RESUMEN
Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
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Consenso , Hormona de Crecimiento Humana/efectos adversos , Seguridad del Paciente/normas , Sociedades Médicas/normas , Adulto , Niño , Educación , Endocrinología/normas , Europa (Continente) , Humanos , Pediatría/normas , Proteínas RecombinantesRESUMEN
"BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required."
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Humanos , Femenino , Raquitismo/terapia , Complicaciones del Embarazo/prevención & control , Raquitismo , Raquitismo/diagnóstico , Deficiencia de Vitamina D/complicaciones , Lactancia , Embarazo , Calcio/deficiencia , Salud Pública , Factores de RiesgoRESUMEN
BACKGROUND: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. METHODS: We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. RESULTS: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. CONCLUSION: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.
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Enfermedades del Desarrollo Óseo/complicaciones , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Discapacidad Intelectual/complicaciones , Anomalías Dentarias/complicaciones , Anomalías Múltiples , Niño , Facies , Trastornos del Crecimiento/complicaciones , Humanos , Masculino , Resultado del TratamientoRESUMEN
High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα(-/-)) or ERαAF-1 (ERαAF-1(0)) were evaluated. Old (16- to 19-mo-old) female ERα(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-1(0) mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-1(0) mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.
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Receptor alfa de Estrógeno/fisiología , Placa de Crecimiento/fisiología , Transactivadores/fisiología , Absorciometría de Fotón , Envejecimiento/fisiología , Animales , Apoptosis/genética , Apoptosis/fisiología , Desarrollo Óseo/efectos de los fármacos , Proliferación Celular , Condrocitos/fisiología , Cartilla de ADN , Estradiol/sangre , Receptor alfa de Estrógeno/genética , Femenino , Placa de Crecimiento/anatomía & histología , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígeno Nuclear de Célula en Proliferación/metabolismo , Maduración Sexual/fisiología , Tibia/crecimiento & desarrollo , Transactivadores/genéticaRESUMEN
BACKGROUND: Growth disorders are commonly observed in children with chronic inflammatory disease. It is likely that these disorders are mediated by a combination of factors, including the disease process and its treatment (with drugs such as glucocorticoids [GCs]). These factors affect the growth hormone-insulin-like growth factor I (IGF-I) axis, which is crucial for promoting linear growth at the level of the growth plate. Recent advances in our knowledge of the effects of GCs and proinflammatory cytokines on the growth plate have led to an improved understanding of the biological rationale for the use of growth-promoting therapy in children with chronic inflammatory disease and concurrent growth retardation. CONCLUSIONS: Both GCs and proinflammatory cytokines can adversely affect a number of components of growth plate chondrogenesis, and these effects can be ameliorated by raising local IGF-I exposure. However, this intervention does not lead to complete normalization of the growth plate. In children with chronic inflammation, the cornerstone of improving growth remains the judicious use of GCs while ensuring effective control of the disease process.
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Antiinflamatorios/uso terapéutico , Placa de Crecimiento/fisiología , Inflamación/fisiopatología , Animales , Células Cultivadas , Niño , Condrogénesis , Glucocorticoides , Crecimiento , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento/uso terapéutico , Placa de Crecimiento/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Interleucina-1beta/efectos adversos , Factor de Necrosis Tumoral alfa/efectos adversosRESUMEN
In vitro studies suggest that the membrane G protein-coupled receptor GPR30 is a functional estrogen receptor (ER). The aim of the present study was to determine the possible in vivo role of GPR30 as a functional ER primarily for the regulation of skeletal parameters, including bone mass and longitudinal bone growth, but also for some other well-known estrogen-regulated parameters, including uterine weight, thymus weight, and fat mass. Three-month-old ovariectomized (OVX) GPR30-deficient mice (GPR30(-/-)) and wild-type (WT) mice were treated with either vehicle or increasing doses of estradiol (E(2); 0, 30, 70, 160, or 830 ng.mouse(-1).day(-1)). Body composition [bone mineral density (BMD), fat mass, and lean mass] was analyzed by dual-energy-X ray absorptiometry, while the cortical and trabecular bone compartments were analyzed by peripheral quantitative computerized tomography. Quantitative histological analyses were performed in the distal femur growth plate. Bone marrow cellularity and distribution were analyzed using a fluorescence-activated cell sorter. The estrogenic responses on most of the investigated parameters, including increase in bone mass (total body BMD, spine BMD, trabecular BMD, and cortical bone thickness), increase in uterine weight, thymic atrophy, fat mass reduction, and increase in bone marrow cellularity, were similar for all of the investigated E(2) doses in WT and GPR30(-/-) mice. On the other hand, E(2) treatment reduced longitudinal bone growth, reflected by decreased femur length and distal femur growth plate height, in the WT mice but not in the GPR30(-/-) mice compared with vehicle-treated mice. These in vivo findings demonstrate that GPR30 is not required for normal estrogenic responses on several major well-known estrogen-regulated parameters. In contrast, GPR30 is required for a normal estrogenic response in the growth plate.
