Chronic adult-onset of growth hormone/IGF-I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats.

AIM: Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities. However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. METHODS: Adult rats were implanted with GC cells and checked 10 weeks later, when a GH/IGF-I-secreting tumour was already formed. RESULTS: Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. CONCLUSION: Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.

An approach to screening for Cushing's syndrome in non-specialized health care settings / Una aproximación al cribado del síndrome de Cushing en un entorno asistencial no especializado

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A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study.

CONTEXT: Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. OBJECTIVE: To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. DESIGN: Observational, prospective, multicenter. SETTING: Referral hospital. PATIENTS: A cohort of 353 patients attending endocrinology units for outpatient visits. INTERVENTIONS: All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. MAIN OUTCOME MEASURES: Diagnosis or exclusion of CS. RESULTS: Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. CONCLUSIONS: We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.

El Registro Molecular de Adenomas Hipofisarios (REMAH): una apuesta de futuro de la Endocrinología española por la medicina individualizada y la investigación traslacional / The Molecular Registry of Pituitary Adenomas (REMAH): A bet of Spanish Endocrinology for the future of individualized medicine and translational research

Los adenomas hipofisarios son tumores infrecuentes de diagnóstico complejo, cuya heterogeneidad y baja incidencia dificultan estudios a gran escala. El Registro Molecular de Adenomas Hipofisarios (REMAH) nació en 2008 en el seno de la Sociedad Andaluza de Endocrinología y Nutrición (SAEN), como estrategia de cooperación clínico-básica y multicéntrica, para mejorar el diagnóstico y tratamiento de tumores hipofisarios mediante la combinación de información clínica, anatomopatológica y molecular. En 2010, la Sociedad Española de Endocrinología y Nutrición (SEEN) lo extendió a nivel nacional, estableciendo 6 nodos con protocolos y métodos comunes de recogida de muestras y datos clínicos, análisis molecular y anotación en un mismo registro (www.remahnacional.com). El registro combina datos clínicos con el fenotipado molecular del adenoma intervenido, mediante PCR cuantitativa en tiempo real de la expresión de 26 genes: hormonas hipofisarias (GH-PRL-LH-FSH-PRL-ACTH-CGA), receptores (somatostatina, dopamina, GHRH, GnRH, CRH, arginina-vasopresina, ghrelina), otros marcadores (Ki67, PTTG1) y genes de control. Hasta 2015 se ha obtenido información molecular de 704 adenomas, de los 1.179 pacientes registrados. Esta estrategia permite abordar análisis comparativos y relacionales entre el perfil molecular de los distintos tipos de adenomas y el fenotipo clínico del paciente, lo que puede ofrecer un mejor conocimiento de la enfermedad y, potencialmente, ayudar en la selección del tratamiento. El REMAH constituye una red única, multicéntrica e interdisciplinar, cimentada en una base de datos compartida, que aporta un enfoque traslacional de gran proyección potencial para el manejo de los adenomas hipofisarios y abre el camino para estudios conjuntos clínico-básicos innovadores con un elevado número de pacientes (AU)

Pituitary adenomas are uncommon, difficult to diagnose tumors whose heterogeneity and low incidence complicate large-scale studies. The Molecular Registry of Pituitary Adenomas (REMAH) was promoted by the Andalusian Society of Endocrinology and Nutrition (SAEN) in 2008 as a cooperative clinical-basic multicenter strategy aimed at improving diagnosis and treatment of pituitary adenomas by combining clinical, pathological, and molecular information. In 2010, the Spanish Society of Endocrinology and Nutrition (SEEN) extended this project to national level and established 6 nodes with common protocols and methods for sample and clinical data collection, molecular analysis, and data recording in a common registry (www.remahnacional.com). The registry combines clinical data with molecular phenotyping of the resected pituitary adenoma using quantitative real-time PCR of expression of 26 genes: Pituitary hormones (GH-PRL-LH-FSH-PRL-ACTH-CGA), receptors (somatostatin, dopamine, GHRH, GnRH, CRH, arginine-vasopressin, ghrelin), other markers (Ki67, PTTG1), and control genes. Until 2015, molecular information has been collected from 704 adenomas, out of 1179 patients registered. This strategy allows for comparative and relational analysis between the molecular profile of the different types of adenoma and the clinical phenotype of patients, which may provide a better understanding of the condition and potentially help in treatment selection. The REMAH is therefore a unique multicenter, interdisciplinary network founded on a shared database that provides a far-reaching translational approach for management of pituitary adenomas, and paves the way for the conduct of combined clinical-basic innovative studies on large patient samples (AU)

The Molecular Registry of Pituitary Adenomas (REMAH): A bet of Spanish Endocrinology for the future of individualized medicine and translational research. / El Registro Molecular de Adenomas Hipofisarios (REMAH): una apuesta de futuro de la Endocrinología española por la medicina individualizada y la investigación traslacional.

