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RESUMEN: Introducción La acromegalia se asocia con un mayor riesgo de morbilidad y mortalidad por cáncer. Sin embargo, los datos respecto de la incidencia de cáncer en acromegalia son controvertidos. Objetivos Describir las características clínicas, bioquímicas e imagenológicas de un grupo de pacientes acromegálicos con carcinoma diferenciado de tiroides (CDT). Analizar las características de riesgo de recurrencia (RR) y respuesta en el seguimiento (RtaSg) y comparar la evolución con la de pacientes con CDT no acromegálicos. Materiales y métodos Se realizó un análisis retrospectivo multicéntrico de pacientes con diagnóstico de acromegalia y CDT. Se realizó un análisis comparativo entre los pacientes de bajo RR inicial acromegálicos con una muestra aleatoria de pacientes no acromegálicos con CDT de bajo RR inicial (1:4). Resultados Se analizaron 16 pacientes con diagnóstico de CDT y acromegalia. En 93,8% se hizo el diagnóstico por ecografía, sólo el 50% tenían un nódulo tiroideo palpable. En el momento del diagnóstico del CDT, los valores de IGF-1 fueron 1,8 ± 1,3 LSN, con 62,5% con acromegalia activa. La histología fue papilar en todos los casos, el 56,3% variedad clásica y el resto papilar variedad folicular. El 75% de los pacientes presentó un Estadio I (12/16), sólo 3 pacientes Estadio II y 1 Estadio IVb. El RR inicial fue bajo en el 87,6% (14/16), intermedio en 1 paciente y alto en 1 paciente. Las respuestas al final del seguimiento fueron: 86,7% (13/15) sin evidencia de enfermedad, 1 paciente bioquímica incompleta y 1 estructural incompleta. La RtaSg no tuvo diferencias con los no acromegálicos. Conclusiones Los pacientes acromegálicos con CDT presentaron predominantemente un bajo RR inicial. Al realizar la comparación con el grupo control, se puede concluir que el CDT en pacientes acromegálicos no presentó una evolución más agresiva.
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The term primary empty sella (PES) makes reference to the herniation of the subarachnoid space within the sella turcica in patients with no history of pituitary tumor, surgery or radiotherapy. To retrospectively assess clinical features, radiological findings and the biochemical endocrine function from the records of 175 patients with a diagnosis of PES. One hundred seventy-five patients (150 females) were studied. The mean age at diagnosis was 48.2 ± 14 year. Most diagnoses were made by magnetic resonance imaging (n = 172). In most patients, the pituitary function was assessed by basal pituitary hormones measurements. Pituitary scans were ordered for different reasons: headache (33.1 %), endocrine disorders (30.6 %), neurological symptoms (12.5 %), visual disturbances (8.75 %), abnormalities on sella turcica radiograph (8.75 %) and others (6.25 %). Multiple pregnancies were observed in 58.3 % of women; headaches, obesity, and hypertension were found in 59.4, 49.5, and 27.3 % of the studied population, respectively. Mild hyperprolactinemia (<50 ng/ml) was present in 11.6 % of women and 17.3 % of men. Twenty-eight percent of our patients had some degree of hypopituitarism. In the male population, hypopituitarism represented 64 % of cases, whereas it accounted for 22 % of all females. PES seems to be more commonly found in middle-aged women, with a history of multiple pregnancies. In most patients, PES was discovered as an incidental finding on imaging studies, while in almost a quarter of patients PES was found during the diagnostic evaluation of anterior pituitary deficiency, which was more common in men.
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Síndrome de Silla Turca Vacía/patología , Adulto , Síndrome de Silla Turca Vacía/diagnóstico por imagen , Femenino , Humanos , Hiperprolactinemia , Hipopituitarismo/diagnóstico por imagen , Hipopituitarismo/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiografía , Estudios Retrospectivos , Silla Turca/diagnóstico por imagen , Silla Turca/patologíaRESUMEN
Introducción: El término Silla Turca Vacía Primaria (STVP) hace referencia a la invaginación del espacio subaracnoideo hacia el interior de la silla turca en pacientes sin antecedentes de tumor, cirugía o radioterapia de la región selar. Aunque usualmente no está asociado con disfunciones endocrinas, diferentes grados de hipopituitarismo e hiperprolactinemia han sido reportados. Objetivo: Analizar retrospectivamente datos clínicos, hallazgos radiológicos y bioquímicos de 117 pacientes con diagnóstico de STVP. Pacientes y Métodos: Se estudiaron 117 pacientes, 98 mujeres (48 ± 14.9 años). Los diagnósticos fueron realizados por Resonancia Magnética Nuclear (n=115) y Tomografía Computada (n=2). La evaluación de la función adenohipofisaria se realizó a través de determinaciones hormonales basales. Resultados: Los motivos que llevaron al pedido de las imágenes fueron: cefaleas (35 %), sospecha clínica y/o bioquímica de deficiencia pituitaria (22 %), trastornos visuales (11 %), anormalidades de la radiografía simple de la silla turca (11 %), hiperprolactinemia (2,6 %), otros (18.4 %). El 48,9 % de las mujeres eran multíparas. Cefaleas, obesidad, hipertensión arterial y autoinmunidad tiroidea fueron halladas en el 60, 67, 24,5 y 22,5 % de la población evaluada respectivamente. Hiperprolactinemia (< 50 ng/ml) estuvo presente en 6,1 % de las mujeres y 15, 8 % de los hombres. El 27 % de los pacientes estudiados presentó algún grado de hipopituitarismo, que fue más frecuente en la población masculina. Conclusiones: STVP fue más frecuente en mujeres multíparas de mediana edad. En la mayoría de los casos fue descubierta incidentalmente por estudios radiológicos, mientras que en un cuarto de los pacientes, fue encontrada durante la evaluación diagnóstica de deficiencia adenohipofisaria, lo cual fue más frecuente en hombres.
