Strong associations of serum selenoprotein P with all-cause mortality and mortality due to cancer, cardiovascular, respiratory and gastrointestinal diseases in older German adults.

BACKGROUND: Selenium is an essential trace mineral. The main function of selenoprotein P (SELENOP) is to transport selenium but it has also been ascribed anti-oxidative effects. METHODS: To assess the association of repeated measurements of serum SELENOP concentration with all-cause and cause-specific mortality serum SELENOP was measured at baseline and 5-year follow-up in 7,186 and 4,164 participants of the ESTHER study, a German population-based cohort aged 50-74 years at baseline. RESULTS: During 17.3 years of follow-up, 2,126 study participants (30%) died. The relationship of serum SELENOP concentration with all-cause mortality was L-shaped, with mortality being significantly higher at SELENOP concentrations < 4.1 mg/L, which is near the bottom tertile's cut-off (4.2 mg/L). All-cause mortality of participants in the bottom SELENOP tertile was significantly increased compared to subjects in the top tertile (hazard ratio [95% confidence interval]: 1.35 [1.21-1.50]). SELENOP in the bottom tertile was further associated with increased cardiovascular mortality (1.24 [1.04-1.49]), cancer mortality (1.31 [1.09-1.58]), respiratory disease mortality (2.06 [1.28-3.32]) and gastrointestinal disease mortality (2.04 [1.25-3.32]). The excess risk of all-cause mortality for those in the bottom SELENOP tertile was more than twice as strong in men as in women (interaction of SELENOP and sex; p = 0.008). CONCLUSIONS: In this large cohort study, serum SELENOP concentration was inversely associated with all-cause and cause-specific mortality. Consistent inverse associations with multiple mortality outcomes might be explained by an impaired selenium transport and selenium deficiency in multiple organs. Trials testing the efficacy of selenium supplements in subjects with low baseline SELENOP concentration are needed. TRIAL REGISTRATION: Retrospectively registered in the German Clinical Trials Register on Feb 14, 2018 (ID: DRKS00014028).

Selenium, Iodine and Iron-Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism.

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H2O2-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus-pituitary-thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as 'thyroxisome' at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

Seizures, ataxia and parvalbumin-expressing interneurons respond to selenium supply in Selenop-deficient mice.

Mice with constitutive disruption of the Selenop gene have been key to delineate the importance of selenoproteins in neurobiology. However, the phenotype of this mouse model is exquisitely dependent on selenium supply and timing of selenium supplementation. Combining biochemical, histological, and behavioral methods, we tested the hypothesis that parvalbumin-expressing interneurons in the primary somatosensory cortex and hippocampus depend on dietary selenium availability in Selenop-/- mice. Selenop-deficient mice kept on adequate selenium diet (0.15 mg/kg, i.e. the recommended dietary allowance, RDA) developed ataxia, tremor, and hyperexcitability between the age of 4-5 weeks. Video-electroencephalography demonstrated epileptic seizures in Selenop-/- mice fed the RDA diet, while Selenop± heterozygous mice behaved normally. Both neurological phenotypes, hyperexcitability/seizures and ataxia/dystonia were successfully prevented by selenium supplementation from birth or transgenic expression of human SELENOP under a hepatocyte-specific promoter. Selenium supplementation with 10 µM selenite in the drinking water on top of the RDA diet increased the activity of glutathione peroxidase in the brains of Selenop-/- mice to control levels. The effects of selenium supplementation on the neurological phenotypes were dose- and time-dependent. Selenium supplementation after weaning was apparently too late to prevent ataxia/dystonia, while selenium withdrawal from rescued Selenop-/- mice eventually resulted in ataxia. We conclude that SELENOP expression is essential for preserving interneuron survival under limiting Se supply, while SELENOP appears dispensable under sufficiently high Se status.

Deiodinases control local cellular and systemic thyroid hormone availability.

