They say that history is written by the victors. Not always. Sometimes histories are written by advocates for the oppressed and disenfranchised.
A common theme on our website is the need to see current practices and thyroid therapy challenges in light of thyroid therapy history. Instead of trusting histories written by scientists, one ought to go to the primary sources to reconstruct that history.
This article connects several key works to examine the history of synthetic T3-T4 combination therapy since the 1990s.
In part 1 of this series, “The foundations of synthetic T3-T4 therapy in the 1990s,” I examined Escobar-Morreale’s inaugural study of T4 monotherapy in the rat.
Here in this second part of the series, I’ll continue the T3-T4 combo therapy saga by jumping ahead almost a decade, after many human trials had been conducted.
How did we get where we are today? Listen to history.
How do we integrate T3 into thyroid therapy to achieve better health outcomes for suffering patients? Stop repeating history.
Part 2 Synopsis
In a nutshell, this is the history that this post uncovers.
The problem at the root of this chapter in thyroid therapy history was that nobody was looking underneath Pilo’s 1990 averages. Escobar-Morreale began a long tradition of citing Pilo superficially for the sake of his non-representative averages.
Click to expand summary of Escobar-Morreale’s rat studies and adoption of Pilo’s average T3 and T4 secretion rates
Escobar-Morreale’s rat studies 1995-1997 boldly articulated the foundational assumptions of the TSH-T4 treatment paradigm and questioned them.
- In 1995, they shook those assumptions to their core by finding tissue T3 levels deficient in T4-dosed thyroidectomized rats.
- In 1996, they showed that a certain T3-T4 combination dose normalized tissue T3 in thyroidectomized rats.
- In 1997, they followed up with a study of deiodinase activity (D1, D2, and D3) in thyroidectomized rats on monotherapies to discover how rats metabolized T4 or T3 in various tissues.
Unfortunately, this team made a fatal mistake when suggesting the translation of their rat study to humans. They presumed the representativeness of the the average estimated ratio of thyroidal secretion from Pilo’s 1990 study (1 mcg T3 for every 16 mcg T4, which is about 1:14 when measured in molar units).
They then presumed this average calculated secretion rate from a living gland should be imitated in pharmaceutical dosing ratios for all humans.
Nobody since then has been interested in fact-checking the representativeness of this average secretion ratio. If only people had looked closely at the raw data set published in Pilo’s study:
- Nobody noticed that the secretion ratio ranged from 1:6.5 to 1:72, and there was no central tendency among the 14 subjects. Only one young man, Subject #7, came close to the average secretion ratio with an estimate of 1:14.5.
- Nobody noticed that each person’s unique thyroidal secretion of T3 compensated for losses in T4-T3 conversion beyond the thyroid, expressing a fundamental physiological principle of synergy to achieve homeostasis.
- Nobody noticed that therefore, a wide variety of T3 secretion rates had no linear relationship to the FT3:FT4 ratio in blood (mean 0.42, range 0.29 to 0.54).
- Nobody noticed that thyroidal secretion of T3 was abnormally limited by the selection of subjects. TSH stimulation in all 14 subjects was no higher than 2.0 at baseline, and if TSH had been higher, the T3:T4 ratio of secretion could have been higher.
Escobar-Morreale’s team translated this idolized secretion ratio into the concept of a fixed pharmaceutical T3-T4 ratio for all hypothyroid patients. They also added the unnecessary idea of an arbitrary T4-T3 ratio limit beyond which one must never trespass. It was not because a T3-throttle was installed on the human thyroid gland, but because including T3 in therapy threatened a slippery slope toward desiccated thyroid’s* 1:4 ratio. (*NDT/ DTE.)
By 2004, certain opinion leaders were upset that scientists were not doing these therapy trials the “right” way according to the “magic” formula.
Wartofsky’s article in 2004 was a wrist-slapping of T3-T4 combo therapy researchers. The right way, apparently, was to adhere to the 1:14 molar ratio of T3 to T4 chosen by Escobar-Morreale and team in 1995-1996.
In the following year, 2005, Escobar-Morreale’s team tested their ratio on humans, reviewed therapy trials to date, and declared the defeat of the T3:T4 ratio they had idolized a decade before.
By 2012, still more trials had been conducted. Wiersinga and the European Thyroid Association (ETA) also chided the errant T3-T4 combo therapy researchers for not adhering to the idolized “physiological” dosing regime. Disqualifying the evidence of T3-T4 therapeutic success for some patients, they reaffirmed the dogma of LT4 monotherapy for all.
Wiersinga’s ETA group not only echoed and mimicked Wartofsky’s language and ideas, but added barriers to T3-T4 combination therapy to discourage people from pursuing it. Prejudicial qualifications limited the types of patients worthy of an individualized, time-limited T3-T4 combo trial. Complex rules for dose-adjustment bowed to a human hierarchy of pharmaceutical and biochemical priorities. T3-T4 combo administration was declared off limits to all but the medical specialists who would probably not want to do it.
Wartofsky’s later writings in 2012 and 2014, coauthored by Biondi, strengthened another of Escobar-Morreale’s barriers to T3-T4 combo therapy, the slow-release T3 formulation. The failures of disabled bodies to conform to “physiological” ratios of T4-T3 combo therapy meant that patients would have to bear with further T3 deferral. Admittedly, fast-release T3 dosed thrice daily could mimic aspects of slow-release T3, but alas! Brain-addled T3-starved thyroid patients could not be trusted to dose T3 more than once a day to set themselves free from suffering. Despite the reputed failure of trials to date, the priests of T3-T4 physiological mimicry over-promised that a slow-release formula could make future trials succeed, even magically mimicking circadian T3 rhythms.
Wartofsky in 2004
By 2004, many T3-T4 combination therapy trials had already been completed.
Wartofsky wrote an article addressing researchers, using this title:
“Combined levotriiodothyronine and levothyroxine therapy for hypothyroidism: are we a step closer to the magic formula?”
In Wartofsky’s view, the main motive for combination therapy had now changed.
Instead of recalling Escobar-Morreale’s motive to test unproven assumptions about standard T4 monotherapy, now it was doctors’ compassion for patients’ psychological well being that motivated them to entertain physiological mimicry:
“impaired psychological well-being in LT4 treated hypothyroid patients with normal TSH levels” had sparked “interest in the concept of adding triiodothyronine (T3) to traditional LT4 therapy in order to perhaps more physiologically mimic normal thyroid gland secretion.”
The experiments were no longer driven by skepticism about the foundational assumptions of the TSH-T4 treatment paradigm.
It was now unthinkable to admit that patients could be T3 deficient in tissues beyond the brain when their TSH was normalized by LT4. By invoking impaired psychological well being as the problem, it protected the standard therapy paradigm.
In addition, this passage made a T3 therapy experiment seem reassuringly minor and superficial. T3 would not be so integrative or transformative if you were just imagining that you were “adding triiodothyronine to traditional LT4 therapy.” Every healthy-thyroid person doses T3 daily from their gland, but for the thyroid-disabled who depend on pharmaceutical hormones, this phrasing made it seem like T3 in tablet form is merely an optional additive. A tweak. An unnecessary bonus. It was implied that LT4 therapy was enough for everyone except those who maintained psychological impairment when TSH was normal.
Wartofsky was addressing researchers, so this passage above expressed a dash of scientific doubt, the hypothesis. It was only a “concept of adding triiothyronine (T3)” that was worth dabbling in. It might work, or it might not, “perhaps.” Implicitly, who cared if a trial of “adding T3” didn’t work, because physiological T3 secretion was imagined to be so minor. A failure to improve with LT3 could be expected because traditional T4 therapy was assumed to be good enough, and some patients will maintain their psychological impairment.
