In thyroid therapy, how many micrograms of Cytomel (T3) are equivalent to how many micrograms of Synthroid (T4)?
Equivalency statements in the product monographs for Pfizer Canada’s Cytomel and for ERFA Canada’s “Thyroid” (NDT brand) claim that a 25 mcg dose of Liothyronine sodium (L-T3) is “considered equivalent” to 100 mcg / μg (0.1 mg) of Levothyroxine sodium (L-T4).
These statements communicate a misleading message to doctors and patients because they do not provide dose ranges, but rather precise doses.
They imply that a simple mathematical calculation can estimate dosages of each pharmaceutical in any ratio, either as a combination, or as monotherapies.
It is naive and potentially harmful to believe that 25 mcg of L-T3 (Liothyronine) is equivalent to 100 mcg of L-T4 (Levothyroxine) at every dose and in every combination and in every patient.
The bulk of historical clinical research and practice disagreed with limiting L-T3 to such a low dose equivalent.
They raised the ceiling — they gave much higher doses and ranges to L-T3.
In this post, I summarize what five (5) historical thyroid science sources had to say about this equivalence between 1968 and 1976, at a time when researchers and clinicians were very familiar with the use of these medications as monotherapies and combinations.
TODAY’S EQUIVALENCY STATEMENTS
Here is a screenshot from Pfizer Canada’s Cytomel monograph showing its statement that 25 μg (25 micrograms, or mcg) of liothyronine is equivalent to approximately 0.1 mg (0.1 milligrams = 100 micrograms) of “L-thyronine” (Levothyroxine)
Here is ERFA Canada’s similar statement of what “is usually considered equivalent.”
In ERFA Canada’s pamphlet, they then provide special dosing guides for children, followed by a table with adult dose equivalents across the three pharmaceuticals.
(NOTE: The equivalency of desiccated thyroid (DTE / NDT) comes under the same criticism of questionable equivalency because it contains a combined dose of T3 and T4. According to the product monograph for Armour brand Thyroid, “one grain,” or 60 mg, “provide[s] 38 mcg levothyroxine (T4) and 9 mcg liothyronine (T3).”)
These statements presume a 1:4 ratio between T3 and T4 pharmaceuticals.
- 25 mcg of L-T3 = 100 mcg of L-T4
- 50 mcg of L-T3 = 200 mcg of L-T4
- 75 mcg of L-T3 = 300 mcg of L-T4
Major clinical problems can arise with this limited, oversimplified math.
In today’s context, many will imagine that TSH response is the basis of this supposed equivalency. Many will mistake that a normalized TSH (hypothalamus & pituitary tissue response) ought to be equally the target of therapy in each and every pharmaceutical modality. They may also assume that the paradigm and guidelines for L-T4 monotherapy provide the standards to which the other two pharmaceuticals must conform.
However, these equivalency statements are completely out of context.
They do not begin to address the complexities of combining L-T4 and L-T3 at various doses, nor the major differences between the two monotherapies.
These equivalencies have their origins in some historical texts in thyroid science, before the rise of the TSH test and before the rise of synthetic L-T4 thyroid hormone replacement surpassed desiccated thyroid and L-T3 monotherapy. This ratio was by no means the standard ratio in those texts.
These historic equivalencies were often expressed as ranges such as “25 – 35,” but they are now being reduced to a single number each.
Even worse, the estimates are distorted in one biased direction — they express only the very lowest “exchange rate” value for L-T3, which is 25 mcg. They do not choose either the midpoint or the highest L-T3 substitution that may be required in patients.
Therefore, these could easily lead to underdose when L-T3 is used either alone or in combination with T4 or desiccated thyroid.
WHY LISTEN TO THYROID SCIENCE HISTORY?
Sources before 1980 are truly the MOST RECENT findings about euthyroid dosing in L-T3 monotherapy.
In these historical sources we find the origins of this 25:100 ratio in today’s product monographs. This equivalence was a point of scientific debate before 1980.
These historical scientists had access to a lot more clinical experience and data about L-T3 therapy. They were far more familiar with the euthyroid clinical and biochemical presentation in long-term L-T3 monotherapy as well as flexible-ratio combination therapies.
After that point, we mainly have studies of short-term L-T3 monotherapy lasting up to 30 days before radioiodine ablation of remnant thyroid tissue after a thyroidectomy for thyroid cancer, and studies of rats or mice dosed with T3.
Beyond this fact, we listen to thyroid science history for some very good reasons.
