Hypopituitarism after traumatic brain injury in adults: Clinical guidelines of the neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition (SEEN).

Traumatic brain injury (TBI) is associated with hypopituitarism with a variable incidence, depending on the time and methods used to diagnosis, and on factors related to the trauma, such as its severity, its anatomical location and the drugs used in the acute phase. The pituitary gland can be damaged directly by the impact or secondary to factors such as ischemia, inflammation, excitotoxicity or immunity. In acute phases ACTH deficiency is the most relevant, since failure to detect and treat it can compromise the patient's life. Clinical manifestations are typical of each hormone deficient axes, although the combination hypopituitarism-trauma has been associated with cognitive deterioration, worse metabolic profile and greater impairment of quality of life. One of the clinical challenges is to determine which patients benefit from a systematic hormonal evaluation, and therefore from hormone replacement, and what is the appropriate time to do so and the most suitable diagnostic methods.

GALIPDIA study: Reaching lipid targets in a population with type 2 diabetes (T2DM) from the Northwest of Spain.

AIM: To assess the degree of compliance with the European ESC/EAS 2016 and 2019 dyslipidaemia guidelines in patients with type 2 diabetes mellitus (T2DM). METHODS: Multicentre retrospective cross-sectional study, conducted in 380 adults with T2DM and dyslipidaemia in 7 Spanish health areas. INCLUSION CRITERIA: minimum follow-up of one year in Endocrinology Units, at least one visit in 2020 and a lipid profile measurement in the last 3 months. EXCLUSION CRITERIA: familial hypercholesterolaemia, recent hospitalisation, active oncological pathology and dialysis. RESULTS: According to the 2016 and 2019 guidelines the majority of patients were classified as being at very high cardiovascular risk (86.8% vs. 72.1%, respectively). LDL-c compliance was adequate in 62.1% of patients according to the 2016 guidelines and 39.7% according to the 2019 guidelines (p<0.001). Clinical conditions such as history of cardiovascular disease and therapy-related aspects (use of statins, especially high-potency statins, combination therapies and good adherence) were significantly associated with greater achievement of lipid targets. CONCLUSION: There is a discrepancy between dyslipidaemia guideline recommendations and the reality of lipid control in patients with T2DM, despite most of these patients being at very high cardiovascular risk. Strategies to optimise lipid-lowering treatments need to be implemented.

Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly.

BACKGROUND: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. METHODS: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized' pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. FINDINGS: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. INTERPRETATION: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. FUND: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1.

Hypopituitarism after traumatic brain injury.

The prevalence of hypopituitarism after traumatic brain (TBI) injury is widely variable in the literature; a meta-analysis determined a pooled prevalence of anterior hypopituitarism of 27.5%. Growth hormone deficiency is the most prevalent hormone insufficiency after TBI; however, the prevalence of each type of pituitary deficiency is influenced by the assays used for diagnosis, severity of head trauma, and time of evaluation. Recent studies have demonstrated improvement in cognitive function and cognitive quality of life with substitution therapy in GH-deficient patients after TBI.

High-risk human papillomavirus in Galicia, Spain: prevalence and evaluation of the sample representativeness.

BACKGROUND: The prevalence of high-risk genotypes of the human papillomavirus (HR-HPV) in Galicia remained unknown before the introduction of the HPV vaccine. The objective of this study was to estimate this prevalence in non-vaccinated women when vaccination against HR-HPV started. Sample representativeness was also evaluated. METHODS: Female volunteers aged 16-64 years, residents in Galicia, Spain, completed a questionnaire and provided biological samples for a virological study and for cytology. The sample was weighted; prevalence rates were estimated and are shown with 95% confidence intervals. RESULTS: Virological results were available for 1703 women. HR-HPV prevalence was 10.1%, decreasing notably at ages above 30 years. HPV-16 was the most frequent genotype and 3.6% of women were infected by more than one genotype. No adjustment was necessary to generalize the results of the study. CONCLUSIONS: In Galicia in 2009 there would be 96 400 women aged 16-64 years infected with HR-HPV. It is possible to estimate HR-HPV prevalence in a population starting from a volunteer sample.

