Thyroid T3 secretion compensates for peripheral T4-T3 conversion

In health, what happens when your tissues don’t convert enough T4 into T3 hormone? Your healthy thyroid secretes more T3.

The healthy thyroid gland’s synthesis of T3 de novo (from raw materials of iodine and tyrosine) under the stimulation of a healthy TSH can maintain your circulating T3 supply. This prevent tissues from becoming hypothyroid when they can’t convert enough T4 into T3 locally.

This principle has been demonstrated in human models in Pilo’s study in 1990, and several other scientific studies. It is

“the capacity of the hypothalamic-pituitary-thyroid axis to compensate for the lack of peripheral T4-to-T3 conversion.”

(Marsili et al, 2011)

The healthy TSH-stimulated thyroid has the flexibility to secrete more T3, when needed, to compensate for poor peripheral T4-T3 conversion (in tissues beyond the thyroid).

Scientists who observed the mouse’s thyroid gland secretion adapt to life without D1 and D2 enzymes, who could not convert T4 to T3, emphasized this lesson:

“the importance of the thyroid per se as a source of T₃.”

(Galton et al, 2009)

However, a common generalization expressed over and over in scientific articles dismisses the thyroid’s importance as a source of T3 in humans.

We are given the impression that peripheral T4-T3 conversion don’t vary much across individuals, and a human thyroid is not capable of adaptive compensation in its T3 secretion rate, because a reduction in conversion rate is unthinkable. The ratio for humans is expressed as if it is fixed in stone:

“20% of daily T3 comes from the thyroid,
80% from peripheral conversion of T4.”

This idea of an inflexible ratio is an inaccurate representation of statistical averages from a famous scientific research article from 1990. It’s a narrow-minded concept that requires correction from the article itself and from confirming studies.

This idea of limited thyroidal T3 secretion, of a fixed, inflexible thyroidal T3 secretion, is found all over thyroid therapy literature, such as in this passage in the American Thyroid Association (ATA) 2014 guidelines by Jonklaas et al:

“Approximately 85 mcg of T4 is secreted by the thyroid gland daily. Of the total daily T3 production of about 33 mcg in normal man, approximately 80% (about 26 mcg) arises from peripheral conversion from T4, and only about 20% (approximately 6.5 mcg) derives from direct thyroidal secretion (34).”

This passage begins by emphasizing T4 and its approximate contribution to daily T3 production rate, and ends by diminishing “only about 20%” from “thyroidal secretion.”

What is item “(34)” cited at the end of the passage? It is Alessandro Pilo and team’s famous 1990 kinetic study of T4 and T3 hormone economy in healthy humans (or as the ATA say, “normal man”).

Most people reading this passage will believe the ATA is providing accurate figures (85 mcg, 33 mcg, 26 mcg, and 6.5 mcg). No. They didn’t count on having a humble thyroid patient fact-checking their calculations.

Pilo’s study, which they cite, did NOT discover, as the ATA states, that “85 mcg of T4 is secreted by the thyroid gland daily.” Nor did it find that 20% was a good estimate of the rate of T3 secretion from all human thyroids. The ATA’s word “approximately” is no excuse. They give extremely precise numbers, and yet they are off by 15 micrograms of T4 based on Pilo’s article.

Why does it matter that they are off by 15 micrograms here or there?

Because such narrow calculations have become fundamental premises on which people have built many narrow, lopsided theories to defend their preferred therapy practices.

Thyroid therapy has become a game of numbers. When medicine tries to replace a flexible gland with a static dose of hormone, people’s health and well being are based on precise microgram doses, lab reference ranges, and theoretical concepts like ratios.

Our systems have to respect the wide ranges of individual variation that nature reveals and science has documented. If they misrepresent the wide variations in secretion and conversion rates as if they are narrow averages that apply to everyone, it can have devastating implications for individuals who aren’t statistically average.

How would you like to live with a suboptimal FT3 level for the rest of your life because your gullible doctor reveres the ATA and believes you are a “normal man” or woman who can live happily on a ratio of 85 mcg / day of LT4 to 6.5 mcg of LT3 as long as it normalizes your TSH?

