Thyroid Hormones

Synthesis and Secretion of Thyroid Hormones

Thyroid hormones are synthesized by mechanisms fundamentally different from what is seen in other endocrine systems. Thyroid follicles serve as both factory and warehouse for production of thyroid hormones.

Constructing Thyroid Hormones

The entire synthetic process occurs in three major steps, which are, at least in some ways, analagous to those used in the manufacture of integrated circuits (ICs):
Production and accumulation of the raw materials (in the case of ICs, a large wafer of doped silicon)
Fabrication or synthesis of the hormones on a backbone or scaffold of precursor (etching several ICs on the silicon wafer)
Release of the free hormones from the scaffold and secretion into blood (cutting individual ICs out of the larger wafer and distributing them)

The recipe for making thyroid hormones calls for two principle raw materials:
Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin, which is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle - colloid is essentially a pool of thyroglobulin. A molecule of thyroglobulin contains 134 tyrosines, although only a handful of these are actually used to synthesize T4 and T3.
Iodine, or more accurately iodide (I-), is avidly taken up from blood by thyroid epithelial cells, which have on their outer plasma membrane a sodium-iodide symporter or "iodine trap". Once inside the cell, iodide is transported into the lumen of the follicle along with thyroglobulin.

Fabrication of thyroid hormones is conducted by the enzyme thyroid peroxidase, an integral membrane protein present in the apical (colloid-facing) plasma membrane of thyroid epithelial cells. Thyroid peroxidase catalyzes two sequential reactions:
Iodination of tyrosines on thyroglobulin (also known as "organification of iodide").
Synthesis of thyroxine or triiodothyronine from two iodotyrosines.

Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the surface of thyroid epithelial cells. Remember that hormone is still tied up in molecules of thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free hormone into blood.

Thyroid hormones are excised from their thyroglobulin scaffold by digestion in lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis proceeds in the following steps:
Thyroid epithelial cells ingest colloid by endocytosis from their apical borders - that colloid contains thyroglobulin decorated with thyroid hormone.
Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes that digest thyroglobluin, thereby liberating free thyroid hormones.
Finally, free thyroid hormones apparently diffuse out of lysosomes, through the basal plasma membrane of the cell, and into blood where they quickly bind to carrier proteins for transport to target cells.
Control of Thyroid Hormone Synthesis and Secretion
Each of the processes described above appears to be stimulated by thyroid-stimulating hormone from the anterior pituitary gland. Binding of TSH to its receptors on thyroid epithelial cells stimulates synthesis of the iodine transporter, thyroid peroxidase and thyroglobulin.

The magnitude of the TSH signal also sets the rate of endocytosis of colloid - high concentrations of TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation. Conversely, when TSH levels are low, rates of thyroid hormone synthesis and release diminish.