Evaluation of ketoconazole as a treatment for Cushing's disease in a retrospective cohort.

Objective: The first-line treatment for Cushing's disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%, even in those with real initial remission. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and the treatment response to ketoconazole in Cushing's disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital. Patients and methods: This was a retrospective cohort of Cushing's disease patients with active hypercortisolism who used ketoconazole at any stage of follow-up. Patients who were followed up for less than 7 days, who did not adhere to treatment, or who were lost to follow-up were excluded. Results: Of the 172 Cushing's disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, five of whom (15%) had also undergone radiotherapy; seven used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years. A total of 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to nine others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Only four patients had serious adverse effects that warranted discontinuation. There were 20 confirmed episodes of hypokalemia among 10/33 patients (30%). Conclusion: Ketoconazole effectively controlled hypercortisolism in 66% of Cushing's disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out. Hypokalemia is a frequent metabolic effect not yet described in other series, which should be monitored during treatment.

Osilodrostat para el síndrome de Cushing endógeno / Osilodrostat for Cushing's syndrome endogenous

INTRODUCCIÓN: El síndrome de Cushing endógeno es un trastorno endocrino severo y multiorgánico causado por la hiperproducción de cortisol por parte de las glándulas adrenales. Las manifestaciones clínicas más habituales incluyen síndrome metabólico, resistencia a la insulina, obesidad visceral, diabetes, hipertensión, dislipemia, osteoporosis, cambios en la piel, daños en el sistema inmune (aumento del riesgo de infecciones), trastornos neuropsiquiátricos, hipogonadismo, desórdenes menstruales en mujeres y un estado de hipercoagulabilidad. Debido a las complicaciones metabólicas y cardiovasculares asociadas, los pacientes mal controlados o sin tratamiento presentan un incremento en la mortalidad. El manejo terapéutico puede incluir cirugía hipofisaria o suprarrenal, tratamiento médico y/o radioterapia. La cirugía es la terapia de elección, cualquiera que sea la causa de base, y que consiste en la resección quirúrgica del tumor subyacente, excepto en los pacientes que presenten un carcinoma suprarrenal metastásico o cuya enfermedad sea de origen desconocido. La segunda línea terapéutica es la irradiación sobre la hipófisis, la suprarrenalectomía bilateral y el tratamiento farmacológico (inhibidores de la enzima adrenal, etomidato, antagonistas de los receptores de glucocorticoides). Algunos de los fármacos mencionados no tienen autorización de comercialización del país aún. TECNOLOGÍA: Osilodrostat (Isturisa®) es un inhibidor de la 11ß-hidroxilasa (CYP11B1), enzima responsable de la etapa final de la biosíntesis de cortisol en la glándula suprarrenal. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de osilodrostat para el tratamiento de adultos con síndrome de Cushing endógeno. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. En PubMed se utilizó la estrategia de búsqueda que se detalla en el Anexo I. La fecha de búsqueda de información fue hasta el 19 de octubre de 2022. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (osilodrostat [Supplementary Concept] OR Isturisa [tiab] OR LCI699 [tiab]) AND ("Cushing Syndrome" [MESH] OR "Cushing Syndrome" [tiab] OR Hypercortisolism [tiab]). RECOMENDACIONES: No se hallaron guías de práctica clínica actualizadas en Argentina que mencionen la tecnología en la indicación evaluada. Un consenso de expertos internacional publicado en 2021 menciona la utilización de osilodrostat como una opción terapéutica junto con otros inhibidores de la esteroidogénesis como el ketoconzol, etomidato, mitotano, metirapona, (estos últimos tres no se encuentran disponibles en nuestro país) o pasireotida, mifepristona. En España se ha emitido resolución de financiación de osilodrostat para el tratamiento del síndrome de Cushing endógeno en adultos, limitando su utilización al tratamiento tras fracaso o contraindicación a otras alternativas farmacológicas. No se hallaron documentos referentes al uso de osilodrostat en la indicación especificada por parte de otras entidades de evaluación de tecnologías sanitarias a nivel mundial como Instituto Nacional para la Excelencia en Salud y Atención (del inglés, National Institute for Health and Care Excellence) de Reino Unido y la Agencia Canadiense de Medicamentos y Tecnologías en Salud (del inglés, Canadian Agency for Drugs & Technologies in Health). CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de osilodrostat por parte de las agencias regulatorias relevadas para el tratamiento de personas adultas con síndrome de Cushing endógeno con enfermedad recurrente o persistente, se basa en ensayos clínicos frente a placebo con un bajo número de pacientes y corto seguimiento. El cuerpo de la evidencia mostraría que el uso de osilodrostat podría normalizar los valores de cortisol libre urinario y mejorar la calidad de vida de forma importante frente a placebo al mediano plazo. Sin embargo, estos estudios mostrarían una elevada incidencia de eventos adversos y de discontinuación del tratamiento por eventos adversos. La seguridad y eficacia frente a otras opciones terapéuticas disponibles no pudo ser establecida debido a que solo se hallaron estudios que comparan osilodrostat contra placebo. Las agencias regulatorias relevadas han autorizado recientemente la comercialización, junto con la designación de medicamento huérfano y vigilancia adicional. No se hallaron guías de práctica clínica actualizadas en Argentina que mencionen la tecnología en la indicación evaluada, mientras que una recomendación internacional la menciona como una opción entre otras alternativas. Agencias de Reino Unido y Canadá no hay evaluado su cobertura hasta el momento, y en España su cobertura se haya limitada al tratamiento del síndrome de Cushing endógeno que ha fracasado o tiene contraindicación a otras alternativas farmacológicas. No se hallaron evaluaciones económicas publicadas, aunque el costo del fármaco es muy elevado.

