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

RT3 inhibits T4-T3 conversion.

Many thyroid patients have learned to fear 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 in different contexts and lower is not always better.
  • 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 blows it out of realistic proportions.

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.

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 tame Holtorf’s Reverse T3 claim and put it in perspective.

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 Reverse T3 if we just learn enough about its role in the larger picture of thyroid hormone conversion. I refer to a separate post 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. You are hiding something you don’t want to quote.

I’ll show you the hidden 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 equal “molar weight” of the two substances. Let’s look at what the abstract of Chopra’s article really says to confirm this. 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.”

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

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

I’ll perform for you the three simple steps to an approximate answer:

  1. First I got the data on molar weight 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.

Thyroid-secretion-Wiersinga-1979-ann

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

  • Reverse T3 production from T4 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 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.
  • 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.

How muchRT3 in PTU

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.

Are you now scared that RT3 could inhibit conversion at 100x the potency of PTU at an equal molar weight?

Now let’s 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.

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 start with.

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, despite their 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 (Maia et al, 2005).

Not the only Reverse T3 misunderstanding

As I’ve shown in previous 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.

NOTE: Other experimental research I’ve seen suggests RT3 indeed has suppressive effects on Deiodinase type 2, but it involves dosing or injecting RT3. The hormones T4 and RT3 are co-present in living beings with parallel concentrations and thus any parallel effects are difficult to disentangle. Nobody doses RT3. The independent impact of RT3 may indeed already be accounted for in the way increasing T4 ubiquitinates D2. We see in nonthyroidal illness 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 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:

– Tania S. Smith

REFERENCES

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

Holtorf Medical Group. (n.d.). Reverse T3: Another Thyroid Component. Retrieved November 17, 2019, from Holtorf Medical Group website: https://www.holtorfmed.com/reverse-t3-another-thyroid-component/

  • ARCHIVED AT https://web.archive.org/web/20191117090156/https://www.holtorfmed.com/reverse-t3-another-thyroid-component/

Holtorf Medical Group. (n.d.). Reverse T3 Suppresses T4 to T3 Conversion. Retrieved from http://www.hormoneandlongevitycenter.com/thyroidtreatments1/

  • ARCHIVED at https://web.archive.org/web/20191117085934/http://www.hormoneandlongevitycenter.com/thyroidtreatments1/

Maia, A. L., Kim, B. W., Huang, S. A., Harney, J. W., & Larsen, P. R. (2005). Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Journal of Clinical Investigation, 115(9), 2524–2533. https://doi.org/10.1172/JCI25083

Wiersinga, W. M. (1979). The peripheral conversion of thyroxine into triiodothyronine (T3) and reverse triiodothyronine (rT3) (PhD, University of Amsterdam). Retrieved from https://inis.iaea.org/collection/NCLCollectionStore/_Public/11/544/11544357.pdf

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Categories: Deiodinase Type 2, Deiodinase Type 3, Deiodinases, Research Reviews, RT3 - Reverse T3

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