Triiodothyronine
Encyclopedia
Triiodothyronine, C15
H12
I3
N
O4
, 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 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.
s 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
.
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.
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.
.
(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.
. Several studies have shown that these compounds increase the metabolization of fatty acids and the burning of adipose fat tissue in rats.
, 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.
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
H12
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
I3
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
O4
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, also known as T3, is a thyroid hormone
Thyroid hormone
The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,...
. It affects almost every physiological
Physiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
process in the body, including growth
Growth
Growth refers to an increase in some quantity over time.The quantity can be:*Physical *Abstract ....
and development
Human development (biology)
Human development is the process of growing to maturity. In biological terms, this entails growth from a one-celled zygote to an adult human being.- Biological development:...
, metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, body temperature, and heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
.
Production of T3 and its prohormone
Prohormone
A prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. The primary function of a prohormone is to enhance the strength of the hormone that already occurs in the...
thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(T4) is activated by thyroid-stimulating hormone
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
(TSH), which is released from the pituitary gland. This pathway is regulated via a closed-loop feedback
Feedback
Feedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
process: Elevated concentrations of T3, and T4 in the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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 that of T4. This is observed in fact because of the short half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
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 the more metabolically active hormone produced from T4. T4 is deiodinated by two deiodinase enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s 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
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
.
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
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
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
Organification
Organification is a biochemical process that takes place in thyroid glands. It is the oxidation of iodide by peroxide, and then its binding to tyrosyl residues within the thyroglobulin molecule....
of iodine. The iodination of specific tyrosines yields monoiodotyrosine
Monoiodotyrosine
Monoiodotyrosine is a precursor of thyroid hormone and results from iodization of tyrosine at the meta- position of the phenol ring.Two units can combine to form 3,3'-diiodothyronine. One unit can combine with diiodotyrosine to form triiodothyronine, as occurs in the colloid of the thyroid...
(MIT) and diiodotyrosine
Diiodotyrosine
Diiodotyrosine is a precursor of thyroid hormone and results from iodization of monoiodotyrosine at the other meta- position on the phenol ring....
(DIT). One MIT and one DIT are enzymatically coupled to form T3. The enzyme is thyroid peroxidase
Peroxidase
Peroxidases are a large family of enzymes that typically catalyze a reaction of the form:For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides...
.
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-lifeHalf-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
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
Serum albumin
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
, but, due to the large availability of albumin, it has a high capacity.
Effects of T3
T3 increases the basal metabolic rateBasal metabolic rate
Basal Metabolic Rate , and the closely related resting metabolic rate , is the amount of daily energy expended by humans and other animals at rest. Rest is defined as existing in a neutrally temperate environment while in the post-absorptive state...
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
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
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
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
.
Lipids
T3 stimulates the breakdown of cholesterol and increases the number of LDL receptors, thereby increasing the rate of lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
.
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
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
.
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
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
, 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
Learned helplessness
Learned helplessness, as a technical term in animal psychology and related human psychology, means a condition of a human person or an animal in which it has learned to behave helplessly, even when the opportunity is restored for it to help itself by avoiding an unpleasant or harmful circumstance...
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 globulinThyroxine-binding globulin
Thyroxine-binding globulin binds thyroid hormone in circulation. It is one of three proteins responsible for carrying the thyroid hormones thyroxine and 3,5,3’-triiodothyronine in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3, but is present in the lowest...
.
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 disorderBipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
(I
Bipolar I disorder
Bipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. There may be episodes of hypomania or major depression as well...
, II
Bipolar II disorder
Bipolar II disorder is a bipolar spectrum disorder characterized by at least one hypomanic episode and at least one major depressive episode; with this disorder, depressive episodes can be more frequent and are more intense than hypomanic episodes...
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 bodybuildingBodybuilding
Bodybuilding is a form of body modification involving intensive muscle hypertrophy. An individual who engages in this activity is referred to as a bodybuilder. In competitive and professional bodybuilding, bodybuilders display their physiques to a panel of judges, who assign points based on their...
. 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 syndromeWilson's syndrome
Wilson’s syndrome, also called Wilson’s thyroid syndrome or WTS, is an alternative medical diagnosis consisting of various common and non-specific symptoms that are attributed to a below-median body temperature and impaired conversion of thyroxine to triiodothyronine , despite normal thyroid...
, an alternative medical
Alternative medicine
Alternative medicine is any healing practice, "that does not fall within the realm of conventional medicine." It is based on historical or cultural traditions, rather than on scientific evidence....
diagnosis not recognized as a medical condition by mainstream medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
. This diagnosis involves various non-specific symptoms that are attributed to the thyroid, despite normal thyroid function tests. The American Thyroid Association
American Thyroid Association
The American Thyroid Association is a professional organization of some 900 medical specialists. It publishes the journals Thyroid, Clinical Thyroidology and Signal through Mary Ann Liebert....
has raised concern that the prescribed treatment with triiodothyronine is potentially harmful.