Growth hormone (GH) deficiency and GH replacement therapy in patients previously treated for Cushing's disease.

Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

Hyperadrenocorticism in a crab-eating fox (Cerdocyon thous) kept under human care / Hiperadrenocorticismo em cachorro-do-mato (Cerdocyon thous) mantido sob cuidados humanos

Hyperadrenocorticism is a relatively common endocrine disease affecting the adrenal glands of domestic dogs. However, there are few reports of this disease in wild canids. A crab-eating fox (Cerdocyon thous) kept under human care was diagnosed with the disease after detection of conformational abnormalities in the adrenal glands visualized by ultrasonography, a cortisol suppression test after low-dose dexamethasone, and the detection of proteinuria and bacteria in urinalysis. After the diagnosis, the patient was treated with trilostane with a satisfactory clinical response. This report aims to report the sonographic and laboratory findings of hyperadrenocorticism and its treatment in a specimen of the species.

O hiperadrenocorticismo é uma doença endócrina que acomete as glândulas adrenais relativamente comum em cães domésticos. Porém, em canídeos selvagens, poucos são os relatos descritos dessa enfermidade. Um exemplar de cachorro-do-mato (Cerdocyon thous), mantido sob cuidados humanos, foi diagnosticado com a doença após detecção de anormalidades conformacionais em glândulas adrenais visibilizadas via ultrassonografia, teste de supressão de cortisol após uso de baixa dose de dexametasona, além de detecção de proteinúria e bactérias em urinálise. Após o diagnóstico, instituiu-se tratamento medicamentoso a base de trilostano com resposta clínica satisfatória. Este relato objetiva reportar os achados ultrassonográficos e laboratoriais de hiperadrenocosticismo e seu tratamento em um exemplar da espécie.

Como manejar doenças metabólicas que interferem na eficiência reprodutiva em éguas / How to manage metabolic diseases that affects reproductive efficiency in mares / Cómo manejar las enfermedades metabólicas que interfieren con laeficiencia reproductiva en yeguas

