The pituitary response is abnormal. Stop TSH worship.

After oversimplifying T4 conversion as if it only converts into T3 (see Part 1 of this post), Canada’s endocrinology association make the claim that:

“Intracellular T3 levels regulate pituitary secretion and blood levels of TSH, as well as the effects of thyroid hormone in multiple organs.” (1)

This may be partially true, but it is not the entire story, and the oversimplification is false and damaging to thyroid patients.

Let’s look closely at the assumptions behind this statement and what it is implying.

First of all, they make it sound like T4-T3 conversion in the pituitary gland is the only factor that regulates TSH.

This simple theory was popular in the 1970s when they were first discovering how thyroid hormone conversion worked.

Proving that T4 converted to T3 beyond bloodstream and that T3 played a role in TSH secretion helped justify T4 monotherapy and built the TSH-T4 empire we see today.

But we know MORE now about the variability in the deiodinases, the way a living gland can actively help normalize serum T3, and the difference a missing or dead thyroid gland makes. (5)

Secondly, Canada’s endocrinologists imply that “intracellular” — rather than bloodstream — levels of T3 are the only levels that matter.

This is another distortion of what we know today about thyroid hormone transport and bloodstream levels, as I’ll show.

Thirdly, they imply that the gland that secretes TSH is capable of judging our entire body’s intercellular levels of T3.

These are all old-fashioned oversimplifications of “intercellular T3” that do not apply in thyroid science anymore, especially under the distortions one sees in thyroid disease and thyroid therapy.

Let’s take on intracellular conversion in general, since it’s the way to rebut all three of their distortions.

VARIABILITY ACROSS ORGANS

It is well known that each of our organs and tissues, such as the pituitary gland and the heart and the liver, differ widely in their ability to perform T4-T3 conversion. (2, 3, 4)

There is no such thing as a static rate of intracellular T4-T3 conversion across all organs and tissues.

Each organ is unique.

In thyroid health, you might get 80% of T4-T3 conversion “on average” beyond the bloodstream IF you are currently healthy.

Even if a healthy person converts 80% on average, that does NOT mean every organ converts at the same rate of 80%, nor does it mean the treated thyroid patient benefits from an 80% average conversion rate.

THE PITUITARY IS ABNORMAL

Science has proven that the hypothalamus and pituitary glands are unlike other tissues in our body. No other organ system is like the hypothalamus and pituitary in their partnership and their unique and complex relationship to circulating thyroid hormones.

As a complex duo, they can respond differently and independently to T4 hormone in serum, versus T3 hormone in serum. (8).

They can continue to convert T4 into T3 rather than Reverse T3 despite a state of excess T4. This is partly because they have an unusually high expression of Deiodinase Type 2 (D2) that performs this conversion. (8, 9)

Due to the pituitary’s unique role and biology, excess T4 does not as quickly “ubiquitinate” (inactivate) the D2 enzyme that converts T4-T3 within hypothalamus & pituitary tissues. (10)

Therefore, long after other organs and tissues have reduced their conversion rate of T4 into T3 in a state of excess T4, the pituitary keeps on converting T4 … abnormally.

As long as the pituitary has enough T4, it can make its own local supply of T3. It can make up for a lack of T3 in bloodstream.

Biologically, this is logical. The pituitary must be protected in case of T3 deficiency, since it secretes so many vital hormones that influence a wide range of endocrine systems.

The pituitary gland can live on Free T3 alone, if it has to. It simply does not care if other organs are T3-deficient.

There’s another biological reason for this unique pituitary response. It is because of the function TSH plays in regulating the thyroid gland — in health.

The pituitary has to be able to continue to respond to very high levels of T4 and keep converting it to T3. Because T4 is the thyroid’s major product, the pituitary is wired to be aware of excess T4 secretion.

If the hypothalamus & pituitary stopped converting excess T4 past the “tipping point” when other organs decrease their T4-T3 conversion, then TSH would be unable to drop low enough to decrease thyroidal stimulation.

No other organ in the human body is required to play this biological role in health.

Therefore, the hypothalamus and pituitary gland are unique.

TSH secretion is intended to stimulate a gland. It is a DISTORTION of its natural role to make it a tool for doctors to guesstimate thyroid hormone levels in blood and beyond.

TSH simply can’t speak for other organs’ local T3 supply. It can never do this in health or disease, and we are distorting its natural role if we want TSH to determine this for us.

TSH FUNCTIONS DIFFERENTLY IN THERAPY

Is TSH really capable of playing the same role in thyroid therapy as it does outside of thyroid therapy? No.

TSH cannot play its normal “sensitive” role to the degree that a patient lacks thyroidal tissue to stimulate and is responding instead to a static dose.

In a-thyrodial or sub-thyroidal life, TSH is like one hand clapping.

TSH is no longer a feedback loop, but a one-way response.

TSH secretion is not capable of understanding that we are supplying exogenous thyroid hormone that can result in unhealthy lower T3:T4 ratios.