What if, under the cover of the statistically normal TSH, this dosing strategy is not providing the T3/T4 ratio your thyroid gland would have provided in health?

The details from Pilo’s 1990 study are more accommodating of individual diversity than the ATA wants them to be.

In this old study of 14 healthy human beings, they estimated one person had 42% of their total T3 supply from their thyroid gland and 58% came from peripheral T4-T3 conversion.

• That’s not a 20/80 T3 secretion / conversion ratio. That’s more than 2x the 20% people are told.

In another patient in the same study, 6.5% came from their thyroid gland and 93.5% from peripheral conversion.

• That’s not a 20/80 ratio, either. That’s less than 1/2 the 20%.

Yet the idea of 20% of T3 supply from the thyroid is cited today over and over as if it is as universal as the law of gravity.

Sadly, squeezing a such a wide range of human variation into a static ratio is harmful when applied to millions of diverse individuals on thyroid therapy. It has caused great injury to those whose peripheral thyroid hormone metabolism produces a significant T3 deficit, people like the man whose thyroid had to step up its game and secrete 42% of his T3 supply. Not every woman or man fits the average “normal man” parameters.

Pilo’s study is by no means perfect, but its published data set is worthy of a detailed look in the new color-coded tables I provide in today’s post.

Summary / Abstract

Pilo’s aims and methods

First, here’s the basics of Pilo’s study.

It had nothing to do with deciding what dosage ratios of T4 and T3 hormone were appropriate for thyroid-disabled or thyroidless people. But that’s how it is often misused today, ever since Escobar-Morreale and team proposed clinical trials of thyroid hormone combination therapy based on Pilo’s averages.

Pilo’s team of researchers were trying to understand how much T4 and T3 were secreted and how much T4 became T3 outside the thyroid gland in healthy people with healthy thyroids who had a TSH between 1 and 2 mU/L.

To learn this, the researchers performed an intensive biochemical experiment involving radioactive-iodine-tagged T4 and T3 molecules ([125-I]T4 and [131-I]T3) injected into healthy patients. They attempted to distinguish the conversion of tagged hormones from the non-tagged hormones secreted by the thyroid gland to find out how much came from the thyroid gland.

Combining complicated mathematics, Sephadex gel filtration chromatography, and radioimunoassay testing methods, they measured hormone concentrations.

Based on these measurements, they used theoretical models to estimate each human subject’s global daily T4-T3 conversion rate (CR) and thyroidal secretion rate (SR) of T4 and T3 as fractions of the total amounts of circulating T3 and T4 in bloodstream.

Key flaws in the study

Contemporary thyroid science’s overreliance on this flawed and outdated study, which has never been replicated, is frankly puzzling.

A lot of these scientist’s work was based on refining older theoretical models of thyroid hormone exchange across “compartments” in the human body. Their models were rough. They embedded at least five major inaccuracies and blind spots:

1. Their study pre-dated our modern understanding of transmembrane thyroid hormone transporters and the three thyroid hormone deiodinases. These are two major pillars of the thyroid hormone economy. As a result, every time we cite 20/80, we are returning to this incomplete, outdated metabolic model.

2. There is no sign of any investigation into the subjects’ conversion of T4 into “Reverse T3” (RT3), which would have made their calculations more precise. By verifying the concentrations of the 3rd most abundant thyroid hormone, the most significant “byproduct” of T4 metabolism, their theory-based mathematical estimates of peripheral T3 would have been confirmed.

Measuring both RT3 and T3 is like measuring how much heat and light is produced from a light bulb when measuring its energy efficiency.

Without this simple check and balance, one wonders whether their mass chromatography techniques could have distinguished T3 from RT3 molecules, given that these two hormones have the same molar mass of 650.97 (according to PubChem).

3. They also did not fully take into account the intrathyroidal conversion of T4 into T3 as blood flows through the thyroid (See Berberich et al, 2018), strangely assuming that thyroid “secretion” was synonymous only with “synthesis,” and that “conversion” was only peripheral outside the thyroid gland.

