Thyroid T3 secretion compensates for T4-T3 conversion

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The shifting percent of T3 from T4-T3 conversion

Now that we’ve considered how silly it is to say 20% thyroidal secretion is representative of humanity, let’s look at the inverse of secretion rate, the 80% side of the ratio.

The ruling myth is that 80% of our daily T3 supply comes from T4-T3 conversion outside the thyroid gland.

This amount is based on the peripheral “conversion rate” (CR), the rate at which X amount of secreted T4 hormone becomes T3 hormone every day, according to Pilo’s team’s estimation.

At the bottom of the table, in the yellow cells where averages are given, you’ll see the rough 20/80 split: 21% and 79%.

In the heat map colors, you see that the two right-hand columns are inversions or mirror images of each other in red and green.

The wide range is what should be noticed here, in addition to the compensatory nature of secretion (red) and conversion (green).

  • If you secrete 42% of your T3 supply, you will obviously convert T4 to obtain the other 58% of your T3.
  • If you secret 6.5% of your T3 supply, you will have to convert 93.5%.

Here’s an important implication for thyroid therapy:

What happens when you take away the thyroid gland of the person who is secreting 42% of their T3 from their thyroid, who happens to be patient #3, a 31-year-old male?

What if you gave Mr. Patient #3 only a daily LT4 hormone pill and said “simply convert this hormone to obtain all the T3 you need!”

What if you have been assured that any thyroid patient, including people with a fully fibrosed, atrophied, or surgically removed thyroid, will always obtain about 80% of the T3 of a healthy person?

You’d be very mistaken.

Standard LT4 monotherapy could steal up to 42% of daily T3 supply from a thyroid-disabled person who suffers inefficient thyroid metabolism.

In fact, by giving them LT4 monotherapy, this person may receive a post-thyroidectomy “T3-ectomy.”

A large chunk of this person’s T3 supply, 42%, would be removed from their body without their consent. But you’d be assured that the excess T4 you dosed them with was healthy.

Oh, you’ll say, “they are metabolically fine because their TSH is fine.” But wait — in thyroid disease and therapy, TSH is not a health outcome.

  1. TSH does not enter the T3 receptor in the nucleus of our cells, so you can’t trade lost T3 for normalized TSH.
  2. TSH is a driver of thyroid secretion only in people who have a thyroid healthy enough to secrete in response.

Why should any thyroid patient suffer even a 20% reduction in daily T3 supply, if dosing is supposed to be adequate as a thyroid gland replacement?

A biochemically normalized TSH due to mild oversupply of T4 is not a gift but a curse to people like patient #3 after thyroid disease or removal.

There is a good reason why circulating T3 levels are “topped up” by the thyroid gland.

Simple everyday changes like eating more “goitrogens” like broccoli, or going on a fast, can reduce our T4-T3 conversion rate.

The human species could not have survived in iodine-deficient regions of the world without the adaptation that increases TSH and produces goiter (a swollen thyroid gland) as it pushes the thyroid to secrete extra T3 to compensate for loss of T4.

Science has also now revealed that our T4-T3 conversion rate differs from organ to organ, tissue to tissue. The circulating level of the active thyroid hormone T3 is absolutely crucial for our organs that depend relatively more on circulating T3 and less on local conversion of T4 into T3.

Common genetic variations exist in DIO1 or DIO2 genes that can make our T4-T3 converting deiodinases function less efficiently. In mice that have these genes completely knocked out, we don’t see a deficit in circulating T3 levels unless the mouse’s thyroid gland is removed.

The survival of our species has depended on a flexible, TSH-regulated thyroid that secretes more T3 to compensate for wide genetic variation and health factors that hinder T4-T3 metabolism.

The total amount of T3 from peripheral conversion

Now let’s return to the tables and sort by another column, the amount of T3 produced by one’s T4-T3 conversion rate.

In the table below, look at the column with the yellow square on its heading.

Here, I used simple math to obtain the total daily “amount” of T3 in micrograms produced by T4-T3 conversion (rather than “rate”) of T3 from conversion, because Pilo calculates the rate by mcg / day per square meter of body surface.

I easily took the daily “rate” of T4 converted into T3 (the column on the left) and multiplied by the patient’s reported body surface area in square meters (this m2 data was reported in another table in Pilo, not shown here).

