Enfermedad de Cushing recurrente con hipercortisolismo catastrófico: reporte de caso y revisión de literatura / Catastrophic hypercortisolism and recurrence in Cushing´s disease: a case report and literature review / Doença de Cushing recorrente com hipercortisolismo catastrófico: relato de caso e revisão da literatura

Resumen: Presentamos un caso de una paciente femenina de 27 años, con síndrome de Cushing ACTH dependiente con hipercortisolismo severo, causado por un macroadenoma hipofisario recurrente y resistente pese a dos cirugías transesfenoidales, radioterapia y terapia médica. Dada la falla en las diferentes terapias se realiza una adrenalectomía bilateral como tratamiento definitivo. La paciente fallece en el posoperatorio por causa no clara. Si bien la adrenalectomía bilateral ha sido reportada como un tratamiento efectivo en pacientes con enfermedad de Cushing, se ha relacionado con una mortalidad significativa vinculada con la severidad del hipercortisolismo y las comorbilidades presentes. En este caso la adrenalectomía izquierda se tuvo que convertir a cielo abierto, asociada con mayor morbimortalidad.

Abstract: The study presents the case of a 27-year-old female patient with adrenocorticotropic hormone (ACTH) dependent Cushing's disease and severe hypercortisolism caused by recurrent pituitary macroadenoma that was resistant to treatment despite two transsphenoidal surgeries, radiotherapy and medical treatment. Upon failure of the different therapies a bilateral adrenalectomy was performed as the final treatment. The patient died in after surgery although the case of death was not clear. Despite bilateral adrenalectomy having been reports as an effective treatment in patients with Cushing's disease, it has been related to significant mortality rates in connection with the severity of hypercortisolism and existing comorbilities. In this case the left adrenalectomy ended up being an open surgery, which is associated to a higher mortality rate.

Resumo: Apresentamos o caso de uma paciente de 27 anos com síndrome de Cushing ACTH-dependente com hipercortisolismo grave causado por macroadenoma hipofisário, recorrente e resistente, apesar de haver sido submetida a duas cirurgias transesfenoidal, radioterapia e terapia medicamentosa. Diante do fracasso das diferentes terapias, foi realizada adrenalectomia bilateral como tratamento definitivo. A paciente faleceu no pós-operatório por causa não esclarecida. Embora a adrenalectomia bilateral tenha sido relatada como tratamento eficaz em pacientes com doença de Cushing, ela tem sido associada a mortalidade significativa relacionada à gravidade do hipercortisolismo e às comorbidades presentes. Neste caso, a adrenalectomia esquerda teve que ser convertida para cirurgia aberta, associada a maior morbimortalidade.

Sampling of the petrosal sinuses. Indications, results and usefulness / Muestreo de senos petrosos. Indicaciones, resultados y utilidad

Abstract Objectives: to analyze, evaluate and describe the usefulness of petrosal sinus sampling for diagnosing central Cushing's syndrome. Materials and methods: the technical aspects and results of bilateral venous sampling of the petrosal sinuses at the Hospital Universitario San Vicente de Paul in Medellín, Colombia, from January 1, 2012 to December 31, 2018, were analyzed. Results: the average age was 43.3 years, with a range from 19 to 69 years. Laterality could be shown in 68.2% of cases, with a tendency to be located on the left in 53.3%. The central source of ACTH production could be shown in 95.4% of cases, with a basal average central/peripheral ratio of 21.7, and 70.8 after stimulation. All samples at 3, 5 and 10 minutes were confirmatory following stimulation. Conclusion: in our retrospective study, petrosal sinus catheterization provided laboratory confirmation of the central source of ACTH production in a high percentage of patients, with no immediate complications.

