The TSH-T3 disjoint in thyroid therapy

The TSH-T3 Disjoint

There’s a deep lie behind today’s TSH-based definition of “euthyroid” status and today’s policies of TSH normalization in therapy.

The lie is that the loss of the thyroid and the initiation of thyroid hormone dosing has NOT altered and skewed natural TSH-FT3-FT4 hormone relationships.

Yes, thyroid disease and therapy DO alter and skew these functional hormone relationships.

Taking the analogy of relationships, who nowadays would believe that a husband’s satisfaction with his marriage determines his wife’s satisfaction with her marriage?

In a diseased relationship, if you listen to both the husband and wife, you’ll see there’s a fundamental disjoint between the way they interpret their relationship.

In thyroid disease and therapy, the thyroid gland and TSH are separated and estranged and can no longer work in partnership to supply thyroid hormone.

TSH can now become like a failed husband: biased, selfish, impotent, and blind to the body’s true T3 status. No magic pill is going to fix this marriage. There’s a divorce. A disjoint. The “feedback loop” is not a closed loop anymore. It’s a one-sided relationship, like some marriages.

Doctors do not yet realize how deeply our thyroid disease and its therapy has affected us. The replacement of a thyroid gland with a thyroid hormone pill is not just incapable of restoring normal HPT axis function. The pill also fundamentally alters the HPT axis.

This is the “TSH-T3 disjoint” in thyroid therapy.

This is the disjoint that the scientists Hoermann, Midgley, Larisch and Dietrich and team have helped to identify and quantify in many journal articles, starting in 2013.

When does the TSH-T3 disjoint occur?

The disjoint is seen in the contrasting TSH-T3 hormone relationships of between two groups of people:

  • A) UNtreated people in all thyroid hormone status categories (hypo, euthyroid, hyper), and
  • B) LT4 thyroid-hormone-treated people with any type of hypothyroidism.

We all know that in the normal “HPT axis” (hypothalamus – pituitary – thyroid axis), TSH and Free T4 shift inversely. That doesn’t change in thyroid therapy.

What does the TSH-T3 disjoint look like?

Hoermann et al, 2013

Title: “Is pituitary TSH an adequate measure of thyroid hormone controlled homoeostasis during thyroxine treatment?”

This study analyzed data from 1,994 patients.

They were classified into five groups:

  • Group 1 consisted of 1,159 untreated people
  • Group 2 consisted of 254 people taking 50-75 mcg/day LT4 /Levothyroxine
  • Group 3 consisted of 343 people taking 100-125 mcg/d Levo
  • Group 4 consisted of 188 people taking 150-200 mcg/d Levo
  • Group 5 consisted of people being treated only with iodine (data not shown here; see their full article for more information).

The following TSH-FT3 graphs in their Figure 1, shown below, reveals how different these populations are. (Images are reproduced within Canadian copyright “fair dealing” and US copyright “fair use” for purposes of education and review: See info.)

The disjoint in standard T4 monotherapy (Synthroid, Levothyroxine, Eltroxin) is most clearly illustrated in the following article’s quotations and graphs.

As you can see in the graphs above,

Patients in Group 1 cluster around an average FT3 of around 4.0 pmol/L. It looks like a bull’s eye.

On the Y axis the TSH scale has been transformed (log TSH) so that values can be graphed.

Group 1’s trendline is flat (horizontal), showing that when medication does not interfere with the HPT axis, the TSH – FT3 relationship is expressed this way.

Keep in mind that there are 1,159 dots in the graph for Group 1.  You can’t see it, but many people’s dots are overlapping each other in the middle of the bulls eye, so it’s more concentrated than it seems.

(NOTE: You’d need to see other graphs in other research articles to learn that FT3 temporarily goes lower in illness, and it goes higher only in rare occasions like Graves’ disease.)

Notice that a bull’s eye pattern of dots is not the same as the negative association that exists between FT4 and TSH (when TSH goes up, FT3 does NOT go down in Group 1, but it does in Group 2, 3 and 4.)

