Diagnosis of adrenal failure in critically ill patients / Diagnóstico de insuficiência adrenal em pacientes críticos

In the last two decades there was important evolution on the knowledge of the function of the hypothalamic-pituitary-adrenal axis. In the last decade, the expression "relative adrenal insufficiency" (RAI) was created, and more recently "critical illness-related corticosteroid insufficiency" (CIRCI) was used to designate those patients in which cortisol production was not sufficiently increased in stress situations. Patients with CIRCI have elevated hospital morbidity and mortality. Currently, there is a wide discussion about diagnostic criteria for this dysfunction. Besides basal cortisol, some publications now study the role of other tests, such as cortrosyn test - either in low (1 μg) or high doses (250 μg); free cortisol, salivary cortisol, metyrapone test and others. With this review, we aimed at summarizing the results of the most influent papers that intended to define diagnostic criteria for CIRCI. We also suggest an approach for CIRCI diagnosis and make it clear that the decision about steroid therapy in septic shock patients is matter apart from RAI.

Nas últimas décadas, houve uma importante evolução no conhecimento sobre a função do eixo hipotálamo-pituitária-adrenal. Na última década, foi cunhada a expressão "insuficiência adrenal relativa" (IAR) e, mais recentemente, a expressão "insuficiência adrenal relacionada à doença grave" (CIRCI) foi utilizada para designar aqueles pacientes nos quais a produção de cortisol não era suficientemente elevada em situações de estresse. Pacientes com CIRCI apresentam elevada morbidade e mortalidade em hospitais. Atualmente, há uma ampla discussão sobre os critérios de diagnóstico para essa desordem. Além do cortisol basal, algumas publicações analisaram o papel de outros testes, tais como o teste de estímulo com ACTH (cortrosina), com doses baixas (1 mg) ou altas (250 mg), cortisol livre, cortisol salivar, teste da metirapona e outros. O objetivo desta revisão foi resumir os resultados dos artigos mais importantes que buscaram definir os critérios de diagnóstico para a CIRCI. Também sugerimos uma abordagem para o diagnóstico da CIRCI e deixamos claro que a decisão sobre a terapia com esteroides em pacientes em choque séptico é uma questão separada da IAR.

Estudo da regulação da eosinopoiese em um modelo experimental de asma alérgica: contribuição dos glicocorticóides endógenos / Study the regulation of eosinophilopoiesis in an experimental model of allergic asthma: contribution of endogenous glucocorticoids

A asma alérgica é uma doença inflamatória crônica, com hiperresponsividade das vias aéreas, inflamação (com infiltrado eosinofílico importante) e obstrução reversível das vias aéreas, cuja prevalência global vem aumentando. Os eosinófilos são produzidos e armazenados na medula óssea, em resposta à interleucina(IL)-5, e posteriormente liberados na circulação, sendo recrutados por fatores quimiotáticos como eoxatina, para sítios inflamatórios, incluindo o pulmão. Estresse é um estado de homeostase ameaçada, apontando por muitos estudos como fator predisponente para a evolução das doenças alérgicas, incluindo a asma. O eixo hipófise-pituitária-adrenal (HPA), componente neuroimunoendócrino central da resposta ao estresse, é ativado por citocinas inflamatórias, incluindo o fator de necrose tumoral (TNF). Os glicocorticóides, em doses terapêuticas, suprimem a eosinofilia no sangue periférico e tecidos, inibindo a produção de IL-5, fator estimulador de colônia de granulócitos e macrófagos (GM-CSF) e IL-3, e induzindo a apoptose em eosinófilos maduros. Contudo, em certas condições, os glicocorticóides são estimulatórios, e não inibitórios, para a eosinopoiese. A provocação alergênica em animais sensibilizados modifica o padrão de resposta das células de medula óssea à IL-5 e à eotaxina. Objetivo: No presente estudo avaliamos o papel desempenhado pelos hormônios de estresse secretados pela adrenal na imunorregulação da eosinopoiese em camundongos sensibilizados, utilizando o tratamento com bloqueadores da produção (metirapone) e da atuação dos glicocorticóides adrenais (mifepristone, RU486). Metodologia: Camundongos BALB/c foram sensibilizados com ovalbumina, submetidos ao pré-tratamento com metirapone ou RU486, antes da provocação alergênica por via intranasal. Vários aspectos foram avaliados: a) a presença de eosinófilos na medula óssea recém-coletada, e após cultura líquida na presença de IL-5; b) a presença de eosinófilos no lavado boncoalveolar (BAL) e no sangue periférico; c) a função pulmonar e a presença de infiltrados inflamatórios no pulmão. Em camundongos C57BL/6 de tipo selvagem, assim como nos animais deficientes para o receptor de tipos I para TNF, do mesmo background genético, avaliamos a resposta da medula óssea à provocação. Resultados: O tratamento com RU486 ou metirapone em animais provocados com OVA aboliu o aumento no número de células EPO(positivo) na medula óssea in vivo e ex vivo. Os níveis de corticosterona aumentam em animais provocados, e o aumento foi inibido pelo metirapone. O tratamento com RU486 impediu o aumento nos números de eosinófilos no BAL em resposta à provocação. O tratamento com RU486 ou metirapone aboliu o aumento na resistência de vias aéreas induzido pela provocação. O tratamento com RU486 bloqueou as mudanças no padrão de resposta da medula óssea ex vivo à eotaxina, induzidas pela provocação. A modulação da resposta das células da medula óssea em resposta à provocação alergênica não foi observada em animais deficientes do receptor do tipo I para TNF-alfa. Conclusão: em conjunto, os dados mostram um importante papel dos glicocorticóides endógenos para a resposta da provocação alegêrnica e modulação de citocinas envolvidas na migração de eosinófilos, assim como para a presença de eosinófilos no BAL e sua função pulmonar.

