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.
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) thyroid-hormone-treated people in all categories.
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.
Here’s the difference:
- In untreated people, as TSH and Free T4 fluctuate, they stabilize Free T3 levels. The healthy body protects FT3, 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. 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 disjoint in standard T4 monotherapy (Synthroid, Levothyroxine, Eltroxin) is most clearly illustrated in the following article’s quotations and graphs.
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 (doses not stated).
They sorted these five categories of people into hypothyroid, subclinical hypo, euthyroid, subclinical hyper, and hyperthyroid categories based on their TSH and FT4 values.
Each group had people in all five categories, except for Group 5, which only had euthyroid and subclinically hyperthyroid people.
They also analyzed their Free T4-T3 conversion efficiency (expressed as “GD”) based on the T3:T4 ratio and further mathematical modeling.
The following screenshot of the TSH-FT3 graphs in their Figure 1 shows you clearly how different these populations are.
(Image reproduced within Canadian copyright “fair dealing” and US copyright “fair use” for purposes of education and review: See info.)
The laboratory reference range was FT3 2.23–5.36 pmol/L.
About how many dots in these scatterplots are below the FT3 reference boundary of 2.23 pmol/L?
On the Y axis the TSH scale has been transformed (log TSH) so that values can be graphed; they range between suppressed (0.01) and high (100 mU/L), with “0” representing the middle of the spectrum (average).
As you can see in Figure 1 above,
Patients in Group 1 cluster around an average FT3 of around 4.0 pmol/L. It looks like a bull’s eye.
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.
Notice that a bull’s eye is not 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.)
Why? This is because in un-dosed thyroid biology, FT3 is not adjusted by TSH alone. The FT3 is adjusted by both FT4 and TSH together, and also by a balance between T4 and T3 secretion and conversion rates. A host of factors keep FT3 stabilized. But this changes in thyroid therapy.
This is telling you something about nature. The human body without the influence of thyroid hormone disease or dosing will gravitate toward keeping FT3 around 4.0, plus or minus 10 percent of range.
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.)
Now scan down to 4.0 on the X axis to see how the scatterplots shift to the left on increasing doses of T4 thyroid hormone — how frequently do you see lower than average FT3 values in medicated people?
Patients in Group 2 on the lowest dose of thyroid hormone were capable of the higher FT3 levels because they likely had some thyroid gland tissue remaining. They were more likely to be overdosed on LT4 therapy than underdosed.
Patients in Group 3 fared the worst — Their TSH ranges widely and their FT3 slope is the most extreme.
The people in the upper left corner with higher TSH and lower FT3 send a clear message: Why should you force a person in this category to endure a TSH higher than the average, which is 1.5 mU/L ? You could be stealing their FT3 even while TSH is “normal”!
This is the category of people whose LT4 doses are in the range of the most severe autoimmune hypothyroid patients: Hashimoto’s, Atrophic thyroiditis, and post-therapy Graves’ disease.
Their TSH cannot be benignly lowered below reference range according to policy because they haven’t had thyroid cancer. Basically, nobody cares if TSH could stimulate the growth of nodules and cancer cells in people who haven’t yet had thyroid cancer diagnosed and removed. So, let’s save some people from recurring cancer by lowering their TSH below reference. Meanwhile let’s doom an unknown number of people within this far huger category of thyroid patients to potentially live T3-hypothyroid for the rest of their TSH-normalized lives.
Patients in Group 4 are mainly those who had had total thyroidectomies due to cancer and were permitted TSH suppression. Fewer patients in this category had FT3 levels below reference range because their dose was allowed to be higher. Nevertheless, Hoermann and team say that a significant number of them still suffer from lower than average FT3 levels.
Patients in Group 5 on iodine were basically euthyroid, retained normal TSH and normal HPT axis function, and their slope was not significantly altered. They were less like patients on thyroid therapy, more like untreated patients.
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.”
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.”