A síndrome cólica é uma das causas mais importante no desenvolvimento de desequilíbrios hidroeletrolíticos e ácido base em equinos e, por conseguinte, geradora de alteração na homeostase do organismo. É imperativo que medidas terapêuticas sejam adotadas na rotina de atendimento clínico do paciente equino com cólica visando corrigir os desequilíbrios hidroeletrolíticos e ácido base. A primordial opção de tratamento desses desequilíbrios é a terapia hidroeletrolítica, ou hidratação, fundamentada na correção e manutenção do estado hídrico, eletrolítico e ácido base do paciente através da administração de soluções eletrolíticas com o intuito de reestabelecer sua homeostase. As Diretrizes Terapêuticas para o Restabelecimento do Equilíbrio Hidroeletrolítico e Ácido Base em Equinos com Síndrome Cólica nas Condições Brasileiras de Atendimento têm como objetivo congregar vários profissionais com visão ampla, embasamento teórico sólido e vasta experiência prática, de forma a oferecer um guia terapêutico prático e específico, que possa ser utilizado por Médicos Veterinários que trabalham com equídeos em todo o Brasil.

Colic syndrome is one of the most important causes in the development of hydroelectrolytic and acid base imbalances in horses and, therefore, causes alteration in the body's homeostasis. It is imperative the adoptions of therapeutic measures in the clinical care routine of equine colic patients in order to correct the hydroelectrolytic and acid-base imbalances. The primary treatment for these imbalances is hydroelectrolytic therapy, or fluid therapy, based on the correction and maintenance of the patient's water, electrolyte and acid base status through the administration of electrolyte solutions to reestablish their homeostasis. The therapeutic guidelines for restoring hydroelectrolytic and acid-base balance in horses with colic syndrome under Brazilian conditions of care has the aim of to bring together several professionals with broad vision, solid theoretical background and extensive practical experience, in order to offer a practical and specific therapeutic guide thatc an be used by Equine Veterinary Doctors throughout Brazil.

El síndrome cólico es una de las causas más importantes en el desarrollo de desequilibrios hidroelectrolíticos y ácido base en equinos y, portanto, causa alteraciones en la homeostasis del organismo. Es imperativo que se adopten medidas terapéuticas en la rutina de atendimiento clínico de los pacientes equinos con cólico para corregir los desequilibrios hidroelectrolíticos y de ácido base. La opción primordialde tratamiento para estos desequilibrios es la terapia hidroelectrolítica, o hidratación, basada en la corrección y el mantenimiento del estado hídrico, electrolítico y ácido base del paciente a través de la administración de soluciones electrolíticas para restablecer su homeostasis. Las Directrices Terapéuticas para el Restablecimiento del Equilibrio Hidroeléctrico y Ácido Base en Equinos con Síndrome Cólico en las condiciones de Atendimiento Brasileras tienen como objetivo reunir a vários profesionales con visión amplia, antecedentes teóricos sólidos y amplia experiencia práctica para proporcionar una guía terapéutica práctica y específica, que pueda ser utilizada por Médicos Veterinarios que trabajan con equinos en todo Brasil.

Eficacia y seguridad de pasireotide para el tratamiento de enfermedad de cushing persistente, recurrente o recidivante a resección de tumor hipofisario, en pacientes con contraindicación de adenectomía transesfenoidal / Efficacy and safety of pasireotide for the treatment of persistent, recurrent or recurrent Cushing's disease after pituitary tumor resection, in patients with contraindication to transsphenoidal adenectomy

