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The aim of the study was to clarify the relationship and the time of aldosterone and renin recoveries at immediate and long-term follow-up in aldosterone-producing adenoma (APA) patients who underwent adrenalectomy. Prospective and longitudinal protocol in a cohort of APA patients was followed in a single center. Among 43 patients with primary aldosteronism (PA), thirteen APA patients were enrolled in this study. Blood was collected for aldosterone, renin, potassium, creatinine, cortisol, and ACTH before and 1, 3, 5, 7, 15, 30, 60, 90, 120, 180, 270, 360 days after adrenalectomy. At diagnosis, most patients (84%) had hypokalemia and high median aldosterone levels (54.8; 24.0-103 ng/dl) that decreased to undetectable (<2.2) or very low (<3.0) levels between fifth to seventh days after surgery; then, between 3-12 months, its levels gradually increased to the lower normal range. The suppressed renin (2.3; 2.3-2.3 mU/l) became detectable between the fifteen and thirty days after surgery, remaining normal throughout the study. The aldosterone took longer than renin to recover (60 vs.15 days; p<0.002) and patients with higher aldosterone had later recovery (p=0.03). The cortisol/ACTH levels remained normal despite the presence of a post-operative hypoaldosteronism. Blood pressure and antihypertensive requirement decreased after adrenalectomy. In conclusion, our prospective study shows the borderline persistent post-operative hypoaldosteronism in the presence of early renin recovery indicating incapability of the zona glomerulosa of the remaining adrenal gland to produce aldosterone. These findings contribute to the comprehension of differences in renin and aldosterone regulation in APA patients, although both are part of the same interconnected system.
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Adenoma , Neoplasias de las Glándulas Suprarrenales , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Hipertensión , Hipoaldosteronismo , Adenoma/cirugía , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Hormona Adrenocorticotrópica , Aldosterona , Humanos , Hidrocortisona , Hiperaldosteronismo/cirugía , Estudios Prospectivos , ReninaRESUMEN
BACKGROUND: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. METHODS: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. RESULTS: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. CONCLUSIONS: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.
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CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (Pâ =â .002), had lower GH at diagnosis (Pâ =â .01), had lower pretreatment GH and IGF-I (Pâ <â .001), and more frequently harbored tumors that were densely granulated (Pâ =â .014) or highly expressed SST2 (Pâ <â .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.
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Acromegalia/tratamiento farmacológico , Reglas de Decisión Clínica , Monitoreo de Drogas/métodos , Aprendizaje Automático , Receptores de Somatostatina/administración & dosificación , Acromegalia/sangre , Adulto , Anciano , Biomarcadores/sangre , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Queratinas , Ligandos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores de Somatostatina/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups. METHODS: Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings. RESULTS: We identified three methylation clusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors. CONCLUSIONS: We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status. These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors.
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Tumores Neuroendocrinos , Neoplasias Hipofisarias , Estudios de Cohortes , Metilación de ADN , Humanos , Tumores Neuroendocrinos/genética , Neoplasias Hipofisarias/genética , PronósticoRESUMEN
Twelve to 66% of patients with clinically non-functioning pituitary adenoma (NFPA) experience tumor recurrence 1-5 years after the first surgery. Nevertheless, there is still no recurrence prediction factor concisely established and reproduced in the literature for NFPA management. The present study evaluates the prognostic value of MRI Radiomics features combined with machine learning models to assess recurrence after the first surgery in patients with clinically non-functioning pituitary adenomas (NFPA). We carried out a retrospective study on 27 patients with NFPA, 10 patients having experienced tumor recurrence after the first surgery and 17 who did not. Preoperative 3D T1 contrast-enhanced MR images of patients were used to extract up to 255 Radiomics features from two and three-dimensional segmented regions. Additionally, gender, age at first surgery, and the presence of remnant tumor tissue were investigated to find the correlation with NFPA recurrence. Conventional statistics tests were used to evaluate whether the outcome patient groups (stable and recurrent) were different considering each feature individually. Additionally, five well-known machine-learning algorithms were used in combination with Radiomic features to classify recurrent and stable lesions. We found statistical evidence (p < 0.02) for 6 two-dimensional and 13 three-dimensional radiomic features. We achieved accuracies of up to 96.3% for 3D-feature based models and up to 92.6% accuracies for 2D-feature based models. 3D-feature based models achieved better performances using considerably fewer features when compared to 2D-feature based models. We concluded that Radiomics have the potential of NFPA recurrence prediction after the first surgery. Three-dimensional Radiomics have superior discrimination power to predict NFPA recurrence than two-dimensional radiomic features. Finally, the combination of Radiomics with machine-learning algorithms can offer computational models capable of non-invasive, unbiased, and quick assessment that might improve the prediction of NFPA recurrence.
