RESUMO
First-line treatment for Cushing´s disease is transsphenoidal surgery. But in cases of persistent or recurrent disease after surgery, contraindications to surgery, severe hypercortisolism control before surgery, or for patients waiting for radiotherapy effects, medical therapy may be indicated. Pituitary-directed agents include cabergoline and pasireotide. Both drugs present similar potential for biochemical control and pasireotide has additionally been proved to reduce tumor volume. Moreover, pasireotide was evaluated in high quality studies. In respect to safety, both drugs are well tolerated and safe, but special attention should be given for cardiac valve disease and psychiatric disorder for cabergoline, and hyperglycemia for pasireotide.
Assuntos
Cabergolina , Hipersecreção Hipofisária de ACTH , Somatostatina , Humanos , Cabergolina/uso terapêutico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/patologia , Hipófise/patologia , Somatostatina/uso terapêuticoRESUMO
ABSTRACT Objective: To present two clinical cases of pediatric Cushing disease caused by adrenocorticotropic hormone secreting pituitary adenomas, which were diagnosed by magnetic resonance imaging using 3 Tesla technology. Case description: Two cases of Cushing disease in 9-year-old children are reported. Both children presented pituitary adenomas that were smaller than 5 mm at their largest diameter, and which were not seen by standard 1.5 Tesla resonance. One of the patients was submitted to bilateral and simultaneous catheterization of the inferior petrosal sinus, but the result was undetermined. In both cases, the pituitary adenoma was detected by 3 Tesla magnetic resonance imaging. Both patients underwent transsphenoidal surgery and were cured. Comments: Cushing disease presents high morbidity. Therefore, early diagnosis and prompt treatment are essential. It is usually caused by adenomas that are smaller than 5 mm in diameter. Surgery is the first line of treatment, and effective methods of locating the adenoma are necessary for greater therapeutic success. This report suggests that the 3 Tesla magnetic resonance imaging is more sensitive, and thus able to detect pituitary microadenomas (largest diameter <10 mm). This exam may be indicated as a low-morbidity diagnostic tool for finding pituitary microadenomas in Cushing disease that are not visualized by 1.5 Tesla magnetic resonance imaging.
RESUMO Objetivo: Apresentar dois casos clínicos de Doença de Cushing infantil decorrentes de adenoma hipofisário secretor de hormônio adrenocorticotrófico, cujo diagnóstico foi realizado por meio da ressonância magnética pela tecnologia 3 Tesla. Descrição do caso: São relatados dois casos de Doença de Cushing em crianças aos nove anos. Ambas apresentavam adenomas menores que 5 mm em seu maior diâmetro que não foram visualizados por meio de ressonância magnética de sela turca utilizando tecnologia 1,5 Tesla. Uma das pacientes foi submetida ao cateterismo bilateral e simultâneo do seio petroso inferior, porém com resultado indeterminado. Nas duas, o adenoma hipofisário foi visualizado mediante ressonância magnética utilizando tecnologia 3 Tesla. Ambas foram submetidas à cirurgia transesfenoidal e evoluíram para cura. Comentários: A Doença de Cushing apresenta alta morbidade, necessitando de diagnóstico e tratamento precoces, e geralmente é causada por adenomas com diâmetro inferior a 5 mm. O tratamento é cirúrgico, sendo preciso utilizar métodos eficazes de localização do adenoma para maior sucesso terapêutico. Esses relatos sugerem que a ressonância magnética 3 Tesla tem mais sensibilidade na detecção de microadenomas hipofisários (maior diâmetro <10 mm), podendo-se indicar esse exame como uma ferramenta diagnóstica de baixa morbidade na localização de microadenomas hipofisários na Doença de Cushing não visualizados pela ressonância magnética 1,5 Tesla.
