Why Reverse T3 is Not A Hormone Supervillain – Dr Fiona McCulloch

When it comes to thyroid hormones, we have come a long way in understanding how they work over the past decade. As a doctor who treats many thyroid patients, I get questions about everything thyroid on a daily basis. I also have the opportunity to treat patients with thyroid medications and monitor their responses. As a naturopathic doctor, it has always been of great interest to see how the thyroid relates to other elements of the hormonal system, immune system, and brain. At the center of this, is a hormone known as reverse T3 (rT3).

If you’re a clinician, or if you follow thyroid groups, you’ll most certainly know about reverse T3. It definitely has a bad reputation.

Reverse T3 was only discovered fairly recently: around 40 years ago.

rT3 and Other Thyroid Hormones

T4 is the hormone produced in largest amounts by the thyroid gland, and is generally weak or inactive in strength.

With the help of deiodinase enzymes in different parts of the body, T4 can transform into T3, which is the active thyroid hormone that makes our cells tick.

The cells can also decide, however, to turn T4 into reverse T3, which is inactive and can’t fit into the thyroid hormone receptor.

This is a purposeful choice by the cell as it tries to adapt to something in the environment. Since rT3 is inactive, the body will do this in order to save energy, essentially deactivating thyroid hormone that is not needed (and which could be potentially harmful)

Back in 1975, it was first noted that when people became sick in a hospital, their rT3 would go up and their T3 would go down.

Hypothyroid Symptoms

As mentioned rT3 is inactive and can’t activate thyroid hormone receptors, so if someone has high levels, they often experience hypothyroidism symptoms.

Although many websites claim this, we don’t have any evidence that rT3 blocks the T3 hormone from attaching to its receptors, and in fact have evidence that it doesn’t compete with T3 for receptor binding.

In fact, rT3 may work on completely different receptors for any activity it does exert.

Deiodinase Enzyme Function (D1, D2, D3)

There are three different enzymes called deiodinase D1, 2, and 3, and these convert T4 into either T3 or rT3.

These are present in different tissues, and the vast majority of conversion happens outside of the thyroid


D1 and D2 are primarily “activating” and convert T4 to T3.

D3 is primarily “deactivating”, and converts T4 to rT3.

Key Points About Thyroid Hormones

Levels in A Person’s Blood Versus Their Cellular Function May be VERY Different

Blood concentrations of fT4 and fT3 are relatively constant… butft3 tissue concentrations vary according to the transport of hormone and intracellular activity of deiodinases .

Most of the actual effects of thyroid hormone occur gradually, after t3 binds to receptors deep in the cell’s nucleus.

The effect of thyroid hormone on the cell’sfunction isn’t always reflected by blood levels—a common issue found by many patients who experience significant thyroid symptoms despite apparently normal labs, or vice versa.

This is why many people’s blood thyroid hormone levels don’t match how they feel. We can’t see tissue levels, so we can’t see intracellular activity whatsoever.

RT3 and Hypothyroid

What Determines rT3 Levels?

There are a few factors.

Too much substrate

Most people taking high doses of T4 medication such as synthroid have been shown to have high levels of rT3

Patients who are hyperthyroid also tend to have high rT3.

This is because there is more T4 as a substrate to turn into either fT3, or fT4. The body must shunt some into rT3 in order to prevent overstimulation by too much T3.

What Causes D3 Activation and rT3 to be Produced?

When it comes to rT3, this is all about your body’s protective mechanisms.

D3 basically protects your tissues from excessive thyroid hormones. This is the body’s natural intelligence.

For example, the fetus/placenta contains high amounts of D3. This helps protect the baby from excessive T3 from the mother’s system, should any happen to head on in there.

Some things we know for certain will increase rT3: When someone is very sick, for example, or inflamed, or starving.

One example of this is doing a very low-carb diet or caloric restriction. The body will purposely reduce its metabolic rate to protect itself, and D3 activity will go up.

Reverse T3 in Injury and Inflammation

D3 Activity Changes as Needed to Deal with Inflammation, Stress or Injury

Interestingly, D3 is minimally active in mature, healthy tissues. That said, it becomes induced in tissues again whenever there is cellular injury. Reverse T3 is a warning gauge.

For example, it has been found that hypoxia (lack of oxygen in a tissue) will induce D3 activity. [1] This is what we see happening in the fat cell inflammation found in women with PCOS, or in those with insulin resistance. Inflammatory cytokines have been found to invoke D3 in tissues as well.

A very diverse number of conditions are associated with increased cytokines, ranging from infections to metabolic issues, inflammation, autoimmunity, low iron, micronutrient deficiency, toxins, caloric restriction, and more.

As you can imagine, it’s essential to work on cellular health, and cause: if D3 is being induced, we need to determine why.

