I’d like to talk about contemporary researchers’ rigid and limited approach to combination therapy.
This is the model whose many limitations I point out with the ridiculously long label “mini-T3-mono-combination” therapy.
I’ll go over some of the history behind this model, the source of the rigid ratios that we learned about in our series on “question the ratios.” I’ll examine some of the fears and biases involved in his model of therapy — often its rivalry with natural desiccated thyroid (NDT).
A separate post will discuss the practicalities of managing a flexible approach to combination therapy.
A RIGID MODEL DESIGNED FOR RESEARCH
This model of combination therapy was developed by research scientists in the late 1990s and early 2000s.
To fit combination therapy into the controlled environment of an experimental clinical trial, researchers usually pre-select a ratio of T3 and T4 based on their paradigms and theories about what would work best for the largest number of people with hypothyroidism. The researchers then apply this single ratio to a diverse group of patients. The ratio usually standardized so that it can be treated as if it’s a new drug, a single entity, that can be compared with T4 monotherapy.
The standard model of T4 monotherapy consists of a very rigid, non-physiological dose ratio of 0:100 T3 to T4. To enable statistical comparisons between T4 therapy and combination therapy group, these combinations have become equally rigid “mono-combo-therapeutic” drugs.
An increasing number of these combination therapy clinical trials over the years has developed a dogmatic belief that there is only ONE physiologically correct T3+T4 dose ratio that should be permitted in any combination of the two hormones. A ratio that began as a theoretical proposition to be hypothesized and tested has now become associated with nature itself.
Thyroid researcher Leonard Wartofsky (2004) even heralded a single molar ratio of T3:T4 as a “magic formula” that researchers and clinicians should seek.
The model of rigidity that we see in non-naturalistic controlled experimental designs has been carried over into a set of guidelines for clinical practice developed by the European Thyroid Association in 2014.
SECRETION RANGES VS AVERAGES IN PILO ET AL
These ratio-limiters have decided to take as their model the statistical average ratio of T3 to T4 secreted from research participants’ thyroid glands in old theoretical & descriptive articles.
The most commonly chosen rigid ratio is the the one from 1990 (by Pilo et al), which I and my colleague Linda have analyzed in depth in several posts on this blog. This article discovered a wide range of secretion ratios from 14 healthy human beings who were heavily dosed with iodine during the study.
From Table 3. SR = secretion rate in micrograms per day per square meter.
|Participant number||SR T4||SR T3||T3:T4 Ratio|
In many areas of medicine including thyroid therapy, normal health is described as a wide range, which enables the calculation of a reference range, rather than a single average value within that range.
Here, the widest range of T3:T4 ratios was from 1: 6.43 to 1: 71.48. Researchers have put complete trust in the mathematical wizardry that Pilo and team used to estimate these 14 human beings’ secretion rates.
The statistical average of this wide range, 1: 16.83 is now being used to calibrate the dosing ratio for all people on combination therapy.
The most common ratios seen in mono-combo-therapy trials are between 1:14 and 1:16.
However, because T4 hormone is so poorly absorbed through the gastrointestinal tract, the higher doses of combination therapy add extra micrograms of T4 to make up for the amount that does not get absorbed, so the ratio can even minimize T3 further, in a ratio of 1:20 T3 to T4.
How did each of the 14 normal human beings respond to the doses and ratios they were being given from their “pharmacy in their neck”?
Each individual body adjusted the ratio at which peripheral tissues converted T4 into T3. Estimated T4-T3 conversion rates ranged from 19.2% to 42.9%.
However, at every stage in Pilo’s calculation, there was a wide range of results, and this range was reduced to an average. The average rate of conversion from T4 to T3 was 27.3%
If you reduce everything to an average at every stage, you will end up blinding yourself to the range of human diversity.
If you take a descriptive average and turn it into a prescriptive dose, it will be just as logical as assigning every individual woman a shoe with the statistical average size of 7 and every man a shoe size with the statistical average of 8, no matter how large or small their feet really are.
Studies like Pilo’s were not meant to be prescriptions for dosing. They were descriptive experiments that were trying to create a model of thyroid health.
Pilo’s team were not studying people with thyroid disabilities. They were not testing which ratios of T3 and T4 hormones could be dosed to adapt to individual disabled people’s degree of thyroid tissue loss and their limited or enhanced metabolic conversion efficiency.