Pharmacological management of Cushing's syndrome: an update

The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. Drugs targeting the hypothalamic-pituitary axis have been investigated but their roles in clinical practice remain limited although PPAR-gamma agonist and somatostatin analogue som-230 (pasireotide) need further investigation. The only drug acting at the periphery targeting the glucocorticoid receptor remains Mifepristone (RU486). The management of Cushing syndrome may well involve combination therapy acting at different pathways of hypercortisolaemia but monitoring of therapy will remain a challenge.

O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-gama e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio.

Characteristics of uptake, transport and efflux of Z- and E-ajoenes in Caco-2 cell monolayers in vitro / 药学学报

The characteristics of uptake, transepithelial transport and efflux of Z- and E-ajoenes isolated from the bulbs of Allium sativum were studied. A human colon cell model Caco-2 cell monolayers in vitro cultured had been applied to study the characteristics of uptake, transepithelial transport and efflux of Z- and E-ajoenes. The quantitative determination of Z- and E-ajoenes was performed by high-performance liquid chromatography. Z- and E-Ajoenes can be detected only in the apical side and can be metabolized, but both compounds can not be transported from apical-to-basolateral and basolateral-to-apical directions in cultured Caco-2 cell monolayers. The metabolism of Z- and E-ajoenes in Caco-2 cell monolayers can be partially inhibited by vitamin C as an anti-oxidant, metyrapone as an inhibitor to subtype CYP3A of cytochrome P450 drug metabolism enzymes, and sodium azide as an inhibitor to ATP production. It is shown that neither Z-ajoene nor E-ajoene can pass through Caco-2 cell monolayers, and that they can be metabolized by the cells. The metabolism might be in correlation with cytochrome P450 drugs metabolism enzymes in Caco-2 cell monolayers.

Diagnostic Value of 1microgram Rapid ACTH Stimulation Test According to the Timing of Sampling of Serum Cortisol in Patients with Suspected Central Adrenal Insufficiency / 대한내분비학회지

