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Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.This Review summarizes current knowledge on non-classic and less common causes of hypopituitarism, such as traumatic brain injury, genetic causes, use of immune checkpoint inhibitors, autoimmune diseases and inflammatory diseases. Furthermore, emerging evidence that posterior pituitary damage can affect oxytocin secretion is highlighted.

Vitamin D system comprises hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. In addition to classical bone-related effects, this system has also been shown to activate multiple molecular mediators and elicit many physiological functions. In vitro and in vivo studies have, in fact, increasingly focused on the “non-calcemic” actions of vitamin D, which are associated with the maintenance of glucose homeostasis, cardiovascular morbidity, autoimmunity, inflammation, and cancer. In parallel, growing evidence has recognized that a multimodal association links vitamin D system to brain development, functions and diseases. With vitamin D deficiency reaching epidemic proportions worldwide, there is now concern that optimal levels of vitamin D in the bloodstream are also necessary to preserve the neurological development and protect the adult brain. The aim of this review is to highlight the relationship between vitamin D and neurological diseases.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.

The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44−9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95−0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00−1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00−11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94−0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00−1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03−1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4−15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2−16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06−1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.

Irisin is conventionally regarded as a myokine involved in the browning of white adipose tissue, energy expenditure and glucose tolerance. Its potential link to fat accumulation and metabolic dysfunction is debated. We sought to explore the relationship between circulating irisin and components of body composition in two different phenotypes of severe obesity. For this purpose, 30 obese adults with Prader-Will syndrome (PWS) (age 35.7 ± 1.5 y, BMI 45.5 ± 1.5 kg/m 2 ) and 30 adult controls with common obesity (age 34.9 ± 1.7 y, BMI 46.8 ± 1.4 kg/m 2 ) underwent analysis of irisin levels, metabolic profile, body composition and resting energy expenditure (REE). Normal irisin levels were obtained from a group of 20 lean donors (age 32.4 ± 1.5 y, BMI 23.8 ± 0.8 kg/m 2 ). Expected differences in body composition and metabolic profile existed between study groups. PWS exhibited lower muscle mass (p < 0.001), FFM (p < 0.001), REE (p < 0.001), as well as insulin (p < 0.05), HOMA-IR (p < 0.05) and triglycerides levels (p < 0.05) than controls with common obesity. In PWS, irisin levels were significantly lower and overall less dispersed than in controls with common obesity (p < 0.05), while being similar to values recorded in lean subjects. To explore the relation between irisin and body composition in obesity, univariate correlation analysis in the obese populations as a whole showed positive associations between irisin and muscle mass (p = 0.03) as well as REE (p = 0.01), which disappeared when controlled for the PWS status. Noticeably, a positive association became evident between irisin and %FM after controlling for the PWS status (p = 0.02). Also positive were associations between irisin and insulin (p = 0.02), HOMA-IR (p = 0.02) and triglycerides (p = 0.04). In stepwise multivariable regression analysis, irisin levels were independently predicted by the PWS status (p = 0.001), %FM (p = 0.004) and triglycerides (p = 0.008). Current results suggest that obese adults with PWS harbor lower irisin levels than individuals with common obesity. The divergent models of obesity herein studied suggest a potential link between circulating irisin and muscle mass and metabolic dysfunction relating to adiposity.

