The molecular structure of Thyroxine (T4) hormone can be visualized as a horse. (1)
This simple visual diagram can help you “see” what is invisible and mysterious — how T3 and other forms of thyroid hormone are created from T4.
Imagine a molecule with two circles and a tail as the body of the horse.
Next, put four iodine atoms around the two circles. Put two iodines on the head circle and two iodines on the body circle.
Now you’ve got the thyroxine hormone — also known as “tetra-iodothyronine” (tetra = four) because it has four iodine atoms.
However, analogies can only go so far until they break down. Here is where this analogy breaks down.
If you remove one iodine atom from this horse, it is NOT like removing a saddle or a blanket.
No, removing one iodine atom changes thyroid hormone completely and irreversibly.
T3 is an utterly different hormone — immensely powerful, and more essential to the body’s health than T4 itself, even though it can be derived from T4. It’s not a workhorse anymore; now it’s a racehorse.
It’s not that T3 is “more active” than T4, it performs biological functions T4 cannot.
Now take T3 and remove one additional iodine atom on the same ring. T2 has lost most of T3’s power. It can still be active, but it now does things that T3 couldn’t do.
These tiny differences in structure between thyroid hormones can make a huge difference. They are not just superficial differences. These hormones act in very different ways. It makes the difference between hypothyroidism, hyperthyroidism, or a balanced euthyroid state.
We need a healthy ratio among these hormones to achieve health, and I’ll explain in this post what can go wrong with thyroid hormone conversion.
WHAT IS DE – IODINE – ATION?
As you can see, there is “iodine” in the middle of the word “deiodination.”
To de-iodinate is to remove iodine.
Deiodination is the process of conversion or metabolism of thyroid hormone by removing one iodine atom at a time from thyroid hormone molecules.
Our bodies have “deiodinase” enzymes that do this job.
The most important function of the deiodinases is to control the amount of T3 that gets into to receptors in the nucleus of cells.
However, in disease states, an imbalance among the deiodinases can result in T3 deficiency or T3 excess.
There are generally two types of deiodination — INNER ring and OUTER ring.
- When deiodinase enzymes remove iodine from the OUTER ring of the hormone, they form biologically ACTIVE forms of T3 and T2. (2, 3)
- When created by INNER-ring deiodination, Reverse T3 and two additional types of T2 are LESS active, but can play some active roles at the cell membrane receptors. (6-8)
Outer-ring deiodination converts T4 into T3
Let’s look more in detail at the conversion that provides T3.
Deiodinase Type 1 and Type 2 can remove an iodine atom from the “outer ring” of the molecule.
If you imagine the molecule as a horse, imagine that the removal of this iodine atom is like the removal of a big horn on its nose that was getting in its way.
Many of the carriers whose job is to transport T4 and T3 across our cell membranes prefer to transport the less “spiky” molecule, T3. (4)
After T4 and T3 are transported into the cell, the thyroid hormone receptor in the nucleus also prefers the less spiky molecule, T3.
It is often said that thyroid hormone receptors have 10 to 15 times more “affinity” for T3 than T4. But even if T4 were to bind one tenth of the time, we have no scientific proof that it does anything at all once it binds.
With this iodine “horn” sticking out, the T4 molecule is just too big and bulky to attach to most thyroid hormone receptors in the nucleus.
But once this iodine atom is out of the way, the T3 molecule is able to enter the thyroid hormone receptor in the nucleus, much like a horse enters her stall in the barn.
T3’s function in the nuclear receptor is the most powerful and important role of thyroid hormone in every organ and tissue throughout our body. We literally cannot live without the proper amount of T3 binding to receptors.
As T3 latches on to the receptor, the receptor significantly changes its role and function. When T3 enters the nucleus of cells in our liver, or in our brain, those receptors can turn on and off genes that enable those tissues and organs to work properly.
T3 is the same hormone wherever it goes, but there are many types of receptors and types of receptor actions on genes.
Each organ’s T3 receptors are wired to do different things. The diversity in receptor types and receptor effects is what enables this single hormone, T3, to accomplish so much throughout our body.
T3 converts to active T2
After the formation of T3 hormone, further outer-ring deiodination creates an active form of T2 hormone.
