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1.
Diabetes Metab ; 46(1): 1-7, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30825519

RESUMO

Shortly after the first description of primary aldosteronism (PA) appeared in the 1950s by Jerome Conn, an association of the condition with diabetes mellitus was documented. However, a clear pathophysiological interrelationship linking the two entities has yet to be established. Nevertheless, so far, many mechanisms contributing to insulin resistance and dysregulation of glucose uptake have been described. At the same time, many observational studies have reported an increased prevalence of the metabolic syndrome (MetS) among patients with PA. Regarding the relationship between aldosterone levels and obesity, a vicious cycle of adipokine-induced aldosterone production and aldosterone adipogenic action may be further contributing to MetS manifestations in PA patients. However, whether aldosterone excess affects lipid metabolism is still under investigation. Also, recent findings of the coexistence of glucocorticoid excess in many cases of PA highlight the need for further studies to examine the presumed link between high aldosterone levels and various metabolic parameters. In the present review, our focus is to comprehensively present the spectrum of available research findings concerning the possible associations between aldosterone excess and metabolic alterations, including impaired glucose metabolism, insulin resistance and, consequently, diabetes, altered lipid metabolism and the development of fatty liver. In addition, the complex relationship between obesity and aldosterone is discussed in detail.


Assuntos
Aldosterona , Complicações do Diabetes , Hiperaldosteronismo , Síndrome Metabólica , Aldosterona/sangue , Aldosterona/metabolismo , Aldosterona/fisiologia , Glicemia , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/fisiopatologia , Insulina , Resistência à Insulina , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Obesidade
3.
Internist (Berl) ; 59(11): 1163-1179, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30280206

RESUMO

Endocrine disorders are the most common causes of secondary hypertension. Early diagnosis and specific treatment are crucial for improvement of the prognosis. This article provides an overview on which clinical constellations point to an increased risk of secondary causes of hypertension. These include spontaneous hypokalemia, young age at onset of hypertension, adrenal incidentaloma and therapy refractive arterial hypertension. The basic diagnostics include determination of the aldosterone to renin ratio, measurement of free plasma metanephrines and a 1 mg dexamethasone suppression test. Borderline results require repeated control testing and/or confirmatory testing under standardized test conditions. In cases of repeatedly conspicuous results referral to a specialized clinic should be considered for further clarification and confirmation of the diagnosis. Imaging diagnostics may constitute an adjunct to laboratory testing after the diagnosis has been confirmed. Therapeutic algorithms vary depending on the underlying endocrine disease.


Assuntos
Doenças do Sistema Endócrino/complicações , Hiperaldosteronismo/complicações , Hipertensão/etiologia , Algoritmos , Humanos , Hiperaldosteronismo/diagnóstico , Hipertensão/diagnóstico
4.
Endocr Relat Cancer ; 25(7): R405-R420, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29794126

RESUMO

This review aims to provide clinicians and researchers with a condensed update on the most important studies in the field during 2017. We present the academic output measured by active clinical trials and peer-reviewed published manuscripts. The most important and contributory manuscripts were summarized for each diagnostic entity, with a particular focus on manuscripts that describe translational research that have the potential to improve clinical care. Finally, we highlight the importance of collaborations in adrenal tumor research, which allowed for these recent advances and provide structures for future success in this scientific field.


Assuntos
Neoplasias das Glândulas Suprarrenais , História do Século XXI , Humanos
5.
Cancer Lett ; 406: 54-63, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28826686

RESUMO

cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (-52 ± 16%, p < 0.001) and human CPA cells (-53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.


Assuntos
Citoesqueleto de Actina/metabolismo , Fatores de Despolimerização de Actina/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , AMP Cíclico/farmacologia , Esteroides/biossíntese , Fatores de Despolimerização de Actina/antagonistas & inibidores , Fatores de Despolimerização de Actina/genética , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/tratamento farmacológico , Adenoma Adrenocortical/patologia , Animais , Colforsina/farmacologia , Humanos , Hidrocortisona/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas , Vasodilatadores/farmacologia
6.
J Mol Endocrinol ; 58(2): 67-78, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27965370

RESUMO

In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Aldosterona/sangue , Aldosterona/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Exoma , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único
7.
Horm Metab Res ; 49(4): 301-306, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27871112