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Desarrollo Óseo/fisiología , Estrógenos/metabolismo , Ovariectomía , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Tejido Adiposo/anatomía & histología , Tejido Adiposo/crecimiento & desarrollo , Animales , Densidad Ósea , Femenino , Fémur/citología , Fémur/crecimiento & desarrollo , Placa de Crecimiento/citología , Placa de Crecimiento/crecimiento & desarrollo , Ratones , Ratones Mutantes , Tamaño de los Órganos , Receptores de Estrógenos/metabolismo , Timo/anatomía & histología , Timo/crecimiento & desarrollo , Útero/anatomía & histología , Útero/crecimiento & desarrolloAsunto(s)
Desarrollo Óseo/efectos de los fármacos , Neoplasias/complicaciones , Inhibidores de Proteasas/efectos adversos , Animales , Ácidos Borónicos/efectos adversos , Bortezomib , Niño , Condrocitos/efectos de los fármacos , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Pirazinas/efectos adversosRESUMEN
A 7-year-old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160,000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C-peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5- and 27-months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C-peptide levels were 0.67 +/- 0.07 and 3.36 +/- 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet-bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long-term clinically significant metabolic control.
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Trasplante de Islotes Pancreáticos/métodos , Pancreatectomía , Pancreatitis/cirugía , Trasplante Autólogo/métodos , Niño , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Músculo Esquelético , Pancreatitis/genética , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: To assess the value of the metacarpophalangeal pattern profile (MCPP) analysis as a diagnostic tool for differentiating between patients with dyschondrosteosis, Turner syndrome, and hypochondroplasia. MATERIAL AND METHODS: Radiographic and clinical data from 135 patients between 1 and 51 years of age were collected and analyzed. The study included 25 patients with hypochondroplasia (HCP), 39 with dyschondrosteosis (LWD), and 71 with Turner syndrome (TS). Hand pattern profiles were calculated and compared with those of 110 normal individuals. Pearson correlation coefficient (r) and multivariate discriminant analysis were used for pattern profile analysis. Pattern variability index, a measure of dysmorphogenesis, was calculated for LWD, TS, HCP, and normal controls. RESULTS: Our results demonstrate that patients with LWD, TS, or HCP have distinct pattern profiles that are significantly different from each other and from those of normal controls. Discriminant analysis yielded correct classification of normal versus abnormal individuals in 84% of cases. Classification of the patients into LWD, TS, and HCP groups was successful in 75%. The correct classification rate was higher (85%) when differentiating two pathological groups at a time. Pattern variability index was not helpful for differential diagnosis of LWD, TS, and HCP. CONCLUSION: Patients with LWD, TS, or HCP have distinct MCPPs and can be successfully differentiated from each other using advanced MCPP analysis. Discriminant analysis is to be preferred over Pearson correlation coefficient because it is a more sensitive and specific technique. MCPP analysis is a helpful tool for differentiating between syndromes with similar clinical and radiological abnormalities.