Introduction: The term Primary Empty Sella (PES) makes reference to the herniation of the subarachnoid space within the sella turcica in those patients with no history of pituitary tumor, neither surgery, nor radiotherapy. Though it is usually not associated with endocrine abnormalities, different degrees of hypopituitarism and mild hyperprolactinemia have been reported. Objective: To assess clinical features, radiological findings and biochemical endocrine function retrospectively from the records of 117 patients with diagnosis of PES. Patients and Methods: One hundred seventeen patients, 98 females, were studied. The mean age at diagnosis was 48 ± 14.9 yr. Most diagnoses were made with magnetic resonance imaging (n = 115), and only 2 through sellar computed tomography scan. Only pituitary basal hormones determinations were made, except for the TRH and ACTH tests which were performed for the diagnosis of primary hypothyroidism and secondary adrenal failure respectively. Results: Pituitary images were requested because of different reasons: headaches (35 %), clinical and biochemical suspicion of pituitary deficiency (22 %), visual disturbances (11 %), abnormalities on the simple sella turcica radiography (11 %) hyperprolactinemia (2.6 %), others (18.4 %): dizziness, seizures, rhinorrhea, loss of consciousness, skull trauma, galactorrhea. Multiple pregnancies were observed in 48.9 % of women; headaches, obesity, arterial hypertension and thyroid autoimmunity were found in 60 %, 67 %, 24.5 % and 22.5 % of the studied population respectively. Mild hyperprolactinemia (< 50 ng/ml) was present in 6.1 % of women and 15.8 % of men. Twenty seven percent of our patients had some degree of hypopituitarism. For male population hypopituitarism comprised 72 %, whereas it took up 19 % for the whole female group. Conclusions: PES seems to be more commonly found in middle-aged women (sex ratio 5/1) with history of multiple pregnancies. In most patients it was discovered as an incidental finding at image studies, while in almost a quarter of patients PES was found during the diagnosis stage of anterior pituitary deficiency, which was more frequently seen among men.
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Introducción: La determinación de IGF-I en suero o plasma es una herramienta esencial en el diagnóstico y seguimiento de la acromegalia. Sin embargo, se deben tener presentes algunos inconvenientes en su medición por diferentes inmunoensayos. Objetivos: Evaluar dos inmunoensayos para la determinación de IGF-I y su correlación con el nadir de GH en el TTOG en pacientes acromegalicos. Materiales y métodos: Se analizaron 37 pacientes acromegálicos, 20 mujeres y 17 hombres. IGF-I fue determinada por Immulite 1000, (IMM) y por IRMA (DSL). Se realizó el TTOG y se determinó glucosa y GH en todos los tiempos (basal, 30, 60, 90 y 120min). Se consideró respuesta normal un nadir de GH <1ng/ml. Nueve pacientes se encontraban bajo tratamiento y 28 sin tratamiento. Análisis estadístico: se utilizaron el test de Wilcoxon, de Bland y Altman y curvas ROC. Se consideró significativa una p<0,05. Resultados: Las concentraciones basales de glucosa fueron 97,86±10,91 mg/dl, de GH 2,8 (1,59-14,4) ng/ml, de IGF-I por IMM 602±318 ng/ml y por DSL 1006±596 ng/ml. IGF-I por IMM y DSL mostró una diferencia significativa con p <0,01 y un bias de - 403,2 ng/ml con valores menores por IMM. IGF-I elevada por IMM y DSL, se encontró en el 84% y en el 97% respectivamente. IGF-I elevada con nadir de GH >1ng/ml se encontró en el 70%, con nadir de GH normal en el 13,5%. IGF-I normal con nadir >1ng/ml en el 2,7% y con nadir de GH normal en el 13,5%. El área bajo las curvas ROC no mostró diferencias significativas. Conclusiones: Los niveles de IGF-I determinados por IMM y DSL fueron significativamente diferentes mostrando un bias negativo para IMM. La mayoría de los valores del nadir de GH fueron consistentes con los niveles de IGF-I observándose una discrepancia en el 30% de los pacientes, estuvieran o no bajo tratamiento.
