RESUMO
We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients' data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.
Assuntos
Hipotireoidismo Congênito/tratamento farmacológico , Nanismo Hipofisário/tratamento farmacológico , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Adulto , Biomarcadores/sangue , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/etnologia , Monitoramento de Medicamentos , Nanismo Hipofisário/sangue , Nanismo Hipofisário/etnologia , Feminino , Seguimentos , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Japão , Perda de Seguimento , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Vigilância de Produtos Comercializados , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Caracteres Sexuais , Adulto JovemRESUMO
Pegvisomant is a GH receptor antagonist and strong inhibitor of insulin-like growth factor I (IGF-I) production. The treatment goal for acromegaly is to normalize serum IGF-I levels and attenuate associated symptoms. The efficacy and safety of pegvisomant as treatment for acromegaly have been reported in Caucasians, but not in Japanese. Here we report the clinical experience of using pegvisomant in Japanese patients with acromegaly. The efficacy and safety data for pegvisomant from two open-labeled clinical studies in Japan, conducted from 2004 to 2007, were re-analyzed using the new Japanese age- and sex-matched normative ranges for IGF-I. Eighteen patients with active acromegaly were enrolled in an initial pivotal study, and 16 of them were moved to a long-term (max 168 weeks) extension study. The dose of pegvisomant in the extension study was adjusted to 10-30 mg per day according to IGF-I levels. IGF-I normalization was observed in 81.3% (13/16 patients) during the extension study. The mean percentage decrease from baseline in serum IGF-I level was 64.7% at the time of last observation. The clinical symptoms and overall health status were improved, and the ring size was reduced over time until Week 12 and maintained. For safety, no clinically significant changes were observed both in the pituitary tumor size and the anti-GH antibody level. Three subjects were withdrawn from the studies due to an abnormal elevation of liver enzymes which resolved after discontinuation. Pegvisomant demonstrated excellent clinical efficacy and was well tolerated in Japanese patients with acromegaly.
Assuntos
Acromegalia/tratamento farmacológico , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Hormônio do Crescimento Humano/análogos & derivados , Acromegalia/sangue , Adulto , Idoso , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Japão , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.
Assuntos
Terapia de Reposição Hormonal/psicologia , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Qualidade de Vida/psicologia , Adulto , Hormônio do Crescimento Humano/deficiência , Humanos , Hipopituitarismo/psicologia , Resultado do TratamentoRESUMO
The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.
Assuntos
Acromegalia/prevenção & controle , Adenoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Gigantismo/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Hipófise/efeitos dos fármacos , Somatostatina/análogos & derivados , Acromegalia/etiologia , Adenoma/sangue , Adenoma/fisiopatologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Monitoramento de Medicamentos , Feminino , Gastroenteropatias/induzido quimicamente , Géis , Gigantismo/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/fisiopatologia , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Japão , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/farmacocinética , Peptídeos Cíclicos/uso terapêutico , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/farmacocinética , Somatostatina/uso terapêuticoRESUMO
This study assessed the effectiveness and safety of growth hormone (GH; Humatrope(®)) therapy in Japanese children with GH deficiency (GHD) or Turner syndrome (TS) enrolled in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). GeNeSIS is an open-label, multinational, multicenter, observational study conducted in 30 countries. In this interim report, there were 1129 GH treatment-naïve children with GHD, with a mean chronological age (± standard deviation) of 8.75 (3.32) years, and 90 girls with TS, with a mean chronological age of 8.93 (3.67) years. The mean height standard deviation score (SDS) increased from -2.73 (0.63) SD and -2.71 (0.63) SD at study entry to -2.22 (0.68) SD and -2.20 (0.60) SD after 1 year of treatment in the GHD and TS groups, respectively. In both groups, mean height SDS increased further with each year of treatment to 4 years; however, the magnitude of change in height SDS declined with time. The mean insulin-like growth factor-I SDS increased from below the mean of the reference population at study entry to a level similar to (GHD group) or higher than (TS group) the mean of the reference population during the 4-year treatment period. The incidence of serious adverse events (AEs), treatment-related AEs, and AEs related to glucose intolerance was low in both groups (0.1% to 3.0%). In conclusion, GH treatment in Japanese children with GHD or TS resulted in increased growth over a 4-year treatment period with a favorable safety profile; however, the improvements in growth declined with time.
