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Summary: 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. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine neoplasia (NEN) with unknown primary site (NEN-CUP tumors) may have a poor prognosis. We evaluated the clinical presentation, therapy, outcome, and risk factors for adverse outcomes in patients who had these tumors. Methods: In 243 patients who had NEN, a retrospective review was performed in 38 patients who had NEN-CUP tumors. The 38 patients who had NEN-CUP tumors were evaluated in three groups: group 1 (surgery; primary tumor detected; ten patients); group 2 (surgery; no primary tumor detected; ten patients); and group 3 (no surgery; 18 patients). Risk factors were evaluated with univariate and multivariate analyses. Results: Most patients who had NEN-CUP tumors [32 patients (84 %)] had World Health Organization (WHO) performance score of 0 or 1, and most tumors [24 patients (63 %)] were well differentiated (WHO grade, G1 or G2; Ki-67 index, ≤20 %). Univariate analysis showed that greater survival was significantly associated with lower patient age, lower WHO performance score, lower WHO grade, lower number of metastatic sites, treatment with surgery, and no treatment with chemotherapy. Multivariate analysis showed that low WHO performance score (hazard ratio 7.63, 95 % confidence interval (CI) 2.63-22.19) and treatment with surgery (hazard ratio 0.10, CI 0.028-0.381) were significant independent predictors of improved survival. Conclusions: In patients with NEN-CUP tumors, surgical treatment is an independent predictor of better survival. Therefore, surgical treatment may be indicated in patients with good general health status and well-differentiated NEN-CUP tumors. [ABSTRACT FROM AUTHOR]

Background A previous study showed an inverse association between the insulin-like growth factor I (IGF-I) and the risk of impaired glucose tolerance or diabetes mellitus. Moreover, myocardial infarction patients with high baseline IGF-I levels had a lower risk of diabetes mellitus. These data suggested a protective effect of IGF-I against the development of metabolic syndrome. However, there are no longitudinal data regarding IGF-I and metabolic syndrome. The aim of the present study was to investigate the longitudinal association between IGF-I and metabolic syndrome. Methods Data from the population-based Study of Health in Pomerania, Germany, were used for cross-sectional ( n = 3903) and longitudinal ( n = 2143) analyses (5-year follow-up). Metabolic syndrome was defined by three or more of the following five components: abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure and elevated nonfasting glucose. Serum IGF-I and IGF binding protein 3 (IGFBP-3) were determined by chemiluminescence immunoassays. Logistic and Poisson regression analyses were performed to determine associations. Results In cross-sectional analyses high IGFBP-3 as well as high and low IGF-I/IGFBP-3 ratio levels were associated with prevalent metabolic syndrome. In longitudinal analyses, the direction of the relation changed: men but not women with high IGF-I or IGF-I/IGFBP-3 ratio levels had an increased, whereas men with low levels had a decreased risk of incident metabolic syndrome. Conclusion In concordance with previous studies, our cross-sectional analyses showed a relation between low IGF-I/IGFBP-3 ratio and the prevalence of metabolic syndrome. In contrast, the longitudinal analyses indicated that a high IGF-I level was a risk marker for incident metabolic syndrome. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

To determine the prevalence of hypothyroidism amongst most adult survivors of childhood cancer in Britain using the British Childhood Cancer Survivor Study (BCCSS). The BCCSS is a population based cohort of individuals diagnosed with childhood cancer between 1940 and 1991 and who survived at least 5 years from diagnosis ( n = 17,981). 10483, 71% of those survivors aged at least 16 years, returned a completed questionnaire, which asked if hypothyroidism had been diagnosed. Of the whole cohort, 7.7% reported hypothyroidism with the highest risk among patients treated for Hodgkin's disease (HD) (19.9%), CNS neoplasms (15.3%), Non-Hodgkin's lymphoma (6.2%) and leukaemia (5.2%). Survivors were more likely to develop hypothyroidism if they had received radiotherapy for HD ( p = 0.0001) or a CNS neoplasm ( p < 0.00005) but not leukaemia ( p = 0.3). In these three patient groups, the frequency of hypothyroidism was similar in men and women. Survivors of irradiated CNS tumours reported a prevalence of hypothyroidism, which was substantially lower if discharged to primary care compared with being on hospital follow-up and which declined substantially with increased follow-up in both primary care ( p = 0.004) and hospital follow-up ( p = 0.023) settings. Hypothyroidism is a common finding amongst adult survivors of childhood malignancy. The substantial differences in reported hypothyroidism prevalence after irradiated CNS neoplasms suggests substantial under-diagnosis, which increased with increased follow-up, and which increased among those followed-up in primary care compared with hospital settings. [ABSTRACT FROM AUTHOR]