Introduction: IGF-I determination in serum or plasma is an essential tool in the diagnosis and follow-up of acromegaly. Hepatic production of IGF-I is regulated by GH and circulates bound to several IGF-I binding proteins which extends its half life. IGF-I is not released in a pulsatile pattern and has no significant variability in 24 h. Objective: To evaluate two different methodologies in IGF-I levels determination and their correlation with GH nadir in OGTT in acromegalic patients. Material and methods: We analyzed 37 acromegalic patients, 20 women and 17 men, mean age was 45±12 years. IGF-I levels were assayed by Immulite 1000, DPC (IMM) and DSL-5600 ACTIVE® IGF-I Coated-Tube IRMA (DSL) and OGTTs (at baseline and at 30, 60, 90 and 120 minutes) were performed by measuring plasma glucose and GH assay by immunochemiluminometric assay (Access); we considered a nadir <1ng/ml as normal response. Nine patients were under medical treatment (cabergoline: 4, octeotride: 4, and cabergoline plus octeotrite: 1) and 28 without treatment. Statistical analysis: Wilcoxon and, Bland and Altman tests and ROC curves. Differences were considered significant at p< 0.05. Results: Basal glucose levels were 97.86±10.91 mg/dl and mean GH was 2.8 (1.59-14.4) ng/ml. Mean IGF-I levels performed by IMM were 602±318 ng/ml and 1006±596 ng/ml by DSL. There was a statistically significant difference between both methodologies (p<0.01). Bland and Altman test showed a bias of - 403.2 ng/ml with lower values by IMM. We observed elevated IGF-I levels in 84% by IMM and in 97% by DSL, and only one patient had normal levels with both methodologies. Elevated IGF-I levels and GH nadir >1ng/ml were observed in 70% of the patients, increased IGF-I with normal GH nadir in 13.5%, normal IGF-I with GH nadir >1ng/ml in 2.7% and normal IGF-I with normal GH nadir in 13.5%. Patients under treatment: 3 showed normal GH nadir with elevated IGF-I levels, in 2 of them by both methodologies, and in the other one it was normal by IMM and elevated by DSL; the other 6 showed GH nadir > 1ng/ml, 5 of them presented elevated IGF-I by both methodologies and the other one showed discrepancy in IGF-I levels. The under ROC curve area and confidence interval (CI) of 95% for IGF-I IMM and DSL were 0.96 (0.90-1.00) and 0.91 (0.82-1.00) respectively. Differences between the ROC curves areas were not significant Conclusions: IGF-I levels determined by IMM and DSL were statistically significantly different. IGF-I levels showed a negative bias by IMM. Most of the results of GH nadir were consistent with IGF-I levels but we observed discrepancy in 30% of the patients, regardless of whether they were under treatment or not.
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Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Acromegalia/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Prueba de Tolerancia a la Glucosa/estadística & datos numéricos , Inmunoensayo/métodos , Interpretación Estadística de Datos , Hormona de Crecimiento Humana/análisisRESUMEN
Objetivos: Estimar la frecuencia de complicaciones maternofetales en mujeres que se embarazaron durante el tratamiento con cabergolina (CAB). Estimar la frecuencia de patología detectada posnacimiento en los niños producto de dichos embarazos. Material y métodos: Estudio retrospectivo y multicéntrico de 86 embarazos en 78 mujeres con hiperprolactinemia idiopática (7) o tumoral (44 micro y 27 macro), en tratamiento con CAB en el momento de la concepción. Edad: 20 a 45 años; PRL inicial: 30 a 1429 ng/ml; duración del tratamiento previo al embarazo 1 a 120 meses; dosis: 0.125 a 4 mg/semana. El rango de exposición embriofetal a la CAB fue de 3 a 27 semanas, el 96.39% de las pacientes la recibió durante el primer trimestre y el 3.61% hasta el segundo. Resultados: No hubo complicaciones mayores durante el embarazo. Se registraron 7 abortos espontáneos (8.1%) y 75 partos, de los cuales 49 fueron vaginales y 26 cesáreas. Se registraron 69 recién nacidos, 63 fueron a término y 6 pretérmino (8.8%), ninguno bajo peso para la edad gestacional. En 3 (5.2%) recién nacidos se observó: 1 malformación mayor (Síndrome de Down) y 2 menores (hernia umbilical e inguinal). Se obtuvo seguimiento de 42 recién nacidos; se diagnosticó epilepsia refractaria en uno y un trastorno generalizado del desarrollo en otro. No se halló una mayor frecuencia de complicaciones en los embarazos ni en los recién nacidos expuestos a CAB que en la población normal. Sería necesario mayor número de pacientes para concluir sobre la seguridad de CAB durante el embarazo.
Objectives: To assess the rate of any potential adverse effects on pregnancy and embryo-fetal development in women who became pregnant under treatment with cabergoline (CAB). To follow up medical data of children who were born from mothers exposed to Cab in early weeks of gestation. Material and methods: Observational, retrospective and multicenter study on 86 pregnancies in 78 women with idiopathic or tumoral hyperprolactinemia. All patients were under Cab at conception. The average age was 29 (range: 20-45). Pituitary images at diagnosis showed 44 microadenomas, 27 macroadenomas and 7 were normal. Serum PRL at baseline was between 30 and 1429 ng/ml. Duration of therapy before pregnancy ranged from 1 to 120 months. Maternal and fetal exposure to cabergoline and doses ranged from 0.125 to 4 mg/week. The mean serum PRL level under which patients achieved pregnancy was 17 ng/ml. Fetal exposure ranged from 3 to 27 weeks; 96.39% of patients received CAB during the first trimester of pregnancy and 3.61% until the second one. Results: No significant complications during pregnancy were found. Seven women (8.1%) had spontaneous abortions. Term deliveries were recorded in 63/69, preterm in six (8.8%), none of them with low weight for gestational age. Neonatal abnormalities were observed in 3 (5.2%): 1 major (Down syndrome) and 2 minor malformations (umbilical and inguinal hernia). Two out of 42, developed abnormalities during the follow- up, one of them was a refractory epilepsy during the second month of life, the other presented a Pervasive Developmental Disorder diagnosed in the third year of life. Conclusion: No significantly higher frequency of complications was found in pregnancies and/or offspring exposed to CAB than in normal population. Larger series of patients are needed to asses the safety.