Iodothyronine deiodinases (DIO) are a family of selenoproteins controlling systemic and local availability of the major thyroid hormone l-thyroxine (T4), a prohormone secreted by the thyroid gland. T4 is activated to the active 3,3'-5-triiodothyronine (T3) by two 5'-deiodinases, DIO1 and DIO2. DIO3, a 5-deiodinase selenoenzyme inactivates both the prohormone T4 and its active form T3. DIOs show species-specific different patterns of temporo-spatial expression, regulation and function and exhibit different mechanisms of reaction and inhibitor sensitivities. The main regulators of DIO expression and function are the thyroid hormone status, several growth factors, cytokines and altered pathophysiological conditions. Selenium (Se) status has a modest impact on DIO expression and translation. DIOs rank high in the priority of selenium supply to various selenoproteins; thus, their function is impaired only during severe selenium deficiency. DIO variants, polymorphisms, SNPs and rare mutations have been identified. Development of DIO isozyme selective drugs is ongoing. A first X-ray structure has been reported for DIO3. This review focusses on the biochemical characteristics and reaction mechanisms, the relationships between DIO selenoproteins and their importance for local and systemic provision of the active hormone T3. Nutritional, pharmacological, and environmental factors and inhibitors, such as endocrine disruptors, impact DIO functions.

Selenium in Endocrinology-Selenoprotein-Related Diseases, Population Studies, and Epidemiological Evidence.

Selenium (Se), apart from iodine, iron, and calcium, is one of the nutrient-derived key elements strongly affecting the endocrine system. However, no specific hormonal "feedback" regulation for Se status has yet been identified, in contrast to the fine-tuned hormone network regulating Ca2+ and phosphate balance or hepcidin-related iron status. Since its discovery as an essential trace element, the effects of Se excess or deficiency on the endocrine system or components of the hypothalamic-pituitary-periphery feedback circuits, the thyroid hormone axis, glucoregulatory and adrenal hormones, male and female gonads, the musculoskeletal apparatus, and skin have been identified. Analysis of the Se status in the blood or via validated biomarkers such as the hepatically derived selenoprotein P provides valuable diagnostic insight and a rational basis for decision making on required therapeutic or preventive supplementation of risk groups or patients. Endocrine-related epidemiological and interventional evidence linking Se status to beneficial or potentially adverse actions of selected selenoproteins mediating most of the (patho-) physiological effects are discussed in this mini-review. Autoimmune thyroid disease, diabetes and obesity, male fertility, as well as osteoporosis are examples for which observational or interventional studies have indicated Se effects. The currently prevailing concept relating Se and selenoproteins to "oxidative stress," reactive oxygen species, radical hypotheses, and related strategies of pharmacological approaches based on various selenium compounds will not be the focus. The crucial biological function of several selenoproteins in cellular redox-regulation and specific enzyme reactions in endocrine pathways will be addressed and put in clinical perspective.

A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans.

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.

Aminoglycoside-driven biosynthesis of selenium-deficient Selenoprotein P.

Selenoprotein biosynthesis relies on the co-translational insertion of selenocysteine in response to UGA codons. Aminoglycoside antibiotics interfere with ribosomal function and may cause codon misreading. We hypothesized that biosynthesis of the selenium (Se) transporter selenoprotein P (SELENOP) is particularly sensitive to antibiotics due to its ten in frame UGA codons. As liver regulates Se metabolism, we tested the aminoglycosides G418 and gentamicin in hepatoma cell lines (HepG2, Hep3B and Hepa1-6) and in experimental mice. In vitro, SELENOP levels increased strongly in response to G418, whereas expression of the glutathione peroxidases GPX1 and GPX2 was marginally affected. Se content of G418-induced SELENOP was dependent on Se availability, and was completely suppressed by G418 under Se-poor conditions. Selenocysteine residues were replaced mainly by cysteine, tryptophan and arginine in a codon-specific manner. Interestingly, in young healthy mice, antibiotic treatment failed to affect Selenop biosynthesis to a detectable degree. These findings suggest that the interfering activity of aminoglycosides on selenoprotein biosynthesis can be severe, but depend on the Se status, and other parameters likely including age and general health. Focused analyses with aminoglycoside-treated patients are needed next to evaluate a possible interference of selenoprotein biosynthesis by the antibiotics and elucidate potential side effects.

Sex-specific and inter-individual differences in biomarkers of selenium status identified by a calibrated ELISA for selenoprotein P.