The hypothalamus & pituitary will continue to assume TSH is stimulating a living thyroid gland that can shift its T4 and T3 production and secretion to compensate for imbalances.

In summary, the past fifteen years of thyroid science has shown that a key influence on TSH secretion is how much TRH is secreted from the hypothalamus to stimulate TSH secretion or to suppress TSH production and release.

TSH is not just regulated by “intercellular” T3 is stimulating pituitary gland tissues. It’s regulated by the hypothalamus.

Both organs are wired to respond to a natural, healthy thyroid status that does NOT exist in thyroid therapy.

HELLO, HYPOTHALAMUS?

Now consider how fickle the hypothalamus can be to T3 hormone dosing.

Look into the historic studies of T3 therapy and you will understand the unique effect oral dosing of T3 has on TSH. Oral T3 therapy is well known to be a TSH suppressant, much more so than T4 therapy.

Science has now given reason to believe that the early TSH suppression seen in T3-T4 combination therapy is very likely to be a side-effect and a localized hypothalamic bias (11, 12, 13).

The TSH is artificially suppressed post-dose long before FT3 levels rise to their post-dose peak, and the long-term TSH suppression remains in effect long after FT3 levels return to moderate or even low levels.

To put it plainly, the hypothalamus is hypersensitive to the quick rise in fT3 that will occur in T3 dosing, long before it has reached excess.

Why is the body doing this?

The hypothalamus is incorrectly assuming the T3 is coming in a steady stream from a hyperstimulated thyroid gland, rather than from a pulsed thyroid hormone dose. In response to the speed of the upward shift in FT3 level, it radically undercuts the pituitary’s ability to secrete TSH.

Meanwhile, TSH suppression in T3 therapy is not necessarily a sign of T3 oversupply from the entire human body’s perspective. D3, the enzyme that inactivates both T4 and T3 in peripheral tissues, is far more powerfully wired to inactivate excess T3. (2)

Therefore, our tissues are protected from bloodstream Free T3 fluctuations. Even mild T3 excess can be inactivated upon entry into cells by local D3 inactivation of T3 into T2.

Despite exaggerated fears that Free T3 fluctuations are dangerous, there is absolutely no proof that this is indeed the case.

Nobody has had the courage to study patients on long-term 100% T3 therapy who have no thyroid glands, no TSH, and no T4 hormone, to discover how much of their “excess” serum T3 is inactivated to T2 in tissues. Until you study these people who have such an unusual thyroid hormone profile, you can’t assume they are in danger.

… AND T2 SUPPRESSES TSH

And here’s a major blind spot. What else powerfully suppresses hypothalamic TRH and therefore pituitary TSH?

T2 hormone. (14)

And when is T2 most likely to be in excess, artificially suppressing TSH?

1. In critical illness, (15)
2. In T3 therapies involving higher doses of T3 and lower doses of T4, and
3. In T4 therapy during excess inactivation of T4 to Reverse T3.

But who measures T2? Nobody but researchers. Therefore modern therapy guidelines are oblivious to the effects of T2 on suppressing TSH.

BLOODSTREAM T3 IS AN IMPORTANT POOL

Each organ depends to a different degree on bloodstream Free T3 vs. intercellular T4-T3 conversion. Some organs depend a lot on the bloodstream pool of Free T3, others depend on it less (2).

Scientists previously thought that one enzyme (D1) converted our bloodstream supply of T3, and a different enzyme (D2) converted our “intracellular” supply of T3. Now we know differently. Serum T3 is largely maintained by “intracellular” conversion of T4-T3. (3)

Science now tells us that thyroid hormone transporters carry T3 and T4 both in and out of cells. (4)

This is two-way traffic, NOT one-way traffic.

After T3 binds with receptors for a while, it detaches and can exit the cell the same way it entered.

The bloodstream is not only a supply pool for T3 and T4, but a place where T3 and T4 are returned once again after exiting our cells. This is also the biological principle behind the healthy thyroid gland’s active defense of serum T3 levels. (7)

Therefore, levels of Free T3 in blood are, in fact, a very good measure of the “net” whole-body level of thyroid hormone conversion beyond the bloodstream.

The Free T3:T4 ratio in blood is a genuine proxy for global T4-T3 “intracellular” conversion efficiency. (5, 6)

In contrast, TSH measurement only tells you how well T4 is converting to T3 locally inside the hypothalamus and the pituitary gland.

WHICH IS THE UNNECESSARY TEST?

In summary:

1. In T4 therapy, the pituitary is able to produce T3 long after almost all other organs have slowed down their T3 production in a state of excess T4 even within the normal range.
2. In T3 therapies, the hypothalamus can radically turn down both TRH and TSH even when T3 levels are low-normal because it responds preemptively to FT3 fluctuations.

These factors distort TSH secretion in ALL possible combinations of thyroid therapy.

And you claim that TSH can be a fair judge that speaks on behalf of our whole body’s “intracellular” conversion of T4 to T3 in thyroid therapy?