Mimicry of Escobar-Morreale’s ratio, without verification
Wartofsky’s 2004 piece also reiterated Escobar-Morreale’s belief in a single molar ratio for all. He asserted that studies must mimic not just anyone’s thyroid, but “the” molar ratio from “the” thyroid!
“truly mimics the molar ratio of T4/T3 secreted by the thyroid gland.”
Wartofsky didn’t give numeric ratios in his article’s body, but it is clear that he was referring to Escobar-Morreale’s 14:1 molar ratio. He did not cite Pilo et al, 1990, but only Escobar-Morreale’s 1996 study of T3-T4 combination therapy in thyroidless rats.
It is clear from this article that:
- He did not go back to Pilo and fact-check the wide range of ratios and T3 secretions to see if the statistical average was representative of all humans.
- He did not learn that Escobar-Morreale’s 14:1 molar ratio (equivalent to a 16:1 ratio in micrograms /day) was only represented by one subject in Pilo’s 1990 study, Subject #7.
- He did not notice that Subject #3 had a secretion ratio of 6.5 to 1, which was also a “magic ratio” for Subject 3’s physiologically-correct body.
- He did not notice that an outlier, Subject #14, biased Pilo’s average with her estimated secretion ratio of 72 to 1. In spite of such a low T3 secretion rate, she had amazingly high Free T3 values, thanks to her T4-to-T3 superconverting metabolism. (Read “Meet a person with the perfect T3:T4 thyroid secretion ratio“)
The only magic formula
Wartofsky considered this mimicry of a pseudo-physiological secretion ratio essential to the
“magic formula”
for T3-T4 combination therapy, which was not just a slow-release T3, but more importantly, a limited amount of T3 combined with an ample supply of T4.
This magic ratio became an entry qualification for an upstanding T3-T4 clinical trial. That’s why he harshly critiqued a study of a slow-release T3-T4 combination formula with
“T4/T3 ratios that were not truly physiologic.”
Of course, the therapy trials compared a T3-T4 combination trial ratios with a T4 monotherapy ratio of 0:100 that was not truly physiologic but yet was assumed to hold unquestionable therapeutic efficacy.
I’ll come back to Wartofsky’s later publications to show where he and his colleagues stood almost a decade after this publication.
Escobar-Morreale’s 10-year anniversary intervention
Escobar-Morreale’s team’s rat studies had inaugurated this journey into physiological mimicry of the average human thyroid gland back in 1995 by proving that TSH-normalized LT4 monotherapy failed to achieve tissue euthyroidism in the thyroidectomized rat. Then in 1996, their team claimed that “only the combined treatment with T4 and T3 ensures euthyroidism in all the tissues of the thyroidectomized rat.”
In the year 2005, Escobar-Morreale’s research team published their own human clinical trial, recruiting 23 hypothyroid (not thyroidectomized) females (not all types of humans) who had been maintained on 100 mcg LT4.
They also published a review of clinical trials in 2005 that portrayed their own recent trial as the most rigorous of them all.
They not only declared their own T3-T4 human therapy trial a methodological success but declared all trials amounted to a therapeutic failure. The scientists generalized that not only their idolized physiological dosing ratio, but all other ratios that included T3, offered no “clear advantage.”
The implied search for an “advantage” indicated that trials were not about demonstrating alternative routes to clinical efficacy, but about demonstrating which single approach was to be used on all patients despite the degree or type of thyroid failure, pituitary failure, or thyroid hormone metabolism failure. It was presumed that this complex metabolic condition that affects the health of every other organ and system should only be treated with one pharmaceutical approach, while the list of medications to treat diabetes may expand endlessly.
Despite the test of T3-T4 ratios yielding equality for many patients, merely biochemical failure for some patients, and benefit for other patients, they reasoned that adding T3 meant therapy failure for all hypothyroid humans.
If even they, the fathers of the fixed-ratio T3-T4 therapy proposal, had given a human clinical trial their best shot and failed, then the entire ratiometric mimicry concept had failed.
Their conclusions attempted to nail the coffin shut on the concept of physiological T3-T4 therapy. We should all go back to non-physiological T4 monotherapy and leave this trail of misguided experiments behind us, because we already knew T4 alone could efficiently do the job of eliciting biochemical reference range mimicry — with or without tissue euthyroidism.
Wiersinga and the European Thyroid Association, 2012
In 2012, this idea of mimicry was taken up in the wording and philosophy of Wiersinga et al’s ETA guidelines for combination T3-T4 therapy.
After their document provided a lengthy and damning review of T3-T4 clinical trials to date, they finally got around to providing guidelines for administration of T3-T4 combination therapy to individual patients.
Like Wartofsky, they opened the subject with the idea of the need to resolve patients’ “complaints” about a favorite therapy (LT4 monotherapy) and its favorite target (normal TSH):
“The goal of L-T4 + L-T3 combination therapy is to resolve persistent complaints despite a normal TSH in L-T4-treated hypothyroid patients.”
In this view, the standard dosing ratio of 100:0 was completely acceptable even though it was not physiological, as long as patients did not complain very persistently.
It was implied that doctors should think the complaint is the primary pathology being treated, and yet you’ll see that therapy targets were not finally achieved when complaints disappeared.
Next, the “mimicry” of a “ratio” that is “physiological” was the keystone assumption underlying the use of combination therapy. Over and over, this word “physiological” appears:
“to approach the physiological T4:T3 thyroidal secretion ratio of 16:1 [1]”
Wiersinga’s team said they based the ratio on reference #1, which is Pilo et al, 1990, but they didn’t fact-check Pilo’s data dispersion and range, either.
Instead, they just re-checked Escobar-Morreale’s math on the ratio.
Why is it 16:1 instead of 14:1 this time? Because Escobar-Morreale had converted Pilo’s 6.9% T3 secretion into chemistry units, “moles,” but Pilo used 56.2 (T4) to 3.34 (T3) micrograms / day / m2 body surface area. Moles vs. Micrograms.
The chemistry was a superficial correction. They still presumed Pilo’s Subject #7 could represent everyone and Subject #3’s robust 6.5 to 1 ratio was unphysiological.
Wiersinga and the ETA didn’t really believe in this ratio magic.
Wiersinga’s 2012 guideline was wise enough to cast doubt on these grand assumptions. Let’s see the full list:
In an attempt to realize this goal [of resolving LT4 patients’ persistent complaints], it is assumed that:
— persistent complaints in this context are related to findings in rats that T4 monotherapy does not ensure euthyroidism simultaneously in all tissues;
— a euthyroid state simultaneously in all tissues of hypothyroid patients can be reached by L-T4 + L-T3 in a dose ratio that mimics the physiological T4 to T3 secretion by the human thyroid gland;
— a euthyroid state simultaneously in all tissues of hypothyroid patients is present if serum TSH, free T4, free T3 and the free T4: free T3 ratio are all within the reference range.”
Immediately underneath these grand presumptions that such ratiometric and biochemical mimicry could magically induce and then confirm “an euthyroid state,” they write this disclaimer:
“None of these assumptions may of course be true…”
These presumptions are overgeneralizations.
We should thank Wiersinga’s team for stating them so plainly and questioning them.
It is a fallacy that statistical average T3 and T4 secretion ratios and ranges of blood concentrations aren’t just descriptive of a thyroid-healthy population, they’re prescriptive of health for a thyroid-disabled population and have the power to achieve a euthyroid state simultaneously in all tissues.
The average secretions of The Healthy Gland, when they are the tools to merely normalize TSH, FT3 and FT4, become the means of effective treatment for all individuals who have Not A Healthy Gland.