Assuntos
Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Síndrome de Turner/tratamento farmacológico , Povo Asiático , Estatura , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Lactente , Masculino , Resultado do TratamentoRESUMO
This large-scale observational study examined the long-term effectiveness and safety of growth hormone (GH) replacement therapy for adult GH deficiency (GHD) in Japanese clinical practice using the Hypopituitary Control and Complications Study database. The study included 402 GHD patients for safety analyses and a subset of 209 patients (149 adult-onset and 60 childhood-onset GHD patients) who had not previously received GH replacement therapy for the efficacy analyses. Data on clinical, metabolic, quality of life (QoL) characteristics, and all adverse events (AEs) were collected at baseline (start of GH treatment), 6 months, 1 year and 2 years. Over the observation period, there were improvements from baseline in insulin-like growth factor-I standard deviation scores (P<0.001), although the changes in metabolic parameters were minimal. QoL (Short Form-36) Z-scores significantly increased from baseline in both onset-type groups for several subscale domains (P<0.05). A total of 145 (36.1%) patients experienced ≥1 AE. Common AEs were hyperlipidaemia (2.7%) and hyperinsulinaemia (2.2%). Some patients experienced recurrent hypothalamic/pituitary tumour (events per 1000 patient-years: 2.78), new benign (0.93), malignant tumour (10.28) or other new tumour (0.93), new diabetes mellitus (7.45), and new stroke (3.71). Seven patients died during the observation period. Our safety findings are inconclusive about the associations between GH replacement and AEs, although the incidence of diabetes mellitus and cardiovascular events are similar to those reported in the Japanese general population. In conclusion, the key beneficial effects of GH replacement therapy for GHD are observed in routine clinical practice in Japan.
Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Adulto , Doenças Cardiovasculares/induzido quimicamente , Diabetes Mellitus/induzido quimicamente , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias/induzido quimicamente , Qualidade de VidaRESUMO
Measurements of insulin-like growth factor-I (IGF-I) are useful not only for diagnosis and management of patients with growth hormone (GH)-related disorders but also for assessing nutritional status. We reported population-based references of serum IGF-I in 1996. However, they did not properly reflect data in the transition period from puberty to maturity. The aim of the present study was to re-establish a set of normative data for IGF-I for the Japanese population. The study included 1,685 healthy Japanese subjects (845 males, 840 females) from 0 to 83 years old. Subjects suffering from diseases that could affect IGF-I levels were excluded. Obese or extremely thin adult subjects were also excluded. IGF-I concentrations were determined by commercially available immunoradiometric assays. The reference intervals were calculated using the LMS method. Median IGF-I levels reached 310 ng/mL in males at the age of 14 years and 349 ng/mL in females at the age of 13 years, falling to 124 ng/mL and 103 ng/mL, respectively, by the age of 70 years. The mean pretreatment IGF-1 SD scores in patients with severe GH deficiency (GHD) obtained from the database of the Foundation for Growth Science and from clinical studies for adult GHD were -2.1±1.6 and -4.9±2.5, respectively. The present study established age- and gender-specific normative IGF-I data for the Japanese population and showed the utility of these references for screening patients with severe GHD.