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Articulación Metacarpofalángica/diagnóstico por imagen , Osteocondrodisplasias/diagnóstico por imagen , Síndrome de Turner/diagnóstico por imagen , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , RadiografíaRESUMEN
The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17beta-estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation (3H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64.1 +/- 5.3 fmol/3 days/10(6) cells). The aromatase inhibitor letrozole (1 microM) and the pure estrogen receptor antagonist ICI 182,780 (10 microM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P < 0.01) and almost 50% (P < 0.001), respectively. Treatment with ICI 182,780 (10 microM) increased apoptosis by 228% (P < 0.05). Co-treatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P < 0.001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 microM) and letrozole (1 microM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P < 0.01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.
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Apoptosis/fisiología , Condrocitos/fisiología , Estrógenos/fisiología , Huesos Metatarsianos/embriología , Animales , Apoptosis/efectos de los fármacos , Inhibidores de la Aromatasa/farmacología , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Estradiol/análogos & derivados , Estradiol/farmacología , Estradiol/fisiología , Antagonistas de Estrógenos/farmacología , Fulvestrant , Humanos , Inmunohistoquímica/métodos , Factor I del Crecimiento Similar a la Insulina/fisiología , Letrozol , Huesos Metatarsianos/efectos de los fármacos , Nitrilos/farmacología , Ratas , Triazoles/farmacologíaRESUMEN
PURPOSE: To analyze the metacarpophalangeal pattern profile (MCPP) in a cohort of individuals with Turner syndrome (TS), and to assess its value as a tool for early diagnosis of TS. MATERIAL AND METHODS: Medical records and radiological material were collected of 71 patients with TS aged between 3 and 21 years. Forty-six patients received growth hormone therapy (33-66 microg kg(-1) day(-1)) and 14 of these were also treated with the anabolic steroid oxandrolone (1.25-3.75 mg day(-1)). A total of 233 frontal hand radiographs were studied and pattern profiles were calculated. Profiles of the TS patients were compared with those of 70 normal females. Mean pattern profiles were calculated for different age groups and extrapolated profiles for newborns and infants were developed. RESULTS: Our results confirm that patients with TS have a distinct MCPP which differs significantly from that of normal individuals. A bone-shortening gradient with increasing shortening from distal phalanges to metacarpals was demonstrated. We also showed that the MCPP in TS is a remarkably constant feature from 3 to 18 years. Pattern profiles did not differ significantly between the patients with 45,X and non-45,X karyotype. MCPP was not affected by treatment with growth hormone of growth hormone plus oxandrolone. Discriminant analysis yielded correct classification in 88%, of analyzed cases. CONCLUSION: TS individuals have a distinct hand pattern profile that is not age-related. MCPP analysis can be applied at any age and may facilitate early diagnosis of TS. Our study showed that MCPP analysis is a specific and sensitive method that should be considered as a routinely used tool for early diagnosis of TS in girls with unexplained short stature.
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Articulación Metacarpofalángica/anomalías , Articulación Metacarpofalángica/diagnóstico por imagen , Síndrome de Turner/diagnóstico , Adolescente , Adulto , Anabolizantes/uso terapéutico , Niño , Preescolar , Estudios de Cohortes , Análisis Discriminante , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Hormona del Crecimiento/uso terapéutico , Humanos , Oxandrolona/uso terapéutico , Valor Predictivo de las Pruebas , Radiografía , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Síndrome de Turner/tratamiento farmacológicoRESUMEN
UNLABELLED: To determine the long-term role of ER beta in the regulation of longitudinal bone growth, appendicular and axial skeletal growth was followed and compared in female ER beta-/-, ER alpha-/-, and ER alpha-/- beta-/- mice. Our results show that ER beta inhibits appendicular and axial skeletal growth and has the capacity to induce fusion of the growth plates. INTRODUCTION: Estrogen affects skeletal growth and promotes growth plate fusion in humans. In rodents, the growth plates do not fuse after sexual maturation, but prolonged treatment with supraphysiological levels of estradiol has the capacity to fuse the growth plates. It should be emphasized that the estrogen receptor (ER) alpha-/- and the ER alpha-/- beta-/-, but not the ER beta-/-, mouse models have clearly increased serum levels of estradiol. MATERIALS AND METHODS: The skeletal growth was monitored by X-ray and dynamic histomorphometry, and the growth plates were analyzed by quantitative histology, calcein double labeling, bromodeoxyuridine (BrdU) incorporation, and TUNEL assay in 4- and 18-month-old female ER beta-/-, ER alpha-/-, and ER alpha-/- beta-/- mice. RESULTS: Young adult (4-month-old) ER beta-/- mice demonstrated an increased axial- and appendicular-skeletal growth, supporting the notion that ER beta inhibits skeletal growth in young adult female mice. Interestingly, the growth plates were consistently fused in the appendicular skeleton of 18-month-old female ER alpha-/- mice. This fusion of growth plates, caused by a prolonged exposure to supraphysiological levels of estradiol in female ER alpha-/- mice, must be mediated through ER beta because old ER alpah-/- beta-/- mice displayed unchanged, unfused growth plates. CONCLUSIONS: Our results confirm that ER beta is a physiological inhibitor of appendicular- and axial-skeletal growth in young adult female mice. Furthermore, we made the novel observation that ER beta, after prolonged supraphysiological estradiol exposure, has the capacity to mediate growth plate fusion in old female mice.