Selenoprotein P (SELENOP) is a liver-derived transporter of selenium (Se) in blood, and a meaningful biomarker of Se status. Se is an essential trace element for the biosynthesis of enzymatically-active selenoproteins, protecting the organism from oxidative damage. The usage of uncalibrated assays hinders the comparability of SELENOP concentrations and their pathophysiological interpretation across different clinical studies. On this account, we established a new sandwich SELENOP-ELISA and calibrated against a standard reference material (SRM1950). The ELISA displays a wide working range (11.6-538.4µg/L), high accuracy (2.9%) and good precision (9.3%). To verify whether SELENOP correlates to total Se and to SELENOP-bound Se, serum samples from healthy subjects and age-selected participants from the Berlin Aging Study II were analyzed by SELENOP-ELISA and Se quantification. SELENOP was affinity-purified and its Se content was determined from a subset of samples. There was a high correlation of total Se and SELENOP concentrations in young and elderly men, and in elderly women, but not in young women, indicating a specific sexual dimorphism in these biomarkers of Se status in young subjects. The Se content of isolated SELENOP was independent of sex and age (mean±SD: 5.4±0.5). By using this calibrated SELENOP-ELISA, prior reports on pathological SELENOP concentrations in diabetes and obesity are challenged as the reported values are outside reasonable limits. Biomarkers of Se status in clinical research need to be measured by validated assays in order to avoid erroneous data and incorrect interpretations, especially when analyzing young women. The Se content of circulating SELENOP differs between individuals and may provide some important diagnostic information on Se metabolism and status.

Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8.

Thyroid hormones (THs) are charged and iodinated amino acid derivatives that need to pass the cell membrane facilitated by thyroid hormone transmembrane transporters (THTT) to exert their biological function. The importance of functional THTT is affirmed by the devastating effects of mutations in the human monocarboxylate transporter (MCT) 8, leading to a severe form of psychomotor retardation. Modulation of THTT function by pharmacological or environmental compounds might disturb TH action on a tissue-specific level. Therefore, it is important to identify compounds with relevant environmental exposure and THTT-modulating activity. Based on a nonradioactive TH uptake assay, we performed a screening of 13 chemicals, suspicious for TH receptor interaction, to test their potential effects on THTT in MCT8-overexpressing MDCK1-cells. We identified silymarin, an extract of the milk thistle, to be a potent inhibitor of T3 uptake by MCT8. Because silymarin is a complex mixture of flavonolignan substances, we further tested its individual components and identified silychristin as the most effective one with an IC50 of approximately 100 nM. The measured IC50 value is at least 1 order of magnitude below those of other known THTT inhibitors. This finding was confirmed by T3 uptake in primary murine astrocytes expressing endogenous Mct8 but not in MCT10-overexpressing MDCK1-cells, indicating a remarkable specificity of the inhibitor toward MCT8. Because silymarin is a frequently used adjuvant therapeutic for hepatitis C infection and chronic liver disease, our observations raise questions regarding its safety with respect to unwanted effects on the TH axis.

The Effects of Thyroid Hormones on Gene Expression of Acyl-Coenzyme A Thioesterases in Adipose Tissue and Liver of Mice.

BACKGROUND: Thyroid hormones (TH) exert pleiotropic effects on glucose and lipid homeostasis. However, it is as yet unclear how TH regulate lipid storage and utilization in order to adapt to metabolic needs. Acyl-CoA thioesterases (ACOTs) have been proposed to play a regulatory role in the metabolism of fatty acids. OBJECTIVES: We investigated the interaction between thyroid dysfunction and Acot expression in adipose tissues and livers of thyrotoxic and hypothyroid mice. METHODS: Ten-week-old female C57BL/6NTac mice (n = 10/group) were made hyperthyroid by the application of L-thyroxine (2 µg/ml in drinking water) for 4 weeks. Hypothyroidism was induced in 10-week-old mice by feeding an iodine-free chow supplemented with 0.15% PTU for 4 weeks. We measured mRNA expression levels of Acot8, 11 and 13 in the liver and epididymal and inguinal white and brown adipose tissues (BAT). Furthermore, we investigated hepatic Acot gene expression in TRα- and TRß-deficient mice. RESULTS: We showed that the expression of Acot8, 11 and 13 is predominantly stimulated by a thyrotoxic state in the epididymal white adipose tissue. In contrast, hypothyroidism predominantly induces the expression of Acot8 in BAT in comparison with BAT of thyrotoxic and euthyroid mice (p < 0.01). However, no significant changes in Acot expression were observed in inguinal white adipose tissue. In liver, Acot gene expression is collectively elicited by a thyrotoxic state. CONCLUSIONS: These data suggest that ACOTs are targets of TH and are likely to influence 3,5,3'-triiodo-L-thyronine-orchestrated mechanisms of lipid uptake, storage and utilization to adapt the regulation of metabolic demands.

