Thyroid hormones in humans

Ingbar SH, Braverman LE, Dawber NA, Lee GY. A new method for measuring the free thyroid hormone in human serum and an analysis of the factors that influence its concentration. J Clin Invest 1965 44 1679-89. 

In KBD subjects, the evolution of thyroid function after correction of iodine was similar in selenium supplemented and nonsupplemented subjects. This finding corroborated previous studies, suggesting only a moderate effect of selenium deficiency on thyroid hormones in human (Calomme et al, 1995 St. Germain and Galton, 1997). In Tibet, the administration of an intramuscular injection of 475-mg of iodine to KBD subjects was sufficient to correct iodine deficiency for 16 months, because at this time serum T3 increased again to pre-iodine levels and mean iodine urinary concentrations had fallen... 

In the human, TTR is one of three plasma proteins involved in the transport of the thyroid hormones in blood (Ingbar, 1963 Oppenheimer, 1968). The principal transport protein for thyroid hormones in human plasma is thyroxine-binding globulin, and TTR plays only a lesser role in the normal transport and metabolism of thyroid hormones in man (Woeber and Ingbar, 1968). In the rat, however, TTR appears to be the major thyroid hormone transport protein (Davis et al., 1970 Sutherland and Brandon, 1976). 

The lARC has determined that there is sufficient evidence for the carcinogenicity of amitrole to experimental animals and inadequate evidence for carcinogenicity to humans. It was noted that amitrole produces thyroid tumors in rodents by a nongenotoxic mechanism that involves interference with the functioning of the thyroid peroxidase, resulting in a reduction in circulating thyroid hormone concentration and an increase secretion of thyroid-stimulating hormone. Amitrole would not be expected to produce thyroid cancer in humans exposed to concentrations that do not alter thyroid hormone homeostasis. 

The same 17 PBDE congeners and three hydroxylated PBDEs were also tested for possible interaction with T4 binding to human TTR, a plasma transport protein of thyroid hormones, in an in vitro competitive binding assay (Meerts et al. 1998, 2000). None of the pure congeners competed with T4 for binding to... 

In rats equilibrated with radioiodine-labelled T4 or T3 roughly half of the radioactivity appears as I- in the urine and the other half as free iodothyronines in the feces [12]. Treatment of the rats with 6-propyl-2-thiouracil (PTU) results in a marked decrease in urinary radioactivity and a reciprocal increase in fecal clearance [12]. Also, in humans, PTU has been shown to inhibit peripheral iodothyronine deiodination besides its well-known effect on thyroid hormone biosynthesis [13]. Compared with the rat, deiodination is an even more important pathway for the clearance of thyroid hormone in man as evidenced by the greater proportion undergoing urinary clearance [2]. Furthermore, estimation of iodothyronine turnover kinetics in humans has demonstrated that a major fraction of T4 disposal is accounted for by plasma production rates of T3 and rT3 [2,3],... 

Figure 5 is a model of the peripheral metabolism of thyroid hormone in normal humans which places the production of plasma T3 and the clearance of plasma rT3 predominantly in tissues with PTU-sensitive, type I deiodinase activity. Although the role of the liver is emphasized, contribution of the kidneys is not excluded. Clearance of plasma T3 and production of plasma rT3 is located mainly in tissues such as brain and perhaps skin with PTU-insensitive, type III deiodinase activity. 

In addition to the obvious deactivating role of deiodinases, there has been recent evidence that a relationship exists between regulation of deiodination of thyroid hormones in target cells and the intracellular effects of T4 and T3 on pituitary and hypothalamus function. In the rat pituitary, and probably the human, type-II deiodinase-catalyzed conversion of T4 to T3 is a prerequisite for inhibition of TRH release. rT3, produced from T4 by type-III deiodinase, is a potent inhibitor of type-II deiodinase. In a postulated regulatory circuit, rT3 formed from T4 by type-III deiodinase in surrounding CNS (Central Nervous System) tissue enters the pituitary and inhibits type-II enzyme. The resulting decrease in T3 concentration, in turn, causes an increase in TSH secretion49. 

