T4 and T3 are two hormones that your thyroid gland produces on a daily basis. Reverse T3 is a degradation product of T4. It is a biologically inactive compound. In contrast to what many people mistakenly think, TSH – Thyroid Stimulating Hormone – is not a thyroid hormone. It simply regulates the production of T4 and T3.

What Is the Thyroid Gland?

The Thyroid Gland is a small endocrine gland, shaped like a butterfly. It sits low in your anterior neck, below the thyroid cartilage (Adam’s Apple.)

Formation of Thyroid Hormones – T4 and T3

The basic functioning unit of the thyroid gland is thyroid follicle. Think of a follicle as a sac, lined by a layer of thyroid cells. These are called follicular cells. These cells produce a special protein called Thyroglobulin, which is then stored in the central cavity of each follicle. Synthesis of thyroid hormones takes place on this preformed thyroglobulin.

Synthesis of thyroid hormones consists of three steps:

1. Iodide Uptake

To synthesize thyroid hormones, thyroid cells need iodine, which primarily comes from diet. Iodine is a trace element which is present in variable amounts in the earth’s crust. However, sea water contains fairly good amounts of iodine. Dietary iodine is converted to inorganic iodide inside the body.

Each thyroid cell has an outer (basal) wall, an inner (apical) wall and two sidewalls. The basal wall actively transports iodide from blood circulation into the cell. The term for this step is Iodide Uptake. Iodide then goes inside the thyroid cell towards its inner apical wall, where synthesis of T4 and T3 takes place.

2. Iodination

In order to produce thyroid hormones, the thyroid cell combines iodide with tyrosine, an essential amino acid present inside the thyroglobulin molecule. Medical term for this process is iodination of tyrosine. This chemical reaction requires an enzyme called TPO (Thyroid Peroxidase) as well as H2O2 (Hydrogen Peroxide.)

As a result of iodination, two compounds are formed: MIT (Monoiodotyrosine) and DIT (Diiodotyrosine). Each MIT molecule contains one iodide atom and each DIT molecule contains two iodide atoms, attached to tyrosine.

3. Coupling

The next step, called coupling, occurs when two DIT molecules fuse to form a molecule that contains four iodide atoms. Medical term for this compound is tetraiodothyronine or thyroxine or T4. Also, one MIT fuses with one DIT, which forms a molecule that contains three iodide atoms. Medical term for this compound is Triiodothyronine or T3. Only T4 and T3 are true thyroid hormones. MIT and DIT do not possess any significant hormonal activity.

Storage of Thyroid Hormones

After synthesis, MIT, DIT, T3 and T4 are stored in the thyroglobulin inside the lumen of the follicle. In this way, the thyroid gland serves as a large reservoir for storing thyroid hormones. A normal thyroid gland stores about 8000 micrograms of iodine, 90% of which is in the form of MIT, DIT, T3 and T4. The remaining 10% is in the form of iodide.

This unique storage function of the thyroid gland provides a safety-net against depletion of thyroid hormones, should synthesis cease for some reason.

Release of T4 and T3

Small amounts of T3 and T4 enter the blood circulation according to your body’s needs. This process involves re-absorption of thyroglobulin from the follicular lumen back into the thyroid cell, where thyroglobulin undergoes breakdown. Consequently, T4, T3, DIT and MIT are freed from the thyroglobulin molecule. T3 and T4, then get into blood circulation. MIT and DIT remain inside the cell and undergo further breakdown, as a result of which iodide is freed from tyrosine. A variable amount of freed iodide gets into blood circulation. The remaining freed iodide stays inside the cell and is recycled for reformation of MIT and DIT.

Under normal circumstances, the thyroid gland releases about 80 – 90 micrograms of T4 and 6 – 8 micrograms of T3 per day.

Transport Of T4 and T3

Most of the T4 and T3 circulates in the blood, tightly bound to proteins, the most important of which is called TBG (Thyroid Binding Globulin). The other two less important binding proteins are TBPA (Thyroid Binding PreAlbumin) and albumin.

T4 and T3 in the bound form are metabolically inactive. Only a tiny fraction, 0.03% of total T4 and 0.3% of total T3, is present as Free T4 and Free T3 respectively. It is these free fractions that are available to tissues. Remember, even Free T4 is metabolically not very active. It has to convert to Free T3, which is the active thyroid hormone.

T4 converts to T3 in the Tissues

T3 is the active thyroid hormone, responsible for all of the biological actions of the thyroid hormone. Daily total production of T3 is about 32 micrograms (mcg), about 75-80% (24-26 mcg) of which comes from T4 to T3 conversion in the peripheral tissues. However, about 20-25% (6-8 micrograms) of the total daily production of T3 comes directly from the thyroid gland.

T4 to T3 conversion takes place under the guidance of an enzyme called 5′-deiodinase (DI). There are two types of 5′-DI: Type 1-DI and Type 2-DI.

Type 1-DI is most abundant in the peripheral tissues, especially in the thyroid, liver, kidneys, and muscles. Type 2-DI is mostly found in the brain and pituitary gland.

T3 Is the Active Thyroid Hormone

Out of all of the thyroid hormones, T3 is the most active hormone. In order to carry out the thyroid hormone function, T3 combines with Thyroid Hormone Receptor (THR) located inside the nucleus of a cell. Then it exerts its effects on almost every organ in the body, in particular the heart, brain, muscles, bones, skin, intestines and reproductive organs.

T4 Is the Reservoir of Thyroid Hormone

On the other hand, T4 serves as a reservoir for the thyroid hormone. It converts into T3 to meet the body’s demands.

