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To investigate changes in brain network organization and possible neurobehavioral similarities to attention-deficit hyperactivity disorder (ADHD), we measured changes in brain resting-state functional connectivity (rs-fMRI) and cognitive domains in patients with resistance to thyroid hormone β (RTHβ) and compared them with those in healthy control subjects. In this prospective case-control study, twenty-one participants with genetically confirmed RTHβ were matched with 21 healthy controls. The Adult ADHD Self-Report Scale (ASRS-v1.1) and ADHD Rating Scale-IV were used to assess self-reported symptoms of ADHD. A voxel-wise and atlas-based approach was used to identify changes in the brain networks. The RTHβ group reported behavioral symptoms similar to those of ADHD. We found evidence of weaker network integration of the lingual and fusiform gyri in the RTHβ group, which was mainly driven by weaker connectivity to the bilateral insula and supplementary motor cortex. Functional connectivity between regions of the default mode network (angular gyrus/middle temporal gyrus) and regions of the cognitive control network (bilateral middle frontal gyrus) was increased in RTHβ patients compared to healthy controls. Increased connectivity between regions of the default mode network and the dorsolateral prefrontal cortex is frequently reported in ADHD and is interpreted to be associated with deficits in attention. Our finding of weaker connectivity of the lingual gyrus to the bilateral insula (salience network) in RTHβ patients has also been reported previously in ADHD and may reflect decreased habituation to visual stimuli and increased distractibility. Overall, our observations support the notion of neuropsychological similarities between RTHβ and ADHD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Göttlich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure., Methods: High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI)., Results: RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus., Conclusion: RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: Headache in patients with tumors of the sellar region (TSR) has previously been attributed entirely to biomechanical causes. This study aimed to investigate the influence of psychological determinants for the occurrence of and disability due to headaches in patients with TSR., Methods: This was a cross-sectional single-center study with a logistic regression approach. Eighty-four patients (75%) with pituitary adenomas and 28 with other TSR prior to first-time neurosurgery were investigated. One-hundred and twelve patients received standardized questionnaires on personality, headache characteristics, and disability due to headache. Fifty-nine patients additionally filled in questionnaires about coping with stress and pain catastrophizing. Separate logistic regression models were used to predict the risk of headache occurrence and disability due to headache by personality, stress coping, and pain catastrophizing., Results: Conscientiousness, neuroticism, and pain catastrophizing were significant predictors of headache occurrence. The amount of explained variance for both models predicting headache occurrence was comparable to that in primary headache. Neuroticism, pain catastrophizing, and humor as a coping strategy predicted disability due to headache with a high variance explanation of 20-40%., Conclusion: For the first time, we report data supporting a strong psychological influence on headache and headache-related disability in patients with TSR, which argue against purely mechanistic explanatory models. Physicians treating patients with TSR and headaches should adopt an integrative diagnostic and treatment approach, taking the biopsychosocial model of pain into account., Competing Interests: The authors declare no conflict of interest with respect to the research reported in this study., (Thieme. All rights reserved.)

Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α, β) with differential tissue distribution. Thyroid hormone receptor β (TRβ) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the β form of the receptor (pituitary, liver). This study seeks to identify the effects of mutant TRβ on pituitary size., Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHβ in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one neuroscientist)., Results: Patients with mutant TRβ (resistance to thyroid hormone β, RTHβ) showed elevated free tri-iodothyronine/thyroxine levels with normal thyroid-stimulating hormone levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHβ patients in comparison to healthy controls (F(1,35) = 7.05, P = 0.012, partial η2 = 0.17)., Conclusion: RTHβ subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.

Context: In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy., Objective: To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy., Methods: Retrospective evaluation in a tertiary cancer center., Results: Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ± 4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ± 9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01)., Conclusion: In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Thyroid hormones are modulators of cognitive functions, and changes in hormone levels affect intelligence, memory, attention and executive function. Single nucleotide polymorphisms (SNPs) of transporter proteins MCT8, MCT10 and deiodinase 2 (DIO2) influence thyroid metabolism and could therefore contribute to inter-individual variance of cognitive functions. This study investigates the influence of these SNPs using an extensive neuropsychological test battery. 656 healthy participants aged 18-39 years were genotyped for four SNPs: MCT8 (rs5937843 and rs6647476), MCT10 (rs14399) and DIO2 (rs225014) and underwent eleven different neuropsychological tests as well as four personality questionnaires. Test results were compared between homo- and heterozygous carriers and for the X-linked MCT8 additionally between men and women. Personality questionnaires revealed that Risk Seeking was reduced in homozygous T carriers and highest in homozygous C carriers of the DIO2 SNP and that both polymorphisms of MCT8 had an additive effect on Physical Aggression in men. Neuropsychological testing indicated that MCT10 affects nonverbal reasoning abilities, DIO2 influences working memory and verbal fluency and MCT8 influences attention, alertness and planning. This pilot study suggests an influence of polymorphisms in thyroid hormone transporter genes and deiodinase on cognitive domains and personality traits., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Determination of the levels of thyroid-stimulating hormone (TSH) and free thyroid hormones (fTHs) is crucial for assessing thyroid function. However, as a result of inter-individual genetic variability and different environmental factors individual set points exist for TSH and fTHs and display considerable variation. Furthermore, under specific pathophysiological conditions like central hypothyroidism, TSH secreting pituitary tumors, or thyroid hormone resistance the established markers TSH and fTH fail to reliably predict thyroid function and adequate supply of TH to peripheral organs. Even in case of overt hyper- and hypothyroidism circulating fTH concentrations do not correlate with clinical symptoms. Therefore, there is a clear need for novel, more specific biomarkers to diagnose and monitor thyroid function. OMICs screening approaches allow parallel profiling of hundreds to thousands of molecules and thus comprehensive monitoring of molecular alterations in tissues and body fluids that might be associated with changes in thyroid function. These techniques thus constitute promising tools for the identification of urgently needed novel biomarkers. This mini review summarizes the findings of OMICs studies in thyroid research with a particular focus on population-based and patient studies as well as interventional approaches investigating the effects of thyroid hormone administration., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.

