For many decades, scientists have been studying the effect of thyroid hormones in promoting cancer proliferation. Aleck Hercbergs and Paul J. Davis and colleagues have been at the forefront of this research.
The bad news is that normal physiological concentrations of T4 hormone, as well as its inevitable byproduct of Reverse T3, both act on receptors on the cell wall called “integrin αvβ3,” and through this receptor, they can cause many types of cancers to grow.
There’s also some good news. In a clinical study, cancer patients who were beyond all hope were able to extend their survival by significantly reducing their circulating T4 hormone and also the variable RT3 concentrations that it brings. They replaced these hormones with synthetic T3 hormone, which provides the active form of thyroid hormone that is essential for life and health.
Hercbergs and Davis and their team call this therapy “euthyroid hypothyroxinemia.”
This name literally means the achievement of metabolically appropriate thyroid hormone supply (euthyroidism) despite having very low T4 (thyroxine) hormone levels (hypo-thyroxin-emia).
In 2019, a helpful review of the therapy and its history was published:
- Hercbergs, A. (2019). Clinical Implications and Impact of Discovery of the Thyroid Hormone Receptor on Integrin αvβ3–A Review. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00565
In this article, I’ll showcase the work Hercbergs and team have been doing.
I’ll also discuss some of the barriers preventing this clinically-tested T3-dominant therapy solution from taking hold in cancer therapy and in thyroid therapy.
Hercbergs et al’s 2015 study of life-extending T3 therapy
As described in their 2015 clinical research report (Hercbergs et al), 23 people opted for a research trial of this therapy as a last resort, after all other cancer therapy efforts had been made. Patients’ T4 levels were already low from pre-existing hypothyroidism or were therapeutically reduced through the anti-thyroid medication methimazole. Replacement synthetic liothyronine (LT3) therapy was administered to them to achieve euthyroid metabolic status.
The experiment was a clear success in 19 patients: “83% of subjects exceeded the expected (median) survival” of more than 12 months.
Within this group of extended cancer survivors, a significant number were granted an additional year of life: “12 of 23 (52%) survived more than 24 months versus an estimated 1 of 23 (4.4%).”
Tumor size also visibly decreased on their scans.
In addition, a small number of patients who had already been taking some L-T3 therapy for hypothyroidism or depression survived “significantly beyond expectation.”
This was not Hercbergs’ first clinical trial employing the alteration of thyroid hormone levels in an attempt to alter the course of cancer (Hercbergs et al, 2003).
This science holds out significant hope: If this degree of life extension was achieved in people whose cancer had progressed to a desperate stage by the time it was initiated, could this T4-reducing euthyroid therapy be used to extend life even more significantly in less aggressive or less advanced cancers? What would happen if it were initiated earlier in the course of disease, rather than as a last resort? Could the therapy significantly reduce cancer risk before a diagnosis in people whose families or genetics reveal a vulnerability?
The T3 hormone receptors in the nucleus of cells are not the problem.
“Classic” thyroid hormone action occurs in the nucleus of cells, where the essential hormone T3, triiodothyronine, binds to receptors and performs “genomic” actions.
These receptors are different from the “integrin αvβ3,” receptors where T4 and Reverse T3 perform cancer-promoting actions.
So, what does “classical” and “genomic” action mean?
T3 hormone triggers transcription of a variety of genes across the human body and in every organ and tissue. It keeps our heart pumping, neurons firing, and lungs breathing. This one simple hormone, T3, has a myriad of complex effects. It does this by binding to receptors in the nucleus of cells.
According to current scientific knowledge, the cell nuclei receptors not only respond to T3 hormone, but also to much lower concentrations of Triac and 3’5′-T2 hormone, which are both derived from T3.
T4 has limited limited affinity to thyroid hormone receptors in the cell nucleus. T4 is reported to have 10-15x less affinity to the nuclear receptor than that of T3 (Bolger & Jorgensen, 1980).
“Affinity” to bind with a receptor is not the same as activity in the receptor. If or when T4 hormone ever binds to nucleus receptors, can T4 do what T3 does? As of 2020, nobody yet knows if T4 does anything at all in those receptors.
What about Reverse T3 in the nucleus?
Reverse T3 (RT3) has less than 1% binding affinity at the nucleus thyroid hormone receptor (Bolger & Jorgensen, 1980). It has even lower chances than T4 of plugging the receptor to prevent T3 from entering. It is missing an iodine atom on its inner ring, and it has two on the outer ring instead. Having a missing atom in the inner ring location is like missing the only key that can enter the receptor’s keyhole.
As a result of RT3’s impotence in this nuclear receptor, researchers have largely dismissed the RT3 hormone’s relevance to health. However, it is a major metabolite with health implications. Total RT3 can sometimes be just as abundant or more abundant in blood as Total T3 (Wiersinga, 1979).