Assuntos
Fator de Crescimento Insulin-Like I/análise , Fatores Etários , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Distribuição Normal , Radioimunoensaio , Valores de Referência , Caracteres Sexuais , Estatística como AssuntoRESUMO
BACKGROUND: Individual responses to growth hormone (GH) treatment are variable, and efficacy should be judged in each individual patient. OBJECTIVE: The aim of this study was to develop a prediction model for the growth response of GH treatment in Japanese prepubertal children with GH deficiency. PATIENTS AND METHODS: Pediatric patients with GH deficiency were enrolled. Auxological measurements, markers of GH status, and markers of bone metabolism were measured at baseline and at 3 and 6 months after the start of GH treatment. Correlations with height velocity (HV) at 36 months of GH treatment were calculated. Prediction models were evaluated by multiple regression analysis. RESULTS: The model, which combined the parameters of HV at 3 months, insulin-like growth factor-binding protein 3, standard deviation score, and pyridinoline at 3 months, best predicted HV at 36 months. CONCLUSIONS: This model can accurately predict the first 3 years of growth response after 3 months of GH replacement therapy in prepubertal Japanese children.
Assuntos
Estatura , Hormônio do Crescimento Humano/deficiência , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Japão , Masculino , Modelos Biológicos , Puberdade , Análise de RegressãoRESUMO
A 21-year-old Japanese man without known diabetes mellitus had abdominal pain. The diagnosis was ketoacidosis and hypertriglyceridemia-induced acute pancreatitis. He had polydipsia and polyuria and had habitually drunk several soft drinks every day for two years. After hospitalization, despite adequate liquid intake, dehydration remained with hypotonic polyuria. Further examinations revealed the coexistence of central diabetes insipidus (CDI), possibly caused by lymphocytic infundibulo-neurohypophysitis, based on anti-rabphilin-3A antibody positivity. Although CDI had been undiagnosed for two years, over-consumption of sugar-rich soft drinks to ease thirst caused ketoacidosis, hypertriglyceridemia, and acute pancreatitis. There are no previous reports of this three-part combination of symptoms caused by CDI.
Assuntos
Diabetes Insípido Neurogênico , Diabetes Insípido , Diabetes Mellitus , Hipertrigliceridemia , Cetose , Pancreatite , Doença Aguda , Adulto , Bebidas Gaseificadas/efeitos adversos , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/diagnóstico , Masculino , Pancreatite/complicações , Pancreatite/diagnóstico , Polidipsia/diagnóstico , Polidipsia/etiologia , Adulto JovemRESUMO
Myxedema coma (MC) is a rare, but often fatal endocrine emergency. The majority of cases that occur in elderly women with long-standing primary hypothyroidism are caused by particular triggers. Conversely, MC of central origin is extremely rare. Here, we report a case of MC with both central and primary origins. A 56-year-old woman was transferred to our hospital due to loss of consciousness; a chest x-ray demonstrated severe cardiomegaly. Low body temperature, bradycardia, and pericardial effusion suggested the presence of hypothyroidism. Endocrinological examination revealed undetectable levels of serum free thyroxine (T(4)) and free triiodothyronine (T(3)), whereas serum thyroid-stimulating hormone (TSH) levels were not elevated. The woman's serum anti-thyroid peroxidase antibody and anti-thyroglobulin antibody tests were positive, indicating that she had Hashimoto's thyroiditis. Provocative tests to the anterior pituitary revealed that she had TSH and growth hormone (GH) deficiency; however, GH levels were restored after supplementation with levothyroxine for 5 months. This was not only a rare case of MC with TSH deficiency and Hashimoto's thyroiditis; the patient also developed severe osteoporosis and possessed transient elevated levels of serum carcinoembryonic antigen (CEA). This atypical case may suggest the role of anterior pituitary hormone deficiencies, as well as hypothyroidism, in the regulation of bone metabolism.
