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1.
Eur J Endocrinol ; 183(1): G1-G7, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32380475

RESUMO

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing's syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2-3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.


Assuntos
Infecções por Coronavirus/prevenção & controle , Síndrome de Cushing/terapia , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Controle de Infecções/métodos , Procedimentos Neurocirúrgicos/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Telemedicina , Inibidores de 14-alfa Desmetilase/uso terapêutico , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma Hipofisário Secretor de ACT/terapia , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/terapia , Infecções por Coronavirus/transmissão , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiologia , Síndrome de Cushing/imunologia , Gerenciamento Clínico , Humanos , Hidrocortisona/sangue , Hospedeiro Imunocomprometido , Cetoconazol/uso terapêutico , Metirapona/uso terapêutico , Educação de Pacientes como Assunto , Pneumonia Viral/transmissão , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença , Fatores de Tempo
2.
Eur J Endocrinol ; 182(4): R29-R58, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31999619

RESUMO

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.


Assuntos
Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/terapia , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Síndrome de ACTH Ectópico/complicações , Síndrome de Cushing/etiologia , Endocrinologia/métodos , Humanos , Tumores Neuroendócrinos/complicações , Resultado do Tratamento
3.
Intern Med ; 59(1): 107-112, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31511478

RESUMO

Paraneoplastic syndromes are frequently observed in lung cancer, especially in small cell lung cancer (SCLC). Although there have been many reports on paraneoplastic syndromes, few reports have been published on SCLC that simultaneously produces antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH), and these reports described the prognosis of such cases as extremely poor. We herein present a rare case of a Japanese woman with SCLC accompanied by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Cushing's syndrome. The survival of the patient was prolonged by the long-term administration of amrubicin.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Vasopressinas/metabolismo , Idoso , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Feminino , Humanos , Síndrome de Secreção Inadequada de HAD/etiologia , Síndrome de Secreção Inadequada de HAD/metabolismo , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/metabolismo , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/metabolismo , Prognóstico , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/metabolismo , Taxa de Sobrevida
4.
Medicina (Kaunas) ; 55(12)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783507

RESUMO

Cushing's syndrome (CS) is a set of clinical symptoms which occur as a result of hypercortisolemia. Endogenous ACTH-dependent CS related to an ectopic ACTH-secreting tumour constitutes 12%-17% of CS cases and is one of the most common causes of paraneoplastic syndromes. This study presents a case of a 31 year-old man with diabetes, hypertension, rosacea, purple stretch marks and hypokalemia. Findings of diagnostic procedures include high concentrations of cortisol and ACTH, pituitary microadenoma and a tumour in the anterior mediastinum. Dynamic hormone tests determined the source of excess hormone secretion and ectopic ACTH-dependent CS was diagnosed. Due to increasing symptoms of superior vena cava syndrome, an emergency resection of almost the whole tumour was performed, with only a small part of the upper pole left because of the proximity of large vessels and a risk of damaging them. On the basis of histopathological tests, an atypical carcinoid tumour of the thymus was identified. Immediately after the surgical procedure, there was a significant reduction of clinical and laboratory traits of hypercortisolemia, yet, during the 46 weeks of postoperative observation, despite chemotherapy, the progression of residual masses of the tumour occurred with metastases and increased hormone indices. The presented case shows and discusses the differentiation of ACTH-dependent hypercortisolemia and its causes, difficulties in surgical therapy and chemotherapy, as well as prognosis for atypical carcinoid of the thymus, which is a rare disease.


Assuntos
Hiperfunção Adrenocortical/etiologia , Tumor Carcinoide/complicações , Síndrome de Cushing/etiologia , Neoplasias Hipofisárias/complicações , Neoplasias do Timo/complicações , Adulto , Humanos , Masculino
6.
BMJ Case Rep ; 12(11)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753824

RESUMO

In this case report, we highlight four different cases of ectopic adrenocorticotropic hormone (ACTH) secretion with different pitfalls in the diagnostic workup. Ectopic ACTH secretion (EAS) is an uncommon cause of Cushing's syndrome that accompanies a variety of tumours. It is associated with significant morbidity and mortality. This underlines the importance of early and adequate diagnosis. We will review the causes of EAS and their presentation to increase awareness of this rare and progressive disease.