Previous studies detected associations between lower insulin-like growth factor I (IGF-I) levels and increased risk of congestive heart failure or ischaemic heart disease. The aim of the present study was to assess the association of IGF-I and its binding protein 3 (IGFBP-3) with the carotid intima-media thickness (IMT) as marker of asymptomatic cardiovascular disease. From the population-based Study of Health in Pomerania (SHIP), a total of 2286 participants aged 45 years or older with readable ultrasound of the carotid arteries were available for the present analyses. Serum IGF-I and IGFBP-3 levels were categorized into three groups (low, moderate, high) according to the sex-specific 10th and 90th percentile. Analyses of variance () and logistic regression analyses adjusted for age, waist circumference, diabetes, hypertension and creatinine clearance were performed. After adjusting for confounding factors, IGF-I and the IGF-I/IGFBP-3 ratio were positively related to IMT in . Logistic regression analyses confirmed these findings and showed that high IGF-I levels, a high IGF-I/IGFBP-3 ratio and low IGFBP-3 levels were associated to higher odds of increased IMT. In conclusion, high IGF-I or high IGF-I/IGFBP-3 ratio values and low IGFBP-3 levels are associated with increased IMT. Therefore, systemic levels of the IGF axis or alterations in the balance of its components are associated with subclinical atherosclerotic disease. [ABSTRACT FROM AUTHOR]

Thyroid disease and type 1 but also type 2 diabetes mellitus (DM) are strongly associated, and this has important clinical implications for insulin sensitivity and treatment requirements. The pathophysiological basis of this association has only recently been better elucidated. It rests on a complex interaction of common signalling pathways and, in the case of type 1 diabetes and autoimmune thyroid disease, on a linked genetic susceptibility. The pathophysiological mechanisms underlying this linked regulation are increasingly being unravelled. They are exemplified in the regulation of 5′ adenosine monophosphate-activated protein kinase (AMPK), a central target not only for the modulation of insulin sensitivity but also for the feedback of thyroid hormones on appetite and energy expenditure. The present review will discuss these concepts and their consequences for the clinical care of patients with DM and thyroid disorders. Moreover, it makes reference to the added effect of metformin in suppressing TSH. [ABSTRACT FROM AUTHOR]

von Berghes C, Brabant G, Biebermann H, Krude H, Wiegand S. Proinsulin and the proinsulin/insulin ratio in overweight and obese children and adolescents: relation to clinical parameters, insulin resistance, and impaired glucose regulation. Background: In adults with impaired glucose regulation (IGR) or type 2 diabetes mellitus (T2DM), proinsulin (PI) and its ratio to insulin (ins; PI/I ratio) are frequently elevated. Objective: Here we assessed the relationship among fasting PI, clinical parameters, and carbohydrate metabolism, a potential difference of the PI/I ratio between overweight and obese youth with or without IGR in an oral glucose tolerance test (OGTT) and the predictive power of PI levels for IGR. Design and Patients: In a cross-sectional study, data of n = 259 children and adolescents attending our obesity clinic were studied. Methods: Fasting PI levels were determined in all patients and matched to the standard assessment of obesity. In n = 154 subjects at risk for T2DM, an OGTT was performed sampling for glucose, ins, and PI. Main outcome measures: ins, glucose, PI, PI/I ratio, insulin resistance [homeostasis model assessment of insulin resistance index (HOMA-IR)]. Results: Puberty (by Tanner) and relative body weight [body mass index (BMI)-standard deviation of BMI (SDS)] showed a linear relationship to fasting PI levels (p < 0.001 for Tanner I vs. II-V; p = 0.04 and p = 0.026 for BMI-SDS <2 vs. 2-2.5 and 2-2.5 vs. >2.5, respectively). Subjects with ins resistance (HOMA-IR >95th percentile, n = 140) had higher fasting PI levels than those without (p < 0.001), with no significant difference in fasting PI/I ratio (p > 0.05). As compared to subjects with normal glucose regulation, subjects with IGR (n = 35) had higher fasting PI (p = 0.001) and an increased PI/I ratio, both during fasting and at 30 min during OGTT (p = 0.049 and p = 0.014, respectively). Conclusions: Children and adolescents with IGR have disproportionately elevated PI levels, both during fasting and after acute glucose stimulation indicating β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden. [ABSTRACT FROM AUTHOR]