Resumen Objetivos: analizar, evaluar y describir la utilidad del muestreo de senos petrosos para diagnóstico del síndrome de Cushing de origen central. Material y métodos: se analizaron los aspectos técnicos y resultados del muestreo bilateral venoso de senos petrosos, desde el 1° de enero de 2012 a 31 de diciembre de 2018 en el Hospital Universitario San Vicente de Paúl en Medellín, Colombia. Resultados: el promedio de edad fue 43.3 años con un rango de edad desde los 19 hasta los 69 años. La lateralidad pudo ser demostrada en 68.2% de los casos con una tendencia a la localización en el lado izquierdo en 53.3%. El origen central de producción de ACTH logró ser demostrado en 95.4% de los casos, con una relación central/periferia basal promedio de 21.7 y postestimulación de 70.8. Todas las muestras a los 3, 5 y 10 minutos fueron confirmatorias tras la estimulación. Conclusión: en nuestro estudio retrospectivo el cateterismo de senos petrosos confirmó la fuente central de producción de ACTH por laboratorio en un alto porcentaje de pacientes sin ninguna complicación inmediata.

Clinical Significance of Radical Surgery in the Treatment of Silent Corticotroph Adenoma

OBJECTIVE: Silent corticotroph adenomas (SCA) are endocrine-inactive pituitary adenomas with positive immunohistochemistry staining for adrenocorticotropic hormone (ACTH). We investigated whether SCA-associated clinical profiles were more aggressive than hormonally negative adenomas (HNA). METHODS: Among 627 patients with pathologically proven endocrine-inactive pituitary adenomas between 2004 and 2013, positive immunohistochemistry revealed 55 SCAs and 411 HNAs. Surgical outcomes and radiological and endocrinological characteristics were compared. RESULTS: Strong female predominance was observed in the SCA group (p<0.001). Cavernous sinus invasion was identified in 22 (40%) SCA patients and 72 (17.6%) HNA patients (p<0.001). There were no differences in ACTH or cortisol levels between the two groups. The incidence of preoperative hypopituitarism and postoperative hormonal outcome did not differ between two groups. Total resection was achieved in 35 patients (63.7%) with SCA and 332 patients (80.8%) with HNA (p=0.007). When tumors were completely removed, recurrence rates were not statistically different between two groups (p=0.60). When complete resection was not achieved, tumors regrew from these remnants in seven patients (35.0%) with SCA and 12 patients (15.2%) with HNA (p=0.05). CONCLUSION: Total surgical resection for SCA is often challenging as these tumors frequently invade a cavernous sinus. Early remnant tumor intervention is justified, because untreated residual pituitary tumors regrow when patients were followed up for a long time. Prophylactic radiotherapy is not warranted for completely resected SCAs as tumor recurrence is uncommon.

Effects of Oxytocin on Cell Proliferation in a Corticotroph Adenoma Cell Line

BACKGROUND: Oxytocin (OXT) has been reported to act as a growth regulator in various tumor cells. However, there is a paucity of data on the influence of OXT on cell proliferation of corticotroph adenomas. This study aimed to examine whether OXT affects cell growth in pituitary tumor cell lines (AtT20 and GH3 cells) with a focus on corticotroph adenoma cells. METHODS: Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were conducted with AtT20 cells to confirm the effects of OXT on hormonal activity; flow cytometry was used to assess changes in the cell cycle after OXT treatment. Moreover, the impact of OXT on proliferating cell nuclear antigen (PCNA), nuclear factor κB, and mitogen-activated protein kinase signaling pathway was analyzed by Western blot. RESULTS: OXT treatment of 50 nM changed the gene expression of OXT receptor and pro-opiomelanocortin within a short time. In addition, OXT significantly reduced adrenocorticotropic hormone secretion within 1 hour. S and G2/M populations of AtT20 cells treated with OXT for 24 hours were significantly decreased compared to the control. Furthermore, OXT treatment decreased the protein levels of PCNA and phosphorylated extracellular-signal-regulated kinase (P-ERK) in AtT20 cells. CONCLUSION: Although the cytotoxic effect of OXT in AtT20 cells was not definite, OXT may blunt cell proliferation of corticotroph adenomas by altering the cell cycle or reducing PCNA and P-ERK levels. Further research is required to investigate the role of OXT as a potential therapeutic target in corticotroph adenomas.