Background: Prader-Willi syndrome (PWS) is conventionally regarded as a model of genetic obesity carrying a metabolically healthier profile and fat compartmentalization than subjects with non-syndromic obesity. Serum uric acid (sUA) is a recognized surrogate marker of metabolic derangement. As no information is currently available on sUA levels in adults with PWS, we aimed to analyze sUA in a large cohort of adult patients with PWS in comparison to a control counterpart; secondly, we aimed to investigate the metabolic and non-metabolic determinants of sUA in PWS. Methods: A cross-sectional study was conducted on 89 consecutive adult patients with genetically confirmed PWS spanning a wide BMI range (17.2–56.7 kg/m2). As controls, 180 age-, sex- and BMI-matched healthy controls were included. sUA levels were analyzed in relation to the PWS status, metabolic variables, hormone status, body composition, and resting energy expenditure (REE). Bivariate correlation and multivariable regression studies were used to test for predictors of sUA in PWS. Results: Despite having similar BMI values, patients with PWS presented with higher FM (p < 0.0001), lower FFM (p < 0.0001) and REE values than controls (p < 0.0001). In PWS, sUA levels were non-significantly different between subjects with and without obesity (5.4 ± 1.3 vs. 4.9 ± 1.1 mg/dL, p = 0.09), and did not vary significantly in relation to genotype, sex steroid or GH replacement, as well as psychiatric treatments. Rates of hyperuricaemia (19.1% vs. 33.7%, p < 0.01) and absolute sUA levels were lower in patients with PWS compared to controls owing to significant differences between subgroups with obesity (5.5 ± 1.4 vs. 6.6 ± 1.6 mg/dL, p < 0.0001). In merged populations, sUA increased in parallel with age, BMI, FM, FFM, REE, glucolipid homeostasis, and inflammatory markers. In a separate analysis in PWS, however, sUA correlations with BMI, FM, and inflammatory markers were null. Stepwise multivariable regression analysis in the PWS group adjusted for karyotype, age, sex, FM, FFM, obesity, triglycerides, and HDL cholesterol, showed that sUA levels were independently associated with FFM (β = 0.35, p < 0.0001) and, albeit less significantly, with triglycerides (β = 0.23, p < 0.05). The introduction of height-normalized FFM (FFM index) in the regression model, however, abrogated the predictive role of FFM on sUA. Conclusions: FFM mass is a strong predictor of sUA. PWS is associated to lower sUA levels than controls likely due to genetic predisposition to different body composition and healthier metabolic phenotype. Further studies are warranted to assess purine metabolism and the clinical significance of the FFM index in PWS.

Regulating thermogenesis is a major task of thyroid hormones (THs), and involves TH-responsive energetic processes at the central and peripheral level. In severe obesity, little is known on the relationship between THs and resting energy expenditure (REE) before and after weight loss. We enrolled 100 euthyroid subjects with severe obesity who were equally distributed between genders. Each was examined before and after completion of a 4-wk inpatient multidisciplinary dieting program and subjected to measurement of thyroid function, REE, fat-free mass (FFM, kg) and percent fat mass (FM). Baseline REE was lower than predicted in 70 obese patients, and overall associated with BMI, FFM and FM but not thyroid-related parameters. By the study end, both BMI and REE decreased (5.5% and 4.1%, p<0.001 vs. baseline) and their percent changes were significantly associated (p<0.05), while no association related percent changes of REE and FFM or FM. Individually, REE decreased in 66 and increased in 34 patients irrespective of gender, BMI and body composition. Weight loss significantly impacted TSH (-6.3%), FT3 (-3.3%) and FT4 levels (3.9%; p<0.001 for all). By the study end, a significant correlation became evident between REE and FT4 (r = 0.42, p<0.001) as well as FT3 (r = 0.24, p<0.05). In stepwise multivariable regression analysis, however, neither THs nor body composition entered the regression equation for REE response to weight loss. In severe obesity, short-term weight loss discloses a positive relationship between REE and THs.

Abstract Context A warning has been recently issued by the European Medicine Agency (EMA) regarding a potential increased risk of acute pancreatitis (AP) in methimazole (MMI) users. Objective To investigate the association between MMI and the diagnosis of AP in a population-based study. Materials and Methods A retrospective analysis of administrative health databases was conducted (2013–2018). Relevant data were obtained from: (1) inhabitants registry, (2) hospital discharge records (ICD-9-CM 577.0), and (3) drug claims registry (ATC H03BB02). We evaluated AP risk in MMI users in 18 months of treatment, stratifying results by trimester. Poisson regression was used to estimate the age- and sex-adjusted rate ratios (RR), and the relative 95% confidence intervals (CI), comparing rates of AP between MMI users and nonusers. The absolute risk of AP in MMI users was also calculated. Results A total of 23 087 new users of MMI were identified. Among them, 61 hospitalizations occurred during the study period. An increase in AP risk was evident during the first 3 trimesters of therapy (RR 3.40 [95% CI: 2.12–5.48]; RR 2.40 [95% CI: 1.36–4.23]; RR 2.80 [95% CI: 1.66–4.73]), but disappeared thereafter. The AP absolute risk in MMI users during the first 18 months of treatment was less than 0.4% in all sex and age classes. Conclusions Our results support the EMA warning, suggesting an increased risk of AP associated with MMI use. However, such an increase seems limited to the first months of MMI treatment. Moreover, in absolute terms, the probability of AP is low among patients, well below 1%.

