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Contempre, Dumont, Thilly
Selenium, the thyroid, and the endocrine system.
Kohrle J, Jakob F, Contempre B, Dumont JE.
Endocr Rev. 2005 Dec;26(7):944-84. Epub 2005 Sep 20. Review.
[abstract only]
"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."
Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.
Kohrle J.
Acta Med Austriaca. 1996;23(1-2):17-30. Review.
[abstract only]
"Development and
tissue-specific deiodination of thyroid hormone leads to both
activation of the prohormone thyroxine to the thyromimetically
active T3 as well as to inactivation of T3 and its conjugates or
inactivation of T4 to yield potential regulatory active rT3. At
least three deiodinase isoenzymes have so far been characterized
and cloned, and the deiodinase isozymes represent a new family of
eukaryotic selenoproteins for which an enzyme function could be
assigned. Selenium status apparently regulates the expression of
these deiodinase isozymes to different extent indicating that a
hierarchy of selenium incorporation exists for those enzymes.
Currently, it appears that selenium deficiency does not affect
expression of type II 5'-deiodinase or 5-deiodinase to a marked
extent in vivo whereas type I 5'-deiodinase at least in liver and
kidney is reduced in severe selenium deficiency. However, daily
selenium intake in normal mideuropeans already saturates the
requirement for the expression of the deiodinase isoenzymes. So
far, only reduced expression of 5'-D I and decreased T 3
production has been observed in specific diets such as for PKU or
in cystic fibrosis, where transport of ions (iodide, selenite?)
might be affected. Further alterations of T3 production by 5'-D I
activity are observed under the conditions of the low T3
syndrome, which comprise a broad spectrum of clinical disorders
from carbohydrate withdrawal to intensive care patients. It is
not yet clear if selenium supplementation or T3 treatment is
beneficial to these patients. The marked tissue-specificity of
expression of the deiodinases requires more detailed examinations
on the relation between these enzymes and the expression of
thyroid hormone action, which is mediated by the nuclear T3
receptor family or receptors and signal transduction molecules in
the mitochondria, plasma membrane, or cytoskeleton. The location
of the deiodinase enzymes either at the inner side of the plasma
membrane or the cytosolic side of the endoplasmic reticulum
positions these enzymes to a strategically important location
enabling them to act as gate-keepers to the nuclear receptors.
Similar to other enzymes involved in the activation or
inactivation of compounds with hormone or signalling function,
the deiodinases are key elements in the intracrine regulation of
hormone activation in target tissues or inactivation in
non-target tissues. Therefore, a detailed molecular, cell
biological and physiological analysis of the function, regulation
and gene structure of these enzymes is required before a
development of tissue- or enzyme-specific pharmacological
intervention is possible. Nevertheless, first data indicate that
reduced 5'-deiodinase type I expression in tumor tissues can be
re-induced by treatment with retinoids at least in follicular
thyroid carcinoma. Further studies are needed to prove that
retinoids might be a useful therapeutic tool for
re-differentiation therapy of thyroid carcinoma which are
inaccessible to surgical intervention or lack radio-iodide uptake
and storage. The important function and regio- and cell-specific
expression of deiodinase isozymes in the central nervous system
is far from being understood. Current first evidence suggests a
close interaction between thyroid hormone deiodination, thyroid
hormone concentration, and expression of thyroid hormone
responsive genes in the adult brain as well as tight regulation
and interaction between thyroid hormone metabolism and
neurotransmitter synthesis release and action."
Selenium deficiency and thyroid fibrosis. A key role for macrophages and transforming growth factor beta (TGF-beta).
Contempre B, Le Moine O, Dumont JE, Denef JF, Many MC.