Selenium and the thyroid.

PURPOSE OF REVIEW: This article provides an update on the role of the essential trace element selenium and its interaction with the other trace elements iodine and iron that together contribute to adequate thyroid hormone status. Synthesis, secretion, metabolism and action of thyroid hormone in target tissues depend on a balanced nutritional availability or supplementation of these elements. Selenium status is altered in benign and malignant thyroid diseases and various selenium compounds have been used to prevent or treat widespread diseases such as goiter, autoimmune thyroid disease or thyroid cancer. RECENT FINDINGS: Several studies, most with still too low numbers of cases, indicate that selenium administration in both autoimmune thyroiditis (Hashimoto thyroiditis) and mild Graves' disease improves clinical scores and well-being of patients and reduces thyroperoxidase antibody titers. However, published results are still conflicting depending on basal selenium status, dose, time and form of selenium used for intervention. Evidence for sex-specific selenium action, lack of beneficial effects in pregnancy and contribution of genetic polymorphisms (selenoprotein S) has been presented. SUMMARY: Adequate nutritional supply of selenium that saturates expression of circulating selenoprotein P, together with optimal iodine and iron intake, is required for a healthy and functional thyroid during development, adolescence, adulthood and aging.

An Improved Nonradioactive Screening Method Identifies Genistein and Xanthohumol as Potent Inhibitors of Iodothyronine Deiodinases.

BACKGROUND: Deiodinases (DIO1, 2, and 3) are key enzymes in thyroid hormone (TH) activation and inactivation with impact on energy metabolism, development, cell differentiation, and a number of other physiological processes. The three DIO isoenzymes thus constitute sensitive rate-limiting components within the TH axis, prone to dysregulation by endocrine disruptive compounds or disease state. In animal models and cell culture experiments, they serve as readout for local TH status and disarrangement of the hormonal axis. Furthermore, some human diseases are characterized by apparent deiodinase dysregulation (e.g., the low triiodothyronine syndrome in critical illness). Consequently, these enzymes are targets of interest for the development of pharmacological compounds with modulatory activities. Until now, the portfolio of inhibitors for these enzymes is limited. In the clinics, the DIO1-specific inhibitor propylthiouracil is in use for treatment of severe hyperthyroidism. Other well-known inhibitors (e.g., iopanoic acid or aurothioglucose) are nonselective and block all three isoenzymes. Furthermore, DIO3 was shown to be a potential oncogenic gene, which is strongly expressed in some tumors and might, in consequence, protect tumor tissue form differentiation by TH. With respect to its role in tumorigenesis, specific inhibitors of DIO3 as a potential target for anticancer drugs would be highly desirable. To this end, a flexible and convenient assay for high-throughput screening is needed. We recently described a nonradioactive screening assay, utilizing the classic Sandell-Kolthoff reaction as readout for iodide release from the substrate molecules. While we used murine liver as enzyme source, the assay was limited to murine DIO1 activity testing. Here, we describe the use of recombinant proteins as enzyme sources within the assay, expanding its suitability from murine Dio1 to human DIO1, DIO2, and DIO3. METHODS: As proof-of-concept, deiodination reactions catalyzed by these recombinant enzymes were monitored with various nonradioactive substrates and confirmed by liquid chromatography-tandem mass spectrometry. RESULTS: The contrast agent and known DIO inhibitor iopanoic acid was characterized as readily accepted substrate by DIO2 and Dio3. In a screening approach using established endocrine disrupting compounds, the natural food ingredient genistein was identified as a further DIO1-specific inhibitor, while xanthohumol turned out to potently block the activity of all three isoenzymes. CONCLUSIONS: A rapid nonradioactive screening method based on the Sandell-Kolthoff reaction is suitable for identification of environmental, nutritive and pharmacological compounds modulating activities of human deiodinase enzymes.