In fact, in undosed people, the average FT3 maintains itself while TSH rises within range! Although it may seem counterintuitive for this hormone to maintain itself on average as FT4 falls, this occurs because sometimes the body needs to raise FT3 to compensate for falling FT4 in order to maintain T3 receptor signaling in cells.

Why doesn’t FT3, the body’s most essential hormone correlate with TSH in a state of health?

Sometimes in medicine, a lack of correlation is a signal that something important is interfering with an expected correlation.

A lack of correlation is not an excuse to throw out either TSH or FT3 as clinically insignificant.

What is statistically insignificant may still be clinically significant.

The wrong answer (promoted since the early 1980s) is the misguided concept that “FT3 does not correlate because circulating FT3 is unimportant, while only intracellular T3 is important.”

It’s the wrong explanation because so many facts express circulating FT3’s power over thyroid status and health outcomes:

  • High FT3 in blood despite high-normal FT4 in people with toxic thyroid nodules, Graves’ disease, and T3 overdose can lead to hyperthyroidism. The body responds to an isolated excess of circulating FT3.
  • Low FT3 in blood, even despite normal TSH and normal FT4, is highly associated with mortality and morbidity in illness. The body responds to an isolated lack of circulating FT3.
  • In early thyroid failure and iodine deficiency, some people maintain euthyroid status despite low FT4 — only as long as their FT3 is high enough in reference to compensate for low FT4. The body responds to maintenance of normal circulating FT3.
  • In people on long-term T3 monotherapy for years or decades, the body and brain are maintained in a state of healthy euthyroidism even though FT4 is undetectable in blood. The body even responds to FT3 in the complete absence of FT4.

So, one cannot dismiss the metabolic significance and power of circulating FT3 by saying “only intracellular T3 matters.”

FT3 gets transported into cells, and some of that FT3 will bypass metabolizing enzymes and get into receptors. Of course T3 is not just created within cells from T4-T3 conversion.

Now think about the logic being used to dismiss circulating FT3 and ask yourself — why is this logic rarely applied to FT4?

How is reasonable to imagine that “intracellular vs. extracellular” argument does not dismiss FT4?

If you think about it logically, FT4 has an intracellular metabolic journey. If all FT4 did was float in blood, it would never get metabolized to T3 or RT3 or any other T4 metabolite like T4-Sulfate or Tetrac. FT4 is also an intracellular hormone, even if it “dies” via metabolic clearance soon after entering a cell expressing an enzyme that can convert it.

Of course various things can happen to FT3 and FT4’s metabolism after they get carried into cells. Of course we can’t see how much FT4 is turning into Tetrac or T4-glucuronide.

We don’t throw away the FT4 test despite our blindness to its intracelluar fate, and why not? Because statistics correlates it with another hormone that scientists decided to value more than our body values FT3. They decided to value TSH for its statistical correlations, despite its apparent lack of control over populations’ circulating FT3 trends. This is a medical-statistical bias, not an objective way of thinking about hormone function in biology.

Metabolic logic and clinical experience all agree — the levels of both circulating hormones matter, regardless of a population-wide lack of correlation between FT3 and TSH in healthy, undosed people with healthy thyroids.

So, back to the question we go with the correct premise: since the body does care a lot about circulating FT3, why isn’t FT3 mathematically correlated with TSH in healthy undosed populations? This is TSH, the hormone that we are all taught to look at as the regulator of thyroid status!

This lack of correlation occurs because the healthy-thyroid body’s FT3 requirements are dictated by other factors:

  • In un-dosed thyroid biology, FT3 is not adjusted by TSH alone.
  • Nor is FT3 adjusted by extrathyroidal T4-T3 conversion alone.

Adjustment of circulating FT3 is so important that there are many complex backup systems involved, and the healthy thyroid gland is an essential backup system.

A host of factors keep FT3 optimal for the individual because it is so essential to human health.  You have to consider concurrent FT4 levels and the individual’s unique metabolic demands.

But this FT3-defense system is lost in thyroid disease and thyroid therapy.

What does this all mean? Hoermann and team say …

The significance of these findings was analyzed in their “Discussion” section:

“In untreated euthyroid subjects, the gradient of the correlation line relating FT3 and log TSH is flat, but in subjects treated by T4 monotherapy, the relationship is different in all cases, the gradient increasing with hormone dosage.”