By this way of thinking, even the narrowest average and the widest reference range can act as a prescriptive magic formula to target when considering a population of individuals with diverse thyroid handicaps and genetic strengths and weaknesses of metabolism.
This is truly magical thinking, much like the idea that eating part of an animal prepared in a ceremonial manner will give you the attributes of that animal, even if you do not have the physiology of that animal.
The third assumption was not established as criteria for tissue euthyroidism in Escobar-Morreale’s research in 1995 through 1997. “— a euthyroid state simultaneously in all tissues of hypothyroid patients is present if serum TSH, free T4, free T3 and the free T4: free T3 ratio are all within the reference range.”
Where did this assumption #3 come from?
It is an assumption inserted by Wiersinga and the ETA.
This final presumption denies the paradigm-shifting demonstration in Escobar-Morreale’s seminal research article in 1995. He and his team discovered that merely having blood levels within reference range did not ensure tissue T3 levels or tissue euthyroidism. In 1996, they showed that adjusting the ratio of dosing had more success in ensuring tissue euthyroidism in rats. The ratio’s success in normalizing rat biochemistry was not its primary success. In 1997, they illustrated the mechanisms: rat tissues metabolized different ratios and doses of T4 or T3 by shifting the three deiodinases that convert T4 and T3.
But Wiersinga and the ETA left behind Pilo’s metabolic insights. They refused to question what normo-thyroid biochemistry meant to diverse human bodies. They put the new wine of T3:T4 therapy into an old wineskin, limiting its revolutionary potential.
They wrote guidelines anyway.
And yet despite casting doubt on this series of assumptions, Wiersinga and the ETA forged ahead to write guidelines:
“Based on these premises, however, suggestions can be made for the most appropriate dose of L-T4 and L-T3 when choosing combination therapy.”
Wiersinga and his crew were just playing along with the trends.
If you insist on integrating LT3 pharmaceuticals into therapy despite the failure of clinical trials, here’s a safe little prison for you to play in that will keep our TSH-T4 therapy paradigm intact!
Their guidelines were more than just “suggestions.” Among them were many recommendations and prohibitions.
Which patients have the right to try the narrow T3-T4 combo?
Wiersinga’s 2012 ETA guidelines recommended that only the most highly qualified patients ought to be permitted this trial of this narrow combination of hormones with the 16:1 T4 to T3 ratio.
The only patients worthy enough were:
- a) compliant, yet continually complaining patients
- b) without a disobedient TSH
- c) who have psychologically come to accept their chronic disease and
- d) who have no symptoms that can be blamed on other autoimmune diseases, and
- e) who can’t be pregnant or have an arrhythmia:
Recommendations
(7) It is suggested that L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously given support to deal with the chronic nature of their disease and associated autoimmune diseases have been ruled out (2/+00).
(8) T4+T3 combination therapy is not recommended in pregnant women and in patients with cardiac arrhythmias (2/+00).
(9) It is suggested that L-T4 + L-T3 combination therapy is discontinued if no improvement is experienced after 3 months (2/++0).
Thankfully, these barriers were only graded as weak (2/+00), (2/+00), and (2/++0), and based on low or moderate quality evidence. However, it is uncertain whether doctors skimming this document for its recommendations will go back to the coding guide to interpret these ratings:
The GRADE system classifies recommendations into one of two grades: strong recommendations receive a grade 1 classification using the term
‘we recommend’, weak recommendations receive a grade 2 classification using the term ‘we suggest’. The quality of the evidence for the recommendations can be +00 (low, grade C), ++0 (moderate, grade B), and +++ (high, grade A).
Only a careful reader may notice that they forgot to use the term “suggest” in their recommendation #8 as stipulated here that they should, on the topic of excluding a) pregnant women and b) people with cardiac arrhythmias.
Click to reveal the problems with excluding pregnant women and people with arrhythmias.
Pregnancy is only mentioned once as an aspect not examined in clinical trials. If you look into the scientific rationale provided in many other articles, it is because of fear of lower T4 harming the fetus’s brain development, not because of isolated transient FT3 excursions due to T3 supplementation. The earliest series of clinical studies in this area, published in nine articles from 1964 to 1976, compared underdosed pregnant patients on desiccated thyroid with sufficiently dosed patients on desiccated thyroid whose children had normal mental development (Man et al, 1991). Therefore, if the patient’s T4 levels are properly monitored and normalized, the imputed risk disappears. (See a discussion of pregnancy risk in desiccated thyroid therapy in “Acella NP Thyroid recall: maternal risk inflated” )
As for cardiac arrhythmias, the 2012 document claims that “The increase of serum free T3 may provoke cardiac arrhythmias in susceptible patients.” Endogenous hyperthyroidism is very different from transient isolated LT3-dose-induced FT3 elevations, but recent studies show that atrial fibrillation risk exists at both ends of the spectrum of low and high T3 in susceptible patients, as well as when LT4 is high-normal as it often is in monotherapy (Wei et al, 2018). Patients with heart failure, for example, who suffer chronic low FT3 while on T4 monotherapy may indeed benefit from raising their FT3 while lowering their FT4, and patients can multi-dose LT3 several times per day to reduce FT3 peaks to less than half their height. (Read our review of what recent researchers in cardiology have to say about “The impact of thyroid hormone dysfunction on ischemic heart disease, and how T3 therapy may help.”)
A striking omission from this list of qualifications is the patient’s low T3:T4 ratio and difficulty raising FT3 above mid-range during LT4 monotherapy.
It is simply logical that patients with lower-normal T3 levels in spite of T4 abundance within range should be targeted for a therapy trial.
Wartofsky admitted this in 2013, but Gullo in 2011 had already questioned whether patients with lower T3 and low T3:T4 ratios were truly euthyroid on LT4 because of deiodinase inefficiency, urging research into a “more physiological treatment.”
People complaining of hypothyroid symptoms may have T3 hormone concentrations below their individual setpoint, since even in thyroid health, Individual thyroid ranges are far narrower than lab ranges, according to research. Some people simply require a FT3 in the upper regions of reference range because of their unique metabolic demands.
Obviously, combination therapy may resolve local tissue T3 deficits, as long as the combination therapy achieves the net result of raising the person’s FT3 rather than lowering it or keeping it the same, and as long as FT4 is not lowered too far without compensating with a rise in FT3.
But the ETA were not interested in resolving tissue T3 deficits because they were reluctant to admit that they existed while TSH was normalized, despite Escobar-Morreale’s proof that tissue T3 deficits were common in thyroidectomized rats on TSH-normalized LT4 monotherapy (1995). A table listing “Possible causes of persistent complaints in L-T4 treated hypothyroid patients” listed four reasons unrelated to LT4’s adequacy before listing “Inadequacy of L-T4 treatment modality.”
Click to learn why lower FT3:FT4 ratios and FT3 levels were excluded as a good reason for a T3-T4 combination trial.
Unwritten paradigmatic presumptions likely led to the omission of this qualification of a patient who deserves a trial:
A low-normal or low Free T3 and a low-normal or low T3:T4 ratio have been presumed to be mere biochemical side effects of LT4 monotherapy whose clinical significance is unknown (Jonklaas et al, 2014), although this presumption has not been rigorously tested by researchers for decades.
- Whenever TSH fails to elevate due to isolated low T3, it is often presumed, without sufficient evidence, that the entire human body beyond the pituitary must therefore be apathetic to the lower T3 level.
- It is often presumed that illness caused the lowered T3, before considering that a lowered T3 may also cause or maintain illness while TSH is normal.
Keeping the FT3 in the lower half of reference, below the mid-range population average, may be a means to achieving an institutionalized biochemical target.
- The oppression of FT3 often enables the normalization of TSH by means of elevating the prohormone, FT4, above the statistical average within range. If FT3 were higher, TSH may fall below range.