No. It does not.

Like the hypothalamus and pituitary, modern medicine has engaged in hypersensitive fearmongering about high T3 while being apathetic about abnormally lower levels of Free T3.

Medicine must stop this blind TSH worship.

The natural biological outcomes of this bias are FT3 blindness and T3 suppression in thyroid therapy.

This unjust T3 suppression can truly ruin the rest of our lives.

You are contributing to the worsening of major illnesses like heart disease, which worsens in a state of higher FT4 and lower FT3, (15). This is the very state you force most patients to maintain.

In general, patients with heart disease on levothyroxine are at much higher risk of death and adverse outcomes. (16). The characteristic T3:T4 ratio distortion induced by T4 monotherapy is likely the reason why.

You must start helping thyroid patients find their true euthyroid level of Free T3.

An individual patient’s optimal Free T3 is often in the upper half of reference range.

You, our doctors, are forbidding many of us from accessing our optimal level of Free T3, due to your outdated, simplistic, and incorrect beliefs about TSH secretion and the draconian therapy guidelines that enforce them.

REFERENCES

(1) #3 in Endocrinology and Metabolism: https://choosingwiselycanada.org/endocrinology-and-metabolism/

(2) Cicatiello, A. G., Di Girolamo, D., & Dentice, M. (2018). Metabolic Effects of the Intracellular Regulation of Thyroid Hormone: Old Players, New Concepts. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00474

(3) Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008). Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences. Cellular and Molecular Life Sciences: CMLS, 65(4), 570–590. https://doi.org/10.1007/s00018-007-7396-0

(4) Führer, D., Brix, K., & Biebermann, H. (2015). Understanding the Healthy Thyroid State in 2015. European Thyroid Journal, 4(Suppl. 1), 1–8. https://doi.org/10.1159/000431318

(5) Dietrich, J. W., Landgrafe-Mende, G., Wiora, E., Chatzitomaris, A., Klein, H. H., Midgley, J. E. M., & Hoermann, R. (2016). Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. Frontiers in Endocrinology, 7. https://doi.org/10.3389/fendo.2016.00057

(6) Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015). Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme, 47(9), 674–680. https://doi.org/10.1055/s-0034-1398616

(7) Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641. https://doi.org/10.1111/cen.12538

(8) Christoffolete, M. A., Ribeiro, R., Singru, P., Fekete, C., da Silva, W. S., Gordon, D. F., … 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

(9) Dietrich, J. W., Landgrafe, G., & Fotiadou, E. H. (2012). TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. Journal of Thyroid Research, 2012. https://doi.org/10.1155/2012/351864

(10) Gereben, B., McAninch, E. A., Ribeiro, M. O., & Bianco, A. C. (2015). Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nature Reviews. Endocrinology, 11(11), 642–652. https://doi.org/10.1038/nrendo.2015.155

(11) Goulart-Silva, F., De Souza, P., & Nunes, M. (2011). T3 rapidly modulates TSH beta mRNA stability and translational rate in the pituitary of hypothyroid rats. Molecular and Cellular Endocrinology, 332(1–2), 277–282. https://doi.org/10.1016/j.mce.2010.11.005

(12) Wang, D., Xia, X., Liu, Y., Oetting, A., Walker, R., Zhu, Y., … Yen, P. (2009). Negative Regulation of TSH alpha Target Gene by Thyroid Hormone Involves Histone Acetylation and Corepressor Complex Dissociation. Molecular Endocrinology, 23(5), 600–609. https://doi.org/10.1210/me.2008-0389

(13) Jonklaas, J., Burman, K. D., Wang, H., & Latham, K. R. (2015). Single Dose T3 Administration: Kinetics and Effects on Biochemical and Physiologic Parameters. Therapeutic Drug Monitoring, 37(1), 110–118. https://doi.org/10.1097/FTD.0000000000000113

(14) Louzada, R. A., & Carvalho, D. P. (2018). Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites. Frontiers in Endocrinology, 9, 394. https://doi.org/10.3389/fendo.2018.00394

(15) Kannan, L., Shaw, P. A., Morley, M. P., Brandimarto, J., Fang, J. C., Sweitzer, N. K., … Cappola, A. R. (2018). Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circulation. Heart Failure, 11(12), e005266. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005266

(15) Dietrich, J. W., Müller, P., Schiedat, F., Schlömicher, M., Strauch, J., Chatzitomaris, A., … Lehmphul, I. (2015). Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling. European Thyroid Journal, 4(2), 129–137. https://doi.org/10.1159/000381543

(16) Einfeldt, M. N., Olsen, A.-M. S., Kristensen, S. L., Khalid, U., Faber, J., Torp-Pedersen, C., … Selmer, C. (2018). Long-term Outcome in Heart Failure Patients Treated with Levothyroxine: An Observational Nationwide Cohort Study. The Journal of Clinical Endocrinology and Metabolism, 103(12). https://doi.org/10.1210/jc.2018-01604