Thyroxine (T4) and Triidotheronine (T3)


Physiologic Functions

Thyroid hormones have wide-ranging metabolic effects on liver, kidney, muscle, and other tissues. Many of these increase the adrenaline response.


Metabolism: Thyroxine's increases ATP production in nearly all cells, raising the basal metabolic rate (BMR). Carbohydrate and lipid catabolism is increased.


Cardiovascular System: Thyroxine is ionotropic and chronotropic, increasing cardiac output.

Sympathetic Nervous System: increases adrenergic receptors in skeletal muscle, adipose tissue, and lymphocytes.




Regulation of Secretion

The hypothalamus secretes TRH, or thyrotropin-releasing hormone, into the median eminence. This hormone diffuses to the anterior pituitary, where GPCRs on thyrotrophs respond by secreting TSH into the circulation.

TSH binds to the GPCR TSH receptor on thyroid follicular cells, activating adenylyl cyclase and cAMP. This stimulates thyroid growth and causes synthesis and release of thyroid hormones T3 and T4.

Conditions that increase TRH and TSH include:



T3 and T4 Biosynthesis

Iodide is taken up by thyroid follicular cells via a Na/I symporter. TSH binding induces synthesis of thyroglobulin fromtyrosine, which is deposited in the colloid for storage and combination with iodide to produce T3 and T4. Once returned to the cytosol, T3 and T4 are cleaved and released into the circulation.

T 1/2 is about 1 week for T4.



Peripheral Effects


Both T3 and T4 are transported bound to thyroixin-binding globulin (TBG) and enter cells by transport of diffusion. This keeps free levels low while maintaining a ready supply of hormone. While T4 levels are higher, T3 is 10x more active, and once inside the cytosol of target cells, T4 is converted to T3. Conversion in both ways is possible.




Cellular Signaling

Thyroid hormones are not steroids, but they are lipid soluble and activate nuclear receptors to activate transcription.

T3 and T4 bind to the thyroid hormone receptor, a member of the nuclear receptor superfamily. It dimerizes with the retinoic acid receptor and binds to TREs on the DNA, activating mulitiple targets including Na-K ATPase, beta adrenergic receptors in the heart, and proteins mediating thermogenesis and lipolysis.





Inhibition of Production

The thyroid can be inhibited by a variety of agents which suppress T3 and T4 synthesis. This increases levels of TSH, leading to hyperplastic enlargement and goiter formation.

Propylthiouracil inhibits the oxidation of iodide and blocks production of thyroid hormones.