Triiodothyronine

Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

Production of T3 and its prohormone thyroxine (T4) is activated by thyroid-stimulating hormone (TSH), which is released from the pituitary gland. This pathway is regulated via a closed-loop feedback process: Elevated concentrations of T3, and T4 in the blood plasma inhibit the production of TSH in the pituitary gland. As concentrations of these hormones decrease, the pituitary gland increases production of TSH, and by these processes, a feedback control system is set up to regulate the amount of thyroid hormones that are in the bloodstream.

As the true hormone, the effects of T3 on target tissues are roughly four times more potent than those of T4. Of the thyroid hormone that is produced, just about 20% is T3, whereas 80% is produced as T4. Roughly 85% of the circulating T3 is later formed in the thyroid by removal of the iodine atom from the carbon atom number five of the outer ring of T4. In any case, the concentration of T3 in the human blood plasma is about one-fortieth of that of T4. This is observed in fact because of the short half-life of T3, which is only 2.5 days. This compares with the half-life of T4, which is about 6.5 days.

Production of T3
T3 is metabolically active hormone that is produced from T4. T4 is deiodinated by two deiodinase enzymes to produce the more-active triiodothyronine:

1. Type I present within the liver and accounts for 80% of the deiodination of T4

2. Type II present within the pituitary gland.

T4 is synthesised in the thyroid gland follicular cells as follows.

1. The Na+/I- symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodine ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I- against its concentration gradient.

2. I- is moved across the apical membranae into the colloid of the follicle.

3. Thyroperoxidase oxidises two I- to form I2. Iodide is non-reactive, and only the more reactive iodine is required for the next step.

4. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.

5. Thyroid-stimulating hormone (TSH) released from the pituitary gland binds the TSH receptor ( a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.

6. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin.

7. These vesicles are then exocytosed, releasing the thyroid hormones.

In the follicular lumen, tyrosine residues become iodinated. This reaction requires hydrogen peroxide. Iodine bonds carbon 3 or carbon 5 of tyrosine residues of thyroglobulin in a process called organification of iodine. The iodination of specific tyrosines yields monoiodotyrosine (MIT) and diiodotyrosine (DIT). One MIT and one DIT are enzymatically coupled to form T3. The enzyme is thyroid peroxidase.



Mechanism of action
The T3 (and T4) bind to nuclear receptors, thyroid receptors. T3 (and T4) are very lipophilic and able to pass through the phospholipid bilayers of target cells. The lipophilicity of T3 (and T4) requires their binding to the protein carrier thyroid-binding protein (TBG) [thyroxine-binding globulins, thyroxine binding prealbumins, and albumins] for transport in the blood. The thyroid receptors bind to response elements in gene promoters, thus enabling them to activate or inhibit transcription. The sensitivity of a tissue to T3 is modulated through the thyroid receptors.

The transportation of triiodothyronine


T3 and T4 are carried in the blood, bound to plasma proteins. This has the effect of increasing the half-life of the hormone and decreasing the rate at which it is taken up by peripheral tissues. There are three main proteins that the two hormones are bound to. Thyronine-binding globulin (TBG) is a glycoprotein that has a higher affinity for T4 than for T3. Transthyretin is also a glycoprotein, but with a higher affinity for T3 than for T4. Finally, both hormones bind with a low affinity to serum albumin, but, due to the large availability of albumin, it has a high capacity.

Effects of T3
T3 increases the basal metabolic rate and, thus, increases the body's oxygen and energy consumption. The basal metabolic rate is the minimal caloric requirement needed to sustain life in a resting individual. T3 acts on the majority of tissues within the body, with a few exceptions including the spleen and testis. It increases the production of the Na+/K+ -ATPase and, in general, increases the turnover of different endogenous macromolecules by increasing their synthesis and degradation.

Protein T3 stimulates the production of RNA Polymerase I and II and, therefore, increases the rate of protein synthesis. It also increases the rate of protein degradation, and, in excess, the rate of protein degradation exceeds the rate of protein synthesis. In such situations, the body may go into negative ion balance.

Glucose T3 potentiates the effects of the β-adrenergic receptors on the metabolism of glucose. Therefore, it increases the rate of glycogen breakdown and glucose synthesis in gluconeogenesis.

Lipids T3 stimulates the breakdown of cholesterol and increases the number of LDL receptors, thereby increasing the rate of lipolysis.

Heart T3 increases the heart rate and force of contraction, thus increasing cardiac output, by increasing β-adrenergic receptor levels in myocardium. This results in increased systolic blood pressure and decreased diastolic blood pressure. The latter two effects act to produce the typical bounding pulse seen in hyperthyroidism.

Development T3 has profound effect upon the developing embryo and infants. It affects the lungs and influences the postnatal growth of the central nervous system. It stimulates the production of myelin, the production of neurotransmitters, and the growth of axons. It is also important in the linear growth of bones.

Neurotransmitters T3 may increase serotonin in the brain, in particular in the cerebral cortex, and down-regulate 5HT-2 receptors, based on studies in which T3 reversed learned helplessness in rats and physiological studies of the rat brain.

Measurement
Triiodothyronine can be measured as free triiodothyronine, which is an indicator of triiodothyronine activity in the body. It can also be measured as total triiodothyronine, which also depends on the triiodothyronine that is bound to thyroxine-binding globulin.

T3 in the treatment of depressive disorders
The addition of triiodothyronine to existing treatments such as SSRIs is one of the most widely studied augmentation strategies for refractory depression, however success may depend on the dosage of T3. An uncontrolled long-term study by Kelly and Lieberman of 17 patients with major refractory unipolar depression found that 14 patients showed improvement of symptoms over an average timespan of two years, in some cases with higher doses of T3 than the traditional 50 mcg required to achieve therapeutic effect, with an average of 80 mcg and a dosage span of 24 months;dose range:25mcg-150mcg. The same authors published a retrospective study of 125 patients with three categories of bipolar disorder (I, II and NOS) whose treatment had previously been resistant to an average of 14 other medications. They found that 84% experienced improvement and 33% experienced full remission. None of the patients experienced hypomania while on T3.

Use as a fat loss supplement
3,5-Diiodo-L-thyronine and 3,3'-Diiodo-L-Thyronine are used as ingredients in certain over-the-counter fat-loss supplements, designed for bodybuilding. Several studies have shown that these compounds increase the metabolization of fatty acids and the burning of adipose fat tissue in rats.

Alternative medicine
Triiodothyronine has been used to treat Wilson's syndrome, an alternative medical diagnosis not recognized as a medical condition by mainstream medicine. This diagnosis involves various non-specific symptoms that are attributed to the thyroid, despite normal thyroid function tests. The American Thyroid Association has raised concern that the prescribed treatment with triiodothyronine is potentially harmful.