Documento de consenso del área de conocimiento de Neuroendocrinología de la Sociedad Española de Endocrinología y Nutrición para el abordaje del hipopituitarismo durante la transición / Consensus document of the Neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition on management of hypopituitarism during transition

Se entiende por periodo de transición del niño al adulto a una etapa de cambios físicos y psicológicos que, de forma arbitraria, se extiende desde el final de la pubertad hasta que la maduración adulta se completa. Comprende, habitualmente, los 6 a 7 años posteriores al momento en que el niño adquiere la talla adulta. Con esta documento pretendemos poner de manifiesto la importancia de la adecuada sustitución de los diferentes déficits hipotálamo-hipofisarios durante este período. Para ello revisamos la reevaluación del status hipofisario en los pacientes deficitarios durante la infancia, tratamos de dar respuesta a las preguntas que pueden surgir y ofrecemos unas recomendaciones claras de cómo abordar la deficiencia de GH en este período. Posteriormente abordamos también la evaluación y la sustitución del eje adrenal, tiroideo y gonadal

The transition period from child to adult represents a crucial phase in the growth process where multiple physical and psychosocial changes occur. It has been arbitrarily defined as the period extending from late puberty to full adult maturity (i.e., from mid to late teenage years until 6-7 years after achievement of final height).The aim of this guideline is to emphasize the importance of adequate hormone replacement during this period and to review reassessment of pituitary function. In patients with GH deficiency diagnosed in childhood, an attempt is made to answer when to retest GH secretion, when to treat and how they should be monitored. Thyroxine, glucocorticoid, and sex steroid replacement are also reviewed

Consensus document of the Neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition on management of hypopituitarism during transition.

The transition period from child to adult represents a crucial phase in the growth process where multiple physical and psychosocial changes occur. It has been arbitrarily defined as the period extending from late puberty to full adult maturity (i.e., from mid to late teenage years until 6-7 years after achievement of final height). The aim of this guideline is to emphasize the importance of adequate hormone replacement during this period and to review reassessment of pituitary function. In patients with GH deficiency diagnosed in childhood, an attempt is made to answer when to retest GH secretion, when to treat and how they should be monitored. Thyroxine, glucocorticoid, and sex steroid replacement are also reviewed.

Subclinical hypopituitarism.

The presence of subclinical or minor pituitary hormone deficiencies could be recognised in clinical practice and might represent intermediate situations among normal pituitary hormone secretion and clinical hypopituitarism. However, this entity has not been correctly identified and associated clinical impairment and even more, long-term consequences regarding to morbidity and mortality, strongly related to clinical hypopituitarism, has not been correctly settled. Furthermore, best test or methods for diagnosis and the cut off to define these intermediate situates are also unknown. With this purpose, long-term controlled studies are needed to define correctly this entity, the appropriate methods for diagnosis and the potential benefits of substitutive hormone therapy in detected cases. The present review will focus on the available evidence concerning the prevalence, clinical features and diagnosis of subclinical hypopituitarism.

Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormone dysfunction and genetic analysis.

OBJECTIVES: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. DESIGN: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. RESULTS: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. CONCLUSION: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset.

Hypopituitarism following traumatic brain injury: determining factors for diagnosis.

Neuroendocrine dysfunction, long recognized as a consequence of traumatic brain injury (TBI), is a major cause of disability that includes physical and psychological involvement with long-term cognitive, behavioral, and social changes. There is no standard procedure regarding at what time after trauma the diagnosis should be made. Also there is uncertainty on defining the best methods for diagnosis and testing and what types of patients should be selected for screening. Common criteria for evaluating these patients are required on account of the high prevalence of TBI worldwide and the potential new cases of hypopituitarism. The aim of this review is to clarify, based on the evidence, when endocrine assessment should be performed after TBI and which patients should be evaluated. Additional studies are still needed to know the impact of post-traumatic hypopituitarism and to assess the impact of hormone replacement in the prognosis.

Pegvisomant-induced liver injury is related to the UGT1A1*28 polymorphism of Gilbert's syndrome.