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de pasireotide comparado con hipofisectomía total o radioterapia de hipófisis más adrenalectomía bilateral para el tratamiento de pacientes con enfermedad de Cushing persistente recurrente o recidivante a resección de tumor hipofisario y en quienes está contraindicada la adenectomía transesfenoidal. La enfermedad de Cushing es causada por un adenoma hipofisario benigno que secreta hormona adrenocorticotrópica (ACTH, por sus siglas en inglés). La enfermedad de Cushing está asociada a problemas sistémicos como: hipertensión, diabetes, obesidad, osteoporosis, enfermedad vascular y menor tiempo de vida. La enfermedad de Cushing es considerada una enfermedad rara cuya prevalencia se encuentra alrededor de 39.1 por cada 1 millón habitantes y su incidencia entre 1.2 y 2.4 casos nuevos por cada 1 millón de habitantes por año. El tratamiento curativo de la enfermedad de Cushing es la extracción del adenoma hipofisario mediante cirugía transesfenoidal (TSS, por sus siglas en inglés). La TSS está asociada a 2 % - 10 % de morbilidad y alrededor de 2 % de mortalidad. Las tasas de remisión inmediatas a la TSS varían entre 59 % y 98 % y las tasas de recurrencia entre 3 % y 46 %. En los casos de enfermedad persistente, recurrente o recidivante puede optarse por una segunda TSS. Sin embargo, si el adenoma no puede ser localizado en los exámenes de imágenes en lugar de la adenectomía selectiva mediante TSS puede recurrirse a: la hipofisectomía total o parcial, la radioterapia de la hipófisis, la adrenalectomía bilateral, el tratamiento farmacológico o una combinación de las anteriores opciones terapéuticas. Actualmente, en ESSALUD, los pacientes con enfermedad de Cushing persistente, recurrente o recidivante son tratados mediante hipofisectomía total o radioterapia de hipófisis más adrenalectomía bilateral. Estos tratamientos aumentan la tasa de remisión y permiten controlar los niveles de cortisol, pero también aumentan el riesgo de complicaciones y eventos adversos (pan-hipopituitarismo y síndrome de Nelson). Debido a esto, los especialistas consideran que pasireotide ayudaría a controlar el crecimiento tumoral y los niveles de cortisol, a la vez que se evitarían las complicaciones asociadas al tratamiento quirúrgico, en pacientes adultos con enfermedad de Cushing persistente, recurrente o recidivante a resección de tumor hipofisario y en quienes está contraindicado la adenectomía transesfenoidal (TSS). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de pasireotide en el tratamiento de pacientes con diagnóstico de Enfermedad de Cushing persistente recurrente o recidivante a resección de tumor hipofisario y tienen contraindicación de adenectomía transesfenoidal (TSS, por sus siglas en inglés). Se realizó tanto una búsqueda sistemática como una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica (GPC) y/o realizan evaluaciones de tecnologías sanitarias (ETS). RESULTADOS: En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se presenta la evidencia recabada sobre la eficacia y seguridad pasireotide en el tratamiento de pacientes con enfermedad de Cushing persistente, recurrente o recidivante a resección de tumor hipofisario y con contraindicación de TSS. Se identificó e incluyó la evidencia de una GPC, dos ETS y dos ECA. El equipo técnico del IETSI valoró los siguientes aspectos: i) La enfermedad de Cushing es causada por un adenoma hipofisario benigno que secreta ACTH; por lo tanto, el tratamiento curativo debe estar dirigido a la extracción del tumor y eliminación de las células metastásicas ii) La evidencia disponible es escasa e insuficiente para disipar la incertidumbre sobre la magnitud del efecto real de pasireotide sobre el control de la enfermedad de Cushing, iii) La ausencia de estudios que comparen pasireotide con otros esquemas de tratamiento impiden formular conclusiones sobre la superioridad de pasireotide y iv) Actualmente, existen otras alternativas disponibles en ESSALUD, tales como la hipofisectomía total y la adrenalectomía bilateral, que han mostrado ser eficaces y forman parte de las recomendaciones para el tratamiento de enfermedad de Cushing persistente, recurrente o recidivante. Por todo lo mencionado, el Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI, no aprueba el uso de pasireotide para el tratamiento de pacientes con enfermedad de Cushing persistente, recurrente o recidivante a resección de tumor hipofisario y con contraindicación de TSS.

Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome.

Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of follow-up developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up.

Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome

Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of follow-up developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up.

Tratamiento farmacológico del síndrome de Cushing / Drug treatment of Cushing's syndrome

El tratamiento farmacológico, aunque no constituye la primera línea de tratamiento en el hipercortisolimo endógeno, desempeña un importante rol en determinados pacientes con síndrome de Cushing. Diversos fármacos pueden ser utilizados, de forma aislada o combinada. El ketoconazol es una opción útil, económica, con determinada seguridad y eficacia a largo plazo. Se realiza una revisión de los medicamentos con mejores resultados, dosis, eficacia, efectos adversos y perspectivas, teniendo en cuenta ensayos clínicos en los que han sido empleados(AU)

Although the drug treatment is not a first line therapy for endogenous hypercortisolism, it plays a key role in certain patients suffering Cushing's syndrome. Several drugs may be used in isolation or in combination. Ketoconazol is a useful, economic, safe and efficacious option at long term. A review was made of drugs with best results, doses, efficacy, adverse effects and perspectives, taking into account clinical assays in which they have been used(AU)

[Laparoscopic adrenalectomy: the best surgical option]. / Suprarrenalectomia laparoscópica: la mejor opción de tratamiento quirúrgico.