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Desarrollo Óseo/fisiología , Placa de Crecimiento/crecimiento & desarrollo , Receptores de Estrógenos/fisiología , Absorciometría de Fotón , Factores de Edad , Animales , Apoptosis/fisiología , Pesos y Medidas Corporales , Recuento de Células , División Celular/fisiología , Tamaño de la Célula/fisiología , Condrocitos/citología , Condrocitos/metabolismo , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Fémur/anatomía & histología , Fémur/citología , Fémur/crecimiento & desarrollo , Placa de Crecimiento/anatomía & histología , Placa de Crecimiento/citología , Disco Intervertebral/anatomía & histología , Ratones , Ratones Noqueados , Receptores de Estrógenos/genética , Columna Vertebral/anatomía & histología , Columna Vertebral/citología , Columna Vertebral/crecimiento & desarrollo , Tibia/citología , Tibia/crecimiento & desarrolloRESUMEN
Glucocorticoids cause significant growth retardation in mammals and humans and decreased proliferation of chondrocytes has been considered as the main local mechanism. Death by apoptosis is an important regulator of homeostasis in multicellular organisms. Here we chose to study the role of apoptosis in growth retardation caused by glucocorticoid treatment. We treated 7-week-old male rats with dexamethasone (5 mg/kg/day) for 7 days. Apoptosis was studied in tibiae growth plates by the TUNEL method. Immunoreactivity for parathyroid hormone-related peptide (PTHrP), caspase-3, and the anti-apoptotic proteins Bcl-2 and Bcl-x was also studied. Apoptosis was mainly localized in terminal hypertropic chondrocytes (THCs) in both control and dexamethasone-treated animals. Dexamethasone caused an increase in apoptosis which was fourfold in THCs (2.45+/-0.12 vs 0.62+/-0.09 apoptotic cells/mm growth plate, P<0.001), and 18-fold in proliferative chondrocytes (0.18+/-0.04 vs 0.01+/-0.007 apoptotic cells/mm growth plate, P<0.001). Increased apoptosis after dexamethasone treatment was accompanied by increased immunoreactivity for caspase-3 and decreased immunoreactivity for the anti-apoptotic proteins Bcl-2 and Bcl-x, which further supports our apoptosis results. Dexamethasone also decreased the immunoreactivity for PTHrP, suggesting a role in the mechanism by which glucocorticoids induce apoptosis in the growth plate. We conclude that apoptosis is one mechanism involved in growth retardation induced by glucocorticoids. Premature loss of resting/proliferative chondrocytes by apoptosis could contribute to incomplete catch-up seen after prolonged glucocorticoid treatment.