The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Thyroid function is conventionally assessed by measurement of thyroid-stimulating hormone (TSH) and free circulating thyroid hormones, which is in most cases sufficient for correct diagnosis and monitoring of treatment efficiency. However, several conditions exist, in which these parameters may be insufficient or even misleading. For instance, both, a TSH-secreting pituitary adenoma and a mutation of thyroid hormone receptor β present with high levels of TSH and circulating hormones, but the optimal treatment is substantially different. Likewise, changes in thyroid hormone receptor α signaling are not captured by routine assessment of thyroid status, as serum parameters are usually inconspicuous. Therefore, new biomarkers are urgently needed to improve the diagnostic management and monitor treatment efficiency for e. g., replacement therapy in hypothyroidism or thyroid hormone resistance. By comparing animal models to human data, the present minireview summarizes the status of this search for new tissue- and pathway-specific biomarkers of thyroid hormone action., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS , MAFA ), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3 ), or pancreatic endocrine progenitors (i.e., FOXA2 ). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17-92 cluster, which have been implicated in b-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial-mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro. Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the "islet/insulinoma tumors" (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as "metastasis-like/primary" (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.

Resistance to thyroid hormone beta (RTHβ) is a syndrome of reduced responsiveness of peripheral tissue to thyroid hormone, caused by mutations in the thyroid hormone receptor beta (THRB). Its cognitive phenotype has been reported to be similar to attention deficit hyperactivity disorder (ADHD). This study used electrophysiological biomarkers of performance monitoring in RTHβ to contribute further evidence on its phenotypical similarity to ADHD. Twenty-one participants with RTHβ aged 18-67 years and 21 matched healthy controls performed a modified flanker task during EEG recording. The RTHβ and control groups were compared on behavioural measures and components of event related potentials (ERPs), i.e. the error related negativity (ERN), the error positivity (Pe) and P3 component. There were no significant group differences with regard to behaviour. RTHβ subjects displayed significantly reduced ERN and Pe amplitudes compared to the controls in the response-locked ERPs. In addition, we observed reduced P3 amplitudes in both congruent and incongruent trials, as well as prolonged P3 latencies in RTHβ subjects in the stimulus-locked ERPs. Our findings reveal alterations in error detection and performance monitoring of RTHβ patients, likely indicating reduced error awareness. The electrophysiological phenotype of RTHß subjects with regard to action monitoring is indistinguishable from ADHD., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiodo-L-thyronine (3,5-T2), a metabolite of the thyroid hormones (TH) thyroxine (T4) and triiodo-L-thyronine (T3), was reported to cause beneficial health effects, including reversal of steatohepatosis and prevention of insulin resistance, in most instances without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample. Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2-metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 μg/day levothyroxine to induce thyrotoxicosis. Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model. Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2 administration observed in animal models and those of coffee consumption demonstrated in large epidemiological studies, one might speculate that coffee-stimulated hepatic 3,5-T2 production or accumulation represents an important molecular link in this connection.

Background: Hypoparathyroidism is a rare and disabilitating disorder characterized by hypocalcemia and low parathyroid hormone levels. Most of the cases occur as a result of the removal of parathyroid glands or damage to the glands during neck surgery. More rare causes include nonsurgical causes such as autoimmune or genetic diseases., Method: In this review, a panel of experts presents the current state of diagnosis and therapy of hypoparathyroidism and explains practical aspects of caring for the affected patients., Results: Common signs and symptoms are abnormal sensations and increased excitability in the lower limbs, paresthesia of perioral areas and nocturnal leg cramps. Renal complications frequently occur, but also basal ganglia calcification. Treatment consists of administration of vitamin D analogs in combination with 0.5-1.0 g calcium daily. An adjunctive treatment with the in April 2017 approved recombinant human parathyroid hormone (1-84) is an option for patients whose hypoparathyroidism is difficult to control by conventional treatment alone. Initially and after dose changes follow-up controls should be performed at least every 2 weeks, in well-controlled patients or in the case of chronic progression every 3-6 months.

The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (<40 years) and older subjects (>60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013-2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8-10 mU/l., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Regulation of body temperature critically depends on thyroid hormone (TH). Recent studies revealed that TH induces browning of white adipose tissue, possibly contributing to the observed hyperthermia in hyperthyroid patients and potentially providing metabolic benefits. Here, we show that browning by TH requires TH-receptor β and occurs independently of the sympathetic nervous system. The beige fat, however, lacks sufficient adrenergic stimulation and is not metabolically activated despite high levels of uncoupling protein 1 (UCP1). Studies at different environmental temperatures reveal that TH instead causes hyperthermia by actions in skeletal muscle combined with a central body temperature set-point elevation. Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The number of patients surviving ≥5 years after initial cancer diagnosis has significantly increased during the last decades due to considerable improvements in the treatment of many cancer entities. A negative consequence of this is that the emergence of long-term sequelae and endocrine disorders account for a high proportion of these. These late effects can occur decades after cancer treatment and affect up to 50% of childhood cancer survivors. Multiple predisposing factors for endocrine late effects have been identified, including radiation, sex, and age at the time of diagnosis. A systematic literature search has been conducted using the PubMed database to offer a detailed overview of the spectrum of late endocrine disorders following oncological treatment. Most data are based on late effects of treatment in former childhood cancer patients for whom specific guidelines and recommendations already exist, whereas current knowledge concerning late effects in adult-onset cancer survivors is much less clear. Endocrine sequelae of cancer therapy include functional alterations in hypothalamic-pituitary, thyroid, parathyroid, adrenal, and gonadal regulation as well as bone and metabolic complications. Surgery, radiotherapy, chemotherapy, and immunotherapy all contribute to these sequelae. Following irradiation, endocrine organs such as the thyroid are also at risk for subsequent malignancies. Although diagnosis and management of functional and neoplastic long-term consequences of cancer therapy are comparable to other causes of endocrine disorders, cancer survivors need individually structured follow-up care in specialized surveillance centers to improve care for this rapidly growing group of patients., (Copyright © 2019 Endocrine Society.)