BACKGROUND: Laparoscopic approach has become the gold standard for the surgical treatment of suprarenal gland. Nevertheless there is still controversy about the laparoscopic treatment of adrenal carcinoma. MATERIAL AND METHODS: From April 2005 to April 2012, 37 laparoscopic adrenalectomies were performed. We describe and analyze retrospectively: age, sex, side, indication for surgery, tumor size, length of hospital stay, complications and conversion rate. RESULTS: 37 Patients, 19 male and 18 female, aged 51.72 ± 14.42 years, were operated on between 2005 and 2012. Twenty-two left-sided lesions (59.45%) and 15 right-sided lesions (40.54%) were operated on. The indications for surgery were non-functioning adenoma larger than 4 cm or rapid growth and hormone-secreting tumours. The diagnosis was confirmed in all the cases with computed tomography and or magnetic resonance imaging and also metaiodobenzylguanidine scintigraphy if pheochromocytoma was suspected. In all the cases we realized a complete pre-operative hormonal study. CONCLUSIONS: Laparoscopic adrenalectomy is a safe procedure and gold standard technique for suprarenal surgery. Our experience is very satisfactory, with comparable results to the reference standard open approach.

Antecedentes: la vía de acceso laparoscópico es la técnica de elección en el tratamiento quirúrgico de la glándula suprarrenal, excepto del carcinoma suprarrenal. Objetivo: revisar nuestra experiencia en suprarrenalectomías laparoscópicas por vía lateral transperitoneal efectuadas entre los años 2005 y 2012. Material y método: estudio descriptivo y retrospectivo efectuado mediante la revisión de historias clínicas de 37 pacientes con diagnóstico, al alta, de tumor adrenal y a quienes se hizo adrenalectomía laparoscópica entre abril de 2005 y abril de 2012. Se consideraron los siguientes datos: edad, sexo, lateralidad, indicación quirúrgica, resultados anatomopatológicos, tamaño de la lesión, estancia hospitalaria, tasa de conversión y complicaciones perioperatorias. Resultados: durante el periodo de estudio se intervinieron 37pacientes (19 varones y 18 mujeres) con edad media de 51.72 ± 14.42 años. Se realizaron 22adrenalectomías izquierdas (59.45%) y 15 derechas (40.54%). Las indicaciones de suprarrenalectomía fueron: incidentaloma mayor de 4 cm o con crecimiento rápido y tumores productores de hormonas. El diagnóstico se confirmó con tomografía computada, resonancia magnética, o ambas, y con gammagrafía metaiodobencilguanidina en el caso de sospecha de feocromocitoma y estudio hormonal completo en todos los pacientes. Conclusiones: la suprarrenalectomía laparoscópica sigue siendo la técnica de elección en el tratamiento de pacientes con afectación de la glándula suprarrenal porque ha demostrado ser segura y eficaz, como quedó confirmado en nuestra serie, que tuvo resultados similares a los de la bibliografía.

Activation of PPARγ by restores mast cell numbers and reactivity in alloxan-diabetic rats by reducing the systemic glucocorticoid levels.

