RT3 inhibits T4-T3 conversion. How worried should we be?

[Post updated May 2, 2021]

Many thyroid patients have acquired concerns about Reverse T3 (RT3) by reading Kent Holtorf’s web pages.

Likely even more have learned by reading Reverse T3 information on the Stop the Thyroid Madness (STTM) thyroid patients’ website, which has been influenced by Holtorf, whom they cite.

On the positive side, both of these websites share a lot of rich resources and truths that have helped many thyroid patients, including myself.

I’m grateful to them. I don’t want to be cruel toward our benefactors.

But we need to continue learning together in thyroid patient communities. Learning includes humbly admitting and fixing mistakes and problems when they’re pointed out. Love of truth is the basis of trust.

Before I attempt to reduce the fear of Reverse T3 to reasonable levels in this post, I want to make clear my stance on Reverse T3 and its testing. It’s a moderate stance:

• Yes, higher levels of Reverse T3 often go hand in hand with illness and poor T4 conversion. But you can have low or no RT3 in blood and still be ill. RT3 is a signal that can mean many things depending on health status and T4 and T3 supply.
• Yes, RT3 testing can inform us about thyroid hormone metabolism. But there are three major enzymes involved in thyroid hormone metabolism. Imbalance between the enzyme that creates most RT3 and the enzyme that clears most RT3 tells us something about what these enzymes are doing to RT3, not necessarily what RT3 is doing to the enzymes. Cause and effect become blurred.
• Yes, Reverse T3 testing can be a useful test for resolving puzzles and confirming problems in thyroid therapy (see part 2 of this post). But it does not have to be tested routinely if you have the wisdom to interpret Free T3 and Free T4.

When claiming Reverse T3 is a powerful inhibitor of T4-T3 conversion, Holtorf takes a fragment of a quotation from a 1977 article and magnifies its significance.

Holtorf’s teachings on Reverse T3 have been lifted by many web pages without enough careful investigation. It’s gone viral long ago. It’s cemented in thyroid internet lore.

It’s not entirely Holtorf’s fault, and it’s gotten out of hand. Such beliefs have fostered unnecessary Reverse T3 paranoid obsession. I’ve seen the signs of it in online thyroid patient support communities.

RT3 obsession has led to some patients and doctors in US and Canada doing Reverse T3 testing too frequently, often charged to the patient’s own credit card.

Some believe RT3 absolutely essential for a “complete thyroid lab test.” But ideally a complete thyroid lab test would include a T2 test and a Triac test, and the list could go on and on.

Decisions based on exaggerated blame of Reverse T3 for “causing” low T3 and illness can sometimes lead to reducing T4 dosing too far and compensating with T3 dosing. A temporary shift away from T4 dosing and toward T3 dosing will lower RT3. But in the long term, appropriate FT4 levels can still support an individual patient despite RT3 levels.

In this post, I present Holtorf’s Reverse T3 claim and put it in perspective.

I give several quotations from Chopra, Holtorf’s source, and explain what they mean.

I explain how RT3 is produced naturally from T4 and is cleared naturally by our deiodinase enzymes and other processes.

I also show a graph demonstrating how, in people dosed with T4 hormone alone, RT3 and T3 rise in parallel, so the rise in one does not cause a fall in the other.

I show how artificial the lab experiments with RT3 are, and how much quantity RT3 or PTU a rat or a human would have to dose to cause the significant inhibition of T4-T3 conversion seen in Chopra’s experiment.

It’s utterly unrealistic to compare the two substances in real living bodies. It’s only a biochemical exercise by Chopra, and it ought not be used to frighten people about the normal RT3 levels circulating in their bodies in a state of health.

Despite all this fear and misunderstanding, I have some good news to share.

We have the ability not just to diminish, but tame or overcome our natural production of Reverse T3 hormone, if we just learn enough about its role in the larger picture of thyroid hormone conversion. I refer to other posts for practical tips on Reverse T3 testing in the context of FT3 and FT4.