Background. For unknown reasons, the prevalence of thyroid autoimmune disorders is higher in patients with Down's syndrome than in the general population. The present case strongly supports a recent evaluation of propagating screening for thyroid disease in this group of patients to assure early diagnosis of hypothyroidism. Methods. In a 25-year-old man diagnosed with Down's syndrome, clinical manifestations of hypothyroidism were lacking, but profound biochemical abnormalities were found with particularly high levels of thyroid stimulating hormone (TSH). Antigenic properties of TSH were characterized using a panel of anti-TSH antibodies. Results. Technical problems not infrequently associated with TSH measurements are convincingly ruled out. Antigenic characterization of the patient's circulating TSH revealed circulating forms of TSH different from pituitary TSH which closely resembled TSH recombinant human hormone. Conclusions. It appears counterintuitive that the bioactivity of TSH decreases in the hypothyroid state as higher bioactivity of TSH is anticipated in hypothyroidism promoted by an increased hypothalamic TRH drive. In contrast, diminished negative thyroid hormone feedback will enhance posttranslational glycosylation of TSH subunits and increase sialylation of the carbohydrate side chains. Both exert a negative effect on TSH bioactivity, only compensated by the very high levels of the hormone as in the present case. [ABSTRACT FROM AUTHOR]

Objective Liquid chromatography-tandem mass spectrometry (LC-MS/MS) eliminates cross-reactivity, which is a major limitation of immunoassays used for the measurement of salivary cortisol (SalC). We aimed to evaluate the potential of SalC measured by LC-MS/MS in patients undergoing assessment of the HPA axis. Design and patients Cross-sectional study of 78 patients admitted for routine testing in a specialized endocrine unit. Measurements Matched serum and saliva samples were collected from 68 patients who had a short synacthen test (SST, 250 mcg im) and 10 patients who had an insulin tolerance test (ITT, insulin 0·15 U/kg iv). Serum cortisol (SerC) was measured with an automated immunoassay and SalC with LC-MS/MS. Adequate SerC responses were >500 nmol/l. Results In all patients with adequate responses, the relative increase in SalC was significantly higher than that in SerC [6·4(0·3–26·1) vs. 1·0(0·3–4·9), P < 0·0001)]. The SerC–SalC relationship was better explained by an exponential rather than a linear model ( R2 = 0·83 vs. R2 = 0·65, both P < 0·0001). Based on 59 patients with adequate SerC responses to an SST, an adequate SalC response was defined as 8·3 nmol/l. Seven patients following an SST and three patients following an ITT showed inadequate responses in both SerC and SalC, but two patients with CBG deficiency showed a low SerC with normal SalC. Conclusions We have shown an excellent diagnostic sensitivity and specificity of LC-MS/MS SalC in the assessment of the HPA axis and superiority over SerC when CBG levels are altered. The exponential relationship between SerC and SalC supports the concept of CBG binding capacity saturation. [ABSTRACT FROM AUTHOR]

In diet-induced obese rats, leptin-mediated natural killer (NK) cell activation has been demonstrated to be impaired by abrogated intracellular JAK2-STAT3 signaling. The contribution of the obese microenvironment to this NK cell dysfunction and its reversibility remains elusive. In this study, the functions of NK cells from diet-induced obese rats after adoptive transfer into lean littermates were investigated using in vivo and in vitro approaches. Endogenous NK cells of normal-weight and diet-induced obese F344 rats were depleted in vivo. Then, NK cells from either normal-weight or obese donors were transferred. The numbers of peripheral blood NK cells were analyzed by fluorescence-activated cell sorting (FACS) and the distribution pattern of NK cells in lung and spleen by immunohistochemistry. Ob-R expression was evaluated by immunohistology and activation of intracellular target proteins of Ob-R by immunoblotting. The numbers of NK cells in blood and lung were significantly higher in obese animals compared to lean ones after transfer of NK cells from obese F344 rats. This was correlated with increased postreceptor signaling (JAK-2p, PKBpT308, ERK-2p) without altered Ob-R expression in those NK cells transferred to lean (ob→nw) vs. obese (ob→ob) animals. These results show for the first time that the altered phenotype of NK cells from obese rats can be normalized by generation of a physiological (metabolic) environment of lean rats. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the long-term effects of adrenalectomy on the blood pressure and antihypertensive medication in patients with primary aldosteronism (PA). Twenty-four patients (15 female and 9 male) with a mean age of 48.3 ± 10.8 years underwent surgery for PA in our institution between 1988 and 2001. All subjects were re-examined with a complete clinical work-up after a mean follow-up period of 86 ± 48 months, including blood pressure readings (<140/90 mmHg defined as normal), endocrine adrenal function, and specific medication. All patients suffered from hypertension (onset 8.5 ± 5.5 years prior to surgery). In 92% of the patients, hypokalemia was present (onset 2.0 ± 2.6 years prior to surgery). The histopathologic examinations revealed unilateral adenomas in 23 patients and a bilateral hyperplasia in one patient. At follow-up, 33% (8) of the patients were completely cured (normal blood pressure and no antihypertensive treatment), with seven of these eight patients being under 50 years of age at the time of surgery. One patient revealed a contralateral aldosterone-secreting adrenal adenoma during the subsequent endocrine and imaging examination 44 months after the first operation. Despite normalized plasma-aldosterone concentration (PAC), plasma-renin-activity (PRA) and serum potassium levels, a long-lasting insufficiently treated hypertension due to the delayed diagnosis in patients with PA may explain the persistent blood pressure elevation, indicating the necessity of a life-long, regular control of the blood pressure and antihypertensive medication. [ABSTRACT FROM AUTHOR]