Clinical Significance of Radical Surgery in the Treatment of Silent Corticotroph Adenoma

OBJECTIVE: Silent corticotroph adenomas (SCA) are endocrine-inactive pituitary adenomas with positive immunohistochemistry staining for adrenocorticotropic hormone (ACTH). We investigated whether SCA-associated clinical profiles were more aggressive than hormonally negative adenomas (HNA).METHODS: Among 627 patients with pathologically proven endocrine-inactive pituitary adenomas between 2004 and 2013, positive immunohistochemistry revealed 55 SCAs and 411 HNAs. Surgical outcomes and radiological and endocrinological characteristics were compared.RESULTS: Strong female predominance was observed in the SCA group (p<0.001). Cavernous sinus invasion was identified in 22 (40%) SCA patients and 72 (17.6%) HNA patients (p<0.001). There were no differences in ACTH or cortisol levels between the two groups. The incidence of preoperative hypopituitarism and postoperative hormonal outcome did not differ between two groups. Total resection was achieved in 35 patients (63.7%) with SCA and 332 patients (80.8%) with HNA (p=0.007). When tumors were completely removed, recurrence rates were not statistically different between two groups (p=0.60). When complete resection was not achieved, tumors regrew from these remnants in seven patients (35.0%) with SCA and 12 patients (15.2%) with HNA (p=0.05).CONCLUSION: Total surgical resection for SCA is often challenging as these tumors frequently invade a cavernous sinus. Early remnant tumor intervention is justified, because untreated residual pituitary tumors regrow when patients were followed up for a long time. Prophylactic radiotherapy is not warranted for completely resected SCAs as tumor recurrence is uncommon.

Evolución de pacientes con adenoma hipofisario después de resección quirúrgica vía transesfenoidal en Hospital Teodoro Maldonado / Evolution of patients with pituitary adenoma after transsphenoidal surgical resection in Hospital Teodoro Maldonado

Los adenomas hipofisarios son tumores cerebrales benignos considerados como el tercer grupo de lesiones intracraneales en frecuencia tras los meningiomas y los gliomas. El tratamiento de esta patología puede ser clínico o quirúrgico, dependiendo del tipo de tumor. El tratamiento quirúrgico puede ser realizado por dos vías: transcraneal o transesfenoidal, la misma que puede ser por abordaje sublabial, transeptal o transnasal con uso de microscopio o endoscopio. Los resultados posquirúrgicos son objetivables a través de la revisión de historias clínicas para valorar sintomatología, niveles hormonales prequirúrgicos y posquirúrgicos, complicaciones para evidenciar los resultados de esta técnica. Objetivos: Determinar los resultados del tratamiento quirúrgico por vía transesfenoidal utilizando abordaje transnasal endoscópico y transeptal microscópico en pacientes con adenomas hipofisarios. Metodología: Estudio descriptivo, retrospectivo, observacional, en el que se analizan 25 pacientes, que fueron hospitalizados para intervención neuroquirúrgica en el periodo comprendido entre enero 2014 a junio 2016 del Hospital Teodoro Maldonado Carbo. Resultados: Se analizaron 25 pacientes que fueron intervenidos por adenoma hipofisario por vía transesfenoidal, de los cuales 14 fueron mujeres y 11 varones. El rango de edad estuvo comprendido entre 13 y 79 años, con una media de 50 años. Según la clasificación por su tamaño, 3 pacientes presentaron microadenoma y 22 macroadenoma; 7 pacientes con adenoma hipofisario funcionante y 18 pacientes con adenoma hipofisario no funcionante. El 60 % de pacientes tuvo mejoría en la visión. En los adenomas hipofisarios funcionantes los niveles hormonales disminuyeron en 6 pacientes y en 1 paciente incrementó. Las complicaciones posquirúrgicas se presentaron en 6 pacientes, que representan un 24 % de pacientes; 2 presentaron fístula de líquido cefalorraquídeo, 2 pacientes empeoraron su sintomatología visual, 1 paciente desarrolló diabetes insípida y 1 paciente falleció en el posquirúrgico mediato. Conclusiones: El procedimiento transesfenoidal sea transeptal micróscopica o transnasal endoscópica son abordajes eficaces para el tratamiento quirúrgico de los pacientes con adenoma hipofisario.