If you apply the same principle to clothing sizes and calories of food consumed, let’s see whether one statistical average really does fit all human beings’ needs. It won’t.
Let’s think about what happens when you choose one ratio for a controlled research experiment.
It will inevitably prove that some people don’t fare very well with a restricted amount and ratio of T3:T4 in their combination therapy. On the other hand, other human beings will be able to adjust to the low amount and ratio of T3 because they are more efficient at converting T4 hormone.
If you average together all the responses to a mono-combo-therapy dosing model, you will get a muddy statistic that hides the suffering of people with the least amount T3 hormone reaching their tissues throughout their body. It will be like hiding the suffering of people forced to wear big, floppy shoes and the people forced to wear too tiny shoes.
RIGGING THE RESEARCH
Not only does averaging human diversity make little sense in research, it makes little sense in real life legislate the average ratio.
It makes even less sense to forget there ever were wide ranges in normal health and declare that the average is now the only physiologically correct ratio, the only safe ratio.
All you are left with is the adjustment of the combination therapy dose size but never, ever the ratio.
That’s basically the same model as T4 monotherapy, which remains at a static ratio of 0:100 no matter how you dose it. That’s why I’ve called this model the mono-combo-therapy model of therapy.
In addition, because the main emphasis seems to be minimizing the amount of T3 in the ratio rather than maximizing it, it can be called the mini-T3-mono-combination therapy model.
It’s not really combination therapy anymore, because there are so many rigid restrictions on it that forbid it from being natural and adaptive like a real thyroid gland and metabolism would be. It’s a T3-minimized, monotonously standardized combination.
If you add to the already restricted research protocol the demand that all doses target a normalized TSH, you add one more element that is just the same as it is in standard T4 thyroid therapy.
You have now ended up with an experiment that takes a model of dosing that is very similar to T4-monotherapy and compares it with T4-monotherapy itself.
It’s no wonder that these studies hardly ever show superiority in the experimental combination protocol, on average!
The studies are rigged. The excessively rigid experimental therapy will be as likely to fail or succeed because it is hardly any different from the model they’re proposing to improve upon by including T3 hormone. Both model permit no adjustment to individual human diversity, but rather aim at a standardized one-size-fits-all model. Both models of therapy bear no relationship to real, flexible thyroid secretion rates and ratios.
T3:T4 RATIO VARIABILITY IS NATURAL
Those who deny a variable T3:T4 dosing ratio in therapy deny the functional purposes of the variable T3:T4 ratios found in health.
Citizens with healthy thyroid glands benefit from a continually variable ratio of T3 synthesized and converted by their thyroid gland. Their ratio of T3 to T4 secretion will adjust as TSH rises and falls within and beyond the statistically normal reference range, according to thyroid science. (Citterio et al, 2017; Köhrle et al, 1990; Tegler et al, 1983; Carpi, et al, 1979)
Indeed, this flexible rate and ratio of T3 and T4 synthesis, secretion, and thyroidal conversion is the behind-the-scenes norm that achieves the appearance of an almost static Free T3 level in serum, even though it achieves a biochemical constant in laboratory test results. That constant at times appears to be the goal, like blood sugar levels, since it is so carefully defended by the body by many backup systems (Abdalla & Bianco, 2014).
Few doctors seem to be aware that Free T3 acts like a biochemical north star in health. Free T3 rarely fluctuates beyond a small percent of variance of its reference range in a state of normally-attained thyroid health, with minor circadian rhythm that follows the daily night-time rise in TSH. (Abdalla & Bianco, 2014).
And it is true that on the contrary, in those who dose T3 hormone, no matter how frequently they dose it, Free T3 fluctuates with “significant excursions” that are feared by some who find something intrinsically dangerous in crossing the upper reference FT3 boundary as well as wandering around up and down within it every day. (Jonklaas & Burman, 2016)
Therefore the current belief is misguided that a “sustained-release T3” pharmaceutical preparation will fix the mini-T3-T4 combination therapy model and render it superior and safe (Jonklaas & Burman, 2016).
