Acute psychosocial stress increases serum BDNF levels: an antagonistic relation to cortisol but no group differences after mental training.

Brain-derived neurotrophic factor (BDNF) is an essential facilitator of neuronal plasticity. By counteracting the adverse effects of excessive stress-induced glucocorticoid signaling, BDNF has been implicated as a resilience factor to psychopathology caused by chronic stress. Insights into the effects of acute stress on peripheral BDNF levels in humans are inconclusive. The short-term interplay between BDNF and cortisol in response to acute psychosocial stress remains unexplored. Furthermore, it is unknown whether mental training that is effective at reducing cortisol reactivity can also influence BDNF during acute stress. In the current study, we investigated serum BDNF levels during an acute psychosocial stress paradigm, the Trier Social Stress Test (TSST), in 301 healthy participants (178 women, mean age = 40.65) recruited as part of the ReSource Project, a large-scale mental training study consisting of three distinct 3-month training modules. Using a cross-sectional study design, we first examined the relationship between BDNF and salivary cortisol in a control group with no mental training. Subsequent analyses focused on differences in BDNF stress levels between control and mental training groups. We show that serum BDNF is indeed stress-sensitive, characterized by a significant post-stress increase and subsequent decline to recovery. While respective increases in BDNF and cortisol were not associated, we found two indications for an antagonistic relationship. Higher BDNF peaks after stress were associated with steeper cortisol recovery. On the other hand, the magnitude of the cortisol stress response was linked to steeper BDNF recovery after stress. BDNF levels were not modulated by any of the mental training modules. Providing novel evidence for the dynamics of BDNF and cortisol during acute stress, our findings may further inform research on the physiological mechanisms involved in stress chronification and the associated health risks.

Effect of Advanced Glycation End Products on Human Thyroglobulin's Antigenicity as Identified by the Use of Sera from Patients with Hashimoto's Thyroiditis and Gestational Diabetes Mellitus.

Advanced glycation end products (AGEs) are formed on proteins after exposure to high concentrations of glucose and modify protein's immunogenicity. Herein, we investigated whether the modification of thyroglobulin (Tg) by AGEs influences its antigenicity and immunogenicity. Human Tg was incubated in vitro with increasing concentrations of D-glucose-6-phosphate in order to produce Tgs with different AGE content (AGE-Tg). Native Tg and AGE-Tgs were used in ELISA to assess the serum antibody reactivity of two patient groups, pregnant women with gestational diabetes (GDM), and patients with Hashimoto's thyroiditis (HT). We produced in vitro AGE-Tg with low and high AGE content, 13 and 49 AGE units/mg Tg, respectively. All HT patients' sera presented the same antibody reactivity profile against native Tg and AGE-Tgs, indicating that the modification of Tg by AGEs did not alter its antigenicity. Similarly, the GDM patients' sera did not discriminate among the two forms of Tg, native or artificially glycated, suggesting that the modification of Tg by AGEs might not alter its immunogenicity. The modification of Tg by AGEs has no obvious effect on neither its antigenicity nor, most likely, its immunogenicity. It seems that other Tg modifications might account for the production of aTgAbs in patients with GDM.

Estradiol levels predict short-term adverse health outcomes in postmenopausal acute stroke women.

BACKGROUND: Data on the role of endogenous sex steroids in cerebrovascular disease are sparse. Estradiol is a hormone with diverse actions on the central nervous system. Our aim was to investigate the role of circulating estradiol levels in a postmenopausal acute stroke population. METHODS: During a time-period of 2 years, we prospectively studied 302 postmenopausal female patients hospitalized for an acute stroke in two tertiary hospitals. We addressed the question whether endogenous estradiol is associated with stroke severity on admission and functional outcome 1 month after stroke, as assessed by the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), respectively. RESULTS: Estradiol levels were significantly related to stroke severity on admission, as expressed by NIHSS, even after correcting for confounding factors in the multivariate analysis (beta 0.353, P < 0.001). Estradiol was an independent determinant of 1-month mortality and adverse functional outcome (mRS ≥ 4), [odds ratio (OR) with 95% confidence intervals (CI): 3.341 (1.617-6.902), P = 0.001 and 2.277 (1.273-4.074), P = 0.006, respectively]. CONCLUSIONS: We identified an independent association of endogenous estradiol levels with stroke severity and short-term mortality and outcome. These findings suggest challenging the role of estradiol as a neuroprotective agent.