Pituitary adenomas are uncommon, difficult to diagnose tumors whose heterogeneity and low incidence complicate large-scale studies. The Molecular Registry of Pituitary Adenomas (REMAH) was promoted by the Andalusian Society of Endocrinology and Nutrition (SAEN) in 2008 as a cooperative clinical-basic multicenter strategy aimed at improving diagnosis and treatment of pituitary adenomas by combining clinical, pathological, and molecular information. In 2010, the Spanish Society of Endocrinology and Nutrition (SEEN) extended this project to national level and established 6 nodes with common protocols and methods for sample and clinical data collection, molecular analysis, and data recording in a common registry (www.remahnacional.com). The registry combines clinical data with molecular phenotyping of the resected pituitary adenoma using quantitative real-time PCR of expression of 26 genes: Pituitary hormones (GH-PRL-LH-FSH-PRL-ACTH-CGA), receptors (somatostatin, dopamine, GHRH, GnRH, CRH, arginine-vasopressin, ghrelin), other markers (Ki67, PTTG1), and control genes. Until 2015, molecular information has been collected from 704 adenomas, out of 1179 patients registered. This strategy allows for comparative and relational analysis between the molecular profile of the different types of adenoma and the clinical phenotype of patients, which may provide a better understanding of the condition and potentially help in treatment selection. The REMAH is therefore a unique multicenter, interdisciplinary network founded on a shared database that provides a far-reaching translational approach for management of pituitary adenomas, and paves the way for the conduct of combined clinical-basic innovative studies on large patient samples.

The Effects of Bariatric Surgery-Induced Weight Loss on Adipose Tissue in Morbidly Obese Women Depends on the Initial Metabolic Status.

BACKGROUND: Adipose tissue (AT) dysfunction in obesity is commonly linked to insulin resistance and promotes the development of metabolic disease. Bariatric surgery (BS) represents an effective strategy to reduce weight and to improve metabolic health in morbidly obese subjects. However, the mechanisms and pathways that are modified in AT in response to BS are not fully understood, and few information is still available as to whether these may vary depending on the metabolic status of obese subjects. METHODS: Abdominal subcutaneous adipose tissue (SAT) samples were obtained from morbidly obese women (n = 18) before and 13.3 ± 0.37 months after BS. Obese women were stratified into two groups: normoglycemic (NG; Glu < 100 mg/dl, HbA1c <5.7 %) or insulin resistant (IR; Glu 100-126 mg/dl, HbA1c 5.7-6.4 %) (n = 9/group). A multi-comparative proteomic analysis was employed to identify differentially regulated SAT proteins by BS and/or the degree of insulin sensitivity. Serum levels of metabolic, inflammatory, and anti-oxidant markers were also analyzed. RESULTS: Before surgery, NG and IR subjects exhibited differences in AT proteins related to inflammation, metabolic processes, the cytoskeleton, and mitochondria. BS caused comparable weight reductions and improved glucose homeostasis in both groups. However, BS caused dissimilar changes in metabolic enzymes, inflammatory markers, cytoskeletal components, mitochondrial proteins, and angiogenesis regulators in NG and IR women. CONCLUSIONS: BS evokes significant molecular rearrangements indicative of improved AT function in morbidly obese women at either low or high metabolic risk, though selective adaptive changes in key cellular processes occur depending on the initial individual's metabolic status.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

Genetically engineered mouse models of pituitary tumors.

Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary-tumor formation remain poorly understood, particularly in sporadic adenomas, thus, making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs) of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, we review various GEMMs of pituitary tumors, highlighting their contributions and limitations, and discuss opportunities for research in the field.