RESUMO

Untargeted, next generation sequencing approaches have provided deep insights into genetic events that result in unopposed steroidogenesis from the adrenal cortex. In particular, somatic mutations in the gene encoding the catalytic subunit α of protein kinase A (PKA) (PRKACA) were identified independently by several groups as the most frequently altered gene in cortisol-producing adenomas. Detailed functional studies could explore the molecular consequences of these hot-spot mutations and large international cohorts have provided the basis to explore the clinical characteristics associated with this mutation. Thereby, PRKACA mutations are highly specific for cortisol over-secretion, while they are absent or very rare in the context of other adrenal diseases. Patients carrying these somatic mutations are affected by a more severe phenotype and are identified at a younger age. Thus, these genotype/phenotype correlations provide further evidence for the importance of PKA-dependent pathways for adrenal physiology and disease.


Assuntos
Adenoma Adrenocortical , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico , Mutação , Proteínas de Neoplasias , Neoplasias do Córtex Suprarrenal/enzimologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/enzimologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Animais , Humanos , Hidrocortisona/genética , Hidrocortisona/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
8.
J Intern Med ; 280(6): 540-550, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27864864

RESUMO

The recently available genomic sequencing techniques have led to breakthroughs in understanding of the underlying genetic mechanisms in adrenocortical tumours. Disease-causing mutations have been described for aldosterone-producing adenomas, cortisol-producing adenomas and adrenocortical carcinomas. Further, knowledge gained from transcriptome analyses and methylation arrays has provided new insights into the development of these tumours. Elucidation of the genomic landscape of adrenocortical tumours and improved techniques may in the future be useful for early diagnosis through the detection of mutated DNA in the circulation. Moreover, compounds that bind specifically to altered proteins may be used as screening targets or therapeutic agents. Regulation of cortisol release by interaction with an altered subunit in adenylate cyclase may be more complex, but may provide a new option for regulating steroid release. Information about derangements in adrenocortical carcinoma is already helpful for determining patient prognosis. With further knowledge, we may be able to identify novel biomarkers that effectively and noninvasively help in differentiating between benign and malignant disease. It is clear that the next few years will provide much novel information that hopefully will aid in the treatment of patients with adrenocortical tumours.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma/genética , Adenoma/metabolismo , Carcinoma/genética , Análise Mutacional de DNA , Genômica , Glucocorticoides/metabolismo , Humanos , Hiperaldosteronismo/genética
9.
Endocrinology ; 157(6): 2489-99, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27035656

RESUMO

Adrenal aldosterone-producing adenomas (APAs) are a main cause for primary aldosteronism leading to arterial hypertension. Physiologically, aldosterone production in the adrenal gland is stimulated by angiotensin II and high extracellular potassium. These stimuli lead to a depolarization of the plasma membrane and, as a consequence, an increase of intracellular Ca(2+). Mutations of the plasma membrane Ca(2+)-ATPase ATP2B3 have been found in APAs with a prevalence of 0.6%-3.1%. Here, we investigated the effects of the APA-associated ATP2B3(Leu425_Val426del) mutation in adrenocortical NCI-H295R and human embryonic kidney (HEK-293) cells. Ca(2+) measurements revealed a higher basal Ca(2+) level in cells expressing the mutant ATP2B3. This rise in intracellular Ca(2+) was even more pronounced under conditions with high extracellular Ca(2+) pointing to an increased Ca(2+) influx associated with the mutated protein. Furthermore, cells with the mutant ATP2B3 appeared to have a reduced capacity to export Ca(2+) suggesting a loss of the physiological pump function. Surprisingly, expression of the mutant ATP2B3 caused a Na(+)-dependent inward current that strongly depolarized the plasma membrane and compromised the cytosolic cation composition. In parallel to these findings, mRNA expression of the cytochrome P450, family 11, subfamily B, polypeptide 2 (aldosterone synthase) was substantially increased and aldosterone production was enhanced in cells overexpressing mutant ATP2B3. In summary, the APA-associated ATP2B3(Leu425_Val426del) mutant promotes aldosterone production by at least 2 different mechanisms: 1) a reduced Ca(2+) export due to the loss of the physiological pump function; and 2) an increased Ca(2+) influx due to opening of depolarization-activated Ca(2+) channels as well as a possible Ca(2+) leak through the mutated pump.