In fact, let’s go further into why we shouldn’t really look at reverse T3 as an evil mastermind plotting our icy demise in hypothyroid land. Instead, let’s look at it as more of a cooling protector, and a warning gauge.

D3 and reverse T3 are actually essential to our health in many ways. In fact, knowing how it protects us can give us clues as to what else is going wrong in the body.

Reverse T3 and the Immune System

D3 has been found to be essential for optimal white blood cell function. [2] During an infection, neutrophils will actually infiltrate the infection site and bring D3 along with them! They’ll then locally change T4 into rT3, which plays a role in mounting a response against invaders.

Animals that had their D3 genes knocked out weren’t able to beat infections as well as those with healthy D3 activity. The neutrophils in this situation were less able to produce NADPH oxidase, and less able to kill bacteria.

Reverse T3

Reverse T3, Circadian Rhythm, and Appetite

Other areas in which D3 is involved are the circadian rhythm and the leptin-melanocortin system. Animals that lack D3 have been shown to have lower body fat. This makes sense, given they’d have no ability to deactivate thyroid hormone.

These animals have also been found to have increased leptin and leptin resistance, as well as a disrupted circadian rhythm and increased activity during sleep. [3]

There are complex regulatory mechanisms involving D3 in the hypothalamus that govern both sleep and appetite.

Reverse T3, Inflammation and Fatty Liver.

That the induction of D3 can improve healing and reduce damage after various types of tissue injury. rT3 is protective to cellular damage in these situations, which we see commonly in obesity, fatty liver ,and cardiovascular disease. [4]

Patients with non-alcoholic fatty liver disease or insulin resistance may have high reverse T3 as a result.

Reverse T3 and the Pancreas

In the pancreas, T3 is required for the pancreatic cells to transform into insulin-secreting beta cells. It has also been found that the deactivating D3 and the subsequent rT3 production plays a fundamental role role in the way pancreatic cells develop and function.

Mice that lack D3 became glucose intolerant or diabetic, and had reduced expression of key genes involved in glucose sensing and insulin synthesis. All of this is a highly regulated, timed process in which various thyroid hormones must play their roles at specific intervals. [5]

Reverse T3 and the Brain

Reverse T3 and the Brain

Looking at the brain, it’s clear that D3 and rT3 play a key role. It has been found that D3 is highly present in both the developing and adult brain. It stands ready to convert T4 to rT3, and inactivate the impact of thyroid hormone (which would be negative if it were in excess).

In fact, the DIO (deiodinase) genes are imprinted across various brain regions. During development, they introduce an additional level of control, delivering hormones in the brain.D3 in the brain is primarily expressed in astrocytes and neurons.

The mechanisms that the DIO genes respond to are complex and very much depend on environmental signals. Read: external things can make your brain convert T4 one way or the other.

A brain’s thyroid hormone conversion brain can influence the thyroid-related genes inside a cell, as well as in neighbouring ones. Thyroid hormone influences the function of brain cells involved in important roles such as sensory perception, cognition, mood, and hormonal control.

It’s now thought that we can actually become “imprinted” during development, with respect to our deodinase enzyme activity.[6] Some of our various tissues may be more or less effective with each enzyme.

This is even the case with imprinting. Once we reach adulthood, our D3 expression is still susceptible to environmental and external factors, such as exposure to dietary changes, stress, and chemicals.

It’s also been found that reverse T3 is involved in the initiator of actin polymerization in astrocytes, a process that is key to brain structure.

Reverse T3 and Muscle Development

In muscle, we once again see the deiodinase enzymes keep intracellular thyroid hormone levels in balance as needed to regulate repair and new muscle growth. [7] The activity of each of the deiodinases in muscle cells depends on the type of muscle cells in which they’re found.

D2, the activating deiodinase, has higher activity in slow twitch muscle. Hypothyroidism and cold exposure increase D2 activity in muscle, allowing energy to be burned to stay warm.

Muscle cells go through what is known as myogenesis, which is the proliferation and differentiation of the muscle stem cell population. Thyroid hormones are involved at each step of this process.

In fact, the process of D3 deactivation is key for certain steps, highlighting again the importance of reverse T3 in physiology.

Interestingly, it’s thought that the D3 enzyme and production of reverse T3 were to help humans survive habitats where iodine deficiency was endemic. D3 could essentially be turned “off” during times of deficiency to both prevent the loss of iodine—which is essential for thyroid hormone production—and improve the effect of the often low levels of T4 seen in the condition.

How To Lower Reverse T3 Levels

Bottom line: the most important thing is to determine why the rT3 is high rather than focusing on lowering it.

The underlying cause of high rT3 may be temporary, or it may be chronic. It might be fully or even partially treatable.

Doesn’t matter which. It needs to be a) fully understood, and then b) treated to the best of its extent to allow for better cell signalling to take hold—a sign of which is often rT3 reduction.