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Humanos , Femenino , Embarazo , Adulto , Persona de Mediana Edad , Complicaciones del Embarazo/etiología , Ergolinas/efectos adversos , Anomalías Congénitas/prevención & control , Embarazo/efectos de los fármacos , Desarrollo Embrionario y Fetal/efectos de los fármacosRESUMEN
The GH receptor antagonist pegvisomant is an efficient agent to achieve biochemical control of acromegaly in those cases refractory to surgery and medical therapy with somatostatin analogs. We conducted an observational multicenter study consisting of data collection in accordance with the standard management of patients with acromegaly in everyday practice. We reviewed the medical records of 28 patients, 23 females, who were treated with pegvisomant due to the lack of biochemical response or intolerance to the somatostatin analogs. The objective was to monitor long-term safety and efficacy of the antagonist. 82% of the patients had previous pituitary surgery, 53.6% radiotherapy and 96.4% received medical therapy for acromegaly. Only 19.2% of the patients had pituitary residual tumor size larger than 1 cm, the remainder harbored a microadenoma or no visible tumor in the pituitary images. In terms of biochemical efficacy, IGF-I levels decreased to normal ranges in 45% and 58.8% of patients after 3 and 6 months of treatment, respectively, the daily mean dose of pegvisomant being 9.6+/-1.1 mg. Adverse events, potentially related to pegvisomant were reported in 6 patients (21.4%), local injection site reaction and elevated liver enzymes being the most frequent. Tumor size did not show enlargement in the evaluated population (15 patients) during the period of the study. This paper presents preliminary data from a small observational study in Argentina which represents the first database in our country.
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Acromegalia/tratamiento farmacológico , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatotropina/antagonistas & inhibidores , Acromegalia/sangre , Adulto , Anciano , Femenino , Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana EdadRESUMEN
Objetivo: Analizar la presentación clínica, radiológica, bioquímica y el comportamiento posquirúrgico de una cohorte de pacientes portadores de gonadotrofinomas. Pacientes y Métodos: Se evaluaron pacientes con gonadotrofinomas estudiados en nueve centros endocrinológicos de la ciudad de Bs.As. durante el período 1983 a 2003. El criterio de inclusión fue la inmunohistoquímica (IH) positiva para hormona luteinizante (LH), folículoestimulante (FSH) y/o alfa subunidad (ASU). Los adenomas plurihormonales fueron excluidos. Resultados: Fueron analizados 66 pacientes de 51,8 ± 12,1 (X +/- DS) años (39 varones). Los síntomas mas frecuentemente observados fueron las alteraciones visuales (72,8%), seguidas por el hipogonadismo y las cefaleas. El 10,6% se diagnosticaron en forma incidental. El 98,5% fueron macroadenomas, 56,9% de los cuales correspondieron a un estadio Hardy (EH) 3 y 29,6% a un EH 4. El tiempo de seguimiento fue de 47,8 meses (r: 5-168). El hipogonadismo definido bioquímicamente se presentó en el 82,4% de los pacientes. En su mayoría presentaban niveles bajos o inapropiadamente normales de gonadotrofinas, pero 4 mujeres y 3 varones presentaron niveles séricos elevados y disociados de FSH y LH. La hiperprolactinemia por desconexión fue observada en 45,2% de la población (X: 65.6 ng/ml r: 30-172). El hipopituitarismo se detectó en 25,7% de los casos. La cirugía fue transeptoesfenoidal (TSE) en 80%; una segunda operación fue realizada en el 28% de la población. La IH fue positiva por orden de frecuencia para LH, FSH y ASU o las 3 combinaciones. La evolución posquirúrgica evidenció mejoría en el campo visual (CV) en el 41%. La presencia de restos tumorales y/o recidiva fue del 84%. Se indicó radioterapia en 37% y la sustitución hormonal fue necesaria en el 65% de los pacientes.
The aim of our study was to describe the clinical-biochemical and radiologic presentation and the post surgery outcome in a cohort of patients with gonadotrophinomas. Patients were selected from nine Endocrinology Units of the city of Buenos Aires from 1983 at 2003. The inclusion criteria was defined by nonfunctinoning pituitary adenomas with positive innmunohistochemical (IH) for luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or alpha subunit (ASU). Innmunohistochemically plurihormonal adenomas were excluded. Sixty six patients were analyzed, aged 51,8 ± 12,1 (X +/- DS) years; (39 men). More prevalent symptoms were visual alterations (72,8%), hypogonadism and headaches. Eleven percent was diagnosed as incidentalomas. Ninety eight percent were macroadenomas, 56,9% was Hardy stage (HS) 3 and 29,6% was HS 4. The patients were followed up for 47,8 months (r: 5-168). Hypogonadism was biochemically found in 82,4%. The majority showed low or inappropriately normal levels of gonadotrophins except for 4 women and 3 men that had high and dissociated levels. Hyperprolactinemia was observed in 45,2% and was interpreted as an interference with normal dopamine inhibition of prolactin secretion (X+/-DS: 65.6+/- ng/ml, r: 30-172). Hypopituitarism was found in 25,7% of the patients. Transsphenoidal surgery was carried out in 80% and in 28% a second surgery was needed. The IH was positive for LH, FSH and ASU in this order of frequency or its combinations. Tumor persistency and/or recurrency were found in 84% of the patients. Forty one percent showed improvement of visual defects. Radiotherapy was indicated in 37% and hormonal replacement was needed in 65% of the patients.