(Hoermann et al, 2013)

Anyone can see the FT3-TSH relationship is a “flat” line of correlation, but the line is steeply angled in LT4 therapy.

The disjoint became larger with larger LT4 doses.

This means something very significant for TSH testing during therapy — it is no longer an accurate measure of euthyroidism:

“This suggests that the balanced relationship between the thyroid hormones themselves and TSH, evident in untreated euthyroids, no longer applies.”

(Hoermann et al, 2013)

One cannot trust TSH to speak for FT3 levels during levothyroxine therapy, just as you can’t trust a husband to speak for his estranged wife.

“[It] shows that in monotherapy added increments of T4 are progressively more effective in suppressing TSH production, but simultaneously less effective in restoring FT3.”

(Hoermann et al, 2013)

As T4 doses rise (presumably in people who have poorer thyroid function), the Free T4 suppresses TSH but becomes less effective at maintaining healthy levels of FT3 in blood.

“Obviously, this is a consequence of the decreasing ability of thyroid homoeostasis
to maintain the normal interrelationships between T3, T4 and TSH.”

(Hoermann et al, 2013)

“Thyroid homeostasis” is a term that describes various aspects of the healthy HPT axis such as thyroid hormone conversion and various feedback loops.

Clearly, the “thyroid homeostasis” becomes increasingly handicapped in people with higher LT4 doses.

“Hence, the results indicate that the observed disjoint between the thyroid/pituitary FT4–TSH feedback mechanism and T3 production noted in hypothyroidism (whether inadequately or untreated) is not fully restored even when sufficient T4 is given to regain an apparently euthyroid state.”

(Hoermann et al, 2013)

Thyroid therapy that normalizes TSH does not necessarily restore healthy levels of Free T3.

And you call my normal TSH “euthyroid”?

People use the TSH range to mistakenly call these people “euthyroid,” but that is a deeply flawed human interpretation because the definition is T3-blind.

It does not mean they are truly euthyroid in all their bodily tissues. It means their TSH secretion rate has been medically manipulated to meet arbitrary human-instituted targets, while concealing global FT3 losses.

Thyroid therapy even creates paradoxical relationships that can’t be classified within the standard TSH-T4 definitions of euthyroidism:

“In several cases, this results in a classification mismatch, for example placing ~ 10% of patients on moderate T4 doses that are judged euthyroid according to their TSH measurements below the FT3 reference range.”

(Hoermann et al, 2013)

In other words, these patients are mistakenly judged “euthyroid” — but they look like cases of “nonthyroidal illness” or “Low T3 syndrome.”

These are states in which critical illness is associated with loss of T3 below reference range while TSH remains normal.

These FT3-starved people have the same normal TSH, low FT3 and normal FT4 biochemistry of people who are severely ill and at great risk of death!

Since when is an average FT3 hyperthyroid?

At the other end of the spectrum, when trying to resolve the FT3 deficit with LT4 therapy, you may get suppressed TSH without true hyperthyroid status:

“Higher L-T4 doses maintained FT3 within its reference limits, though frequently only in conjunction with suppressed TSH.”

(Hoermann et al, 2013)

Outside of the context of thyroid therapy, a suppressed TSH is never the price you have to pay for merely “statistically average” FT3 levels.

But that lower TSH is what’s often required in thyroid therapy to raise the FT3 up to, or above, mid-reference, when you lack thyroid tissue.

What causes this TSH-FT3 disjoint?

A disjoint between Central vs. Peripheral T4-T3 conversion rates.

  • “Central T3” is the level of T3 activating hypothalamus and pituitary receptors, which regulates TSH secretion.
  • “Peripheral T3” is the level of T3 in bloodstream that exchanges with all tissues in the human body and activates receptors in the nucleus of cells in every other organ and tissue, from the hair on your head to the tip of your toe.

In thyroidless LT4 patients, Free T3 can only be created by T4-T3 conversion within cells and tissues. Obviously, no T3 can come from the thyroid gland if you don’t have one.