These sources are free of today’s “thyroid pharmaceutical prejudice” — a prejudice that leads to severe limitations on T3 hormone dosing today.
Before the tide turned against desiccated thyroid as the gold standard in thyroid therapy (during the 1970s), many scientists had an open-minded curiosity and excitement about both of the two synthetic pharmaceuticals, L-T3 and L-T4.
Unlike the writings of some today who vigorously defend L-T4 monotherapy and disparage the T3-based hormone preparations, these historical scientists were not trying to protect or praise the “gold standard” thyroid pharmaceutical (desiccated thyroid), nor were they making unfounded accusations of L-T3 or L-T4 preparations of being dangerous and causing thyrotoxicosis.
Next, these sources do not have their clinical judgment clouded by “in or out” thinking about hormone reference range boundaries.
Unlike the writings of some thyroidologists today, these historical scientists’ descriptions of L-T3 pharmaceutical action were not laced with fearful rhetoric about “excursions” and “fluctuations” in T3 levels in blood. Instead, these historical scientists often discussed very precisely and objectively how TSH, T3 and T4 concentrations differed between the two synthetic therapies, and they understood how their patients’ bodies responded to these fluctuations in L-T3 dosing.
But most importantly, going back to history brings clarity to L-T3 and L-T4 dosing ratios that are currently muddled with confusion, mythology, and fear.
On the one hand, a 1:4 “L-T3 = L-T4 pharmaceutical equivalency” is stated in product monographs.
But on the other hand, a 1:14 ratio is being promoted by modern clinical research trials on T3-T4 combination therapy.
(NOTE: The 1:14 ratio is a modern myth based on a misapplication of kinetic studies like Pilo et al, 1990. It is truly a “myth” to say “the thyroid gland secretes T3 and T4 at a 1:14 ratio” because it overlooks the huge range of ratios of thyroidal secretion and the compensatory rates of T4-T3 conversion found among the 14 iodine-overdosed people in Pilo’s study. This wide range was achieved despite their extremely narrow range of variation in thyroidal stimulation by TSH (1.0 – 2.0 mU/L). It is also a myth because it overlooks the well-known differences between the FT3 : FT4 ratio in a normo-thyroid individual and one who has no living thyroid tissue and is taking static doses of thyroid hormone via the GI tract.)
Today, these two ratios (1:4 versus 1:14) represent two completely different theories about L-T3 and L-T4 dosing, and they are sending mixed messages to doctors who tend to judge by one ratio rather than the other.
Today, believers in this 1:14 myth have promoted the idea that 140 micrograms L-T4 for every 10 micrograms of L-T3 is the only correct physiological ratio at which combination therapy dosing should ever occur, beyond which lies the danger of thyrotoxicosis.
Patients today are telling each other that their doctors, who now have an exaggerated fear of T3 thyrotoxicosis, are subtracting far too much L-T4 when adding tiny doses of L-T3, resulting in net underdose. This is setting up their L-T3 trial for failure.
In contrast to this muddled thinking about L-T3 dosing since the late 1990s, thyroid science history before 1980 is a source of clear-headed and unbiased clinical findings about the physiological equivalency of L-T3 and L-T4 dosing.
Much of thyroid science history speaks “inconvenient truths” about T3 dosing, and these truths are lying buried in the archives, largely unexamined today.
Let’s hear what they said.
SELENKOW & ROSE, 1976
I start with Selenkow & Rose because they reveal the origin of the low L-T3 : L-T4 equivalency ratio, and they disagree with it.
Their main goal is revealed in their title: “Comparative clinical pharmacology of thyroid hormones.”
They state “The usual equivalence given is 25 mcg daily by mouth of liothyronine being comparable to 60 mg dessicated thyroid, USP,” — BUT they did NOT believe it. I’ll show how they put this statement into context and continually question it.
In their Table 2, they provide the equivalencies based on multiple references, mainly giving them in the form of ranges rather than exact figures.
The only dosage they give as an exact figure is the dose of the “standard” medication of the day, desiccated thyroid, then called “Thyroid, USP.” (USP stands for United States Pharmacopeia). Everything else is being compared to one grain or 65 mg.
EQUIVALENCE // Daily maintenance dose in mg/day
- Thyroid USP Armour 65 mg // 120-180 mg
- L-T4 Levothyroxine 100-125 mcg // 0.15 – 0.40
- L-T3 Liothyronine 25-35 mcg // 0.075 – 0.125
In the section on Liothyronine [L-T3] they state the following regarding dosage:
“The usual maintenance dosage of liothyronine (Table 2) for athyreotic patients ranges between 50-125 mcg/day orally with the usual dosage being 75-100 mcg/day.”
