Biochemistry of thyroid production

Introduction

There are two  hormones in humans are triiodothyronine (T3) and thyroxine (T4) that are responsible for the effects of thyroid function  however, there is a cascade of events that must occur beforehand to make their production possible  moreover, the presence of specific molecules and nutrients must be sufficient to produce these hormones in the first place  Both of these hormones are composed of tyrosine and iodine, however T3 contains three iodine molecules and T4 contains four. T4 is considered the inactive form of thyroid hormone, and T3 is the active form. That is, in the cell T3 is the necessary form of the hormone for thyroid activity. T4 is very easily converted into T3, as we will discuss in a moment. Through a series of signals through the hypothalamic pituitary axis (HPA), we somehow come out on the other side with T3 and T4 being secreted into the bloodstream by the thyroid gland. However, there are many prerequisites that must take place before any of that can ensue. 

Hypothalamic pituitary axis. 

The thyroid is a gland that sits in your neck that will secrete both T3 and T4 into the bloodstream for cellular functions. The production of thyroid hormone actually begins in the hypothalamus, the brain region that is in most part responsible for maintaining stable homeostasis. The hypothalamus regulates functions such as hunger, body temperature, and heart rate by modulating the nervous system and hormone production. The hypothalamus does not directly interact with the thyroid gland, rather it interacts with the pituitary gland. The pituitary gland is a subsection of the brain at the bottom of the hypothalamus that secretes that is the true location of most hormonal production. Finally, the pituitary gland will eventually interact with the thyroid gland to uptake the necessary constituents for thyroid hormone production, and begin producing and secreting T3 and T4. 

TRH

The hypothalamus contains neurons, which are cells within the brain that send chemical signals throughout the body to stimulate function. Within the hypothalamus there is a subset of neurons called the paraventricular nucleus. The paraventricular neurons  produce a chemical called thyrotropin releasing hormone (TRH). There is a vascular system between the hypothalamus and the pituitary gland that allows for TRH to travel to the pituitary gland. This system is called the hypophyseal portal system. TRH will travel to and enter into  the pituitary gland and excite a group of cells called thyrotropic cells. Thyrotropic cells begin to produce another hormone called thyroid stimulating hormone (TSH). 

TSH

TSH may sound familiar, as it is often a hormone measure on a blood test as a surrogate marker of thyroid function. TSH is the hormone chiefly responsible to signal the production of thyroid hormone. The thought is that if TSH is high, but a patient has symptoms of low thyroid, there is an issue within the synthesis of T3, thus evoking the hypothalamic pituitary axis to continue to signal for production of thyroid hormone to raise it to ideal levels.

TSH enters the blood, and will bind to a receptor on the exterior of the thyroid cells called a thyroid follicular cell. The receptor is conveniently named TSH-receptor. TSH does not actually enter into the thyroid cells, rather it causes a cascade of events inside of the cell that leads to thyroid hormone production. The TSH-receptor is a specific type of receptor called a G-Protein receptor. Simply, the TSH-receptor activates a G-Protein inside of the cell, which interacts with a specific enzyme called adenylyl cyclase. Adenylyl cyclase takes ATP and converts it into cyclic AMP (cAMP). cAMP interacts with another enzyme called protein kinase A (PKA). PKA transiently modulates thyroid cells to begin producing thyroid hormone. PKA phosphorylates transcription factors within the cell. That is just a fancy way of saying it stimulates specific pieces of DNA within the cell that code for genes related to the production of, in this case, thyroid hormone. In short, PKA causes a cell to start the process of thyroid production. 

Production of T3 and T4 

I will now take you back to high school biology for a moment. 

The gene that is phosphorylated is transcribed, producing mRNA. The mRNA is taken to the ribosome by a "nuclear envelope." The mRNA is modified and transcribed in the endoplasmic reticulum, sent to the golgi apparatus, and packs the fully developed protein into a vesicle. That protein that was created is called thyroglobulin. The vesicle carrying the thyroglobulin will bind and fuse to the membrane of the thyroid cells, and release thyroglobulin into the the interstitial portion of the thyroid gland where thyroid hormones are produced, called the  follicular lumen.

