For many decades, scientists have been studying the effect of thyroid hormones in promoting cancer proliferation.
Confusion and contradictions often arise in “cancer & thyroid” research reviews because the relationship between cancer and thyroid hormones is very complex. For example, a recent review of science since the 1940s attempted to reclassify research findings under poorly defined generalizations of “hypothyroidism,” “euthyroidism” or “hyperthyroidism” and variable “high T3” or “low T4” conditions (Krashin et al, 2019).
Such reviews can muddy the science more than clarify it.
Fortunately, Aleck Hercbergs and Paul J. Davis and colleagues have been at the forefront of research that clarifies the effect of T3 versus T4 hormones in the context of cancers by focusing on a special cell membrane receptor for thyroid hormones.
Back in 2005 (Bergh et al, 2005), Davis and Hercbergs’ research team announced the details of T3 and T4 activity at the “integrin” cell membrane receptor. Their insights into this receptor clarified T4’s role (and RT3’s role) in thyroid hormone signaling.
It turns out that T3 and T4 have different non-genomic signaling at this cell membrane receptor that are very significant to cancer because this receptor is highly expressed in cancers, and T4 signaling more directly affects cancer proliferation rates.
All researchers prior to 2005 (and many other research teams since 2005) were ignorant of T4’s unique effects at this key thyroid hormone receptor. Since 2005, research on this receptor has advanced. Not all cancer researchers have kept up with the developing scientific knowledge of this thyroid hormone receptor’s role in cancer, but Davis and Hercbergs’ team of researchers certainly have.
The bad news for cancer patients with high-normal FT4 levels is that Davis, Hercbergs and their team of scientists have discovered that physiological concentrations of T4 hormone, as well as its inevitable byproduct of Reverse T3, act on receptors on the cell membrane called “integrin αvβ3,” and through this receptor, they can cause many types of cancers to grow.
In certain cancer patients, it can be a health risk to have high-normal T4 concentrations regardless of their concurrent T3 and TSH levels.
There’s also some good news. In Hercbergs and team’s recent preclinical 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 can maintain life and health even in the absence of T4.
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 “euthyroid hypothyroxinemia” 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 in the science of T3, T4, RT3, and Tetrac activity at the integrin receptor, and its specific relevance to cancer therapy. 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 in general.
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, raising new questions about the potential applications:
- 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?
But the implications of this research requires some understanding of T3 and T4’s effect on cancer at the molecular level.
The complexity of thyroid hormone signaling in cancer
The complexity in understanding thyroid hormones and cancer occurs at many levels. Davis & Hercbergs’ team’s understanding of cell membrane receptors and their T3-focused preclinical trial in real cancer patients brings a lot of clarity to a complex matter.
At the core of the complexity is the interplay between thyroid hormone metabolism and signaling and how these relate to T3 and T4 concentrations in bloodstream.
Both in health and in disease, T4 converts to T3 at variable rates in different tissues and yields different FT3:FT4 ratios and levels in blood depending on the person’s overall health status and individual metabolic demands.
Thyroid hormone metabolic variability is significant to cancer and other health outcomes because metabolism directly impacts signaling.
T3 hormone’s receptor affinity and signaling activity differs qualitatively from that of T4 at many locations where T3 is active, such as:
- 1) in nuclear thyroid hormone receptors,
- 2) in mitochondria, and
- 3) at cell membrane “integrin αvβ3” receptors.
Signaling at location #3, cell membrane integrin αvβ3 receptors, is directly influenced by FT3, FT4, and RT3 concentrations in blood before they enter cells and can be metabolized to other forms of thyroid hormone.
In addition, T4 and T3 hormone effects in a state of health are different from those in the context of a chronic disease like cancer, and in various types and stages of cancer, and in the context of thyroid disorders and various thyroid hormone treatments.
Complicating these two hormones’ very different signaling pathways is the fact that various thyroid hormone metabolites beyond T4 and T3 can also modify cancer, such as Reverse T3 (RT3) and Tetrac.
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 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).
But mere “Affinity” to bind with a receptor is not the same as scientifically observed “activity” in the receptor. If or when T4 hormone ever binds to nucleus receptors, can T4 do what T3 does? No.