Mast cell function and survival have been shown to be down-regulated under diabetic conditions. This study investigates the role of the peroxisome proliferator-activated receptor (PPAR)-γ in reducing mast cell number and reactivity in diabetic rats. The effect of rosiglitazone on mast cell apoptosis was also evaluated. Diabetes was induced by intravenous injection of alloxan into fasted rats and PPARγ agonist rosiglitazone and/or specific antagonist 2-chloro-5-nitrobenzanilide (GW9662) were administered 3 day after diabetes induction, once daily for 18 consecutive days. Mast cell apoptosis and plasma corticosterone levels were evaluated by TUNEL and radioimmunoassay, respectively. Treatment with rosiglitazone restored mast cell numbers in the pleural cavity and mesenteric tissue of diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced reduction of histamine release by mast cells, as measured by fluorescence, following activation with the antigen in vitro. Increased apoptosis in mast cells from diabetic rats were inhibited by rosiglitazone. Moreover, we noted that the increase in plasma corticosterone levels in diabetic rats was inhibited by rosiglitazone. In addition, GW9662 blocked the ability of rosiglitazone to restore baseline numbers of mast cells and plasma corticosterone in diabetic rats. In conclusion, our findings showed that rosiglitazone restored the number and reactivity of mast cells in diabetic rats, accompanied with a suppression of apoptosis, in parallel with impairment of diabetes hypercorticolism, indicating that PPARγ has an important role in these phenomena.

Macrocorticotropinoma shrinkage and control of hypercortisolism under long-term cabergoline therapy: case report.

Cushing's disease is the result of chronic overproduction of ACTH by a pituitary tumor. Although the optimal treatment is surgical removal of the adenoma, medical treatment might be an option in selected cases. A 40-year old woman with Cushing's disease was treated with cabergoline, a neuromodulatory drug, for a corticotrophic macroadenoma. Treatment was initiated at a weekly dose of 0.5 mg and then, on the basis of the evolution of UFC values, adjusted until it reached 6 mg/week. With cabergoline treatment the patient was asymptomatic, the pituitary adenoma showed a significant shrinkage on MRI and urinary cortisol excretion remained within the normal range during 7 years. We show the effectiveness of cabergoline in maintaining long-term biochemical control of hypercortisolism with significant reduction and stabilization of macroadenoma volume in a patient with Cushing's disease.

Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing's disease: comparison with GH-releasing peptide-6 (GHRP-6).

BACKGROUND: In Cushing's disease (CD), adrenocorticotrophic hormone (ACTH)/cortisol responses to growth hormone secretagogues (GHS), such as ghrelin and GHRP-6, are exaggerated. The effect of clinical treatment of hypercortisolism with ketoconazole on ACTH secretion in CD is controversial. There are no studies evaluating ACTH/cortisol responses to GHS after prolonged ketoconazole use in these patients. OBJECTIVE: To compare ghrelin- and GHRP-6-induced ACTH/cortisol release before and after ketoconazole treatment in patients with CD. DESIGN/PATIENTS: Eight untreated patients with CD (BMI: 28.5 +/- 0.8 kg/m(2)) were evaluated before and after 3 and 6 months of ketoconazole treatment and compared with 11 controls (BMI: 25.0 +/- 0.8). RESULTS: After ketoconazole use, mean urinary free cortisol values decreased significantly (before: 613.6 +/- 95.2 nmol/24 h; 3rd month: 170.0 +/- 27.9; 6th month: 107.9 +/- 30.1). The same was observed with basal serum cortisol (before: 612.5 +/- 69.0 nmol/l; 3rd month: 463.5 +/- 44.1; 6th month: 402.8 +/- 44.1) and ghrelin- and GHRP-6-stimulated peak cortisol levels (before: 1183.6 +/- 137.9 and 1045.7 +/- 132.4; 3rd month: 637.3 +/- 69.0 and 767.0 +/- 91.0; 6th month: 689.8 +/- 74.5 and 571.1 +/- 71.7 respectively). An increase in basal ACTH (before: 11.2 +/- 1.6 pmol/l; 6th month: 19.4 +/- 2.7) and in ghrelin-stimulated peak ACTH values occurred after 6 months (before: 59.8 +/- 15.4; 6th month: 112.0 +/- 11.2). GHRP-6-induced ACTH release also increased (before: 60.7 +/- 17.2; 6th month: 78.5 +/- 12.1), although not significantly. CONCLUSIONS: The rise in basal ACTH levels during ketoconazole treatment in CD could be because of the activation of normal corticotrophs, which were earlier suppressed by hypercortisolism. The enhanced ACTH responses to ghrelin after ketoconazole in CD could also be due to activation of the hypothalamic-pituitary-adrenal axis and/or to an increase in GHS-receptors expression in the corticotroph adenoma, consequent to reductions in circulating glucocorticoids.