BACKGROUND: Traditional testing of the hypothalamic-pituitary-adrenal axis function has essentially relied upon the insulin tolerance test or the metyrapone test(both tests are not only uncomfortable, but are also dangerous). The standard ACTH stimulation test uses an extremely supra-physiologic amount(250f microgram) of ACTH to evaluate a physiological response, which may result in a false normal response. The 1microgram rapid ACTH stimulation test is more physiological and more sensitive than the standard test, but there exist much controversy about when the serum cortisol should be measured or what the most appropriate cut-off point is for normality or whether the 1microgram ACTH commercial solution is needed. The aims of this study were to investigate 1) whether 1microgram of ACTH is an appropriate amount to stimulate the adrenal gland of patients that have suspected central adrenal insufficiency compared with insulin tolerance test(ITT) and 2) the diagnostic value of the 1microgram rapid ACTH stimulation test according to timing of sampling of serum cortisol. METHODS: In order to evaluate the dose-response relationship between ACTH and cortisol, we performed the ITT in 77 patients with suspected central adrenal insufficiency with serial measurements of serum cortisol and plasma ACTH. We drew the blood samples in 10 min intervals between 10 and 60 min after the administration of 1microgram ACTH in 39 patients with central adrenal insufficiency and in 38 pituitary control patients with pituitary. ITT was used to confirm the diseases for the patients of central adrenal insufficiency, but for pituitary control patients, the ITT indicated normality in the patients. Also, all subjects underwent the 250microgram rapid ACTH stimulation test, and we compared the diagnostic value of the 1microgram ACTH stimulation test with the 250microgram test. RESULTS: 1) The plasma ACTH level after the 1microgram ACTH stimulation test, even if it was be assumed as approximately 300pg/mL, was expected to be sufficient enough to stimulate the adrenal cortex normally(serum cortisol levels >18microgram/dL) compared to the plasma ACTH level in the ITT. 2) The sensitivity and specificity of the 1microgram rapid ACTH stimulation test was highest with 92.3% and 84.2%, respectively, when serum cortisol levels were measured at 20, 30, and 40 min after the ACTH injection. The 1microgram rapid ACTH stimulation test was more sensitive than the 250microgram ACTH test(sensitivity: 92.3%, specificity: 71.8%). CONCLUSION: The 1microgram rapid ACTH stimulation test was more sensitive test in patients with suspected central adrenal insufficiency, and blood samples for cortisol levels should be drawn at 20, 30, and 40 min after ACTH administration.

A Case of Cushing's Syndrome Complicating Pregnancy Adrenalectomized after Delivery / 대한내분비학회지

Pregnancy is rare in women with Cushing's syndrome, as the associated infertility is related to excess cortisol and/or androgen. However, approximately 100 such cases have been reported, with 50% due to an adrenal cortical adenoma. Establishing a diagnosis and cause can be difficult. Clinically, striae, hypertension and gestational diabetes are common features in pregnancy, with hypertension and diabetes being the most common signs of Cushing's syndrome in pregnant women. Furthermore, biochemically, a normal pregnancy is associated with a several fold increase in plasma cortisol, as the increased cortisol production rate also increases the cortisol binding protein. Untreated, the condition results in high maternal and fetal morbidity and mortality. An adrenal or pituitary adenoma should be excised, but a metyrapone, which is not teratogenic, has been effective in controlling many cases of excess cortisol. Here, a case of Cushing's syndrome, complicating a pregnancy due to an adrenal cortical adenoma, with thorough obstetric and medical management, including a metyrapone, which was adrenalectomized after delivery, is reported.

A Case Diagnosed to Cushing's Syndrome Caused by Adrenal Cortical Adenoma during Pregnancy after Ovulation Induction / 대한산부인과학회잡지

This woman was a secondary infertile patient with amenorrhea, hirsutism, and hyperprolactinemia due to excessive secretion of androgen. We had an impression that her disease was polycystic ovary syndrome, and she became pregnant after ovulation induction. Complications arised, such as hypertension, diabetes and pulmonary edema at 23rd week of pregnancy and physical findings of Cushing's syndrome were observed. Cushing's syndrome caused by adrenal cortical adenoma was diagnosed through endocrine and radiologic examination. We let her keep pregnancy through adjusting hypercorticolism with metyrapone to restrain abnormal steroidogenesis during pregnancy. After delivery, we carried out adrenalectomy through laparoscopic surgery and then can't find out any problem to be appeared to the mother and her neonate. We report this case with brief discussion.

Efeito do veneno de abelha na artrite induzida por antígeno em coelhos / Effect of bee venom on antigen induced arthritis in rabbit

O efeito do veneno de abelha foi avaliado na artrite induzida por antígeno, em coelhos. O veneno de abelha foi ministrado 7 dias antes da indução da artrite, por via subcutânea, nas doses de 1,5; 3,0 e 6,0 mg/Kg/dia. O líquido sinovial foi coletado, para avaliação do número total e diferencial de células; permeabilidade vascular; determinação de prostaglandina E2 e metabólitos de óxido nítrico. A influência de glicocorticóides endógenos foi investigada com metopirona e RU 38 486, em animais que receberam veneno de abelha (1,5 mg/Kg/dia). O pré-tratamento com veneno de abelha (1,5 mg/Kg/dia) reduziu o influxo de leucócitos para a articulação inflamada, assim como os níveis de prostaglandina E2. Esse efeito não foi observado nos animais que receberam metopirona. O RU 38 486 não alterou a atividade antiinflamatória do veneno de abelha.The effect of bee venom was evaluated on antigen induced arthritis, in rabbits. Bee venom was administrated subcutaneously, 7 days before arthritis was induced, in different doses: 1,5; 3,0 and 6,0 g/Kg/day. Total and differential leucocyte migration, protein leakage, intraarticular concentration of prostaglandina E2 and nitric oxide metabolites were quantified in sinovial fluid. The influence of endogenous glucocorticoids was investigated with metyrapone and RU 38 486, in animals treated with bee venom (1,5g/Kg/day). Pre-treatment with bee venom (1,5g/Kg/day) were effective in reducing leucocyte afflux, compared with control animals. Prostaglandin E2 levels were also significantly reduced in this group. This effect was not observed in animals treated with metyrapone. The anti-inflammatory activity of bee venom was not affected by RU 38 486...