- However, this hierarchy of biochemical priorities, “defend the TSH at all costs, using T4 elevation above the norm” is not followed by nature.
- You will rarely see a case of hypothyroidism naturally compensated by the rise of FT4 alone. Instead, nature compensates untreated hypothyroidism by elevating TSH in an attempt to raise T3 higher in its range as FT4 falls. This distortion of TSH is not pathological when it succeeds in defending circulating T3 and compensating for a lowered T4 with a higher T3.
- During recovery from T3 depletion caused by nonthyroidal illnesses, the TSH may rise above reference range. In a healthy thyroid, raising TSH stimulation always amplifies the T3 in the T3:T4 ratio of secretion. This is a method of restoring T3 levels, which is more physiologically urgent for recovery than resupplying T4.
The T3 hormone’s potency is feared in cases of endogenous hyperthyroidism (Graves’ disease or autonomous thyroid nodules) when T4 is also high normal or elevated.
- In light of this fear, T3’s subordination to T4 dominance in non-endogenous therapy appears an acceptable means of subduing T3’s power.
- By this logic, even a transient elevation in FT3 appears to signify risk despite the mitigating context of a lower-normal FT4
- This fear is blind to the function of deiodinase type 3 (D3) to cancel out mild or transient T3 or T4 excursions at a local tissue level.
Because of the above presumptions, FT3 is routinely not ordered as a laboratory test — unless TSH is low and FT4 is normal and the physician wants to know if a higher FT3 is the cause of TSH suppression.
If the ETA were to raise concerns about the health risks of maintaining a lower FT3 or FT3:FT4 ratio., it would appear contradictory to also consider FT3 an unnecessary test during the monitoring of hypothyroid therapy
Only an elevated FT3 is to be feared in the standard paradigm.
The paradigm continues to ignore research showing that tissue T3 deficits and low T3:T4 ratios are associated with many pathologies outside the context of hypothyroid therapy.
As for the qualifications and exclusions they listed, many of them were unfair and prejudicial, putting far too much power in the hands of the physician and denying treatment to the vulnerable who may need T3 in their therapy.
The recommendations put the doctor in the position of judging how “compliant” their patient was, something that the doctor cannot easily prove or disprove.
The doctor was also the only judge of how “persistent” the complaints were and whether the complaints related to therapy or some other illness. Did persistence mean 2 years of complaining or 10 years?
If the achievement of normal TSH values while complaining was a prerequisite, it disqualifies many innocent patients:
- people with LT4 absorption problems who could benefit from LT3’s far better gastrointestinal absorption profile,
- people with central hypothyroidism whose pituitary or hypothalamus cannot induce normal TSH secretion while T3 and T4 are within reference,
- people with persistently suppressed TSH due to persistent Graves’ TSH receptor stimulating antibodies after a thyroidectomy or RAI ablation, and
- people whose TSH cannot be controlled despite high-normal LT4 due to T3 receptor insensitivity or persistent TSH receptor-blocking antibodies.
The recommended “support to deal with the chronic nature of their disease,” implies that many patients’ suffering is merely psychosomatic. The belief was that patients have psychological distress about having lost their thyroid function and becoming dependent on medication. Paradoxically, in such persistent patients, complaining persistently (a qualification) may be misinterpreted disqualifying evidence they have not yet dealt with the chronic nature of their disease.
If other autoimmune diseases must be ruled out, then it may be interpreted to mean that a therapy trial is not permitted in patients whose persistent symptoms may be associated with other autoimmune conditions — despite the fact that such syndromes could well be worsened by tissue T3 deficiencies under LT4 monotherapy.
The “improvement” was to be experienced within 3 months, because that was the limit in the published clinical trials due to resources and funding. But the constraints of a formal trial are different from those of real life. Such a time frame could easily be far too short a trial to allow for testing followed by dose adjustments described (below), followed by re-testing.
Wiggling in the rigid-ratio T3:T4 straitjacket?
Wiersinga and team anticipated that within the scope of a 3 month trial, some patients undergoing a dose adjustment would be incapable of producing TSH, FT3, and FT4 levels all within the normal range even while following their precise advice on T3-T4 dosing.
Therefore, they provided an implied hierarchy in which one hormone, TSH, provided the ultimate biochemical target and another hormone, T3, had to adjust and make way to achieve TSH and FT4 targets:
“If dose adjustment of L-T4 + L-T3 combination therapy is necessary to achieve a normal serum TSH, free T4, free T3 and free T4/free T3 ratio, it is suggested the dose of just one of the components is changed, preferably of L-T3“
In practice, this means T3 hormone is of very low status in their pharmaceutical and biochemical hierarchy. The list is given in traditional priority order, often reflected in laboratory testing flowcharts:
- The adjustment of TSH as an isolated hormone, despite the fact that this represents only pituitary euthyroidism. Judging TSH in isolation from FT4 and FT3 unfortunately means that if pituitary or hypothalamic failure occurs during therapy, it will often go unnoticed. This hormone’s priority is followed by
- The adjustment of FT4 as an isolated hormone within its reference range, followed by
- The adjustment of FT3 as an isolated hormone within its reference range, of lowest priority despite its metabolic potency.
The “additional” LT3 tool burdens the clinician with more metabolic complexity in achieving these paradigmatic targets.
Clinically-experienced readers: Click to read the complex “what ifs” of dosage adjustments according to this hierarchy.
Increase LT3 to lower FT4?
What do we do if the FT4 rises too high while TSH and all else is normal?
They recommended this:
“If serum free T4 is too high, an increase of L-T3 dose will lower serum free T4.”
Illogically, they did not recommend lowering the LT4 dose, the easiest fix, since they had declared (see above) that only the LT3 should be adjusted to make everything fit.
This indirect mechanism of raising T3 to lower T4 relies on a variety of shifts in metabolism, some of which depend on thyroid gland health status, and some of whose effects on tissue health are unpredictable:
- Increasing the FT3 post-dose peak, which increases its rate of conversion to 3,5-T2 and Triac, hormones that have more potent signaling effects in the pituitary than on peripheral tissues, which lowers TSH, which then decreases thyroidal T4 secretion, if that has been contributing to FT4,
- And/or increasing T3 clearance rate, shifting bound vs. free hormone balance, or altering the rates at which T4 and T3 become sulfates (T4S, T3S) or glucoronidated (T4G, T3G),
- And potentially upregulating deiodinase type 3 (D3) via mild hormone excess in some tissues so that both T4 and T3 are converted at higher rates to RT3 and T2, respectively.
But if this didn’t work, both the LT4 dose and the LT3 dose would have to be reduced to maintain the LT3:LT4 dosing ratio. In effect, the patient would have to suffer the metabolic consequences of less of both thyroid hormones and a higher TSH in blood.
A simple scenario … with a potential dilemma
They also decided to give details on the easiest of clinical scenarios:
If serum free T3 is too low, an increase of L-T3 dose is logical, as a higher L-T4 dose is likely to increase serum free T4.
But what shall we do if the patient’s Free T3 level falls below reference but raising only the FT3 causes TSH to fall below reference? Now you’d be forced to choose between the health risks of lower FT3 on the one hand, and faith in TSH. No guidance was given.
Not mentioned in the guidelines: what do we do if the FT3 rises too high? They would say: That’s really easy. You take away T3, not T4.
By this rule, if you reduce the T3 but not the T4, you have now a T4-heavier ratio. But that’s okay! Why? Because it is closer to the 0:100 ratio of LT4 monotherapy which they already think is acceptable and safe. Throw the 1:16 ideal out the window, and go beyond 1:20 if you must.
An omitted clinical scenario
The ETA mentioned the FT3:FT4 ratio as a therapy target.