Aim: Validation of epigenome-wide association studies is sparse. Therefore, we evaluated the methylation markers cg06500161 ( ABCG1 ) and cg11024682 ( SREBF1 ) as classifiers for diabetes stratification. Patients & methods: DNA methylation was measured in blood (n = 167), liver (n = 99) and visceral adipose tissue (n = 99) of nondiabetic or Type 2 diabetic subjects by bisulfite pyrosequencing. Results: DNA methylation at cg11024682 in blood and liver correlated with BMI. Methylation at cg06500161 was influenced by the adjacent SNP rs9982016. Insulin-resistant and sensitive subjects could be stratified by DNA methylation status in blood or visceral adipose tissue. Conclusion: DNA methylation at both loci in blood presents a promising approach for risk group stratification and could be valuable for personalized Type 2 diabetes risk prediction in the future.

To study the interplay of metabolic state (hungry vs. satiated) and glucose administration (including hormonal modulation) on brain function, resting-state functional magnetic resonance imaging (rs-fMRI) and blood samples were obtained in 24 healthy normal-weight men in a repeated measurement design. Participants were measured twice: once after a 36 h fast (except water) and once under satiation (three meals/day for 36 h). During each session, rs-fMRI and hormone concentrations were recorded before and after a 75 g oral dose of glucose. We calculated the amplitude map from blood-oxygen-level-dependent (BOLD) signals by using the fractional amplitude of low-frequency fluctuation (fALFF) approach for each volunteer per condition. Using multiple linear regression analysis (MLRA) the interdependence of brain activity, plasma insulin and blood glucose was investigated. We observed a modulatory impact of fasting state on intrinsic brain activity in the posterior cingulate cortex (PCC). Strikingly, differences in plasma insulin levels between hunger and satiety states after glucose administration at the time of the scan were negatively related to brain activity in the posterior insula and superior frontal gyrus (SFG), while plasma glucose levels were positively associated with activity changes in the fusiform gyrus. Furthermore, we could show that changes in plasma insulin enhanced the connectivity between the posterior insula and SFG. Our results indicate that hormonal signals like insulin alleviate an acute hemostatic energy deficit by modifying the homeostatic and frontal circuitry of the human brain.

Objective: The aim of this study was to experimentally evaluate the effects of subclinical mild hypothyroidism on brain network connectivity as determined by resting state fMRI (rsfMRI) which serves as a proxy for global changes in brain function., Methods: Fifteen otherwise healthy patients with complete hypothyroidism under stable, long term levothyroxine substitution volunteered for the study. They reduced their pretest levothyroxine dosage by 30% for 52-56 days. Basally and after partial levothyroxine withdrawal, rsfMRI along with a neuropsychological analysis was performed. RsfMRI was subjected to graph-theory-based analysis to investigate whole-brain intrinsic functional connectivity., Results: The desired subclinical hypothyroidism was achieved in all subjects. This was associated with a significant decrease in resting-state functional connectivity specifically in the cuneus (0.05 FWE corrected at cluster level) which was mainly caused by a weaker functional connectivity to the cerebellum and regions of the default mode network, i.e. the medial prefrontal cortex, the precuneus and the bilateral angular gyri. The decrease in cuneus connectivity was correlated to the increase in TSH serum levels. A working memory task showed a slightly longer reaction time and less accuracy after partial levothyroxine withdrawal., Conclusion: Even short-term partial levothyroxine partial withdrawal leads to deficits in working memory tasks and to a weaker integration of the cuneus within the default mode network., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hypothyroidism is associated with memory impairments. The present study aimed to evaluate the effects of partial withdrawal of levothyroxine on working memory tasks and brain function. Fifteen subjects under long-term levothyroxine substitution as a result of complete hypothyroidism participated in the present study. Functional magnetic resonance imaging (MRI) was performed using a working memory task (n-back task) and neuropsychological tests were performed before and 52-54 days after the induction of subclinical hypothyroidism by reducing the pretest levothyroxine dosage by 30%. Reaction time of subjects under partial levothyroxine withdrawal was significantly longer and less accurate with respect to solving the working memory tasks. Functional MRI revealed significant activation changes after medication withdrawal in the cerebellum, insula, parietal, frontal, temporal and occipital lobes, lingual gyrus, and the cuneus. Partial withdrawal of levothyroxine may lead to deficits in a working memory task and to an activation of brain areas associated with working memory ability., (© 2019 British Society for Neuroendocrinology.)