Diurnal ACTH and plasma cortisol variations in healthy dogs and in those with pituitary-dependent Cushing's syndrome before and after treatment with retinoic acid.

Daytime variations in ACTH and plasma cortisol were studied in healthy dogs and in dogs with pituitary-dependent hypercortisolism (PDH), before and after treatment with retinoic acid. In control dogs ACTH showed a higher concentration at 8.00 AM and between 2.00 and 6.00 PM, with the lowest concentration registered at 10.00 AM (p<0.05 vs. 8.00 AM and 2.00 PM and p<0.01 vs. 4.00 PM). Cortisol did not show significant differences. In dogs with PDH, ACTH was lower at 8.00 AM (ACTH: p<0.01 vs. 2.00 and 4.00 PM; and p<0.05 vs. 6.00 PM). The lowest cortisol concentration was registered at 8.00 AM and 8.00 PM and the highest at 4.00 PM (p<0.05 vs. 8.00 AM and p<0.01 vs. 8.00 PM). After treatment, the lowest ACTH concentration was registered at 10.00 AM (p<0.01 vs. 2.00 and 4.00 PM). To conclude, the adrenal is desensitized in PDH possibly showing negative in diagnostic tests.

Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome.

A 4 month-old girl presented with severe Cushing syndrome caused by McCune-Albright syndrome. After undergoing 19 months of pharmacologic suppression of cortisol production, she has been in clinical remission for more than 6 years. Adrenalectomy may be avoidable even in severe cases of Cushing syndrome associated with McCune-Albright syndrome.

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with Cushing's disease.

GH responses to ghrelin, GHRP-6, and GHRH in Cushing's disease (CD) are markedly blunted. There is no data about the effect of reduction of cortisol levels with steroidogenesis inhibitors, like ketoconazole, on GH secretion in CD. ACTH levels during ketoconazole treatment are controversial. The aims of this study were to compare the GH response to ghrelin, GHRP-6, and GHRH, and the ACTH and cortisol responses to ghrelin and GHRP-6 before and after one month of ketoconazole treatment in 6 untreated patients with CD. Before treatment peak GH (microg/L; mean +/- SEM) after ghrelin, GHRP-6, and GHRH administration was 10.0 +/- 4.5; 3.8 +/- 1.6, and 0.6 +/- 0.2, respectively. After one month of ketoconazole there was a significant decrease in urinary cortisol values (mean reduction: 75%), but GH responses did not change (7.0 +/- 2.0; 3.1 +/- 0.8; 0.9 +/- 0.2, respectively). After treatment, there was a significant reduction in cortisol (microg/dL) responses to ghrelin (before: 30.6 +/- 5.2; after: 24.2 +/- 5.1). No significant changes in ACTH (pg/mL) responses before (ghrelin: 210.9 +/- 69.9; GHRP-6: 199.8 +/- 88.8) and after treatment (ghrelin: 159.7 +/- 40.3; GHRP-6: 227 +/- 127.2) were observed. In conclusion, after short-term ketoconazole treatment there are no changes in GH or ACTH responses, despite a major decrease of cortisol levels. A longer period of treatment might be necessary for the recovery of pituitary function.

Effect of hypercortisolism control on high blood pressure in Cushing's syndrome.

