decreased during treatment with GnRH agonist from -2.3 +/- 0.9 to -2.7 +/- 0.7 SD score (P < 0.0001). We conclude that 2 yr of depot triptorelin-induced pubertal delay has a limited effect on near-final height in girls with constitutional short stature and that the growth benefit observed does not currently justify the use of GnRH agonists, given their cost and potential side-effects.
Asunto(s)
Estatura , Pubertad , Pamoato de Triptorelina/uso terapéutico , Adolescente , Determinación de la Edad por el Esqueleto , Niño , Preparaciones de Acción Retardada , Costos de los Medicamentos , Femenino , Humanos , Pamoato de Triptorelina/efectos adversos , Pamoato de Triptorelina/economíaRESUMEN
The impact of treatment of central precocious puberty (CPP) with GnRH agonists on final statural height (FH) remains controversial, and guidelines on the optimal time point for interruption of these treatments have not been established. We analyzed the long term results of 58 girls and 8 boys uniformly treated with triptorelin slow release formulation (Decapeptyl, triptorelin-SR) for CPP and compared their FH with predicted height before treatment and with the FH of a historical group of patients not treated with GnRH agonist. The FH SD score was close to 0 and was not different from the genetic target height. In girls, FH was improved by 4.8 +/- 5.8 cm compared with predicted height before treatment and by 8.3 cm by comparison with a historical group. In boys, comparison with a historical group revealed a 13.7-cm improvement, whereas predicted height before treatment was similar to FH. Three variables were independently associated with FH in girls: the bone age/statural age ratio at the onset of treatment (negatively), the height SD score at the end of treatment, and the posttreatment growth spurt (delta FH - height at the end of treatment). The influence of the posttreatment growth spurt, itself dependent on age and bone age at the interruption of treatment, suggests that continuing treatment beyond the age of 11 yr in girls does not improve and could actually decrease FH. This point should be evaluated in a formal controlled trial.
Asunto(s)
Estatura/efectos de los fármacos , Crecimiento/efectos de los fármacos , Luteolíticos/uso terapéutico , Pubertad Precoz/tratamiento farmacológico , Pamoato de Triptorelina/uso terapéutico , Edad de Inicio , Niño , Preescolar , Preparaciones de Acción Retardada , Femenino , Estudios de Seguimiento , Humanos , Luteolíticos/administración & dosificación , Luteolíticos/efectos adversos , Masculino , Pamoato de Triptorelina/administración & dosificación , Pamoato de Triptorelina/efectos adversosRESUMEN
Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance or factor, is produced by Sertoli cells from fetal life until puberty. In the present study, AMH, testosterone (T), LH, and FSH were measured by immunochemical methods in the serum of 50 boys with normal or delayed pubertal development, 4 patients with suspected androgen insensitivity, and 11 patients with either central (CPP) or gonadotropin-independent (GIPP) precocious puberty to investigate the hormonal regulatory mechanisms of AMH secretion at puberty. An inverse relationship between AMH and T levels was demonstrated. In boys with normal or delayed puberty with T concentrations below 6.7 nmol/L, AMH values were elevated (mean +/- SEM, 22.4 +/- 3.1 micrograms/L) and widely dispersed. In subjects with T levels over 6.7 nmol/L, AMH levels were uniformly low (3.4 +/- 0.5 micrograms/L), except in patients with suspected androgen insensitivity. No significant relationship was found between AMH and gonadotropin levels. Similar results were obtained in patients with either CPP or GIPP. Longitudinal studies were performed on four boys with CPP and two with GIPP before and after treatment. At the time of diagnosis, the T concentration was high, and AMH levels were usually low in CPP and GIPP patients alike. When appropriate treatment was initiated, the T concentration was normalized within 2-4 weeks, but restoration of prepubertal AMH levels required several months. Mature Sertoli cells were observed in testicular biopsies performed in three patients with untreated GIPP. Our results suggest that gonadotropins are not directly implicated in repression of AMH synthesis at puberty, but, rather, that the decrease in AMH production is the consequence of an androgen-mediated, long term, reversible chain of events leading to morphological and functional maturation of the Sertoli cells. Thus, the fall in serum AMH levels appears to be an excellent marker of Sertoli cell pubertal development.
Asunto(s)
Glicoproteínas , Inhibidores de Crecimiento/sangre , Pubertad Precoz/sangre , Hormonas Testiculares/sangre , Adolescente , Andrógenos/fisiología , Hormona Antimülleriana , Niño , Resistencia a Medicamentos , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Masculino , Conductos Paramesonéfricos/fisiología , Pubertad Tardía/sangre , Valores de Referencia , Testosterona/sangreRESUMEN
Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from 1973-1989. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD.
Asunto(s)
Hormona del Crecimiento/sangre , Hormona del Crecimiento/deficiencia , Adolescente , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Masculino , Métodos , Sistema de Registros , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Deficiency of protein Gs (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright's hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS 1, the gene encoding the alpha-subunit of Gs. Obesity is a classical feature of patients with Gs deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with Gs deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in Gs-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in Gs-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in Gs deficiency. Besides beta-adrenergic receptors, Gs protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.