This active T2 hormone has an important role in
- regulating basal metabolic rate,
- promoting weight loss and metabolizing fats,
- reducing blood glucose independently of insulin, and
- helping us stay warm (thermogenesis). (2, 3)
Active T2 also powerfully suppresses TSH secretion. (9) This may help to explain why T3 and desiccated thyroid therapy suppresses TSH more powerfully than T4 monotherapy. As T3 peaks in bloodstream a few hours after a dose containing T3, more of this active T2 flows into the hypothalamus and pituitary than normal.
The fragility of Deiodinase Type 2
Deiodinase Type 2 is the enzyme responsible for the vast majority of our T4-T3 conversion, but it is very fragile and sensitive.
Even a slightly abnormal excess of T4 within the normal reference range can inactivate some Deiodinase Type 2 molecules. (5) Adding more T4 medication will only worsen the situation and result in even less T3. The excess T4 that is not converted by D2 may be excreted or converted into Reverse T3.
In addition, many patients suffer a genetic polymorphism in the Deiodinase Type 2 gene, DIO2, that handicaps the deiodinase and can cause hypothyroidism in peripheral tissues.
In short, anything that inactivates or handicaps this sensitive Deiodinase Type 2 will result in a loss of T3 hormone from a person who depends on T4 hormone conversion.
Patients without a functioning thyroid gland are less able to compensate for a loss of conversion to T3.
Reverse T3 and less active T2
Deiodinase Type 3 and Type 1 can also remove an iodine atoms from the “inner ring” of the molecule.
This converts T4 into Reverse T3 hormone.
Imagine that the Reverse T3 thyroid hormone molecule is like a “crippled” horse that can’t walk toward the receptor located in the nucleus.
Reverse T3 is incapable of binding with the receptor in the nucleus of the cell.
Every day, a healthy human body will deiodinate T4 into some Reverse T3. A healthy rate of conversion to Reverse T3 prevents excess amounts of the storage hormone T4 from converting to T3 and rendering you thyrotoxic.
The vigilance of Deiodinase type 3
The main enzyme that removes iodine from the inner ring is Deiodinase Type 3 (D3).
It functions like an army, vigilantly watching and waiting for T4 or T3 to step over the healthy boundary into a state of excess. (6)
In health, Deiodinase type 3 is a safety-net, a defensive army.
D3’s primary enemy is T3 (it is the enzyme’s “preferred substrate”). D3 is always on the lookout for T3 excess, because T3 is so powerful. D3 swiftly deiodinates it into a less active form of T2 (3, 3′ diiodothyronine) once it oversteps the boundary.
D3’s secondary enemy is T4. When T4 oversteps the boundary into excess, it cuts off the iodine atom located at the foot of the horse, crippling it.
D3 can also convert Reverse T3 into another form of T2 (3′, 5′ diiodothyronine), but this hormone has rarely been studied.
Overactive Deiodinase Type 3 can harm
The most problematic situation occurs when T4 is overabundant and T3 is less abundant, an imbalance in the T3:T4 ratio that can be induced by T4 monotherapy for hypothyroidism, but may occur in any therapy involving T4 hormone.
At the same time that D3 disables T4, it also disables T3.
By cutting off that one iodine atom, it handicaps both of them.
In thyroid therapy, D3 enzyme can take care of T4 excess, but while stopping T4, it also cripples T3, leaving us hypothyroid in a state of low T3.
To make things worse, excess Reverse T3 can play some harmful secondary roles at the cell membrane’s “integrin” receptor.
Reverse T3 has some beneficial activities in the some parts of the brain when it’s not excessive, (7) but even in mild excess, both T4 and Reverse T3 can
- promote the proliferation of some types of cancer cells and
- excessively stimulate endothelial cells in blood vessels, (8) which may trigger microvascular angina, atrial fibrillation, or endothelial dysfunction.
Conclusion: Deiodinases complicate thyroid therapy
Some people believe that 80% of our T3 is always converted from T4 outside the thyroid gland, but that may only be true in perfect health in a person with a thyroid gland.
Even in people with thyroid glands, the deiodinase system is not static. It is designed to be adaptive.