RT3’s overabundance is a confirmation of metabolic pathology when it is either accompanied by abnormal T3 depletion — in nonthyroidal illness such as Cancer — or by T4 excess, as in Graves’ hyperthyroidism or LT4 overdose (Burman et al, 1977).
RT3 has pathological activity at another receptor where it has affinity.
Instead, a receptor on the cell wall is the problem.
Instead of having activity in thyroid receptors in the nucleus of cells, T4 and Reverse T3 both bind to thyroid hormone receptors on the cell wall (plasma membrane) and have “non-classical, non-genomic” activity there.
The discovery of nongenomic T4 action
“Nongenomic actions of thyroid hormone” were discovered long ago and were reviewed and described by Paul J. Davis and Faith B. Davis in a 1996 article by this title. The many actions included a powerful influence over the way our blood vessels contract or relax (vascular smooth muscle cells, VSMC).
However, at that time in the late 1990s, they had not yet discovered where and how these actions occurred at a molecular level, they just knew that they occurred in various places outside the nucleus of cells, including the “plasma membrane,” or cell wall.
Ten years later, in 2006, Faith B. Davis and colleagues (including Paul J. Davis, Aleck Hercbergs, and many others) published another article by the same title to announce that a cell wall receptor initiating nongenomic action was found at Integrin αvβ3. There are many integrin receptors, but only αvβ3 is known to bind with thyroid hormone.
Davis’s 2006 article abstract began by naming T4 and cancer:
“Recent evidence suggests that the thyroid hormone l-thyroxine (T4) stimulates growth of cancer cells via a plasma membrane receptor on integrin αVβ3.”
The type of cancer they focused on was glioblastoma, a brain cancer. At that time, they already had “clinical observations that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients.”
S1 and S2 binding sites and pathways
As of 2019, our knowledge of thryoid hormone activity at this integrin receptor has advanced even further.
There are two binding sites (like plugins) on this receptor. They are called S1 and S2. Hercbergs et al, 2019 explan that
- “S1 binds T3 and activates the PI3K/AKT-pathway whereas
- S2 binds T4 and, with lower affinity, T3, and activates PI3K/AKTpathway and MAPK-pathway.”
As you can see, the two receptors lead down different pathways of activation, one of them not activating the MAPK pathway at all.
The MAPK pathway is uniquely pathogenic because it prevents the death of cancer cells (it prevents their apoptosis). As Lin et al discovered in 2007, activating the MAPK pathway is “anti-apoptotic.” It was found that “Resveratrol-induced gene expression and apoptosis were inhibited more than 50% by physiological concentrations of T(4).”
Even thyroid cancer.
In 2007, Lin’s article on T4 activity pointed to the proliferation of thyroid cancer specifically:
“plasma membrane-initiated activation of the MAPK cascade by thyroid hormone promotes papillary and follicular thyroid cancer cell proliferation in vitro.”
T4 cancer risk is within reference range.
Again, it is “physiological” concentrations of T4 that activate cancer cell proliferation: “T4 in physiological free hormone concentrations stimulates
proliferation of cancer cells in vitro and in xenografts.”
“Physiological” concentrations mean within the normal statistical reference range.
T4 has a dose-dependent effect on a wide continuum. Hercbergs et al, 2019 say this:
“It is of note that there is a declining continuum of risk for free thyroxine levels from high supraphysiological (hyperthyroidism) to frank hypothyroxinemia and to blocking of the integrin avb3 thyroid hormone receptor, which would equate to a zero ambient free T4.”
Risk is absent when FT4 is absent or the receptor is blocked, but risk does not suddenly spike when FT4 rises above a statistical boundary.
According to Hercbergs and team, risk rises each pmol/L that your FT4 rises even within reference range. This means that high-normal Free T4 presents relatively more cancer risk than low-normal Free T4.
Reverse T3’s activity
Even more recently, Reverse T3 has been proven active at this integrin receptor. In September 2019, Lin et al published an article confirming the following, which had previously been hypothetical:
- “rT3 is known to bind to the thyroid hormone analog receptor on plasma membrane integrin αvβ3. This integrin is generously expressed by tumor cells and is the initiation site for the stimulation by L-thyroxine (T4) at physiological free concentrations on cancer cell proliferation. In the present studies, we show that rT3 caused increases of proliferation in vitro of 50% to 80% (P < 0.05-0.001) of human breast cancer and glioblastoma cells. Conclusion: rT3 may be a host factor supporting cancer growth.”
To put this hormone in perspective, Reverse T3 is always present when T4 is present, but in much lower quantities than T4. Total RT3 normally constitutes less than 1% of the concentration of Total T4. (Burman et al, 1977).