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Aprendizaje Automático , Imagen por Resonancia Magnética , Neoplasias Hipofisarias , Algoritmos , Humanos , Neoplasias Hipofisarias/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
The present study was designed to evaluate the relationship between bone traits [bone mineral density (BMD) and trabecular bone score (TBS)] and the accumulation of fat in adipose tissues [abdominal subcutaneous (SAT), visceral (VAT), marrow (MAT) and intrahepatic lipids (IHL)], as well as insulin resistance, in subjects with Cushing's disease (CD). The study included control (C = 27), paired (P = 16) and Cushing's disease (CD = 10) groups, which underwent biochemical assessment, dual X-ray absorptiometry, TBS, and magnetic resonance imaging to determine fat deposits. The CD group showed higher serum levels of glucose and insulin, as well as HOMA-IR values, but lower circulatory levels of osteocalcin, in comparison to C and P. The CD group exhibited lower L1-L4 BMD than P (P = 1.059 ± 0.141 vs CD = 0.935 ± 0.093 g/cm2, p < 0.05) (Fig 1A). The lumbar spine BMD from the C group was similar to the other groups. TBS was lower in CD than in P and C (C = 1.512±0.077 vs P = 1.405±0.150 vs CD = 1.135±0.136; p<0.05); there was also significant difference between C and P (p<0.05). MAT, VAT, and IHL were higher in CD than in C and P (p<0.05). Considering all subjects, there was a positive association between TBS with both lumbar spine BMD (R2 = 0.45; p<0.0001) and osteocalcin (R2 = 0.44; p = 0.05). TBS was negatively associated with MAT (R2 = 0.49; p = 0.01), VAT (R2 = 0.55; p<0.05), and HOMA-IR (R2 = 0.44; p<0.01). MAT was positively related with VAT (R2 = 0.44; p<0.01) and IHL (R2 = 0.41; p<0.05). In CD, insulin resistance and adipose tissue dysfunction, including high MAT, are active players in bone deterioration, as confirmed by lower lumbar spine BMD and lower TBS. Thus, our findings point to an additional component of the already well-known complex mechanisms of osteoporosis associated with hypercortisolism.
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Tejido Adiposo/patología , Médula Ósea/patología , Huesos/patología , Síndrome Metabólico/complicaciones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/complicaciones , Adiponectina/metabolismo , Adulto , Peso Corporal , Densidad Ósea , Hueso Esponjoso/patología , Humanos , Resistencia a la Insulina , Leptina/metabolismo , Modelos Lineales , Lípidos/análisisRESUMEN
BACKGROUND: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months). METHODS: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal. RESULTS: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found. CONCLUSION: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients.