CONTEXT: Pegvisomant (PEG) therapy has been associated with drug-induced liver dysfunction in acromegalic patients. The mechanism of its toxicity remains unknown. OBJECTIVE: The primary objective was to determine whether or not the UGT1A1*28 polymorphism associated with Gilbert's syndrome influences the development of liver dysfunction during PEG treatment. DESIGN AND SETTING: A cross-sectional study was conducted in four Spanish university hospitals. PATIENTS: Thirty-six acromegalic patients with active disease, resistant to somatostatin analogs, participated. RESULTS: The prevalence of the UGT1A1*28 homozygous and heterozygous genotypes in acromegalic patients was 14 and 44%, respectively. Ten patients (28%) developed liver function test (LFT) abnormalities. There was a tendency for more frequent liver function abnormalities in males (70% males vs. 30% females, P = 0.058). Carriers of the UGT1A1*28 polymorphism had a higher incidence of LFT abnormalities than the UGT1A1 wild type (43% carriers vs. 7% wild type, P = 0.024). This difference persisted when adjusted in an all-factors multiple regression analysis [coefficient of determination (R(2)) = 0.463; P = 0.008] for age, gender, alcohol consumption, and UGT1A1*28 polymorphism. A stepwise multivariate likelihood binary logistic regression analysis (R(2) = 0.40; P = 0.003) identified male gender (beta = 7.21; P = 0.033) and UGT1A1*28 polymorphism (beta = 14.1; P = 0.028) as the only significant predictors for the development of LFT abnormalities. CONCLUSIONS: The UGT1A1*28 genotype and male gender predict an increased incidence of LFT abnormalities during PEG therapy in acromegaly.

The exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly.

CONTEXT: The deletion of exon 3 in the GH receptor (GHR) has been associated with a different biochemical picture and response to therapy in acromegaly. OBJECTIVE: The aim of the study was to determine whether or not the GHR genotype influences the efficacy of pegvisomant treatment. DESIGN AND SETTING: A cross-sectional study was conducted in six Spanish university hospitals. PATIENTS: Forty-four acromegalic patients with active disease and resistance to somatostatin analogs participated in the study. RESULTS: The prevalence of the full-length GHR and the exon 3-deleted GHR homozygous and heterozygous genotypes was 41, 2, and 57%, respectively. There were no differences in IGF-I or GH pre-pegvisomant levels related to GHR genotype. The exon 3-deleted patients required approximately 20% lower doses of pegvisomant per kilogram of weight (28 +/- 11 compared to 22 +/- 7 mg per kg of weight; P = 0.033) to normalize IGF-I. A stepwise multivariate linear regression analysis (R(2) = 0.27; P = 0.003) identified male gender (beta = -0.79; P = 0.03) and d3-GHR genotype (beta = -0.64; P = 0.007) as the only significant predictors of the dose of pegvisomant per kilogram of weight. In addition, d3-GHR carriers required fewer months for IGF-I normalization (P < 0.01). A stepwise multivariate linear regression analysis (R(2) = 0.40; P = 0.001) revealed that the only significant predictor of the time to IGF-I normalization was the dose of pegvisomant per kilogram of weight (beta = 0.451; P = 0.001). CONCLUSIONS: The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.

The pituitary-adrenal axis and body composition.

The activity of the pituitary-adrenal axis can profoundly impact on body composition. This is dramatically seen in Cushing's syndrome (CS) but changes in body composition are also implicated in depression and alcoholic pseudocushing's. The pathophysiological mechanisms underlying these changes remain poorly understood. Changes to body composition in CS include increased fat mass, decreased bone mass, thinning of the skin and reduced lean mass. Why these tissues are affected so dramatically is unclear. Additionally, the change in body composition between individuals varies considerably for reasons which are only now becoming evident. This paper reviews the phenotypic changes with altered pituitary-adrenal axis activity and discusses the mechanisms involved. The primary focus is on adipose, bone, muscle and skin since the most dramatic changes are seen in these tissues.

Severe hypertension and hypokalemia as first clinical manifestations in ectopic Cushing's syndrome.

Ectopic ACTH production occurs in about 10% of all cases of Cushing's syndrome, and about 25% of cases of ACTH-dependent Cushing's syndrome. Diverse tumor types are able to produce ACTH ectopically, including small cell lung carcinoma. Ectopic ACTH secretion by malignant neoplasm has been reported to have earlier and more aggressive metabolic effects. We report a 59-year-old male patient with severe hypertension, metabolic alkalosis and hypokalemia as the first clinical manifestations of an ACTH-secreting small cell lung carcinoma, although the typical phenotypic features of Cushing's syndrome were not present. Ectopic Cushing's syndrome should always be ruled out in patients with severe hypertension and hypokalemia.