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Adenoma Cromófobo/sangre , Adenoma Cromófobo/diagnóstico por imagen , Neoplasias Hipofisarias/etiología , Adenoma Cromófobo/cirugía , Estudios Retrospectivos , Gonadotropinas Hipofisarias/inmunologíaRESUMEN
Two of the most potent cytokines regulating anterior pituitary cell function are leukemia inhibitory factor (LIF) and interleukin (IL)-6, which belong to the cytokine family using the common gp130 signal transducer. Recently, the expression and action of two other members of this family, IL-11 and ciliary neurotrophic factor (CNTF), on different cell lines has also been demonstrated. We studied the expression of the specific receptor subunits for CNTF in mammotropic, non-functioning and somatotropic tumors and the action of CNTF and IL-11 in the regulation of hormone secretion in these and normal pituitary cells. The mRNA for the alpha chain specific for the CNTF receptor was detected by Northern blot in tumors secreting prolactin (PRL) and GH and in non-functioning tumors. We found that both IL-11 and CNTF exerted a similar stimulatory effect on GH mRNA expression in somatotropic monolayer cell cultures from acromegalic tumors, but these cytokines had no significant influence on GH secretion. CNTF stimulates prolactin secretion in lactotropic monolayer cell cultures from patients with prolactinoma. In monolayer cell cultures from normal rat anterior pituitary, IL-11 and CNTF had no significant effect on the release of either GH or PRL, or on GH mRNA. However, when the cells were cultured in aggregate cultures, in which the three-dimensional structure of the cells is reconstituted, both cytokines, in doses at which they had no effect on monolayer cultures, significantly stimulated both PRL and GH secretion. These data show that IL-11 and CNTF may act as regulatory factors in anterior pituitary cells, in which the three-dimensional structure of the gland is of critical importance.
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Adenoma/metabolismo , Factor Neurotrófico Ciliar/farmacología , Interleucina-11/farmacología , Adenohipófisis/efectos de los fármacos , Neoplasias Hipofisarias/metabolismo , Animales , Agregación Celular , Técnicas de Cultivo de Célula , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hormona de Crecimiento Humana/biosíntesis , Hormona de Crecimiento Humana/genética , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Adenohipófisis/citología , Prolactina/metabolismo , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptor de Factor Neurotrófico Ciliar/metabolismo , Células Tumorales CultivadasRESUMEN
Two of the most potent cytokines regulating anterior pituitary cell function are leukemia inhibitory factor and interleukin-6 (IL-6), which belong to the cytokine receptor family using the common gp130 signal transducer. We studied the actions of two other members of this family, IL-11 and ciliary neurotropic factor (CNTF), on folliculostellate (FS) cells (TtT/GF cell line) and lactosomatotropic cells (GH3 cell line). The messenger RNA (mRNA) for the alpha-chain specific for the IL-11 receptor (1.7 kb) and CNTF receptor (2 kb) are expressed on both cell types. In addition, we detected CNTF receptor mRNA in normal rat anterior pituitary cells. IL-11 (1.25-5 nM) dose dependently stimulated the proliferation of FS cells. CNTF, at doses from 0.4-2 nM, also significantly stimulated the growth of these cells. In addition, both cytokines significantly stimulated proliferation of lactosomatotropic GH3 cells, and CNTF stimulated hormone production (GH and PRL) at 24 h by these cells. At 16-72 h, IL-11 stimulates the secretion of the angiogenic factor vascular endothelial growth factor by FS cells. In addition, both GH3 and FS cells express CNTF mRNA. These data suggest that IL-11 and CNTF may act as growth and regulatory factors in anterior pituitary cells.
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Factor Neurotrófico Ciliar/fisiología , Interleucina-11/fisiología , Lactancia/fisiología , Adenohipófisis/fisiología , Receptor de Factor Neurotrófico Ciliar/biosíntesis , Receptores de Interleucina/biosíntesis , Animales , División Celular , Línea Celular , Factores de Crecimiento Endotelial/metabolismo , Femenino , Subunidad alfa del Receptor de Interleucina-11 , Linfocinas/metabolismo , Masculino , Adenohipófisis/citología , Ratas , Ratas Sprague-Dawley , Receptor de Factor Neurotrófico Ciliar/genética , Receptores de Interleucina/genética , Receptores de Interleucina-11 , Proteínas Recombinantes/farmacología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
UNLABELLED: To facilitate the estimation of acromegalic activity a prospective study was done comparing, against a clinical score, the effectiveness of serum IGF-I, IGFBP3 and the IGF-I/IGFBP3 molar ratio. Sixty nine observations were distributed in three groups: Group I=patients before surgery; group II=patients improved but still clinically active; group III=patients clinically inactive. Suppression of serum GH levels one hour after an oral glucose load was in agreement with the clinical score in 21/22 observations. Increases in serum IGF-I and IGFBP3 levels were similarly frequent: both 100% in group I, 80% and 95% in group II, 9% and 36% in group III, respectively. The frequency of abnormal molar ratios was 95%, 40% and 0% in the same groups. Log IGF-I, log IGFBP3, and log molar ratio correlated significantly with the clinical scores (r=0.873, r=0.692, and r=0.829, respectively). CONCLUSIONS: The IGF-I/IGFBP3 molar ratio was not better than either IGF-I or IGFBP3 in detecting activity in the three groups of patients studied. Both IGF-I and IGFBP3 appear comparably useful for the diagnosis and follow-up of acromegalic patients. Since IGF-I is a more biologically meaningful parameter it might be preferable.
