• The three levels of thyroid regulation
  • Thyroid hormones and conversion of T4 to T3 and to reverse-T3
  • Free T4 and Free T3

Hormones are chemicals produced by our body to regulate an infinite number of activities. Cells throughout our body contain specific receptors for particular hormones, and hormones fit into their corresponding receptors. When a hormone activates its receptor, it initiates a designated process or function. Because every cell in the body has receptors for thyroid hormone, thyroid hormones are responsible for the most basic aspects of body function, impacting all major systems of the body.
Thyroid hormone directly acts on the brain, the G.I. tract, the cardiovascular system, bone metabolism, red blood cell metabolism, gall bladder and liver function, steroid hormone production, glucose metabolism, lipid and cholesterol metabolism, protein metabolism and body temperature regulation. Thyroid hormone stimulates vitamin metabolism. The thyroid regulates proper development and differentiation of all cells of the human body, growth, puberty. Thyroid hormone helps the necessary enzymes and electrolytes to pass into the cell, and helps the processes of energy production in the mitochondria (in the form of adenosine triphosphate - ATP) (Click Here). In fact, thyroid hormones regulate the speed in which body's chemical functions proceed (metabolic basal rate).

Hypothyroidism is a condition characterized by a decreased hormones thyroid production. You can think of the thyroid as the central gear in a sophisticate engine. If that great gear breaks, the entire engine goes down with it. In other words, deficiency in thyroid hormones is not compatible with normal health.

• The three levels of thyroid regulation
The thyroid gland makes hormones (T4, and T3) which regulate the metabolic basal rate, e.g. the utilization of the energy by all the cells of the body. The metabolic activity of the thyroid is controlled by the hypothalamus (located in the brain) which watches and modulates the levels of the thyroid hormones by liberating an hormone, called TRH (thyrotropin Releasing Hormone) which, itself, stimulates the liberation of another hormone in the pituitary gland (located at the base of the brain), the TSH (Thyroid Stimulating Hormone), which gives signals (orders) to the thyroid gland to make more or less thyroid hormones. That is how is done the regulation of the metabolic basal rate. In other words, a feedback loop exists between the hypothalamus (via TRH) and the pituitary gland in response to the circulating levels of TSH, another between the pituitary gland (via TSH) and the thyroid gland in response to the level of T4 and T3 in the bloodstream, and a third one back to the hypothalamus depending on the circulating level of these hormones.

• Thyroid hormones and Conversion of T4 to T3 and to reverse-T3
The thyroid gland produces its two most important thyroid hormones from iodine which it gets from a diet of fish, seafood, table salt and sea salt. Tetra-iodothyronine, or thyroxine (T4), contains four molecules of iodine, and tri-iodothyronine (T3) contains three molecules of iodine. Although the thyroid gland produces more T4 (80 %) compared with T3 (20%), T3 is 300 percent more active than T4. T3 is the actual active hormone affecting the body's metabolism. T4 is the storage form of thyroid hormone (sometime described as a pro-hormone). Both hormones are present in the serum either bound to their proteins-carrier or in the free-state (unbound). The only hormone which can really have its effect on the metabolism is the free hormone.

Once introduced into the blood, a large proportion of the T4 hormone is converted by an enzyme named 5'-deiodinase to the active hormone T3 in the liver and inside the cells themselves of whatever organ is being affected (T4 is converted into T3 by removing an iodine from the T4 molecule at the 5' position). Then the T3 free combines with the receptor inside the cell, to have its effect. Without this conversion of T4 to T3, cells have too little T3 to maintain normal metabolism; as a result, metabolism slows down – this is an important point to keep in mind. For the most part, T4 is metabolically inactive. T4 "drives" metabolism only after the deiodinase enzyme converts it to T3 in target tissues. So, we may say that T3 does not come primarily from the thyroid gland.

Another enzyme called 5-deiodinase continually converts some T4 to reverse-T3 (rT3). Reverse-T3, which is a stereoisomer of T3, does not stimulate metabolism, it has no biological activity. It is produced as a way to help clear some T4 from the body. But reverse-T3 can bind to the T3 receptors of the cells in the body. Under normal conditions, T4 is continually converted in the cells into equal amounts of T3 and reverse-T3, with slight shifts. Under normal conditions, the body eliminates reverse-T3 rapidly. Other enzymes quickly convert reverse-T3 to T2 and T2 to T1, and the body eliminates these molecules within roughly 24-hours. The process of deiodination by these enzymes is dynamic and constantly changing, depending on the body's needs.
However, if there is a preferential conversion of T4 to reverse-T3, the reverse-T3 can act as an antagonist to T3 at the receptor level. This scenario leads to symptoms of low thyroid since reverse-T3 can be considered inactive (it only has 1 percent of the activity of T3). (Click Here)

Under certain conditions, food deprivation (as during fasting or starvation), any illness, physical and emotional stress (that increase the blood level of the stress hormone called cortisol), the percentages of conversion change, less T4 is converted to T3 and more is converted to reverse-T3 (the conversion of T4 to T3 decreases about 50%, and the conversion of T4 to reverse-T3 increases about 50% [Source: Dr. John C. Lowe]). The reduce T3 level that occurs under such conditions slows the metabolism of many tissues. Because of the slowed metabolism, the body does not eliminate reverse-T3 as rapidly as usual, allowing the reverse-T3 level in the blood to increase considerably. Reverse-T3 exerts its negative feedback and ties up thyroid receptors. In fact, reverse-T3 creates more powerful negative feedback on the production of T3 than vice versa. Thus, reverse-T3 works against us causing all the symptoms of hypothyroidism. 

A study described in The Journal of Clinical Endocrinology & Metabolism 2005; 90 (12): 6403-6409, demonstrates that the best estimate of tissue thyroid effect is rT3 (reverse-T3) and the T3/rT3 ratio. Unfortunately, rT3 is missed by standard testing (more commonly done in USA). (Click Here)

• Free T4 and Free T3
Thyroid hormones circulate in the blood bound to three proteins, mainly thyroxin-binding globulin (TBG), along with transthyretin and albumin. T4 is 99.97% protein bound, the rest is free T4; T3 is 99.70% protein bound, the rest is free T3. Thyroxin-binding globulin (TBG) production in the liver can be modified by factors such as estrogen levels, corticosteroid levels, or liver failure – this is an important point, as well, to keep in mind. Increased or decreased TBG does not affect free T4 or free T3 measurements. T3 is less tightly bound to plasma proteins than T4 and is therefore more readily available for cellular uptake. T3 free is biologically more active than T4 because it binds to a much greater extent than T4 with specific receptors localized in the membrane, mitochondria, cytoplasm and nucleus of responsive cells.

Total T4 and total T3 measure both bound to protein and unbound to protein (floating free in the blood), and they fail to tell what is free and useable. Only free T4 and free T3 have to be tested. For some doctors, the active free T3 can be the most important lab to do. A low free T3 in the range with a so-called "normal" TSH may be for them a strong sign of hypothyroid status. I share this point of view. I will discuss later on the capital point of the so-called "normal" TSH. A free T4 level in range doesn't mean that the body is converting it into T3 like it should be. Many people, especially women, do not adequately convert T4 to the active T3, resulting in symptoms of underactive thyroid with a so-called "normal" TSH.
Unfortunately, physicians do not usually ask free T3 measurement. (Click Here)
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