4. They didn’t account for the way TSH hormone can powerfully shift ratios of T3 and T4 synthesis (Citterio et al) and T4-T3 conversion. They didn’t study humans at various TSH levels to observe this conversion-boosting factor in action. They only studied people with TSH in the narrow range from 1-2 pmol/L. They also used a TSH assay that only gave one digit after the decimal point: likely an old, 2nd generation assay.

5. Their subjects were iodine-overdosed every day during the study. This was a common practice in such kinetic studies of the era because it flooded the body with non-radioactive iodine and lowered the percent of injected radioactive iodine that could be recirculated through the thyroid gland as T4 and T3 during the 8-day experiment.

However, acute iodine overdosing also biases T4 and T3 secretion rate from the thyroid–the rate their experiment was trying to discover.  

Despite these flaws and others revealed below, the details and insights found within Pilo’s study are still valuable.

One should not throw away gems of truth just because they are rough-hewn. Older studies in thyroid science still have a lot to say.

Findings

Older studies like Pilo’s often provided detailed data tables in their articles, with patient-by-patient data, not just averages and ranges. This detail enables intelligent analysis of human variation. This is invaluable to clinicians who treat individuals, not averages.

Pilo’s article contains many complex tables, like Table 2 shown below. (No, dear reader, you don’t have to read the fine print! I’m just giving you an idea of how much data is in Table 3 alone.)

Data tables like this one form the basis of my reformatted tables below.

From this table, I’ve obtained the Secretion Rates of T4 and T3 (SR-T4, SR-T3) on the right two columns, and the daily Production Rate of T3 (PR-T3) per day, per square meter of body surface. Other data used below come from their additional tables.

Thyroidal T4:T3 Secretion Rates and Ratios

One of the major misrepresentations of Pilo’s article comes from relying on the average thyroidal secretion rates and ratios.

The mere averages do not begin to represent the wide range of diverse data.

In an earlier post, I provided a scatterplot to show how ridiculous it is to imagine that “the” thyroid gland secretes approximately 14 micrograms of T4 for every microgram of T3, an average ratio derived from this study.

Each person’s T4-T3 secretion ratio is a blue dot.

Where is the pattern?

Do you see a central tendency or cluster of dots?

Does the dotted trendline help you see a trend in this constellation?

Case seven (C7) represents a ratio closest to the statistical average ratio of 1 mcg T3 to 14.5 mcg T4. Could you have guessed that dot was the average?

This is a situation in statistics when an average is not meaningful.

Table view

The dots in the scatterplot graph above correlate with the data in the right-hand column in the table below.

As you can see, patient 3 (in row 3 of the table body) has a thyroidal secretion ratio of 6.4 micrograms of T4 per microgram of T3.

Sorting a heat-mapped table by a single column helps one see patterns, if they exist.

This table’s data is sorted by the middle column in green that has the smooth gradation of white at the top to dark green at the bottom: the T4 secretion rate.

The yellow-colored cells in the averages are derived from Pilo’s Table 3 above. The blue averages are calculated from his data using simple math.

As you can see in the graph below, once I multiplied Pilo’s data on the daily thyroidal secretion rate of T4 by the surface area of the 14 patients’ bodies in square meters (given elsewhere by Pilo), I obtained the second green column of data showing these patients’ T4 secretion amount per day.

The average T4 secretion in this small population is not 85 mcg as the ATA said (Jonklaas et al 2014, quoted above), but 99.4 mcg/day.

However, before we jump to the conclusion that we should dose LT4 100 mcg per day to imitate the average daily amount of thyroid secretion, here’s an important fact to remember:

Thyroidal secretion of T4 or T3 is not physiologically or pharmacologically equivalent to oral dosing of thyroid hormone medication.

Let’s consider the adjustments that make today’s standard levothyroxine monotherapy incapable of approximating natural thyroidal secretion.

First of all, the dosing rate per day must be higher than the healthy human secretion rate per day partly because LT4 is poorly absorbed through the small intestine in the GI tract (Wiersinga et al, 2012).