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Acromegalia/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Acromegalia/cirugía , Adolescente , Adulto , Anciano , Hormona de Crecimiento Humana/sangre , Humanos , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The biosynthesis of met-enkephalin in human pituitary and human pituitary adenomas is still not well known. In this work, we studied the processing of proenkephalin-derived peptides in postmortem human pituitary (PMHP), ACTH-producing adenomas (ACTH-PA), nonfunctioning adenomas (NFA), and GH-producing adenomas (GH-PA). ACTH-PA contained at least 10 times more proenkephalin-derived peptides than PMHP, NFA,and GH-PA. Proenkephalin processing was different in the four tested tissues. In ACTH-PA, proenkephalin was processed to high-, intermediate-, and low-mol-wt products. The highest met-enkephalin-containing peptides levels corresponded to intermediate and low-mol-wt materials, although met-enkephalinArg-Phe and synenkephalin immunoreactivity appeared only in high-mol-wt peptides. In PMHP and NFA, met-enkephalin-Arg-Phe immunoreactivity was detected in intermediate- and low-mol-wt materials, and it was absent in GH-PA. Immunoblotting of ACTH-PA showed that met-enkephalin-Arg-Phe immunoreactivity corresponded to peptides of 44, 32-30, 27, and 17 kDa. The 32-30 and 17-kDa molecules were localized in the nuclear fraction where they were extracted after enzymatic digestion with DNase I. Plasmatic met-enkephalin levels did not increase in patients with Cushing's disease, suggesting that the pentapeptide stored in ACTH-PA was not released to the general circulation. In conclusion, we demonstrated that only ACTH-PA contained high levels of proenkephalin peptides, which were stored in cytoplasm organelles and in the nucleus, probably bound to chromatin. These results suggest an adenoma-specific physiological role of proenkephalin products.
Asunto(s)
Adenoma/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Encefalinas/metabolismo , Neoplasias Hipofisarias/metabolismo , Precursores de Proteínas/metabolismo , Adulto , Anciano , Carboxipeptidasa B , Carboxipeptidasas/metabolismo , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Desoxirribonucleasa I/metabolismo , Encefalina Metionina/metabolismo , Femenino , Hormona de Crecimiento Humana/metabolismo , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Peso Molecular , Hipófisis/metabolismo , Procesamiento Proteico-Postraduccional , Tripsina/metabolismoRESUMEN
Cabergoline (CAB) is a long-acting dopamine agonist. In the first national study with CAB--as part of an international multicentric study--39 adult and adolescent females (16 to 44 years old) with hyperprolactinemic amenorrhea (18 microadenomas and 21 idiopathic hyperprolactinemias) were evaluated. CAB or bromocriptine (BEC) was administered for 24 weeks: over 8 weeks, treatment was given under double-blind conditions, and over the remaining 16 weeks (open period) 18 patients received CAB and 21 received BEC as a result of a random distribution. Maximum dosage: CAB = 1.5 mg in 2 or 3 weekly doses; BEC = up to 10 mg in 2 daily doses. Prolactin was measured at base line and 2, 4, 6, 8, 12, 14, 16, 20 and 24 weeks after the initiation of treatment. When vaginal bleeding was restored, progesterone was measured as an ovulation sign. The 4 adolescents continued with CAB treatment for 1 more year. Prolactin was statistically evaluated according to Man Whitney Test (general population) or Wilcoxon Test (adolescents). There were no significant differences between basal levels of prolactin (ng/ml) in patients treated with BEC or CAB: (173.86 +/- 28.23 and 152.11 +/- 14.06 respectively); at the fourth week of treatment the decrease was smaller (p = 0.005) in patients treated with BEC (36.36 +/- 5.71) than in those treated with CAB (14.06 +/- 3.60) and at 24 weeks differences disappeared: BEC = 19.88 +/- 4.48 and CAB = 9.63 +/- 2.62 (p = NS). The adolescents showed a marked decrease in prolactin with no significant differences between BEC and CAB: basal levels = 168.17 +/- 75.47 and 213 +/- 96.99 (p = NS); 4 weeks = 48.00 +/- 8.72 and 35.00 +/- 12.58 (p = NS); 24 weeks = 34.33 +/- 10.17 and 21.75 +/- 7.23 respectively. At 48 weeks (23.25 +/- 11.23) levels remained the same as those of week 24 (p = NS). Some patients treated with BEC had nausea, vomits and epigastralgia; these symptoms were not observed with CAB. All patients resumed menstrual cycles, except one treated with BEC; 6 patients treated with CAB became pregnant, and the 5 patients who continued under our control gave birth to healthy infants. It is concluded that CAB is a useful therapy. This is specially true for adolescents (an age group difficult to manage) because of its easy administration and the almost complete absence of side effects.