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease / El test de la desmopresina en el diagnóstico y seguimiento de la enfermedad de Cushing cíclica

OBJECTIVE: To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. MATERIAL AND METHODS: Laboratory tests included morning and midnight serum cortisol levels, 24 h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. RESULTS: A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. CONCLUSIONS: Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis

OBJETIVO: Evaluar la utilidad de la prueba de la desmopresina (DDAVP) en el diagnóstico y seguimiento de un caso de enfermedad de Cushing cíclica (ECC). MATERIAL Y MÉTODO: Se realizaron mediciones de cortisol sérico diurno y nocturno, cortisol libre en orina de 24 h, cortisol en saliva nocturno, cortisol sérico tras dosis elevadas y bajas de dexametasona, ACTH plasmática y cortisol tras la DDAVP, y resonancia magnética (RM) para valorar la presencia de un adenoma hipofisario. El tumor extirpado fue analizado mediante técnicas histológicas, inmunohistoquímicas y de biología celular. RESULTADOS: Se presenta una paciente enviada a nuestra unidad con el diagnóstico de síndrome de Cushing (SC) para evaluación más completa y tratamiento. No obstante durante un periodo de seguimiento de 2 años no se encontró evidencia alguna de hipercortisolismo en los análisis realizados en nuestro laboratorio. Durante este tiempo, la paciente mostró fluctuaciones de los síntomas y signos típicos del SC. De manera interesante, la prueba de DDAVP mostró hiperrespuesta de cortisol y ACTH en todas las evaluaciones. La exploración por RM mostró un adenoma hipofisario que tras extirpación resultó ser positivo para ACTH. El SC se resolvió tras la cirugía y la respuesta a la prueba de DDAVP desapareció en las evaluaciones de seguimiento posquirúrgico. Se incubaron muestras del tumor mostrando este un aumento en la secreción in vitro de ACTH. CONCLUSIONES: Este caso ilustra la utilidad de la prueba de DDAVP en la evaluación de pacientes con sospecha de SCC. Esta prueba podría facilitar el manejo del SCC acortando el tiempo de diagnóstico

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease.

OBJECTIVE: To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. MATERIAL AND METHODS: Laboratory tests included morning and midnight serum cortisol levels, 24h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. RESULTS: A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. CONCLUSIONS: Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.

GDNF is required for neural colonization of the pancreas.

The mammalian pancreas is densely innervated by both the sympathetic and parasympathetic nervous systems, which control exocrine and endocrine secretion. During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.

Neurocognitive function in acromegaly after surgical resection of GH-secreting adenoma versus naïve acromegaly.

Patients with active untreated acromegaly show mild to moderate neurocognitive disorders that are associated to chronic exposure to growth hormone (GH) and insulin-like growth factor (IGF-I) hypersecretion. However, it is unknown whether these disorders improve after controlling GH/IGF-I hypersecretion. The aim of this study was to compare neurocognitive functions of patients who successfully underwent GH-secreting adenoma transsphenoidal surgery (cured patients) with patients with naive acromegaly. In addition, we wanted to determine the impact of different clinical and biochemical variables on neurocognitive status in patients with active disease and after long-term cure. A battery of six standardized neuropsychological tests assessed attention, memory and executive functioning. In addition, a quantitative electroencephalography with Low-Resolution Electromagnetic Tomography (LORETA) solution was performed to obtain information about the neurophysiological state of the patients. Neurocognitive data was compared to that of a healthy control group. Multiple linear regression analysis was also conducted using clinical and hormonal parameters to obtain a set of independent predictors of neurocognitive state before and after cure. Both groups of patients scored significantly poorer than the healthy controls on memory tests, especially those assessing visual and verbal recall. Patients with cured acromegaly did not obtain better cognitive measures than naïve patients. Furthermore memory deficits were associated with decreased beta activity in left medial temporal cortex in both groups of patients. Regression analysis showed longer duration of untreated acromegaly was associated with more severe neurocognitive complications, regardless of the diagnostic group, whereas GH levels at the time of assessment was related to neurocognitive outcome only in naïve patients. Longer duration of post-operative biochemical remission of acromegaly was associated with better neurocognitive state. Overall, this data suggests that the effects of chronic exposure to GH/IGF-I hypersecretion could have long-term effects on brain functions.

Rationale and design of PATRO Adults, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope(®) for the treatment of adult patients with growth hormone deficiency.