Short- and long-term treatment with glucocorticoids is widely used in clinical practice and frequently induces features of iatrogenic Cushing syndrome, such as abdominally centered weight gain. Despite decades of glucocorticoids usage, the mechanisms underlying these side effects are still only partly understood. One possibility is that glucocorticoids impact subcortical (hypothalamus, amygdala, insula) and cortical (orbitofrontal and cingulate cortex) brain regions involved in appetite regulation and reward processing. In the present study, we used functional magnetic resonance imaging (fMRI) to study the acute effects of a prednisolone infusion on reactivity of brain reward systems to food stimuli. Twenty healthy normal-weight men were tested in a randomized, double-blind, cross-over study. After an overnight fast and infusion of either 250 mg prednisolone or placebo (always administered between 8 and 9 A M), fMRI scans were taken while presenting food and object pictures in a Go/NoGo (GNG) task. At home, participants were asked to register what they had eaten. On the following morning they came back to the lab and had a supervised ad libitum breakfast at a standardized buffet. Food-Go in contrast to Object-Go pictures yielded increased blood oxygen level dependent (BOLD) activity in hippocampus, amygdala, orbitofrontal cortex, insula and anterior cingulate cortex. Prednisolone increased activation in the bilateral amygdala and right insula for approach-associated food pictures. The buffet test did not reveal significant differences in calorie consumption or preferences of different macronutrients. However, prednisolone-induced insula reactivity to Food-Go images was associated with greater caloric intake, both at home and in the standardized buffet. In sum, we observed a specific effect of prednisolone on the BOLD response of the amygdala and insula to approach-associated food stimuli. As these brain areas have previously been implicated in hedonic eating, the present pattern of results may reflect an increased anticipated reward value of food modulated by glucocorticoids. These effects might potentially drive increased food intake and weight gain under prolonged glucocorticoid treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Cranial irradiation for brain tumours or leukaemias has been related to cognitive, endocrine and psychosocial late effects as well as sleep disturbances and increased daytime sleepiness. Studies suggest that cranial irradiation might impact on pineal melatonin secretion. Melatonin is an important regulator in human circadian rhythms and the sleep-wake cycle. The objective of this study was to investigate melatonin secretion, subjective sleep parameters and their interplay in a cohort of cranially irradiated head and brain tumour and leukaemia survivors at least 3 years after radiotherapy., Design: Cross-sectional study., Patients: Thirty-eight adults., Measurements: Melatonin secretion was evaluated by measuring its metabolite 6-sulphatoxymelatonin in collected overnight urine. Subjective sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. The Beck Depression Inventory II was used to screen for depressive symptoms because of their impact on sleep., Results: Patients irradiated in the brain midline had significantly lower melatonin secretion (P = 0.008). Subjects exhibited a high prevalence of sleeping difficulties, daytime sleepiness and depression, with females and overweight subjects particularly affected. Melatonin values and subjective sleep parameters did not correlate with each other or with treatment and most patient variables., Conclusions: Our data suggest that radiation exposure to the pineal gland negatively affects melatonin secretion. This lack of pineal melatonin does not influence subjective sleep quality. As melatonin has important antioxidant and cancer-protective effects, further research is necessary to elucidate whether these patients have an increased risk of developing secondary neoplasms and other radiation late effects., (© 2018 John Wiley & Sons Ltd.)

Objectives: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence., Study Design: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH., Results: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years)., Conclusions: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.

Background: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin., Methods: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked., Results: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test., Conclusions: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).

The incidence of neuroendocrine neoplasias (NEN) continues to increase. Since the primary tumor cannot be diagnosed in some cases of metastatic disease, new biomarkers are clearly needed to find the most probable site of origin. Tissue samples from 79 patients were analyzed and microRNA profiles were generated from a total of 76 primary tumors, 31 lymph node and 14 solid organ metastases. NEN metastases were associated with elevated levels of miR-30a-5p, miR-210, miR-339-3p, miR-345 and miR-660. Three microRNAs showed a strong correlation between proliferation index and metastatic disease in general (miR-150, miR-21 and miR-660). Further, each anatomic location (primary or metastatic) had one or more site-specific microRNAs more highly expressed in these tissues. Comparison between primary tumors and metastases revealed an overlap only in pancreatic (miR-127) and ileal tumors (let-7g, miR-200a and miR-331). This thorough analysis of gastroenteropancreatic neuroendocrine tumors demonstrates site-specific microRNA profiles, correlation with proliferation indices as well as corresponding nodal and distant metastases. Using microRNA profiling might improve NEN diagnostics by linking metastases to a most probable site of origin., Competing Interests: CONFLICTS OF INTEREST There is no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

To date, germline or somatic genetic events can be detected for at least 60% of paragangliomas. Strong genotype-phenotype associations have been recognized and become increasingly refined. Characteristics closely linked with genotype include syndromic presentation, age of onset, risk of metastatic disease and predominant anatomic site. In contrast, profiles of catecholamine secretion appear to be largely determined by anatomic location or cell type of origin. This review summarizes current knowledge of genotype-phenotype correlations for paragangliomas in different locations and scrutinizes previous publications on the respective tissues of origin to find potential explanations for site-related differences. We hypothesize that differential sensitivities of distinct chromaffin cell populations to hypoxia are major determinants of these differences, with increased sensitivity to hypoxia likely exacerbating vulnerability to mutation-derived disruption of hypoxic signaling pathways. Potential involvement of endothelin-1, tumor necrosis factor type 1 receptor-associated protein and the hypoxia-inducible miR-210 in the development of abdomino-thoracic or head and neck paragangliomas are discussed. Recognition of factors that predispose to chromosomal losses, or amplify sub-threshold molecular alterations towards tumorigenic events in different (chromaffin) cell types, may facilitate the leap from developing targeted therapies towards establishment of tumor preventative measures.

Thyroid hormones (TH) are of central importance for thermogenesis, energy homeostasis and metabolism. Here, we will discuss these aspects by focussing on the physiological aspects of TH-dependent regulation in response to cold exposure and fasting, which will be compared to alterations in primary hyperthyroidism and hypothyroidism. In particular, we will summarise current knowledge on regional thyroid hormone status in the central nervous system (CNS) and in peripheral cells. In contrast to hyperthyroidism and hypothyroidism, where parallel changes are observed, local alterations in the CNS differ to peripheral compartments when induced by cold exposure or fasting. Cold exposure is associated with low hypothalamic TH concentrations but increased TH levels in the periphery. Fasting results in a reversed TH pattern. Primary hypothyroidism and hyperthyroidism disrupt these fine-tuned adaptive mechanisms and both, the hypothalamus and the periphery, will have the same TH status. These important mechanisms need to be considered when discussing thyroid hormone replacement and other therapeutical interventions to modulate TH status., (© 2018 Society for Endocrinology.)