3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling.

Most in vivo effects of 3-iodothyronamine (3-T1AM) have been thus far thought to be mediated by binding at the trace amine-associated receptor 1 (TAAR1). Inconsistently, the 3-T1AM-induced hypothermic effect still persists in Taar1 knockout mice, which suggests additional receptor targets. In support of this general assumption, it has previously been reported that 3-T1AM also binds to the α-2A-adrenergic receptor (ADRA2A), which modulates insulin secretion. However, the mechanism of this effect remains unclear. We tested two different scenarios that may explain the effect: the sole action of 3-T1AM at ADRA2A and a combined action of 3-T1AM at ADRA2A and TAAR1, which is also expressed in pancreatic islets. We first investigated a potential general signaling modification using the label-free EPIC technology and then specified changes in signaling by cAMP inhibition and MAPKs (ERK1/2) determination. We found that 3-T1AM induced Gi/o activation at ADRA2A and reduced the norepinephrine (NorEpi)-induced MAPK activation. Interestingly, in ADRA2A/TAAR1 hetero-oligomers, application of NorEpi resulted in uncoupling of the Gi/o signaling pathway, but it did not affect MAPK activation. However, 3-T1AM application in mice over a period of 6 days at a daily dose of 5 mg/kg had no significant effects on glucose homeostasis. In summary, we report an agonistic effect of 3-T1AM on the ADRA2A-mediated Gi/o pathway but an antagonistic effect on MAPK induced by NorEpi. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.

Hepatic metabolite profiles in mice with a suboptimal selenium status.

Selenium is an essential trace element and mediates its functions via various selenoproteins such as glutathione peroxidases or thioredoxin reductases. A suboptimal selenium supply causes metabolic disturbances and is associated with an increased risk to develop different disorders, including cancer or cardiovascular diseases. This study aimed to assess the impact of a suboptimal selenium status on the hepatic metabolome of male mice analyzed by a targeted liquid chromatography/tandem mass spectrometry and a method based on non-targeted gas chromatography hyphenated with mass spectrometry. Feeding animals a diet with about half of the recommended selenium content supplied as selenomethionine caused liver glutathione peroxidase and thioredoxin reductase activities to decline and lipid peroxidation to increase. Serum T3 thyroid hormone concentration also declined via a reduced hepatic deiodinase activity. Metabolite profiling revealed predominantly changes in cysteine and carbon-1 metabolism as well as in selected lipid subclasses. In particular the concentrations of palmitoylcarnitines and oleoylcarnitines (C18:1 and C16:1) and various phosphatidylcholine species containing saturated fatty acids were elevated. Increased taurine levels suggested an enhanced cysteine flux through the salvage pathway whereas increased homocysteine levels appeared to be a consequence of a massive down-regulation of cystathionine ß lyase (cystathionine ß synthase) and a reduced flux through the transsulfuration pathway. The findings demonstrate that a suboptimal selenium status causes alterations in lipid and carbon-1 metabolism in mouse liver. These changes may contribute to the development of diseases associated with a suboptimal selenium status.

Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies.