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Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Octreótido/uso terapéutico , Acromegalia/sangre , Adulto , Anciano , Femenino , Hormona del Crecimiento/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Estudios Retrospectivos , Síndrome de Abstinencia a Sustancias/etiología , Factores de Tiempo , Adulto JovenRESUMEN
Food access restriction is associated to changes in gene expression of the circadian clock system. However, there are only a few studies investigating the effects of non-photic synchronizers, such as food entrainment, on the expression of clock genes in the central oscillators. We hypothesized that different feeding restriction patterns could modulate the expression of clock genes in the suprachiasmatic nucleus (SCN) "master" clock and in extra-SCN oscillators such as the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei. Wistar rats were divided into four groups: Control group (CG; food available ad libitum), Restricted night-fed (RF-n; food access during 2 h at night), Restricted day-fed (RF-d; food access during 2 h at daytime), Day-fed (DF; food access during 12 h at daytime). After 21 days, rats were decapitated between ZT2-ZT3 (0800-0900 h); ZT11-ZT12 (1700-1800 h), or ZT17-18 (2300-2400 h). Plasma corticosterone was measured by radioimmunoassay (RIA). The expression of Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, Rev-erbα, and Rorα were assessed in SCN, PVN, and ARC hypothalamic nuclei by RT-PCR and calculated by the 2[-DeltaDeltaCT(Cyclethreshold)](2-ΔΔCT) method. Restricted food availability during few h led to decreased body weight in RF-n and RF-d groups compared to controls and DF group. We also observed an anticipatory corticosterone peak before food availability in RF-n and RF-d groups. Furthermore, the pattern of clock gene expression in response to RF-n, RF-d, and DF schedules was affected differently in the SCN, PVN, and ARC hypothalamic nuclei. In conclusion, the master oscillator in SCN as well as the oscillator in PVN and ARC, all brain areas involved in food intake, responds in a tissue-specific manner to feeding restriction.
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BACKGROUND: Inflammation is a key feature of aldosterone-induced vascular damage and dysfunction, but molecular mechanisms by which aldosterone triggers inflammation remain unclear. The NLRP3 inflammasome is a pivotal immune sensor that recognizes endogenous danger signals triggering sterile inflammation. METHODS: We analyzed vascular function and inflammatory profile of wild-type (WT), NLRP3 knockout (NLRP3-/-), caspase-1 knockout (Casp-1-/-), and interleukin-1 receptor knockout (IL-1R-/-) mice treated with vehicle or aldosterone (600 µg·kg-1·d-1 for 14 days through osmotic mini-pump) while receiving 1% saline to drink. RESULTS: Here, we show that NLRP3 inflammasome plays a central role in aldosterone-induced vascular dysfunction. Long-term infusion of aldosterone in mice resulted in elevation of plasma interleukin-1ß levels and vascular abnormalities. Mice lacking the IL-1R or the inflammasome components NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In vitro, aldosterone stimulated NLRP3-dependent interleukin-1ß secretion by bone marrow-derived macrophages by activating nuclear factor-κB signaling and reactive oxygen species generation. Moreover, chimeric mice reconstituted with NLRP3-deficient hematopoietic cells showed that NLRP3 in immune cells mediates aldosterone-induced vascular damage. In addition, aldosterone increased the expression of NLRP3, active caspase-1, and mature interleukin-1ß in human peripheral blood mononuclear cells. Hypertensive patients with hyperaldosteronism or normal levels of aldosterone exhibited increased activity of NLRP3 inflammasome, suggesting that the effect of hyperaldosteronism on the inflammasome may be mediated through high blood pressure. CONCLUSIONS: Together, these data demonstrate that NLRP3 inflammasome, through activation of IL-1R, is critically involved in the deleterious vascular effects of aldosterone, placing NLRP3 as a potential target for therapeutic interventions in conditions with high aldosterone levels.