However, a method of adjusting doses to achieve normalization of the FT3:FT4 ratio was not mentioned at all.
The only sample scenarios given have to do with single-hormone reference ranges, not the ratio reference range.
What is the reference range? A normal FT3:FT4 ratio reference range (95% intervals among 3,800 healthy controls) was established in Gullo et al’s 2011 study, which was cited and summarized in the ETA guidelines.
However, Gullo’s ratio reference range for the FT3:FT4 ratio (0.20 to 0.50 pmol/L) was not quoted in the guidelines.
This reference range appears to be missing because Wiersinga and the ETA refused to calculate ratios as FT3 divided by FT4, always preferring the inverse expression of FT4 per unit of FT3. Nevertheless, Wiersinga and the ETA could have converted Gullo’s ratio reference range mathematically, as a different number yielded by dividing FT4 by FT3.
In all their instructions, they made a superficial mention of targeting a FT3:FT4 ratio within the normal reference range. No instructions were given for this adjustment, and Gullo’s 2011 reference range for the ratio was not provided in text.
None of these wiggling scenarios involved any confirmation that the patients’ complaints, which occasioned a combo therapy trial, were resolved.
Only the experts can manage it?
Wiersinga and the ETA went to great trouble to provide detailed tables and three methods of calculating the dosage based on estimates. The ratios vary from 13:1 to 20:1 T4 to T3 in micrograms per day.
Expert readers: Click to view their three complex methods of calculating dose ratios.
These three methods attempt to enable the pharmaceutical delivery of T3 and T4 at the “physiological” ratio
- A. Assuming “that therapeutic substitution of L-T3 for L-T4 was achieved at an approximately 1:3 ratio” by Celi et al, 2010, who employed both monotherapies, not a T4-T3 combination therapy.
- This yields ratios of 14:1 and 13:1 in mcg
- B1. “Assuming 80% absorption of L-T4 and 100% absorption of LT3,” when in fact it is acknowledged that “It has been reported that 65–75% of oral L-T4 and 69–99% of oral L-T3 is absorbed,” depending on gut health factors. Therefore B2. “Assuming 70% absorption” is provided.
- This yields ratios of 14:1 and 20:1 in mcg
- C. “The simplest protocol” which respects “the availability of L-T3 strength” — because in practice, you’re not going to be able to dose precisely 4.12 mcg or 9.41 mcg of LT3, but you may be able to access tablets in 5, 10, 20, or 25 mcg strengths.
- This yields a ratio of 17:1
None of these achieve the 16:1 target. The doctor can choose.
All this precision ignores the fact that L-T4 may vary in potency from 95 to 105% of its labeled potency and L-T3 may vary in potency from 90 to 110% of the stated dosage, if European pharmaceutical guidelines conform to FDA guidelines.
But they deemed it beyond the mental capacity and pay grade of GPs to arbitrarily pick a preferred dose ratio from their table and start tweaking.
They limited the administration of this therapy to only select specialist doctors:
“accredited specialists in the field of internal medicine/endocrinology.”
Raising and narrowing the qualifications of the physician was just another way to limit patients’ access to T3-T4 combination therapy. Few endocrinologists will want to be saddled with this chore of managing a patient’s “persistent complaints” by adjusting T3-T4 hypothyroid therapy. It is known that endocrinology today gives far higher priority to treating patients with other chronic endocrine conditions like diabetes, Addison’s disease, or hyperthyroidism.
However, the document did not provide full guidelines for experts to manage it. Some critical dose adjustment scenarios, such as adjusting LT3 to achieve a normalized FT3:FT4 ratio, are not addressed (see above). The majority of the document consists of a review of T3-T4 clnical trial literature, and the final sections giving mere “suggestions” is like a much smaller appendix. These are clear signals that this document is not really functioning as its title, “guidelines,” leads one to expect.
- Instead, it appears to be a document that provides justification for taking T3-T4 combination therapy out of the majority of doctors’ hands, just as the para-health organization Choosing Wisely issues paradigm-based “toolkits” to justify taking “unnecessary” FT3 and FT4 testing out of the hands of doctors and putting it into the hands of laboratory technicians who mechanistically follow test-cancellation flowcharts.
This limitation also appears to be a way to keep behind closed doors the awkward adjustments and patients’ complaints. Indeed, it can induce some suffering if the doctor arbitrarily selects one of the many calculated dosing ratios in their table as a starting point for T3-T4 therapy.
- One may take away too much of a low-T3 patient’s T4 and supply insufficient T3 in its place.
- One may overload another patient with unnecessary T3 when their complaint may arise from their high-normal FT4 signaling too much at the integrin receptor on the cell membrane.
But patients’ continued suffering becomes beside the point when the specialist must force-fit a thyroid-disabled person’s metabolism to achieve selective biochemical targets.
Another barrier: Slow-release T3
Guidelines between 2004 and 2014 raised another physiological barrier well beyond the dose ratio of Pilo’s Subject #7.
They raised the bar of physiological mimicry so high that it became out of reach for the present, to be deferred until the unlikely future.
In Wiersinga’s ETA guidelines, under a heading on further research, it is said that
The introduction of a slow-release preparation of L-T3 might be very useful. A slow-release formula of L-T3 may prevent the marked rise of free T3 after ingestion of the current L-T3 tablets.
Escobar-Morreale’s 1995 and 1996 trials in rats, which dosed the rats subcutaneously with an “osmotic minipumps,” concluded with this suggestion of methodological mimicry for experimental humans:
“the route of administration should warrant a constant steady supply of both iodothyronines. This might be achieved by combining the oral administration of T4 with that of sustained enteric release forms of T3, also given orally.
Other possible approaches might involve implantation of preparations with sustained release of T4 and T3 or the transdermal delivery of both iodothyronines.”
Certainly, implants and transdermal delivery are attractive to patients as well as doctors. But it appears that Escobar-Morreale’s team was going too far in recommending a “constant steady supply of both” T3 and T4. Slow-release T4 is relatively unnecessary, was not a priority to most people who managed clinical trials, and was not utilized by their own clinical trial in 2005.
Biondi and Wartofsky in 2012 proposed a perfect “thyroid transplant” is achievable only if a slow-release form of T3 is dosed.
Pilo did not measure T3 secretion pulsatility or release rate, but we must now imagine that the thyroid gland always secretes at a slow rate to achieve
“steady-state T3 concentrations,”
but at the same time as believing sustained slow release from a thyroid achieves a
“circadian T3 rhythm”
(Biondi and Wartofsky, 2012).
Again, in 2014, Biondi and Wartofsky claimed that
“A long-acting slow-release form of T3 will be required to obtain physiological and stable TSH levels with a circadian T3 rhythm over 24 hours.”
(Biondi and Wartofsky, 2014)
This is surprising. Did they not know that TSH varies in a circadian rhythm, and that its variability induces FT3 to vary in a circadian rhythm in health as well? Why would they make it seem like a “stable TSH” was physiological when huge daily fluctuations in TSH within reference range stimulate the thyroid to contribute to a significant natural FT3 elevation every night? (See Circadian rhythms of TSH, Free T4 and Free T3 in thyroid health.)
Did Biondi and Wartofsky not read Escobar-Morreale’s 1996 article? It pointed out that achieving this diurnal rhythm was not possible with their subcutaneous infusion of T3 and T4, a type of slow-release delivery:
Obviously, with this mode of administration, diurnal rhythms of circulating T4 and T3, which might be dependent on the circadian variations in TSH (24), would be abolished.
(Escobar-Morreale et al, 1996)
(See our posts on the physiological significance of circadian T3 rhythm to understand how unlikely it is that the thyroid gland uses a steady rate or ratio to achieve this daily rhythm, given current science.)