The cells that convert T4 into T3 all over the body gradually exchange a significant portion of their converted T3 hormone with bloodstream so that it can be recirculated and used by other tissues and cells.

This is what makes the FT3-FT4 ratio a good measure of peripheral T4-T3 conversion efficiency as well as an index of T3 supply to the whole body. You cannot dismiss the biological significance of blood levels of FT3.

In thyroid therapy, peripheral conversion rates can be low because the main enzyme that converts T4 to T3, Deiodinase type 2 (D2), becomes progressively “ubiquitinated” or deactivated as Free T4 rises. Essentially, the T4 hormone that requires conversion can easily overload the bloodstream during thyroid therapy, and as too much FT4 is carried into D2-expressing cells, it slows down the peripheral T4-T3 conversion rate by that enzyme.

Meanwhile, paradoxically, as Free T4 levels rise in bloodstream, the “central” organs, the hypothalamus and pituitary, can increase or maintain their T4-T3 conversion rate, because ….

The central organs’ local D2 enzyme does not seem to suffer from ubiquitination! Scientists like Hoermann and team have puzzled over why this disjunct between central and peripheral conversion rates exists. Some scientists have theorized that these central organs’ unique “super-converter” status is likely built into our bodies. The unique roles of the hypothalamus and pituitary are to be co-regulators of a thyroid gland whose main product is T4 hormone. These glands must remain sensitive to T4 levels even when they are higher, otherwise they could not adjust TRH and TSH as FT4 rises. Therefore D2 in the pituitary functions differently from D2 in any other tissue (Christoffolete et al. 2006).

Meanwhile, as the hypothalamus and pituitary are focusing on metabolizing FT4 via their robust D2 enzyme, they are not sensitized to respond to concurrently lower FT3 levels in blood while FT4 remains normal.

These central glands are not intelligent beings! They haven’t gotten the memo that the thyroid is damaged, dead or gone. Central glands operate mechanically by presuming (incorrectly) that there’s still a thyroid gland assisting in maintaining FT3 levels at a given level of FT4.

This leads to the final piece of the puzzle:

We, the thyroid-disabled, have lost our “TSH-T3 shunt.”

We have a TSH-T3 disjoint because to varying degrees, we lack a TSH-T3 shunt. We have lost a significant amount of living thyroid tissue.

The thyroid gland not only secretes thyroid hormones T4 and T3, but it is also one of the most efficient glands at converting thyroid hormone as TSH-containing blood flows through it.

This dual role of the thyroid in health is called the “TSH-T3 shunt.” (Berberich et al, 2018)

  1. Higher levels of TSH in blood will stimulate synthesis of more T3 in living thyroid tissue and significantly raise the gland’s T3:T4 secretion ratio. (Citterio et al, 2017)
  2. In addition, as TSH-containing blood flows through thyroid tissue, it enhances T4-T3 conversion within living thyroid cells.
  3. Thyroid tissue loss eliminates natural T3 daily circadian fluctuations that untreated patients use to regulate their bloodstream FT3 levels (Berberich et al, 2017).

To some degree, even when TSH is low or suppressed, living thyroid tissue can passively continue to convert T4 into T3.

Therefore, a thyroid is not just a T3 synthesis factory, it’s also arguably one of our body’s most powerful T4-T3 conversion machines. It rivals the role of the liver in thyroid hormone conversion.

As you lose more and more of your natural TSH-T3 shunt, you can experience a significant TSH-T3 disjoint when you add thyroid hormone dosing into the picture.

Essentially, in thyroid health, two basic systems complement each other:

