Health-Related Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome characterized by the triad of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (pNETs), and pituitary tumors. Patients are confronted with substantial morbidity and are consequently at risk for an impaired quality of life (QOL). Meticulous assessment of QOL and associated factors in a representative population is needed to understand the full spectrum of the burden of the disease. PATIENTS AND METHODS: A cross-sectional study was performed using the national Dutch MEN1 cohort. Patients with a confirmed MEN1 mutation received the SF-36 Health Related Quality of Life questionnaire and questions regarding sociodemographic and medical history. RESULTS: A total of 227 of 285 (80%) eligible MEN1 patients returned the questionnaires. Health-related QOL scores (HRQOL) in MEN1 patients were significantly lower for the majority of subscales of the SF-36 in comparison with the general Dutch population. The most consistent predictor for HRQOL was employment status, followed by the presence of a pituitary tumor. 16% of patients harboring a pNET and 29% of patients with a pituitary tumor according to the medical records, reported that they were unaware of such a tumor. These subgroups of patients had several significant better QOL scores than patients who were aware of their pNET or pituitary tumors. CONCLUSION: Patients with MEN1 have an impaired QOL in comparison with the general Dutch population warranting special attention within routine care. For daily practice, physicians should be aware of their patients' impaired QOL and of the impact of unemployment on QOL.

Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group.

OBJECTIVE: To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and preventing liver metastasis. BACKGROUND: MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager. METHODS: MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment. RESULTS: Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, [adjusted hazard ratio (HR) = 0.73 (0.25-2.11)]. Adjusted HR's after stratification by tumor size were: NF-pNETs <2 cm = 2.04 (0.31-13.59) and NF-pNETs 2-3 cm = 1.38 (0.09-20.31). Five out of the 6 patients with NF-pNETs >3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery. CONCLUSIONS: MEN1 patients with NF-pNETs <2 cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in NF-pNETs 2 to 3 cm requires further research. In patients with NF-pNETs >3 cm, watchful waiting seems not advisable.

Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome.

Hypocortisolism has been found in CFS patients in blood, urine, and saliva. It is unclear if hypocortisolism can also be demonstrated using long-term cortisol measurements, such as cortisol in hair. In addition, the interaction between the HPA axis and the immune system, both expected to play an important role in CFS, is unclear. The objective of the current study was to compare hair and salivary cortisol concentrations in a cohort of female CFS patients to those in healthy controls, and to test the effect of an interleukin-1 receptor antagonist (anakinra) on the HPA axis. Salivary cortisol concentrations of 107 CFS patients were compared to 59 healthy controls, with CFS patients showing a decreased cortisol awakening response (4.2 nmol/L ±â€¯5.4 vs 6.1 nmol/L ±â€¯6.3, p = 0.036). Total cortisol output during the day did not differ significantly in saliva, but there was a trend to lower hair cortisol in a subset of 46 patients compared to 46 controls (3.8 pg/mg ±â€¯2.1 vs 4.3 pg/mg ±â€¯1.8, p = 0.062). After four weeks of treatment with either daily anakinra (100 mg/day) or placebo, there was a slight decrease of hair cortisol concentrations in the anakinra group compared to an increase in the placebo group (p = 0.022). This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long-term cortisol measures.

Prognostic value of WHO grade in pancreatic neuro-endocrine tumors in Multiple Endocrine Neoplasia type 1: Results from the DutchMEN1 Study Group.

BACKGROUND: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. METHODS: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. RESULTS: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs ≥3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors ≤2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000). CONCLUSION: High mitotic count is correlated with poor prognosis in MEN1 patients with large non-functioning PanNETs.

Health-Related Quality of Life and Mental Health in Primary Aldosteronism: A Systematic Review.