Pituitary adenomas are benign brain tumors considered the third group of intracranial lesions in frequency after meningiomas and gliomas. The treatment of this pathology may be clinical or surgical depending on the type of tumor. Surgical treatment can be performed by 2-way transcranial or transsphenoidal, which can be by sublabial, transseptal or transnasal approach using a microscope or endoscope. The postoperative results are objectivable through the review of clinical histories to evaluate symptoms, pre-surgical and postsurgical hormone levels, complications to evidence the results of this technique. Objectives: To determine the results of transsphenoidal surgical treatment using transnasal endoscopic and microscopic transeptal approach in patients with pituitary adenomas. Methodology: A descriptive, retrospective, observational study in which 25 patients were analyzed, who were hospitalized for neurosurgical intervention in the period between 2014 and June 2016 of the Hospital Teodoro Maldonado Carbo. Results: We analyzed 25 patients who underwent transsphenoidal pituitary adenoma, 14 of whom were women and 11 men. The age range was between 13 and 79 years, with an average of 50 years. According to the classification by their size 3 patients presented microadenoma and 22 macroadenoma; 7 patients with functioning pituitary adenoma and 18 patients with nonfunctioning pituitary adenoma. Sixty percent of patients had improvement in vision. In functional pituitary adenomas, hormonal levels decreased in 6 patients and in 1 patient increase. Postoperative complications were presented in 6 patients representing 24% of patients, 2 had cerebrospinal fluid fistula, 2 patients worsened their visual symptomatology, 1 patient developed diabetes insipidus and 1 patient died in the postoperative period. Conclusions: The transsphenoidal procedure is transosseous or endoscopic transnasal micróscopica are effective approaches for the surgical treatment of patients with pituitary adenoma.

Perfil epidemiológico e clínico de uma amostra populacional de pacientes com acromegalia no estado de Alagoas / Clinical and epidemiological profile of a sample population of patients with acromegaly in the state of Alagoas

Objetivo: determinar o perfil epidemiológico e clínico de pacientes com acromegalia no Estado de Alagoas. Métodos: trata-se de um estudo descritivo, observacional, que foi realizado na Farmácia de Medicamentos Excepcionais do Estado de Alagoas, abrangendo 12 pacientes com acromegalia dessa instituição, correspondendo a 85% dos acromegálicos do Estado de Alagoas. Resultados: dos 12 pacientes estudados, a média de idade foi de 50,8 +/- 12,1 anos e, no momento do diagnóstico, uma média de idade de 44,5 +/- 11,6 anos. Foram realizados exames de imagem em 91,6% dos pacientes, em que se evidenciou macroademona hipofisário no momento do diagnóstico. A octreotida foi o medicamento principal, utilizado em 92% dos pacientes. Conclusão: O estudo corrobora, em boa parte dos dados, a literatura atual e revela a necessidade de maior precocidade de diagnóstico e início de terapêutica adequada, evitando o surgimento de comorbidades e complicações típicas da doença. (AU)

Objective: to determine the clinical and epidemiological profile of patients with acromegaly in the state of Alagoas. Method: This is a descriptive and observational study, which was held at the Exceptional Drug Pharmacy of the State of Alagoas. This study included 12 patients with acromegaly of this institution, corresponding to 85% of acromegaly in the State of Alagoas. Results: The mean age of the patients was 50.8 +/- 12.1 year and the mean age at diagnosis was 44.5 +/- 11, 6 years. Medical imaging exams were performed in 91.7% of patients, showing pituitary macroadenoma at the moment of diagnosis. Octreotide was the main medication, used in 91,7% of patients. Conclusion: The study corroborates, in most of the data, the current literature and reveals the need for earlier diagnosis and appropriate therapy, which avoids the appearance of typical comorbidities and complications of this disease. (AU)