What Happens With High T4 and T3

If levels of T4 and T3 go high, a person develops symptoms of overactive thyroid – hyperthyroidism.

What Happens With Low T4 and T3

On the other hand, if T4 and T3 level go down a person develops symptoms of underactive thyroid – hypothyroidism.

T4 Also Converts to Reverse T3 (rT3)

T4 also converts into Reverse T3 (rT3). This conversion takes place under the guidance of another enzyme, called 5-deiodinase or Type 3 DI. Daily production of reverse T3 (rT3) is about 19 micrograms. It important to realize that Reverse T3 is an inactive thyroid hormone.

Deiodination Of T4 And T3

Deiodination means removal of one iodide atom. Each T4 molecule contains 4 atoms of iodide located at 3 ,3′, 5 and 5′ positions inside the molecule. Removal of one iodide atom at 5′ position leads to formation of T3 molecule. Thus, each molecule of T3 contains 3 iodide atoms, located at 3 , 3′, and 5 positions. On the other hand, deiodination of one iodide atom at 5 location leads to the formation of Reverse T3. Each molecule of Reverse T3, therefore contains 3 iodide atoms, located at 3 , 3′, and 5′ positions.

Further deiodination of T3 and Reverse T3 leads to the formation of T2, which is then deiodinated to T1 and ultimately to T0. Clinically speaking, T2, T1 and T0 do not possess any significant biologic activity.

Metabolism Of T4 To Other Inactive Compounds

About 70% of circulating Free T4 converts to Free T3 and rT3 in a ratio of about 60% T3 to 40% rT3. The remaining 30% of Free T4 converts into Inactive compounds through mechanisms independent of deiodinases. These mechanisms are sulfation, glucuronidation, deamination and decarboxylation of T4, primarily in the liver. medically speaking, we call them the alternative pathways of T4 degradation.

These alternative pathways of T4 degradation become clinically important when someone is on high dose of Levothyroxine. Typically, these are the patients who have undergone total thyroidectomy for thyroid cancer. A high dose of Levothyroxine causes a shift to increased T4 degradation into inactive compounds through alternative pathways. Consequently, less T4 is left for conversion into T3. Therefore, these individuals suffer from a Low T3 state due to two reasons: a marked decrease in the peripheral T4 to T3 conversion and a lack of about 20% of daily production of T3 from the thyroid gland itself.

Regulation of Thyroid Hormone

The function of the thyroid gland is regulated in several ways:

1. TSH Regulates Thyroid Hormone Production

TSH is short for Thyroid Stimulating Hormone. It is a hormone that the Pituitary Gland produces in response to the level of T3 inside the pituitary cells.

For example, the pituitary produces more TSH if T3 is low, and less TSH if T3 is high. In this way, there is a reciprocal relationship between the amount of T3 inside the pituitary and production of TSH by the pituitary.

After its release into blood circulation, TSH goes to the thyroid gland and tries to increase or decrease the production of thyroid hormones: high TSH increases and low TSH decreases the production of thyroid hormones.

The function of the pituitary gland itself is regulated by another endocrine gland, called the hypothalamus, which is located above the pituitary gland. The hypothalamus regulates the function of the pituitary gland by producing a number of hormones. In terms of thyroid regulation, it produces a hormone called TRH (Thyrotropin Releasing Hormone), which fine-tunes the production of TSH, which in turn regulates the production of thyroid hormones by the thyroid gland.

The hypothalamus itself is influenced by the limbic system, as well as various chemicals (neurotransmitters) in the brain. The Limbic system is the center of our emotions. In this way, stress as well as psychiatric illnesses as well as medications can affect the production of your thyroid hormones, by influencing your hypothalamus, pituitary gland and TSH level.

2. Autoregulation of Thyroid Gland Function

The Thyroid also has an incredible auto-regulation. For example, if there is an acute load of a large amount of iodine/iodide, the thyroid gland gets saturated with the amount of iodine it needs. Subsequently, there is a decrease in the amount of further uptake of iodine/iodide for a few days, after which uptake of iodine resumes normally. A large dose of iodine/iodide also temporarily decreases the release of thyroid hormones into circulation.

These are primarily protective mechanisms against the production and release of excessive thyroid hormones in case there is a sudden supply of large quantities of iodine/iodide. For example, contrast agents used during CT scans and angiograms contain huge quantities of iodine. In the same way, cough syrups usually contain large quantities of iodine. In addition, Iodine is an antiseptic for skin cuts and wounds. Thanks to the auto-regulatory mechanisms, the vast majority of people do not become hyperthyroid or hypothyroid after a large load of iodine.

However, hypothyroidism or hyperthyroidism may rarely develop due to the chronic use of iodine in large doses. This has been reported in individuals with pre-existing Hashimoto’s thyroiditis or Graves’ disease. However, the vast majority of people do not become hyperthyroid or hypothyroid if they consume large amounts of iodine. The Japanese are the best evidence in this regard. The average Japanese consumes more than 12,000 micrograms of iodine per day, as compared to the typical American who consumes only about 240 micrograms of iodine per day. The incidence of hyperthyroidism or hypothyroidism is not significantly different between these two populations.

In Summary

The Thyroid Gland primarily produces two thyroid hormones – T4 and T3. The production of these thyroid hormones is complex. Only a tiny fraction is present in the blood as FreeT4 and Free T3. Out of these two, T4 serves as a reservoir while T3 functions as the main active thyroid hormone, responsible for the effects of thyroid hormone on the body. The production of thyroid hormones is under strict regulation which aims to keep thyroid hormones at a steady level.