UNLABELLED: Many hypertensive patients affected by endogenous Cushing's syndrome (CS) persist with high blood pressure (HBP) despite good control of cortisol excess. We assessed the effect of preoperative ketoconazole administration and of definitive treatment of CS on arterial hypertension and analysed the factors involved in the persistence of hypertension. We assessed retrospectively 71 patients with CS and HBP (60 women, 11 men; 50 pituitary, 21 adrenal) successfully treated by surgery and/or radiotherapy; 19 of them received ketoconazole (KNZ) before surgery. After treatment, patients were divided into those with persistent high blood pressure (PHBP) and those with normal blood pressure (NBP). As possible predictive factors for PHBP we analysed age, duration and family history of HBP, pre-treatment 24 hour urinary free cortisol (24h-UFC) and body mass index (BMI). HBP normalized in 53 out of 71 patients (74.6%), regardless of the origin of Cushing's syndrome. PHBP patients were older (p=0.003), had longer duration (p=0.007) and higher systolic blood pressure before treatment (p=0.046) than NBP patients. Thirteen out of 19 patients (68.4%) treated with ketoconazole, normalized their hypertension and remained normotensive after successful surgery. Five patients became normotensive only after surgery. IN CONCLUSION: a) blood pressure levels normalized in most patients after remission of CS; b) ketoconazole was effective for the Control of HBP and seems to be a good indicator of post-surgical outcome, and c) higher age at presentation, longer duration of hypertension and higher systolic blood pressure figures before treatment negatively influence normalization of blood pressure after resolution of Cushing's syndrome.

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.

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

GH responses to ghrelin, GHRP-6, and GHRH in Cushing’s disease (CD) are markedly blunted. There is no data about the effect of reduction of cortisol levels with steroidogenesis inhibitors, like ketoconazole, on GH secretion in CD. ACTH levels during ketoconazole treatment are controversial. The aims of this study were to compare the GH response to ghrelin, GHRP-6, and GHRH, and the ACTH and cortisol responses to ghrelin and GHRP-6 before and after one month of ketoconazole treatment in 6 untreated patients with CD. Before treatment peak GH (mg/L; mean ± SEM) after ghrelin, GHRP-6, and GHRH administration was 10.0 ± 4.5; 3.8 ± 1.6, and 0.6 ± 0.2, respectively. After one month of ketoconazole there was a significant decrease in urinary cortisol values (mean reduction: 75 percent), but GH responses did not change (7.0 ± 2.0; 3.1 ± 0.8; 0.9 ± 0.2, respectively). After treatment, there was a significant reduction in cortisol (mg/dL) responses to ghrelin (before: 30.6 ± 5.2; after: 24.2 ± 5.1). No significant changes in ACTH (pg/mL) responses before (ghrelin: 210.9 ± 69.9; GHRP-6: 199.8 ± 88.8) and after treatment (ghrelin: 159.7 ± 40.3; GHRP-6: 227 ± 127.2) were observed. In conclusion, after short-term ketoconazole treatment there are no changes in GH or ACTH responses, despite a major decrease of cortisol levels. A longer period of treatment might be necessary for the recovery of pituitary function.

Na doença de Cushing (DC), as respostas do GH à ghrelina, ao GHRP-6 e ao GHRH estão diminuídas. Não existem dados sobre o efeito da redução dos níveis de cortisol, após cetoconazol, na secreção de GH na DC. Nessa situação, os níveis de ACTH são variáveis. Os objetivos do estudo são comparar as respostas do GH à administração de ghrelina, GHRP-6 e GHRH, e de ACTH e cortisol à ghrelina e ao GHRP-6 antes e após um mês de tratamento com cetoconazol em 6 pacientes com DC não tratados. Antes do tratamento, o pico de GH (mg/L; média ± EPM) após a administração de ghrelina, GHRP-6 e GHRH foi de 10,0 ± 4,5; 3,8 ± 1,6 e 0,6 ± 0,2, respectivamente. Após um mês de cetoconazol, ocorreu diminuição significante do cortisol urinário (redução média: 75 por cento), mas as respostas de GH permaneceram inalteradas (7,0 ± 2,0; 3,1 ± 0,8; 0,9 ± 0,2, respectivamente). Após o tratamento, houve redução da resposta de cortisol (mg/dL) à ghrelina (antes: 30,6 ± 5,2; após: 24,2 ± 5,1), mas não ocorreram mudanças nas respostas de ACTH (pg/mL) (ghrelina antes: 210,9 ± 69,9; após: 159,7 ± 40,3; GHRP-6 antes: 199,8 ± 88,8; após: 227 ± 127,2). Assim, o tratamento a curto prazo com cetoconazol não modificou as respostas de GH ou ACTH, apesar da redução do cortisol. Para a recuperação da função hipofisária deve ser necessário um período de tratamento maior.