Association of thyroid autoimmunity with acne in adult women.

BACKGROUND: During the last decades an increase has been observed regarding acne in adults and especially women. OBJECTIVE: To evaluate the association between thyroid disorder and the presence of post-adolescent acne in adult women, comparing with healthy controls. METHODS: 107 adult women with post-adolescent acne and 60 healthy controls were included. Complete blood count and standard biochemical profile of C-Reactive Protein (CRP) and levels of thyroid hormones and antibodies [triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), free T3 (FT3), free T4 (FT4), antithyroglobulin antibodies (anti-TG) and anti-thyroid peroxidase antibodies (anti-TPO)] were determined in all subjects of both the acne and control groups. A thyroid ultrasound was also performed. RESULTS: There was a statistically significant difference (P=0.008) in the prevalence of positive anti-TG antibodies, with 25.2% of the acne group and 8.3% of the control group having elevated (>40 U/mL) anti-TG levels, respectively. Adult women with acne had a statistically significant increased relative risk to have high levels of anti-TG in comparison with healthy controls (odds ratio 3.89, P=0.011). This association was independent of age. Values for TSH, FT4, FT3, T4 and anti-TPO did not significantly differ between the two groups. No significant difference was found regarding the thyroid ultrasound findings. Although there was no significant difference between cases and controls regarding CRP levels, it is interesting that we observed a significant elevation in CRP in those acne patients who had positive antithyroglobulin antibodies. CONCLUSIONS: It is likely that thyroid autoimmunity might be more frequent in the adult acne patients and this should be kept in mind when screening women with post-adolescent acne.

Clinical and biochemical impact of BCL1 polymorphic genotype of the glucocorticoid receptor gene in patients with adrenal incidentalomas.

BACKGROUND: Adrenal incidentaloma (AI) is a common clinical problem. Subtle hormonal abnormalities are present in a substantial proportion of patients. BCL1 gene polymorphism of the glucocorticoid receptor (GR) is associated with increased sensitivity to glucocorticoid action. The genotype- phenotype associations of this polymomorphism in patients presenting with AI has not been extensively investigated. AIM: A cross-sectional study in secondary/tertiary care centers. SUBJECTS/METHODS: Ninety-five subjects with AI were genotyped for the BCL1 GR gene polymorphism. Patients underwent an oral glucose tolerance test and a dexamethasone suppression test (DST). The presence of subclinical hypercortisolism, features of metabolic syndrome, and osteoporosis/ osteopenia were also assessed. RESULTS: No significant differences in markers of adrenal function between BCL1 carriers and non-carriers were revealed. Also, no difference was found in the features of metabolic syndrome, as well as in bone metabolism and density between these 2 groups. However, DST suppressor patients belonged more frequently to the BCL1 carriers group (41 out of 69 patients, 59.4% vs 9 out of 26 patients, 34.6%, p=0.0039), had smaller total adenoma size (2.4±0.2 cm vs 3.5±0.4 cm, p=0.04), and lower incidence of bilateral adrenal masses (18.8% vs 46.2%, p=0.01). CONCLUSIONS: AI patients who also carry the polymorphic BCL1 variant exhibit smaller size adrenal nodules. Those AI patients with complete DST suppression had a higher incidence of the polymorphic BCL1 variant. However, this study failed to demonstrate any significant impact of BCL1 GR polymorphism on the frequency of cortisol-dependent co-morbidities in patients with AI.

Effect of gestational diabetes and intrauterine growth restriction on the offspring's circulating galanin at birth.