Hiperprolactinemia idiopática / Idiopathic hyperprolactinemia

La hiperprolactinemia es uno de los trastornos neuroendocrinológicos más frecuentes; la causa común de la hiperprolactinemia es la presencia de un adenoma hipofisario productor de prolactina o prolactinoma. El país cuenta con escasa referencia bibliográfica sobre la patología presentada, por lo que resulta importante realizar la exposición de este caso. Objetivo: documentar el abordaje de hiperprolactinemia en el país. Caso clínico: paciente femenina de 22 años, con antecedentes familiares de macroprolactinoma; se presenta con historia de amenorrea de 6 años y caída de cabello de 2 años de evolución; prurito intenso en ambas mamas con predominio en la areola derecha desde hace 1 año; alteraciones en los niveles de prolactina presentando valores de 33.5ng/mL y ultrasonografía abdominal ausente de anormalidades. Tratada con cabergolina, sin éxito evidente en el tratamiento. Conclusión: en pacientes con hiperprolactinemia, su abordaje debe hacerse de manera ordenada, integral, secuencial y detallada con el fin de descartar previo al tratamiento, situaciones que secundariamente elevan los valores de prolactina. Esto lo demuestra el caso expuesto donde se integran diferentes pruebas clínicas y laboratoriales para descartar la etiología de la hiperprolactinemia en el país...(AU)

Resonancia magnética en pacientes con tumores más frecuentes en la región selar / Magnetic resonance in patients with more frequent tumors in the selar region

La resonancia magnética constituye el examen ideal en pacientes con presunción clínica de tumores en la región selar, pues no emite radiaciones ionizantes y debido a su visión multiplanar y discriminación tisular, posibilita adoptar una conducta terapéutica adecuada y un seguimiento sin riesgos en estos casos. Se describen las imágenes obtenidas con esa técnica sobre los principales tumores selares, correspondientes a macroadenomas hipofisarios, meningioma intraselar, craneofaringioma supraselar y como caso interesante perteneciente a esta región: el cordoma del clivus, por poseer en la actualidad mejores posibilidades diagnósticas que en décadas anteriores

Magnetic resonance constitutes the ideal exam in patients with clinical presumption of tumors in the selar region, because it doesn't emit ionizing radiations and due to its multiplanar vision and tissular discrimination, it facilitates the adoption of an appropriate therapeutic behavior and a follow up without risks in these cases. The images obtained with that technique on the main selar tumors are described, corresponding to hypophysary macroadenomas, intraselar meningioma, supraselar craneopharyngioma and as an interesting case belonging to this region: the clivus chordoma, for having better diagnostic possibilities at the present time than in previous decades

Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing's disease in Brazil

ABSTRACT 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. Arch Endocrinol Metab. 2016;60(3):267-86.

Diagnosis of cyclic Cushing syndrome using the morning urine free cortisol to creatinine ratio

No abstract available.

Paresia del III par craneal como manifestación de un corticotropinoma silente / Third nerve palsy as an expression of a corticotroph adenoma

Silent corticotroph adenomas (SCA) are pituitary adenomas inmunoreactive to ACTH without hormonal overproduction and they form the 3 percent of the pituitary adenomas. Unlike the ademonas that cause the Cushing’s disease, frequently the SCA are aggressive macroademonas and their clinical expressions are the compromise of nearby structures with or without pituitary apoplexy. Frequently, the treatment chosen is a surgical procedure, albeit the total resection difficulties. The SCA are not diagnosed until an anatomopathological and immunohistochemical study is carried out. In this document, a case study of a woman diagnosed with a clinically silent macrocorticotroph adenomadiscovered by a third nerve palsy is explained.

Effect of Cabergoline Treatment on Cushing's Disease Caused by Pituitary Macroadenoma after Incomplete Transsphenoidal Surgery

The present case involves a 56-year-old woman with Cushing's disease due to pituitary macroadenoma. The patient had suffered from central obesity, general weakness for 1 year. Her serum cortisol levels were elevated throughout the observation period and the dexamethasone test failed to suppress the cortisol secretion. Plasma adrenocorticotropic hormone (ACTH) levels were significantly elevated (386 pg/mL). Sellar magnetic resonance imaging revealed a 3.1-cm pituitary tumor occupying the sellar region with extension to parasellar area. The pituitary mass was removed by transsphenoidal surgery incompletely and was pathologically identified as compatible to ACTH-producing pituitary adenoma by immunohistochemistry. Thereafter, cabergoline (1 mg/wk) was administered for the remnant adenoma, which gradually reduced ACTH levels in 7 days before starting radiation therapy. This case demonstrates the efficacy of cabergoline to treat Cushing's disease caused by pituitary macroadenoma.

