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OBJECTIVE: Hyperandrogenism in congenital adrenal hyperplasia (CAH) provides an in vivo model for exploring the effect of androgens on erythropoiesis in women. We investigated the association of androgens with haemoglobin (Hb) and haematocrit (Hct) in women with CAH. DESIGN: Cross-validation study. PATIENTS: Women with CAH from Sheffield Teaching Hospitals, UK (cohort 1, the training set: n = 23) and National Institutes of Health, USA (cohort 2, the validation set: n = 53). MEASUREMENTS: Androgens, full blood count and basic biochemistry, all measured on the same day. Demographic and anthropometric data. RESULTS: Significant age-adjusted correlations (P < 0·001) were observed for Ln testosterone with Hb and Hct in cohorts 1 and 2 (Hb r = 0·712 & 0·524 and Hct r = 0·705 & 0·466), which remained significant after adjustments for CAH status, glucocorticoid treatment dose and serum creatinine. In the combined cohorts, Hb correlated with androstenedione (P = 0·002) and 17-hydroxyprogesterone (P = 0·008). Hb and Hct were significantly higher in cohort 1 than those in cohort 2, while there were no group differences in androgen levels, glucocorticoid treatment dose or body mass index. In both cohorts, women with Hb and Hct in the highest tertile had significantly higher testosterone levels than women with Hb and Hct in the lowest tertile. CONCLUSIONS: In women with CAH, erythropoiesis may be driven by androgens and could be considered a biomarker for disease control.
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Hiperplasia Suprarrenal Congênita/fisiopatologia , Eritropoese , Testosterona/fisiologia , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/complicações , Adulto , Feminino , Hematócrito , Hemoglobinas/metabolismo , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/etiologia , Hiperandrogenismo/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Life expectancy of cancer survivors has doubled in the past four decades; however, death due to cardiovascular disease is more prevalent in survivors than the general population. OBJECTIVE, DESIGN AND METHODS: We evaluated novel and traditional cardiometabolic risk factors in young male cancer survivors in a cross-sectional study of male cancer survivors aged 25-45 years compared with age-matched noncancer controls. Demographic and anthropometric data were recorded and biochemical and hormonal parameters assayed from fasting blood samples in 176 survivors and 213 controls (lipids were measured in all survivors and 97 controls). RESULTS: Compared with controls, survivors had significantly higher body mass index, adipocytokines, insulin resistance, total cholesterol and triglyceride levels and lower free androgen index (FAI). Handgrip strength, smoking, alcohol consumption, free oestrogen index, insulin-like growth factor 1 and high-density lipoprotein cholesterol levels did not differ between cancer survivors and controls. Risk factors were analysed simultaneously using stepwise multivariable logistic regression, and this showed that high leptin: adiponectin ratio (odds ratio = 2·63; 95% confidence interval: 1·34-5·15; P = 0·005), hypercholesterolaemia (odds ratio = 1·85; 95%CI: 1·08-3·17; P = 0·025) and low FAI (odds ratio = 2·01; 95% confidence interval: 1·07-3·79; P = 0·030) were independently more common in survivors. The odds ratio in survivors for having at least two of these three risk factors rose to 6·58 (95% confidence interval: 3·30-13·12; P < 0·001). Among survivors, risk factors were not different between cancer therapies but worse in survivors who had radiotherapy involving the testes (hyperleptinaemia and insulin resistance) or age at diagnosis above group median (hypertriglyceridaemia and hypercholesterolaemia). CONCLUSIONS: A high leptin: adiponectin ratio, hypercholesterolaemia and low FAI are observed in young male cancer survivors, especially those who received radiotherapy involving the testes or were diagnosed at a later age. In view of their youth and known increased risk of cardiovascular death, treatment strategies are required to address this cardiovascular risk.