Asunto(s)
Amenorrea/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Ergolinas/uso terapéutico , Hiperprolactinemia/tratamiento farmacológico , Adolescente , Adulto , Amenorrea/complicaciones , Bromocriptina/uso terapéutico , Cabergolina , Método Doble Ciego , Tolerancia a Medicamentos , Femenino , Humanos , Hiperprolactinemia/complicaciones , Prolactina/sangre , Resultado del TratamientoRESUMEN
We have previously shown that interleukin-2 (IL-2) and IL-6, which are expressed in the anterior pituitary, affect anterior pituitary cell proliferation in normal rats and cell lines. Here we examined their effects on the c-fos expression by human anterior pituitary adenomas. Adenoma cells in culture do not express c-fos mRNA. In adenoma explants, however, c-fos expression was detected and was regulated by IL-2 or IL-6. In different tumors (ACTH-, PRL-, GH-secreting and non functioning adenomas), these interleukins had inhibitory or stimulatory effects but the kind of response does not seem to be associated to tumor type or size. Using blocking antibodies, we observed that intrinsic IL-2 and IL-6 regulate c-fos expression in the same way. Our data suggest that IL-2 and IL-6 are not only involved in the regulation of pituitary adenoma function but may also, given the role of c-fos in cell proliferation, be implicated in the development of human pituitary adenomas.
Asunto(s)
Adenoma/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Genes fos/genética , Interleucina-2/farmacología , Interleucina-6/farmacología , Neoplasias Hipofisarias/genética , Adenoma/patología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenohipófisis , Neoplasias Hipofisarias/patología , ARN Mensajero/análisis , ARN Neoplásico/análisis , Células Tumorales CultivadasRESUMEN
Against a clinical score we compared the effectiveness of three biochemical markers of acromegalic activity: a) growth hormone response to i.v. thyrotropin-releasing hormone, b) growth hormone suppression one hour after an oral glucose load, c) basal plasma IGF-I levels. In 21 patients we obtained 39 observations comprising the four parameters. According to the clinical score, patients were divided into three groups: group I = patients before surgery; group II = improved but still clinically active; group III = clinically inactive. After i.v. thyrotropin-releasing hormone, abnormal observations increased although the patients improved clinically, so that this test was excluded from statistical analysis. Abnormalities in plasma IGF-I levels and in GH suppression after oral glucose were similarly frequent in the groups studied: both 100% in group I, both 71.4% in group II, 27.3% vs. 18.2% in group III (p > 0.05). Both tests made exactly the same contribution to the other's capacity to detect acromegalic activity: 3 out of 39 observations (5.1%). We conclude that basal plasma IGF-I is the single best biochemical marker to detect acromegalic activity, since it is statistically at least as useful as growth hormone suppression, and is far more simple for the patient and the laboratory.
Asunto(s)
Acromegalia/diagnóstico , Factor I del Crecimiento Similar a la Insulina/análisis , Hormona Liberadora de Tirotropina , Acromegalia/sangre , Biomarcadores/sangre , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa , Hormona del Crecimiento/efectos de los fármacos , Humanos , Estudios Prospectivos , Factores de TiempoRESUMEN
Tomando como base un score clínico comparamos la efectividad de tres marcadores bioquímicos de actividad de acromegalia: a) la respuesta de hormona de crecimiento a la inyección endovenosa de TRH, b) el grado de supresión de los niveles de hormona de crecimiento una hora después de una sobrecarga oral de glucosa, c) los niveles plasmáticos basales de IGF-I. en 21 pacientes se realizaron 39 observaciones que comprendían los cuatro parámetros. De acuerdo con su score clínico los pacientes se dividieron en tres grupos: grupo I = prequirúrgicos; grupo II = mejorados pero aún clínicamente activos, grupo III = clínicamente inactivos. Como la frecuencia de resultados anormales luego de la inyección de TRH aumentó en vez de disminuir cuando los pacientes mejoraban clínicamente, este test se excluyó del análisis estadístico. En los grupos I, II y III tanto la presencia de valores de IGF-I plasmático por en cima de lo normal como la falta de supresión adecuada de hormona de crecimiento luego de una sobrecarga de glucosa aparecieron con frecuencias muy semejantes: la misma en el grupo I (100 por ciento) en el grupo II (71.4 por ciento); y 27.3 por ciento vs. 18.2 por ciento en el grupo III (p > 0.05). La contribución de un test al poder de detección del otro fue igual para ambos: 3 observaciones sobre un total de 39(5.1 por ciento). Considerando que el nivel plasmático basal de IGF-I es estadísticamente tan útil como la supresión de hormona de crecimiento y teniendo en cuenta que el primero es mucho más simple para el paciente y el laboratorio, concluímos que el nivel plasmático basal de IGF-I es el mejor marcador bioquímico de actividad de acromegalia (AU)
Asunto(s)
Estudio Comparativo , Humanos , Acromegalia/diagnóstico , Glucosa/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/análisis , Hormona Liberadora de Tirotropina/administración & dosificación , Acromegalia/metabolismo , Hormona del Crecimiento/efectos de los fármacos , Biomarcadores , Factores de Tiempo , Estudios Prospectivos , Estudios de SeguimientoRESUMEN