Assuntos
Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/fisiopatologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Glândulas Suprarrenais/metabolismo , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , Angiotensina II/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Imunofluorescência , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Sódio/metabolismo
10.
Horm Metab Res ; 47(13): 933-4, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26667799

RESUMO

Hypertension is a major cardiovascular risk factor that affects between 10-40% of the general population in an age dependent manner. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid volume, and the vascular response to injury and inflammation 1. Chronic RAAS activation in the presence of sufficient sodium consumption leads to persistent hypertension, setting off a cascade of inflammatory, thrombotic, and atherogenic effects eventually leading to end-organ damage 2 3. Accordingly, numerous studies have demonstrated that elevated renin and/or aldosterone levels are predictors of adverse outcome in hypertension 4, heart failure 5 6, myocardial infarction 7, and renal insufficiency 8 and influence insulin resistance 9. Primary aldosteronism (PA) is the most common secondary form of hypertension with an estimated prevalence between 4 and 12% of hypertensives 10 11 12 and 11-20% in patients that are resistant to combined antihypertensive medication 13 14. Given the severe cardiovascular adverse effects of aldosterone excess that are independent of high blood pressure levels 15 16 17 18 detection and treatment of PA has important impact on clinical outcome and survival.


Assuntos
Hiperaldosteronismo/patologia , Pesquisa Translacional Biomédica , Ensaios Clínicos como Assunto , Feminino , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/genética , Mutação/genética
11.
Horm Metab Res ; 47(13): 953-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26566104

RESUMO

Somatic mutations have been identified in the KCNJ5 gene (encoding the potassium channel GIRK4) in aldosterone-producing adenomas (APA). Most of these mutations are located in or near the selectivity filter of the GIRK4 channel pore and several have been shown to lead to the constitutive overproduction of aldosterone. KCNJ5 mutations in APA are more frequent in women; however, this gender dimorphism is a reported phenomenon of Western but not East Asian populations. In this review we discuss some of the issues that could potentially underlie this observation.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Mutação/genética , Seleção Genética , Caracteres Sexuais , Cloreto de Sódio na Dieta/efeitos adversos , Adenoma/genética , Aldosterona/biossíntese , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/química , Humanos , Masculino
12.
Ann Oncol ; 26(10): 2119-25, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26392430

RESUMO

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Neoplasias Ósseas/secundário , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Recidiva Local de Neoplasia/patologia , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/mortalidade , Neoplasias Ósseas/mortalidade , Europa (Continente) , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
13.
Oncogenesis ; 4: e161, 2015 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-26214578

RESUMO

Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/ß-catenin signaling pathway. However, the adrenal-specific targets of oncogenic ß-catenin-mediating tumorigenesis have not being established. A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous ß-catenin activating mutation was done to identify the Wnt/ß-catenin targets. Seven genes were consistently identified in the three studies. Among these genes, we found that AFF3 mediates the oncogenic effects of ß-catenin in ACC. The Wnt response element site located at nucleotide position -1408 of the AFF3 transcriptional start sites (TSS) mediates the regulation by the Wnt/ß-catenin signaling pathway. AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R. AFF3 is located in nuclear speckles, which play an important role in RNA splicing. AFF3 overexpression in adrenocortical cells interferes with the organization and/or biogenesis of these nuclear speckles and alters the distribution of CDK9 and cyclin T1 such that they accumulate at the sites of AFF3/speckles. We demonstrate that AFF3 is a new target of Wnt/ß-catenin pathway involved in ACC, acting on transcription and RNA splicing.

