TSH-secreting pituitary tumors: two case reports and literature review

INTRODUÇÃO: Tumores hipofisários secretores de hormônio estimulante da tireoide (TSH), tireotropinomas, são raros e correspondem a menos de 2% de todos os adenomas da hipófise. Manifestam-se clinicamente com sintomas e sinais de tireotoxicose, eventualmente associados a sintomas compressivos, sobretudo visuais, devido ao efeito de massa do tumor. Esses tumores se caracterizam pela presença de níveis séricos elevados de hormônios tireoidianos e níveis séricos elevados, ou inapropriadamente normais, de TSH. Frequentemente, ao diagnóstico, há relato de tratamento prévio cirúrgico, medicamentoso e/ou ablativo, por hipótese de hipertireoidismo primário por doença de Graves. OBJETIVO: Relatar dois casos de tireotropinomas acompanhados na Unidade de Neuroendocrinologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) e revisar a literatura visando ao manejo desta afecção. CONCLUSÃO: Na presença de hormônios tireoidianos elevados e níveis de TSH inapropriadamente normais ou elevados, a possibilidade de adenoma hipofisário produtor de TSH deve ser considerada com vistas à realização da terapia adequada.INTRODUCTION: TSH-secreting pituitary adenomas are rare pituitary functioning tumors accounting for less than 2% of the pituitary adenomas. The clinical feature consists of thyrotoxicosis occasionally associated to tumoral symptoms due to mass effect. The biochemical feature consists of elevated thyroid hormones levels and normal or high TSH concentrations. This disease is often wrongly diagnosed as Grave's disease, and the ablative therapy is frequently conducted prior to the diagnosis. OBJECTIVE: To report two cases followed in the Neuroendocrine Unit of Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo and to review the literature aiming at the management of this affection. CONCLUSION: In the presence of elevated thyroid hormone levels associated with inappropriate normal or increased TSH levels, the possibility of a TSH-secreting pituitary adenoma should be considered for the proper medical treatment

Brazilian multicenter study on pegvisomant treatment in acromegaly

Objective Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. Subjects and methods Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. Results 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. Conclusions In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies

Recommendations of the neuroendocrinology department of the Brazilian society of endocrinology and metabolism for the diagnosis of Cushing’s disease in Brazil

Although it is a rare condition, the accurate diagnosis and treatment of Cushing’s disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing’s syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing’s syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing’s disease, recommending follow-up of these patients at experienced referral centers

Recommendations of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism for diagnosis and treatment of acromegaly in Brazil

A acromegalia é uma doença associada à elevada morbidade e à redução da expectativa de vida. Em virtude do seu caráter insidioso e do seu não reconhecimento, o diagnóstico é frequentemente realizado com atraso, o que, associado às complicações relacionadas ao excesso do GH/IGF-I, determina elevada morbimortalidade. No entanto, um diagnóstico precoce e um tratamento efetivo minimizam a morbidade e normalizam a taxa de mortalidade. Nesta publicação, o objetivo do Departamento de Neuroendocrinologia da Sociedade Brasileira de Endocrinologia e Metabologia é divulgar quando suspeitar clinicamente da acromegalia e como diagnosticá-la. Além disso, discute-se a maneira mais eficaz e segura de realizar o tratamento da acromegalia, enfatizando que este deve ser realizado em centros de referência. Assim, com base em dados publicados em periódicos de nível científico reconhecido e na experiência dos autores, são apresentadas as recomendações para o diagnóstico e tratamento da doença.Acromegaly is a disease associated with increased morbidity and reduced life expectancy. Because of its insidious character and its non-recognition, the diagnosis is often made with delay, which, along with the complications related to GH/IGF-I excess, determines high morbidity and mortality. However, an early diagnosis and an effective treatment reduce the morbidity and normalize the mortality rate. In this publication, the goal of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism is to disclose which clinical set should arouse the suspicious of acromegaly and how to diagnose it. Furthermore, we discuss the most effective and safe approach to perform the treatment of acromegaly, emphasizing that it must be carried out in reference centers. Therefore, based on data published in journals with recognized scientific level and authors' experience, recommendations are presented for diagnosis and treatment of the disease

RETRACTED ARTICLE: Fatal factitious Cushing\ud syndrome (Münchhausen’s syndrome) in a patient with macroprolactinoma and silent\ud corticotrophinoma: case report and literature review