This could be yet another detour on the way to a more enlightened understanding. Such an innovation may indeed help some, especially those with adrenal hormone disorders that can respond adversely to T3 dosing. But it will very likely not be medically necessary for the majority of those who dose T3 hormone, since splitting the daily dose is manageable for so many and is effective in reducing fluctuations. (Ben-Shachar et al, 2012, fig. 8)
Those with healthy thyroid hormone metabolisms, those who don’t need any thyroid medications or who metabolize T4 monotherapy well, are physiologically capable of converting T4 into T3 at a continually variable rate in each organ as well. This works together with the classic HPT axis to defend an euthyroid Free T3 level in blood.
These fully thyroid-healthy and untreated people, and likely only they, can obtain the healthy, euthyroid, near-average ratios and stable levels of Free T4 and Free T3 in their bloodstream, but they won’t stay at those static averages every month or throughout their entire lives. Imposing a static Free T3 norm on them would be just as artificial and potentially harmful.
THYROID PHARMA PREJUDICE
Unfortunately for pharmaceutical companies that want to innovate new drugs, there are only two major bioidentical thyroid hormones that are necessary and potentially effective in thyroid pharmaceuticals, T3 and T4. They can be used either alone or in combination. It’s generally the mode of delivery that can innovate, like having a pump or a gelcap or a sustained release version.
Unfortunately for thyroid patients, pharmaceutical simplicity has resulted in the pharmaceutical boundaries being more rigidly and jealously defended; few actors on the stage makes it easier to create a monotherapy or mono-combo monopoly — an empire.
Consider an illustrative contrast with another disease’s pharmaceutical competition and diversity and its associated relative openness to ratio flexibility. In diabetes therapy, a list of more than 50 diverse slow-acting and fast-acting combinations of pharmaceuticals has resulted in a more flexible open mind to variable dose combinations. THEY get to vary their pharmaceutical ratios as their disease progresses, and also to some degree, according to the patient’s preferences.
The ratio-limiters and their prejudice against using a higher ratio of T3 to T4 is just as wrong-headed and un-biological as someone believing that no thyroid patient should ever be on T3 monotherapy or desiccated thyroid medication.
As soon as anyone fights any thyroid medication or ratio for being harmful in itself, they take up a form of thyroid pharma prejudice.
Essentially all thyroid medications include bioidentical hormones that our bodies recognize as their own, even if they are modified in slight ways. These are not man-made chemicals, but synthetic or animal-derived hormone molecules that function as our own hormones in our bodies.
Who’d like to be prejudiced against a human hormone?
Thyroid pharma prejudice, whether used by people who favor T4 monotherapy or people who favor desiccated thyroid, can be extremist. It can be blind to the situations in which any thyroid medication, regardless of its source or ratio, can be useful, necessary, and safe. In fact it’s making one medical tool the enemy of the another, and it threatens to divide patients and doctors, and it’s not very productive in moving thyroid therapy forward for us all.
It’s better to fight against the fallacious thinking and scientific prejudices that surround thyroid pharmaceuticals.
What is so fearful that makes it so hard to accept a larger T3:T4 ratio?
What they seem to be worried about is that some people might need and benefit from and safely dose a robust T3:T4 ratio of 1:4.2 or even more T3 than what they allow. Gasp! Anything that creeps from 1:14 in the direction of 1:4.2 comes too close to the old “gold standard” of desiccated thyroid therapy, which they fear might make a comeback.
It’s a fear of T3 hormone, a fear of the unknown. Along with therapies that emphasize T3 comes a fear of low T4 in early pregnancy damaging a fetal brain, and fear of hyperthyroid elevations of T3 causing heart and bone disorders. All of the areas where fear exists need more research.
To remove fear, it helps to remove ignorance.
A historical study is needed that examines the likelihood that animal-derived thyroid combination therapy harmed a large percentage of the millions of people worldwide who were treated with it before synthetic T4 was a viable medication and before it rose to prominence. Do we really have any records of there being major health problems in this group of patients?
An even better approach to remove the fear and ignorance is to conduct a study of current people who are or have been willingly being treated to euthyroidism, not necessarily to a target TSH, on a variety of larger T3:T4 ratios in combination therapy.
You don’t need to study mice or history when so many people are alive and thriving on this therapy that could participate in research on their biomarkers and health outcomes.