The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women.Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls.Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = −0·516,P < 0·001), fasting insulin (r = −0·404,P < 0·001), homeostasis model sensitivity (HOMA %S) (r = −0·424,P <0·001) and testosterone (r = −0·279,P < 0·01), but no correlation with androstenedione (r = −0·112,P = 0·325), 17-OH-progesterone (r =−0·031,P = 0·784) or the LH/FSH ratio (r =−0·033,P = 0·753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0·55;P < 0·001), BMI (r =−0·575;P < 0·001), waist-to-hip ratio (WHR) (r =−0·48;P = 0·001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA)[Dexa-fat (total) (r = −0·61;P < 0·001) and Dexa-fat (trunk) (r = −0·59;P < 0·001)] and with testosterone (r = −0·42;P = 0·001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOSper sedid not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0·59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia.PCOSper seis not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity. [ABSTRACT FROM AUTHOR]

The age-dependent decline of the gonadal and somatotopic axis has been causally linked to frailty in the elderly by their effects on muscle mass and bone mineral density. However, for healthy men data on serum oestrogens and androgens, as well as IGF-1, as a common outcome measure covering the whole adult age range are scarce. We therefore studied healthy, nonobese male subjects between 20 and 80 years of age to asses their morning concentrations of total (T), free (FT), bioavailable testosterone (bT), oestradiol (E2), bioavailable oestradiol (bE2), oestrone (E1), sex-hormone binding globulin (SHBG), and insulin-like growth factor 1 (IGF-1). Five hundred and seventy-two male healthy volunteers with a BMI < 30 kg/m2 recruited from regular blood donors and senior sports clubs participated in the study. Serum samples were obtained during morning hours and T, FT, E2, E1, SHBG, albumin and IGF-1 were measured by radio-immunoassay systems. In addition, bT and bE2 were calculated. A potential relationship between sex hormones and IGF-1 was tested by multiple regression analysis including age and BMI. Ageing was negatively related to serum levels of sex steroids and IGF-1 (both P < 0·0001) with a mean decrease (youngest vs. oldest) of 51% for T, 64% for FT, 78% for bT, 32% for E2, 62% for bE2, 29% for E1 and 51% for IGF-1 starting in early adulthood whereas SHBG increased after the 5th decade of life (anova P < 0·001). The decline of sex hormones and IGF-1 remained relatively unchanged after adjustment for BMI. Multiple regression analysis revealed an age-and BMI– independent association between oestradiol and IGF-1. In contrast to the female situation sex hormones in healthy, nonobese men decline continuously with age. This process has already started in the third decade, and is paralleled by a decline of IGF-1 serum levels leading to a substantial proportion of elderly men with markedly lowered serum levels of bioavailable sex hormones and... [ABSTRACT FROM AUTHOR]

Presents a study which evaluated the hepatic alterations of leptin signaling due to diet induced obesity (DIO). Effects of DIO on insulin cross-signaling in the liver; Measurement of leptin receptor expression in the liver of obese animals; Role of nutrition in regulating leptin and insulin signaling.

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. [ABSTRACT FROM AUTHOR]