This study examines the information potential of comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOF MS) and variable ionization energy (i.e., Tandem Ionization™) to study changes in saliva metabolic signatures from a small group of obese individuals. The study presents a proof of concept for an effective exploitation of the complementary nature of tandem ionization data. Samples are taken from two sub-populations of severely obese (BMI > 40 kg/m2) patients, named metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Untargeted fingerprinting, based on pattern recognition by template matching, is applied on single data streams and on fused data, obtained by combining raw signals from the two ionization energies (12 and 70 eV). Results indicate that at lower energy (i.e., 12 eV), the total signal intensity is one order of magnitude lower compared to the reference signal at 70 eV, but the ranges of variations for 2D peak responses is larger, extending the dynamic range. Fused data combine benefits from 70 eV and 12 eV resulting in more comprehensive coverage by sample fingerprints. Multivariate statistics, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) show quite good patient clustering, with total explained variance by the first two principal components (PCs) that increases from 54% at 70 eV to 59% at 12 eV and up to 71% for fused data. With PLS-DA, discriminant components are highlighted and putatively identified by comparing retention data and 70 eV spectral signatures. Within the most informative analytes, lactose is present in higher relative amount in saliva from MHO patients, whereas N-acetyl-D-glucosamine, urea, glucuronic acid γ-lactone, 2-deoxyribose, N-acetylneuraminic acid methyl ester, and 5-aminovaleric acid are more abundant in MUO patients. Visual feature fingerprinting is combined with pattern recognition algorithms to highlight metabolite variations between composite per-class images obtained by combining raw data from individuals belonging to different classes, i.e., MUO vs. MHO.Graphical abstract

BackgroundThe role of insulin resistance and adipocytokines in determining the phenotype and recurrence of differentiated thyroid cancer (DTC) is still unknown. In a previous study, we observed an association between metabolic setting, circulating adipocytokines and thyroid cancer phenotype. The aim of this study was to evaluate the clinical follow-up of patients with DTC and the predictive role of metabolic setting on the risk of tumour relapse.MethodsBetween September 2016 and January 2017, 57 patients were admitted to our institution to undergo total thyroidectomy because of suspected DTC. Thirty patients with post-surgical histological diagnosis of DTC were included in the study. Each subject underwent pre-surgical analysis of anthropometric parameters, thyroid function and autoimmunity, glucose metabolism, insulin resistance (HOMA-IR) and levels of unacylated and acylated ghrelin, obestatin, leptin and adiponectin. Tumour recurrence at 1 and 3 years from diagnosis was assessed.ResultsMost patients were females (21F, 9M) with a median age at diagnosis of 50.0 (41.0–58.8). At baseline, overweight was found in 7 patients and obesity in 6 cases. Insulin resistance was detected in 14 patients. Overall, 17 patients (56.7%) underwent radioiodine treatment after surgery. During the follow-up, we observed a persistent biochemical disease in one patient whereas tumour relapse was found in six patients at 1 year from diagnosis (lymph node metastases) and in one patient at 3 years from diagnosis (lung metastases). Independently from age, sex, stage of disease and the presence of lymph node metastasis at diagnosis, higher BMI, leptin and insulin levels as well as HOMA-IR were associated with a higher risk of tumour relapse (p < 0.05 for all).ConclusionsOur results highlight a possible role for BMI, leptin and insulin resistance as predictors of early DTC relapse.