Background: Childhood cancer survivors are at risk for therapy-related sequelae and, therefore, require long-term follow-up. At 2 university hospitals in Germany collaborative multidisciplinary late effects clinics were installed to provide specialized care and to evaluate the current health status of these patients in a clinical setting. Patients andMethods: Every patient who visited the late effects clinics at the university hospital in Lübeck and Erlangen over a period of 3 years and met the inclusion criteria was included in the study. Patients' characteristics as well as cancer diagnosis, treatment related factors and the prevalence of chronic health conditions were assessed., Results: 220 patients attended the late effects clinics during the observation period. The median follow-up period was 16 years (range 5-45 years). In total over 64% of the patients were affected by at least 1 chronic health condition, including endocrine disruptions in 19.1% of the patients. Moreover, secondary neoplasms occurred in 9.1% of the study participants., Conclusion: German childhood cancer survivors are affected by multiple therapy-related sequelae. A comprehensive network of late effects clinics should be established to ensure specialized and risk-adapted care for every childhood cancer survivor in Germany., (© 2018 S. Karger GmbH, Freiburg.)

Background: The detailed pathomechanism of Takotsubo syndrome (TS) is still elusive. Due to the predominance of postmenopausal females, a potential role of sex hormones has been suggested. However, the limited available data are contradictory. The aim of this study was to comprehensively assess the role of sex hormone levels in a large cohort of TS patients., Methods: Serum samples of 57 female TS patients and 57 female patients with myocardial infarction (MI), matched for age (±2years) and repolarization disturbances were analyzed for estradiol (E2), estrone (E1), testosterone and androstenedione using liquid chromatography-tandem mass spectrometry., Results: There was no difference concerning the concentrations of E1 [pmol/l (IQR): 89.1 (62.5, 132.0) vs. 98.8 (63.3, 156.0), p=0,441], testosterone [nmol/l (IQR): 0.67 (0.46, 1.00) vs. 0.80 (0.49, 1.08), p=0.382] and androstenedione [nmol/l (IQR): 2.03 (1.57, 3.11) vs. 2.98 (1.48, 5.27), p=0.244] between female TS and MI patients. Regarding E2, the majority of patients demonstrated concentrations below the detection limit of 30pmol/l (TS: n=41/54, 75.9%; MI: n=32/53, 60.4%; p=0.078). The remaining individuals with detectable E2 concentrations did not show a significant difference between TS and MI patients [pmol/l (IQR): 40.5 (33.0, 53.3) vs. 54.1 (37.9, 60.9); p=0.20]., Conclusions: Altered sex hormone levels, especially an estradiol deficiency, could not be identified as a risk factor for TS., (Copyright © 2017. Published by Elsevier B.V.)

Cardiometabolic risk factors like abdominal obesity, hyperglycemia, low high-density lipoprotein (HDL) cholesterol, elevated triglycerides, and hypertension are defined as metabolic syndrome (MetS), which represents one of the most frequent endocrine disorders particularly in a society with increasing weight problems. As more and more evidence is accumulated that thyroid hormones affect components of the MetS, the present review aims to summarize the rapidly expanding knowledge on the pathophysiological interaction between thyroid hormone status and MetS. The review is based on a PubMed search for combinations of thyroid hormone action and MetS, blood pressure, hypertension, hyperlipidemia, cholesterol, HDL cholesterol, glucose, diabetes mellitus, body weight, or visceral fat. A special focus was given for manuscripts published after 2000 but we included seminal papers published before year 2000 as well., (© 2018 S. Karger AG, Basel.)

This study investigated sleep quality and health-related quality of life (HRQOL) among long-term survivors of Hodgkin (HL) and non-Hodgkin lymphoma (NHL). The aim was to explore the impact of personal and health-related factors on sleep quality as well as associations between sleep quality and HRQOL. For the postal survey, participants with a minimum age of 18 years initially treated between 1998 and 2008 were recruited via the population-based cancer registry in Schleswig-Holstein, Northern Germany. Questionnaires included amongst others the Pittsburg Sleep Quality Index (PSQI) and the 36-Item Short Form Health Survey (SF-36v1). Descriptive and comparative statistics were performed. Additionally, a regression analysis was conducted to identify predictors of sleep quality. In total, we recruited 515 participants (398 NHL, 117 HL) with a mean age of 63.1 years. Approximately half of the survivors were classified as good sleepers. HRQOL scores differed between good and poor sleepers with lower scores in poor sleepers. In a prediction model, self-reported depression, exhaustion, higher age, inability to work, endocrinological disorders and female gender classified as predictors of sleep quality. This study highlights the impact of sleep quality on HRQOL in long-term survivors of NHL and HL. Thus, sleep quality should be routinely assessed during follow-up of cancer survivors with special attention to patients with potential risk factors.

Background: Copeptin (pre-proAVP) secreted in equimolar amounts with vasopressin closely reflects vasopressin release. Copeptin has been shown to subtly mirror stress potentially mediated via corticotrophin-releasing hormone. To further test a potential direct interaction of corticotrophin-releasing hormone with copeptin release, which could augment vasopressin effects on pituitary function, we investigated copeptin response to corticotrophin-releasing hormone., Patients and Methods: Cortisol, adrenocorticotropin and copeptin were measured in 18 healthy controls and 29 subjects with a history of pituitary disease during standard corticotrophin-releasing hormone test., Results: Patients with previous pituitary disease were subdivided in a group passing the test (P1, n = 20) and failing (P2, n = 9). The overall copeptin response was higher in controls than in subjects with pituitary disease (area under the curve, p = 0.04 for P1 + P2) with a maximum increase in controls from 3.84 ± 2.86 to 12.65 ± 24.87 pmol/L at 30 min, p < 0.05. In contrast, both groups of pituitary patients lacked a significant copeptin response to corticotrophin-releasing hormone, and even in P1, where adrenocorticotropin concentrations increased fourfold (mean, 21.48 vs. 91.53 pg/mL, p < 0.01), copeptin did not respond (e.g., 4.35 ± 5.81 vs. 5.36 ± 6.79 pmol/L, at 30 min, p = ns)., Conclusions: Corticotrophin-releasing hormone is able to stimulate copeptin release in healthy controls suggesting a direct interaction of corticotrophin-releasing hormone and vasopressin/vasopressin. Interestingly, this relation is altered already in the group of pituitary patients who pass the standard corticotrophin-releasing hormone test indicating (1) the corticotrophin-releasing hormone-adrenocorticotropin-cortisol response is largely independent from the vasopressin system, but (2) the corticotrophin-releasing hormone-vasopressin interaction reflected by copeptin may be much more sensitive to reveal subtle alterations in the regulation of pituitary function.