Mol Cell Endocrinol. 1996 Nov 29;124(1-2):7-15
[abstract only]
"Free radical damage and fibrosis caused by selenium deficiency are thought to be involved in the pathogenesis of myxoedematous cretinism. So far, no pathway explains the link between selenium deficiency and tissue fibrosis. Pharmacological doses of iodine induce necrosis in iodine-deficient thyroids. Necrosis is much increased if the glands are also selenium-deficient, which then evolve to fibrosis. This rat model was reproduced to explore the role of selenium deficiency in defective tissue repair. At first, proliferation indexes of epithelial cells and fibroblasts were comparable between selenium-deficient and control groups. Then, in selenium-deficient thyroids the inflammatory reaction was more marked being mainly composed of macrophages. The proliferation index of the epithelial cells decreased, while that of the fibroblasts increased. These thyroids evolved to fibrosis. TGF-beta immunostaining was prominent in the macrophages of selenium-deficient rats. Anti TGF-beta antibodies restored the proliferation indexes, and blocked the evolution to fibrosis. In selenium deficiency, an active fibrotic process occurs in the thyroid, in which the inflammatory reaction and an excess of TGF-beta play a key role."
Effects of selenium deficiency on thyroid necrosis, fibrosis and proliferation: a possible role in myxoedematous cretinism.
Contempre B, Dumont JE, Denef JF, Many MC.
Eur J Endocrinol. 1995 Jul;133(1):99-109.
[abstract only]
"It has been suggested that selenium deficiency is a co-factor to iodine deficiency in the pathogenesis of myxoedematous cretinism. The mechanism proposed is that the generation of hydrogen peroxide is greatly increased in iodine-deficient thyroid glands, and that selenium is involved in the control of hydrogen peroxide and its derived free radicals. This study was carried out to investigate the effect of the possibly impaired cellular defence mechanism associated with selenium deficiency on thyroid necrosis and tissue repair. For this purpose, we studied thyroid tissue from selenium- (SE-) and/or iodine-deficient (I-) rats before and after an acute toxic iodine overload. In I- thyroids, necrotic cells were numerous. Acute iodine administration increased this effect. Necrosis was associated with transient infiltration of inflammatory cells. In I-SE+ thyroids the tissue resumed its normal appearance. In I-SE- thyroid glands, the iodide toxicity was stronger, with greater necrosis and inflammatory reaction. The inflammation resolved but was replaced by fibrotic tissue. Fifteen days after the toxic overload, the connective tissue volume was twice the control value. Before iodide overload, the proportion of dividing cells was equal in I-SE+ and I-SE- thyroids. Three days after the iodide overload, this proportion was increased in I-SE+ thyroids but reduced in the I-SE- thyroids. Overall, the I-SE- thyroids had four times fewer dividing cells than the I-SE+ thyroids. In summary, selenium deficiency coupled to iodine deficiency increased necrosis, induced fibrosis and impeded compensatory epithelial cell proliferation. These results are compatible with histological and functional description of thyroid tissue from myxoedematous cretins."
Selenium deficiency aggravates the necrotizing effects of a high iodide dose in iodine deficient rats.
Contempre B, Denef JF, Dumont JE, Many MC.
Endocrinology. 1993 Apr;132(4):1866-8.
"The effect of selenium deficiency associated with various iodide intake was investigated in rats in order to better understand its possible role in the etiopathogeny of myxedematous cretinism. Groups of rat pups were fed from birth a low selenium diet (Se-) and submitted to goitrogenic treatment (1% perchlorate in water) for one month. Some animals were refed iodide after perchlorate withdrawal. The gland morphology was analyzed in correlation with the glutathione peroxidase (GPX) activity and the thyroid hormone plasma levels. In all Se- rats, the GPX activity was strongly reduced as compared to selenium sufficient (Se+) animals (P < 0.01). Goitrous rats were hypothyroid whatever the selenium intake. After iodide refeeding, plasma T4 and T3 levels were increased by 160% in Se- rats and by respectively 330% and 580% in Se+ rats. The thyroid morphology was different according to the selenium intake: necrotic cells were about three times more numerous in Se- than in Se+ rats (P < 0.01) and the inflammatory reaction was increased. These experimental data demonstrate the detrimental role of selenium deficiency in one experimental case of thyroid disease. Such reduction of cell defences could contribute to the thyroid failure of African myxedematous cretins."
Selenium and the thyroid: how the relationship was established.
Corvilain B, Contempre B, Longombe AO, Goyens P, Gervy-Decoster C, Lamy F, Vanderpas JB, Dumont JE.