Assuntos
Síndrome de ACTH Ectópico/diagnóstico , Síndrome de Cushing/etiologia , Síndrome de ACTH Ectópico/complicações , Síndrome de ACTH Ectópico/tratamento farmacológico , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
Monaldi Arch Chest Dis ; 89(3)2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31631643

RESUMO

Nocardia spp. is a genus of Gram-positive bacteria which can cause cutaneous, pleuropulmonary, or disseminated disease. The latter two forms are encountered in immunocompromised patients, with prolonged usage of corticosteroids being a well-recognized risk factor. However, endogenous Cushing's syndrome is less frequently associated with nocardiosis. We report on a 40-year-old woman who presented for further workup of abnormal findings in the chest computed tomography (three lung nodules, one of which being cavitary). She underwent trans-thoracic fine-needle lung aspiration of the cavitary nodule, which led to the diagnosis of lung nocardiosis. Moreover, the identification of cushingoid features from the history and clinical examination initiated further investigation with hormonal laboratory assessment and bilateral inferior petrosal sinus sampling which established the diagnosis of pituitary adrenocorticotropic hormone (ACTH) hypersecretion (Cushing's disease).  We conclude that pulmonary nocardiosis can be an opportunistic infection as well as a presenting manifestation of Cushing's disease.


Assuntos
Adenoma Hipofisário Secretor de ACT/complicações , Síndrome de Cushing/etiologia , Nocardiose/diagnóstico por imagem , Nocardiose/etiologia , Adenoma Hipofisário Secretor de ACT/sangue , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma Hipofisário Secretor de ACT/cirurgia , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Síndrome de Cushing/sangue , Síndrome de Cushing/diagnóstico , Feminino , Humanos , Nocardiose/tratamento farmacológico , Nocardiose/microbiologia , Infecções Oportunistas/epidemiologia , Tomografia Computadorizada por Raios X/métodos , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
8.
Clin Nucl Med ; 44(11): 881-882, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31524683

RESUMO

Approximately 5% to 15% cases of endogenous Cushing syndrome are due to ectopic adrenocorticotrophic hormone (ACTH)-producing neuroendocrine tumors, which are commonly located in bronchopulmonary system, thymus, and gastrointestinal tract including pancreas. Although carcinoid tumors of the appendix are revealed in 0.3% of patients undergoing routine appendectomy, ACTH-secreting appendicular carcinoid is a rare entity. We present a case of a 22-year-old woman with ectopic ACTH-dependent Cushing syndrome due to an appendicular carcinoid, which was localized with the help of Ga-DOTATATE PET/CT scan.


Assuntos
Neoplasias do Apêndice/complicações , Síndrome de Cushing/diagnóstico por imagem , Síndrome de Cushing/etiologia , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Síndrome de Cushing/patologia , Feminino , Humanos , Adulto Jovem
10.
J Endocrinol Invest ; 42(12): 1435-1442, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456173

RESUMO

PURPOSE: Subclinical hypercortisolism (SCH) leads to metabolic derangements and increased cardiovascular risk. Cortisol autonomy is defined by the overnight 1 mg dexamethasone suppression test (DST). Saliva cortisol is an easier, stress-free, and cost-effective alternative to serum cortisol. We compared 23 h and post-1 mg DST saliva with serum cortisol to identify SCH in adrenal incidentalomas (AI). METHODS: We analyzed 359 DST obtained retrospectively from 226 AI subjects (173F/53 M; 19-83 years) for saliva and serum cortisol. We used three post-DST serum cortisol cutoffs to uncover SCH: 1.8, 2.5, and 5.0 µg/dL. We determined post-DST and 23 h saliva cortisol cutoffs by ROC curve analysis and calculated their sensitivities (S) and specificities (E). RESULTS: The sensitive 1.8 µg/dL cutoff defined 137 SCH and 180 non-functioning adenomas (NFA): post-DST and 23 h saliva cortisol S/E were: 75.2%/74.4% and 59.5%/65.9%, respectively. Using the specific 5.0 µg/dL cortisol cutoff (22 SCH/295 NFA), post-DST and 23 h saliva cortisol S/E were 86.4%/83.4% and 66.7%/80.4%, respectively. Using the intermediate 2.5 µg/dL cutoff (89 SCH/228 NFA), post-DST and 23 h saliva cortisol S/E were 80.9%/68.9% and 65.5%/62.8%, respectively. CONCLUSION: Saliva cortisol showed acceptable performance only with the 5.0 µg/dL cortisol cutoff, as in overt Cushing's syndrome. Lower cutoffs (1.8 and 2.5 µg/dL) that identify larger samples of patients with poor metabolic outcomes are less accurate for screening. These results may be attributed to pre-analytical factors and inherent patient conditions. Thus, saliva cortisol cannot replace serum cortisol to identify SCH among patients with AI for screening DST.


Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Síndrome de Cushing/diagnóstico , Hidrocortisona/análise , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Feminino , Humanos , Hidrocortisona/sangue , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Testes de Função Adreno-Hipofisária , Estudos Retrospectivos , Saliva/química , Sensibilidade e Especificidade , Adulto Jovem
12.
J Pak Med Assoc ; 69(6): 899-901, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31201401

RESUMO

Treatment of Cushing syndrome depends on diagnosis of etiology responsible for hypercortisolism in the body, which sometimes presents with a challenge. Inferior petrosal sinus sampling for ACTH levels, followed by peripheral venous sampling is a proven tool to be a gold standard for differentiating between peripheral and central cause of ACTH dependent Cushing syndrome. This case report is of an elderly female who presented as an outpatient in the endocrinology clinic of Aga Khan university hospital on 22/6/2017 with clinical features of hypercortisolism. After workup she was found to have cushing syndrome secondary to ACTH secreting bronchial carcinoid tumour.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Neoplasias Brônquicas/diagnóstico por imagem , Tumor Carcinoide/diagnóstico por imagem , Síndrome de Cushing/diagnóstico , Idoso , Neoplasias Brônquicas/complicações , Neoplasias Brônquicas/metabolismo , Tumor Carcinoide/complicações , Tumor Carcinoide/metabolismo , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Feminino , Humanos , Hidrocortisona/urina , Tomografia Computadorizada por Raios X
13.
BMC Endocr Disord ; 19(1): 63, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208392

RESUMO

BACKGROUND: Co-existing Cushing's syndrome and primary aldosteronism caused by bilateral adrenocortical adenomas, secreting cortisol and aldosterone, respectively, have rarely been reported. Precise diagnosis and management of this disorder constitute a challenge to clinicians due to its atypical clinical manifestations and laboratory findings. CASE PRESENTATION: We here report a Chinese male patient with co-existing Cushing's syndrome and primary aldosteronism caused by bilateral adrenocortical adenomas, who complained of intermittent muscle weakness for over 3 years. Computed tomography scans revealed bilateral adrenal masses. Undetectable ACTH and unsuppressed cortisol levels by dexamethasone suggested ACTH-independent Cushing's syndrome. Elevated aldosterone to renin ratio and unsuppressed plasma aldosterone concentration after saline infusion test suggested primary aldosteronism. Adrenal venous sampling adjusted by plasma epinephrine revealed hypersecretion of cortisol from the left adrenal mass and of aldosterone from the right one. A sequential bilateral laparoscopic adrenalectomy was performed. The cortisol level was normalized after partial left adrenalectomy and the aldosterone level was normalized after subsequent partial right adrenalectomy. Histopathological evaluation of the resected surgical specimens, including immunohistochemical staining for steroidogenic enzymes, revealed a left cortisol-producing adenoma and a right aldosterone-producing adenoma. The patient's symptoms and laboratory findings resolved after sequential adrenalectomy without any pharmacological treatment. CONCLUSIONS: Adrenal venous sampling is essential in diagnosing bilateral functional adrenocortical adenomas prior to surgery. Proper interpretation of the laboratory findings is particularly important in these patients. Immunohistochemistry may be a valuable tool to identify aldosterone/cortisol-producing lesions and to validate the clinical diagnosis.


Assuntos
Adenoma Adrenocortical/complicações , Síndrome de Cushing/etiologia , Hiperaldosteronismo/etiologia , Adrenalectomia , Adulto , Síndrome de Cushing/patologia , Síndrome de Cushing/cirurgia , Humanos , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Masculino , Prognóstico
14.
Pituitary ; 22(5): 561-568, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31041631

RESUMO

Cushing's syndrome (CS) secondary to corticotropin releasing hormone (CRH) producing tumors is rare. In this paper we present an Iranian patient who was admitted to our hospital with classic signs and symptoms of CS. Laboratory evaluation revealed high serum and urine cortisol which could not be suppressed with dexamethasone. Abdominal CT scan revealed a mass in abdominal cavity. A percutaneous needle biopsy was performed and histopathologic evaluation revealed that the mass was a neuroendocrine tumor. A multi-disciplinary approach including resection of the mass, bilateral adrenalectomy somatostatin analogue and chemotherapy was applied for management of the disease. Extensive review of English literature focusing on the topic from 1971 to 2018 revealed that there have been only 75 similar cases. Clinical, laboratory, imaging, histopathologic characteristics and managements of these patients will also be discussed in this paper.