Every hour we spend learning about the deiodinases that convert thyroid hormones is money saved and potentially health earned. As this knowledge grows among more and more people, it can help improve thyroid therapy for everyone.

What Holtorf says vs. what Chopra said

Here’s what Holtorf says on his Reverse T3 web page:

“Strong Thyroid Inhibitor

Studies have demonstrated that rT3 is an extremely potent inhibitor of T4 to T3 conversion. When compared to Propylthiouracil (PTU), a crystalline compound used to treat hyperthyroidism, rT3 demonstrated to be 100 times more potent in reducing conversion.

If you’ve undergone standard thyroid tests, but are still experiencing hypothyroid symptoms such as cold hands/feet, dry skin, brittle nails, weight gain/difficulty losing weight, etc., it may be time to have a full thyroid panel ran, complete with rT3.”

As scientific backing, Kent Holtorf has cited Chopra’s study on a different web page.

In 1977, Chopra experimented with rat liver and kidney tissue fragments incubated with T4 hormone. Kent Holtorf writes this summary about the study:

“In fact, rT3 is 100 times more potent than PTU at reducing T4 to T3 conversion. Clearly, rT3 not just an inactive metabolite. The authors conclude, “reverse t3 appeared to inhibit the conversion of t4 with a potency which is about 100 times more than PTU…'”

What is missing from the final “…” at the end of Holtorf’s quotation?

Come on, dear Holtorf. Why omit the last phrase of Chopra’s quote?

Of course, Holtorf could have omitted the final phrase because it contains technical terminology, and not everyone is a scientific reader.

I’ll show you the omitted words. It’s on page 461 of Inder J. Chopra’s individually-authored article:

“Reverse T3 appeared to inhibit the conversion of T4 to T3 with a potency which was about 100 times more than PTU on a molar basis.“

On a molar basis. This means that the potency of RT3 versus PTU to hinder T4-T3 conversion depends on delivery an equal number of molecules of the two substances to the cell.

What is molar mass (and molar weight)?

It’s valuable to understand these units so we can put them in perspective.

I will convert the units later in this post to compare them with the micrograms of T4 and T3 hormone that we dose pharmaceutically, and the pmol/L concentrations that show up in our blood.

As explained by a chemistry website, WebQC, molar mass is normally roughly equivalent to molar weight, but they are different conceptually because the latter involves the effect of gravity. They are sometimes used as near synonyms:

“Computing molar mass (molar weight): […]

Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

(WebQC)

Mass and weight are often are expressed in different units, but turn out to be similar numbers:

“Molecular weight is often used interchangeably with molecular mass in chemistry, although technically there is a difference between the two. For example,

C12H22O11 has a molecular weight of 342.299 amu.

A mole of C12H22O11 would have a mass of 342.299 grams. ”

(Vulcanchem)

In the early days of thyroid science, they were still transitioning from measuring hormone concentrations like Total T4 and Total T3 in ng/dL (nanograms per decileter) — a weight in grams per volume — to nmol/L (nanomoles per liter) — molar mass per volume, and that’s why Chopra gave both weight and molar relationships. Each hormone or chemical has a different molar mass, so T4, RT3 hormones and PTU drugs would each have a different conversion factor when converting from ng/dL to nmol/L. (See Mayo Clinic’s conversion chart, which lists Total T3 and Total T4)

More from Chopra

Let’s look at what the abstract of Chopra’s article really says to confirm the equality of molar units “per mole” was the basis of comparing the two substances.

You don’t have to understand everything Chopra said. Just notice the highlighted words:

“several thyroid analogues and propylthiouracil (PTU) inhibited T4 to T3 conversion in a dose-dependent manner.

Inhibitory thyroid analogues, in order of their potency, were rT3, 3′,5′-diiodothyronine, tetraiodothyroacetic acid, 3,3′-diiodothyronine and 3-monoiodothyronine; on a molar basis, the relative potency of these agents was approximately 100:100:5:1:1. PTU was about 3% as potent as rT3 on a weight basis and only 1% as potent as rT3 on a molar basis.