The aim of this review was to determine the impact of primary aldosteronism on health-related quality of life (HRQoL) and mental health. We performed a systematic literature search up to July 2017 in six electronic databases. First, we screened the articles derived from this search based on title and abstract. Second, the selected studies were systematically reviewed and checked for our predefined inclusion criteria. The search yielded 753 articles, of which 15 studies met our inclusion criteria. Untreated patients with primary aldosteronism showed an impaired physical and mental HRQoL as compared to the general population. Multiple domains of HRQoL were affected. This applied to patients with both an aldosterone-producing adenoma and bilateral adrenal hyperplasia. Adrenalectomy improves HRQoL. Conflicting results have been reported on the extent of this improvement, the improvement after initiation of medical treatment, and whether there is a difference in HRQoL after both treatments. Similarly, psychopathological symptoms of anxiety, demoralization, stress, depression and nervousness were more frequently reported in untreated patients with primary aldosteronism than in the general population and patients with hypertension. Also an impaired sleep quality has been reported. Improvement of these symptoms was observed after treatment with both adrenalectomy and mineralocorticoid receptor antagonists. This review shows that HRQoL is impaired and psychopathology is more frequently reported in patients with primary aldosteronism. This seems to be at least partly reversible after treatment but the extent of improvement remains unknown. To assess HRQoL in these patients more precisely a primary aldosteronism-specific HRQoL questionnaire is required.

Conditioning Immune and Endocrine Parameters in Humans: A Systematic Review.

BACKGROUND: Conditioned pharmacological effects may provide relevant clinical opportunities to improve treatment for patients with a variety of conditions. The aim of this systematic review was to create an overview of studies in this field of research and to investigate whether specific characteristics of the study design make for successful conditioning. METHODS: The protocol of this review was registered in Prospero (PROSPERO 2015: CRD42015024148). A systematic literature search was conducted in the databases PubMed, Embase, and PsychInfo. Studies were included if they were placebo-controlled trials in humans in which the effects of a pharmacological agent on immune or endocrine outcomes (e.g., interleukin-2 and cortisol) were conditioned, using a specific conditioned stimulus. The risk of bias of each study was assessed using the Cochrane risk-of-bias tool. RESULTS: The final selection included 16 studies. Overall, those studies indicate that conditioning of immunosuppression, conditioning of allergic responses, and conditioning of insulin and glycemic responses is possible. Regarding immunostimulants, antiallergic effects, and cortisol conditioning, the preliminary results are promising, but additional studies are needed. CONCLUSIONS: This systematic review shows classical conditioning of immune and endocrine responses for various pharmaceutical substances. The studies reviewed here indicate that the number of acquisition and evocation sessions, and characteristics of the unconditioned and conditioned stimuli, are important determinants of the effectiveness of pharmacological conditioning on immune and endocrine parameters. In the future, conditioned pharmacological effects may be used clinically as adjunct therapy in various patient populations.

PROGNOSTIC FACTORS FOR SURVIVAL OF MEN1 PATIENTS WITH DUODENOPANCREATIC TUMORS METASTATIC TO THE LIVER: RESULTS FROM THE DMSG.

OBJECTIVE: Duodenopancreatic neuroendocrine tumors (DP-NETs) develop in a majority of patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Overall survival (OS) and prognostic factors for patients with liver metastases from DP-NETs are not known. METHODS: This was a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population treated between 1990 and 2014. OS was assessed with time to event analysis, and prognostic factors were evaluated. RESULTS: A total of 56% of the MEN1 patients (n = 220) were diagnosed with a DP-NET, of who 34 (15%) developed DP-NET liver metastases. Median age at liver metastases diagnosis was 53 years (range 31-74). Of those patients, 16 patients (47%) had died after a median follow-up of 4 years (range 0.3-12.3). OS at 2, 5, and 10 years were 91%, 65%, and 50%, respectively. A trend towards worse survival was seen in males compared to females (5-year OS 58% versus 75%, P = .07) and also in patients with multiple liver metastases compared to patients with solitary liver metastasis (59 versus 83%, P = .09). CONCLUSION: Despite the fairly indolent course of DP-NET liver metastases in MEN1 patients, half of the population was deceased after 10 years. Sex and tumor load at diagnosis of liver metastases are possible prognostic factors for worse survival. ABBREVIATIONS: DMSG = DutchMEN1 Study Group; D-NET = duodenal neuroendocrine tumor; DP-NET = duodenopancreatic neuroendocrine tumor; HPF = high-power field; Ki67 LI = Ki67 labeling index; MEN1 = multiple endocrine neoplasia type 1; NET = neuroendocrine tumor; OS = overall survival; P-NET = pancreatic neuroendocrine tumor; PPI = proton pump inhibitor; ULN = upper limit of normal; WHO = World Health Organization.

MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients.

BACKGROUND: Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up. METHODS: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. RESULTS: A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001). CONCLUSIONS: Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors.

Incidence of adrenal crisis in patients with adrenal insufficiency.

BACKGROUND: An adrenal crisis (AC) is a potential life-threatening event in patients with adrenal insufficiency (AI). This study aims to determine the incidence, causes, and risk factors of AC in AI. METHODS: Patients with AI diagnosed and treated at the University Medical Center Utrecht for the past 30 years were identified, and all medical records were assessed by two independent investigators. The observed frequency of AC was determined as incidence rate, calculated as the number of AC divided by person-years (PY). In addition, precipitating factors and risk factors were assessed. RESULTS: We observed an incidence rate of 5·2 AC (95% CI 4·3-6·3) per 100 PY in primary adrenal insufficiency (PAI, a total of 111 patients), and 3·6 AC (95% CI 3·1-4·1) per 100 PY in secondary adrenal insufficiency (SAI a total of 319 patients). Patients with an established diagnosis of tertiary (glucocorticoid-induced) adrenal insufficiency (a total of 28 patients) had 15·1 AC (95% CI 11·0-19·9) per 100 PY. The most important risk factor was the existence of comorbidity. Gastro-enteritis and other infections were the most common precipitating factors for AC. CONCLUSION: AC still occurs relatively frequent in patients with AI, mostly precipitated by infections and particularly in patients with high comorbidity. This should be taken into account in the education and follow-up of patients with AI.

Decreased physical activity, reduced QoL and presence of debilitating fatigue in patients with Addison's disease.

BACKGROUND: Health-related quality of life in patients with Addison's disease has been assessed in various European countries, indicating a reduced quality of life. However, no studies have addressed the impact of Addison's disease on physical activity. OBJECTIVE: The aim of this study was to investigate the quality of life in Dutch patients with Addison's disease particularly regarding the presence of fatigue and the ability to be physically active. METHODS: In this cross-sectional study, a postal survey was performed among Dutch patients with Addison's disease on stable glucocorticoid replacement therapy with hydrocortisone or cortisone acetate. For quality of life and physical activity assessment, patients completed general and health-related quality of life and physical activity questionnaires, and scores were compared to Dutch controls. RESULTS: A total of 328 patients with Addison's disease were studied. In patients with Addison's disease, only 45·7% met the standard of physical activity (Combinorm) compared to 67·8% of Dutch controls (P < 0·01). Forty-eight per cent of patients showed abnormal fatigue, while 61% had severe fatigue. The CIS fatigue scores were significantly higher compared to controls (P < 0·01). We found reduced general subjective health-related QoL scores in both male and female patients, especially in younger patients <65 years of age. CONCLUSION: Physical activity is decreased in patients with Addison's disease, combined with a reduced subjective health-related QoL and increased fatigue.

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma.

Interleukin (IL)-32 is an intracellular proinflammatory mediator that strongly modulates the inflammatory reaction. Recent studies have suggested the involvement of IL-32 in the pathogenesis of malignancies. We aimed to assess whether a known germ-line polymorphism in the IL32 promoter modulates IL-32 expression, and whether it influences susceptibility and/or outcome of epithelial cell-derived thyroid carcinoma (TC). In this study, IL32 genotype was assessed in 139 TC patients and 138 healthy controls and was correlated with TC susceptibility and clinical outcome. Furthermore, IL-32 messenger RNA expression and protein were assessed in TC tissues and functional consequences of genetic variants of IL32 were studied in a model of human primary immune cells. Results demonstrate substantial IL-32 expression in TC tumor tissue. Lipopolysaccharide (LPS) stimulation of primary immune cells revealed 2-fold higher expression of IL-32γ, but not IL-32ß, in cells homozygous for the ancient T allele. Furthermore, production of LPS-induced cytokines was increased in cells bearing this T allele. Genetic analysis revealed that the ancient T allele was overrepresented in TC patients with odds ratio (95% confidence interval) = 1.71 (1.06-2.75). In addition, the cumulative radioactive iodine (RAI) dose received after total thyroidectomy was significantly higher in TC patients bearing the ancient T allele. In conclusion, individuals bearing genetic variants of IL32 that lead to an increased IL-32γ gene expression and higher production of proinflammatory cytokines have higher risk for developing epithelial cell-derived TC. Subsequently, they require higher dosages of RAI to achieve successful tumor remission. These data suggest an important role of IL-32 in the pathogenesis of TC.