OBJECTIVE: To describe the rationale and design of PATRO Adults, a postmarketing surveillance study of the long-term efficacy and safety of somatropin (Omnitrope(®)) for the treatment of adult patients with growth hormone deficiency (GHD). METHODS: PATRO Adults is an observational, multicentre, open, longitudinal, noninterventional study being conducted in hospitals and specialized endocrinology clinics across several European countries. The primary objective is to assess the safety and efficacy of Omnitrope(®) in adults treated in routine clinical practice. Eligible patients are male or female adults who are receiving treatment with Omnitrope(®) and who have provided informed consent. Patients who have been treated with another human growth hormone (hGH) product before starting Omnitrope(®) therapy will also be eligible for inclusion. Efficacy assessments will be based on the analysis of the following: insulin-like growth factor-1 levels within age- and gender-adjusted normal ranges; anthropometric measures (weight, waist circumference, total fat mass, lean body mass, total body water); bone mineral density; lipids; effects on cardiovascular risk factors such as glucose metabolism, blood pressure and inflammatory markers (e.g. C-reactive protein); and quality of life. All adverse events will be monitored and recorded. Particular emphasis will be placed on long-term safety, the recording of malignancies, the occurrence and clinical impact of antirecombinant hGH antibodies, the incidence, severity and duration of hyperglycaemia, and the development of diabetes during treatment with Omnitrope(®). CONCLUSIONS: PATRO Adults is a large, long-term, postmarketing surveillance study that will extend the safety database for Omnitrope(®), as well as contributing to the available data for all recombinant hGH products. Of particular interest, the study will provide important data on the impact of long-term GH replacement therapy on the development of diabetes mellitus, the recurrence/regrowth of hypothalamic-pituitary tumours, and de novo malignancy or recurrence of other (non-hypothalamic-pituitary) tumours.

Measurement of oxidative stress and endothelial dysfunction in patients with hypopituitarism and severe deficiency adult growth hormone deficiency.

Patients with adult GH deficiency (AGHD) have a high cardiovascular risk and probably an alteration of the oxidative balance, although evidence is lacking. To evaluate the presence of endothelial dysfunction and oxidative stress in patients with AGHD. Biochemical parameters of oxidative stress and endothelial dysfunction were compared in 25 patients with previously untreated AGHD and 25 healthy controls matched by age and sex. Multivariate analysis was performed to identify independent predictors of oxidative stress. Vascular function of subcutaneous resistance arteries was also analyzed by means of wire myography in 7 patients with untreated AGHD and in 7 healthy controls with similar characteristics. The values of C-reactive protein, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α), were higher in the AGHD group (4.6 vs. 0.2 µg/L, P = 0.02; 5.6 vs. 1.2 pg/mL, P = 0.001; 6.7 vs. 2.1 pg/mL, P = 0.04; respectively). The levels of type-1 vascular cell adhesion molecule, total anti-oxidant state, oxidized LDL (LDL-ox) were also greater in AGHD patients (678 vs. 423 ng/mL, P = 0.004; 1235.6 vs. 1002.3 µmol/L, P = 0.01; 172.2.5 vs. 42.3 ng/mL, P = 0.02; respectively). Nitric oxide (NO), reduced glutathione (GSH) and reduced/oxidized glutathione ratio (GSH/GSSG) values were lower than controls (18.7 vs. 31.6 mmol/mg protein, P = 0.01; 372.2 vs. 756.2 µmol/L, P = 0.03; 17.2 vs. 38.4, P = 0.04; respectively). Multiple regression analysis showed that AGHD was an independent predictor of increased LDL-ox (P = 0.002) and decreased GSH (P = 0.000). Furthermore, the degree of vascular relaxation to repeated exposure of acetylcholine was lower in AGHD (P = 0.025). Patients with AGHD have an increased degree of oxidative stress and endothelial dysfunction that could already be present in early stages of the disease. Studies with a greater number of patients are needed in order to confirm our findings.

Budget impact of using midnight salivary cortisol in the diagnosis of hypercortisolism.