Spontaneous remission of hypercortisolism presumed due to asymptomatic tumor apoplexy in ACTH-producing pituitary macroadenoma / Remissão espontânea do hipercortisolismo devido a provável apoplexia tumoral assintomática em paciente com macroadenoma produtor de ACTH

Cushing's disease (CD) is usually caused by secretion of ACTH by a pituitary corticotroph microadenoma. Nevertheless, 7%-20% of patients present with ACTH-secreting macroadenomas. Our aim is to report a 36-year-old female patient with CD due to solid-cystic ACTH-macroadenoma followed up during 34 months. The patient presented spontaneous remission due to presumed asymptomatic tumor apoplexy. She showed typical signs and symptoms of Cushing's syndrome (CS). Initial tests were consistent with ACTH-dependent CS: elevated urinary free cortisol, abnormal serum cortisol after low dose dexamethasone suppression test, and elevated midnight salivary cortisol, associated with high plasma ACTH levels. Pituitary magnetic resonance imaging (MRI) showed a sellar mass of 1.2 x 0.8 x 0.8 cm of diameter with supra-sellar extension leading to slight chiasmatic impingement, and showing hyperintensity on T2-weighted imaging, suggesting a cystic component. She had no visual impairment. After two months, while waiting for pituitary surgery, she presented spontaneous resolution of CS. Tests were consistent with remission of hypercortisolism: normal 24-h total urinary cortisol and normal midnight salivary cortisol. Pituitary MRI showed shrinkage of the tumor with disappearance of the chiasmatic compression. She has been free from the disease for 28 months (without hypercortisolism or hypopituitarism). The hormonal and imaging data suggested that silent apoplexy of pituitary tumor led to spontaneous remission of CS. However, recurrence of CS was described in cases following pituitary apoplexy. Therefore, careful long-term follow-up is required.

A doença de Cushing (DC) é usualmente causada por um microadenoma produtor de ACTH. Entretanto, 7%-20% dos pacientes apresentam um macroadenoma. O objetivo deste trabalho é reportar uma paciente de 36 anos, feminina, com diagnóstico de DC devido a macroadenoma hipofisário sólido-cístico com seguimento de 34 meses que apresentou remissão espontânea presumidamente em decorrência de uma apoplexia tumoral assintomática. Inicialmente, ela apresentava sinais e sintomas típicos da síndrome de Cushing (SC). Na admissão, os testes foram consistentes com o diagnóstico de SC ACTH-dependente: cortisol urinário livre de 24h elevado, não supressão do cortisol sérico após dose baixa de dexametasona e cortisol salivar noturno elevado, associado a concentrações elevadas do ACTH plasmático. Ressonância magnética (RM) de hipófise revelou uma massa selar de 1.2 x 0.8 x 0.8 cm com extensão suprasselar levando a uma discreta compressão do quiasma óptico e mostrando região de hipersinal na imagem ponderada em T2 sugerindo um componente cístico. A paciente não apresentava queixas visuais. Após dois meses, enquanto aguardava o tratamento cirúrgico, a paciente apresentou remissão espontânea da SC. A repetição dos exames indicou remissão do hipercortisolismo: normalização do cortisol urinário livre de 24h e normalização do cortisol salivar noturno. Nova RM de hipófise revelou redução do volume tumoral com desaparecimento da compressão quiasmática. A paciente permanece livre da doença por 28 meses (sem hipercortisolismo ou hipopituitarismo). Os dados hormonais e de imagem sugerem que tenha ocorrido uma apoplexia tumoral assintomática, levando à remissão espontânea da SC. Entretanto, como há relatos de recorrência após apoplexia hipofisária, cuidadoso seguimento a longo prazo faz-se necessário.