Analyses of the data by Lineweaver-Burk plot suggested that rT3 is a competitive inhibitor and PTU, an uncompetitive inhibitor of conversion of T4 to T3.”

One is a “weight” basis and the other is a “molar basis.” 3 percent, and 1 percent, different due to the conversion rate but also very small.

It makes it seem like RT3 is extremely potent compared to PTU!

However, we ought to ask about human concentrations of RT3 and real doses of PTU.

But before we do… let’s consider how artificial the study was, AND how artificial this comparison is.

Keep in mind Chopra’s was an in vitro study (cells in a lab)

The title of Chopra’s study is ” A study of extrathyroidal conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro.”

The study was giving “doses” to cells in dishes in laboratories, not oral pills that were absorbed through the GI tract and then affected a body in the context of many other hormones.

How much T3 was in the medium around the cells, before the cells produced T3 from T4? …..

“Aliquots of tissue homogenates were incubated with non-radioactive T4 for a certain period of time and the amount of T3 generated was measured by radioimmunoassay (RIA) in an ethanol extract of tissue.”

This is an artificial environment. There is no situation in a living human body where T3 levels are nonexistent as input into cells.

Nevertheless, the pharmaceutical T4 they used had a very small degree of contamination with T3 hormone (“5.2-7.6 ng/tube when 5 mcg T4 was employed”), so they subtracted that T3 from the experiment’s result.

There’s a huge difference between bathing a tissue sample in RT3- or PTU-rich medium with T4 but very little T3, and giving a person RT3 or PTU in a pill and seeing what it does to their circulating hormone levels in the presence of naturally circulating levels of T3 and T4.

PTU and RT3 Effect on Kidney and Liver versus other tissues

Science has informed us that RT3 is metabolized differently in Deiodinase type 1 (D1)-rich liver than in other Deiodinase type 2 (D2)-rich tissues.

In the peripheral metabolism, PTU medication largely interferes with D1, not with D2.

T4-T3 conversion continues in peripheral cells expressing D2.

In 1977, when Chopra published, they did not have the ability to discriminate between the two deiodinases, they simply talked about T4-T3 conversion.

RT3 is a natural metabolite, but PTU disrupts thyroid metabolism.

The two cannot easily be compared because PTU is dosed as an anti-thyroid medication, whereas people naturally convert a flexible percent of T4 to RT3 every day they have FT4 floating in blood.

• PTU = drug.
• RT3 = natural metabolite of T4.

As of the late 1990s and early 2000s, scientists learned much more about RT3’s natural appearance and clearance.

• Deiodinase type 3 (D3) is likely responsible for most of RT3’s appearance, while
• Deiodinase type 1 (D1) is responsible for most of the job of clearing RT3 from blood.
• Although D2 may technically be responsible for some RT3 conversion to 3,3′-T2, it has very low levels of affinity to RT3 compared to D1, so it does not play a major role.

In a state of health, both of D1 and D3 are upregulated by T3 hormone signaling in nuclear receptors (Gil-Ilbanez et al, 2014; Van Beeren et al, 2012).

D2, the enzyme responsible for much of our T4-T3 conversion, is not directly regulated by T3.

The more T3 you have entering nuclear receptors that regulate D1 and D3 enzymes, the more RT3 you will make from T4 in circulation via D3, and the more RT3 you will clear. It’s like a flexible tug of war.

In health, the RT3 level is then largely based on how much FT4 you have in relationship to FT3 in blood, and how much T3 is signaling in receptors.

RT3 is like a tax you pay for the convenience of converting T4 to T3 every minute of every day within D1- and D2-expressing cells.

When FT4 is present but RT3 does not appear in blood, it is only because it is being converted to 3,3-T2, 3′,5′-T2, or to another inactive form, and/or cleared via urine at a faster rate than it is being created.

In contrast to the power of T3 over T4 metabolism, RT3 plays very little role in “regulating” D1, D2 or D3 because the enzyme can’t “hear” it signaling very loudly when it is in normal quantities produced in the body. RT3 signaling is limited to a receptor on the membrane of cells, where it merely adds a teaspoon to the mountain of T4 signaling at that receptor (See “Cancer scientists point finger at T4 & RT3 hormones“)

You can gain RT3 and T3 at the same time. It’s not either-or.