Assuntos
Hormônio Liberador da Corticotropina/sangue , Hormônio Liberador da Corticotropina/urina , Síndrome de Cushing/etiologia , Adrenalectomia , Síndrome de Cushing/sangue , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/cirurgia , Dexametasona/uso terapêutico , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico
15.
Open Vet J ; 9(1): 27-32, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31086762

RESUMO

The epidemiological characteristics of spontaneous hypercortisolism (HC) were derived from 21,281 client-owned dogs selected from four private veterinary clinics and one university reference center for endocrinology. The odds ratio (OR) method was employed to investigate the risk of developing HC related to breed, gender, and sexual status. The estimated prevalence of HC in the four private clinics was 0.20% [95% confidence interval (CI), 0.13-0.27] and was significantly different compared to the university reference center (1.46%; 95% CI, 1.12-1.80). Sex, breed, and age resulted in risk factors for HC. Mean (± SD) age for dogs with HC was 9.8 (± 2.5) yr. Females had higher risk for HC compared to males (OR 1.85; 95% CI, 1.24-2.75); all neutered dogs (both males and females) had higher risk than intact dogs (OR 2.54; 95% CI, 1.72-3.73); and neutered females had higher risk compared to intact females (OR 2.61; 95% CI, 1.54-4.42). Using the mixed breed dogs as a control population (OR = 1), the risk of developing HC was significantly higher in the Standard Schnauzer (OR 58.1; p < 0.0001) and Fox Terrier (OR 20.33; p < 0.0001). With regard to HC, this study identified an overall prevalence of 0.20%. The data support the existence of sex predisposition, with the highest risk for neutered females.


Assuntos
Síndrome de Cushing/veterinária , Doenças do Cão/epidemiologia , Animais , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/etiologia , Doenças do Cão/etiologia , Cães , Feminino , Itália/epidemiologia , Masculino , Prevalência
16.
Eur J Endocrinol ; 181(1): K1-K9, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31048558

RESUMO

Context: Cabergoline has been shown to have some effect in the treatment of moderate Cushing's disease, but its effectiveness in Cushing's syndrome of ectopic or occult origin remains to be investigated. Case series: In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing's syndrome of ectopic or occult origin. Cabergoline's effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases. Review of the literature: In the literature, we found only 11 cases of ectopic or occult Cushing's syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded. Conclusions: Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing's syndrome.


Assuntos
Cabergolina/uso terapêutico , Síndrome de Cushing/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Síndrome de ACTH Ectópico/complicações , Síndrome de ACTH Ectópico/diagnóstico , Adulto , Idoso , Tumor Carcinoide/complicações , Tumor Carcinoide/diagnóstico por imagem , Tumor Carcinoide/patologia , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Feminino , Humanos , Hidrocortisona/metabolismo , Cetoconazol/uso terapêutico , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Neoplasias Intraductais Pancreáticas/complicações , Neoplasias Intraductais Pancreáticas/diagnóstico por imagem , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Retais/complicações , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/patologia , Inibidores da Síntese de Esteroides/uso terapêutico , Neoplasias do Timo/complicações , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/patologia , Resultado do Tratamento
17.
World Neurosurg ; 126: 331-335, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30898745

RESUMO

BACKGROUND: When distinct pituitary hypersecretory manifestations coexist, the differential diagnosis includes plurihormonal or double pituitary adenomas. We describe a rare case of hypercortisolemia and hyperprolactinemia caused by 2 noncontiguous adenomas that required 2 surgeries. CASE DESCRIPTION: A 37-year-old woman presented with 6 months of weight gain, amenorrhea, joint pain, leg swelling, and skin changes. She received prednisone for possible systemic lupus erythematosus. Four months later, she presented with headaches and new-onset diabetes with glucose >1000 mg/dL. Work-up revealed a right-sided 1.1-cm pituitary adenoma and prolactin level of 152.9 ng/mL (normal: 3-27 ng/mL). She was advised to stop the prednisone, start bromocriptine, and see a pituitary specialist. Examination revealed centripetal obesity, supraclavicular and dorsocervical fat pads, violaceous wide striae, bilateral leg edema, and galactorrhea. Workup confirmed adrenocorticotrophic hormone-dependent Cushing syndrome, with a central-to-peripheral gradient on inferior petrosal sinus sampling bilaterally. Transsphenoidal adenenomectomy yielded an adenoma diffusely positive for prolactin. Postoperatively prolactin normalized, hypercortisolemia persisted, and magnetic resonance imaging findings raised suspicion for a 2-mm microadenoma. The patient underwent a second operation when an adrenocorticotrophic hormone-positive adenoma was identified. After 4 years, both hypersecretory syndromes remain in biochemical remission. CONCLUSIONS: A complete clinical and biochemical evaluation is necessary in patients with pituitary adenomas. Repeat surgery may be necessary for noncontiguous double adenomas.