Tomando como base un score clínico comparamos la efectividad de tres marcadores bioquímicos de actividad de acromegalia: a) la respuesta de hormona de crecimiento a la inyección endovenosa de TRH, b) el grado de supresión de los niveles de hormona de crecimiento una hora después de una sobrecarga oral de glucosa, c) los niveles plasmáticos basales de IGF-I. en 21 pacientes se realizaron 39 observaciones que comprendían los cuatro parámetros. De acuerdo con su score clínico los pacientes se dividieron en tres grupos: grupo I = prequirúrgicos; grupo II = mejorados pero aún clínicamente activos, grupo III = clínicamente inactivos. Como la frecuencia de resultados anormales luego de la inyección de TRH aumentó en vez de disminuir cuando los pacientes mejoraban clínicamente, este test se excluyó del análisis estadístico. En los grupos I, II y III tanto la presencia de valores de IGF-I plasmático por en cima de lo normal como la falta de supresión adecuada de hormona de crecimiento luego de una sobrecarga de glucosa aparecieron con frecuencias muy semejantes: la misma en el grupo I (100 por ciento) en el grupo II (71.4 por ciento); y 27.3 por ciento vs. 18.2 por ciento en el grupo III (p > 0.05). La contribución de un test al poder de detección del otro fue igual para ambos: 3 observaciones sobre un total de 39(5.1 por ciento). Considerando que el nivel plasmático basal de IGF-I es estadísticamente tan útil como la supresión de hormona de crecimiento y teniendo en cuenta que el primero es mucho más simple para el paciente y el laboratorio, concluímos que el nivel plasmático basal de IGF-I es el mejor marcador bioquímico de actividad de acromegalia
Asunto(s)
Humanos , Acromegalia/diagnóstico , Glucosa/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/análisis , Hormona Liberadora de Tirotropina/administración & dosificación , Acromegalia/metabolismo , Estudios de Seguimiento , Hormona del Crecimiento/efectos de los fármacos , Biomarcadores , Estudios Prospectivos , Factores de TiempoRESUMEN
Against a clinical score we compared the effectiveness of three biochemical markers of acromegalic activity: a) growth hormone response to i.v. thyrotropin-releasing hormone, b) growth hormone suppression one hour after an oral glucose load, c) basal plasma IGF-I levels. In 21 patients we obtained 39 observations comprising the four parameters. According to the clinical score, patients were divided into three groups: group I = patients before surgery; group II = improved but still clinically active; group III = clinically inactive. After i.v. thyrotropin-releasing hormone, abnormal observations increased although the patients improved clinically, so that this test was excluded from statistical analysis. Abnormalities in plasma IGF-I levels and in GH suppression after oral glucose were similarly frequent in the groups studied: both 100
in group I, both 71.4
in group II, 27.3
vs. 18.2
in group III (p > 0.05). Both tests made exactly the same contribution to the others capacity to detect acromegalic activity: 3 out of 39 observations (5.1
). We conclude that basal plasma IGF-I is the single best biochemical marker to detect acromegalic activity, since it is statistically at least as useful as growth hormone suppression, and is far more simple for the patient and the laboratory.
RESUMEN
Searching for differences in gene expression between different types of human pituitary adenomas, we evaluated the concentration of mRNA from hormonal genes (prolactin and growth hormone) and oncogenes (c-myc and c-fos) in 12 growth hormone-secreting 7 prolactin-secreting and 11 nonsecreting adenomas. We found a positive correlation between clinical diagnoses and hormonal gene expression in all the cases. Our reports indicate the presence of c-myc and c-fos mRNA in all the adenomas evaluated. The concentration of c-myc mRNA was higher in somatotrophic adenomas than in prolactinomas and nonsecreting adenomas whereas c-fos mRNA concentration was similar in the different types of tumours analysed. Oncogenes products, in turn, might stimulate DNA synthesis and cell proliferation and eventually lead to the formation of pituitary adenomas. This is a working hypothesis.
Asunto(s)
Adenoma/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Hormona del Crecimiento/metabolismo , Neoplasias Hipofisarias/genética , Prolactina/metabolismo , Adenoma/metabolismo , Adulto , Femenino , Hormona del Crecimiento/genética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/metabolismo , Prolactina/genética , ARN Mensajero/análisisRESUMEN
En los acromegálicos la respuesta somatotrófica al estímulo hipoglucémico es variable. En éstos, la bromocriptina disminuye las concentraciones basales de STH. Investigamos si el tamaño tumoral y/o el compromiso hipotalámico por expansión supraselar de los mismos condicionaba la respuesta hormonal, y si la bromocriptina modificaba la amplitud de las mismas. Se obtuvo hipoglucemia insulínica en 6 controles normales y en 12 acromegálicos, que se agruparon en: portadores de tumores intraselares (n=6) e invasivos (n=6), de éstos, con expansión supraselar (n=5) y sin expansión (n=7). En 6 se administró bromocriptina 10 mg/día/7 días al cabo de los cuales se repitió el test de hipoglucemia. La STH basal fue 28,4+ ou - 4,9, alcanzando un pico Mx de 45,5+ ou - 7,9 y un DELTAMx de 17,1+ ou - 5,2, NS en relación a los normales. La respuesta somatotrófica fue similar en los 4 grupos. En el 41,7% de los acromegálicos, ésta fue insuficiente y ello no se correlacionó con las características anatomorradiológicas de los tumores. La bromocriptina descendió la STH basal (p<0,02) y la respuesta a la hipoglucemia fue cuali y cuantitativamente similar a la del pretratamiento. En conclusión, la somatotrófica a la hipoglucemia en los acromegálicos fue similar a la de los normales. La negatividad o positividad e intensidad de la misma son indenpendientes de las características anatomorradiológicas tumorales. La bromocriptina no inhibe la respuesta somatotrófica a la hipoglucemia