Deiodination shifts in response to various illnesses, medications, and substances. (1)
When the deiodinases get imbalanced in a person with a healthy thyroid, their TSH and thyroid gland act as the failsafe.
- The thyroid gland can “top up” Free T3 levels in blood to maintain them just above the mid-point in reference range.
- If a person with a healthy thyroid experiences low T3 during illness, their thyroid gland will be their saviour, rescuing them during recovery by resupplying the T3 they need.
Something else also shifts deiodinases — thyroid therapy.
Thyroid therapy is different from an adaptive thyroid gland — it can never perfectly imitate nature. Thyroid hormone dosing directly manipulates and distorts the availability of T4, T3, and the ratio between T4 and T3 in the bloodstream and in cells.
Thyroid therapy can directly induce powerful deiodinase imbalances.
The medication meant to remedy us can harm us.
Most patients on T4 monotherapy have subnormal levels of Free T3 — much less than the median of healthy people with thyroid glands.
Many hypothyroid patients on medication lack the healthy thyroid as failsafe. They have no compensatory mechanism to maintain Free T3 levels in the upper-mid range.
Patients who still have some functioning thyroid tissue will not suffer as much T3 loss, but those who have suffered total gland failure or thyroidectomy are most at risk of T3 deficiency.
Including T3 in therapy gives patients back the “failsafe” they lack without a viable thyroid gland.
If we gave some T3 to all hypothyroid patients, thyroid therapy would more closely imitate a real thyroid gland.
If doctors were to trust patients more and give them a little “wiggle room” to shift their dose timing and slightly increase or decrease their dose as colder climate and health status changes, that would allow them to adapt therapy to their individual biological needs, just like the thyroid gland adapts.
Putting thyroid sufficiency into the joint control of patients and doctors would enable us to work with our deiodinases to maintain healthy Free T3 levels.
(1) [This molecular visualization was inspired by figures in this article] Chatzitomaris, A., Hoermann, R., Midgley, J. E., Hering, S., Urban, A., Dietrich, B., … Dietrich, J. W. (2017). Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00163
(2) da Silva Teixeira, S., Filgueira, C., Sieglaff, D. H., Benod, C., Villagomez, R., Minze, L. J., … Nunes, M. T. (2017). 3,5-diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. Acta Physiologica (Oxford, England), 220(2), 238–250. https://doi.org/10.1111/apha.12821
(3) Cioffi, F., Gentile, A., Silvestri, E., Goglia, F., & Lombardi, A. (2018). Effect of iodothyronines on thermogenesis: focus on brown adipose tissue. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00254
(4) Karapanou, O., & Papadimitriou, A. (2011). Thyroid hormone transporters in the human. Hormones (Athens, Greece), 10(4), 270–279.
(5) Werneck de Castro, J. P., Fonseca, T. L., Ueta, C. B., & McAninch, E. A. (2015). Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. Journal of Clinical Investigation, 125(2), 769–781. https://doi.org/10.1172/JCI77588
(6) Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008). Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences. Cellular and Molecular Life Sciences: CMLS, 65(4), 570–590. https://doi.org/10.1007/s00018-007-7396-0
(7) Domingues, J. T., Cattani, D., Cesconetto, P. A., Nascimento de Almeida, B. A., Pierozan, P., Dos Santos, K., … Zamoner, A. (2018). Reverse T3 interacts with [alpha]v[beta]3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms. Molecular and Cellular Endocrinology, 470, 281. https://doi.org/10.1016/j.mce.2017.11.013
(8) Davis, P. J., Tang, H.-Y., Hercbergs, A., Lin, H.-Y., Keating, K. A., & Mousa, S. A. (2018). Bioactivity of Thyroid Hormone Analogs at Cancer Cells. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00739
(9) Padron, A. S., Neto, R. A. L., Pantaleão, T. U., de Souza Dos Santos, M. C., Araujo, R. L., de Andrade, B. M., … de Carvalho, D. P. (2014). Administration of 3,5‐diiodothyronine (3,5‐T2) causes central hypothyroidism and stimulates thyroid‐sensitive tissues. Journal of Endocrinology, 221(3), 415–427. https://doi.org/10.1530/JOE-13-0502