One cannot trust TSH to speak for FT3 levels during levothyroxine therapy, just as you can’t trust a husband to speak for his 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.”
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.”
“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.”
Thyroid therapy that normalizes TSH does not necessarily restore healthy levels of Free T3.
And you call this euthyroidism?
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.
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.”
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. They have the same 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.”
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’s what’s often required in thyroid therapy to raise the FT3 up to, or above, mid-reference.
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.
The T4 hormone that requires conversion can easily overload the bloodstream during thyroid therapy and slow down the peripheral conversion rate.
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.
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. (Christoffolete et al. 2006)
Meanwhile, as the hypothalamus and pituitary are focusing on FT4, 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 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)
- 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)
- In addition, as TSH-containing blood flows through thyroid tissue, it enhances T4-T3 conversion within living thyroid cells.
- 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.
A list of possible TSH-T3 disjoint causes
The TSH-T3 disjoint is more extreme in:
- 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.
- Treated patients who have significant loss of active thyroid tissue, since thyroid tissue loss reduces both T3 secretion and T4-T3 conversion capacity.
- 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.
- 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.
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.
Doctors, you can become just as selfish, blind and impotent as the biased TSH you are told to worship.
By denying biology and imagining a pill can save this pituitary-thyroid marriage, you are denying the fact of our internal divorce.
You must listen to science and admit that in thyroid therapy, the HPT axis is broken and the pill-bribed TSH is biased low.
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.
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.
Let’s just call the TSH-T3 disjoint a blatant lie. It breaks faith and ruins trust. In therapy, TSH can lie about our body’s true T3 supply.
It’s also a lie to believe that a pill can fix hypothyroidism by replacing the thyroid gland. There is no thyroid pill that can modify its T3:T4 secretion ratio or act as a T4-T3 conversion machine.
No pharmaceutical can play the role of the TSH-T3 shunt, the living thyroid gland that adjusts its T3:T4 secretion ratio and optimizes thyroid hormone conversion to protect FT3 supply in blood.
The goal of all good thyroid therapy is body-wide “tissue T3 euthyroidism.”
The doctor’s job is not to tend the sacred secretion of the pituitary gland at all costs to the rest of the human body.
Therefore, we must stop forcing all thyroid patients to maintain a TSH above 0.4 mU/L or wherever statistical wizardry and consensus has placed the boundary.
Effective thyroid therapy should permit a suppressed TSH whenever it is necessary to supply sufficient Free T3 to tissues. Nevertheless, a normalized TSH may be healthy and feasible in many patients, especially in Group 2 on lower doses of thyroid hormone who have some functional TSH-T3 shunt thyroid tissue.
Fears and safety concerns about low TSH can also be alleviated by understanding that all TSH-risk research studies to date are seriously flawed — they do not measure FT3 levels, T3-T4 ratios, and do not divide data into cohorts to analyze patients in different FT3 ranges. Most thyroid therapy research has been designed to defend the rigid boundaries of LT4 standard therapy and TSH testing, not to question its presumptions.
Thyroid hormone health is best judged holistically by FT3 and FT4 plus a “jury” of tissues and organs, not just by this sole judge who was voted into his seat by efficiency-minded endocrinologists. Other objective measures of thyroid hormone status in various tissues do exist, and they are used in studies by Ito et al, 2017 and Celi et al, 2011.
- Tania S. Smith
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. https://doi.org/10.3389/fendo.2018.00091
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. https://doi.org/10.1210/jc.2011-1329
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. https://doi.org/10.1210/en.2005-1300
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. https://doi.org/10.1074/jbc.M117.784447
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. https://doi.org/10.1530/EJE-12-0819
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. https://doi.org/10.1089/thy.2016.0426
Talaei, A., Rafee, N., Rafei, F., & Chehrei, A. (2017). TSH cut off point based on depression in hypothyroid patients. BMC Psychiatry, 17(1), 327. https://doi.org/10.1186/s12888-017-1478-9