Here’s a graph (in patients with a total thyroidectomy dosed on only T4 hormone) showing that as FT4 rises in concentration, so does RT3 and Total T3, in parallel, on average, across many patients. When RT3 rises in this population, it does not cause T3 other hormone to reduce in this population:

Notice that the RT3 and TT3 are in the same unit, but the concentration of TT3 always dominates over the concentration of RT3 in blood at a given FT4 concentration.

However, in severe illness (not shown in the graph), the T3/RT3 relationship changes because the deiodinases are dysregulated. D3 is upregulated by cytokines and hypoxia, and D1 and D2 are downregulated by similar methods. In a study of the transformation in metabolism, scientists discovered that

“Serum T3/rT3 ratio correlated positively with liver D1 activity (P < 0.001)

and negatively with liver D3 activity”

(Peeters et al, 2003)

Now let’s look at the properties of PTU.

PTU is an anti-thyroid medication for people who are hyperthyroid. Here’s how it works.

“Propylthiouracil inhibits the production of new thyroid hormone in the thyroid gland.[2] 

It acts by inhibiting the enzyme thyroid peroxidase, which usually functions to convert iodide to iodine molecule and incorporate the iodine molecule into amino acid tyrosine.

Hence, DIT (diiodotyrosine) or MIT (monoiodotyrosine) does not get produced, which are the main constituents in the production of thyroxine (T4) and triiodothyronine (T3).[3] 

Peripherally, it acts by inhibiting the conversion of T4 to T3.

It has effects on the existing thyroid hormones stored in the thyroid gland or circulating in the blood.”

(Amisha & Rhehman, 2018)

Chopra’s laboratory experiment with PTU only considered the peripheral effects, not the major effects that it has on the thyroid gland’s synthesis of thyroid hormones.

Chopra was not considering PTU’s holistic effect on the entire body, only on isolated liver cells.

When Chopra says “PTU was about 3% as potent as rT3 on a weight basis and only 1% as potent as rT3 on a molar basis,” he is only figuring in a fraction of PTU activity in the whole body.

It’s difficult to quantify what percentage of PTU’s total activity is exerted at the level of thyroid inhibition vs. inhibiting T4-T3 conversion via deiodinases (D1, D2) outside the thyroid gland.

When dosed as a drug, PTU has unique “pharmacokinetic” properties (how it behaves as a pharmaceutical), which are very different from RT3, that is not dosed in pulses but continually created in cells:

• Absorption: 75%

• Distribution: 80 to 85% of the drug is bound to plasma proteins (lipoproteins and albumin are the major binding proteins), Vd 0.4 L/kg.

It concentrates in the thyroid gland.

• Onset: 24 to 36 hours are necessary for a significant therapeutic effect.  

• Duration: 12 to 24 hours

• Half-life elimination: 1 hour approximately 

• Metabolism: PTU primarily undergoes metabolism in the liver to glucuronides or inorganic sulfates.

• Elimination: 35% gets excreted as metabolites in the urine.

(Amisha & Rehman, 2021)

Unlike RT3, the majority of PTU does not get de-iodinated (i.e. via D1), but it goes through other metabolic pathways to glucuronide, sulfate, and urine.

PTU shares with thyroid hormone only albumin as a binding protein.

RT3 and PTU work in very different ways.

Chopra’s additional finding on “little or no effect” of RT3

The same paper by Chopra in 1977 contains a passage that provides counterbalance to the one cited by Holtorf:

“Reverse T3 had little or no inhibitory effect when the T4 to rT3 concentration ratio (T4/rT3) in the incubation medium was 200 (and corresponding T4/rT3 molar ratio, 167) or more.

As expected of a competitive inhibitor, it manifested an increasing inhibitory effect on the conversion of T4 to T3 as the T4/rT3 concentration ratio decreased; inhibition was clearly apparent when T4/rT3 concentration ratios were 100 or less.