BACKGROUND: A single midnight serum cortisol (MSC) test has been reported to possess the best sensitivity and specificity for diagnosing Cushing's syndrome (CS). However, this test requires patient hospitalization, making it costly. This paper aims to compare the hospital budget impact and accuracy of using midnight salivary cortisol (MSVC), as opposed to MSC, in the diagnosis of hypercortisolism. METHODS: 77 patients with at least two high urinary free cortisol (UFC) values (>360 nmol/24 h) were selected from 611 patients with clinical symptoms of CS. The costs of the method to confirm the diagnosis of hypercortisolism was calculated comparing Option A using MSC (UFCx2, low-dose dexamethasone suppression test [LDDST]) that requires patient hospitalization versus Option B using MSVC (UFCx2, LDDST) in which the evaluation is done outside the Hospital. A budget impact analysis for one year was developed, and a sensitivity analysis in different scenarios was performed. Reproducibility and diagnostic performance of MSVC and MSC were also measured. RESULTS: Salivary cortisol is a sound analytical method for evaluating free serum cortisol due to its classification accuracy, good imprecision, linearity, and stability. AUC(ROC) comparison between MSVC and MSC shows no significant differences. The substitution of the MSC for MSVC in our hospital could save between €16,762 and €132,804 in one year. CONCLUSIONS: The use of MSVC in the diagnosis of hypercortisolism can result in a substantial decrease in the budget impact, without losing diagnosis accuracy and reliability, a significant advantage considering the current emphasis on reducing the financial burden of health care.

Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10.

CONTEXT: KISS1 was originally identified as a metastasis-suppressor gene able to inhibit tumor progression. KISS1 gene products, the kisspeptins, bind to a G-protein-coupled receptor (KISS1R, formerly GPR54), which is highly expressed in placenta, pituitary, and pancreas, whereas KISS1 mRNA is mainly expressed in placenta, hypothalamus, striatum, and pituitary. OBJECTIVE AND DESIGN: KISS1/KISS1R pituitary expression profile, coupled to their anti-tumoral capacities, led us to hypothesize that this system may be involved in the biology of pituitary tumors. To explore this notion, expression levels of KISS1R and KISS1 were evaluated in normal and adenomatous pituitaries. Additionally, functionality of this system was assessed by treating dispersed pituitary adenoma cells in primary culture with kisspeptin-10 and evaluating intracellular calcium kinetics and apoptotic rate. RESULTS: Both KISS1 and KISS1R were expressed in normal pituitary, whereas this simultaneous expression was frequently lost in pituitary tumors, where diverse patterns of KISS1/KISS1R expression were observed that differed among distinct types of pituitary adenomas. Measurement of calcium kinetics revealed that kisspeptin-10 elicits a remarkable increase in [Ca(2+)](i) in individual cells from four out of the five GH-producing adenomas studied, whereas cells derived from non-functioning pituitary adenomas (NFPA, n=45) did not respond. In contrast, kisspeptin-10 treatment increased the apoptotic rate in cells derived from both GH-producing and NFPA. CONCLUSIONS: These results provide primary evidence that KISS1 and KISS1R expression can be differentially lost in pituitary tumor subtypes, where this system can exert functional, proapoptotic actions, and thereby offer novel insights to investigate the biology and therapeutic options to treat these tumors.

Evidence of cognitive and neurophysiological impairment in patients with untreated naive acromegaly.

CONTEXT: Recent studies have suggested that long-term exposure to high levels of GH and IGF-I affect brain and cognitive functions. However, very few human studies have challenged this hypothesis. OBJECTIVE: The aim of this study is to explore whether GH/IGF-I excess in naive patients with acromegaly alters cognitive functions, particularly memory, and whether these alterations are accompanied by neurophysiological correlates. DESIGN: We conducted a comprehensive neuropsychological and neurophysiological exam on 16 naive acromegaly patients and 16 strictly matched healthy controls. Comparative analyses were carried out on major neurocognitive domains (executive functions, visual/verbal memory, attention, visuoconstructive abilities, and verbal fluency) and on quantitative electroencephalogram and low-resolution brain electromagnetic tomography sources. Results were correlated with GH and IGF-I hormone concentrations. RESULTS: Short- and long-term memory were the most severely impaired cognitive functions. Moreover, memory performance correlated negatively with GH and IGF-I concentrations. No association was detected between depression and memory impairment, and only a marginal association was found with quality of life. Finally, acromegaly patients showed power attenuation in fast frequency electroencephalogram bands, as well as decreased activity in prefrontal and middle temporal cortices, that was associated to cognitive performance. CONCLUSIONS: Results provide evidence of cognitive and neurophysiological impairment, characterized by moderate-to-severe memory impairment and decreased neural activity in specific brain areas. High levels of GH and IGF-I in acromegaly patients could be the basis for these findings.

Avances en biología molecular en patología neuroendocrina / No disponible

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