Thyroid hormones
[2] A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.
[8] In 2020, levothyroxine, a manufactured form of thyroxine, was the second most commonly prescribed medication in the United States, with more than 98 million prescriptions.
However, the thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals and the moulting behaviour of birds.
Some patients feel they do better on desiccated thyroid hormones; however, this is based on anecdotal evidence and clinical trials have not shown any benefit over the biosynthetic forms.
[14] Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia, which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.
[48] Each thyroglobulin molecule contains approximately 100–120 tyrosine residues, a small number of which (<20) are subject to iodination catalysed by thyroperoxidase.
[49] The same enzyme then catalyses "coupling" of one modified tyrosine with another, via a free-radical-mediated reaction, and when these iodinated bicyclic molecules are released by hydrolysis of the protein, T3 and T4 are the result.
[49] Hydrolysis (cleavage to individual amino acids) of the modified protein by proteases then liberates T3 and T4, as well as the non-coupled tyrosine derivatives MIT and DIT.
[56] Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism.
[60] Most of the thyroid hormone circulating in the blood is bound to transport proteins, and only a very small fraction is unbound and biologically active.
Thyroid hormone in the blood is usually distributed as follows:[citation needed] Despite being lipophilic, T3 and T4 cross the cell membrane via carrier-mediated transport, which is ATP-dependent.
Contrary to common belief, thyroid hormones cannot traverse cell membranes in a passive manner like other lipophilic substances.
The iodine in o-position makes the phenolic OH-group more acidic, resulting in a negative charge at physiological pH.
These receptors, together with corepressor molecules, bind DNA regions called thyroid hormone response elements (TREs) near genes.
The deiodinase catalyzed reaction removes an iodine atom from the 5′ position of the outer aromatic ring of thyroxine's (T4) structure.
[66] More recently genetic evidence has been obtained for a second mechanism of thyroid hormone action involving one of the same nuclear receptors, TRβ, acting rapidly in the cytoplasm through the PI3K.
In fact, amphibian frog Xenopus laevis serves as an ideal model system for the study of the mechanisms of apoptosis.
[74] A related parameter is the free thyroxine index, which is total T4 multiplied by thyroid hormone uptake, which, in turn, is a measure of the unbound TBG.
[75] Additionally, thyroid disorders can be detected prenatally using advanced imaging techniques and testing fetal hormone levels.
[89] Congenital hypothyroidism occurs in every 1 in 1600–3400 newborns with most being born asymptomatic and developing related symptoms weeks after birth.
Compounds such as goitrin, carbimazole, methimazole, propylthiouracil can reduce thyroid hormone production by interfering with iodine oxidation.
- Thyroglobulin is synthesized in the rough endoplasmic reticulum and follows the secretory pathway to enter the colloid in the lumen of the thyroid follicle by exocytosis .
- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide (I − ) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms.
- This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin , in a purportedly passive manner.
- In the colloid, iodide (I − ) is oxidized to iodine (I 0 ) by an enzyme called thyroid peroxidase .
- Iodine (I 0 ) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain (in total containing approximately 120 tyrosyl residues).
- In conjugation , adjacent tyrosyl residues are paired together.
- Thyroglobulin re-enters the follicular cell by endocytosis .
- Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules
- Efflux of thyroxine and triiodothyronine from follicular cells, which appears to be largely through monocarboxylate transporter (MCT) 8 and 10 , [ 32 ] [ 33 ] and entry into the blood.