CONTEXT: Euthyroid thyroid peroxidase (TPO-Ab)-positive subjects are at risk for progression to subclinical and overt autoimmune hypothyroidism. Previous studies have shown a decrease in TPO-Ab and improvement of quality-of-life (QoL) in L-T4-treated hypothyroid patients upon selenium supplementation. OBJECTIVES: To evaluate in euthyroid TPO-Ab-positive women without thyroid medication whether selenite decreases TPO-Ab and improves QoL. DESIGN: Randomized, placebo-controlled, double-blind study. PATIENTS AND METHODS: Euthyroid (TSH 0·5-5·0 mU/l, FT4 10-23 pm) women with TPO-Ab ≥ 100 kU/l were randomized to receive 200 mcg sodium selenite daily (n = 30) or placebo (n = 31) for 6 months. TSH, FT4, TPO-Ab, selenium (Se), selenoprotein P (SePP) and QoL were measured at baseline, 3, 6 and 9 months. RESULTS: There were no differences in baseline characteristics between the Se group and the placebo group. During selenite supplementation, serum Se and SePP did not change in the placebo group, but increased in the Se group. TPO-Ab and TSH did not change significantly in any group. TPO-Ab in the Se group were 895 (130-6800) at baseline, 1360 (60-7050) kU/l at 6 months, in the placebo group 1090 (120-9200) and 1130 (80-9900) kU/l, respectively (median values with range). TSH in the Se group was 2·1 (0·5-4·3) at baseline, 1·7 (0·0-5·3) mU/l at 6 months, in the placebo group 2·4 (0·7-4·4) and 2·5 (0·2-4·3) mU/l, respectively. QoL was not different between the groups. CONCLUSION: Six months selenite supplementation increased markers of selenium status but had no effect on serum TPO-Ab, TSH or quality-of-life in euthyroid TPO-Ab-positive women.

Selenium status in patients with autoimmune and non-autoimmune thyroid diseases from four European countries.

CONTEXT: Selenium supplementation has been suggested for Hashimoto thyroiditis and Graves' ophthalmopathy. Objective, Design: Our aim is to measure selenium status (p-Se, p-SePP), urine iodine (UI) levels and urine iodine/creatinine ratio (UI/C) in different thyroid diseases (n = 416) from four European countries and to compare the results between patients with and without thyroid autoimmunity. RESULTS: p-Se and p-SePP showed positive correlation and did not correlate with UI/C. Also, these measurements were higher in patients from Italy in comparison with the other countries. Austria had the lowest UI/C ratios. Selenium deficiency exists in these four European countries. Selenium status was lower in patients with Hashimoto thyroiditis and Graves' disease in comparison with non-autoimmune thyroid disease patients and did not differ between autoimmune patients with or without thyroid peroxidase antibodies. The latter correlated positively with age. CONCLUSIONS: Our findings suggest that Se supplementation might have a beneficial effect in autoimmune thyroid patients.

Selenium and the thyroid.

PURPOSE OF REVIEW: To provide information on the role of the essential trace element selenium, which enables appropriate thyroid hormone synthesis, secretion, and metabolism, and to discuss supplementation with various selenium compounds, which prevent thyroid diseases such as goiter and exert beneficial effects in thyroid autoimmune diseases. RECENT FINDINGS: Selenium administration in both autoimmune thyroiditis (M. Hashimoto) and mild Graves' disease improves clinical scores and well-being of patients and reduces autoimmune antibody titres in several prospective, placebo-controlled supplementation studies. SUMMARY: Adequate nutritional supply of selenium, together with the two other essential trace elements iodine and iron, is required for a healthy thyroid during development and adolescence, as well as in the adult and aging populations.

Serum selenium is low in newly diagnosed Graves' disease: a population-based study.

CONTEXT: Selenium deficiency may play an important role in the initiation and progression of autoimmune thyroid disease. OBJECTIVE: To compare serum selenium (s-Se) values in patients with newly diagnosed autoimmune thyroid disease and controls from the Danish population. DESIGN AND SETTINGS: S-Se was measured in triplicate by a fluorimetric method. PARTICIPANTS: Patients with newly diagnosed Graves' disease (GD) (n = 97) or autoimmune overt hypothyroidism (AIH) (n = 96), euthyroid subjects with high serum levels of thyroid peroxidase antibody (TPO-Ab) (TPO-Ab > 1500 U/ml, n = 92) and random controls (n = 830). MAIN OUTCOME MEASURE: Differences in s-Se values. RESULTS: S-Se was lower in patients with GD than in controls (mean (SD), GD: 89·9 µg/l (18·4); controls: 98·8 µg/l (19·7), P < 0·01). This was confirmed in a multivariate logistic regression model adjusting for age, sex, mineral supplements, smoking, geographical region and time of sampling (P < 0·01). In a linear model, s-Se was similar in patients with AIH (mean (SD): 98·4 µg/l (24·9)) and in controls (P = 0·86). In the multivariate model however, s-Se was marginally lower in patients with AIH compared to controls (P = 0·04). There was no significant difference in s-Se between euthyroid participants with high TPO-Ab and random controls (linear: P = 0·97; multivariate: P = 0·27). CONCLUSION: Patients with newly diagnosed GD and AIH had significantly lower s-Se compared with random controls. Our observation supports the postulated link between inadequate selenium supply and overt autoimmune thyroid disease, especially GD.