As explained by Yang et al, 2021, before T3 can be active in receptors, the T3-bound receptor must move or “translocate” into the nucleus of the cell, where it lets go of “co-repressors” that would hinder receptor signaling activity. T4 is involved in the “process of co-repressor releasing,” that is, T4 assists in removing a biochemical straitjacket or hindrance to T3 signaling. While T4 paves the way to T3 nuclear receptor signaling, T4 “does not start the transcription” of genes. Only T3 can do that.
As of 2020, nobody yet knows if T4 has any genomic activity at all in nuclear receptors prior to being converted to T3.
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).
RT3 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. The effect of diminished T3 signaling in the presence of high levels of RT3 is not due to the RT3 hormone, but is largely due to T3 inactivation by Deiodinase type 3. (See “Deiodinase Type 3 plays the T3-blocking role“)
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.
In some circumstances, Total RT3 can become 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 membrane 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 membrane (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.”
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 membrane receptor initiating nongenomic action was found at Integrin αvβ3.
In this 2006 article, they referred to their own recent research on this receptor (Bergh et al 2005) as a foundation for their breakthrough. In 2005 it was discovered that there are many integrin receptors, but only αvβ3 is known to bind with thyroid hormone T4, and T4 hormone activates the “MAPK” signaling pathway.
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 (T3 at S1) not activating the MAPK pathway at all.
The T4 – MAPK signal is important in thyroid cancer.
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).”
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 found 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 explain:
“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.
It is well known that T3 signaling through TRβ thyroid hormone receptors in the nucleus has a tumor-suppressive effect.
“TRβ has shown to be a potent tumor suppressor in several types of cancer including breast and thyroid cancer”
“thyroid hormone receptor beta (TRβ) acts as a tumor suppressor in ATC through repression of several pathways important for tumor growth“(Davidson et al, 2020)
Paradoxically, T3 does this beneficial action at the nuclear TRβ receptor by suppressing the PI3K signal that T3 can send from the integrin receptor.
Davidson’s study in 2020 elaborated, for the first time, how these T3-bound beta-receptors regulated and suppressed the T3- integrin receptor’s PI3K signal. The anti-cancer pathway of T3 signaling can counterbalance the pro-cancer pathway of T3 signaling under the right conditions: either the T3-TR-beta signal has to be strong enough or the T3-PI3K signal has to be weak enough.
- One problem is that many cancer cells, due to their mutations, lack sufficient expression of anti-cancer T3-TRβ receptors, making them less capable of regulating T3-driven PI3K signaling at the integrin receptor.
- However, since T4 activates the integrin receptor and tetrac can block that receptor, PI3K signaling can be reduced or stopped by reducing or removing T4 or by adding the integrin-receptor-blocker, tetrac.
The concentration of FT4 is a major variable, since
“At physiological concentrations, thyroid hormone (T4) but not T3, initiates at the iodothyronine receptor on cell surface integrin αvβ3.”(Yang et al, 2021)
While T4 is active at physiological concentrations (within the FT4 reference range) at this receptor, only supraphysiological levels of T3 send signals from this receptor. (Davis et al, 2020).
Placing FT4 levels below physiological concentrations can reduce this receptor’s overall level of activation by both T4 and T3.
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 occur, 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.
The essential nature of T3 signaling for health
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.
Tetrac can block T4 at the 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.”
Having a 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 lower in its range, at around 30-40% of reference, while Free T3 is around 50% or mid-point of its reference range (Gullo et al, 2011; Hoermann et al, 2014).
The only view in which T4 deficiency is pathological is one in which T3 is largely derived from T4. In our modern era, we don’t need to derive T3 from T4. 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, as shown in the clinical study.
The clinical study by Hercbergs et al. in 2015 proved that T3 above the mean, in the context of reduced or absent T4, does not raise cancer risk in vivo.
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 integrin receptor signaling.
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).
Responses to this research
Despite the hope and the caution, the medical community prefers to do something very different than therapeutically or preventively reduce T4 concentrations.
1. Cancer therapy chooses a more lucrative pathway
Research articles are being published about ways to block the integrin αvβ3 receptor that T4 and Reverse T3 activate to make cancer cells grow. They want to develop an additional blocking drug that can be marketed to cancer patients. In a similar way, arthritis patients who are prescribed Diclofenac are routinely also prescribed a protein-pump inhibitor (PPI) to mitigate the gastrointestinal damage that can be done by the drug.