“The calorigenic actions of T3 are difficult to equate to desiccated thyroid (USP), levothyroxine [L-T4] or liotrix [a synthetic T3+T4 combo] because of the rather unique rapidity of action of liothyronine [L-T3].”
“The usual equivalence given is 25 mcg daily by mouth of liothyronine [L-T3] being comparable to 60 mg desiccated thyroid, USP. It is regrettable that there are so few studies with sufficient objective data to substantiate this comparison, which, from our investigations would indicate that 30-35 mcg daily by mouth would be more comparable to 65 mg desiccated thyroid for maintenance of euthyroidism.”
“Metabolic studies of liothyronine indicate that the acute calorigenic action of T3 given as a single dose is three to five times that of the equimolar dose of T4 but that the total calorigenic effects are almost equivalent.” (The term “calorigenic” means “producing or increasing production of heat or energy; increasing oxygen consumption.” – Medical dictionary. Equimolar = equal molar weight in chemistry.)
Notice that they explain a difference between “acute” action of a single dose and “total effects,” so it matters whether you are testing maintenance therapy or not.
Selenkow and Rose’s article is objective, fair, and scientific. It engages in a rich dialogue with the people they disagree with, and they provide ample citation and reasoning for their own stance. I have omitted the abundant citations from these quoted passages, but you can see the many footnotes on their equivalency table above.
Defending the expectation of lower T4 and suppressed TSH levels in L-T3 therapy, they say the following:
“Normal maintenance dosages [of L-T3] given to normal subjects alter the serum T4 to produce, in time, depressed serum T4 concentrations in the presence of increased serum T3 concentrations, along with almost complete suppression of pituitary thyrotropic [TSH] action in normal subjects. This latter action is the basis for its use in the [T3] thyroid suppression test.”
They then explain that L-T3 was limited in use not because it was unsafe or ineffective, but mainly due to a minor difference in cost.
Next, they mention the drawbacks of L-T3 dosing inconvenience, which are implied to be less important than cost, likely because they can be overcome:
“Despite the fact that liothyronine [L-T3] action is qualitatively indistinguishable from the metabolic effects of other thyroid hormone preparations, its rapid onset and offset of action and the problems associated with use of laboratory tests for its measurement have limited its clinical usage.”
Notice that they say, above, that the effectiveness of L-T3 monotherapy is “qualitatively indistinguishable” from desiccated thyroid and L-T4 — it is not an inferior pharmaceutical, but an alternative.
As for “the problems with use of laboratory tests for its measurement,” the main “problem” is easily overcome by measuring thyroid hormones at the same number of hours post-dose, long after the volatile post-dose peak in concentration has passed, when the passage of time makes less of a difference in hormone concentration (See Saberi & Utiger’s graphs, below).
For this very reason, Selenkow and Rose strongly caution against using the upper limit of the T3 normo-thyroid reference range as the limit for dosing L-T3 monotherapy:
“Thus, when liothyronine is given in a single daily dosage of 75-100 mcg, the resultant early serum T3 peak is well into the range of T3-toxicosis. The calorigenic response to this acute load is well known to be delayed and evanescent and the patient does not experience an acute metabolic effect or any toxic reaction which might be anticipated by the high serum T3 levels.”
Are high T3 fluctuations harmful? No, they didn’t think so: “The calorigenic response to this acute load is well known to be delayed and evanescent” — no toxic reaction.
(Of course, one cannot generalize this statement to a person who has adrenal insufficiency, since dosing T3 hormone increases tissues’ demand for cortisol and may cause vulnerable patients to have an adrenal crisis, as noted in the Pfizer Canada monograph for Cytomel.)
These clinicians have found that most patients tolerate fast-release LT3 well. This peak T3 in blood is a fleeting effect, and the body cares far more about the average level, which is the main factor that yields true euthyroidism on L-T3 therapy.
They also caution against use of the TSH test as sole judge of any thyroid therapy, including L-T4:
“Because of the ‘lag time’ for the metabolic actions of thyroid hormones and because of the inadequate data regarding conversion of T4 to T3 in humans, changes in serum TSH levels should not be used as the only quantitative measure of the adequacy of thyroid hormone therapy.”
“The ultimate determinant of ‘normalcy’ is still the clinical well-being of the patient, not necessarily the serum concentrations of thyroid hormone parameters.”
I wish we could shout these quotations from the rooftops.