High level of distress in long-term survivors of thyroid carcinoma: results of rapid screening using the distress thermometer.

CONTEXT: Cancer patients are at increased risk for distress. The Distress Thermometer (DT) and problem list (PL) are short-tools validated and recommended for distress screening in cancer patients. OBJECTIVE: To investigate the level of distress and problems experienced by survivors of differentiated non-medullary thyroid carcinoma (DTC), using the DT and PL and whether this correlates with clinical and demographical variables. PARTICIPANTS, DESIGN AND SETTING: All 205 DTC patients, under follow-up at the outpatient clinic of our university hospital, were asked to fill in the DT and PL, hospital anxiety and depression scale (HADS), illness cognition questionnaire (ICQ) and an ad hoc questionnaire. Receiver Operator Characteristic analysis (ROC) was used to establish the optimal DT cut-off score according to HADS. Correlations of questionnaires scores with data on diagnosis, treatment and follow-up collected from medical records were analyzed. RESULTS: Of the 159 respondents, 145 agreed to participate [118 in remission, median follow-up 7.2 years (range 3 months-41 years)]. Of these, 34.3% rated their distress score ≥5, indicating clinically relevant distress according to ROC analysis. Patients reported physical (86%) over emotional problems (76%) as sources of distress. DT scores correlated with HADS scores and ICQ subscales. No significant correlations were found between DT scores and clinical or demographical characteristics except for employment status. CONCLUSION: Prevalence of distress is high among patients with DTC even after long-term remission and cannot be predicted by clinical and demographical characteristics. DT and PL are useful screening instruments for distress in DTC patients and could easily be incorporated into daily practice.

Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype.

OBJECTIVE: To identify the optimal surgical strategy for multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism (pHPT). To describe the course of postoperative hypoparathyroidism and to assess whether genotype is associated with persistent/recurrent pHPT. BACKGROUND: Surgery is the preferred treatment in MEN1-related pHPT, but the surgical procedure of choice is still uncertain. METHODS: This retrospective cohort study was performed at the Departments of Endocrinology of the University Medical Centers of Utrecht and Nijmegen, the Netherlands. Patients were selected from the Dutch MEN1 database, including all patients 16 years or older treated for MEN1 from 1990 to 2009. Data were collected by medical record review. RESULTS: Seventy-three patients underwent parathyroid surgery. Persistent/recurrent pHPT occurred in 53% after less than 3 parathyroids resected (

TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.

Results of endoscopic transsphenoidal pituitary surgery in 40 patients with a growth hormone-secreting macroadenoma.

OBJECTIVE: Transsphenoidal pituitary surgery (TS) is the primary treatment of choice for patients with acromegaly. Macroadenomas (>1 cm) are more difficult to resect than microadenomas (remission rate ± 50% compared to ± 90%). Besides the conventional microscopic TS, the more recently introduced endoscopic technique is nowadays frequently used. However, no large series reporting on its results have yet been published. We evaluated the outcome of endoscopic TS in 40 patients with a growth hormone (GH)-secreting macroadenoma treated in our hospital between 1998 and 2007. METHODS: Medical records were retrospectively reviewed. Remission was defined as disappearance of clinical symptoms of acromegaly, normal serum insulin-like growth factor-1 levels (≤2 SD) and serum GH levels suppressed to <2 mU/l after an oral glucose tolerance test within the first 4 months after TS. RESULTS: In four patients TS aimed at debulking of the tumour. In the remaining 36 patients, remission was achieved in 20 patients. In the first 5 years remission was achieved in 6 out of 18 patients (33%) compared to 14 out of 22 patients (63%) in the following 5 years (p = 0.06). Thirteen patients had a mild perioperative complication. Before TS 15 patients received hormonal substitution therapy compared to 12 patients (33%) after TS. CONCLUSION: Endoscopic TS is a good primary therapeutic option for patients with a GH-secreting macroadenoma, resulting in a remission rate of up to 63% in experienced hands. This technique can potentially improve the outcome of TS in these patients.