However, the comparison between RT3 and T3 in a state of health is more significant, at a ratio of around 1:10 at their low end of reference, and 1:7 at their high end of reference:
- Reverse T3 range = 8 – 25 ng/dL in adults (LCMS assay, Quest Diagnostics)
- Total T3 range = 76-181 ng/dL in adults (immunoassay, Quest Diagnostics).
In nonthyroidal illness syndrome (NTIS), including severe illness from cancer, RT3 can rival the concentration of Total T3 as RT3 rises above reference (except in kidney failure) and TT3 falls below reference.
In health, the free fraction of RT3 is approximately the same as it is for T3, at 0.03 percent free (Burman et al, 1977). This is the fraction of the concentration that is capable of binding to integrin receptors.
So much for “Normal” Reverse T3 activity.
In cancer, RT3 activity at the integrin receptor is emphasized because tumours highly upregulate the enzyne Deiodinase Type 3 (D3) that converts T4 into RT3.
Peeters & Visser, 2017 explains:
“The balance between [cellular] proliferation and differentiation is disturbed in cancer, and D3 [Deiodinase type 3] is turned on in several malignant cell lines and human cancers. D3 activity in these cancers can be very high and may even lead to so-called consumptive hypothyroidism.”
Consumptive hypothyroidism occurs when D3 enzyme is so powerful at converting T4 into RT3 and simultaneously converting T3 into 3,3′-T2, that T3 hormone is lost at a rate that exceeds T3 production from the thyroid gland and from T4-T3 conversion. D3 overexpression “consumes” (or depletes) T3 hormone. It also increases RT3 and 3,3′-T2 byproducts in its wake.
Therefore, locally increased RT3 at the site of the tumour is more significant in cancer cells than in normal healthy cells. RT3 binds to the integrin receptor to enhance cancer proliferation, adding to the effect of T4 hormone.
An euthyroid supply of T3 hormone is not the problem.
As explained above, T3 is absolutely essential for the maintenance of euthyroid status in tissues and cells.
As confirmation of this fact, rats bred without the SECISBP2 (SBP2) gene that is essential to creates deiodinases are without any ability to convert T4 into T3 hormone. They die in utero, before being born (Fu et al, 2017). A significantly low T3:T4 ratio is commonly found in many critical and chronic illnesses, but not in health.
We all convert T4 to T3, or we die. Low T3 directly causes hypothyroidism in tissues. Without sufficient T3, we cannot live a healthy life.
We know that euthyroid T3 is essential at the nuclear receptor. But what makes euthyroid T3 less dangerous at the integrin receptor?
T3’s lower quantity in blood
Back in 2006, Faith Davis’s team explained that T3 was equally potent at this integrin αvβ3 receptor, but there were key differences.
T3 has a slightly different set of effects at this receptor than T4, and T3 is far less abundant in bloodstream. In fact, considering Total T3 versus Total T4 supply in normal adults, “physiologic concentrations of T3 are 50-fold lower than those of T4.”
Therefore, T3 is 50-fold less likely to cause a problem.
As of 2019, Hercberg confirmed that T3 hormone can also cause cancer to grow, but it often takes abnormally high, “supraphysiological” levels of T3 to achieve this effect.
S2 Receptor affinity for T3 is much lower
A second factor diminishes T3’s role as a cancer-promoter: The cancer-promoting integrin αvβ3 binding site prefers to bind with T4 and Reverse T3 far more than to T3. In other words, The “affinity” of the offending receptor to T3 is significantly lower, because T3 does not bind with great affinity to the binding site at S2, which activates the pathogenic MAPK pathway.
T4 is the essential activator, not T3.
Finally, Hercbergs et al in 2019 revealed that you need T4 to be present to enable the signaling of this receptor to occcur, even if it is bound to T3.
- “The availability of T4 is the crucial step for activation of the integrin and consequent trans-membrane signaling into the cell.”
- “Total withdrawal or depletion of T4 will arrest this entire process, with consequences for the viability of the tumor and/or vascular cell.”
T3 in isolation can’t cause harm.
Tetrac can block integrin receptor
Tetrac is an acetic acid metabolite of T4. (3,3,5′,5′-tetraiodothyroacetic acid)
Hercbergs and team have found that “Blocking the thyroid hormone receptor on the integrin (equivalent to total thyroxine depletion) downregulates multiple pro-oncogenic genes and upregulates pro-apoptotic genes.”
Either depleting T4 OR using therapeutic doses of Tetrac, therefore, can stop tumor growth in many types of cancer: “renal cell carcinoma (13), non-small cell lung carcinoma (46), medullary carcinoma of the thyroid (41), pancreatic carcinoma (43), and multi-drug resistant breast cancer (47).”