Am J Clin Nutr. 1993 Feb;57(2 Suppl):244S-248S. Review.
[abstract only]
"Several hypotheses
concerning consequences of selenium deficiency on iodine metabolism
can be proposed on the basis of experimental studies in rats and from
epidemiological and experimental studies in humans. By decreasing
intracellular GSH peroxidase activity, selenium deficiency may
increase hydrogen peroxide (H2O2) supply and lead over several weeks
to the thyroid atrophy observed in myxoedematous cretins. By improving
thyroid hormone synthesis and by decreasing peripheral thyroxin (T4)
deiodination, selenium deficiency could protect fetal brain T4 supply
and thus prevent neurologic cretinism. Selenium deficiency may protect
against iodine deficiency by decreasing T4 metabolism--and thus iodide
leakage and--perhaps also by increasing H2O2 supply and thyroid
hormone synthesis and thus thyroid efficiency."
Selenium deficiency mitigates hypothyroxinemia in iodine-deficient subjects.
Vanderpas JB, Contempre B, Duale NL, Deckx H, Bebe N, Longombe AO, Thilly CH, Diplock AT, Dumont JE.
Am J Clin Nutr. 1993 Feb;57(2 Suppl):271S-275S.
[abstract only]
"Studies were performed to
assess the role of combined selenium and iodine deficiency in the
etiology of endemic myxedematous cretinism in a population in Zaire.
One effect of selenium deficiency may be to lower glutathione
peroxidase activity in the thyroid gland, thus allowing hydrogen
peroxide produced during thyroid hormone synthesis to be cytotoxic. In
selenium-and-iodine-deficient humans, selenium supplementation may
aggravate hypothyroidism by stimulating thyroxin metabolism by the
selenoenzyme type I iodothyronine 5'-deiodinase. Selenium
supplementation is thus not indicated without iodine or thyroid
hormone supplementation in cases of combined selenium and iodine
deficiencies."
Effect of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: the possible danger of indiscriminate supplementation of iodine-deficient subjects with selenium.
Contempre B, Dumont JE, Ngo B, Thilly CH, Diplock AT, Vanderpas J.
J Clin Endocrinol Metab. 1991 Jul;73(1):213-5.
[abstract only]
"Selenium and seleno dependent glutathione peroxidase (GPX) deficiency has been described in endemias of myxedematous cretinism. In northern Zaire, a selenium supplementation trial has been conducted. Beside correcting the GPX activity, two months of selenium supplementation was shown to modify the serum thyroid hormones parameters in clinically euthyroid subjects and to induce a dramatic fall of the already impaired thyroid function in clinically hypothyroid subjects. These results further support a role of selenium in thyroid hormone metabolism. In an iodine deficient area, this selenium deficiency could lead to opposite clinical consequences: protect the general population and the fetus against iodine deficiency and brain damage; and in turn, favour the degenerative process of the thyroid gland leading to myxoedematous cretinism."
Iodine and selenium deficiency associated with cretinism in northern Zaire.
Vanderpas JB, Contempre B, Duale NL, Goossens W, Bebe N, Thorpe R, Ntambue K, Dumont J, Thilly CH, Diplock AT.
Am J Clin Nutr. 1990 Dec;52(6):1087-93.
[abstract only]
"Selenium status was
determined in an endemic-goiter area and in a control area of Zaire.
Compared with the reference values of a noniodine-deficient area,
serum selenium in subjects living in the core of the northern Zaire
endemic-goiter belt (Karawa villages) was seven times lower in 52
school-children and similarly low in 23 cretins; erythrocyte
glutathione peroxidase (RBC-GPX) was five times lower in
schoolchildren and still two times lower in cretins (P = 0.004). In a
less severely iodine-deficient city of the same endemia (Businga),
selenium status was moderately altered. RBC-GPX activity was linearly
associated with serum selenium concentration up to a value of 1140
nmol/L and leveled off at approximately 15 U/g Hb at greater selenium
concentration. At Karawa villages, selenium supplementation normalized
both the serum selenium and the RBC-GPX. This combined iodine and
selenium deficiency could be associated with the elevated frequency of
endemic myxedematous cretinism in Central Africa."
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