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .

Differential gene expression by fiber-optic beadarray and pathway in adrenocorticotrophin-secreting pituitary adenomas / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Adrenocorticotrophin (ACTH)-secreting pituitary adenomas account for approximately 7% - 14% of all pituitary adenomas, but its pathogenesis is still enigmatic. This study aimed to explore mechanisms underlying the pathogenesis of ACTH-secreting pituitary adenomas.</p><p><b>METHODS</b>We used fiber-optic beadarray to examine gene expression in three ACTH-secreting adenomas compared with three normal pituitaries. Four differentially expressed genes from the three ACTH-secreting adenomas and three normal pituitaries were chosen randomly for validation by reverse transcriptase-real time quantitative polymerase chain reaction (RT-qPCR). We then analyzed the differentially expressed gene profile with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway.</p><p><b>RESULTS</b>Fiber-optic beadarray analysis showed that the expression of 28 genes and 8 expressed sequence tags (ESTs) were significantly increased and the expression of 412 genes and 31 ESTs were significantly decreased. Bioinformatic and pathway analysis showed that the genes HIGD1B, EPS8, HPGD, DAPK2, and IGFBP3 and the transforming growth factor (TGF)-β signaling pathway and extracellular matrix (ECM)-receptor interaction pathway may play important roles in tumorigenesis and progression of ACTH-secreting pituitary adenomas.</p><p><b>CONCLUSIONS</b>Our data suggest that numerous aberrantly expressed genes and several pathways are involved in the pathogenesis of ACTH-secreting pituitary adenomas. Fiber-optic beadarray combined with pathway analysis of differential gene expression appears to be a valid method of investigating tumour pathogenesis.</p>

Papel da via lkaros-FGFR4 na evolução pós-cirúrgica dos pacientes com Doença de Cushing / Ikaros-FGFR4 pathway role in the postoperative outcome of Cushing's Disease

Os mecanismos envolvidos na patogênese molecular dos tumores hipofisários corticotróficos são complexos, heterogêneos e permanecem na maioria dos casos desconhecidos. Alterações da expressão de componentes da via Ikaros (Ik), tais como do receptor 4 dos fatores de crescimento de fibroblastos (FGFR4) têm sido detectadas em tumores hipofisários, inclusive nos corticotropinomas. O desbalanço entre as isoformas longas e curtas do Ikaros resulta em um início de transcrição alternativa do FGFR4, codificando uma isoforma truncada do gene (pdt- FGFR4) que foi associada a tumores hipofisários maiores e mais invasivos. A isoforma curta Ik6 promove a expressão do fator anti-apoptótico Bcl-XL in vitro, um efeito independente da interação com as isoformas longas. Além disso, um polimorfismo do FGFR4, com substituição da glicina por arginina no códon 388 (G388R), tem sido associado à evolução desfavorável em vários tipos tumorais humanos. Objetivos: Analisar a expressão do Bcl-XL, das isoformas do Ikaros (Ik1+Ik2/Ik total) e do FGFR4 em corticotropinomas humanos. Avaliar a freqüência dos genótipos do códon 388 do FGFR4 nos pacientes com doença de Cushing e sua associação com a evolução pósoperatória após a primeira cirurgia transesfenoidal. Métodos: Noventa e sete pacientes com diagnóstico de doença de Cushing foram estudados. Os dados clínicos, hormonais e histopatológicos foram avaliados retrospectivamente. O estudo da expressão do Bcl-XL, do Ikaros, e do FGFR4 foi realizado por PCR em tempo real em 20 amostras de corticotropinomas, sendo dois tumores correspondentes à síndrome de Nelson. A determinação dos genótipos no códon 388 do FGFR4 foi realizada nos 97 pacientes e em 103 indivíduos controles, por PCR de fragmento do exon 9 do gene FGFR4 seguida de digestão com a enzima de restrição BstNI. A evolução pós-operatória (remissão/recidiva) da doença de Cushing foi avaliada em 76 pacientes. Foram considerados em remissão aqueles pacientes com níveis normais...