Ultimately here’s why this deferral to slow-release T3 is unfair to patients: Economics.
- If the vast majority of doctors are limited by guidelines from prescribing the T3 currently on the market, when would such a small pharmaceutical market demand ever justify the cost of development?
- How could the pharmaceutical companies recover their costs and make a profit without making this slow-release T3 prohibitively expensive? How many countries or health care systems will exclude therapies based on their price rather than their efficacy and safety?
And, finally, there’s a third reason this slow-release T3 barrier is unfair:
Because they refused to trust patients to dose T3 three times a day.
Biondi and Wartofsky insulted all patients by saying that we probably could not handle dosing it three times a day if we were told how it would benefit us.
“Although the use of three daily doses of T3 can improve the T3 serum levels during the day, it is likely to be associated with less than optimal compliance to therapy. ”
Let’s understand this.
Patients must not be permitted to try dosing fast-release T3 three times a day to remove persistent complaints of hypothyroidism, but the average person eats three meals a day without trouble?
To aid in dosing at any time of day, LT3 is easily absorbed with little interference from meals or supplements (see LT3 product monographs).
How many times a day might a Diabetes type 1 patient take a dose of a vital hormone? or an Addison’s disease patient with primary adrenal gland failure?
The leaders of this paradigm believed patients were just too incompetent to handle T3, though it seems this prejudice was based on their perceived noncompliance with once-a-day T4.
Perhaps one should consider that brains may not remember to take doses very well until you give them enough T3.
Also, consider that when a dose is divided into 3 times a day, only 1/3 of the daily dose is lost if one of the three doses is accidentally skipped, which is less of a loss than missing the whole day’s dose, even if the dose is slow-release T3.
The idolized T3-T4 ratio was set up to fail.
Historically, the idol of a single “physiologically correct” ratio backfired and became a barrier to the use of LT3 in therapy.
Claiming that they were pursuing “physiological” mimicry, scientists erected a narrow straw-man T3-T4 ratio as a false idol that was far too easy to topple. They then took pleasure in seeing this false idol fail to meet diverse human metabolic demands while jumping through clinical trial hoops.
They established an antagonistic relationship between the two therapy modalities, requiring either one or the other to be better for all patients, rather than taking a “both and” approach to accommodate both therapies as alternative options.
During a clinical trial, some will be better off by good luck, and others will be worse off by bad luck, and on average, and it is unsurprising if one reaches clinical and statistical insignificance on average. The flaw of over-dependency on the average result, refusing to stratify the sample of thyroid patients by type of hypothyroidism and other confounding factors, has been explained in detail by Hoermann et al’s 2018 article “Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism.”
When this T3-T4 ratio failed to prove superior to LT4 monotherapy, it appeared to excuse LT4 monotherapy from the charge of not mimicking physiological T3-T4 thyroidal secretion.
But while LT4 monotherapy could always be excused for being a nonphysiological ratio, T3-T4 therapy would remain forever in the straitjacketed mimicry of the physiological secretions of Pilo’s Subject #7.
The T3-T4 combo clinical trials and reviews of trials gave scientists many opportunities to defend the boundaries of their domain. They could repeatedly maintain T3’s exclusion from T4-dominant standard therapy guidelines.
The project of narrow ratiometric mimicry distracted medical minds from the more fundamental question of whether the mimicry of normo-thyroid biochemistry induces extrapituitary tissue euthyroidism in all hypothyroid humans. This was the core question raised by the inaugural therapy trials on rats in 1995-1997.
There is no pressing need to allow other therapies to share the throne as long as the goal is merely to make the patient pass through standard thyroid function screening tests while concealing their thyroid disabilities and metabolic dysfunction. Compared to using a single hormone as a tool to achieve such superficial surrogate endpoints, T3-T4 combos are less medically convenient for doctors.
The guidelines’ anti-LT3 blockade
Wiersinga and the ETA included a dismal summary of the therapy trials. In fact, a reader had to skim through their review of this research before they arrived at their concluding T3-T4 therapy combo recommendations.
They concluded their review and summary of these trials with this advice to keep standard treatment guidelines unchanged:
Recommendations
(4) There is insufficient evidence that L-T4 + L-T3 combination therapy serves the hypothyroid patient better than T4 monotherapy (1/++0).
(5) It is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism (1/+++).
Such a summary mentions “the” hypothyroid patient as if we are all the same.
“LT4-LT3 combination therapy” was treated as if all combinations were the same to all patients.
Their scope is far too narrow when they claim “insufficient evidence” on the basis of synthetic combination trials since 1995 only. They make it seem as if combination thyroid therapy was not commonly practiced or studied before then.
Combinations of synthetic and animal derived thyroid preparations have been trialled since the 1950s, alongside both LT3 and LT4 monotherapies (See Trials of T3, desiccated thyroid and thyroxine in 1958 ). The clinical trial design we now practice was unknown at that time, and experiments were more individualized and grounded in data from real therapy situations and patients’ long term histories and symptoms.
Later, tables detailing the range of pharmaceutical equivalency between synthetic LT3, LT4, and desiccated thyroid were published in the 1960s and 1970s to aid those who may change their therapy. Enough was known from clinical experience to realize that their pharmaceutical equivalency ranged from patient to patient when combining them or using them alone (See No, 25 mcg of L-T3 Liothyronine isn’t equivalent to 100 mcg L-T4 )
Desiccated thyroid is the oldest form of T3-T4 combination therapy. Indeed, desiccated thyroid (NDT) has been the most successful long-term real-life “experiment” of 1:4 ratio T3-T4 combination therapy ever performed. It was so successful that it took about 15 years after LT4 became available on the market for LT4 monotherapy to be convincing to the majority of doctors (McAninch & Bianco, 2016).
However, NDT has a T3-enriched ratio below 1:13, which the 2012 guidelines placed strictly off-limits:
(12) As the currently available L-T4 + L-T3 combination preparations contain a L-T4/L-T3 dose ratio lower than 13: 1, it is recommended to use separate L-T4 and L-T3 tablets in L-T4 + L-T3 combination therapy (1/+00).
The year after the ETA publication forbade ratios below 1:13, Hoang et al (2013) published a double-blind clinical trial of desiccated thyroid therapy and found it was capable of making many patients’ bodies mimic normal bioichemistry. Unfortunately, the patients’ lower T4 levels made it likely that some were underdosed to achieve the scientists’ unfairly narrowed TSH targets. (See Review: Hoang’s 2013 conversion table for desiccated thyroid )
To assist some patients whose unique thyroid disability requires a dosing ratio with less T3 than desiccated thyroid, (for example, a ratio closer to 1:14), one may beneficially combine desiccated thyroid with LT4. Many preparations list their T4 and T3 content in micrograms per 60 mg or 65 mg tablet. By this means, one can obtain a cheaper form of LT3 than synthetics often provide. Desiccated thyroid provides a form of T3 that releases slightly more slowly than synthetic LT3, with a delayed FT3 peak at 4-8 hours post-dose (Hershman, 2009).
Mimicry as a cloak for professional conformity
So, in the end, what is the most important reason why opinion leaders say LT3 must be minimized to a set ratio of 13:1 and no “lower”? Because of thyroid therapy history, not because it will harm all hypothyroid patients.
Now you, the doctor, are being persuaded to prescribe Pilo’s Subject #7’s ratio so that you can conform to the Escobarian-Wartofskian T3:T4 ratio along with Wiersingite / ETA restrictions … if you ever have the opportunity to trial a T3-T4 combination therapy on an individual patient.
Without your acceptance of narrow T3-T4 combo restrictions, you may suffer a fate worse than the depression, illness, or early decease of your patient. You’ll be ridiculed and pilloried by all the Wiersingites and Wartofskians!