In this regard, it appears interesting to recall that the ratio of serum concentration of T4 to rT3 which normally approximates 215 (9) is low (about 90) in certain situations (e.g., hepatic cirrhosis and the newborn) where serum T3 is generally clearly subnormal (8,9,11,34).”

(Chopra, 1977)

In other words, at normal healthy T4/RT3 ratios, RT3 is impotent! Harmless!

The exception appears to be when the T4/RT3 ratio falls (or synonymously, the RT3/T4 ratio rises).

Fetal life (not just newborns) and critical illness are two situations in which Deiodinase type 3 (D3) enzyme are overexpressed, creating a high level of RT3 from the FT4 present in blood.

What Chopra may not have realized yet in 1977 is this:

• In a state of fetal life or illness, Deiodinase type 3 is upregulated, and this D3 enzyme not only converts T4 to RT3 but also converts T3 into an inactive form of T2, thereby lowering T3 levels.
• When T3 is low, D1 is downregulated and cannot efficiently clear RT3 from blood.
• In fetal life and illness, RT3 itself is not necessarily the inhibitory agent! Instead, it is the byproduct of D3 enzyme, which secondarily reduces D1 enzyme by depleting T3, permitting RT3 to build up in blood.
• When D1 is slowed down by low T3 levels, D1’s efficiency of RT3-T2 conversion and T4-T3 conversion are reduced at the same time.

The T4/RT3 ratio is an artifact of his experiment that cannot truly reproduce the situation in which low T3 signaling levels are involved in D1 downregulation while illness upregulates D3.

How much RT3 in blood is like a real dose of PTU in humans?

I’ll perform for you the three simple steps to an approximate answer (of course the pharmacodynamics are going to be very complex in a real body):

1. First I got the data on molar mass for the two substances.
2. Then I got data on human RT3 concentrations and normal PTU doses.
3. Then I converted them into equal doses in micrograms.

Skip down to the results if you’re not interested in the detective work and math.

Step one: I simply Googled molar mass:

• PTU (propylthiouracil) molecule (170.233 g/mol).
• Reverse T3 molecule (650.97 g/mol).
• In fact, the T3 molecule has the same molar weight of 650.97 g/mol.

Step two: Get RT3 concentrations and PTU doses

The RT3 production rate varies even in health, and scientific estimates vary widely. I decided use Wiersinga’s 1979 estimate of maximal normal RT3 production in the human body because he wisely uses a range rather than an average.

In the bottom right hand corner, in the box, you will see the number I’m using:

• Reverse T3 production from T4 in humans varies from 23-100 nanomoles / litre / day.

This is different from the RT3 reference range. Quest Laboratories offers a the highest quality type of RT3 laboratory test you can get, using LC/MS techniques:

• Reverse T3 reference range: 8-25 ng/dL. “Nanograms per decileter.”
• The SI Unit calculator says this is equal to 0.12 to 0.39 nmol/L.

Why is it different from Wiersinga’s “production rate” per day? It’s because Wiersinga considered the continual process of RT3 clearance and conversion to other metabolites like T2 over 24 hours.

Let’s take Wiersinga’s upper estimate of 100 because it is expressed like an internal “dose” of 100 nmol/L per day, which is something we can compare to a PTU dose.

What are the ranges of PTU doses?

• PTU dosages vary from 50 milligrams (mg)/day to 1200 mg a day (Medscape, n.d.)

STEP 3: Convert RT3 and PTU to equal doses in milligrams

I used the conversion tool at GraphPad calculator

• Making 100 nmol/L/day RT3 is a little like taking a 65 microgram pill of RT3 / day.
  • (NOTE: Its absorption and metabolism as a pill is not well understood, but imagine a given absorption rate for argument’s sake, even though we don’t “dose” RT3.)
• It takes 1000 micrograms (mcg / µg) to make one (1) milligram (mg)
• A 50 mg dose of PTU, the smallest dose is 50,000 micrograms per day.
• A 1,200 mg dose of PTU, the highest dose, is 1,200,000 micrograms per day.