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CONTEXT: Children with congenital adrenal hyperplasia (CAH) and adrenal insufficiency (AI) require daily hydrocortisone replacement with accurate dosing. OBJECTIVE: Prospective study of efficacy and safety of hydrocortisone granules in children with AI and CAH monitored by 17-OHP (17-hydroxyprogesterone) saliva profiles. METHODS: Seventeen children with CAH (9 male) and 1 with hypopituitarism (male), aged from birth to 6 years, had their hydrocortisone medication changed from pharmacy compounded capsules to hydrocortisone granules. Patients were followed prospectively for 2 years. In children with CAH, the therapy was adjusted by 17-OHP salivary profiles every 3 months. The following parameters were recorded: hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis. RESULTS: The study medication was given thrice daily, and the median duration of treatment (range) was 795 (1-872) days, with 150 follow-up visits. Hydrocortisone doses were changed on 40/150 visits, with 32 based on salivary measurements and 8 on serum 17-OHP levels. The median daily mg/m2 hydrocortisone dose (range) at study entry for the different age groups 2-8 years, 1 month to 2 years, <28 days was 11.9 (7.2-15.5), 9.9 (8.6-12.2), and 12.0 (11.1-29.5), respectively, and at end of the study was 10.2 (7.0-14.4), 9.8 (8.9-13.1), and 8.6 (8.2-13.7), respectively. There were no trends for accelerated or reduced growth. No adrenal crises were observed despite 193 treatment-emergent adverse events, which were mainly common childhood illnesses. INTERPRETATION: This first prospective study of glucocorticoid treatment in children with AI and CAH demonstrates that accurate dosing and monitoring from birth results in hydrocortisone doses at the lower end of the recommended dose range and normal growth, without occurrence of adrenal crises.
Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Insuficiência Adrenal/tratamento farmacológico , Hidrocortisona/administração & dosagem , 17-alfa-Hidroxiprogesterona/análise , 17-alfa-Hidroxiprogesterona/metabolismo , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/metabolismo , Insuficiência Adrenal/complicações , Insuficiência Adrenal/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Formas de Dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Hidrocortisona/efeitos adversos , Hidrocortisona/farmacocinética , Lactente , Recém-Nascido , Masculino , Saliva/química , Saliva/metabolismoRESUMO
BACKGROUND: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. METHODS: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. RESULTS: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (Pâ <â 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (Pâ =â 0.43), respectively. CONCLUSIONS: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.
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Hiperplasia Suprarrenal Congênita/epidemiologia , Insuficiência Adrenal/complicações , Insuficiência Adrenal/epidemiologia , Doença Aguda , Adolescente , Hiperplasia Suprarrenal Congênita/complicações , Assistência Ambulatorial/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Geografia , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Sistema de RegistrosRESUMO
OBJECTIVES: To evaluate the risks of depression and all-cause mortality, healthcare utilisation costs and treatment adherence in congenital adrenal hyperplasia (CAH) in the United Kingdom. DESIGN AND METHODS: A retrospective, matched-cohort study using UK primary-care data from the Clinical Practice Research Datalink linked to hospital and death certification data. Patients diagnosed with CAH and having ≥1 corticosteroid prescription were matched 1:10 to reference subjects. Risk of death and lifetime prevalence of depression were compared using Cox regression models. Direct financial costs were estimated for healthcare contacts. Treatment adherence was measured by medical possession ratio (MPR). RESULTS: 605 patients with CAH were identified; 562 were matched. 270 CAH patients (2700 controls) were linkable to death-certificate data, with adjusted hazard ratio for all-cause mortality 5.17 (95% CI 2.81-9.50). Mean (s.d.) age at death in CAH patients was 54.8 (23.9) vs 72.8 (18.0) years in control patients. The prevalence ratio of depression in CAH vs control patients was 1.28 (95% CI 1.13-1.45). Mean (s.d.) annual healthcare costs were higher in CAH than controls: at age 0-6 years, £7038 (£14 846) vs £2879 (£13 972, P < 0.001); 7-17 years, £3766 (£7494) vs £1232 (£2451, P < 0.001); 18-40 years, £1539 (£872) vs £1344 (£1620, P = 0.007) and ≥41 years, £4204 (£4863) vs £1651 (£2303, P < 0.001). Treatment adherence was lowest in adults, with 141 (36%) of 396 eligible patients having an MPR <80%. CONCLUSIONS: This first analysis of CAH in routine UK healthcare suggests that patients with CAH have increased mortality, depression and healthcare utilisation and low treatment adherence.