However, LT3 therapies are available today, and integrin αvβ3 receptor blockers are not yet available and on the market.
When the thyroid integrin receptor blockers become available, they will likely be expensive. Drugs for rare conditions, and drugs “orphaned” by changes in physician prescribing practices, can suffer unethical, arbitrary price inflation (See Dirty Money “Drug Short” episode and thyroid T3 Liothyronine.)
Excluding the inflated cost of LT3 in the UK, what is the average cost of LT3 therapy in Germany, France, Canada, US, Thailand, Mexico and Turkey compared to surgeries and chemotherapy and a potentially shorter lifespan? (See our blog post on “Global thyroid pharma economics: T3 meds.”)
The degree of human suffering involved in a cancer therapy is something to ponder. When cancer therapies are offered to people without damaged or removed thyroid glands, why would people rather engage in surgeries and chemotherapy than alter their thyroid hormone concentrations by replacing T4 with LT3 hormone, when there is rarely any human suffering involved in the latter therapy if you have a doctor that knows how to render you truly euthyroid on LT3?
2. Thyroid therapy retrenches its paradigm
Thyroid therapy leaders are also largely ignoring or diminishing this research, not because of profit. Levothyroxine is cheap and there is no further drug development necessary. It is because of a staunch attitude of conservatism.
First of all, a conservative stance of medical isolationism or departmentalization points to the fact that people who suffer cancer do not necessarily have a thyroid gland productivity problem. They have a healthy thyroid, pituitary and hypothalamus. Those people are not supposed to take thyroid medication because they have a thyroid hormone supply. It’s considered not indicated, non-physiological and potentially harmful just because they have functioning equipment.
However, this stance does not take into account the dysfunctional and pathological response to normal T4 thyroid hormone in Cancer.
Of course thyroid hormone derangement can occur and cause widespread health problems even while a thyroid gland and HPT axis is healthy.
There is no law of medicine that says one must not interfere with a healthy HPT axis when altering it can extend someone’s life or prevent harm.
Clearly, this prohibition of thyroid hormone therapies to people with non-thyroidal illnesses is a defensive, territorial, imaginary barrier created by departmentalizing the human body organ by organ and disease by disease, ignoring the derangements that occur when thyroid hormones interact with cancer cells. Cancer does not respect the professional boundaries we erect between medical fields and diseases. Thyroid hormones cross all barriers in the body.
Secondly, a major barrier is conservatism within thyroid therapy, a defense of therapy policy decisions made in the 1970s and 1980s.
It is still acceptable to raise T4 concentrations above reference range to suppress or lower TSH secretion in high-risk thyroid cancer patients. This is based on the understanding that some cancer types and pathways of cancer development are “TSH-dependent” because of TSH’s direct effects on thyroid cells (Fiore & Vitti, 2012).
It may indeed be true that in some cases,
“patients take advantage of TSH suppressive treatment with LT4 with a decreased disease progression, recurrence rates, and cancer-related mortality” (Fiore & Vitti, 2012).
But could decreases in cancer be even greater with the use of T3-dominant therapies that also suppress TSH?
Given that both TSH and T4 are implicated in cancer, T3 therapy is effective at suppressing TSH while also lowering T4, achieving both goals at once in thyroid cancer patients.
In contrast, the status quo is not very attractive. Given the research done by Hercbergs and Davis, there is reason to believe LT4 monotherapy is the more risky means of achieving TSH suppression. Science has long known that today’s standard thyroid therapy modality raises T4 concentrations significantly above the population mean while reducing T3 concentrations below the mean, even while both hormones usually stay within reference range (Midgley et al, 2015).
Today, given the dose-dependent effect of T4 at this receptor throughout the normal FT4 reference range, endocrinologists should be concerned about cancer risk being higher in hypothyroid patients being treated with T4 monotherapy compared to people treated with T4-lowering T3-dominant replacement therapies.
What else is holding endocrinologists back from offering T3 monotherapy to hypothyroid patients on therapy who have no cancer yet, but risk of cancer?
LT3-induced “euthyroid HYPOthyroxinemia” is directly opposite to the “euthyroid HYPERthyroixinemia” in T4 monotherapy currently permitted by thyroid therapy guideline-writers.