Objective: Thyroid hormone (TH) transporters are expressed in thyrocytes and most play a role in TH release. We asked whether expression of the monocarboxylate transporter 8 (MCT8) and the L-type amino acid transporters LAT2 and LAT4 is changed with thyrocyte dedifferentiation and in hyperfunctioning thyroid tissues., Design and Methods: Protein expression and localization of transporters was determined by immunohistochemistry in human thyroid specimen including normal thyroid tissue (NT, n  = 19), follicular adenoma (FA, n  = 44), follicular thyroid carcinoma (FTC, n  = 45), papillary thyroid carcinoma (PTC, n  = 40), anaplastic thyroid carcinoma (ATC, n  = 40) and Graves' disease (GD, n  = 50) by calculating the 'hybrid' (H) score. Regulation of transporter expression was investigated in the rat follicular thyroid cell line PCCL3 under basal and thyroid stimulating hormone (TSH) conditions., Results: MCT8 and LAT4 were localized at the plasma membrane, while LAT2 transporter showed cytoplasmic localization. MCT8 expression was downregulated in benign and malignant thyroid tumours as compared to NT. In contrast, significant upregulation of MCT8, LAT2 and LAT4 was found in GD. Furthermore, a stronger expression of MCT8 was demonstrated in PCCL3 cells after TSH stimulation., Conclusions: Downregulation of MCT8 in thyroid cancers qualifies MCT8 as a marker of thyroid differentiation. The more variable expression of LATs in distinct thyroid malignancies may be linked with other transporter properties relevant to altered metabolism in cancer cells, i.e. amino acid transport. Consistent upregulation of MCT8 in GD is in line with increased TH release in hyperthyroidism, an assumption supported by our in vitro results showing TSH-dependent upregulation of MCT8., (© 2017 European Society of Endocrinology.)

Purpose: Headache is a common presenting feature of patients with pituitary adenomas and other tumors of the sellar region. However, at present, it still is unclear whether the headache is actually caused by the tumor. To explore whether there is a relation, we examined in detail the headache types, their relationship to the underlying pathology, and if the headache responded to neurosurgery in a prospective study design., Methods: One hundred twelve patients with tumors of the sellar region scheduled for neurosurgery in a single center were analyzed for presence and quality of headache before surgery and at least 3 months after surgery. Patients received headache and depression self-rating inventories, presented on a handheld computer (PainDetect ® ). Clinical variables thought to impact on headache were analyzed in conjunction with the inventories., Results: Fifty-nine (53%) patients reported headache in the 3 months prior to neurosurgery, 49 (44%) had headache at the time of filling in the questionnaires. The four patients with pituitary apoplexy described thunderclap headache. In the other patients diverse headache types were encountered, most frequently migraine. Untreated gonadotroph deficiency was significantly associated with absence of headache, while none of the other clinical and morphological variables related to headache. Presence of headache and disability due to headache were not significantly reduced after surgery., Conclusion: Apart from pituitary apoplexy we detected no specific headache type in our patient group and no significant improvement of headache after neurosurgery. Headache alone constitutes neither a valid diagnostic marker for the presence of tumors of the sellar region nor a sufficient indication for tumor removal.

Background: Determinations of thyrotropin (TSH) and free thyroxine (FT 4 ) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT 4 -associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model., Methods: A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT 4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure., Results: Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT 4 . A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT 4 . Main FT 4 -associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels., Conclusion: Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT 4 , we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.

Testosterone and cortisol have been proposed to influence aggressive behavior by altering the neural processing of facial threat signals. However, this has not been investigated in direct social interactions. Here, we explored the joint impact of testosterone, cortisol, and brain reactivity to anger expressions on women's reactive aggression in the Social Threat Aggression Paradigm (STAP). The STAP is a competitive reaction time task in which the purported opponent displays either an angry or a neutral facial expression at the beginning of each trial and delivers increasingly loud sound blasts to the participants, successfully provoking them. Strikingly, salivary testosterone at scan-time was negatively related to both aggression and basolateral amygdala (BLA) reactivity to angry faces, whereas cortisol had no effect. When the opponent looked angry, BLA-orbitofrontal coupling was reduced, and BLA reactivity was positively related to aggression. The latter relationship was fully mediated by bilateral superior temporal gyrus (STG) activation. Our results thus support previous neurobiological models of aggression, and extend them by demonstrating that fast amygdala responses to threat modulate STG activity in order to favor aggressive retaliation. Furthermore, our study agrees with recent evidence underscoring a fear-reducing and strategically prosocial effect of testosterone on human social behavior.

Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment. Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed. FTC-xenografts were treated with 5 × 2 Gy, ± 50 mg/kg GDC-0941 (twice-daily; orally) for 14 days and PIKK-activation and tumour-growth assessed. PIKK-expression was additionally assessed in 12 human papillary thyroid-carcinomas, 13 FTCs and 12 ATCs. GDC-0941 inhibited radiation-induced activation of Ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inhibition of ATM and DNA-PKcs was PI3K-dependent, since activation was reduced in PTEN-reconstituted FTC-133s. Inhibition of PIKK-activation was greater under anoxia: Consequently, whilst DNA-damage was increased and prolonged under both normoxia and anoxia, PI3K-inhibition only reduced clonogenic-survival under anoxia. GDC-0941 abrogated radiation-induced cell cycle arrest, an effect most likely linked to the marked inhibition of ATR-activation. Importantly, GDC-0941 inhibited radiation-induced PIKK-activation in FTC-xenografts leading to a significant increase in time taken for tumours to triple in size: 26.5 ± 5 days (radiation-alone) versus 31.5 ± 5 days (dual-treatment). PIKKs were highly expressed across human thyroid-carcinoma classifications, with ATM scoring consistently lower. Interestingly, some loss of ATM and DNA-PKcs was observed. These data provide new insight into the mechanisms of hypoxia-associated radioresistance in thyroid-carcinoma.