But smarter, more courageous medical minds have seen through the flaws of this clinical trial tradition (Hoermann et al, 2018). We can too.
Fortunately, medical opinions and therapy practices may be changing. In 2019, a report of a 2017 prescribing survey showed that members of the American Thyroid Association were moving ahead compassionately and using their training to manage T3-T4 combination therapy, to the chagrin of opinion leaders who concluded they were moving ahead too fast (Jonklaas et al, 2019).
You won’t be alone when you push for a true T3 paradigm shift.
Summary: how did we get where we are today?
By insisting that only one magic formula for thyroid therapy may be recommended for all hypothyroid patients, while other gland failures and hormone deficiencies permit multiple therapeutic options.
By mimicking Pilo’s average thyroidal secretion ratio, not acknowledging Pilo’s full data set showing the gland’s flexibility across its full range of 14 healthy subjects, and failing to notice that different ratios and rates of T3 secretion compensated for different individual rates of T4-to-T3 conversion.
By designing a series of flawed T3-T4 combination therapy trials that rested on the physiological assumptions and pharmaceutical preferences that Escobar-Morreale articulated and questioned in his inaugural 1995 rat study.
By damning the set of flawed trials as insufficient evidence of benefit on ANY dose ratio of T3 and T4, when the series only shows that combos were non-inferior to T4 on average, within the TSH-T4 paradigm’s unquestioned criteria and priorities.
By establishing narrow pathways for only a few rare qualified patients to access T3, by permitting only highly qualified specialists to meddle with T3 and T4 combos, and leaving it up to the doctors to subjectively decide whether it was “effective” after only 3 months.
By claiming that slow-release T3 mimics physiology without enough examination of circadian TSH-T3 rhythms, and by claiming slow-release is necessary because thyroid patients would be noncompliant with multiple doses of fast-release T3 per day.
By using guidelines to bully physicians and imprison patients, confining all to a narrow and superficial paradigm that has not always dominated thyroid therapy.
How can we get out of this straitjacket?
Give up on the concept of mimicking a static ratio or rate of glandular secretion in an average human being and then forcing that idol on diversely disabled human beings.
- Instead, examine the full range of effective flexible-ratio T3-T4 combination therapy, research what makes T3 excursions harmless to so many and harmful to a few, and inquire into the methods of approximating natural T3 circadian rhythms that are associated with health and longevity.
Stop overrelying on TSH and mere biochemical normalization as the surrogate endpoints of thyroid therapy.
- Instead, embrace the art of targeting health outcomes, use T3 and T4 and their ratio as our closest indicators of metabolism in light of supply, and use multiple biomarkers of tissue euthyroidism. Beyond biochemistry, ankle reflex testing is cheap and does not require a blood draw. Patient-managed metabolic monitoring can be accomplished via smart devices like wristbands.
Embrace the compassionate goal of optimizing therapy to the individual, not treating an individual as a representative of an average.
- Trust patients to be at least as competent as patients with any other endocrine disorders, monitoring their vital signs as needed and dosing more than once a day if needed.
Question conformity to an old paradigm that rests on questionable biochemical assumptions, pharmaceutical prejudice, and unexplored medical fears.
- Induce health by renewing the paradigm of thyroid therapy.
References
Click to view reference list
Biondi, B., & Wartofsky, L. (2012). Combination Treatment with T4 and T3: Toward Personalized Replacement Therapy in Hypothyroidism? The Journal of Clinical Endocrinology & Metabolism, 97(7), 2256–2271. https://doi.org/10.1210/jc.2011-3399
Biondi, B., & Wartofsky, L. (2014). Treatment with thyroid hormone. Endocrine Reviews, 35(3), 433. https://doi.org/doi: 10.1210/er.2013-1083
Celi, F. S., Zemskova, M., Linderman, J. D., Babar, N. I., Skarulis, M. C., Csako, G., Wesley, R., Costello, R., Penzak, S. R., & Pucino, F. (2010). The pharmacodynamic equivalence of levothyroxine and liothyronine. A randomized, double blind, cross-over study in thyroidectomized patients. Clinical Endocrinology, 72(5), 709–715. https://doi.org/10.1111/j.1365-2265.2009.03700.x
Escobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G. (1995). Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. The Journal of Clinical Investigation, 96(6), 2828–2838. https://doi.org/10.1172/JCI118353
Escobar-Morreale, H. F., Del Rey, F. E., Obregón, M. J., & de Escobar, G. M. (1996). Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology, 137(6), 2490–2502. https://doi.org/10.1210/en.137.6.2490
Escobar-Morreale, H. F., Obregón, M. J., Hernández, A., Escobar del Rey, F., & Morreale de Escobar, G. (1997). Regulation of Iodothyronine Deiodinase Activity as Studied in Thyroidectomized Rats Infused with Thyroxine or Triiodothyronine. Endocrinology, 138(6), 2559–2568. https://doi.org/10.1210/endo.138.6.5212
Gullo, D., Latina, A., Frasca, F., Le Moli, R., Pellegriti, G., & Vigneri, R. (2011). Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients. PLoS ONE, 6(8). https://doi.org/10.1371/journal.pone.0022552
Hershman, J. M. (2009). Hyperthyroidism and Hypothyroidism. In N. Lavin (Ed.), Manual of endocrinology and metabolism (4th ed., pp. 435–448). Wolters Kluwer/Lippincott Williams & Wilkins Health.
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives? Journal of Thyroid Research, Article ID 3239197. https://doi.org/10.1155/2018/3239197
Hoang, T. D., Olsen, C. H., Mai, V. Q., Clyde, P. W., & Shakir, M. K. M. (2013). Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study. The Journal of Clinical Endocrinology & Metabolism, 98(5), 1982–1990. https://doi.org/10.1210/jc.2012-4107
Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., & Sawka, A. M. (2014). Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid, 24(12), 1670–1751. https://doi.org/10.1089/thy.2014.0028
Jonklaas, J., Tefera, E., & Shara, N. (2019). Short-Term Time Trends in Prescribing Therapy for Hypothyroidism: Results of a Survey of American Thyroid Association Members. Frontiers in Endocrinology, 10, 31. https://doi.org/10.3389/fendo.2019.00031
Man, E. B., Brown, J. F., & Serunian, S. A. (1991). Maternal hypothyroxinemia: Psychoneurological deficits of progeny. Annals of Clinical & Laboratory Science, 21(4), 227–239. http://www.annclinlabsci.org/content/21/4/227
McAninch, E. A., & Bianco, A. C. (2016). The history and future of treatment of hypothyroidism. Annals of Internal Medicine, 164(1), 50–56. https://doi.org/10.7326/M15-1799
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
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
Wartofsky, L. (2013). Combination L-T3 and L-T4 therapy for hypothyroidism. Current Opinion in Endocrinology, Diabetes, and Obesity, 20(5), 460–466. https://doi.org/10.1097/01.med.0000432611.03732.49
Wiersinga, W. M. (2008). L-T4 and L-T3 combined treatment vs L-T4 alone. Annales d’Endocrinologie, 68(4). https://doi.org/Doi : 10.1016/j.ando.2007.06.008
Wiersinga, W. M., Duntas, L., Fadeyev, V., & Nygaard, B. (2012). 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. European Thyroid Journal, 1(2). https://doi.org/10.1159/000339444
Wei, S., Wang, W., Liu, N., Chen, J., Guo, X., Tang, R., Yu, R., Long, D., Sang, C., Jiang, C., Li, S., Wen, S., Wu, J., Bai, R., Du, X., Dong, J., & Ma, C. (2018). U-shaped association between serum free triiodothyronine and recurrence of atrial fibrillation after catheter ablation. Journal of Interventional Cardiac Electrophysiology, 51(3), 263–270. https://doi.org/10.1007/s10840-018-0337-z
This is stunningly good. I was cheering along with your so eloquent words. Having gone through the Pilo paper with you, that helped with following the thread. Escobar-Morreale I have only dipped into, but will go back and read thoroughly. Wartofsky I managed to have a short email chat with before he retired.