Secondly, because thyroid patients with damaged or missing thyroid glands talking levothyroxine alone have no replacement for their T3 secretion, they need to achieve FT4 levels that are significantly higher than the population average (Jeon et al, 2019). This high-normal FT4 is necessary to maintain enough converted T3 in circulation to produce an euthyroid state when judged by TSH alone.

Even a mildly elevated FT4, once honestly called “chemical hyperthyroidism,” has long been considered acceptable in levothyroxine thyroid therapy (Rendell & Salmon, 1985). It’s essential to provide sufficient thyroid hormone even when FT4 in the top 1/5th of statistical reference range is a risky state associated with “sudden cardiac death” in males (van Noord et al, 2008).

As you can see, our traditions of levothyroxine therapy already prove that endocrinologists treating hypothyroidism cannot make dosing (and its biochemical results) perfectly imitate the average secretion rates and ratios found in untreated human beings.

Endocrinologists have accepted both the abnormality and the health risks within their preferred mode of LT4 monotherapy.

A ratio of 0% T3 from thyroidal secretion to 100% T3 from peripheral metabolism is physiologically incorrect, but it has been deemed acceptable in LT4 monotherapy.

Therefore, limiting either levothyroxine therapy or combination T3-T4 thyroid therapies strictly to the narrow statistical averages of thyroidal secretion found in Pilo’s healthy patients is unacceptably restrictive.

Yet this is exactly what our contemporary guidelines for T3-T4 combination therapy attempt to do (Wiersinga et al, 2012). It is a double standard to permit the unnatural, risky aspects of levothyroxine monotherapy while strictly forbidding all LT3 doses higher than the “physiological” average represented by patient #7 alone.

Bar graph of T3 secretion

Now instead of focusing on T3:T4 ratios and T4 secretion, let’s look at T3 secretion data using a bar graph.

The myth is that 20% of our daily T3 supply is secreted from the thyroid gland.

There is no central tendency in the data.

Which patient comes closest to the 20% average? It’s patient 8 this time.

Therefore, saying “the thyroid secretes 20% of one’s daily T3 supply” is extremely misleading.

Let’s do the endocrine math.

If your thyroid secretes a certain amount of T4 into your blood over a 24 hour period, you may convert anywhere from 16.9% to 42.9% of this T4 into T3 hormone (conversion “rate,” shown later, in graphs below).

This conversion “rate” of micrograms per day per meter of body surface area, when multiplied by each research subject’s body surface area, yields the net “amount” of thyroidal T3 in micrograms per day for each person.

You can then express the “thyroidal” micrograms of T3 as a percentage of their total micrograms of T3 produced per day. That’s what you see in the blue bar graph above.

The thyroid glands in this study contributed between 6.5% to 42.0% of the total daily T3 supply.

That is, you might be lucky to get that much T3 from your thyroid IF your TSH is between 1-2 and you have a healthy thyroid gland, as these 14 subjects did.

Even in a person whose T4 secretion is well regulated by a statistically-average TSH like these people’s was, it’s a roll of the dice how much T3 they’ll convert from their T4 in peripheral tissues. This wide-ranging, individualized conversion rate determines how much T3 their gland secretes daily to compensate.

Continue to Page 2:

• The shifting percent of T3 from peripheral conversion
• The total amount of T3 from peripheral conversion
• How does TSH affect secretion and conversion rate?
• How do sex and age influence these rates?
• What about health factors?
• Solutions?
• References

Page 2

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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.
3. TSH secretion is not a proxy for T3 levels in the cardiovascular system, gastrointestinal tract, or the Achilles tendon. It is not even a proxy for T3 supply in blood or the FT3:FT4 ratio in blood.

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 to keep them from falling too low for our individual demands.

Simple everyday changes like eating more “goitrogens” like broccoli, or going on a fast, may 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)

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.

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 explain, a higher T4 is not 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.”

(Bianco et al, 2019)

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. However, DIO2 is weakened as Free T4 rises, so the rate of T4-T3 conversion can be reduced in D2-expressing cells.

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

Gullo’s lower-T3 thyroid patients in winter are merely statistical 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, whose feet stayed cold all night long during winter in Sicily.