Now the pattern that appears in the left two columns is very different from the table sort above, where there was a perfect mirror between the red secretion column and the green conversion column.

You can certainly see a general pattern shown in the red column, with the darker/higher values at the top:

Here, the pattern is not so perfect.

On average, the less T3 the person obtained from estimated peripheral conversion, the more T3 they generated from thyroidal secretion.

However, once again, averages are deceptive.

Stark individual anomalies in the data are seen in the middle of the table with patients 9, 3, and 14, where reversals in the expected shading occur, revealing an occasional inversion of the direction of correlation.

First of all, the patient with the lowest amount of peripheral T3 (15.9 mcg/day, patient 2) did not have the highest T3 secretion rate to compensate for it.

  • Two other patients had higher thyroidal T3 secretion rates together with higher conversion rates.

The patient with the highest amount of peripheral T3 (41.5%, patient 12) did not have the lowest T3 secretion level (SR-T3, 11.3%).

  • Three other patients had lower secretion rates as well as lower conversion rates.

Why do human differences exist in the degree of secretion rate /conversion rate compensation?

In other words, “Why, in some people, do secretion and conversion rates not compensate as fully as expected?

It’s logical within the theory of thyroid hormone homeostasis.

Thyroid hormone economy is not static, but capable of adaptation and change.

Our cells are fueled by T3, and there’s only two ways our cells can get access to T3 hormone:

  • T3 is secreted by our thyroid gland directly into our circulation, or
  • T3 is converted locally via T4-T3 conversion in cells, which then transport most of that converted T3 back into the circulation so that it can enter other cells in other tissues (see my summary of Bianco et al, 2019).

Think about the need to turn up your home’s furnace in the winter and turn off the furnace in the summer.

Our circulating T3 is an essential part of our thyroid hormone “fuel supply” because it does not depend on variable local T4-T3 conversion rates.

  • When the body is increasing its overall metabolic rate, TSH rises, thyroidal T3 secretion rate rises and T3 from conversion rises. This happens during recovery from illness and increased caloric intake. (Van den Berghe, 2014)
  • When the body is lowering its overall metabolic rate, TSH lowers or remains stable, while T3 secretion rate lowers and/or T3 from conversion lowers. This happens during acute illness and fasting. (Van den Berghe, 2014)
  • When the body is maintaining metabolic homeostasis (there is no demand for change but a need to keep good balance), the T3 secretion rate compensates for the T4-T3 conversion rate, and the two are in complementary or inverse relationship. (Berberich et al, 2018)
[See Hoermann et al, 2020’s explanation (free PDF) of TSH “feedforward control” over T3 secretion (and T4-T3 conversion) along with a critique of outdated models not accounting for deiodinases.]

What are the implications for thyroid therapy?

People who don’t have a healthy thyroid gland are missing half the metabolic equipment needed for either secretion / conversion counterbalance on the one hand, or secretion / conversion mutual enhancement on the other hand.

Thyroid-disabled people don’t have all the equipment needed to maintain metabolic flexibility and homeostasis, especially if their thyroid hormone metabolism is handicapped, too.

Other studies prove that we, the thyroid-disabled, can’t enhance both secretion and conversion enough when our bodies need to increase our metabolic rate in response to environmental or health challenges.

For example, Gullo et al’s 2017 study demonstrated that can’t just get more T3 hormone supply in the cold season when we maintain the same LT4 dose all year.

As a result of thyroid loss, in the winter, the Free T3 falls significantly lower in patients without thyroids on LT4 monotherapy.

[Read the post providing Gullo’s data translated to “percent of reference range”]

Meanwhile, in winter, the people with healthy thyroids get a boost to their FT3 and maintain their FT4. They can turn up their metabolic thermostat to stay warm and maintain a mildly higher T3 required for health.

Why did even the thyroidless pepole’s FT4 levels drop so much in winter, despite an elevated TSH?

  1. Both T3 and T4 are vulnerable to “accelerating disposal of thyroid hormones in cold” (Lamichhane et al, 2018).
  2. They had no thyroid glands. They did not have the ability to synthesize T4 or T3 de novo.
  3. As thyroid hormone levels fell, clearance rates and other metabolic factors shifted to try to compensate, but without synthesis of new T4 and T3, they were unable to compensate to achieve the levels seen in healthy controls.