CONTEXT: Experimental studies linked gestational diabetes mellitus (GDM) and intrauterine growth restriction (IUGR) with altered expression of the offspring's hypothalamic galanin mRNA, possibly contributing to the development of obesity and metabolic syndrome in later life. We hypothesized that plasma galanin levels at birth would reflect presumably altered hypothalamic galanin expression and production that cannot be assessed in the human offspring. OBJECTIVE: Our objective was to investigate whether neonates born to GDM mothers or being IUGR differ from healthy ones in circulating galanin at birth. DESIGN, PATIENTS, AND METHODS: Twenty-five neonates born to GDM mothers, 25 with IUGR, and 15 healthy neonates (controls) were prospectively studied. Neonatal plasma galanin levels were assayed immediately after birth by using enzyme immunoassay. RESULTS: Neonatal plasma galanin showed a high variability within each group and did not differ significantly among the three groups of neonates. No correlation between plasma galanin and anthropometric maternal and neonatal data was found. Multiple linear regression confirmed that the neonatal group (infants of diabetic mothers, IUGR, and controls) was not an independent predictor for galanin levels at birth after controlling for possible confounders, i.e. maternal body mass index and weight gain during pregnancy and neonatal body mass index. CONCLUSIONS: Circulating galanin levels at birth are not affected by GDM and IUGR, providing no evidence for alternations in hypothalamic galanin expression and secretion in humans, as they were previously documented in experimental models. This fact precludes the use of plasma galanin as an early indicator for the development of obesity and metabolic syndrome in this high-risk population.

Gender, age, puberty, and BMI related changes of TSH and thyroid hormones in schoolchildren living in a long-standing iodine replete area.

The aim of the work was to assess thyroid function in children and adolescents in an iodine replete area and to explore possible effects of age, gender, puberty, and adiposity. Thyrotropin (TSH), total triiodothyronine (T (3)), total thyroxine (T (4)), free thyroxine (FT (4)), and the T (4)/T (3) ratio were determined for 440 schoolchildren (200 boys and 240 girls), aged 5-18 years, living in an iodine replete region. Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), and Body Surface Area (BSA) were calculated. In girls there was a negative correlation of TSH, T (3), and FT (4) values with age. In boys there was a negative correlation only of T (3) values with age. Girls had lower TSH, T (4), and T (3) values, whereas boys had only lower T (3) values at puberty compared to the prepubertal stage. Girls had lower TSH values than boys (p<0.03) only at puberty. BMI-SDS in boys and girls were 0.21 and 0.03, respectively. BMI-SDS was not related to TSH, T (4), or T (3) in either gender, whereas it was negatively related to T (4)/T (3) ratio in boys and to FT (4) in girls. We conclude that estrogens may exert a suppressive effect on the pituitary-thyroid axis after puberty. TSH values are not correlated with BMI-SDS, whereas T (4)/T (3) ratio in boys and FT (4) in girls are negatively correlated with BMI-SDS.

Estrogen receptor beta gene variants may be associated with more favorable metabolic profile in postmenopausal women undergoing coronary angiography.

AIM: Estrogen action is exerted on the vasculature through estrogen receptors ER alpha and ER beta. We have previously reported significant association of ER alpha gene (ESR1) variants with more severe coronary artery disease (CAD) in postmenopausal women. The influence of ER beta gene (ESR2) variants on the cardiovascular system is not well established. We investigated the association of common ESR2 variants with risk factors for cardiovascular disease and with the severity of CAD in postmenopausal women. METHODS: ESR2 polymorphisms Alu I (1730 G > A) and Rsa I (1082 G > A) were studied in 174 postmenopausal women undergoing coronary angiography (age 45 - 88 yrs). The severity of CAD (0 - 3 vessels with > 50 % stenosis), indices of obesity and other predisposing risk factors for cardiovascular disease, biochemical and hormonal parameters were recorded. RESULTS: 75 women had 0, 39 had one, 37 had two and 23 had three vessels with severe stenosis in the coronary angiography. There was no association between Alu I (allele frequency = 40.2 %) and Rsa I (allele frequency = 2.6 %) variants and CAD severity. Carriers of Alu I had lower BMI (p = 0.044), lower waist perimeter (p = 0.029) and lower total cholesterol (p = 0.033) and LDL levels (p = 0.029). There was no association between Rsa I polymorphism and any metabolic risk factors. CONCLUSIONS: ESR2 Alu I polymorphism may have a favorable influence on risk factors for cardiovascular disease such as obesity indices and cholesterol levels. It does not appear to be associated with the severity of CAD in women.