Assuntos
Coma/etiologia , Doença de Hashimoto/complicações , Mixedema/etiologia , Tireotropina/deficiência , Autoanticorpos/sangue , Antígeno Carcinoembrionário/sangue , Cardiomegalia/diagnóstico por imagem , Feminino , Doença de Hashimoto/diagnóstico , Hormônio do Crescimento Humano/deficiência , Humanos , Hidrocortisona/uso terapêutico , Pessoa de Meia-Idade , Mixedema/diagnóstico , Osteoporose/etiologia , Derrame Pericárdico/diagnóstico por imagem , Radiografia , Tiroxina/deficiência , Tiroxina/uso terapêutico , Tri-Iodotironina/deficiência , UltrassonografiaRESUMO
The clinical characteristics of Caucasian adults with growth hormone (GH) deficiency (GHD) have been well defined. However, no large-scale clinical practice study has examined the clinical characteristics of Japanese adults with GHD. The aim of our study was to describe the clinical characteristics of Japanese adults with GHD by reviewing the records of participants who were GH-naive at the time of enrollment in the Hypopituitary Control and Complications Study (N = 349). The majority of participants (280 of 349; 80.2%) had adult-onset rather than childhood-onset GHD. Hypothalamo-pituitary tumors were the most common cause of GHD in Japanese adults (247 of 349; 70.8%); these tumors were primarily pituitary adenomas in participants with adult-onset GHD (156 of 243; 64.2%), and germ cell tumors (19 of 40; 47.5%) and craniopharyngiomas (18 of 40; 45.0%) in participants with childhood-onset GHD. Most participants (310 of 349; 88.8%) had multiple pituitary hormone deficiencies. Dyslipidemia (195 of 349; 55.9%), visual field loss (67 of 349; 19.2%), hypertension (59 of 349; 16.9%), and liver disease (54 of 349; 15.5%) were the most common pre-existing conditions in Japanese adults with GHD. Quality of life was decreased in seven of the eight short form-36 domains in participants with GHD compared with age- and sex-matched healthy Japanese individuals. Our findings confirm that the clinical characteristics of Japanese adults with GHD are similar to those of Caucasian adults with GHD. Confirmation of these clinical characteristics will enhance the ability of clinicians to identify and treat Japanese adults with GHD.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/fisiopatologia , Adenoma/complicações , Adolescente , Adulto , Idade de Início , Povo Asiático , Composição Corporal , Criança , Craniofaringioma/complicações , Dislipidemias/complicações , Feminino , Humanos , Hipertensão/complicações , Japão , Hepatopatias/complicações , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicações , Qualidade de Vida , Campos VisuaisRESUMO
OBJECTIVE: To identify factors affecting adult height in Japanese patients with idiopathic growth hormone deficiency (GHD), who received growth hormone (GH) treatment during childhood. METHODS: A retrospective pharmaco-epidemiological study of the effect of GH treatment on adult height standard deviation scores (SDS) was conducted in 374 Japanese patients with idiopathic GHD. During childhood, GH (0.146 +/- 0.023 mg/kg/week) was administered for a mean of 6.4 +/- 2.6 years. RESULTS: The mean adult height was 160.6 +/- 6.3 cm (-1.75 SD; n = 232) in boys and 146.9 +/- 7.3 cm (-2.20 SD; n = 158) in girls after GH therapy. The mean increases in height SDS in boys and girls with severe GHD were 2.13 SD and 1.66 SD, respectively (p < 0.05). These increases were greater than those observed in patients with moderate GHD and mild GHD. The mean adult height of male patients with GHD and gonadotropin deficiency (166.8 cm) was significantly higher (p < 0.05) than that of isolated GHD patients who were either receiving (159.1 cm) or not receiving (160.5 cm) gonadal suppression therapy. The mean adult heights of female patients were 149.6, 146.7, and 146.9 cm, respectively, and these values did not significantly differ. CONCLUSION: Linear multiple regression analyses of Japanese patients with severe GHD (n = 61) revealed three independent variables that influenced adult height: gonadotropin deficiency, initial height SDS and height velocity during the first year after the initiation of GH therapy.