Aims: Disturbed levels of thyroid hormones are associated with neuropsychiatric disorders, including memory impairments. The aim of this study was to evaluate effects of mild induced thyrotoxicosis on working memory and its neural correlates., Methods: Twenty-nine healthy, male subjects with normal thyroid state participated in the study. Functional MRI was acquired during a working memory task (n-back task) before and after ingesting 250 μg L-thyroxin per day for a period of eight weeks. In addition, neuropsychological tests were performed., Results: In the hyperthyroid condition the subjects showed slower reaction times, but a higher accuracy in the 0-back version of the memory tasks. Fewer differences between euthyroid and hyperthyroid state were seen for the more difficult conditions of the n-back task. FMRI revealed effects of difficulty in the parahippocampal gyrus, supplementary motor area, prefrontal cortex, anterior cingulate cortex, posterior cerebellum, rolandic operculum and insula (p<0.05, FWE corrected). When comparing euthyroid and hyperthyroid condition in relation to task-induced activation, differences of activation were found in the right prefrontal cortex as well as in the right parahippocampal area. In the psychological assessment, the alerting effect in the Attention Network Task (ANT) and four out of five parameters of the auditory verbal learning test (AVLT) showed an increase from euthyroid to hyperthyroid state., Conclusions: It can be concluded that even a short-term intake of thyroid hormones leads to an activation of brain areas associated with working memory and to an improvement of accuracy of working memory tasks.

Thyroid hormones play a major role in body homeostasis, regulating energy expenditure and cardiovascular function. Given that obese people or athletes might consider rapid weight loss as beneficial, voluntary intoxication with T4 preparations is a growing cause for thyrotoxicosis. However, the long-lasting effects of transient thyrotoxicosis are poorly understood. Here we examined metabolic, thermoregulatory, and cardiovascular function upon induction and recovery from a 2-week thyrotoxicosis in male C57BL/6J mice. Our results showed that T4 treatment caused tachycardia, decreased hepatic glycogen stores, and higher body temperature as expected; however, we did not observe an increase in brown fat thermogenesis or decreased tail heat loss, suggesting that these tissues do not contribute to the hyperthermia induced by thyroid hormone. Most interestingly, when the T4 treatment was ended, a pronounced bradycardia was observed in the animals, which was likely caused by a rapid decline of T3 even below baseline levels. On the molecular level, this was accompanied by an overexpression of cardiac phospholamban and Serca2a mRNA, supporting the hypothesis that the heart depends more on T3 than T4. Our findings therefore demonstrate that a transient thyrotoxicosis can have pathological effects that even persist beyond the recovery of serum T4 levels, and in particular the observed bradycardia could be of clinical relevance when treating hyperthyroid patients.

Exogenous glucocorticoids are known to trigger affective changes, but these are highly variable across individuals. A better understanding of how synthetic glucocorticoids impact the processing of negative emotions in the human brain might help to predict such changes. In the present functional magnetic resonance imaging (fMRI) study, we sought to uncover the slow effects of a synthetic glucocorticoid infusion on the neural response to socio-emotional scenes using a within-participant, double-blind, placebo-controlled design. In two separate sessions, 20 young males were given either an intravenous prednisolone dose (250mg) or placebo in a cross-over, randomized order. Four hours later, they were scanned while viewing drawings of persons in a neutral or negative emotional situation. On the next morning participants provided a blood sample for serum cortisol measurement, which served as a manipulation check. Prednisolone strongly suppressed morning cortisol, and heightened brain reactivity to emotional stimuli in left amygdala, left caudate head, right inferior frontal gyrus, bilateral supplementary motor area, and right somatosensory cortex. Amygdala reactivity was related to lower self-reported fatigue and higher irritability in the prednisolone condition. Moreover, prednisolone blunted inferior frontal and amygdala connectivity with other regions of the emotion-processing neural circuitry. Our results suggest specific brain pathways through which exogenous glucocorticoids may labilize affect., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Stimulation of growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion by glucagon is a standard procedure to assess pituitary dysfunction but the pathomechanism of glucagon action remains unclear. As arginine vasopressin (AVP) may act on the release of both, GH and ACTH, we tested here the role of AVP in GST by measuring a stable precursor fragment, copeptin, which is stoichiometrically secreted with AVP in a 1:1 ratio. ACTH, cortisol, GH, and copeptin were measured at 0, 60, 90, 120, 150, and 180 min during GST in 79 subjects: healthy controls (Group 1, n = 32), subjects with pituitary disease, but with adequate cortisol and GH responses during GST (Group 2, n = 29), and those with overt hypopituitarism (Group 3, n = 18). Copeptin concentrations significantly increased over baseline 150 and 180 min following glucagon stimulation in controls and patients with intact pituitary function but not in hypopituitarism. Copeptin concentrations were stimulated over time and the maximal increment correlated with ACTH, while correlations between copeptin and GH were weaker. Interestingly, copeptin as well as GH secretion was significantly attenuated when comparing subjects within the highest to those in the lowest BMI quartile (p < 0.05). Copeptin is significantly released following glucagon stimulation. As this release is BMI-dependent, the time-dependent relation between copeptin and GH may be obscured, whereas the close relation to ACTH suggests that AVP/copeptin release might be linked to the activation of the adrenal axis.