Serum 25-hydroxyvitamin d and cancer risk in older adults: results from a large German prospective cohort study.

BACKGROUND: Several observational studies assessed the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and the risk of cancer but results were inconclusive. METHODS: We measured 25(OH)D concentrations in a population-based cohort study of 9,949 men and women ages 50 to 74 years in Saarland, Germany. Comprehensively adjusted Cox regression models were applied to estimate HRs and 95% confidence intervals (CI) for the association between season-standardized 25(OH)D concentrations and total and site-specific cancer incidence. RESULTS: Overall, during a median of 8 years of follow-up, 873 subjects developed cancer; the most common being prostate (171), breast (137), lung (136), and colorectal (136) cancer. Low season-standardized 25(OH)D (<30, 35, 40, or 36 nmol/L in winter, spring, summer, and autumn, respectively) was neither significantly associated with total cancer incidence (HR, 1.10; 95% CI, 0.93-1.30) nor with site-specific cancer incidence. However, a significantly increased overall cancer risk was observed for low 25(OH)D among men, nonobese subjects and subjects reporting low fish consumption and for high 25(OH)D in nonsmokers and nonobese subjects. Accordingly, restricted cubic splines to investigate dose-response relationships curves showed an inverse association of 25(OH)D levels and total cancer risk in men but not in women. CONCLUSIONS: 25(OH)D concentrations were significantly associated with overall cancer incidence in subgroups of this large cohort from Germany. No significant association was observed with site-specific cancers but this could be due to a limited statistical power for these endpoints. IMPACT: Further research should clarify whether and to what extent specific risk groups might profit from vitamin D supplementation.

Bone turnover and bone mineral density are independently related to selenium status in healthy euthyroid postmenopausal women.

CONTEXT: Selenium status may have direct effects on bone and indirect effects through changes in thyroid hormone sensitivity. OBJECTIVE: We hypothesized that variation in selenium status in healthy euthyroid postmenopausal women is associated with differences in bone turnover, bone mineral density (BMD) and fracture susceptibility. DESIGN: The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. SETTING: The study was comprised of a population-based cohort from five European cities. PARTICIPANTS: A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1144. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: We measured selenium (micrograms per liter); selenoprotein P (milligrams per liter); free T(4) (picomoles per liter); free T(3) (picomoles per liter); TSH (milliunits per liter); bone turnover markers; BMD; and vertebral, hip, and nonvertebral fractures. RESULTS: Higher selenium levels were associated with higher hip BMD at study entry (ß = 0.072, P = 0.004) and lower levels of bone formation (osteocalcin: ß = -0.101, P < 0.001; procollagen type 1 N-terminal propeptide: ß = -0.074, P = 0.013) and resorption markers (C-telopeptide of type 1 collagen: ß = -0.058, P = 0.050; N-telopeptide of type 1 collagen: ß = -0.095, P = 0.002). Higher selenoprotein P was associated with higher hip (ß = 0.113, P < 0.001) and lumbar spine BMD (ß = 0.088, P = 0.003) at study entry, higher hip BMD after the 6-yr follow-up (ß = 0.106, P = 0.001) and lower osteocalcin (ß = -0.077, P = 0.009), C-telopeptide of type 1 collagen (ß = -0.075, P = 0.012), and N-telopeptide of type 1 collagen (ß = -0.110, P < 0.001). CONCLUSION: Selenium status is inversely related to bone turnover and positively correlated with BMD in healthy euthyroid postmenopausal women independent of thyroid status.