Assuntos
Povo Asiático , Transtornos do Crescimento/tratamento farmacológico , Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Antagonistas de Androgênios/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Bases de Dados Factuais , Antagonistas de Estrogênios/uso terapêutico , Feminino , Gonadotropinas/deficiência , Transtornos do Crescimento/complicações , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
CONTEXT: Paradoxical increases in serum cortisol in the dexamethasone suppression test (DST) have been rarely observed in Cushing disease (CD). Its pathophysiology and prevalence remain unclear. CASE DESCRIPTION: A 62-year-old woman with suspected CD showed paradoxical increases in cortisol after both 1-mg and 8-mg DST (1.95-fold and 2.52-fold, respectively). The initiation of metyrapone paradoxically decreased plasma adrenocorticotropic hormone (ACTH) levels and suppressed cortisol levels. Moreover, the pituitary tumor considerably shrank during metyrapone treatment. EX VIVO EXPERIMENTS: The resected tumor tissue was enzymatically digested, dispersed, and embedded into Matrigel as 3D cultured cells. ACTH levels in the media were measured. In this tumor culture, ACTH levels increased 1.3-fold after dexamethasone treatment (P < 0.01) while control tumor cultures exhibited no increase in ACTH levels, but rather a 20% to 40% suppression (P < 0.05). CLINICAL STUDY: A cross-sectional, retrospective, multicenter study that included 92 patients with CD who underwent both low-dose and high-dose DST from 2014 to 2020 was performed. Eight cases (8.7%) showed an increase in serum cortisol after both low-dose and high-dose DST. CONCLUSION: This is the first report of a patient with glucocorticoid (GC)-driven positive feedback CD who showed both ACTH suppression and tumor shrinkage by metyrapone. Our cohort study revealed that 8.7% of patients with CD patients possibly possess GC-driven positive-feedback systems, thereby suggesting the presence of a new subtype of CD that is different from the majority of CD cases. The mechanisms exhibiting GC positive feedback in CD and the therapeutic approach for these patients remain to be investigated.
RESUMO
CONTEXT: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. CASE DESCRIPTION: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. CONCLUSION: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.
Assuntos
Gigantismo/genética , Gigantismo/metabolismo , Histona-Lisina N-Metiltransferase/genética , Hormônio do Crescimento Humano/metabolismo , Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/diagnóstico , Malformação de Arnold-Chiari/genética , Gigantismo/diagnóstico , Heterozigoto , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/genética , Linhagem , Convulsões/complicações , Convulsões/diagnóstico , Convulsões/genética , Transdução de Sinais/fisiologia , Síndrome , Regulação para Cima/genética , Adulto JovemRESUMO
We investigated the utility of branched-chain amino acids (BCAA) in dexamethasone-induced muscle atrophy. Dexamethasone (600 microg/kg, intraperitoneally) and/or BCAA (600 mg/kg, orally) were administered for 5 days in rats, and the effect of BCAA on dexamethasone-induced muscle atrophy was evaluated. Dexamethasone decreased total protein concentration of rat soleus muscles. Concomitant administration of BCAA reversed the decrease. Dexamethasone decreased mean cross-sectional area of soleus muscle fibers, which was reversed by BCAA. Dexamethasone increased atrogin-1 expression, which has been reported to play a pivotal role in muscle atrophy. The increased expression of atrogin-1 mRNA was significantly attenuated by BCAA. Furthermore, dexamethasone-induced conversion from microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II, which is an indicator of autophagy, was blocked by BCAA. These findings suggest that BCAA decreased protein breakdown to prevent muscle atrophy. BCAA administration appears to be useful for prevention of steroid myopathy.
Assuntos
Aminoácidos de Cadeia Ramificada/uso terapêutico , Dexametasona/efeitos adversos , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/prevenção & controle , Animais , Tamanho Corporal , Primers do DNA , Dexametasona/administração & dosagem , Gliceraldeído-3-Fosfato Desidrogenases/genética , Injeções Intraperitoneais , Masculino , Proteínas Musculares/genética , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Ligases SKP Culina F-Box/genética , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/genéticaRESUMO
CONTEXT: Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. CASE DESCRIPTION: A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. CONCLUSIONS: This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.