14.
Eur J Endocrinol ; 173(1): 43-52, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25916394

RESUMO

OBJECTIVE: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs. DESIGN: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers. RESULTS: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease. CONCLUSION: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Biomarcadores Tumorais/metabolismo , Mutação/genética , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Células-Tronco/metabolismo , Succinato Desidrogenase/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Europa (Continente) , Feminino , Humanos , Imuno-Histoquímica , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Receptores de Fator de Crescimento Neural/genética
16.
Endocrinology ; 155(4): 1353-62, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24506072

RESUMO

Somatic mutations of the potassium channel KCNJ5 are found in 40% of aldosterone producing adenomas (APAs). APA-related mutations of KCNJ5 lead to a pathological Na(+) permeability and a rise in cytosolic Ca(2+), the latter presumably by depolarizing the membrane and activating voltage-gated Ca(2+) channels. The aim of this study was to further investigate the effects of mutated KCNJ5 channels on intracellular Na(+) and Ca(2+) homeostasis in human adrenocortical NCI-H295R cells. Expression of mutant KCNJ5 led to a 2-fold increase in intracellular Na(+) and, in parallel, to a substantial rise in intracellular Ca(2+). The increase in Ca(2+) appeared to be caused by activation of voltage-gated Ca(2+) channels and by an impairment of Ca(2+) extrusion by Na(+)/Ca(2+) exchangers. The mutated KCNJ5 exhibited a pharmacological profile that differed from the one of wild-type channels. Mutated KCNJ5 was less Ba(2+) and tertiapin-Q sensitive but was inhibited by blockers of Na(+) and Ca(2+)-transporting proteins, such as verapamil and amiloride. The clinical use of these drugs might influence aldosterone levels in APA patients with KCNJ5 mutations. This might implicate diagnostic testing of APAs and could offer new therapeutic strategies.


Assuntos
Adenoma/genética , Neoplasias das Glândulas Suprarrenais/genética , Aldosterona/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Mutação , Adenoma/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/metabolismo , Amilorida/química , Bário/química , Venenos de Abelha/química , Cálcio/química , Linhagem Celular Tumoral , Citosol/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas de Patch-Clamp , Permeabilidade , Potássio/química , Isoformas de Proteínas/genética , RNA/metabolismo , Sódio/química , Verapamil/química
17.
Dtsch Med Wochenschr ; 138(8): 375-80, 2013 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-23404326

RESUMO

Autonomous secretion of adrenal hormones can follow a subclinical course or even be masked by other frequent diseases. Patients with incidentally discovered adrenal masses (incidentaloma) represent another diagnostic challenge. Their frequency has increased through the growing number of medical imaging procedures. Although the proportion of malignant or hormonally active lesions is low, patients with adrenal incidentalomas (> 1cm) should undergo an endocrine work-up in order to detect subclinical courses of Cushing's syndrome, pheochromocytoma or primary aldosteronism. Enhanced CT is of help in the assessment of the dignity of discovered lesions. In order to evaluate the hormonal activity, it is recommended to perform low dose dexamethason suppression test and to determine the plasma metanephrines and the aldosterone to renin ratio (in hypertensive patients). The therapy of suclinical Cushing's syndrome (operative vs. medicamentous therapy) remains a single-case decision in the absence of randomised prospective studies. All tumors with criterias for malignancy (> 4cm) and subclinical pheochromocytoma and aldosterone producing adenomas should undergo surgery. In the case of non operated tumors annual bichemical follow-up controls should be performed over a duration of 5 years. In the case of a significant gain of tumor size during follow-up, adrenalectomy should be considered.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Achados Incidentais , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia , Adulto , Fatores Etários , Idoso , Estudos Transversais , Síndrome de Cushing/sangue , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/cirurgia , Dexametasona , Diagnóstico Diferencial , Feminino , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirurgia , Masculino , Metanefrina/sangue , Pessoa de Meia-Idade , Feocromocitoma/diagnóstico , Feocromocitoma/cirurgia , Renina/sangue
18.
Horm Metab Res ; 45(2): 124-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23111829