DESICCATED THYROID THE INVINCIBLE
A long history of safe and effective use of desiccated thyroid medication has made it relatively invincible to attacks by the ratio-limiters. It started with giving patients slices of raw sheep or pig thyroid, which worked, and it evolved into the carefully regulated pharmaceutical-quality medication it is today.
You can oppress desiccated thyroid, but you can’t stamp it out, because it cannot be proven to be an intrinsically harmful pharmaceutical combination.
From the point of view of medical publications, the vast majority of the knowledge on using it well and safely was published prior to the vitriolic attack article by Jackson and Cobb titled “Why does anyone still use desiccated thyroid USP?” in 1978. A lot more useful and objective articles were published before that, or even in the same year, “A comparison of thyroxine and desiccated thyroid in patients with primary hypothyroidism” by Sawin et al in 1978.
Science seems to be illogically prejudiced against older publications even when nothing better has superseded it since then, and even though the human body has basically not changed.
Some of this scientific material on desiccated thyroid was written by some of the most highly respected thyroidologists of the day, including Robert Utiger, who was involved in the development of the TSH test.
He and a collaborator were honestly puzzled over the illogical response of the TRH-stimulated TSH to desiccated thyroid as one neared a dose that would render one truly euthyroid (Snyder & Utiger, 1978).
In the next post in the series, I’ll discuss how each patient achieves T3 sufficiency in combination therapy, sometimes at the expense of benignly suppressing TSH.
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
Ben-Shachar, R., Eisenberg, M., Huang, S. A., & DiStefano, J. J. (2012). Simulation of Post-Thyroidectomy Treatment Alternatives for Triiodothyronine or Thyroxine Replacement in Pediatric Thyroid Cancer Patients. Thyroid, 22(6), 595–603. https://doi.org/10.1089/thy.2011.0355
Carpi, A., Bianchi, R., Zucchelli, G. C., Del Corso, L., Levanti, C., Cocci, L. F., … Mariani, G. (1979). Effect of endogenous thyroid stimulating hormone levels on the secretion of thyroid hormones in man. Acta Endocrinologica, 92(1), 73–84.
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
Diabetes Canada Clinical Practice Guidelines Expert Committee. (2018). 2018 guidelines. Retrieved from https://guidelines.diabetes.ca/cpg/
Jackson, I. M., & Cobb, W. E. (1978). Why does anyone still use desiccated thyroid USP? The American Journal of Medicine, 64(2), 284–288.
Jonklaas, J., & Burman, K. D. (2016). Daily Administration of Short-Acting Liothyronine Is Associated with Significant Triiodothyronine Excursions and Fails to Alter Thyroid-Responsive Parameters. Thyroid, 26(6), 770–778. https://doi.org/10.1089/thy.2015.0629
Köhrle, J. (1990). Thyrotropin (TSH) action on thyroid hormone deiodination and secretion: One aspect of thyrotropin regulation of thyroid cell biology. Hormone and Metabolic Research. Supplement Series, 23, 18–28.
Pilo, A., Iervasi, G., Vitek, F., Ferdeghini, M., Cazzuola, F., & Bianchi, R. (1990). Thyroidal and peripheral production of 3,5,3’-triiodothyronine in humans by multicompartmental analysis. The American Journal of Physiology, 258(4 Pt 1), E715-726. https://doi.org/10.1152/ajpendo.1990.258.4.E715
Sawin, C. T., Hershman, J. M., & Chopra, I. J. (1977). The comparative effect of T4 and T3 on the TSH response to TRH in young adult men. The Journal of Clinical Endocrinology and Metabolism, 44(2), 273–278. https://doi.org/10.1210/jcem-44-2-273
Snyder, P. J., & Utiger, R. D. (1972). Inhibition of thyrotropin response to thyrotropin-releasing hormone by small quantities of thyroid hormones. Journal of Clinical Investigation, 51(8), 2077–2084. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292364/
Tegler, L., Gillquist, J., Lindvall, R., Almqvist, S., & Roos, P. (1983). Thyroid hormone secretion rates: Response to endogenous and exogenous TSH in man during surgery. Clinical Endocrinology, 18(1), 1–9.
Wartofsky, L. (2004). Combined levotriiodothyronine and levothyroxine therapy for hypothyroidism: Are we a step closer to the magic formula? Thyroid: Official Journal of the American Thyroid Association, 14(4), 247–248. https://doi.org/10.1089/105072504323030898
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