As Bianco et al, 2019 state, the higher T4 is no a metabolic compensation for a lower of T3. They explain that “a drop in plasma T3 will reduce TR [thyroid receptor] occupancy in most tissues as well.” The cells and tissues with less T3 occupying receptors are relatively hypothyroid. The only exception is that “cells that express DIO2” may have higher levels of T3 in them, but DIO2 is weakened as Free T4 rises, so the rate of T4-T3 conversion is reduced.

Therefore, the thyroidless population are not blessed by FT4’s abundance, but are cursed by the reduction of their FT3. This is the signature of a population whose TSH is regulated by T4 supplementation without a T3-synthesizing gland.

These are merely averages. If Pilo’s study of human metabolic diversity reveals the truth, there were extreme individuals in this data set, with far lower T3 levels, buried within the averages, who were shivering at night.

If our body needs to reduce T3 supply, that’s pretty easy. It is easier to lose or destroy than create. All our body needs to do is trust in Deiodinase Type 3 (DIO3 / D3) expression, which awakens as FT4 and FT3 rise above one’s individual metabolic range and wanders into mild thyrotoxicosis. This D3 enzyme will increase the rate of conversion of T4 to Reverse T3 and of T3 into T2.

This loss is what happens naturally in acute illness–the syndrome called Nonthyroidal Illness Syndrome (NTIS), or “Low T3 Syndrome” (LT3S).

The T3 concentration quickly plummets long before TSH and FT4 reduce concentration. This brings the metabolic rate down fast.

However, the body can’t stay in the low T3 state for long. Mortality risk is highest when T3 circulation is at its lowest and stays there too long.

Recovery from NTIS and the illness or injury that caused it depends on the timely replenishment of circulating T3. Recovery occurs as TSH rises, sometimes even above reference range, to restimulate the thyroid gland and refill the depleted T3 concentrations.

Unfortunately, thyroid-disabled people are equipped to enter NTIS, but they are handicapped on the T3 recovery / replenishment side of the equation. The assumption that T4 therapy is always enough to support NTIS recovery has led to the exclusion of thyroid-disabled people from almost all studies of NTIS mortality rates.

What are the implications of this scientific knowledge?

  • Some thyroid patients may need an external supply of T3 thyroid hormone, either temporarily during NTIS recovery, or permanently because of an underactive thyroid metabolism.
  • Some thyroid patients may need to be on the upper edge of their individual range of optimal thyroid hormone supply so that they can absorb the shock of minor to moderate bumps in the road.

Just as type 1 diabetes patients inject themselves with more insulin when needed, some thyroid patients need a T3 supply buffer in case we fall short.

We may not have a diabetes tool like a Dexcom sensor implant that beeps when T3 falls low, but it’s easy to diagnose a problem when we can’t fall asleep every night because our feet are like blocks of ice that never warm up.

Let’s bring the TSH into the mix now.

Learn more on Page 3:

  • How does TSH affect T3 secretion and conversion rate?
  • How do sex and age influence these rates?
  • What about health factors?
  • Solutions?
  • References

Pages: 1 2 3

Categories: Healthy thyroid axis

2 replies

  1. I have this in my blood test. All the symptons of low thyroid whit above range TSH but my Free T3 is also high on the range. No Hashimoto and my thyroid gland is perfect in the ultrasoud.

    • Dear Lucas, if your TSH is above range and your FT3 is high within range, it makes sense that you have a healthy thyroid gland pushing T3 higher. Your case looks like one of two things that come immediately to mind:

      1) the higher T3 seen in obese patients with “metabolic syndrome,” and

      2) people with Resistance to Thyroid Hormone often have the paradox of higher TSH along with higher T3 and T4.

      In your case I would suspect #1 before #2. Metabolic syndrome is MUCH more common. “Resistance to Thyroid Hormone” requires a genetic mutation.

      I wish I could link to articles on our blog on these two topics, but I haven’t had time to cover them yet, so all I can do is refer you to literature.

      Here is a reference for you on higher T3 + TSH in metabolic syndrome:

      Kim, H. J., Bae, J. C., Park, H. K., Byun, D. W., Suh, K., Yoo, M. H., Kim, J. H., Min, Y. K., Kim, S. W., & Chung, J. H. (2016). Triiodothyronine Levels Are Independently Associated with Metabolic Syndrome in Euthyroid Middle-Aged Subjects. Endocrinology and Metabolism (Seoul, Korea), 31(2), 311–319.

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