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 natural T3 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 metabolically equipped to enter NTIS, but they are handicapped to exit from it. They may struggle with the T3 recovery / replenishment side of the visual model above. 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

Page 3

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How does TSH affect T3 secretion and conversion rate?

This study’s data shows that TSH is by no means a proxy for T3 secretion and conversion rate, even in the healthy.

You can see it in this table — now re-sorted by FT3 in pg/ml, which they measured before the 8 days of iodine dosing and injection of the radioiodine-tagged T4 and T3.

As you can see, there is no pattern in relationship to this middle FT3 column that ranges from 2.6 to 5.7.

The T3 secretion/conversion ratio in the final two columns used to show that smooth gradation from dark to light colors.

Now when you re-sort by the TSH column, the TSH does not correlate with T3 secretion or T3 conversion ratios at all.

The lack of a pattern is metabolically significant.

Why doesn’t TSH fully regulate the T3 portion of thyroid metabolism? Because our T3 supply doesn’t all depend on TSH.

• Deiodinase enzymes D1, D2, and D3 in tissues throughout our bodies are in control of peripheral thyroid hormone conversion.
• Deiodinase type 2 (D2) can be upregulated by TSH, but it will still function when TSH is suppressed.
• Deiodinase enzymes D2 and D1 in the hypothalamus and pituitary control TSH secretion locally by negative feedback. The T4-T3 conversion rate in these central organs is different from the conversion rate in other organs.
• Powerful feed-forward mechanisms can signal TSH to take a leading role in shifting metabolic rate higher or lower, such as during adaptation to cold, or recovery from nonthyroidal illness (NTIS).

Central regulation of TSH is just as complex as thyroid metabolism; it is not just a passive hormone regulated by thyroid hormone feedback.

Instead of trying to understand the complex systems that regulate Free T3 levels, the old paradigm of thyroid therapy decided to focus on TSH and ignore Free T3 altogether.

The body never ignores FT3.

It’s foolish to ignore what we don’t understand.

Even though T3 is not the most abundant hormone, it is the most important and powerful thyroid hormone. In health, it is so important that Free T3 blood levels are individually customized.

T3 is not singlehandedly regulated by the TSH level, but by the complex metabolic dance between thyroidal secretion and peripheral conversion seen in the graphs above this one.

This individual variation in FT3 levels accords with the phenomenon observed since Anderson and team published an article in 2002 showing that each individual has an unique “optimal” level and ratio for FT3 and FT4 thyroid hormones in blood, and their individual ranges are much narrower than the population-wide reference range.

A later study by Ankrah-Tetteh in 2008 in ten healthy people discovered how carefully each individual’s body regulated their FT3 supply.

Overall,

Ankrah-Tetteh found that each individual’s TSH and FT3 pair was unique and tightly controlled.

The image from Ankrah-Tetteh below shows individualized FT3 levels in relationship to TSH.

You can see by the varying sizes and heights of the rectangles of data that in each of these 10 patients,

• the TSH levels are generally flatter and in the lower half of the reference range. They don’t seem to relate to the FT3 levels in a consistently inverse way as one may expect.
• The TSH was not inversely related to FT3 as one would expect, but rather mildly positively related to FT3 in some patients.
• the Free T3 levels are highly varied in different positions across the full reference range for the population.
• Each individual does not wander far from their TSH and FT3 anchor points over time, and each stays within a narrow range.

Based on mathematical calculations, the “index of individuality” (IOI) for FT3 was 0.38.

This is low, and the result is statistically significant in an interesting way. According to Petersen et al, 1999,

• Any low IOI below 0.6 makes the width of the population reference range significantly wider than the range of variation for each individual.
• Such a low IOI means that individuals’ levels are not tightly clustered around an average, but vary significantly from each other within the population.
• A low IOI also makes the FT3 level in health very dependable, with not much change expected from one test result to the next. The FT3 level is just as dependable as FT4 in health, since the IOI for FT4 was 0.41.

In contrast to FT3, the IOI for the TSH in Ankrah-Tetteh’s study was significantly higher, at 0.68, according to their calculations. This is because TSH lab results in the population were more tightly clustered around a mean of 1.58 mU/L, which is consistent with the average TSH in larger populations.