RESULTS:

• It would take 769 times our 65 microgram daily production of RT3 to equal the molar mass of 50 mg daily PTU.
  • If RT3 is 100x more potent than PTU, it would take 7.69 x 65 mcg pills, or a total dose of 499.85 mcg of RT3, to have equal potency.
• It would take 18,461 RT3 internal 65 mcg daily “doses” to equal a single 1200 mg daily dose of PTU.
  • To achieve equal potency, you’d have to dose 11,999 mcg of RT3.

Okay, so these are very inexact approximations because we don’t dose RT3 and can’t really compare the two concentrations in blood in vivo.

But, it’s an intellectual exercise.

Are you now less worried that RT3 could inhibit conversion at 100x the potency of PTU at an equal molar weight (or mass)?

Cettour-Rose’s rat PTU+RT3 dosing experiment in 2005

Finally, let’s look at an in vivo experiment in rats to see what happened.

Cettour-Rose and team overdosed hypothyroid rats with RT3 and studied their deiodinase type 2 (D2) activity.

Their abstract explains their methods:

“Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo.

During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day.

[then,] 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4.”

(Cettour-Rose et al, 2005)

The rats had two things going against them: They were dosed with both PTU and RT3 at the same time.

The RT3 was a mammoth dose for a rat: Adult weight of rats for males is 300-500g, females 250-300g (Johns Hopkins University, Animal Care and Use Committee: The Rat).

The infusion of T4 was 1.6% of the amount of RT3 or 3.2% of the amount of RT3 they were dosed with. Remember what Chopra said about the high RT3:T4 ratio being the key to inhibition of T4-T3 conversion.

Using the “nmol to mcg calculator” provided by Horizon Discovery, entering 25 nmol and the molar weight of RT3 at 650.97, I obtained 48.823 mcg.

Each rat was dosed with almost 50 micrograms per day of RT3. That’s a human sized dose for a tiny little rat.

Humans weigh an average of 80.7 kg in North America, according to one website. That’s 80,700 grams, which is 269 times the weight of a rat. The equivalent dose in a human would be 13,133 micrograms of RT3.

Let’s look at the results of the experiment:

“Results: Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels,

0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values.

The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism.

Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal.

Conclusions: We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

(Cettour-Rose et al, 2005)

Yes, large pharmaceutical doses of RT3 can depress T4-T3 conversion enzyme function in rat tissues. But consider the huge overdoses of RT3 that the rats were given.

They also said that T3 levels didn’t change much! TSH did not rise! They did not become more hypothyroid from the 3 days of extreme RT3 dosing and PTU dosing!

Mind you, it’s a short-term experiment, only 3 days of RT3 inhibition, but the in vitro lab experiments with rat tissues by Chopra almost 30 years earlier did not last very long, either.

In real life, since T4 is the only source of RT3, the ratio would rarely fall in RT3’s favor to this degree. If you were not dosing RT3, you’d have to generate RT3 naturally by upregulating D3 enzyme. How do you upregulate D3 naturally? By means of dosing a rat or human with excess T4. Next, to keep the RT3 high in blood, you’d have to prevent RT3 from being cleared out of blood, as Cettour-Rose did, by adding PTU to inhibit D1 enzyme. How artificial is this experiment?

In humans, you would only use PTU if a person is hyperthyroid. You would not bother to dose them with RT3 because they’re already making as much RT3 as they can from their excess T4.

Now let’s summarize. Put RT3 in context.

Reverse T3 can only come from circulating T4 in the body.

Thyroidless people may take on average between 100-200 mcg of LT4 (levothyroxine), depending on their body mass and absorption rate from GI tract. Your body will always convert some T4 to T3. The sickest thyroid patient on LT4 monotherapy could not possibly make enough RT3 to equal the smallest dose of PTU.

You’d have to massively overdose RT3 in a pill form to move toward the potency of a PTU-like effect.

Chopra did a laboratory bench experiment, not an experiment with dosing a living rat or living human. He studied rat liver tissue incubated for 2 hours at 37 degrees Celsius bathed in T4 hormone in a laboratory. T3 hormone was measured in an ethanol abstract rather than blood.