  • FT3 is partly adjusted by a TSH-stimulated thyroid gland’s shifting T4/T3 secretion rate and ratio. As TSH rises, the gland doesn’t just secrete more of both hormones to try to compensate for falling FT4 and FT3 in blood. The thyroid also expresses the body’s richest density of D1 and D2 enzymes per volume, and these metabolize T4 to T3 as blood carries thyroid hormones in and out of the thyroid gland. As TSH rises, the thyroid doesn’t just synthesize more hormones from raw ingredients, it also converts T4 to more T3, enhancing the T3 side of its secretion ratio.
  • FT3 is also partly adjusted by the activity of peripheral enzymes (D1, D2, D3) that metabolize T4 to T3 in tissues and organs all over the body.
    • Cells expressing D1 and D2 can convert T4 to T3. As D1 and D2 are upregulated or more active, more T3 hormone will exit those cells and enter the circulation.
    • Meanwhile, this T3-generating process can be counterbalanced by other cells expressing D3 enzyme, which can take apart T4 and T3 into their inactive metabolites, preventing T3 from signaling in their cells’ nuclei. Instead of T3 exiting those cells, RT3 and an inactive T2 hormone will exit those D3-expressing cells and enter the circulation.

This is telling you something about the priority of FT3 in human biology. The human body — when unhindered by the interference of thyroid disease or hormone dosing — will gravitate toward keeping FT3 around mid range, plus or minus 10 percent of range.

Essentially, the circulating FT3 is adjusted by the TSH-regulated healthy thyroid gland plus peripheral enzymes that metabolize circulating FT4 and FT3.

  • Inside the thyroid, D1 and D2 and hormone synthesis processes are regulated primarily by TSH.
  • Outside the thyroid gland, peripheral D1, D2 and D3 enzymes are not primarily regulated by TSH — but by FT4 and FT3 levels and many other substances.

In health, there is a healthy balance between TSH-guided T4 and T3 secretion rates on the one hand, and extrathyroidal T4-T3 conversion rates on the other hand.

Here’s the difference:

  • In untreated people, as TSH and Free T4 move inversely, they stabilize Free T3 levels to maintain health. The healthy body normally protects FT3 as TSH rises within range, as you’ll see in a graph below.
  • But in thyroid therapy, we can’t protect our FT3 without expert doctors’ help. Free T3 becomes unstable and may fall steeply as TSH rises. This is abnormal. You can’t predict where FT3 will end up within or below reference based only on TSH or FT4 results.

The most common problem in thyroid therapy is having FT3 levels that are too LOW for an individual’s health.

For example, science has shown it is extremely rare that a treated thyroid patient will have optimized FT3 when the TSH is “normal” but is above 2.5 mU/L. Levels above 2.5 are associated with depression in treated patients (Talaei et al, 2017).

Even more importantly, Ito and colleagues (2017) have discovered that patients without thyroid gland function on T4 monotherapy achieve optimal biomarkers of tissue euthyroidism (health), on average, when their TSH is below reference range!

The science speaks: The servant of thyroid gland stimulation, TSH, does not reign supreme over the queen of thyroid hormones in blood, FT3, who acts side by side with her trusty royal consort, FT4.

A list of possible TSH-T3 disjoint causes

The TSH-T3 disjoint is more extreme in:

  1. Treated patients who, due to higher LT4 doses, have higher Free T4 levels but convert T4 poorly, yielding a very low Free T3:T4 ratio.
  2. Treated patients who have significant loss of active thyroid tissue, since thyroid tissue loss reduces both T3 secretion and T4-T3 conversion capacity.
  3. Treated patients with genetic handicaps in T4-T3 conversion (DIO1, DIO2, and/or SECISBP2 genes), for which the loss of thyroid tissue can no longer compensate.
  4. All patients dosing T3 hormone or desiccated thyroid can have TSH-T3 disjoint, since the T3 dosing effect is known to oversuppress TSH at euthyroid levels (See Snyder & Utiger, 1972 for scientific confirmation of this fact). In these therapies a person can be anywhere from underdosed to euthyroid at a normal or low TSH. They may range anywhere from euthyroid to thyrotoxic at a fully suppressed TSH. This is why wise doctors test FT3 at least 12 hours after the most recent dose — after the post-dose peak FT3 subsides, to get average or baseline levels — for safety and to optimize the dose to other measurable signs of tissue euthyroidism.

Less common cases of TSH-T3 disjoint:

  • Treated patients who have TSH-Receptor antibodies that interfere with the TSH ultrashort feedback loop at the pituitary gland. These antibodies can fluctuate and give misleading TSH results that can change significantly from test to test even without a change in dose.
  • Treated patients with T3-secreting thyroid nodules or Hashitoxicosis. These can change the ratio of T3:T4 delivered from the diseased thyroid gland.