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Aldosterona/farmacología , Arterias Mesentéricas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Acetilcolina/farmacología , Animales , Células de la Médula Ósea/citología , Trasplante de Médula Ósea , Caspasa 1/deficiencia , Caspasa 1/genética , Humanos , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-1beta/sangre , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Arterias Mesentéricas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Nigericina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Interleucina-1/deficiencia , Receptores de Interleucina-1/genética , Transducción de Señal/efectos de los fármacos , Enfermedades Vasculares/inducido químicamenteRESUMEN
CONTEXT: The comparison of variability, reproducibility, and diagnostic performance of late-night salivary cortisol (LNSF) and urinary free cortisol (UFC) using concurrent and consecutive samples in Cushing's syndrome (CS) is lacking. Objectives, Patients, and Methods: In a prospective study, we evaluated 3 simultaneous and consecutive samples of LNSF by RIA and UFC by liquid chromatography associated with tandem mass spectrometry in Cushing's disease (CD) patients (n = 43), adrenal CS patients (n = 9), and obese subjects (n = 18) to compare their diagnostic performances. In CS patients, we also performed a modified CS severity index. RESULTS: There was no difference in the coefficient of variation (percentage) between LNSF and UFC among the 3 samples obtained for each patient with Cushing's disease (35 ± 26 vs 31 ± 24), adrenal CS (28 ± 14 vs 22 ± 14), and obesity (39 ± 37 vs 48 ± 20). LNSF confirmed the diagnosis of hypercortisolism even in the presence of normal UFC in 17.3% of CS, whereas the inverse situation was not observed for UFC. The area under the receiver-operating characteristic curves for LNSF was 0.999 (95% credible interval [CI] 0.990-1.00) and for UFC was 0.928 (95% CI 0.809-0.987). The ratio between areas under the curve was 0.928 (95% CI 0.810-0.988), indicating better performance of LNSF than UFC in diagnosing CS. There was no association between the CS severity index and the degree of biochemical hypercortisolism. CONCLUSION: Our data show that despite similar variability between both methods, LNSF has a superior diagnostic performance than UFC and should be used as the primary biochemical diagnostic test for CS diagnosis.
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Síndrome de Cushing/diagnóstico , Técnicas de Diagnóstico Endocrino , Hidrocortisona/análisis , Saliva/química , Adolescente , Adulto , Anciano , Ritmo Circadiano , Síndrome de Cushing/orina , Femenino , Humanos , Hidrocortisona/orina , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6.
Apresentamos os dados clínicos e moleculares de dois pacientes com acromegalia tratados com octreotide LAR após cirurgia não curativa, com diferentes respostas a essa terapia medicamentosa. As expressões do receptor de somatostatina tipo 2 e 5 (SSTR2 e SSTR5) e da proteína de interação com o receptor aril hidrocarbono (AIP) foram analisadas por qPCR. Em ambos os casos, foi encontrada uma expressão elevada de SSTR2 e baixa do SSTR5. No entanto, o controle da doença foi obtido após tratamento com octreotide LAR em apenas um dos pacientes. Quando analisamos a expressão do AIP em ambos os casos, o paciente cuja doença foi controlada após a terapia medicamentosa apresentou uma expressão duas vezes maior do que a do paciente não controlado com o tratamento. Conclui-se que esses dois casos ilustram que, embora os análogos de somatostatina atualmente disponíveis se liguem preferencialmente ao SSTR2, alguns pacientes não respondem ao tratamento, apesar de uma elevada expressão desse receptor. Isso poderia ser explicado por alterações nas vias de sinalização pós-receptor, incluindo o envolvimento recentemente descrito da AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6.