Abstract\ud Münchhausen’s syndrome (MS) is a chronic factitious disorder\ud characterized by the intentional production of clinical symptoms without external\ud incentive. One type of MS is factitious Cushing syndrome, an extremely rare clinical\ud situation in which the diagnosis is challenging mainly due to interference of the\ud exogenous medication in cortisol immunoassays. We described a 26-year-old woman who\ud was originally diagnosed with a macroprolactinoma and during follow-up developed\ud clinical and laboratorial hypercortisolism. A transsphenoidal surgery was performed\ud and immunohistochemistry revealed positive and diffuse staining for both hormones.\ud Four years later, her hypercortisolism recurred and the confirmation of factitious\ud Cushing syndrome was delayed due to conflicting laboratorial results.\ud There are few cases in the literature of factitious Cushing syndrome,\ud and only one had a fatal outcome. The diagnosis of this condition is complex and\ud includes cyclic Cushing syndrome in the differential diagnosis. These patients have\ud high morbidity and increased mortality risk and are likely to have other psychiatric\ud disorders. Prednisone was identified as the culprit in the majority of the\ud cases.We would like to thank Dr. Wagner Farid Gattaz and Dr. Jose Gallucci Neto,\ud from the Psychiatric Division, for providing assistance during hospitalization.\ud This work was partially supported by grants from Conselho Nacional de\ud Desenvolvimento Científico e Tecnológico – CNPq (301339/2008-9 to B.B.M.)

Efficacy and safety of once-monthly pasireotide in Cushing's disease: A 12 month clinical trial

© 2017 Elsevier Ltd. Background: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to < 2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings: Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7] ) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%] ), cholelithiasis (15 [20%] and 34 [45%] ), diabetes mellitus (14 [19%] and 18 [24%] ), and nausea (15 [20%] and 16 [21%] ). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation: Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding: Novartis Pharma AG

Rare sellar lesions

Sellar masses are associated most commonly with pituitary adenomas. Many other neoplastic, inflammatory, infectious, and vascular lesions, however, may affect the sellar region and mimic pituitary tumors. These lesions must be considered in a differential diagnosis. This article describes the characteristics of rare sellar masses that provide clues to their differential diagnosis

Influence of the Fibroblast Growth Factor Receptor 4 Expression and the G388R Functional Polymorphism on Cushing`s Disease Outcome

Context: Abnormal FGFR4 expression has been detected in pituitary tumors, especially in larger and invasive adenomas. In addition, the FGFR4 functional polymorphism G388R has been associated with poor outcome in several human malignancies. Then, we hypothesized that FGFR4 expression and genotype could be markers of adverse outcome of Cushing`s disease after transsphenoidal surgery. Objectives: The objective was to investigate whether there is an association between the postoperative outcome of Cushing`s disease (remission/recurrence) and the FGFR4 G388R genotype or the FGFR4 expression in corticotrophinomas. Design and Patients: Clinical, hormonal, and pathological data of 76 patients who underwent the first transsphenoidal surgery were retrospectively reviewed. All patients were genotyped for G388R polymorphism. FGFR4 expression was assessed by real-time PCR in 18 corticotrophinomas. Main Outcome Measures: The outcome measures included the FGFR4 G388R genotype and FGFR4 expression in postoperative remission and recurrence of Cushing`s disease. Results: Homozygosis for FGFR4 glycine (Gly(388)) allele was associated with reduced disease-free survival, in the univariate analysis (hazard ratio of 6.91; 95% confidence interval of 1.14-11.26; P = 0.028). Male gender (P = 0.036), lack of pathology confirmation (P = 0.009), and cortisol levels more than 2 mu g/dl in the early postoperative period (P < 0.001) were also significant predictors of Cushing`s disease recurrence in the univariate analysis. FGFR4 overexpression was found in 44% of the corticotrophinomas, and it was associated with lower postoperative remission rate (P = 0.009). Conclusions: Our data suggest that homozygosis for FGFR4 Gly(388) allele and FGFR4 overexpression are associated with higher frequency of postoperative recurrence and persistence of Cushing`s disease, respectively. (J Clin Endocrinol Metab 95: E271-E279, 2010)FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[06/52492-0