Josef Köhrle

Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H 2 O 2 produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins. (Endocrine Reviews 26: 944 -984, 2005) I. Historical Aspects II. Biosynthesis and Degradation of Eukaryotic Selenoproteins III. Recently Discovered Eukaryotic Selenoproteins A. Selenoenzymes and new selenoproteins with unknown functions B. Preferential selenium supply of the vital endocrine organs during deficiency and repletion IV. Hormonal Regulation of the Thioredoxin/Thioredoxin Reductase System A. Expression and secretion of thioredoxin and thioredoxin reductase B. Biochemistry and structure of thioredoxin reductase C. Thioredoxin reductase and thioredoxin are involved in signal transduction and regulation of gene expression V. Selenium, Cell Defense, and Thyroid Pathology A. Selenium and thyroid pathology in humans: endemic cretinism B. Experimental thyroid model C. Selenium deficiency and neurological cretinism VI. Selenoproteins and the Thyroid Axis A. Deiodinase enzymes-selenoproteins activating and inactivating thyroid hormones B. Selenium and thyroid function-the role of selenium in thyroid hormone synthesis C. Selenium status and supplementation in the "low-T 3 syndrome," nonthyroidal illness, sepsis, and related pathophysiological conditions D. Selenium, the thyroid axis, and chronic hemodialysis VII. Selenium and the Endocrine System A. Selenium and the pituitary hormones B. Selenium accumulation in the pineal gland C. Selenium and selenoproteins during lactation and in the mammary gland D. Selenium and the adrenals E. Selenium, pancreas, and diabetes F. Selenium and selenoproteins in the female reproductive tract G. Selenium and male reproduction H. Selenoproteins in bone I. Selenium, the hormonal system of the skin, and selenoproteins in muscle J. Selenoproteins and the hormonal regulation of endothelial function I. Historical Aspects

Selenoprotein P (SePP), the major selenoprotein in plasma, has been implicated in selenium transport, selenium detoxification or antioxidant defence. We generated SePP-knockout mice that were viable, but exhibited reduced growth and developed ataxia. Selenium content was elevated in liver, but low in plasma and other tissues, and selenoenzyme activities changed accordingly. Our data reveal that SePP plays a pivotal role in delivering hepatic selenium to target tissues.

Several minerals and trace elements are essential for normal thyroid hormone metabolism, e.g., iodine, iron, selenium, and zinc. Coexisting deficiencies of these elements can impair thyroid function. Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase. Iron-deficiency anemia blunts and iron supplementation improves the efficacy of iodine supplementation. Combined selenium and iodine deficiency leads to myxedematous cretinism. The normal thyroid gland retains high selenium concentrations even under conditions of inadequate selenium supply and expresses many of the known selenocysteine-containing proteins. Among these selenoproteins are the glutathione peroxidase, deiodinase, and thioredoxine reductase families of enzymes. Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland from damage by excessive iodide exposure. In regions of combined severe iodine and selenium deficiency, normalization of iodine supply is mandatory before initiation of selenium supplementation in order to prevent hypothyroidism. Selenium deficiency and disturbed thyroid hormone economy may develop under conditions of special dietary regimens such as long-term total parenteral nutrition, phenylketonuria diet, cystic fibrosis, or may be the result of imbalanced nutrition in children, elderly people, or sick patients.