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Hiperplasia Suprarrenal Congênita/complicações , Depressão/etiologia , Custos de Cuidados de Saúde/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Adolescente , Corticosteroides/uso terapêutico , Hiperplasia Suprarrenal Congênita/economia , Hiperplasia Suprarrenal Congênita/mortalidade , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Depressão/epidemiologia , Depressão/psicologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Atenção Primária à Saúde/economia , Atenção Primária à Saúde/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Reino Unido/epidemiologia , Adulto JovemRESUMO
Extreme forms of insulin resistance are a rare cause of type 2 diabetes. However, individuals with severe insulin resistance pose unique diagnostic and therapeutic challenges, and have often acted as 'experiments of nature' providing important novel information regarding endocrine physiology and mechanistic insights relevant to the study of more common disorders. Progress in understanding the molecular pathogenesis of such syndromes is also beginning to yield novel therapeutic options. Severe insulin resistance typically presents in 1 of 3 ways: (1) disordered glucose metabolism including both diabetes and/or paradoxical hypoglycaemia; (2) acanthosis nigricans, a velvety hyperpigmentation of axilliary and flexural skin often associated with skin tags; or (3) hyperandrogenism in girls (hirsutism, oligo-/amenorrhoea and polycystic ovaries). Lipodystrophy is a major cause of severe insulin resistance and needs to be looked for very carefully, particularly in the patients with significant dyslipidaemia and fatty liver. Specific treatments are now available for some forms of severe insulin resistance; for example, leptin replacement in patients with generalized lipodystrophy. In the absence of a specific diagnosis and therapy, metformin is a useful insulin sensitizer and should be used in conjunction with aggressive diet and exercise interventions.
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Resistência à Insulina/fisiologia , Síndrome Metabólica/terapia , Adolescente , Algoritmos , Feminino , Humanos , Síndrome Metabólica/classificação , Síndrome Metabólica/diagnóstico , LinhagemRESUMO
CONTEXT: A natural missense mutation in the signal transducer and activator of transcription (STAT) 5b gene was recently identified in association with a female patient presenting with severe growth failure and immune dysfunction. The mutation results in an alanine to proline substitution at residue 630 (A630P) in the src-homology-2 domain, a region essential for docking of STATs to phospho-tyrosines on activated receptors, STAT dimerization, and stabilization of phospho-STAT-DNA interactions. OBJECTIVE: The purpose of this study was to explore the molecular mechanisms underlying the GH insensitivity and IGF-I deficiency caused by the A630P-mutated STAT5b. RESULTS: In reconstitution experiments using HEK293 cells, both GH and interferon-gamma were unable to activate mutant STAT5b (A630P), as demonstrated by lack of immunodetectable phospho-tyrosyl-STAT5b (A630P) and inability to drive luciferase reporter activity. However, the Src family of nonreceptor kinases [constitutively active v-src and epithelial growth factor-induced c-src] tyrosine-phosphorylated STAT5b(A630P). The v-src-induced phospho-STAT5b(A630P) translocated to the nucleus but, unlike wild-type Stat5b, was unable to bind DNA. CONCLUSIONS: The A630P mutation disrupts the src-homology-2 architecture such that: 1) mutant STAT5b most likely cannot dock to phospho-tyrosines on ligand-activated receptors; and 2) stable interactions with DNA are prevented. Because STAT5b (A630P) is an inefficient signal transducer and transcription factor, the detrimental impact on signaling pathways important for normal growth and immunity explains, in part, the complex clinical phenotype of GH insensitivity and immune dysfunction.