How can this be compared to live human dosing of PTU & RT3 affecting multiple T4-T3 conversion in organs and tissues simultaneously? Nobody knows for sure because we do not dose RT3.

PTU only hinders a small portion of T4 conversion. “PTU is also a potent inhibitor of mammalian D1 but has no effect on D2 and D3 (1–3).” (Sanders et al, 1997).

• In health, 34% of our T3 (15 nmol/day) is made by Deiodinase type 1, which converts T4 to about 50% Reverse T3 and 50% T3.
• The majority of our T3 is converted by D2 — In a normal healthy human. (Maia et al, 2005)

What makes Deiodinase type 1 convert less efficiently, besides PTU / RT3? Low Free T3 concentrations in blood.

• When you have Low T3, your D1 converts less T4 to T3 and RT3. D1 is upregulated by T3 hormone. It becomes more active in people who have more T3, and less active in people who have less T3.
• D1’s main role is to convert Reverse T3 into T2. Therefore, when D1 is less active, RT3 builds up in bloodstream, and RT3 levels can escalate.

How much T3 was available to power D1 in the tissues in Chopra’s lab experiment? He only bathed tissues in T4. They had to make all their T3 without the aid of any circulating T3 to jump-start D1.

Nobody uses Reverse T3 to suppress T3 in Graves’ disease. We don’t see RT3 pills sold on the market. This is because Graves’ disease will naturally have RT3 concentrations that far exceed the reference range to the degree that their FT4 is above reference. They become thyrotoxic anyway.

In hyperthyroidism, a lot of excess T4 gets converted to T3 by Deiodinase type 1, and yet they still have a very high RT3.

In hyperthyroid people not taking PTU medication, about 67% of their T3 comes from Deiodinase type 1 conversion, because D1 is upregulated by their high T3 levels regardless of their high RT3 also in circulation (Maia et al, 2005).

Not the only Reverse T3 misunderstanding

As I’ve shown in other posts, another myth about Reverse T3 is shared by the same page on the Holtorf Medical Group website that cites Chopra’s 1977 article.

No, RT3 cannot block circulating Free T3 from getting into D2 or D1-expressing cells.

• Visualizing thyroid hormone activity in cells: T3 and RT3 in context
• Deiodinase Type 3 plays the T3-blocking role

Other experimental research I’ve seen suggests RT3 indeed has suppressive effects on Deiodinase type 2, but it involves dosing or injecting RT3 in humans. I discuss these human experiments briefly in another article:

• Reverse T3 in the context of health status, dosages, and thyroid levels

We see in “nonthyroidal illness syndrome” that levels of T4 above an illness-reduced metabolic setpoint can trigger Deiodinase type 3 dominance, which can result in FT3 depletion and reduced T3 nuclear receptor binding, which is the ultimate harm.

Thus, low T3 syndrome is a genuine health risk because of low T3, but not because of RT3, and the Free T3 level and Free T3:T4 ratio have health impacts we already see in research and practice.

Want practical Reverse T3 tips?

See the next post:

• Principles & Practical tips for Reverse T3, FT3, FT4

– Tania S. Smith

REFERENCES

Amisha, F., & Rehman, A. (2021). Propylthiouracil (PTU). In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK549828/

Cettour-Rose, P., Visser, T. J., Burger, A. G., & Rohner-Jeanrenaud, F. (2005). Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats. European Journal of Endocrinology, 153(3), 429–434. https://doi.org/10.1530/eje.1.01984

Chopra, I. J. (1977). A study of extrathyroidal conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro. Endocrinology, 101(2), 453–463. https://doi.org/10.1210/endo-101-2-453

Gil-Ibáñez, P., Bernal, J., & Morte, B. (2014). Thyroid hormone regulation of gene expression in primary cerebrocortical cells: Role of thyroid hormone receptor subtypes and interactions with retinoic acid and glucocorticoids. PloS One, 9(3), e91692. https://doi.org/10.1371/journal.pone.0091692

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