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Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Resistencia a Antineoplásicos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Octreótido/uso terapéutico , Neoplasias Hipofisarias/tratamiento farmacológico , Acromegalia/metabolismo , Neoplasias Hipofisarias/metabolismo , Receptores de Somatostatina/metabolismoRESUMEN
OBJECTIVES: Idiopathic central precocious puberty and its postponement with a (gonadotropin-releasing hormone) GnRH agonist are complex conditions, the final effects of which on bone mass are difficult to define. We evaluated bone mass, body composition, and bone remodeling in two groups of girls with idiopathic central precocious puberty, namely one group that was assessed at diagnosis and a second group that was assessed three years after GnRH agonist treatment. METHODS: The precocious puberty diagnosis and precocious puberty treatment groups consisted of 12 girls matched for age and weight to corresponding control groups of 12 (CD) and 14 (CT) girls, respectively. Bone mineral density and body composition were assessed by dual X-ray absorptiometry. Lumbar spine bone mineral density was estimated after correction for bone age and the mathematical calculation of volumetric bone mineral density. CONEP: CAAE-0311.0.004.000-06. RESULTS: Lumbar spine bone mineral density was slightly increased in individuals diagnosed with precocious puberty compared with controls; however, after correction for bone age, this tendency disappeared (CD = -0.74 + 0.9 vs. precocious puberty diagnosis = -1.73 + 1.2). The bone mineral density values of girls in the precocious puberty treatment group did not differ from those observed in the CT group. CONCLUSION: There is an increase in bone mineral density in girls diagnosed with idiopathic central precocious puberty. Our data indicate that the increase in bone mineral density in girls with idiopathic central precocious puberty is insufficient to compensate for the marked advancement in bone age observed at diagnosis. GnRH agonist treatment seems to have no detrimental effect on bone mineral density.
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Composición Corporal/fisiología , Densidad Ósea/fisiología , Hormona Liberadora de Gonadotropina/agonistas , Pubertad Precoz/tratamiento farmacológico , Pubertad Precoz/patología , Absorciometría de Fotón , Adolescente , Factores de Edad , Composición Corporal/efectos de los fármacos , Índice de Masa Corporal , Densidad Ósea/efectos de los fármacos , Estudios de Casos y Controles , Niño , Femenino , Humanos , Valores de Referencia , Estadísticas no Paramétricas , Resultado del Tratamiento , Adulto JovenRESUMEN
We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP.
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Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Resistencia a Antineoplásicos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Octreótido/uso terapéutico , Neoplasias Hipofisarias/tratamiento farmacológico , Acromegalia/metabolismo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/metabolismo , Receptores de Somatostatina/metabolismoRESUMEN
OBJECTIVES: Idiopathic central precocious puberty and its postponement with a (gonadotropin-releasing hormone) GnRH agonist are complex conditions, the final effects of which on bone mass are difficult to define. We evaluated bone mass, body composition, and bone remodeling in two groups of girls with idiopathic central precocious puberty, namely one group that was assessed at diagnosis and a second group that was assessed three years after GnRH agonist treatment. METHODS: The precocious puberty diagnosis and precocious puberty treatment groups consisted of 12 girls matched for age and weight to corresponding control groups of 12 (CD) and 14 (CT) girls, respectively. Bone mineral density and body composition were assessed by dual X-ray absorptiometry. Lumbar spine bone mineral density was estimated after correction for bone age and the mathematical calculation of volumetric bone mineral density. CONEP: CAAE-0311.0.004.000-06. RESULTS: Lumbar spine bone mineral density was slightly increased in individuals diagnosed with precocious puberty compared with controls; however, after correction for bone age, this tendency disappeared (CD = -0.74 + 0.9 vs. precocious puberty diagnosis = -1.73 + 1.2). The bone mineral density values of girls in the precocious puberty treatment group did not differ from those observed in the CT group. CONCLUSION: There is an increase in bone mineral density in girls diagnosed with idiopathic central precocious puberty. Our data indicate that the increase in bone mineral density in girls with idiopathic central precocious puberty is insufficient to compensate for the marked advancement in bone age observed at diagnosis. GnRH agonist treatment seems to have no detrimental effect on bone mineral density.