Background: A significant number of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) present with metastatic disease and with unknown primary in about 15% of cases., Materials and Methods: We analyzed 163 primaries of GEP NET and 115 metastases for expression of caudal type homebox 2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), somatostatin receptor 2a (SSTR2a) and Ki67., Results: PR was most often positive in pancreatic NET and only rarely in non-pancreatic NET (p<0.001). ER was more frequently expressed in non-pancreatic NET (p<0.001) and was more often positive in females than males (p=0.019). CDX2 was positive in all primaries of the duodenum, ileum and appendix, but was also detected in 24% of metastases with pancreatic primary. SSTR2a and Ki67 did not differ significantly between primaries and metastases., Conclusion: Our data substantiate the value of PR, ER and CDX2 in GEP NET, and steroid hormone receptors, being differentially expressed in male and female patients. Differences between primaries and metastases were small but potentially relevant., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Context and Objectives: The association of endogenous androgens and sex hormone-binding globulin (SHBG) with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) mostly 23562 refers to small and selected study samples with immunoassay-based measurements. Thus, we investigated the association of hormone levels with MetS and T2DM in women from a large population-based sample., Design, Setting, and Participants: A total of 2077 women from the Study of Health in Pomerania were assessed at baseline (N = 3160, 1997-2001) and 5-year follow-up (N = 1711, 2002-2006)., Main Outcomes and Measures: We investigated associations of total testosterone (T) and androstenedione measured by liquid chromatography-tandem mass spectrometry, SHBG by immunoassay, and free T and free androgen index with MetS and T2DM., Results: Baseline prevalence of MetS and T2DM was 23.1% (N = 365) and 9.5% (N = 196), with an incidence of 17.7 and 7.0 per 1.000 person-years, respectively. Cross-sectional analyses yielded inverse associations of SHBG with MetS (relative risk [RR], 0.67; 95% confidence interval [CI], 0.60-0.74) and T2DM (RR, 0.61; 95% CI, 0.50-0.74) after multivariable adjustment. In longitudinal analyses, only age-adjusted models showed an inverse association of baseline SHBG with incident MetS (RR, 0.61; 95% CI, 0.51-0.73) and T2DM (RR, 0.58; 95% CI, 0.43-0.78). Multivariable-adjusted models stratified by menopausal status revealed an inverse association between SHBG and incident MetS risk in postmenopausal women (RR, 0.65; 95% CI, 0.51-0.81)., Conclusions: This longitudinal population-based study revealed independent inverse associations of SHBG with MetS and T2DM, suggesting low SHBG as a potential risk marker for cardiometabolic morbidity, especially among postmenopausal women.

Objectives: The aims of this study were to ascertain whether women with high levels of serum total testosterone (TT) or low levels of sex hormone-binding globulin (SHBG) are more likely to develop cardiovascular disease (CVD), and to investigate potential associations between sex hormones and mortality (all-cause, as well as cause-specific) in the general population., Study Design and Main Outcome Measures: Data on 2129 women with a mean age of 49.0 years were obtained from the population-based Study of Health in Pomerania over a median follow-up of 10.9 years. Associations of baseline levels of TT, SHBG, and rostenedione (ASD), and free testosterone (fT), and of the free androgen index (FAI), with follow-up CVD morbidity, as well as all-cause and CVD mortality, were analyzed using multivariable regression modeling., Results: At baseline the prevalence rate of CVD was 17.8% (378 women) and the incidence of CVD over the follow-up was 50.9 per 1000 person-years. We detected an inverse association between SHBG and baseline CVD in age-adjusted models (relative risk per standard deviation increase: 0.83; 95% confidence interval: 0.74-0.93). We did not detect any significant associations between sex hormone concentrations and incident CVD in age- and multivariable-adjusted Poisson regression models. Furthermore, none of the sex hormones (TT, SHBG, ASD, fT, FAI) were associated with all-cause mortality., Conclusions: This population-based cohort study did not yield any consistent associations between sex hormones in women and incident CVD or mortality risk., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyper-as well hypothyroidism have an effect on behavior and brain function. Moreover, during development thyroid hormones influence brain structure., Objectives: This study aimed to demonstrate an effect of experimentally induced hyperthyroidism on brain gray matter in healthy adult humans., Methods: High-resolution 3D T1-weighted images were acquired in 29 healthy young subjects prior to as well as after receiving 250 µg of T4 per day for 8 weeks. Voxel-based morphometry analysis was performed using Statistical Parametric Mapping 8 (SPM8)., Results: Laboratory testing confirmed the induction of hyperthyroidism. In the hyperthyroid condition, gray matter volumes were increased in the right posterior cerebellum (lobule VI) and decreased in the bilateral visual cortex and anterior cerebellum (lobules I-IV) compared to the euthyroid condition., Conclusions: Our study provides evidence that short periods of hyperthyroidism induce distinct alterations in brain structures of cerebellar regions that have been associated with sensorimotor functions as well as working memory in the literature.

Background: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease., Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis., Methods: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT4 levels were calculated using a Pearson correlation., Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT4, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels., Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.

Objective: Due to the increasing success and survival rates in the primary treatment of malignancies derived from the CNS as well as the hematopoietic system, endocrine late effects of cancer and its therapy are of growing importance. Despite evaluation of these late effects in patients treated for cancer in childhood, the impact on adults remains largely unclear., Methods: 1035 adult patients primarily diagnosed with a CNS malignancy, a Hodgkin (HL) or non-Hodgkin lymphoma (NHL) between 1998 and 2008 were recruited via the regional epidemiological cancer registry covering ∼ 2.8 million inhabitants in the federal state of Schleswig-Holstein, Northern Germany. The prevalence of endocrine disorders and current psychosocial impairment was assessed employing several questionnaires (SF-36v1, WHO-5)., Results: Fully completed questionnaires of 558 patients were available for subsequent analysis showing markedly reduced overall performance and psychological status when compared to German reference data. Thyroid disorders were reported in 16.3% of patients with 10.4% suffering from hypo- and 5.9% from hyperthyroidism. Overall, 17.6% stated to be affected by diabetes mellitus with an increased rate of 21.1% among NHL patients and 11.5% of participants were affected by osteoporosis., Conclusion: Compared to German population based studies on the prevalence of diabetes mellitus, osteoporosis and thyroid disorders the frequency of all these endocrine problems was significantly increased in CNS, HL, and NHL cancer survivors. These data confirm that not only children and adolescents but also adult cancer patients are at risk for therapy associated endocrine late effects., (© 2015 European Society of Endocrinology.)

Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach., (© 2015 European Society of Endocrinology.)