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Apoptosis , Condrocitos/efectos de los fármacos , Dexametasona/efectos adversos , Glucocorticoides/efectos adversos , Placa de Crecimiento/citología , Animales , Caspasa 3 , Caspasas/análisis , Genes bcl-2 , Masculino , Proteína Relacionada con la Hormona Paratiroidea , Hormonas Peptídicas/análisis , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Ratas , Ratas Sprague-Dawley , Tibia , Proteína bcl-XRESUMEN
Indian Hedgehog (Ihh) has been reported to control the rate of cartilage differentiation during skeletal morphogenesis in rodents through a negative feedback loop involving parathyroid hormone related protein (PTHrP). The role of Ihh and PTHrP in the regulation of human epiphyseal chondrocytes is unknown. The aim of the current study was to examine the expression and localization of Ihh and PTHrP in the human growth plate at various pubertal stages. Growth plate biopsies were obtained from patients subjected to epiphyseal surgery and the expression of Ihh and PTHrP was detected by immunohistochemistry. We show that Ihh and PTHrP are expressed mainly in early hypertrophic chondrocytes in the human growth plate. The levels of expression of Ihh and PTHrP are higher in early stages of puberty than later. Our results suggest that Ihh and PTHrP are present in the human growth plate and that Ihh and PTHrP may be involved in the regulation of pubertal growth in humans.
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Placa de Crecimiento/química , Proteínas/análisis , Pubertad/metabolismo , Transactivadores/análisis , Adolescente , Niño , Femenino , Proteínas Hedgehog , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica/métodos , Masculino , Proteína Relacionada con la Hormona ParatiroideaRESUMEN
Estrogen regulates skeletal growth and promotes epiphyseal fusion. To explore the mechanisms underlying these effects we investigated the expression of estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in rat and rabbit growth plates during postnatal development, using immunohistochemistry. Immunoreactivity for ERalpha and ERbeta was observed in resting zone and proliferative zone chondrocytes at all ages studied for both rat (7, 14, 28 and 70 days of age) and rabbit (1, 7, 28 and 120 days of age). In the rat distal humerus and the rabbit proximal tibia, expression of both receptors in the hypertrophic zone was minimal at early ages, increasing only at the last time point prior to epiphyseal fusion. Expression was rarely seen in the hypertrophic zone of the rat proximal tibia, a growth plate that does not fuse until late in life. Therefore, we conclude that ERalpha and ERbeta are both expressed in the mammalian growth plate. The temporal and anatomical pattern suggests that ER expression in the hypertrophic zone in particular may play a role in epiphyseal fusion.
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Envejecimiento/fisiología , Placa de Crecimiento/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Condrocitos/química , Condrocitos/metabolismo , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Placa de Crecimiento/química , Húmero , Inmunohistoquímica/métodos , Masculino , Conejos , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/análisis , TibiaRESUMEN
The introduction of transgenic mice as animal models in medical research has increased the need for methods to study the phenotype of mice. The aim of the present study was to develop and evaluate a method for in vivo prediction of fat content in living mice. We combined a modified dual-energy X-ray technique with an image analysis procedure. This combined procedure calculates the percentage of fat area, defined as the percentage of the total area of the mice consisting of >50% fat. A high correlation between the percentage of fat area and dissected adipose tissue was seen in both male and female mice (males, r = 0.92, P < 0.001; females, r = 0.88, P < 0.001). A high correlation was also seen between the percentage of fat area and serum levels of leptin (males, r = 0.95, P < 0.001; females, r = 0.86, P < 0.001). An additional experiment demonstrated a very strong correlation between the percentage of fat area and total body fat as determined by chemical extraction (r = 0.97, P < 0.001). In summary, the percentage of fat area, as measured with the dual-energy X-ray/image combined procedure, provides a good in vivo estimation of total body fat content in mice.
