Physiology

The primary function of the thyroid is production of the hormones T3, T4 and calcitonin. Up to 80% of the T4 is converted to T3 by organs such as the liver, kidney and spleen. T3 is several times more powerful than T4, which is largely aprohormone, perhaps four[15] or even ten times more active

T3 and T4 production and action

Thyroxine (T4) is synthesised by the follicular cells from free tyrosineand on the tyrosine residues of the protein called thyroglobulin (Tg).Iodine is captured with the “iodine trap” by the hydrogen peroxidegenerated by the enzyme thyroid peroxidase (TPO)[20] and linked to the 3′ and 5′ sites of the benzene ring of the tyrosine residues on Tg, and on free tyrosine. Upon stimulation by the thyroid-stimulating hormone (TSH), the follicular cells reabsorb Tg and cleave the iodinated tyrosines from Tg in lysosomes, forming T4 and T3 (in T3, one iodine atom is absent compared to T4), and releasing them into the blood. Deiodinase enzymes convert T4 to T3.[21] Thyroid hormone secreted from the gland is about 80-90% T4 and about 10-20% T3.[15][16]

Cells of the developing brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a particularly crucial role in brain maturation during fetal development.[22] A transport protein that seems to be important for T4 transport across the blood–brain barrier(OATP1C1) has been identified.[23] A second transport protein (MCT8) is important for T3 transport across brain cell membranes.[23]

Non-genomic actions of T4 are those that are not initiated by liganding of the hormone to intranuclear thyroid receptor. These may begin at the plasma membrane or within cytoplasm. Plasma membrane-initiated actions begin at a receptor on the integrin alphaV beta3 that activates ERK1/2. This binding culminates in local membrane actions on ion transport systems such as the Na+/H+ exchanger or complex cellular events including cell proliferation. These integrins are concentrated on cells of the vasculature and on some types of tumor cells, which in part explains the proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on some cancers including gliomas. T4 also acts on the mitochondrial genome via imported isoforms of nuclear thyroid receptors to affect several mitochondrial transcription factors. Regulation of actin polymerization by T4 is critical to cell migration in neurons and glial cells and is important to brain development.

T3 can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alpha V beta3.

In the blood, T4 and T3 are partially bound to thyroxine-binding globulin (TBG), transthyretin, and albumin. Only a very small fraction of the circulating hormone is free (unbound) – T4 0.03% and T3 0.3%. Only the free fraction has hormonal activity. As with the steroid hormones and retinoic acid, thyroid hormones cross the cell membrane and bind to intracellular receptors (α1, α2, β1 and β2), which act alone, in pairs or together with the retinoid X-receptor as transcription factors to modulate DNA transcription.[24]

T3 and T4 regulation

The production of thyroxine and triiodothyronine is regulated by thyroid-stimulating hormone (TSH), released by theanterior pituitary. The thyroid and thyrotropes form a negative feedback loop: TSH production is suppressed when the T4levels are high.[25] The TSH production itself is modulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold exposure (to stimulate thermogenesis). TSH production is blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones (estrogen andtestosterone), and excessively high blood iodide concentration.

An additional hormone produced by the thyroid contributes to the regulation of blood calcium levels. Parafollicular cellsproduce calcitonin in response to hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to the effects of parathyroid hormone (PTH). However, calcitonin seems far less essential than PTH, as calcium metabolism remains clinically normal after removal of the thyroid (thyroidectomy), but not the parathyroids.

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