Can’t wait to read your next article, and will share this one. Thank you so much.
Thanks Linda!
Thanks Linda, there is so much more I could say about Escobar Morrale’s work. I’ve drafted enough material for about four other posts on his T4-T3 combination publications.
[…] We must reach beyond the mistakes of thyroid therapy past, when researchers and doctors demanded of each other the mimicry of unphysiologically rigid average dosing ratios with TSH reference range targets playing double-duty as surrogate endpoints by which therapy is judged. (See our thyroid therapy history review articles “The foundations of synthetic T3-T4 therapy in the 1990s,” “Mimicry: The idol of T3-T4 combo therapy 2004-2014.”) […]
[…] team in 1990. (See “The foundations of synthetic T3-T4 therapy in the 1990s” and “Mimicry: The idol of T3-T4 combo therapy 2004-2014” […]
I am still trying to get it right. At 88 mcg, T4 is at upper end of normal and T3 barely in normal range. I am an extremely ‘poor converter’of T4 to T3 (I have no thyroid, due to RAI in 2005 for Graves hyperthyroid disease). Endocrinologist says Cytomel is too dangerous? Why I don’t know. Went to an integrative medicine doctor and got NPThyroid (natural pig thyroid), and then a few weeks later it was recalled for being sub-potent. Sigh! So now I am trying 88 mcg Synthroid with 5 mcg of Cytomel. I have cut the pill in half and will take half in morning and half in evening. If that feels like too much, I will only take half (2.5) every day. Something has to work.
Doctors should give patients more credit. I know what hyperthyroid feels like…and I know what hypothyroid feels like.
Ah, Mary, Yes, you should know what hypo and hyper feel like more than anyone else who has not experienced both. Sad thing about the NP Thyroid, but hopefully you can find a good dosing ratio with Synthroid & Cytomel. Using mcg of dosing as a guide is not necessarily a wise idea since absorption and urinary losses may vary — blood levels of FT3 and FT4 are often necessary as hard evidence to compare with symptoms. A good approach is to anchor the FT4 somewhere rational, like somewhere mid-range, and then alter your T3 dose cautiously and slowly as a topper, watching your symptoms. Yes, dosing 2x a day due to its short half-life may be wisest. Always test 12+ hours after your T3 dose to avoid bias from the temporary FT3 peak post-dose, and continue to measure the same number of hours post-dose to get reliable results between tests.
I just sigh! I feel a rant coming on…. Cytomel is too dangerous? When your T3 is barely normal, what can dosing T3 do to harm you? The brief rise in FT3 post dose after a T3 or NDT dose is not the same metabolic condition as excess T3 and T4 continually secreted by an overactive thyroid. It certainly will not be the same as being hyper with Graves, when FT3 and FT4 are both continually high.
Is T3 a toxin? I suppose people may mistakenly think it is because of the term “T3-toxicosis” being used for early Graves’ disease. Then there’s the old term “toxic nodule” — and the 5% of thyroid nodules that secrete hormones usually hypersecrete T3.
Nobody talks about “T4-toxicosis” in post-thyroid cancer TSH-suppressive levothyroxine monotherapy. But maybe they should think about renaming it such. High-normal or high FT4 may enter the integrin avB3 receptor on cell membranes and there, its signal can worsen some cancers, worsen atrial fibrillation, worsen blood clotting (See our review of Anderson 2020’s research on hormone levels in atrial fibrillation, and Davis and Hercbergs’ work on the integrin receptor.)
If T3 is not a benign endogenous hormone essential to life, but rather something evil, then all people with healthy thyroids should stop secreting T3 immediately! They should especially stop FT3 from rising during their sleeping hours, which it is wont to do every day in every human with a healthy thyroid. How is the nightly rise of FT3 any different from taking a dose of T3? Everyone with a healthy thyroid has a T3 pharmacy in their neck.
Thank you for such an excellent article. The one size fits all model of T4/t3 ratio makes the informed patient instantly wary and sadly less inclined to trust their endocrinologist. Because of such an inflexible approach, I avoided switching from T3 dominant therapy to T4 dominant therapy even though as it turns out, this time it is working out (due to my recently increased conversation capabilities). Doctors have no idea that simply demonstrating a good understanding of patient variability and conditional variability would both help them to better treat their patients but also gain their patients’’ trust in turn. Thyroid replacement therapy is an ongoing fluid process that often changes with age and health. There is no set in stone as I have learned – what worked for me in my late 30’s early 40’s no longer works now after going through menopause – and I have had to confront my own biases and learn to keep an open mind. Certainly one would hope that a doctor would also share such an approach especially given their access to a much larger pool of patients and experiences. Thank you for such a balanced approach to presenting this complex subject.
Dear Mary, thanks for the kind note of appreciation for my work here. I’m very glad to hear that your T4 dominant therapy is working out as your T4-T3 conversion rate increased. Yes this is so true, our metabolism can change with age and health. I felt fine on T4 monotherapy for quite some time, until I didn’t anymore. I’m approaching menopause and feeling some dread because my mom lost most of her bone density shortly after menopause, and had a lot of insomnia. Let’s hope I weather it okay with the aid of adjustable thyroid hormone dosing, as needed.
Cheers,
Tania.
I am so glad I found this site, and many thanks for all your work on this subject.
I have a question that I have not yet seen addressed anywhere or in your work, but perhaps I haven’t encountered it yet on your site….this is my question:
If your T4 and T3 are at good levels (eg high normal) but TSH is low (eg negligible) is that cause for concern? to lower I have had more than 1 doctor tell me that low TSH is a risk to bones and heart. Because if this I have allowed them to adjust my meds so that I am only on T4 now and I am miserable.
A bit of my history….I am hypothyroid sufferer in the US (Southern California). I was “diagnosed” as hypothyroid in 2017 and later was informed that I have Hashimoto’s disease. I have been to about 5 different doctors for treatments and consultations, 3 of them endocrinologists who only measure T4 and TSH. One doctor put me on NDT where I was feeling better but my TSH was negligible. She then overprescribed supplements causing my liver enzymes to become very high. I then sought other opinions and because she scared me with the TSH and bone/heart risks my current doctor now has me in 50mcg Synthroid and no T3. She refuses to measure T3 (saying it fluctuates throughout the day) and is adamant that low TSH is a risk to my bone and heart health. Thus my question. She says my labs are “perfect” now at .74 T4 and 1.318 TSH. Yet I have gained 10 pounds, have a very low resting heart rate 63) have brain fog, slow metabolism, cannot wake up in the mornings, and no energy. I eat extremely healthy (logging everything I eat) and have a healthy lifestyle so I am very frustrated. It feel like I have been sentenced to a miserable quality of life and have Ben told several times that “it must be something else” when I complain about my continued hypothyroid symptoms.
I am not a stupid person (I work in IT in higher education and have an executive MBA) yet what I am experiencing and what I am being told do not match up. I am analytical and have been doing my own research and your work is a such relief but also a concern since it seems that the issues I am experiencing are common and not taken seriously in the medical arena. I have so many friends and relatives who have similar stories. I am open to any advice on how to take this into my own hands and find a doctor who will work with me to find and OPTIMAL level of medication for me. But if I could could get some more insight into the low/negligible TSH question I would be extremely grateful. Thanks again for creating and maintaining this website…