The Circulating Thyroid Hormone

There has been much speculation in the past on the nature of the circulating thyroid hormone whether it was a simple amino acid, a peptide or polypeptide of thyroxine, or thyroglobulin itself. In 1948 Taurog and Chaikoff produced a considerable amount of evidence that the plasma hormone was indeed thyroxine. Labeled plasma iodine behaved chemically in a manner identical with that of thyroxine added to plasma it was nondialyzable it was precipitated with plasma proteins with zinc hydroxide it was extractable with butanol, and it could be fractionated with carrier thyroxine by its partition between immiscible solvents. This work received confirmation from Laidlaw (1949), and it then became generally accepted that thyroxine alone was the circulating hormone. 

Our knowledge of the high thyroidal activity of triiodothyronine requires that it should be included in the term the thyroid hormone and the sequence of events leading to the appearance of the hormone in the blood can be pictured as follows (1) synthesis of thyroxine and triiodothyronine in the thyroid, either simultaneously or consecutively (2) liberation of thyroxine and triiodothyronine from thyroglobulin by 

Normal plasma to which synthetic radiothyroxine of high activity had been added was similarly electrophoresed, and the position of the thyroxine on the paper strip compared with the positions of the natural hormone in the patients sera. Both were found to be associated with a protein having a mobility similar to that of ai-globulin. Triiodothyronine does not appear to be specifically associated with this protein in the circulation (Gross unpublished). 

Recent work on the three main functions of the thyroid gland— the collection of iodide from the plasma, the transformation of iodide into organically bound iodine and the release of the hormone into the circulation—has been reviewed. 

Various factors controlling thyroid hormone synthesis have been discussed, and evidence has been presented on the nature of the reactions 

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The T4 and T3 that are released from the thyroid gland are firmly but reversibly bound to several plasma proteins. More than 99% of the circulating thyroid hormone is protein bound, with only the free hormone available to enter cells (Table 65.1).The amount of T4 or Tj entering the cells and the ultimate physiological response are directly related to the plasma concentrations of free T4 and free Tj It is the concentrations of free T4 and T3 in the plasma that are regulated by the HPTA (Fig. 65.2) rather than the total (i.e., free plus protein-bound) plasma T4 and Tj concentrations. 

Thyroxine (T4) and the more potent triiodothyronine (T3) are cleaved from a large precursor protein called thyroglob-ulin. Thyroglobulin exists as a dimer of two identical polypeptides (Mr 330,000). It is a storage protein for iodine and can be considered a prohormone of the circulating thyroid hormones. Thyroglobulin is secreted into the lumen of the thyroid gland, where specific residues are iodinated in... 

G7. Gordon, A. H., Gross, J., O Connor, D., and Pitt-Rivers, R., Nature of the circulating thyroid hormone-plasma protein complex. Nature 169, 19 (1952). 

Each of these steps in thyroid hormone synthesis will be considered separately, and evidence on the nature of the circulating thyroid hormone will be presented. 

The circulating thyroid hormone consists of thyroxine loosely attached to plasma protein. 

Iodine is found in the blood as inorganic and protein-bound iodine, the latter fraction probably representing the circulating thyroid hormone. The total iodine content of normal whole blood is about 8 to 12 /xg. per 100 ml. (range 3 to 30 /xg.) protein-bound iodine varies from 3 to 8 /xg. per 100 ml., with a mean of 5 to 6 /xg. (Chapter 22). The level of protein-bound iodine is increased in pregnancy and in hyperthyroidism and decreased in hypothyroidism. 

In several European countries, where the dally iodine supply is reduced to about 50 (ig/day, the concentrations of the circulating thyroid hormones and of TSH remaiin in the physiological range (10). This situation does not however preclude possible deleterious effects of a moderate iodine deficienry in subjects at risk, as newborn far instance (11). 

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. 

Treatment is thyroid hormone replacement. The goal of the therapy is to relieve the symptoms of hypothyroidism by normalizing the levels of circulating thyroid hormones. In addition to the amelioration of symptoms, the clinical effectiveness of the thyroid hormone replacement may be monitored by periodically measuring the serum TSH concentration. The lowest dose of thyroid hormone that is needed to normalize the serum TSH concentration is usually the appropriate dose. Most or all of the symptoms of hypothyroidism should improve with appropriate thyroid hormone replacement, but this may require weeks or months of therapy. 