Eight-week exercise training in humans with obesity: Marked improvements in insulin sensitivity and modest changes in gut microbiome.

OBJECTIVE: Obesity is associated with impaired gut microbiota diversity, which has been linked to the development of type 2 diabetes. This study aims to examine the effects of an 8-week aerobic exercise intervention on insulin sensitivity, visceral adiposity, and gut microbiota diversity and composition in participants with obesity. METHODS: Fourteen participants (mean [SD], age 51 [11] years; BMI 34.9 [4.9] kg/m2 ) performed an 8-week exercise intervention (2 to 4 times/week on 65% to 85% of heart rate reserve). Insulin sensitivity (hyperinsulemic euglycemic clamp), cardiorespiratory fitness (maximal oxygen uptake), visceral adiposity (dual-energy X-ray absorptiometry scan) and gut microbiota composition (16S rRNA gene sequencing) were measured before and after the intervention. RESULTS: Insulin sensitivity showed a significant increase (pre: 3.8 [1.9] mg/min/kg; post: 4.5 [1.7] mg/min/kg; p = 0.007) after training, whereas visceral adiposity decreased (pre: 959 [361] cm3 ; post: 897 [364] cm3 ; p = 0.02). No change in gut microbiota α- or ß-diversity was found. At the genus level, the abundance of Ruminococcus gauvreauii (p = 0.02); Lachnospiraceae FCS020 group (p = 0.04), and Anaerostipes (p = 0.04) significantly increased after exercise training. Significant positive correlations were present for M-value (R. gauvreauii) and VO2 max (R. gauvreauii and Anaerostipes). CONCLUSIONS: Eight-week exercise training in humans with obesity leads to marked improvements in insulin sensitivity and body composition and is accompanied by modest changes in 3 gut microbiome genera, all belonging to the Firmicutes phylum.

Conditioning cortisol in healthy young women - A randomized controlled trial.

BACKGROUND: Learned placebo effects induced by pharmacological conditioning affect immune and endocrine outcomes and may offer new possibilities for clinical applications. Whether or not cortisol is subject to this type of associative learning processes, and whether conditioning may affect responses to stress, is currently unclear. METHOD: A randomized placebo-controlled trial was conducted in 48 healthy young women. During acquisition, participants received a pill containing either 100 mg hydrocortisone (unconditioned stimulus) or placebo, paired with a gustatory conditioned stimulus on three consecutive days. During evocation, all participants received placebo paired with the conditioned stimulus, again on three consecutive days. During the third evocation trial, participants underwent a psychosocial stress task. The main outcome parameter salivary cortisol and secondary outcome parameters salivary alpha-amylase, self-reported positive affect and tension, heart rate, and skin conductance level were measured at several time points. RESULTS: Significant baseline group differences on cortisol were found at several time points, which complicate the interpretation of group differences. During the first evocation session, the conditioned group showed a moderately smaller cumulative decrease in salivary cortisol from baseline than the placebo control group. No significant differences were found between the groups on cortisol during the second and third evocation or in response to stress, nor on other outcome measures. CONCLUSION: Although the results provide potential further indications for effects of conditioning on cortisol, baseline differences make it impossible to draw clear conclusions. No indications for possible effects of conditioning on the cortisol stress response or autonomous or affective responses to stress were found.

Unfavourable trends in cardiovascular and metabolic risk in paediatric and adult patients with congenital adrenal hyperplasia?

CONTEXT: As a result of the introduction of treatment with glucocorticoids and mineralocorticoids, now 60 years ago, congenital adrenal hyperplasia has become a lifelong chronic disease. Whether long-term treatment of the disease leads to long-term side effects remains unknown. In this respect, especially cardiovascular risk seems to be important. EVIDENCE SYNTHESIS: We reviewed the reported prevalence of conventional cardiovascular risk factors, i.e. obesity, insulin resistance, high blood pressure and dyslipidaemia in patients with congenital adrenal hyperplasia. Overall, the studies suggest a tendency towards an increased body mass index and fat mass, the presence of insulin resistance and hypertension, although data are relatively scarce and obtained in heterogeneous populations. CONCLUSIONS: Our findings suggest that adult CAH patients tend to have a cluster of metabolic risk factors, which are consistent with the metabolic syndrome. This notion may have consequences for the care for this group of patients.