Assuntos
Hormônio do Crescimento Humano/fisiologia , Fator de Crescimento Insulin-Like I/deficiência , Mutação/fisiologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Adenoviridae/genética , Western Blotting , Linhagem Celular , Citocinas/biossíntese , Citocinas/genética , DNA/biossíntese , DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Fibroblastos/metabolismo , Genes src/genética , Genes src/fisiologia , Vetores Genéticos , Humanos , Imuno-Histoquímica , Interferon gama/metabolismo , Mutação de Sentido Incorreto/genética , Fosforilação , Plasmídeos/genética , Proteínas Tirosina Fosfatases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/genética , TransfecçãoRESUMO
Nutritional status has a major impact on the immune response and this is in part mediated by leptin, a pro-inflammatory cytokine. Preliminary data suggest that antagonism of leptin may offer a therapeutic approach for the treatment of some inflammatory disorders. We have tested monoclonal antibodies (mAbs) to the human leptin receptor (ObR) for antagonist activity using a leptin signalling bioassay. We identified a mAb, 9F8, which demonstrated dose-dependent antagonist activity in the leptin bioassay. Specificity of the mAb for ObR was confirmed using a plate binding assay. The 9F8 mAb displaced leptin binding to human ObR and enzymatically generated Fab fragments of 9F8 retained antagonist activity. Therefore the Fab fragment of 9F8 was cloned and recombinant 9F8 Fab (rFab) was purified from E. coli periplasmic fraction using a C-terminal His tag. Purified 9F8 rFab bound to human ObR and exhibited leptin antagonist activity. In vitro studies demonstrated that the 9F8 mAb inhibited leptin induced TNF-alpha production from human monocytes and anti-CD3 mAb induced proliferation of human T cells in PBMC culture. In conclusion, this study has identified a mAb to the human leptin receptor which inhibits leptin signalling and acts as a leptin antagonist in vitro.
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Anticorpos Monoclonais/farmacologia , Monócitos/efeitos dos fármacos , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/imunologia , Linfócitos T/efeitos dos fármacos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/isolamento & purificação , Relação Dose-Resposta Imunológica , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/genética , Ativação Linfocitária/efeitos dos fármacos , Monócitos/imunologia , Receptores para Leptina , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Transdução de Sinais , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Ghrelin exerts various metabolic activities, including regulation of glucose levels in humans. To verify whether the glucose response to ghrelin reflects a modulation of an insulin-independent hepatic phenomenon, we studied glucose output by primary porcine hepatocytes in suspension culture, after incubation with acylated ghrelin (AG), unacylated ghrelin (UAG), and hexarelin (HEX). AG induced glucose output dose dependently after 20 min of incubation (P < 0.001), whereas HEX, a GH secretagogue receptor type 1a (GHS-R1a) agonist, had no effect. UAG inhibited glucose release also dose dependently and after 20 min (P < 0.001). Moreover, UAG completely reversed AG-induced glucose output (P < 0.01). Using real-time PCR, GHS-R1a gene expression was undetectable in all the hepatocyte preparations studied. The lack of efficacy of HEX, the efficacy of UAG, and the absence of GHS-R1a expression indicate the involvement of a yet uncharacterized ghrelin receptor type. In conclusion, glucose output by primary hepatocytes is time- and dose-dependently stimulated by AG and inhibited by UAG. Moreover, UAG counteracts the stimulatory effect of AG on glucose release. These actions might be mediated by a different receptor than GHS-R1a, and apparently, we must consider AG and UAG as separate hormones that can modify each other's actions on glucose handling, at least in the liver.
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Glucose/metabolismo , Hepatócitos/metabolismo , Hormônios Peptídicos/farmacologia , Animais , Células Cultivadas , Feminino , Grelina , Hepatócitos/efeitos dos fármacos , Homeostase , Humanos , Cinética , Oligopeptídeos/farmacologia , SuínosRESUMO
The human IGF-I gene has six exons, four of which are alternatively spliced. Variations in splicing involving exon 5 may occur, depending on the tissue type and hormonal environment. To study the regulation of splicing to IGF-I exon 5, we established an in vitro splicing assay, using a model pre-mRNA containing IGF-I exons 4 and 5 and part of the intervening intron. Using a series of deletion mutants, we identified an 18-nucleotide purine-rich splicing enhancer in exon 5 that increases the splicing efficiency of the upstream intron from 6 to 35%. We show that the serine-arginine protein splicing factor-2/alternative splicing factor specifically promotes splicing in cultured cells and in vitro and is recruited to the spliceosome in an enhancer-specific manner. Our findings are consistent with a role for splicing factor-2/alternative splicing factor in the regulation of splicing of IGF-I alternative exon 5 via a purine-rich exonic splicing enhancer.
