Thyroid Hormone Synthesis Pathway: Step-By-Step Guide
Thyroid hormone synthesis step-by-step guide! We walk through the pathway in which thyroid hormone is produced. Includes flow charts and diagrams!
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Thyroid Hormone Synthesis
Thyroid hormone plays an important role in metabolism, development, and the function of many organ systems.
Thyroid hormone must first be synthesized or produced in order for the body to use it.
In this lecture, we will walk through the synthesis of thyroid hormone step-by-step.
There will be simple diagrams included that will help you better visualize the pathway.
There is a great study guide above that summarizes everything - Make sure to get your copy today!
There is also a chart at the bottom of this lecture summarizing the steps, so make sure to read the entire post!
Hypothalamic-Pituitary-Thyroid Axis
There are 3 main structures involved in thyroid hormone regulation and synthesis.
They include the hypothalamus, anterior pituitary gland, and thyroid gland.
The 3 structures communicate and work together to synthesize and regulate thyroid hormone.
Together they are called the hypothalamic-pituitary-thyroid axis, or HPT axis for short.
The HPT axis is a self-regulatory circuit that balances thyroid hormone levels in the blood and maintains thyroid homeostasis in the body.
The self-regulation is to prevent hyperthyroidism vs hypothyroidism (too high or too low of thyroid hormone) from occurring.
The HPT axis begins with the hypothalamus, followed by the anterior pituitary gland, followed by the thyroid gland.
There is also a negative feedback loop on these structures to maintain thyroid homeostasis.
Let’s walk through each structure step-by-step and discuss the pathway in which thyroid hormone is synthesized.
Hypothalamic-Pituitary-Thyroid Axis (HPT Axis): Involved in regulating thyroid hormone synthesis to maintain thyroid homeostasis.
Memory Trick
The easy way to remember the order of the 3 structures involved in the HPT axis is to go in alphabetical order!
First is the “H” for Hypothalamus, followed by the “P” for Pituitary gland, and lastly the “T” for Thyroid gland.
Thyroid Hormone Synthesis Steps
The thyroid hormone synthesis pathway includes the following steps:
TRH Release (Hypothalamus)
TSH Release (Anterior Pituitary Gland)
Thyroid Hormone Synthesis (Thyroid Gland)
Thyroglobulin Production
Iodide Uptake
Iodide Oxidation
Thyroglobulin Iodination
MIT/DIT Coupling
Thyroglobulin Proteolysis
Thyroid Hormone Release (Thyroid Gland)
Let’s walk through each of these steps below!
Step 1: TRH Release (Hypothalamus)
As previously mentioned, the first structure involved in the HPT axis and with thyroid hormone synthesis/regulation is the hypothalamus.
The hypothalamus is located deep in the brain below the thalamus.
The hypothalamus contains neurons that have the ability to secrete different hormones onto the anterior pituitary gland.
One of these groups of neurons is called the paraventricular nucleus (PVN).
The PVN secretes a hormone called thyrotropin-releasing hormone (TRH), which will stimulate the anterior pituitary gland.
The anterior pituitary gland is located below the hypothalamus.
TRH is released from the PVN and reaches the anterior pituitary gland via the hypophyseal portal system, which are the blood vessels connecting the hypothalamus and anterior pituitary gland.
TRH will then stimulate the anterior pituitary gland, which brings us to step 2!
Thyroid Hormone Synthesis Pathway: Step 1 - The paraventricular nucleus (PVN) of the hypothalamus releases thyrotropin-releasing hormone (TRH), which will stimulate the anterior pituitary gland.
Step 2 - TSH Release (Pituitary)
As previously mentioned, the second structure involved in the HPT axis and with thyroid hormone synthesis/regulation is the anterior pituitary gland.
TRH released from the hypothalamus will stimulate the anterior pituitary gland to release another hormone.
TRH stimulates cells in the anterior pituitary gland, called thyrotropes, to release a hormone called thyroid-stimulating hormone (TSH).
The easy way to remember TRH comes before TSH is to go in alphabetical order using the “R” and “S”.
This will help you remember the releasing hormone (TRH) comes before the stimulating hormone (TSH).
TSH will then enter the bloodstream and travel to the thyroid gland, which brings us to step 3!
Thyroid Hormone Synthesis Pathway: Step 2 - The thyrotropes of the anterior pituitary gland release thyroid-stimulating hormone (TSH) into the bloodstream, which will stimulate the thyroid gland.