Therefore, Pilo’s data are consistent with the modern research on TSH and thyroid hormone level differences between individuals.

All Pilo’s study could not do was measure change over time, data which studies like Ankrah-Tetteh et al’s and Andersen et al’s now provide.

Human variation within a wider population range is the principle of thyroid hormone economy.

Optimal FT3 thyroid hormone levels and FT3:FT4 ratios are highly individualized.

A FT3 level anywhere within the population reference range is not precise enough for the health of the individual.

Unfortunately, basic flaws of Pilo’s study prevent us from understanding how TSH influenced T3 secretion, T4-T3 conversion, and overall thyroid hormone supply:

• No reference ranges were given for TSH, FT3 or FT4, so we cannot see how levels varied across the reference range.
• Nobody in Pilo’s study had a TSH level outside the narrow range of 1-2 mU/L, so it was impossible to see how TSH variation could affect the results.
  • We now know that higher TSH levels seen in untreated hypothyroidism can push a failing thyroid to secrete and convert relatively more T3 than T4 (Citterio et al, 2017; Hoermann et al, 2020).
• Pilo’s study could not account for huge circadian rhythms seen in TSH, and their article did not specify the time of day at which baseline TSH was measured.

How do sex and age influence these rates?

Next, let’s look at a fundamental feature of Pilo’s data–their unbalanced selection of 14 young, old, male, and female participants.

In a study of only 14 people, it’s difficult to come to conclusions about how sex may or may not be a variable in secretion and conversion rates of T4 and T3.

However, we can notice the bias in selection of participants:

• the smaller number of women (5) were generally older (43-59, average 49.4)
• the larger number of men (9) were generally younger (19-65, average 35.7).

Does the sex bias in participants bias the calculated averages in Pilo’s study?

Let’s take a look.

The table below is sorted primarily by sex and secondarily by age.

The younger women had more T3 coming from their thyroid gland, and the oldest woman had the least thyroidal T3 secretion rate among all subjects in the study.

Hmm, why did the older women have the lowest T3 secretion rates?

Among women, the secretion/conversion ratio was 16% / 84%,

• but if you remove one outlier, the youngest 43-year-old patient #2 with a high T3 secretion of 36.2%, the ratio would be 11% / 89%.

Among men, the secretion/conversion ratio was 24.1% / 75.9%,

• but if you remove the highest outlier, the 31-year old male patient #3 with a high T3 secretion of 42%, the ratio would be 21.8% / 78.2%

This next table was sorted by Age, allowing Sex to fall where it may:

There is clearly an age pattern in the secretion/conversion ratio. The older participants between 44 and 59 years of age had less T3 coming from their thyroids, according to Pilo’s team’s estimates.

Exceptions existed in a few men, such as the 36-year-old male and the 20-year-old male who had significantly lower T3 secretion ratios than the rest of their cohort, and I’ve already explained why these anomalies exist.

Surprisingly, the oldest patient in the cohort, a 65-year-old male, had quite a robust thyroidal T3 secretion of 24.9%.

What are the implications of this imbalanced group?

Older women represent the majority of patients with thyroid disease.
They are the people whose thyroid therapy is being influenced by misrepresentations of Pilo’s findings.

The younger men’s data compensated for the older women’s data, making the study’s averages less applicable to older women.

Middle-aged women’s health problems during thyroid therapy can too easily be blamed on stress, diet, exercise, and sex hormones.

One can only wonder how different the “average” 20/80% ratio estimate would have been with improvements in sampling and interpretation:

• a larger sample size,
• a balance of both sexes,
• a balance of ages, and
• the choice to specify age- and sex- specific ranges of thyroidal secretion and conversion.

What about health factors?

Finally, let’s ponder how health factors may have influenced the wide human diversity seen in Pilo’s estimates.

Pilo’s article gave no information about how they screened their 14 patients for health factors.