Tratamiento médico de los tumores hipofisiarios productores de corticotrofina y tirotrofina / Medical treatment of adrenocorticotrophin and thyrotrophin-secreting pituitary tumors

Se analiza el estado actual del tratamiento médico de los tumores hipofisiarios productores de corticotrofina (ACTH) y tirotrofina (TSH). Se presentan las investigaciones comunicadas por diversos autores en el tratamiento de la enfermedad de Cushing y el síndrome de Nelson con moduladores de la secreción de ACTH, la bromocriptina, la ciproheptadina, la ritanserina, el ácido valproico y la somatostatina. Los resultados positivos cubren un pequeño número de casos. La primera opción de tratamiento de estos tumores es la cirugía seguida de la radioterapia. Cuando no se logra extirpar completamente los tumores, el uso de drogas que actúan inhibiendo la esteroidogénesis suprarrenal constituye una terapia paliativa. Entre estas drogas se cuentan el ketoconazol, la aminoglutetimida, la metopirona, el mitotano y el trilostan, con diversos grados de efectividad y tolerancia. Los pacientes que presentan tumores hipofisiarios productores de TSH han sido tratados con éxito con análogos de la somatostatina de acción prolongada, octreotide y lanreotide SR. Se ha logrado dramática supresión de la TSH y de la subunidad alfa, así como control del hipertiroidismo y disminución del tamaño de los tumores. Estas drogas ofrecen posibilidades de tratamiento médico para los pacientes que no logran control de su enfermedad con la cirugía

Effect of certain pharmacological agents on some neuropepyides and adrenal hormones in stressed rats. an evidence for a specific role in stress ulcerogenesis

This work aimed to study the effect of certain pharmacological agents [6-hydroxydopamine [6HD], metyrapone and naloxone]] on plasma adrenal hormones [corticosterone, epinephrine, norepinephrine and dopamine], brain and mucosal somatostatin and prostaglandin E2 [PGE2] as well as mucosal beta-endorphin in rats exposed to restraint stress. The specific actions of the different drugs used in this study helped to delineate the relative contribution of the different components in the pathogenesis of stress ulceration. The sympatho-adrenal medullary activity appears to be protective and neutralize the ulcerogenic effects involving the vagal activation and opioid mechanisms. Meanwhile, the adreno-cortical activity through the glucocorticoids appear to offer a permissive role in ulcer development

Supresion nocturna con alta dosis de dexametasona y test de metopirona en el diagnostico etiologico del sindrome de Cushing / Night supression with high doses of dexamethasone and metyrapone tests for the etiological diagnosis of Cushing syndrome

El síndrome de Cushing (SC) es un trastorno grave aunque curable para el que se han propuesto diferentes estrategias de diagnóstico etiopatogénico. Entre ellas, los tests que exploran la regulación de la secreción de cortisol son de gran utilidad aunque no existe homogeneidad de criterios respecto a la elección de los mismos. En este estudio se investigaron 61 pacientes de 13-61 años con SC, quienes fueron classificados según hallazgos quirúrgicos, patológicos y evolución post-tratamiento, en: de origen pitutario 41, por tumor adrenal 16 y SC ectópico 4. En la totalidad de los pacientes se realizó una prueba de inhibición de la cortisolemia con una dosis nocturna de 8 mg de dexametasona. En 43 de ellos, se efectuó edemás un test metopirona con medición de 11-desoxicortisol sérico. Ambas pruebas evidenciaron valores elevados de sensibilidad, especificidad, índice de validez y poder predictivo positivo, obteniéndose los porcentajes mayores (97, 100, 98 y 100 por ciento, respectivamente) con su empleo conjunto. El uso combinado de ambos tests constituye un medio simple y con elevados criterios de validez para el diagnóstico etiológico del SC.

Adrenocortical influence on histokinetics and lipid components of uropygial gland of immature chick.