Practical implications

You know have the tools to estimate the status of our thyroid gland’s function: If we are on the equivalent of a full-replacement dose, and our FT3 falls as our TSH rises, it’s likely that the TSH is no longer driving thyroidal hormone secretion or thyroidal hormone conversion. TSH is now mostly impotent in inducing health if we don’t have a TSH-T3 shunt.

When doctors don’t acknowledge or understand this disjoint and believe with blind faith in TSH, it causes a parallel disjoint, distrust, and disagreement between thyroid patients and doctors.

By imagining a pill can save this pituitary-thyroid marriage, you would deny the fact of our biological divorce.

Perhaps to keep impotent TSH symbolically in control, medical men have invested it with false tyrannical power over our dosing in thyroid therapy. Nature didn’t give it that role.

Doctors, you don’t have to become just as selfish, T3-blind and impotent as the biased TSH you may have been taught to worship.

TSH normalization is a means to an end if there is enough thyroid to stimulate.

Certainly, a normalized TSH may be healthy and feasible in some patients, especially in Hoermann’s “Group 2” on lower doses of thyroid hormone who still depend on some TSH-stimulated T4 and T3 secretion.

The goal of all good thyroid therapy is body-wide “tissue T3 euthyroidism.”

It ruins trust between doctor and patient when the patient knows, by personal experience, that she is hypothyroid in many or all tissues beyond the pituitary.

Thyroid hormone health is best judged holistically by FT3 and FT4 plus a “jury” of tissues and organs, not just by this sole TSH judge who was voted into his seat by efficiency-minded endocrinologists who wanted to simplify thyroid therapy.

Let’s just realize the TSH-T3 disjoint tells the truth of LT4-treated patients’ hidden T3 loss, and it’s concealed by a blatant TSH-T4 lie. In therapy, TSH and FT4 can lie about our body’s true T3 supply.

Let’s all be thankful to Hoermann and team for revealing the suffering and vulnerability of these neglected, mistreated individuals in their scatterplot graphs.

  • Tania S. Smith, PhD,
    Thyroid patient and thyroid science analyst
    Founder and president of Thyroid Patients Canada


Click to view reference list

Berberich, J., Dietrich, J. W., Hoermann, R., & Müller, M. A. (2018). Mathematical Modeling of the Pituitary–Thyroid Feedback Loop: Role of a TSH-T3-Shunt and Sensitivity Analysis. Frontiers in Endocrinology, 9.

Celi, F. S., Zemskova, M., Linderman, J. D., Smith, S., Drinkard, B., Sachdev, V., … Pucino, F. (2011). Metabolic effects of liothyronine therapy in hypothyroidism: A randomized, double-blind, crossover trial of liothyronine versus levothyroxine. The Journal of Clinical Endocrinology and Metabolism, 96(11), 3466–3474.

Christoffolete, M. A., Ribeiro, R., Singru, P., Fekete, C., Silva, D., S, W., … Bianco, A. C. (2006). Atypical Expression of Type 2 Iodothyronine Deiodinase in Thyrotrophs Explains the Thyroxine-Mediated Pituitary Thyrotropin Feedback Mechanism. Endocrinology, 147(4), 1735–1743.

Citterio, C. E., Veluswamy, B., Morgan, S. J., Galton, V. A., Banga, J. P., Atkins, S., … Arvan, P. (2017). De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. The Journal of Biological Chemistry, 292(37), 15434–15444.

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2013). Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? European Journal of Endocrinology, 168(2), 271–280.

Ito, M., Miyauchi, A., Hisakado, M., Yoshioka, W., Ide, A., Kudo, T., … Amino, N. (2017). Biochemical Markers Reflecting Thyroid Function in Athyreotic Patients on Levothyroxine Monotherapy. Thyroid, 27(4), 484–490.

Talaei, A., Rafee, N., Rafei, F., & Chehrei, A. (2017). TSH cut off point based on depression in hypothyroid patients. BMC Psychiatry, 17(1), 327.

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