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Tejido Adiposo , Índice de Masa Corporal , Absorciometría de Fotón , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Leptina/sangre , Modelos Lineales , Masculino , Ratones , Ratones Endogámicos C57BL , Valor Predictivo de las PruebasRESUMEN
OBJECTIVE: To measure the delays in diagnosis of Turner's syndrome (TS) and to propose strategies for earlier screening and diagnosis. METHODS: The medical records of 81 girls with TS were reviewed for age at diagnosis, reason(s) for karyotype analysis, and clinical features including growth failure. Delay in diagnosis was calculated as equal to age at diagnosis for children born with lymphedema and/or 2 or more of the following dysmorphic features: webbed neck, nail dysplasia, high palate, and short fourth metacarpal. For all others, delay in diagnosis was calculated as the difference between the age at which height fell below the 5th percentile and the age at which the diagnosis of TS was made. RESULTS: Lymphedema was the key to diagnosis in 97% of the girls diagnosed with TS in infancy, and short stature was the key to diagnosis for 82% of the girls diagnosed in childhood or adolescence. For girls diagnosed in childhood or adolescence, the delay in diagnosis averaged 7.7 +/- 5.4 years. Many had dysmorphic features and/or a history of lymphedema at birth, and diagnosis was made an average of 5.3 years after patients had fallen below the 5th percentile for height. By the time of diagnosis, patients were very short, averaging -2.9 SD in height. CONCLUSIONS: The diagnosis of TS is often delayed. We recommend karyotype analysis for all girls with unexplained short stature, delayed puberty, webbed neck, lymphedema, or coarctation of the aorta. Furthermore, karyotype analysis should be strongly considered for those who remain above the 5th percentile for height but have 2 or more features of TS, including high palate, nail dysplasia, short fourth metacarpal, and strabismus.
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Síndrome de Turner/diagnóstico , Adolescente , Niño , Preescolar , Protocolos Clínicos , Femenino , Humanos , Lactante , Recién Nacido , Cariotipificación , Embarazo , Diagnóstico Prenatal , Factores de Tiempo , Síndrome de Turner/genéticaRESUMEN
Estrogens play an important role in the regulation of longitudinal bone growth in man, as demonstrated by recent descriptions of individuals with estrogen insensitivity or aromatase deficiency. Two estrogen receptors, ERalpha and ERbeta, have been cloned. The aim of the present study was to investigate the function of ERalpha in the regulation of body growth and skeletal growth. Adult female mice with inactivated ERalpha (ERalpha-/-) demonstrated an increased body weight compared with wild-type mice (114% of control). However, the length of the appendicular skeleton was decreased in adult ERalpha-/- mice (femur 93% of control). In contrast, the axial skeleton was normal (crown-rump length 98% of control). The decreased growth of the appendicular skeleton was associated with decreased serum levels of IGF-I (77% of control), indicating that the GH/IGF-I axis may be involved in the decreased longitudinal bone growth seen in female ERalpha-/- mice.
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Desarrollo Óseo/fisiología , Crecimiento/fisiología , Receptores de Estrógenos/fisiología , Animales , Secuencia de Bases , Peso Corporal/genética , Peso Corporal/fisiología , Desarrollo Óseo/genética , Cartilla de ADN/genética , Receptor alfa de Estrógeno , Femenino , Crecimiento/genética , Placa de Crecimiento/crecimiento & desarrollo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tamaño de los Órganos/genética , Tamaño de los Órganos/fisiología , Fenotipo , Receptores de Estrógenos/genética , Especificidad de la EspecieRESUMEN
Voluntary fasting is practiced by many humans in an attempt to lose body weight. Conflicting results have been published on the effects of food deprivation on serum lipids. To study the effect of acute starvation on serum lipids, 10 nonobese (93-124% of ideal body weight), healthy adults (6 men, 4 women, 21-38 y old) fasted (no energy) for 7 d. Fasting increased total serum cholesterol from 4.90 +/- 0.23 to 6.73 +/- 0.41 mmol/L (37.3 +/- 5.0%; P < 0.0001) and LDL cholesterol from 2.95 +/- 0.21 to 4.90 +/- 0.36 mmol/L (66.1 +/- 6. 6%; P < 0.0001). Serum apolipoprotein B (apo B) increased from 0.84 +/- 0.06 to 1.37 +/- 0.11 g/L (65.0 +/- 9.2%; P < 0.0001). The increases in serum cholesterol, LDL and apo B were associated with weight loss. Fasting did not affect serum concentrations of triacylglycerol and HDL cholesterol. Serum concentrations of insulin-like growth factor-I (IGF-I) decreased from 246 +/- 29 (prefast) to 87 +/- 10 microg/L after 1 wk of fasting (P < 0.0001). We conclude that, in nonobese subjects, fasting is accompanied by increases in serum cholesterol, LDL and apo B concentrations, whereas IGF-I levels are decreased.