Observations in experimental animals have shown that some PCBs (specifically 3,3, 4,4 -tetrachlorobiphenyl, TCB) can interfere with thyroid hormone levels. It seems that a metabolite of the TCB is similar to the thyroid hormone thyroxine and therefore competes with it for binding to a specific receptor. One of the consequences is loss of thyroxine and vitamin A from the blood. There is evidence for similar effects in humans in that higher levels of PCBs in breast milk correlated with lower levels of certain thyroid hormones in mothers and infants. 

Oatp4al was isolated from rat retina. It transports thyroid hormone in various peripheral tissues. Oatp4al is composed of 722 amino acids. The overall homology between rat Oatp4al and human OATP4A1 was 72.6% at the amino add level, and the transmembrane domains and their surrounding areas were highly conserved [64]. 

Some evidence for adverse effects on the endocrine system has also been found following intermediate and chronic oral exposure to elevated levels of dietary selenium in humans and animals. Human studies have demonstrated a decrease in triiodothyronine levels in response to increased dietary selenium, although the hormone levels remained within the normal range. Intermediate-duration studies of rats have shown reductions in type-I-deiodinase activity in response to selenium. However, the levels of thyroid hormones in these animals did not show a consistent pattern. 

Iodine is an essential trace element for humans and animals. It forms an indispensable part of thyroid hormones. In the case of deficient thyroid hormone production (due to lack of iodine, etc.) cretinism results. Iodine deficiency constitutes a major public health problem. It represents one of the most common preventable causes of mental impairment in the world today. 

Iodine plays a key structural role in the thyroid hormones of humans and other mammals, primarily in the form of T3 (triiodothyronine) and T4 (thyroxine). In such samples precursor forms such as MIT (monoiodotyrosine) and DIT (diiodotyrosine) or isomer forms such as rT3 (reverse triiodothyronine) may also be measured. Iodine accounts for 65% of the molecular weight of T4 and 59% of the T3.15-20 mg of iodine is concentrated in the thyroid and hormones with 70% distributed in other tissues. In the cells of these tissues, iodide enters via the sodium-iodide symporter (NIS). 

Thyroid follicular cells are present and can synthesize thyroid hormones by 70-80 days of human gestation (1). However, the capacity of these cells to produce thyroid hormones in response to TSH increases with advancing gestation age. Table 2 summarizes available information regarding the time of appearance of important follicular cell functions during development. 

Human prealbumin is involved in the transport of thyroid hormones in plasma. V-Bromoacetyl-L-thyroxine [BrAcT4 (II) in Scheme 2], an analog of L-thyroxine [T4 (I) in Scheme 2], differs from T< only in the... 

Iodine is essential for normal growth, since it is a requisite part of the thyroid hormone. In cretinism, or congenital hypothyroidism, which is observed in goitrogenous areas, growth may be stimulated by administration of dessicated thyroid. Iodine also plays a role in human and animal fertility and in lactation. Simple goiter and cretinism are still prevalent in many areas of the world prophylaxis could be obtained through the universal use of iodized salt. 

The only other endocrine disrupting effect that has been evaluated related to antimony in the human population has been an analysis of urinary antimony levels in relation to certain serum thyroid hormones in the U.S. general population as assessed through the NHANES 2007-08 survey (Yorita Christensen 2012). There were no reported significant associations between concentrations of urinary antimony and levels of serum free and total T3 and T4 or with serum thyroid stimulating hormone (TSH). 

Thyroid-stimulating hormone can be used clinically to test thyroid function but has not found practical apphcation in the treatment of human thyroid insufficiency. Direct replacement therapy with thyroid hormone is easy and effective, owing to a simple molecular stmcture. TSH has been used in the veterinary treatment of hypothyroidism, and preparations of TSH ate produced by Cooper Animal Health, Inc. and Armour Pharmaceuticals. 

The main role of the human thyroid gland is production of thyroid hormones (iodinated amino acids), essential for adequate growth, development, and energy metaboHsm (1 6). Thyroid underfunction is an occurrence that can be treated successfully with thyroid preparations. In addition, the thyroid secretes calcitonin (also known as thyrocalcitonin), a polypeptide that lowers excessively high calcium blood levels. Thyroid hyperfunction, another important clinical entity, can be corrected by treatment with a variety of substances known as antithyroid dmgs. 

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