Tetrac, like T4 depletion, also “inhibits angiogenesis, and potentiates ionizing radiation-induced cell death” according to Hercbergs’ team.
However, Tetrac is not yet available as a prescription pharmaceutical.
In contrast, the reduction of T4 and its replacement with LT3 is a currently available pharmaceutical option, unless you are in a country with an unethical and harmful LT3 shortage or policy restriction.
Preventive therapy potential
Hercbergs and team are very hopeful about “euthyroid hypothyroxinemia” potential, more than the development of integrin-blocking drugs. They write in 2019,
- “The capacity/ability to impact on cancer progression in the occult or preclinical stage with only a molecular diagnosis and identification by altering endogenous thyroid hormone (thyroxine) levels might become a minimally morbid, but effective, treatment approach to pre-emptively treat solid tumor types prior to their emergence as clinically evident disease.”
Essentially, they are saying if you already have a benign solid tumor, why not initiate a shift in T3:T4 ratio by reducing T4 and raising T3 to compensate, before it becomes cancerous?
In addition, if you are already on LT4 monotherapy and already diagnosed with cancer, why not consider a T3 therapy regime? Hercbergs et al suggested this in 2016 for “the occasional patient”:
- “l-Thyroxine (T4) is the principal replacement hormone for patients who have hypothyroidism. Some preclinical and clinical evidence supports the possibility that T4 can at least permissively affect certain features of established cancers and cancer-relevant angiogenesis. Thus, in the occasional patient with hypothyroidism and concomitant cancer, it appears reasonable to consider thyroid hormone replacement exclusively with 3,3′,5-triiodo-l-thyronine (T3). This use of T3 has been shown to be effective and safe in early experience with medical induction of euthyroid hypothyroxinemia in patients with advanced solid tumors.”
The replacement of reduced T4 with higher T3 is not unnatural
Nature already replaces T4 with T3 in two circumstances in which the body can maintain full function and health despite T4 deficiencies:
- Prior to initiating thyroid therapy, TSH pushes a failing thyroid gland to enhance its rate of synthesis of T3 “de novo” (anew, not derived from T4), and enhances both intrathyroidal and extrathyroidal conversion of T4 into T3 (Hoermann et al, 2020)
- In iodine deficiency, the TSH rises to enhance T3 as T4 falls (Dayan and Panicker, 2009), and if T3 rises enough, it can result in euthyroidism despite thyroid swelling — goiter — and hypothyroxinemia (Führer et al, 2012).
In addition, during the recovery phase of nonthyroidal illness, also known as “low T3 syndrome,” after T4 also finally reaches a low enough point, TSH is then triggered to rise, and it often rises above reference, to resupply T3 using the same mechanism of T3 enhancement (Peeters et al, 2005).
Finally, even if Total T4 dominates over Total T3 quantitatively in blood, the natural Free T3:T4 ratio in health is one in which Free T3 is mildly dominant over Free T4 within their respective statistical reference ranges. In various studies of large populations of healthy controls, one can see that the mean Free T4 is skewed lower, at around 30-40% of reference, while Free T3 is around 50% or mid-point of reference. (Gullo et al, 2011; Hoermann et al, 2014)
The only view in which T4 deficiency is seen as always pathological is one which imagines that T3 is always dependent on T4’s existence. In our modern era, we have LT3 as a pharmaceutical tool.
Ever since LT3 monotherapy was available, thyroid science has proven that a complete T4 deficiency can be euthyroid as long as enough T3 is supplied to maintain not only “normal” circulating T3 levels, but also the “bonus” amount of T3 that would have been converted from circulating T4 within cells.
Is high T3 a risk in euthyroid hypothyroxinemia?
Is T3 too abundant in euthyroid T3 monotherapy, enough to cause risk of cancer proliferation?
No, not according to its quantity in pmol/L, nor the proof of the clinical study.
Historic data on T3 monotherapy in thyroidless individuals dosed at 3x a day shows that Free T3 peaks at mildly elevated and TSH is suppressed wthout any clinical sign of thyrotoxicosis. (Busnardo et al, 1980, 1983).
Even an elevated Free T3 of 8.0 pmol/L (If the FT3 reference range is 3.5 to 6.5) is significantly less abundant than the average Free T4 level around 14-16 pmol/L (if the range is 10-25).
The clinical study by Hercbergs et al. in 2015 proved that T3 above the mean does not raise cancer risk.
Most cancer & thyroid hormone studies reviewed by Krashin et al, 2019 show T3 abundance poses a significantly greater cancer risk when T4 is also normal or overabundant at the same time. Hercbergs’ team’s research as of 2019 has confirmed that T4 is necessary to activate the integrin recetor signalling.