Severe hypertension and hypokalemia as first clinical manifestations in ectopic Cushing's syndrome / Hipertensão grave e hipocalemia como primeiras manifestações clínicas em casos de síndrome de Cushing ectópica

Ectopic ACTH production occurs in about 10 percent of all cases of Cushing's syndrome, and about 25 percent of cases of ACTH-dependent Cushing's syndrome. Diverse tumor types are able to produce ACTH ectopically, including small cell lung carcinoma. Ectopic ACTH secretion by malignant neoplasm has been reported to have earlier and more aggressive metabolic effects. We report a 59-year-old male patient with severe hypertension, metabolic alkalosis and hypokalemia as the first clinical manifestations of an ACTH-secreting small cell lung carcinoma, although the typical phenotypic features of Cushing's syndrome were not present. Ectopic Cushing's syndrome should always be ruled out in patients with severe hypertension and hypokalemia.

A produção de ACTH ectópico ocorre em aproximadamente 10 por cento dos casos de síndrome de Cushing, e em aproximadamente 25 por cento dos casos de síndrome de Cushing dependentes de ACTH. Diversos tipos de tumores são capazes de produzir ACTH ectopicamente, incluindo carcinoma pulmonar de células pequenas. Relatórios indicam que a secreção de ACTH ectópico por neoplasma maligno causa efeitos metabólicos prematuros e mais agressivos. Apresentamos um paciente, 59 anos, com hipertensão grave, alcalose metabólica e hipocalemia, tendo estas como as primeiras manifestações clínicas de um carcinoma pulmonar de células pequenas com secreção de ACTH, embora as características fenótipas típicas da síndrome de Cushing não estavam presentes. A síndrome de Cushing ectópica deveria ser excluída sempre em pacientes com hipertensão grave e hipocalemia.

Incidentaloma suprarrenal unilateral como presentación de tuberculosis adrenal / Unilateral adrenal incidentaloma as a presentation adrenal tuberculosis

Los incidentalomas suprarrenales son tumores que se detectan durante una prueba radiológica realizada por motivos distintos del estudio de la glándula suprarrenal. El uso extenso de la ecografía, la tomografía computarizada (TC) y la resonancia magnética ha dado lugar a un aumento en el diagnóstico de estas masas. Presentamos el caso de una mujer de 69 años con un incidentaloma suprarrenal izquierdo, que simulaba un adenoma no funcionante, y con atrofia en la adrenal derecha. Los resultados de la TC con contraste y, posteriormente, el estudio histopatológico confirmaron el diagnóstico de tuberculosis suprarrenal. El estudio hormonal reveló una insuficiencia suprarrenal parcial como resultado de la afección bilateral característica de la tuberculosis suprarrenal (AU)

Adrenal incidentalomas are adrenal masses detected during radiologic examination performed for an indication other than evaluation of adrenal disease. Diagnosis of these masses has increased due to the widespread use of ultrasonography, computed tomography (CT) and magnetic resonance imaging. We report the case of a 69-year-old woman with a left adrenal incidentaloma simulating a non-functioning adenoma and right adrenal atrophy. The results of contrast-enhanced CT and subsequent histopathological study confirmed the diagnosis of adrenal tuberculosis. Hormonal study revealed partial adrenal insufficiency as a result of bilateral involvement of the adrenal tuberculosis (AU)

Unilateral adrenal incidentaloma as a presentation of adrenal tuberculosis.

Adrenal incidentalomas are adrenal masses detected during radiologic examination performed for an indication otherthan evaluation of adrenal disease. Diagnosis of these masses has increased due to the widespread use of ultrasonography, computed tomography (CT) and magnetic resonance imaging. We report the case of a 69-year-old woman with a left adrenal incidentaloma simulating a non-functioning adenoma and right adrenal atrophy. The results of contrast-enhanced CT and subsequent histopathological study confirmed the diagnosis of adrenal tuberculosis. Hormonal study revealed partial adrenal insufficiency as a result of bilateral involvement of the adrenal tuberculosis.