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Adolescente , Niño , Femenino , Humanos , Adulto Joven , Composición Corporal/fisiología , Densidad Ósea/fisiología , Hormona Liberadora de Gonadotropina/agonistas , Pubertad Precoz/tratamiento farmacológico , Pubertad Precoz/patología , Absorciometría de Fotón , Factores de Edad , Índice de Masa Corporal , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Estudios de Casos y Controles , Valores de Referencia , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
The objective of this study was to describe a case of giant myelolipoma associated with undiagnosed congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency. Five seven year-old male patient referred with abdominal ultrasound revealing a left adrenal mass. Biochemical investigation revealed hyperandrogenism and imaging exams characterized a large heterogeneous left adrenal mass with interweaving free fat tissue, compatible with the diagnosis of myelolipoma, and a 1.5 cm nodule in the right adrenal gland. Biochemical correlation has brought concerns about differential diagnosis with adrenocortical carcinoma, and surgical excision of the left adrenal mass was indicated. Anatomopathologic findings revealed a myelolipoma and multinodular hyperplasic adrenocortex. Further investigation resulted in the diagnosis of CAH due to 21OH deficiency. Concluded that CAH has been shown to be associated with adrenocortical tumors. Although rare, myelolipoma associated with CAH should be included in the differential diagnosis of adrenal gland masses. Moreover, CAH should always be ruled out in incidentally detected adrenal masses to avoid unnecessary surgical procedures.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/diagnóstico , Hiperplasia Suprarrenal Congénita/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Mielolipoma/diagnóstico , Neoplasias de la Corteza Suprarrenal/complicaciones , Hiperplasia Suprarrenal Congénita/complicaciones , Carcinoma Corticosuprarrenal/complicaciones , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Mielolipoma/complicaciones , Esteroide 21-Hidroxilasa/genéticaRESUMEN
INTRODUCTION: Central diabetes insipidus (DI) characterized by polyuria, polydipsia and inability to concentrate urine, has different etiologies including genetic, autoimmune, post-traumatic, among other causes. Autosomal dominant central DI presents the clinical feature of a progressive decline of arginine-vasopressin (AVP) secretion. OBJECTIVE: In this study, we characterized the clinical features and sequenced the AVP-NPII gene of seven long-term follow-up patients with idiopathic central DI in an attempt to determine whether a genetic cause would be involved. METHODS: The diagnosis of central DI was established by fluid deprivation test and hyper-tonic saline infusion. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction and sequenced. RESULTS: Sequencing analysis revealed a homozygous guanine insertion in the intron 2 (IVS2 +28 InsG) of the AVP-NPII gene in four patients, which represents an alternative gene assembly. No mutation in the code region of the AVP-NPII gene was found. CONCLUSIONS: The homozygous guanine insertion in intron 2 (IVS2 +28 InsG) is unlikely to contribute to the AVP-NPII gene modulation in DI. In addition, the etiology of idiopathic central DI in children may not be apparent even after long-term follow-up, and requires continuous etiological surveillance.
Asunto(s)
Diabetes Insípida Neurogénica/diagnóstico , Diabetes Insípida Neurogénica/genética , Neurofisinas/genética , Precursores de Proteínas/genética , Vasopresinas/genética , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Intrones/genética , Masculino , Mutagénesis Insercional/genéticaRESUMEN
The objective of this study was to describe a case of giant myelolipoma associated with undiagnosed congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency. Five seven year-old male patient referred with abdominal ultrasound revealing a left adrenal mass. Biochemical investigation revealed hyperandrogenism and imaging exams characterized a large heterogeneous left adrenal mass with interweaving free fat tissue, compatible with the diagnosis of myelolipoma, and a 1.5 cm nodule in the right adrenal gland. Biochemical correlation has brought concerns about differential diagnosis with adrenocortical carcinoma, and surgical excision of the left adrenal mass was indicated. Anatomopathologic findings revealed a myelolipoma and multinodular hyperplasic adrenocortex. Further investigation resulted in the diagnosis of CAH due to 21OH deficiency. Concluded that CAH has been shown to be associated with adrenocortical tumors. Although rare, myelolipoma associated with CAH should be included in the differential diagnosis of adrenal gland masses. Moreover, CAH should always be ruled out in incidentally detected adrenal masses to avoid unnecessary surgical procedures.