The mechanisms involved in the molecular pathogenesis of corticotroph pituitary tumors are complex, heterogeneous and in most cases remain unknown. Changes in the expression of components of Ikaros (Ik) pathway, such as receptor 4 of fibroblast growth factor (FGFR4), have been detected in pituitary tumors including corticotropinomas. Imbalance between long and short Ik isoforms results in alternative transcription initiation of FGFR4 and encodes a truncated isoform of the gene (pdt-FGFR4) which was associated with larger and more invasive pituitary tumors. The Ik6 short isoform promotes Bcl-XL expression in vitro, an effect independent of the interaction with the long isoforms. In addition, a polymorphism of FGFR4 gene, the substitution of glycine by arginine at codon 388 (G388R), has been associated with adverse outcome in several human tumor types. Objectives: To analyze the expression of Bcl-XL, Ikaros isoforms (Ik1 + Ik2/Ikaros total), and FGFR4 in human corticotropinomas. To determine the frequency of each genotype at codon 388 of FGFR4 in patients with Cushing's disease and its association with the postoperative outcome after the first transsphenoidal surgery. Methods: Ninety-seven patients with Cushing's disease were evaluated. Clinical, hormonal and histopathological findings were assessed retrospectively. The expression of Bcl-XL, Ikaros and FGFR4 were evaluated by real-time PCR in 20 samples of corticotropinomas, including two samples of Nelson's syndrome. The FGFR4 genotype was determined in the 97 patients and 103 control subjects by PCR fragment of exon 9 of the FGFR4 gene, followed by digestion with the BstNI restriction enzyme. The postoperative outcome (remission/relapse) of Cushing's disease was assessed in 76 patients. The patients with normal urinary cortisol levels during the first year after surgery, in the absence of hormone replacement therapy, and those who...

Adenoma corticotrópos silente de la glándula pituitaria / Silent corticotroph adenomas of the pituitary gland

Objetivos: En el presente trabajo se revisará nuestra serie de casos de Adenomas Corticotrópos silentes y revisar la literatura acerca de esta patología fascinante. Material y Método: Se revisaron las historias clínicas de 5 pacientes del Hospital Universitario Fundación Santa Fé de Bogotá en el periodo de enero de 1990 a enero de 2008, que se le realizó tratamiento para una masa sellar y se le realizó diagnóstico patológico de Adenoma Corticotrópos Silente. Discusión: Los adenomas de hipófisis corresponden entre el 17 por ciento de los tumores intracraneales. El 60 por ciento de estas lesiones se asocian a hipersecreción hormonal. Los adenomas corticotropos silentes son tumores hipofisarios que histológicamente muestran diferenciación corticotrópica con algún grado de secreción de ACTH pero sin la evidencia clínica de síndrome de Cushing. Conclusión: Aunque estos tumores sean clínicamente significativos y su histopatología fascinante, hay poca literatura y estudios clínicos con enfoque especial sobre estas lesiones. Estos tumores son muy importantes tenerlos en cuenta en la patología selar ya que su tratamiento requiere mayor dedicación y seguimiento a estos pacientes.

Objectives: In the present paper we want to review our series of silent corticotrofic adenomas and review the literature concerning this fascinating pathology. Material and Methods: we review the clinical history of 5 patients treated and diagnosed with Silent corticotrofic adenomas in University Hospital Fundacion Santa Fe de Bogota in the period of January 1990 till January 2008. Discussion: Pituitary adenomas count for 10 to 15 percent of intracranial tumors. In 60 percent of the cases there is a hormonal hypersecretory syndrome associated with these mass. Silent Corticotophic adenomas are pituitary tumors which histologically show a corticotrophic differentiation with secretion of ACTH but do not present with clinical evidence of Cushing disease. Although silent corticotophic adenomas are clinically significant and histologically fascinating there are only few clinical studies and medical literature with regard to these tumors. Conclusion: Although silent corticotophic adenomas are clinically significant and histologically fascinating there are only few clinical studies and medical literature with regard to these tumors. It is very important to take in regard this tumor in the pathology of the selar region since these patients demand a major dedication and a strict follow up.