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Processamento Alternativo/fisiologia , Elementos Facilitadores Genéticos/fisiologia , Éxons/fisiologia , Fator de Crescimento Insulin-Like I/genética , Proteínas Nucleares/fisiologia , Precursores de RNA/genética , Éxons/genética , Células HeLa , Humanos , Músculo Esquelético/fisiologia , Proteínas Nucleares/farmacologia , Proteínas de Ligação a RNA , Fatores de Processamento de Serina-Arginina , Spliceossomos/fisiologiaRESUMO
BACKGROUND: Androgen deficiency is increasingly recognized in young male cancer survivors; however, its impact on quality of life (QOL) is not established. The authors investigated the relationship between androgen levels, QOL, self-esteem, fatigue, and sexual function in young male cancer survivors compared with control subjects. METHODS: A cross-sectional, observational study of 176 male cancer survivors and 213 male controls aged 25 to 45 years was performed. Subjects completed 3 QOL scales (Medical Outcomes Study 36-Item Short-Form Health Survey version 2, the 12-item General Health Questionnaire [GHQ-12], and Aging Male Scale), and measures of self-esteem (Rosenberg Self-Esteem Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and sexual function (Derogatis Interview for Sexual Functioning-II Self-Report-Male). RESULTS: Cancer survivors had lower scores for all components of the Short-Form Health Survey, Aging Male Scale, and Functional Assessment of Chronic Illness Therapy-Fatigue, and for 4 of 5 subsections of the Derogatis Interview for Sexual Functioning than controls. The majority of these differences remained after adjusting by linear regression analysis. Levels of psychiatric disorder or self-esteem did not differ between the 2 groups. In cancer survivors, those with androgen deficiency (serum testosterone < or = 10 nmol/L) had lower scores than those without for all components of the Short-Form Health Survey, the General Health Questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Derogatis Interview for Sexual Functioning. Serum testosterone only weakly correlated with health measures. CONCLUSIONS: Young male cancer survivors self-report a marked impairment in QOL, energy levels, and quality of sexual functioning, and this was exacerbated in those with androgen deficiency. However, psychological distress was not elevated, self-esteem was normal, and sexual relationships were not impaired. The relationship with testosterone is complex, and appears dependent on a threshold level rather than direct correlation. Interventional trials are needed to determine whether testosterone replacement would improve QOL in young male cancer survivors.
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Androgênios/deficiência , Fadiga/etiologia , Neoplasias/fisiopatologia , Neoplasias/psicologia , Qualidade de Vida , Autoimagem , Disfunções Sexuais Fisiológicas/etiologia , Sobreviventes , Adulto , Estudos Transversais , Nível de Saúde , Humanos , MasculinoRESUMO
Leptin, the satiety hormone, appears to act as a link between nutritional status and immune function. It has been shown to elicit a number of immunoregulatory effects, including the promotion of T cell proliferative responses, and the induction of proinflammatory cytokines. Leptin deficiency is associated with an increased susceptibility to infection. As polymorphonuclear neutrophils (PMN) play a major role in innate immunity and host defense against infection, this study evaluated the influence of leptin on PMN activation. The presence of leptin receptor in human PMN was determined both at mRNA and protein levels, and the effect of leptin on PMN activation, as assessed by CD11b expression, was evaluated using flow cytometry. In contrast to monocytes, which express both the short and long forms of the leptin receptor (Ob-Ra and Ob-Rb, respectively), PMN expressed only Ob-Ra. Leptin up-regulated the expression of CD11b, an early marker of PMN activation, on PMN in whole blood, yet it had no effect on purified PMN, even those treated by submaximal doses of TNF-alpha or PMA. The kinetics of leptin-induced activation in whole blood were consistent with an indirect effect mediated by monocytes, and 71% of the leptin-stimulatory effect on PMN was blocked by a TNF-alpha inhibitor. Leptin-mediated induction of CD11b expression was observed when purified PMN were coincubated with purified monocytes. In conclusion, although leptin activates PMN, it does so indirectly via TNF-alpha release from monocytes. These findings provide an additional link among the obesity-derived hormone leptin, innate immune function, and infectious disease.