Assuntos
Adenoma/diagnóstico , Síndrome de Cushing/diagnóstico , Hiperprolactinemia/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Adenoma/complicações , Adenoma/patologia , Adulto , Síndrome de Cushing/etiologia , Feminino , Humanos , Hiperprolactinemia/etiologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Resultado do Tratamento
18.
Endocrinology ; 160(2): 447-459, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30615103

RESUMO

Cushing syndrome is a severe endocrine disorder of cortisol excess associated with major metabolic and cardiovascular sequelae. We recently identified somatic mutations in PRKACA, the gene encoding the catalytic (C) α subunit of protein kinase A (PKA), as being responsible for cortisol-producing adrenocortical adenomas (CPAs), which are a major cause of Cushing syndrome. In spite of previous studies on the two initially identified mutations (L206R, 199_200insW), the mechanisms of action of the clinically highly relevant PRKACA mutations remain poorly understood. Here, by investigating a large panel of PRKACA mutations, including all those identified so far in Cushing syndrome, we unexpectedly found that not all mutations interfere with the binding of regulatory (R) subunits as previously hypothesized. Because several mutations lie in a region of PKA Cα involved in substrate recognition, we investigated their consequences on substrate specificity by quantitative phosphoproteomics. We found that all three mutations analyzed (L206R, 200_201insV, and d244-248+E249Q) cause major changes in the preference of PKA for its targets, leading to hyperphosphorylation of several PKA substrates, most notably including histone H1.4 at Ser36, which is required for and promotes mitosis. This is reflected by a ninefold hyperphosphorylation of H1.4 in CPAs carrying the L206R mutation. Thus, our findings suggest that in addition to hampering binding to R subunits, PRKACA mutations act by altering PKA substrate specificity. These findings shed light on the molecular events leading to Cushing syndrome and illustrate how mutations altering substrate specificity of a protein kinase may cause human disease.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Síndrome de Cushing/etiologia , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Mutação , Fosforilação , Especificidade por Substrato
19.
BMC Endocr Disord ; 19(1): 13, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670014

RESUMO

BACKGROUND: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS). CASE PRESENTATION: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated. CONCLUSIONS: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome.


Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Adenoma Adrenocortical/complicações , Cromograninas/genética , Síndrome de Cushing/sangue , Dexametasona/administração & dosagem , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Hidrocortisona/sangue , Mutação , Neoplasias das Glândulas Suprarrenais/patologia , Adenoma Adrenocortical/patologia , Idoso , Anti-Inflamatórios/administração & dosagem , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/etiologia , Feminino , Humanos , Prognóstico
20.
Endocr J ; 66(3): 207-214, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30674738

RESUMO

Adrenal Cushing's syndrome (CS) is caused by cortisol-producing adrenal adenoma and is frequently accompanied by glucose metabolism disorders, which are characterized by increased insulin resistance and insufficient ß-cell compensation. However, considering the rarity of CS, few studies have assessed whether the glucose metabolism disorders could be ameliorated by surgical treatment. In this case series, we evaluated glucose metabolism before and after surgery in 11 patients (10 women and 1 man) who underwent unilateral adrenalectomy for overt adrenal CS between 2005 and 2016. Patients with pre-diagnosed diabetes mellitus (DM) were excluded. Pre- and post-operative 75-g oral glucose tolerance tests were performed. Cortisol secretion decreased significantly after surgery (median 24-h urinary free cortisol: 582.0 µg/day [interquartile range: 321.0-743.0 µg/day] to 31.3 µg/day [23.6-40.6 µg/day], p = 0.001). The results of the OGTT generally improved after surgery (normal glucose tolerance/impaired glucose tolerance/DM: 2/8/1 to 8/3/0), with significant decreases in the immunoreactive insulin and glucose levels. We also found a decrease in the median homeostatic model assessment of insulin resistance (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and increases in the median Matsuda index (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001), median insulinogenic index (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.08), and median disposition index (609.1 [237.8-1,095.2] to 1,286.0 [1,034.6-1,857.6], p = 0.002). These findings indicate that adrenalectomy for adrenal CS without overt DM may help ameliorate glucose metabolism disorders, and improve both insulin resistance and insulin secretion.


Assuntos
Glicemia/metabolismo , Síndrome de Cushing/sangue , Intolerância à Glucose/sangue , Hidrocortisona/metabolismo , Resistência à Insulina/fisiologia , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Adenoma Adrenocortical/sangue , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/cirurgia , Adulto , Síndrome de Cushing/etiologia , Síndrome de Cushing/cirurgia , Feminino , Intolerância à Glucose/complicações , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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