The tradition since the 1980s is to prefer the use of synthetic T4 monotherapy and to normalize its unnatural thyroid hormone derangements because they are “usually within reference range,” while casting fear and disapproval on therapies involving the dosing of T3 hormone, which can reduce T4 concentrations and mildly elevate T3 to compensate.
All thyroid hormone interventions are unnatural. The diseases that thyroid hormones compensate for are abnormal. Therapeutic compensations will sometimes overcompensate for a handicap and result in biochemical anomalies and side effects. One must ask the more important question about which kind of unnatural therapy is more therapeutic for the cancer patient.
A prejudice toward defend the current T4-therapy tradition at all costs is just another chimaera standing in the way of medical progress and harm reduction.
Why must we perpetuate a warfare between two or three bioidentical thyroid hormone pharmaceuticals when none of them are intrinsically harmful except when underdosed or overdosed or when its use worsens another illness such as Cancer?
This old thyroid pharmaceutical war might have served industry or medical interests in the 1970s and 1980s, but whose interests does it serve in 2020? Drugs like Humira now make far more profit than Synthroid does for Abbvie, if you look at their financial reports. Many generic brands of Levothyroxine have arisen to compete since 2000.
On the medical evidence front, the belief that T4 monotherapy is superior to all other forms of thyroid therapy was never derived from any double-blind studies comparing long-term health outcomes between levothyroxine alone and the wide range of T3-dominant therapy alternatives that were in common use. No such studies were done in the 1970s or 1980s, only polemical studies that attacked other bioidentical hormones for having different biochemical profiles. The superficial bickering continues to act as a smokescreen for the lack of core evidence of LT4 superiority. Look in the thyroid clinical guidelines and you will find no such comparative health outcome studies cited.
The very first double-blind controlled comparative study of desiccated thyroid and LT4 occurred in 2013 by Hoang and colleagues, and it proved neither therapy was superior to the other in terms of short term outcomes and biochemistry, not long term health outcomes.
Even more importantly for our most vulnerable patients, no evidence proves LT4 superiority over desiccated thyroid or T3 monotherapy at critical junctures in life and death, such as the ability to recover from a critical nonthyroidal illness like a stroke, heart attack, or kidney failure without a thyroid gland. Instead, treated thyroid patients have been excluded from almost all studies of nonthyroidal illness.
Likewise, no one has proven the superiority of LT4 monotherapy over T3-based therapies within chronic illnesses like type 1 diabetes, adrenal insufficiency, heart failure, or liver failure, or cancer.
An entire field’s reluctance to perform this essential comparative research on health outcomes in extremely vulnerable patients is proof of its reluctance to risk a favorite therapy from being proven inferior in certain dire circumstances.
Resources for effective and safe euthyroid hypothyroxinemia
Fortunately, there is knowledge within the field of thyroid science and clinical practice to guide effective and safe “euthyroid hypothyroxinemia” as proposed by Hercbergs.
T3 monotherapy has long been used in six to eight weeks of preparation for radioiodine (RAI) ablation of thyroid fragments after thyroidectomy for thyroid cancer patients. At least since the late 1970s (see Busnardo et al, 1980, 1983) and even today (see Celi et al, 2010, 2011 and Yavuz et al, 2013), it has been viewed as more compassionate to use T3 monotherapy in this circumstance. This is because using the more quickly-dissipating T3 hormone significantly reduces the duration of hypothyroidism when thyroid medication is withdrawn to raise TSH prior to RAI therapy. (See some of Busnardo’s, Celi’s & Yavuz’s graphs and findings discussed our article on Free T3 peaks and valleys.)
One may also follow confident consensus of those who have mastered T3 monotherapy in the past, such as those who gave guidance on dosage equivalency to LT4 (Selenkow & Rose, 1976; Refetoff, 1975; Chopra et al, 1973; Green, 1968) – see their equivalency tables showing T3 monotherapy dose here.
And finally, even today, a global community of thyroid patients is maintained long term on T3 monotherapy; they flourish as leaders provide online communities and books to support their safe titration of LT3 (Robinson, 2018). This community of patients may be consulted and studied at any time if approached with respect by honest, unbiased researchers.
- Tania S. Smith