Assuntos
Humanos , Feminino , Criança , Sela Túrcica/diagnóstico por imagem , Imageamento por Ressonância Magnética , Hipersecreção Hipofisária de ACTH/diagnóstico por imagem , Sela Túrcica/patologia , Valor Preditivo dos Testes , Hipersecreção Hipofisária de ACTH/patologiaRESUMO
OBJECTIVE: To present two clinical cases of pediatric Cushing disease caused by adrenocorticotropic hormone secreting pituitary adenomas, which were diagnosed by magnetic resonance imaging using 3 Tesla technology. CASE DESCRIPTION: Two cases of Cushing disease in 9-year-old children are reported. Both children presented pituitary adenomas that were smaller than 5 mm at their largest diameter, and which were not seen by standard 1.5 Tesla resonance. One of the patients was submitted to bilateral and simultaneous catheterization of the inferior petrosal sinus, but the result was undetermined. In both cases, the pituitary adenoma was detected by 3 Tesla magnetic resonance imaging. Both patients underwent transsphenoidal surgery and were cured. COMMENTS: Cushing disease presents high morbidity. Therefore, early diagnosis and prompt treatment are essential. It is usually caused by adenomas that are smaller than 5 mm in diameter. Surgery is the first line of treatment, and effective methods of locating the adenoma are necessary for greater therapeutic success. This report suggests that the 3 Tesla magnetic resonance imaging is more sensitive, and thus able to detect pituitary microadenomas (largest diameter <10 mm). This exam may be indicated as a low-morbidity diagnostic tool for finding pituitary microadenomas in Cushing disease that are not visualized by 1.5 Tesla magnetic resonance imaging.
Assuntos
Imageamento por Ressonância Magnética , Hipersecreção Hipofisária de ACTH/diagnóstico por imagem , Sela Túrcica/diagnóstico por imagem , Criança , Feminino , Humanos , Hipersecreção Hipofisária de ACTH/patologia , Valor Preditivo dos Testes , Sela Túrcica/patologiaRESUMO
INTRODUCTION: Pituitary adenomas (PA) occur mainly as sporadic disease, but familial syndromes are found in approximately 5% of cases. Identification of these syndromes is important in order to diagnose individuals at risk at an earlier stage. AIMS: To evaluate the frequency of familial PA in a reference outpatient clinic devoted to PA treatment and to identify family members suspected to have pituitary disease. METHODS: Patients with PA were interviewed with respect to the presence of family members with diagnosis of PA or with signs or symptoms suggestive of them. The family members who had a clinical picture suggestive of pituitary disease were further evaluated in an attempt to identify new PA cases. In families with familial disease, the AIP gene was sequenced. RESULTS: 262 patients were evaluated and familial syndrome was found in 13 (5%). Ten (3.8%) patients had familial isolated PA (FIPA) and three (1.2%) had multiple endocrine neoplasia type 1. After evaluation of family members' symptomatology, 110 were considered suspected of having pituitary disease, but only 24 participated in the study. Of these 24, 1 was diagnosed with a corticotropinoma. AIP mutations were found in 20% of FIPA families. CONCLUSION: We found a frequency of familial PA similar to that previously described, as well as a similar frequency of AIP mutations among FIPA families. An active search of the affected family members was able to identify one case of Cushing´s disease. Patients should be aware of pituitary disease's clinical picture to identify possibly affected family members.
Assuntos
Predisposição Genética para Doença , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Hipersecreção Hipofisária de ACTH/epidemiologia , Neoplasias Hipofisárias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Estudos Transversais , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/genética , Hipersecreção Hipofisária de ACTH/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Prognóstico , Padrões de Referência , Síndrome , Adulto JovemRESUMO
OBJECTIVE: Reported rates of response to medical therapies used in Cushing's disease (CD) vary widely. The aim of this review is to analyse systematically the efficacy of medical therapies for CD and to assess the strength of the supporting evidence. METHODS: Systematic PubMed searches identified studies of medical treatment in CD. The GRADE criteria were imposed to assess the strength of evidence supporting each medication. RESULTS: Fifteen studies were included. Ten studies specifically reported response rates for patients with CD. Pasireotide was the only treatment to be assessed in a randomized trial and was supported by a 'moderate' level of evidence. Response rates with pasireotide from three prospective studies were 17-29%. The remaining medications were supported by a 'low' or 'very low' level of evidence. The highest response rates were reported in small retrospective studies of metyrapone (75%, one study) and mitotane (72%, one study). Response rates were 25-50% for cabergoline (four studies) and 45% for ketoconazole (one study). Among studies that included patients with other forms of Cushing's syndrome, response rates were 53-88% for ketoconazole (three studies), 70% for mitotane (one study), 57% for metyrapone (one study) and 38-60% for mifepristone. Again, all of these medications are supported by a 'low' level of evidence. CONCLUSIONS: There is a paucity of high-quality studies of medical therapy in CD, with only one medication achieving a 'moderate' level of evidence. Caution should be employed when comparing efficacy rates owing to the variability in study design and quality.
Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Cabergolina , Ergolinas/uso terapêutico , Feminino , Humanos , Cetoconazol/uso terapêutico , Masculino , Metirapona/uso terapêutico , Mitotano/uso terapêutico , Hipersecreção Hipofisária de ACTH/patologia , Somatostatina/análogos & derivados , Somatostatina/uso terapêuticoRESUMO
SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing's disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing's disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G(i) α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing's disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing's disease.
Assuntos
Hormônio Adrenocorticotrópico/biossíntese , Corticotrofos/efeitos dos fármacos , Corticotrofos/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Somatostatina/análogos & derivados , Hormônio Adrenocorticotrópico/sangue , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Linhagem Celular Tumoral , Colesterol/sangue , Creatinina/urina , Cães , Feminino , Hidrocortisona/urina , Testes de Função Hepática , Imageamento por Ressonância Magnética , Masculino , Hipersecreção Hipofisária de ACTH/patologia , Somatostatina/farmacologia , Triglicerídeos/sangue , alfa-MSH/sangueRESUMO
UNLABELLED: In the early postoperative period of Cushing's disease patients, desmopressin may stimulate ACTH secretion in the remnant corticotrophic tumour, but not in nontumour suppressed cells. OBJECTIVE: The aim of this study is to evaluate the serum cortisol responses to desmopressin after pituitary surgery, establishing an optimal cut-off for absolute increment (Delta) of serum cortisol (F) suitable to predict recurrence risk. DESIGN: Retrospective case record study. PATIENTS: Fifty-seven Cushing's disease patients submitted to pituitary surgery and desmopressin stimulation in the early postoperative with a long-term follow-up (20-161 months) were studied. METHODS AND MEASUREMENTS: Serum cortisol levels after desmopressin test (10 microg i.v.) 15-30 days after adenomectomy were used to determine DeltaF (absolute increment of F: F peak - F baseline). Sensitivity and specificity of DeltaF were calculated and a ROC curve was performed to establish an optimal cut-off for DeltaF to predict recurrence risk. RESULTS: Fifteen patients had immediate postoperative failure (basal F > 165 nmol/l; 6 microg/dl) and one patient was lost during the follow-up. Forty-one patients achieved initial remission and were followed-up. Five of 11 patients who recurred had DeltaF > 193 nmol/l (7 microg/dl), but none of 30 patients who remained in prolonged remission showed DeltaF > 193 nmol/l after postoperative desmopressin stimulation. CONCLUSIONS: Persistence of cortisol response (DeltaF > 193 nmol/l) to desmopressin in the early postoperative period can help to identify Cushing's disease patients with initial remission who present risk for later recurrence.
Assuntos
Desamino Arginina Vasopressina/farmacologia , Hidrocortisona/sangue , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/cirurgia , Complicações Pós-Operatórias/diagnóstico , Adolescente , Adulto , Idoso , Antidiuréticos/administração & dosagem , Antidiuréticos/farmacologia , Criança , Desamino Arginina Vasopressina/administração & dosagem , Técnicas de Diagnóstico Endócrino , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/sangue , Hipersecreção Hipofisária de ACTH/patologia , Complicações Pós-Operatórias/sangue , Período Pós-Operatório , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
We report a female patient who developed severe Cushing's disease during the fifth month of life due to a basophilic pituitary adenoma Histological findings showed a basophilic microadenoma of the pituitary gland, leading to the diagnosis of Cushing's disease. The infant died because of untreatable septic shock. The importance of the present report resides in the age of the child at diagnosis, and that it was the necropsy finding of microadenoma which clarified the cause of the Cushing's syndrome, since it was not diagnosed during life. Cushing's disease is most often diagnosed in children older than 7 years, and our patient was only 5 months old when we detected the pituitary adenoma, the earliest case diagnosed so far. Cushing's syndrome in pediatric patients has been rarely reported and most cases are due to functioning adrenal tumors, usually a malignant carcinoma but occasionally a benign adenoma. The present case shows that the pituitary of these patients should be investigated with important implications in terms of therapeutic approaches, such as pituitary radiotherapy, which can cure the patient when treatment is started very soon.
Assuntos
Adenoma Basófilo/complicações , Hipersecreção Hipofisária de ACTH/etiologia , Neoplasias Hipofisárias/complicações , Adenoma Basófilo/patologia , Evolução Fatal , Feminino , Histocitoquímica , Humanos , Lactente , Hipersecreção Hipofisária de ACTH/patologia , Neoplasias Hipofisárias/patologiaRESUMO
Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.