 T3 and T4 are made of two different molecules. Iodine and tyrosine. Thyroglobulin is the source of tyrosine, but we also need to get iodine from the bloodstream. Thus, the thyroid must locate iodine, and transport it into the follicular lumen. In the bloodstream, iodine (I) is typically in the form of iodide (I−), meaning it has an additional electron in respect to iodine. Thus, iodide will commonly bind to sodium, and enter into the thyroid cell. There is a protein on the thyroid cell called pendrin, which will pump iodide into the follicular lumen. However, because iodide is missing an electron it is considered unstable. No fear, because there is an enzyme in follicular lumen called thyroid peroxidase (TPO) which oxidizes iodide. Oxidation is the process by which an electron is transferred to oxygen, thus iodide loses an electron and forms iodine! Not only that, but TPO takes iodine and links it to the tyrosine molecules within thyroglobulin  and makes both monoiodotyrosine (T1)  and diiodotyrosine (T2). Just when you thought it has done enough, TPO then takes these two molecules and combines them to make both T3 and T4, the thyroid hormones! 

There is only one problem. 

Thyroglobulin has 67 tyrosine molecules within it, and not all of it is used for thyroid hormone synthesis. Therefore we need to take the synthesized T3 and T4 into the cell, while leaving behind the rest to be recycled and reused elsewhere. The thyroglobulin is taken into the thyroid follicle by endocytosis, meaning the thyroglobulin is now inside of the cell with a vesicle around it. There are proteolytic enzymes within the cells. Proteolytic simply means they interact with protein molecules. These enzymes begin cutting thyroglobulin into T3 and T4. It should be noted, it is estimated to be about a 4:1 ratio of T4 to T3, meaning 80% of the thyroid hormone produced is in an inactive form. 

Finally, T3 and T4 are isolated, and taken by a vesicle, fused to the cell membrane. T3 and T4 are transported in the bloodstream inside of a protein called thyroxine binding globulin (TBG), thyroxine binding prealbumin (TBPA), or albumin. Thyroid hormones are mainly transported by TBG however. 

Function of T3 and T4

The thyroid hormone does not have a single location in the body in which it exudes its effects. Rather, thyroid hormone affects almost every cell in the body. Thyroid hormone seems to diffuse into the cell, however emerging research is being done about the possibility of it being mediators by receptors on cells, meaning that its entrance into cells may be more complicated than simply "waking right in." With that being said, when T3 is inside of the cell, it has a multitude of functions. However, T4 is slightly more complex. 

As mentioned, T3 is the active form of thyroid hormone, and T4 must be modulated into T3 inside of the cell before it can exude its effects. The process of T4 to T3 is simple. 5' deiodinase will simply remove an iodine from T4, turning it into T3. T3 does not act alone, rather it works with arachidonic acid within the cell to turn on transcription factors within cells. 

METABOLISM 

Sodium/potassium ATPase 

Depending on the tissue, the transcription factors have different effects, however all of these effects seem to increase protein synthesis. The proteins synthesized are often referred to as sodium/potassium ATPase. These proteins orient themselves on the outside of cells, and increase the rate that sodium exits the cell, and potassium enters. As the name might imply, this process requires ATP, the energy currency of the cell. Increased thyroid hormone increases the number of these pumps on our cells, thus, metabolic rate will increase to facilitate the requisite oxygen consumption to meet increased ATP demands. Moreover, heat is produced as a byproduct of ATP production, therefore internal body temperature will begin to increase, which is a Hallmark indicator of hyperthyroidism, or overactive thyroid. 

Mitochondrial function 

At the initial stage of gene transcription, the cell is somewhat unprepared for an increase in ATP requirements. Thus, there is a transient state of low ATP within the cell (that is undetectable by the human). The result is an increase in mitochondrial production, making more mitochondria, and an increase in the size of these mitochondria. Well, the mitochondria are the organelle that create ATP, thus we can now metabolize more energy, and create more ATP. The thyroid hormone increases the ability and the necessity to metabolize energy for ATP production. 

Fuel utilization

Well, we are in a bit of a situation. Simply, the presence of thyroid causes our cells to need more energy. Don’t worry, thyroid hormones do that too. While the exact mechanism is slightly unclear, when energetic demands increase, lipolysis, glycogenolysis, and gluconeogenesis all increase. That is a fancy way of saying we begin to use the energy we currently have in our body( lipids, carbohydrates, and proteins) to produce more ATP. The liver will begin to take glycogen, and gluconeogenic constituents within the liver and begin to produce and excrete glucose into the bloodstream. The result is a transient increase in blood glucose. 

Blood pressure and heart rate 

The heart has a specific receptor referred to as a beta one adrenergic receptor. Within the heart, the transcription factor T3 will increase synthesis of codes for the beta(1)-adrenergic receptor. beta(1)-adrenergic  receptors are bound to by a chemical called adrenaline. Upon binding, these receptors will increase cardiac output, meaning more blood will be sent out of the heart, increasing our blood pressure. Moreover, on a different portion of the heart, the SA node, the function of these receptors is to increase heart rate.