Many factors could lower T3 secretion, such as:

• Mild central hypothyroidism. TSH secretion rate may be too low in people with genetic handicaps in pituitary TSH signalling, permanent damage to the central glands, and even degenerative diseases such as “empty sella” and autoimmune pituitary disease. Central hypothyroidism varies in severity from person to person and will hinder both T4 and T3 secretion.
• An undiagnosed nonthyroidal illness. Measuring Reverse T3 would have revealed whether any of these people were having even a mild case of “Low T3 syndrome” in which the TSH is normal but T3 drops while RT3 rises above the healthy mean.
• Iodine excess. Perhaps some patients with lower body weight had a more extreme reaction to the drops of Lugol’s iodine that all patients were forced to take during the 8 days of the study.
• Substances that limit T4-T3 conversion.
• DIO1 and DIO2 genetic handicaps that changed peripheral conversion rate.

Unfortunately, this study showed only biochemistry, not health outcomes.

It did not measure biomarkers that are sensitive to circulating T3 thyroid hormone and are commonly used to verify tissue euthyroid status, such as

• heart rate,
• body temperature,
• cholesterol,
• ankle reflex,
• creatine kinase,
• liver health,
• bone metabolism biomarkers,
• kidney health,
• mental health, or
• cardiovascular health.

(Ito et al, 2017; Meier et al, 2003)

Solutions?

1. Respect T3 flexibility and diversity.

Spread awareness of Berberich et al’s 2018 update on Pilo’s study, which acknowledges the wide flexibility of thyroid homeostasis.

“the HPT axis is a much more dynamic system than has been previously thought. In particular, the interrelationships between FT₃, FT₄, and TSH are less constantly fixed, rather conditional and contextually adaptive.”

(Berberich et al, 2018)

2. change the mantra.

State the wide range!

3. Study how to optimize each thyroid patient’s FT3 and FT4

This study by Pilo is not focused on thyroid therapy.

It’s about the “normal, healthy” TSH- and thyroid-gland-driven thyroid hormone economy.

In thyroid therapy, each patient has unique thyroid gland disabilities.

Each patient has unique thyroid metabolism handicaps.

Only recently have researchers begun to study how to optimize FT3 levels during thyroid therapy to achieve tangible health outcomes:

• Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019). Individualised requirements for optimum treatment of hypothyroidism: Complex needs, limited options. Drugs in Context, 8, 1–18. https://doi.org/10.7573/dic.212597
• Ito, M., Miyauchi, A., Hisakado, M., Yoshioka, W., Kudo, T., Nishihara, E., Kihara, M., Ito, Y., Miya, A., Fukata, S., Nishikawa, M., & Nakamura, H. (2019). Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients. Endocrine Journal, 66(11). https://doi.org/10.1507/endocrj.EJ19-0094
• Ito, M., Kawasaki, M., Danno, H., Kohsaka, K., Nakamura, T., Hisakado, M., Yoshioka, W., Kasahara, T., Kudo, T., Nishihara, E., Fukata, S., Nishikawa, M., Nakamura, H., & Miyauchi, A. (2019). Serum Thyroid Hormone Balance in Levothyroxine Monotherapy-Treated Patients with Atrophic Thyroid After Radioiodine Treatment for Graves’ Disease. Thyroid: Official Journal of the American Thyroid Association. https://doi.org/10.1089/thy.2019.0135
• Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018). Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 126(9), 546–552. https://doi.org/10.1055/s-0043-125064

If we really want to respect natural human diversity, flexibility and adaptation in thyroid hormone economy, we have to give doctors the tools to optimize Free T3 to the individual using FT3 and FT4 evidence.

We don’t need to do fancy genetic studies to identify why some people do not fare well on TSH-normalized therapy using LT4 alone or fixed ratios of T3-T4 combination therapy that supply limited T3.

All we need to understand is that some individuals require more T3 than others, and that our T3 needs can change over time as our bodies and metabolic demands change throughout life.

Let’s respect that the individualized thyroid hormone economy may require a wide diversity of thyroid therapy approaches, just as each person’s T3 secretion and T4-T3 conversion rate adapts to challenges like iodine supply, childhood, pregnancy, cold climates, and nonthyroidal illness.

References