Step 3 - Thyroid Hormone Synthesis (Thyroid Gland)
As previously mentioned, the third structure involved in the HPT axis and with thyroid hormone synthesis/regulation is the thyroid gland.
The thyroid gland is a butterfly shaped structure located at the base of the anterior neck.
The thyroid gland is made up follicles, which are the structural and functional units of the thyroid gland.
Each follicle is lined by follicular cells, also known as thyrocytes.
The lumen (center) of the follicle is filled with a substance called the colloid.
The TSH released from the anterior pituitary gland will travel through the bloodstream and bind to the thyroid follicular cells.
Thyroid Hormone Synthesis Pathway: Step 3 - Thyroid-stimulating hormone (TSH) binds to thyroid follicular cells, which will stimulate thyroid hormone synthesis.
TSH will stimulate the thyroid follicular cells to synthesize thyroid hormone (TH).
Thyroid hormone synthesis occurs in a number of steps:
Thyroglobulin Production
Iodide Uptake
Iodide Oxidation
Thyroglobulin Iodination
MIT/DIT Coupling
Thyroglobulin Proteolysis
Let’s walk through these steps below.
Step 3.1 - Thyroglobulin Production
The thyroid follicular cells produce a protein called thyroglobulin and release it into the colloid, a process known as exocytosis.
The colloid is rich in thyroglobulin as a result.
The TSH that is released from the anterior pituitary gland will travel through the bloodstream and bind to TSH receptors on thyroid follicular cells.
When TSH binds to follicular cells, the production of thyroglobulin is enhanced.
Thyroglobulin is an important precursor for thyroid hormone.
However, there is one more ingredient we need from the blood to make thyroid hormone, which brings us to the next step!
Thyroid Hormone Synthesis Pathway: Step 3.1 - TSH binds to TSH receptors on thyroid follicular cells, which enhances thyroglobulin production in the follicular cell and release into the colloid of the follicle.
Step 3.2 - Iodide Uptake
The production of thyroid hormone requires 2 main ingredients: Thyroglobulin (see above) and Iodine.
In order to get iodine, we first need to take up iodide from the blood.
Do not confuse iodide and iodine, as we will be discussing both.
We mainly get iodine from our diet, which then gets absorbed from the intestines into the bloodstream as iodide.
In addition to enhancing thyroglobulin production, TSH also stimulates the follicular cells to increase iodide uptake from the blood.
The concentration of iodide is greater in the follicular cells than the blood, so iodide uses the help of sodium to travel against its concentration gradient.
The phenomenon is known as iodide trapping.
Sodium and iodide enter the follicular cells via a sodium/iodide symporter.
TSH will increase the expression and activity of sodium/iodide symporters in order to facilitate increased iodide uptake.
Once in the follicular cell, iodide will then enter the colloid via a transporter called pendrin.
Iodide is now in the colloid with thyroglobulin.
However, we said we needed iodine and not iodide, which brings us to the next step!
Thyroid Hormone Synthesis Pathway: Step 3.2 - TSH increases the expression and activity of Na+/I- Symporters, which increases iodide uptake from the blood into the thyroid follicular cell (Iodide Trapping). Iodide is transported into the colloid via Pendrin.
Step 3.3 - Iodide Oxidation
Now that iodide is inside the lumen of the follicle, we need to convert iodide into iodine.
The thyroid uses an enzyme called thyroid peroxidase (TPO) to oxidize iodide into iodine.
This process is known as iodide oxidation because we are losing electrons to form iodine.
TSH also increases the activity of TPO, so you can see how this is all coming together now!
Now we have our 2 ingredients to make thyroid hormone: Thyroglobulin and Iodine.
Now it’s time to combine these 2 ingredients, which brings us to the next step!
Thyroid Hormone Synthesis Pathway: Step 3.3 - Thyroid peroxidase (TPO) oxidizes iodide into iodine (Iodide Oxidation).
Step 3.4 - Thyroglobulin Iodination
Now that we have thyroglobulin and iodine in the colloid, it is time to combine them.
As previously mentioned, thyroglobulin is a protein and proteins are made of amino acids.
Thyroglobulin contains tyrosine amino acids.
The thyroid will again use the enzyme TPO to place iodine onto tyrosine, a process known as organification or iodination of thyroglobulin.
We know from our medical terminology lecture that the prefix “mono” means one and “di” means two.