Secondary to the societal concerns around chemical-related endocrine disruption, the OECD407 subacute 28-day toxicity study protocol has been updated in 2007 with parameters relating to endocrine homeostasis. Specifically, circulating thyroid hormones and detailed assessment of reproductive organ parameters were added to the protocol. Reproductive hormones were suggested as additional parameters but they were deemed not informative in view of their large variability in untreated animals. 

In 50 women taking levothyroxine either for primary thyroid failure or for hypothyroidism secondary to radioiodine treatment for hyperthyroidism, there was no difference between the two groups in terms of bone density at the hip or spine and no difference from the reference population (31). In addition, there was no correlation between bone density and circulating thyroid hormone concentrations or duration of levothyroxine replacement. These findings are reassuring, although large studies of fracture risk are required, in view of previous evidence of an adverse effect of levothyroxine on bone mineral density, especially in post-menopausal women (32). 

Hypothyroidism developed within 2 weeks of rifampicin therapy in these patients and resolved when it was withdrawn. Rifampicin increases thyroxine clearance, possibly by enhancing hepatic thyroxine metabolism and the biliary excretion of iodothyronine conjugates. In healthy volunteers rifampicin reduces circulating thyroid hormone concentrations without affecting thyrotropin, suggesting that rifampicin directly reduces thyroid hormone concentrations. 

Thyroid hormones can have a re-partitioning effect upon body composition or muscle-to-fat ratio. As example were the many athletes whose weight was 250 LBS but only 10% bodyfat when total daily circulating thyroid hormone levels were elevated 10-50%. This would be due to thyroid hormone activity inducing improved nutrient metabolization and cellular efficiency combined with other hormone synergy. Of course, this is what "Absolute Anabolic Phases" were all about. But those who read about" Frank N. Steroid" already know about this effect and how it was created. 

Since myxedema frequently occurs in older persons, it is often associated with underlying coronary artery disease. In this situation, the low levels of circulating thyroid hormone actually protect the heart against increasing demands that could result in angina pectoris or myocardial infarction. Correction of myxedema must be done cautiously to avoid provoking arrhythmia, angina, or acute myocardial infarction. 

Several lines of evidence indicate that macromolecules of as yet unidentified chemical nature, produced by cancers and released into the systemic circulation, are responsible for the biochemical alterations in the liver and other host organs. In view of the diverse regulatory properties of the many different enzymes that increase or decrease towards their immature level (see Table III), a deficiency or excess in any given endocrine or dietary factor can clearly not explain the phenomenon. Nor has it been possible to implicate reductions in the efficacy of these factors. Subnormal concentration of the nuclear thyroid hormone receptor has been noted in the liver of tumor-bearing animals(24) however, since losses in the T3-inducible catalysts of the same liver occurred at much earlier stages of tumor-bearing,(24) the subnormal receptor concentration could clearly not be the cause of these losses but was probably another, and rather late, reflection of the process of biochemical undifferentiation. 

Regulation of secretion Secretion of TSH by the anterior pituitary is stimulated by the hypothalamic TRH. Feedback inhibition of both TRH and TSH secretion occurs with high levels of circulating thyroid hormone or iodide. Most of the hormone (T3 and T4) is bound to thyroxine-binding globulin in the plasma. 

Because thioamides inhibit the synthesis of new thyroid hormone and do little to inhibit the activity of circulating thyroid hormone, p blockers are needed to control the hypertension and tachycardia of hyperthyroidism in the first few weeks of therapy. In addition, adrenergic receptors are upregulated (there is a higher population in the vasculature) in the hyperthyroid patient, this it is important to block these P receptors and thereby reduce the blood pressure. With return to euthryroid condition, the receptor number decreases. 

Q9 Secretion of T3 and T4 is normally stimulated by TSH, released from the anterior pituitary. A rise in circulating thyroid hormone concentration reduces the production of TSH by negative feedback. If the gland fails to produce adequate thyroid hormone, production of TSH is not inhibited and its secretion continues to increase. Patients with hypothyroidism generally have reduced T3 and T4 production and raised plasma TSH, which is seen in Zadie s case. 

Thyroid function. Some xenobiotics reduce the quantities of circulating thyroid hormone levels. This can result in altered hormone metabolism. 

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