O objetivo deste trabalho foi descrever um caso de mielolipoma gigante associado à hiperplasia adrenal congênita (HAC) por deficiência da 21-hidroxilase (21OH). Paciente do sexo masculino, 57 anos de idade, encaminhado por achado ultrassonográfico de massa adrenal esquerda. Investigação bioquímica revelou hiperandrogenismo e exames de imagem revelaram grande lesão sólida em adrenal esquerda de aspecto heterogêneo, entremeada de tecido gorduroso, compatível com diagnóstico de mielolipoma, e um nódulo de 1,5 cm na adrenal direita. Os achados bioquímicos sugeriam o diagnóstico de carcinoma adrenocortical, indicando cirurgia para retirada da massa adrenal esquerda. O anatomopatológico confirmou mielolipoma e hiperplasia multinodular do córtex adrenal. A investigação subsequente diagnosticou HAC por deficiência da 21OH. Concluiu-se que a HAC tem sido descrita em associação com tumores adrenocorticais. Apesar de raro, o mielolipoma associado à HAC deve ser incluído nas possibilidades diagnósticas de massa adrenal. Adicionalmente, a HAC deve ser sempre afastada nos casos de massa adrenal de achado incidental, evitando cirurgias desnecessárias.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Corteza Suprarrenal/diagnóstico , Hiperplasia Suprarrenal Congénita/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Mielolipoma/diagnóstico , Neoplasias de la Corteza Suprarrenal/complicaciones , Hiperplasia Suprarrenal Congénita/complicaciones , Carcinoma Corticosuprarrenal/complicaciones , Diagnóstico Diferencial , Mielolipoma/complicaciones , /genéticaRESUMEN
INTRODUCTION: Central diabetes insipidus (DI) characterized by polyuria, polydipsia and inability to concentrate urine, has different etiologies including genetic, autoimmune, post-traumatic, among other causes. Autosomal dominant central DI presents the clinical feature of a progressive decline of arginine-vasopressin (AVP) secretion. OBJECTIVE: In this study, we characterized the clinical features and sequenced the AVP-NPII gene of seven long-term follow-up patients with idiopathic central DI in an attempt to determine whether a genetic cause would be involved. METHODS: The diagnosis of central DI was established by fluid deprivation test and hyper-tonic saline infusion. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction and sequenced. RESULTS: Sequencing analysis revealed a homozygous guanine insertion in the intron 2 (IVS2 +28 InsG) of the AVP-NPII gene in four patients, which represents an alternative gene assembly. No mutation in the code region of the AVP-NPII gene was found. CONCLUSIONS: The homozygous guanine insertion in intron 2 (IVS2 +28 InsG) is unlikely to contribute to the AVP-NPII gene modulation in DI. In addition, the etiology of idiopathic central DI in children may not be apparent even after long-term follow-up, and requires continuous etiological surveillance.
INTRODUÇÃO: O diabetes insípido (DI) central, caracterizado por poliúria, polidipsia e inabilidade em concentrar a urina, apresenta diferentes etiologias, incluindo causas genética, autoimune, pós-traumática, entre outras. O DI central autossômico dominante apresenta a característica clínica de falência progressiva da secreção da arginina-vasopressina (AVP). OBJETIVO: No presente estudo, caracterizou-se a apresentação clínica e sequenciou-se o gene AVP-NPII de sete pacientes com DI central idiopático seguidos de longa data na tentativa de determinar se uma causa genética estava envolvida na etiologia. MÉTODOS: O diagnóstico do DI central foi estabelecido por meio do teste de jejum hídrico e infusão de salina hipertônica. Para a realização da análise molecular, o DNA genômico foi extraído e o gene AVP-NPII foi amplificado pela reação em cadeia da polimerase e, posteriormente, sequenciado. RESULTADOS: A análise do sequenciamento do gene AVP-NPII revelou uma inserção em homozigose de uma guanina no íntron 2 (IVS2 +28 InsG) em quatro pacientes, correspondendo a um arranjo alternativo do gene. Nenhuma mutação da região codificadora do gene AVP-NPII foi encontrada. CONCLUSÕES: A inserção em homozigose de uma guanina no íntron 2 (IVS2 +28 InsG) provavelmente não contribui na modulação do gene AVP-NPII no DI. Adicionalmente, a etiologia do DI central idiopático em crianças pode não se tornar evidente mesmo após um longo período de seguimento, necessitando de contínua vigilância da etiologia.
