Thyroid gland

In most mammals, the thyroid lies just caudal to the larynx on the first or second tracheal ring and consists of two lobes connected by a narrow isthmus. In birds, the thyroid gland forms two lobes lying on either side of the trachea at the level of the clavicle.

The thyroid gland is made up of follicles filled with a material called the colloid which contains a protein – iodine complex called thyroglobulin. The thyroglobulin is secreted by the epithelial cells i.e. the follicular cells that line the follicle.

Synthesis of thyroid hormones

In the body, the iodine is in two forms: the inorganic iodide (ingested / dietary iodine) and organically bound iodine. Organic bound form of iodine includes-

1. Mono-iodotyrosine (T₁)
2. Di-iodotyrosine (T₂)
3. Tri-iodothyronine (T₃)
4. Thyroxine (T₄)
5. Reverse tri-iodothyronine (_rT₃)

The first stage in the formation of thyroid hormone is transport of iodides from blood into the thyroid follicular cells. The basal membrane of thyroid cell actively transports iodide by iodide-pump into the interior of the cell, which is called as iodide trapping. The iodide pump can concentrate iodide up to 30 times in the gland than the level in blood.

The trapped iodide is oxidized to iodine (I₂) by thyroid peroxi­dase enzyme (integral membrane protein present in the apical (colloid-facing) plasma membrane of thyroid follicular cells) and H₂O₂ helps this reaction.

Thyroid peroxidase catalyzes two sequential reactions-

1. Iodination of tyrosines on thyroglobulin
2. Synthesis of thyroxine (or triiodothyronine) from two iodotyrosines

The I₂ is transported to the lumen of the thyroid follicle, where it iodinates tyrosine present in thyroglobulin.

The thyroid cells are protein-secreting cells, synthesize and secrete thyroglobulin (TGB) which is a glyco­protein. Each molecule of TGB contains 134 tyrosine amino acids of which 30 amino acids combine with iodine to form iodothyrosines – mono-iodotyrosine (MIT) and di-iodotyrosine (DIT) by the enzyme thyroid peroxidase.

The coupling of the iodotyro­sines occurs to form iodothyronines by two possible routes, the combination of two DIT molecules to form thyroxine (T4-3,5,3’,5’) or the combination of one DIT with one MIT to form triiodothyronine (T3–3,5,3’) or to form reverse triiodothyronine (rT3-3,3’,5’) (has no biological function).These reactions are enzymatically controlled. The binding of I₂ with TGB is called organification of TG molecule.

Release and transport of thyroid hormones

Two of the iodinated amino acids T₃ and T₄ are stored extracellularly in the colloid on the thyroglobulin and secreted into the blood stream when required.

Thyroglobulin enters the thyroid cells by endocytosis. Thyroid hormones are excised from their thyroglobulin by protease digestion in lysosomes of thyroid epithelial cells and diffuse into blood.

In contrast, the two iodotyrosines (MIT and DIT) are deiodinated within the gland by an enzyme 5′ monodeiodi­nase. This cycle, which can be regarded as intrathyroidal, reclaims the iodine from tyrosine for use in the manufacture of the more active iodinated thyronines-T₃ and T₄.

Thyroxine is predominant in all animals, i.e., T₄ is 3 to 4 times more than T₃.

Most of the circulating T₃ are derived from peripheral deiodination of T₄ by the enzyme 5′ monodeiodinase present in all the cells of the body.

The T4/T3 ratio varies from 15:1 to 44:1 in most species of animals. In the blood, the thyroid hormone is transported bound with a serum globulin, the thyroid‑binding globulin(TBG – present in all animals except cat).

In many species, thyroid hormones are also transported with an albumin, the thy­roid‑binding pre‑albumin (TBPA also termed as transthyrectin – specifically transports T4) and albuminitself is a thyroid hormone carrier;

Collectively the iodine that is bound to all serum proteins is known as protein‑bound iodine or PBI.

Transthyrectin transports thyroxine and vitamin A and thyroxine helps to convert carotene to vitamin A in liver cells.

Less than 1% of T4 and T3 are transported as free hormones in the blood.

T₄ has 3 to 4 times more affinity for the binding proteins than T₃, whereas T₃ in the free form is considerably more active as a thyroid hormone.

T₄ may be a prohormoneor a source of T₃ and T₃ is the active hormone – T₃ is five times more potent than T₄.

T₄ has slower onset of action than T₃. The half life of T3 is about 1 day and for T4 it is about 6 to 7 days, which is very remarkable since other hormones have a half life in minutes only.

Regulation of thyroid secretion

TSH from anterior pituitary stimulates the secretion of T₄ and T₃ by the thyroid gland. The TSH promotes iodide trapping, increases iodination of tyrosine and coupling of iodotyrosines to form thyroid hormones.

TSH increases follicular cell size and number thereby thyroid hormones synthesis.

TSH and T₄ secretions are controlled by the level of hormones in blood by long ‑ loop negative feedback or servomecha­nism.

TRH from hypothalamus regulates thyroxine release through TSH release.

Exposure to cold increases TRH secretion from hypotha­lamus causes increased secretions of TSH and thyroid hormones and increased meta­bolic rate.