If one iodine is placed on tyrosine, then it becomes monoiodotyrosine (MIT).
If two iodine are placed on tyrosine, then it becomes diiodotyrosine (DIT).
MITs and DIT molecules then get combined to form T3 and T4, which are the main thyroid hormones.
This brings us to our next step!
Thyroid Hormone Synthesis Pathway: Step 3.4 - Thyroid peroxidase (TPO) places iodine on thyroglobulin tyrosine amino acids (Organification or Iodination) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
Step 3.5 - MIT/DIT Coupling
In order to make T3 and T4, we need to combine our MITs and DITs from above.
If we combine one DIT (which contains 2 iodine) with one MIT (which contains 1 iodine), then we will have 3 iodine.
This will give us triiodothyronine, also known as T3.
DIT + MIT = T3
If we combine two DITs (which each contain 2 iodine on them), then we will have 4 iodine.
This will give us tetraiodothyronine, also known as T4 or thyroxine.
DIT + DIT = T4
The process of combining MIT and DIT molecules to form T3 and T4 is known as coupling.
Guess what enzyme the thyroid uses again? You guessed it….TPO!
So we can see thyroid peroxidase has 3 important roles:
Iodide Oxidation
Thyroglobulin Iodination
MIT/DIT Coupling
Our thyroglobulin protein now has T3 and T4 bound to it.
Now we have to cut the T3 and T4 out of the thyroglobulin, which brings us to our final thyroid hormone synthesis step!
Thyroid Hormone Synthesis Pathway: Step 3.5 - Thyroid peroxidase (TPO) combines monoiodotyrosine (MIT) and diiodotyrosine (DIT) to form T3 and T4 (Coupling). Thyroid peroxidase has 3 roles: Oxidation, Iodination, Coupling (3 Stars)
Step 3.6 - Thyroglobulin Proteolysis
We now have thyroglobulin containing T3 and T4.
Therefore, we have to cut the T3 and T4 out of the protein.
In order to do this, thyroglobulin exits the colloid and enters back into the follicular cell, a process known as endocytosis.
TSH increases thyroglobulin endocytosis.
Lysosomes in the follicular cell fuse with the thyroglobulin endosome.
The lysosomes contain proteolytic enzymes called proteases that cleave (split) the T3 and T4 from thyroglobulin.
T3 and T4 then enter the bloodstream again, which brings us to our final overall step!
Thyroid Hormone Synthesis Pathway: Step 3.6 - Thyroglobulin with T3 and T4 bound to it re-enters the thyroid follicular cell (Endocytosis) and T3 and T4 are cleaved using lysosomal proteases.
Step 4 - Thyroid Hormone Release
T3 and T4 have now been cleaved from thyroglobulin in the follicular cell.
T3 and T4 will then exit the follicular cell and enter the bloodstream to act on target tissues and organs.
Collectively T3 and T4 are known as thyroid hormone (TH).
About 20% of thyroid hormone released from the thyroid is T3, and 80% is T4.
The majority of T3 and T4 are bound to carrier proteins as they travel through the blood.
One of the main carrier proteins is thyroxine-binding globulin (TBG).
Although T3 and T4 can both have effects on target tissues, T3 is considered the active form of thyroid hormone.
Much of T4 gets converted into T3 peripherally, with some of it getting converted in the thyroid.
Thyroid Hormone Synthesis Pathway: Step 4 - T3 and T4 are released into the bloodstream where they act on target tissues. Most T3 and T4 is bound to thyroxine-binding globulin (TBG).
Thyroid Hormone Synthesis Pathway: Summary
Below is a summary of all the main thyroid hormone synthesis steps we discussed!
The summary includes the pathway, an explanation of the process, and the main structures or enzymes involved with each step.
Thyroid Hormone Synthesis: Flow chart of the pathway and steps involved in thyroid hormone production
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Referenceshttps://www.uptodate.com/contents/image?imageKey=ENDO%2F76931https://www.biosciencenotes.com/synthesis-of-thyroid-hormones/https://www.ncbi.nlm.nih.gov/books/NBK500006/https://www.ncbi.nlm.nih.gov/books/NBK499850/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654752/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682920/#:~:text=The%20paraventricular%20nucleus%20of%20the%20hypothalamus%20(PVN)%20has%20emerged%20as,autonomic%20functions%20(gastrointestinal%2C%20renal%20and