Asunto(s)
Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Diabetes Insípida Neurogénica/diagnóstico , Diabetes Insípida Neurogénica/genética , Neurofisinas/genética , Precursores de Proteínas/genética , Vasopresinas/genética , Estudios de Seguimiento , Intrones/genética , Mutagénesis Insercional/genéticaRESUMEN
The present study investigated the hypothalamic-pituitary-adrenal (HPA) axis activity in response to stress in adult male rats submitted to pituitary stalk compression (PSC) or sham operation. Animals received water or oral salt loading (2% NaCl) for one or eight days before the day of the experiment. On the 14th day post-surgery rats were killed under basal conditions or after 15 min immobilization stress. In the PSC group urine output increased significantly and plasma vasopressin (AVP) levels failed to respond to osmotic stimuli. Short-term salt load induced a significant increase in AVP levels in the sham-operated group. The PSC group presented higher adrenocorticotrophin (ACTH) and corticosterone levels compared with sham-operated rats, both in water intake and salt load conditions. Immobilization stress induced a similar increase in plasma ACTH and corticosterone concentrations in sham-operated and PSC groups under water intake. However, long-term salt load blunted the ACTH and corticosterone responses to immobilization stress in sham-operated rats. PSC rats submitted to short- and long-term salt loading presented no changes in ACTH and corticosterone levels after immobilization. Immobilization stress caused neither AVP responses nor plasma osmolality changes in sham and PSC groups. There was no difference in median eminence AVP content among all groups. In conclusion, the high ACTH and corticosterone levels found in PSC rats under water intake and salt loading conditions suggest an up-regulation of the HPA axis, with a preserved adaptive mechanism to chronic stress.
Asunto(s)
Corteza Suprarrenal/fisiopatología , Diabetes Insípida/fisiopatología , Hipotálamo/fisiopatología , Hipófisis/fisiopatología , Estrés Fisiológico/fisiopatología , Adaptación Fisiológica , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/sangre , Corticosterona/sangre , Ingestión de Líquidos , Masculino , Modelos Animales , Concentración Osmolar , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Familial autosomal dominant neurohypophyseal diabetes insipidus (FNDI) is a rare form of central diabetes insipidus (DI), which is caused by mutations in the vasopressin-neurophysin II (AVP-NPII) gene. The present study evaluated the AVP secretion over time and analysed the structure of the AVP-NPII gene in a Brazilian family with FNDI. SUBJECTS AND DESIGN: Four affected members and one nonaffected member from one Brazilian family with FNDI were studied. The diagnosis of central DI was established by fluid deprivation test and hypertonic saline infusion. Two affected members were assessed twice within a 6-year interval. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction. RESULTS: The functional assessment of patients with FNDI over time confirmed a progressive loss in AVP secretion. Two patients were first diagnosed as partial central DI and, several years later, they developed severe central DI. Sequencing analysis revealed a heterozygous new point mutation in the nucleotide 1892 in the coding sequence for neurophysin-II of the AVP-NPII gene (1892G>C) predicting an amino acid substitution (A68P) in all affected members. CONCLUSION: Our data demonstrate a gradual vasopressinergic deficiency due to a novel mutation in the AVP-NPII gene in a Brazilian family with FNDI. The accumulation of A68P mutated precursor might have a cytotoxicity effect, leading to a gradual death of magnocellular neurones, and a progressive decline in AVP secretion.