Assuntos
Neoplasias do Córtex Suprarrenal/complicações , Adenoma Adrenocortical/complicações , Fumarato Hidratase/genética , Deleção de Genes , Neoplasias Cardíacas/etiologia , Hidrocortisona/metabolismo , Mixoma/etiologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/patologia , Adulto , Neoplasias Cardíacas/patologia , Humanos , Masculino , Mixoma/patologia , PrognósticoRESUMO
The effect of amino acid on muscle protein degradation remains unclear. Recent studies have elucidated that proteolysis in catabolic conditions occurs through ubiquitin-proteasome proteolysis pathway and that muscle-specific ubiquitin ligases (atrogin-1 and MuRF1) play an important role in protein degradation. In the present study, we examined the direct effect of 5 mM amino acids (leucine, isoleucine, valine, glutamine and arginine) on atrogin-1 and MuRF1 levels in C2C12 muscle cells and the involved intracellular signal transduction pathway. Leucine, isoleucine and valine suppressed atrogin-1 and MuRF1 mRNA levels (approximately equal to 50%) at 6 and 24 h stimulations. Arginine showed a similar effect except at 24 h-treatment for atrogin-1 mRNA. However, glutamine failed to reduce atrogin-1 and MuRF1 mRNA levels. The inhibitory effect of leucine, isoleucine or arginine on atrogin-1 mRNA level was reversed by rapamycin, although wortmannin did not reverse the effect. PD98059 and HA89 reduced basal atrogin-1 level without influencing the inhibitory effects of those amino acids. The inhibitory effect of leucine, isoleucine or arginine on MuRF1 mRNA levels was not reversed by rapamycin. Taken together, these findings indicated that leucine, isoleucine and arginine decreased atrogin-1 mRNA levels via mTOR and that different pathways were involved in the effect of those amino acids on MuRF1 mRNA levels.
Assuntos
Aminoácidos de Cadeia Ramificada/farmacologia , Arginina/farmacologia , Proteínas Musculares/genética , Proteínas Quinases/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Animais , Linhagem Celular , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Isoquinolinas/farmacologia , Camundongos , Proteínas Musculares/metabolismo , Fosfoproteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Inanição , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR , Fatores de Tempo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína LigasesRESUMO
Parathyroid hormone (PTH) exerts an anabolic action on bone but the mechanisms are incompletely understood. We showed previously that PTH interacts with the canonical Wnt-beta-catenin signaling pathway via the transforming growth factor (TGF)-beta signaling molecule, Smad3, to modulate osteoblast differentiation and apoptosis. Here, we examined which actions of Smad3 are TGF-beta-independent in stimulating the osteoblast phenotype and PTH-induced Wnt-beta-catenin signaling. For this, the TGF-beta receptor type 1 [activin receptor-like kinase (ALK5)] inhibitor (SB431542), and a Smad3 mutant in which the site normally phosphorylated by ALK5 is mutated from SSVS to AAVA, was used. PTH induced total beta-catenin and reduced phosphorylated beta-catenin levels at 1, 6, and 24 h in mouse osteoblastic MC3T3-E1 cells. Transient transfection of Smad3AAVA inhibited the PTH induction of total beta-catenin and reduction of phosphorylated beta-catenin levels at 6 and 24 h, but not at 1 h, indicating that the early effects occur independently of TGF-beta receptor signaling. On the other hand, MC3T3-E1 cell clones in which Smad3AAVA was stably expressed demonstrated elevated beta-catenin levels, although alkaline phosphatase (ALP) activity and mineralization were unaltered. In contrast, MC3T3-E1 cell clones in which wild-type Smad3 was stably expressed exhibited increased ALP activity and mineralization that were decreased by the ALK5 inhibitor, SB431542, although the beta-catenin levels induced in these cells were not modulated. In conclusion, the present study indicates that PTH induces osteoblast beta-catenin levels via Smad3 independently of, and dependently on, TGF-beta in the early and later induction phases, respectively.
Assuntos
Osteoblastos/metabolismo , Hormônio Paratireóideo/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular , Humanos , Camundongos , Fenótipo , Proteína Smad3/genética , Transfecção , beta Catenina/genéticaRESUMO
AIM: Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria. METHODS: Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4-160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy. RESULTS: No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80-120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses. CONCLUSION: ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.