Endogenous subclinical hyperthyroidism: Metabolic and cardiac parameters.

BACKGROUND: Subclinical hyperthyroidism (SH) is defined by suppressed TSH and normal levels of thyroid hormones. Endogenous subclinical hyperthyroidism (ESH) is probably less common than exogenous SH. Adverse effects of SH due to exogenous administration of thyroxine have been well studied, while the impact of ESH on the cardiovascular system and metabolic parameters remains controversial. METHODS: In a cross-sectional study, we examined patients with endogenous clinical hyperthyroidism (ECH; n=20), ESH (TSH<0.1 muU/mL, n=25), and mild ESH (TSH=0.1-0.3 muU/mL, n=32), as well as healthy controls (n=50). Biochemical and metabolic parameters influenced by thyroid hormones were assessed and cardiac parameters were studied using echocardiography and 24-hour ECG-blood pressure monitoring. RESULTS: Biochemical and metabolic parameters did not differ significantly between ESH and healthy subjects. The ECH group had significantly higher sex hormone-binding globulin, osteocalcin, and carboxy-terminal telopeptide levels than healthy subjects. No significant differences were noted in echocardiographic parameters between ESH patients and healthy subjects. The ECH group had a significantly higher heart rate, cardiac output, and cardiac index than the control group, as well as end-diastolic and end-systolic diameters of the left ventricle, and end-diastolic and end-systolic volumes of the left ventricle. The 24-hour ECG-blood pressure monitoring parameters did not differ significantly either between SH and healthy subjects while, in the ECH group, mean heart rate, maximum heart rate, and mean tachycardia episodes were significantly increased. CONCLUSION: Only subjects with ECH showed differences in metabolic and cardiac parameters from controls, while no significant effects were noted in the endogenous subclinical forms.

Lack of substantial effects of raloxifene on thyroxine-binding globulin in postmenopausal women: dependency on thyroid status.

Long-term estrogen therapy can modify thyroid hormone kinetics by increasing serum concentration of thyroxine-binding globulin (TBG). Raloxifene is a recently developed selective estrogen receptor modulator (SERM) for the treatment of osteoporosis, which possesses estrogenic and antiestrogenic properties. In a prospective and randomized study, we investigated the effects of raloxifene on TBG levels and on the serum concentrations of free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) in controls and in patients receiving TSH-suppressive doses of levothyroxine (LT4). Twenty-nine postmenopausal osteopenic (n = 14) and osteoporotic (n = 15) women were investigated over a period of 6 months. Group 1 (n = 15) included control patients and group 2 (n = 14) patients receiving TSH-suppressive dose of LT4. All patients were treated with raloxifene hydrochloride, 60 mg/d, for a period of 6 months. Serum basal TBG values were found higher in Group 1 compared to Group 2 (26.2 2 microg/mL vs. 21.4 2.1 microg/ml; p < 0.01). The TBG levels raised slightly in group 1 from 26.2 2 microg/mL to 28.6 3.1 microg/mL; p < 0.05 (in group 2 from 21.4 2.1 microg/mL to 22.2 2.3 microg/mL, not significant) after 3 months of treatment and failed to show any further significant change until the end of the study. Serum concentrations of T4, FT4, T3, and TSH levels changed insignificantly in both groups up to the completion of the study. Moreover, patients remained clinically euthyroid. Our findings may provide evidence that TBG levels, and consequently, thyroid function are not substantially affected by treatment with raloxifene. Additionally, TBG levels may also be influenced by small variations of thyroid function as subclinical hyperthyroidism.

Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism.

Sideropenia affects ca. 20% of the world population, and iron dependent anemia is the most frequent type of anemia worldwide. The aim of the study was to investigate the incidence of sideropenia and dependent anemia in patients with subtle changes of the thyroid function, such as subclinical hypothyroidism (SH). 57 women with SH and 61 euthyroid controls (CG) were studied. Serum concentrations of T4, T3, TSH, anti-TPO, anti-Tg, ferrum (Fe), ferritin (Frt) total iron binding capacity (TIBC) and blood count were determined. In SH 17 patients (29.8%) presented low Fe levels (<50 microg/dl). 9 (15.7%) also had decreased Frt, confirming iron deficiency, whereas 8 patients presented additionally diminished hematocrit and hemoglobin levels, suggesting manifested sideropenic anemia. In CG, 10 persons (16%) had sideropenia, 6 (9.8%) had low Fe and Frt and only 3 (4.9%) had blood count alterations suggesting manifested sideropenic anemia. In SH, anti-TPO were positive in 39 patients (68%), whereas, in CG only 2 (3.2%) were positive. 8 patients with SH and manifested sideropenic anemia were treated with ironproteinsuccinylate (I-PSL), (80 mg Fe /day, for three months), a new iron compound. The repletion treatment safely led to the clinical and laboratory correction of sideropenia and showed a good tolerability. Furthermore, iron treatment provoked a minor increase of T4 and a mild decline of TSH, but the levels were not significant. These results suggest that sideropenia is a common finding in patients with slightly decreased thyroid activity, and that determination of Frt should be routinely advised. Finally, in the assessment of sideropenia and dependent anemia, evaluation of the thyroid function must be taken into account.

Inhibitory action of oral thyrotropin-releasing hormone on the glucoregulatory response of the oral glucose tolerance test.

Thyrotropin-releasing hormone (TRH) has been found in the gastrointestinal tract, where it mainly exerts an inhibitory action. We used oral TRH, a stable and powerful formulation, to explore the glucoregulatory response of oral glucose tolerance test (OGTT) on obese patients with impaired glucose tolerance (IGT). Seven obese patients with IGT and eight controls were investigated. Three tests were performed on three separate days. On day 1, An oral TRH test: a 40 mg TRH tablet, was given. Blood samples for blood glucose (BG), proinsulin (PI), insulin (INS), C-peptide (CP), thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were collected every 30 minutes for 3 hours. On day 2, an OGTT with 75 g glucose was performed. On day 3, an oral TRH test was administered 30 minutes before the OGTT, and blood was collected every 30 minutes for 3 hours. Oral-TRH had no effect on basal BG and on pancreatic hormone secretion. Oral TRH, coupled with OGTT in both controls and obese patients, led to a significant inhibition of BG (p < 0.01), of CP (p < 0.001), and of INS (p < 0.001) during the first hour of administration, and afterward, there was only a very slight increase, compared with levels after only OGTT treatment. After OGTT, PI peaked at 90 minutes (9.4+/-3 ng/mL) in controls and at 60 minutes (12.7+/-2.5 ng/mL) in obese patients. TRH application prior to OGTT inhibited PI secretion for 90 minutes in controls, whereas in obese patients PI levels were decreased, not inhibited, during the OGTT. The mechanism of the inhibitory TRH action on OGTT-induced increase of BG and pancreatic hormone secretion is not clear. It could be due to inhibition of gastric motility, and on a paracrine effect that enhances secretion of somatostatin that then suppresses INS, CP, and possibly PI levels. The partial escape of PI from the TRH blockade in obese patients with IGT might indicate a diminished functioning capability of beta-cells and that TRH cannot affect the INS processing within the beta-cells in these patients.