Adrenocortical influence on uropygial gland of 10-day old male white leghorn chicken was assessed by suppressing glucocorticoid level with metyrapone and following corticosterone and deoxycorticosterone acetate (DOC) treatments (im), 100 micrograms each on alternate day for a period of 15 days. Metyrapone treatment resulted in significant atrophy of the uropygial gland with a severe regression of the glandular alveoli due to cytopycnosis, cellular disintegration and drastic cell loss. Concomitantly, there was a depletion of glandular lipid and its diester wax fraction. Corticosterone, administered simultaneously with metyrapone, counteracted severe adverse effects of the latter on the uropygial gland. In the normal chicken also corticosterone alone caused glandular hypertrophy with increased rate of cell renewal and cell growth within the alveoli and, to a lesser extent, augmented output of the glandular lipids. Simultaneous administration of corticosterone and testosterone propionate (TP), on the other hand, caused a moderate suppressive influence on this gland. DOC treatment alone or with metyrapone and TP failed to exert any noteworthy change in the uropygial gland excepting a moderate reduction of gland weight and a rise of glandular lipids observed after combined injections of DOC with TP and with metyrapone respectively.

Effect of dexamethasone and metopirone on hypothalamic gamma-aminobutyric acid (GABA) and plasma cortisol levels in the female catfish, Clarias batrachus (L.)

Em C. batrachus, o GAMA hipotalâmico aumentou significativamente em resposta ao tratamento durante 7 dias com dexametasona (50 ug/peixe/dia : i.p.). Entretanto, a metopirona (CIBA, 50 ug/peixe/dia : i.p.) baixou acentuadamente o conteúdo do GABA hipotalâmico já a partir do 3. dia de tratamento. Nos peixes submetidos a tratamentos com dexametasona e metopirona o nível de cortisol plasmático apresentou-se significativamente menor. Estes resultados sugerem que o aumento e decréscimo dos níveis do GABA hipotalâmico podem ter um papel estimulador ou inibidor em resposta aos tratamentos com dexametasona ou metopirona

ß-Lipotropin/adrenocorticotropic hormone responses to corticotropin releasing hormone, hypoglycemia, metyrapone and dexamethasone in normal human subjects

1. The possible correlation between secretions of adrenocorticotropic hormone (ACTH) and of ß-lipotropin (ß-LPH), two pro-opiomelanocortin (POMC)-derived peptides, was investogated in 27 normal subjects under basal conditions (circadian rhythmz0, after the administration of 1 mg dexamethasone and in tests involving acute (human corticotropin releasing hormone, hCRG, and insulin tolerance test, ITT) and chronic (metyrapone) simulation. 2. All subjects presented circadian rhythm and an operating negative feedback mechanism. Plasma ACTH and ß-LPH concnetrations were correlated in al tests. The increase in ACTH and ß-LPH levels after hCRH was lower than that detected after ITT, though both increases were more discrete than those detected after stimulation with metyrapone. 3. The data suggest that, under hypoglycemic conditions, ACTH and ß-LPH secretion involves other POMC secretagogues in addition to endogenous CRH. The batyre of these factore remains undefined. The greater efficacy of metyrapone treatment in elevating ACTH and ß-LPH levels is most likely mediated by sustained reduction in cortisol production and interrruption of the rapid steroid feedback on the pituitary. The molar peak ratios of the acute tests, vere similar to one another, differed from the peak ratio obtained during the metyrapone test, suggesting that corticotrophs may present polls with differentiated ACTH and ß-LPH content and release according to the type and/or duration of the stimulus

Avaliacao da reserva hipofisaria de ACTH atraves do teste da metopirona com dosagem do 11-desoxicortisol serico (RIE). / Evaluation of the pituitary reserve of ACTH using metyrapone test with determination of seric 11-deoxycortisol

m pacientes com hipopituitarismo, a metopirona nao removeu a elevacao do S. Os niveis baixos do cortisol comprovaram a efetividade da droga. Em ppacientes submetidos a cirurgia hipofisaria, o aumento do S apos a metopirona foi semelhante ao dos normais em 3 casos, inferior em 3 e nulo em 1 caso. Uma das respostas subnormais foi acompanhada de um valor nao suprimido do cortisol, nao sendo, assim, valorizada. Os pacientes com hipotiroidismo primario apresentaram respostas do S a metopirona semelhantes as dos normais. O S elevou-se apos a metopirona nos 5 pacientes com sindrome de Cushing porem de forma variavel, independentemente da patologia primaria. Nos pacientes com nanismo hipofisario, a resposta subnormal nao foi considerada devido ao cortisol nao suprimido.