RESUMO

In depth analysis of key molecular mechanisms involved in functional autonomy of aldosterone secretion is hampered by the lack of tumor cell lines that reflect functional characteristics of aldosterone producing adenomas. Herein, we describe the characteristics of the adrenocortical carcinoma cell line NCI-H295R and its suitability as a model of hyperaldosteronism in relation to different culture conditions. Steroid profiling revealed that NCI-H295R cells predominantly secrete cortisol, while aldosterone and other steroids are released at much lower concentrations. However, aldosterone output specifically increased in response to different stimuli such as ACTH and angiotensin II, and in particular to potassium in a dose dependent manner. NCI-H295R cells readily formed spheroids under specific culture conditions, a method widely used for the enrichment of progenitor cells. Unexpectedly, spheroid cells excelled with higher aldosterone concentration and higher expression levels of the steroidogenic enzymes StAR, 3ßHSD, CYP17, SF-1, and the MC2-receptor. Further investigations revealed that this phenomenon is mainly attributed to epithelial growth factor (EGF) and particularly fibroblast growth factor (FGF), which are both essential ingredients in the spheroid culture medium. Aldosterone release under the combinatory influence of EGF and FGF was not higher than the effect of FGF alone. Spheroid growth per se, therefore, does not ensure an enrichment of less differentiated cell types in this cell line.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Linhagem Celular Tumoral , Hiperaldosteronismo/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Aldosterona/biossíntese , Aldosterona/metabolismo , Adesão Celular , Citocromo P-450 CYP11B2/biossíntese , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrocortisona/biossíntese , Hidrocortisona/metabolismo , Hiperaldosteronismo/enzimologia , Hiperaldosteronismo/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Concentração Osmolar , Potássio/metabolismo , RNA Mensageiro/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
19.
Dtsch Med Wochenschr ; 137(48): 2480-4, 2012 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-23168980

RESUMO

Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as "Conn-Trias" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary.


Assuntos
Hiperaldosteronismo/diagnóstico , Hipertensão/etiologia , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/terapia , Glândulas Suprarrenais/patologia , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/terapia , Adenoma Adrenocortical/sangue , Adenoma Adrenocortical/diagnóstico , Adenoma Adrenocortical/terapia , Aldosterona/sangue , Anti-Hipertensivos/uso terapêutico , Diagnóstico Diferencial , Eplerenona , Hiperaldosteronismo/sangue , Hiperaldosteronismo/tratamento farmacológico , Hiperaldosteronismo/etiologia , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipopotassemia/sangue , Hipopotassemia/diagnóstico , Hipopotassemia/tratamento farmacológico , Imageamento por Ressonância Magnética , Programas de Rastreamento , Renina/sangue , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Tomografia Computadorizada por Raios X
20.
Horm Metab Res ; 44(9): 670-5, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22723268

RESUMO

The melanocortin system is involved in central and peripheral regulation of energy homeostasis. In adipocytes, the melanocortin 2 receptor (MC2R) transmits ACTH-dependent signaling and its expression rises substantially during adipocyte differentiation. An in vitro system of retrovirally expressed shRNA directed against Mc2r mRNA in 3T3-L1 cells was established and effects of Mc2r knockdown (kd) in comparison to cells expressing non-targeting shRNA (control) were explored in differentiated adipocytes. Morphology, gene expression, lipolysis and fatty acid composition were analyzed. While gross morphology was unchanged extractable amount of lipids was reduced to 70-80% in kd cell lines (p<0.01). Moreover, expression changes of Pparγ2, aP2, and Pref1 indicated reduced differentiation in Mc2r kd cells. Intriguingly, not only ACTH, but also norepinephrine stimulated lipolysis were substantially reduced demonstrating functional significance of MC2R for general lipolysis pathway. Analysis of fatty acid composition in triglyceride and phospholipid fractions showed a lowered ratio of C16:1/C16:0 and C18:1/C18:0, but increased concentrations of arachidonic acid upon Mc2r knockdown. Reduction of mono-unsaturated fatty acids (MUFAs) was associated with lower expression of stearoyl-Coenzyme A desaturase 1 and 2 in kd cells (21 ± 8% vs. 100 ± 13%, p=0.01 and 32 ± 3% vs. 100 ± 15%, p=0.046). Conversely, high doses of ACTH resulted in gene expression changes, mirroring Mc2r knockdown (higher Pparγ2, Scd1, Hsl expression). MC2R plays an important role for regular lipolytic function and lipid composition in 3T3-L1 adipocytes. Of interest, desaturase expression was reduced and MUFA content accordingly altered in kd cells.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular , Lipídeos/química , Receptor Tipo 2 de Melanocortina/genética , Células 3T3-L1 , Adipócitos/química , Animais , Expressão Gênica , Técnicas de Silenciamento de Genes , Metabolismo dos Lipídeos , Lipólise , Camundongos , Receptor Tipo 2 de Melanocortina/metabolismo , Transdução de Sinais
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