It’s actually relatively easy to bring down rT3 levels with T3-containing medications like natural desiccated thyroid, but this can be a mistake if an underlying issue is still present.

Adding additional thyroid hormone and depleting rT3 before checking for a response to treatment will only take away your gauge.

Sometimes, even when everytyhing else is taken care of, high reverse T3 persists. Why is that?

We now know that thyroid deiodinase genetic polymorphisms may be involved in this. Different people can have different genetic tendencies to convert thyroid hormones through D1, 2, and 3.

A new report found that Thr92Ala-DIO2 polymorphism exhibits lower D2 catalytic activity and localized/systemic hypothyroidism. [8]

This could explain why certain groups of T4-only treated hypothyroid patients,even when otherwise healthy, have improved quality of life when also treated with the aformentioned T3-contiaining meds like natural desiccated thyroid. Also, as previously mentioned, there may be imprinting of the gene.

Therefore, look first for the underlying causes of D3 induction/high reverse T3.

When that is addressed and there’s still a conversion issue, it may actually be genetic.

Of course, at some point, having low T3 and high rT3 over the long run has its own set of harms.

After a prolonged time, low T3 levels can cause a variety of negative consequences very similar to those found in hypothyroidism. As such, clinical intervention with T3-containing medication is often required.

This is especially true in those dealing with chronic inflammation such as autoimmune disease, infections, or metabolic syndrome. We treat many patients like this in the clinic.

Image © DC Comics

Intricate Healing Mechanisms

As naturopathic doctors, one of our principles is Vis Medicatrix Naturae:“The healing power of nature”.

Reverse T3 gives is a perfect example of how our body has developed intricate healing mechanisms; ones that we’re still learning about.

So, no matter what you may read, just know that reverse T3 is actually not a hormone supervillain—it’s a lot more like the DC superhero known as “Icemaiden”.

“Originally a member of the Global Guardians, this Norwegian superhero gained her powers through scientific experimentation. As a young woman, Sigrid Nansen decided to submit to government experiments in an attempt to please her scientist mother.

The government was attempting to replicate the powers of the legendary ice-people, and with Sigrid, they succeeded. Her skin was turned blue and her hair white, but she gained the ability to project snow and ice from her body, and to create cold.

Unlike most other superheroes with cryokinesis, Icemaiden can also create ice shields over parts of her body to protect herself in battle.”

Quote from: Screenrant

Article References:

  1. Bauab, R. C. M., Perone, D., Castro, A. V. B., Cicogna, A. C., Nogueira, C. R.Low triiodothyronine (T3) or reverse triiodothyronine (rT3) syndrome modifies gene expression in rats with congestive heart failure.Endocrine Research2005;31(4):397-405.https://www.ncbi.nlm.nih.gov/pubmed/16433258
  2. Rastogi, L., Godbole, M. M., Sinha, R. A., Pradhan, S.Reverse triiodothyronine (rT3) attenuates ischemia-reperfusion injury.Biochemical and Biophysical Research Communications2018;506(3):597-603.https://doi.org/10.1016/j.bbrc.2018.10.031
  3. van der Spek AH, Jim KK, Karaczyn A, van Beeren HC, Ackermans MT, Darras VM,Vandenbroucke-Grauls CMJE, Hernandez A, Brouwer MC, Fliers E, van de Beek D,Boelen A.The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential forOptimal Neutrophil Function: Observations From Three Species.Endocrinology2018 Feb 1;159(2):826-835.
  4. Wu, Z., Martinez, M. E., St. Germain, D. L., Hernandez, A.Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity.Endocrinology2016;158(2):en.2016-1680.https://doi.org/10.1210/en.2016-1680
  5. Rastogi, L., Godbole, M. M., Sinha, R. A., Pradhan, S.Reverse triiodothyronine (rT3) attenuates ischemia-reperfusion injury.Biochemical and Biophysical Research Communications2018;506(3):597-603.https://doi.org/10.1016/j.bbrc.2018.10.031
  6. Medina, M. C., Molina, J., Gadea, Y., Fachado, A., Murillo, M., Simovic, G., … Bianco, A. C.The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion.Endocrinology2011;152(10):3717-3727.https://doi.org/10.1210/en.2011-1210
  7. Bloise, F. F., Cordeiro, A., Ortiga-Carvalho, T. M.Role of thyroid hormone in skeletal muscle physiology.Journal of Endocrinology2018;236(1):R57-R68.https://doi.org/10.1530/JOE-16-0611
  8. Bianco, A. C., Kim, B. S.Pathophysiological relevance of deiodinase polymorphism.Current Opinion in Endocrinology Diabetes and Obesity2018;25(5):1.https://doi.org/10.1097/MED.0000000000000428

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