According to the authors, the goal is not to achieve biochemical normalcy (to imitate the hormone secretion of a normo-thyroid person), but “the clinical well-being of the patient.”
Going back in time almost a decade earlier, Green, 1968, in “Guidelines for the treatment of myxedema” (at that time, “myxedema” was a synonym for “hypothyroidism”) stated the equivalency ratios in Table 2:
- 120 mg desiccated thyroid
- = 0.2 mg levothyroxine [L-T4]
- = 0.05 – 0.075 mg liothyronine [L-T3].
Notice that the “average dose” for liothyronine (L-T3) is 50 to 75 micrograms, and either end of this range could be roughly equivalent to 200 micrograms.
The range, therefore, is from 25 to 37.5 micrograms L-T3 to 100 micrograms L-T4.
However, upon inspecting the text, it seems Green’s table is based on intravenous administration, not oral dosing!
He writes, “When administered intravenously, T3 is about 2 1/2 times as potent as T4.” — so it matters how you administer it, and it’s different when it does not go through the GI tract.
Green continued his reasoning about oral doses: “When given orally, T4 is about 66 per cent absorbed; thus, an oral replacement dose would be 260 mcg daily.”
Notice that the table above gives 200 micrograms (0.2 mg) as the replacement dose, but he really means taking 260 mcg orally.
And, “Similarly, total replacement with T3 would require about 70 mcg. intravenously per day; assuming 85 per cent absorption, the oral dose would be about 80 mcg daily. With either agent, the dose would have to be adjusted for weight and age.”
Green’s text also includes the claim his colleagues would echo, which would now be considered revolutionary:
He claimed that TSH to the point of suppression (but not beyond it), rather than TSH normalization, was the natural goal of thyroid therapy:
“When the dose of exogenous hormone is equivalent to the normal endogenous hormone production, TSH secretion ceases and thyroid function is reduced to the very low levels seen after total hypophysectomy [pituitary removal]. Still higher doses of exogenous hormone will be required to produce changes in metabolism characteristic of thyroid hormone excess. In normal subjects, therefore, the minimum dose required to suppress thyroid function [by suppressing TSH] should equal full replacement, and the minimum dose to produce sustained hyper-metabolic effects should be in excess of full replacement.”
Samuel Refetoff stated the following in 1975 in “Thyroid Hormone Therapy,” and this is the historical record, regardless of the degree to which he would edit and say differently today:
“POTENCY EQUIVALENTS AND DOSAGE. The dose equivalents for the various commercial hormone preparations are approximately
- 1 gr [grain] (60 mg) of the crude thyroid extract for
- 0.1 mg of L-thyroxine and
- 30 mcg of L-triiodothyronine.
Ranges were not given here, but the word “approximately” is of some help. The ratio is more favorable for T3, being not 25 but 30 mcg per 100 mcg L-T4.
In addition, ranges are given in other expressions of the relationship: “Adult doses range from 1 1/2 to 2 1/2 gr (mean = 2 gr) of desiccated thyroid or the equivalent of one or a combination of the synthetic derivates.”
How did Refetoff determine equivalency? Again, it is based on how the profession assessed therapy success, first and foremost by clinical benefits to the patient’s health:
“EVALUATION OF THE RESPONSE TO THYROID HORMONE AND DOSE ADJUSTMENT. The earliest clinical evidence for a response to thyroid hormone in the adult hypothyroid patient is diuresis accompanied by loss of weight and puffiness. It is followed by a general improvement in well being, increase in pulse rate and pulse pressure, and increased appetite and psychomotor activity. Constipation disappears and skin texture and hair normalize. The rapidity of response is dependent upon the severity and longevity of the hypothyroidism, the size of the dose, and the type of preparation used. The therapeutic experience is gratifying and when judiciously applied is not accompanied by side effects or a great risk to the patient.”
Now notice the place of laboratory tests. They are only mentioned after the transformation described above, and they are introduced by a strong “Although” clause:
“Although the effects of hormone replacement should be monitored by careful clinical observation and the regimen thus tailored according to individual needs, sometime along the line there is a place for a laboratory evaluation.”
SABERI AND UTIGER, 1974
In 1974, Mansour Saberi, along with Robert Utiger, “the father of the TSH test” and a historic leader in the field of endocrinology, illustrated that a dose of 50 mcg T3 was not equivalent to 200 mcg of T4, by the best measures of their day.
This study compared the first-generation TSH test response to
- two doses in T4 monotherapy (100mcg, 200 mcg) versus
- two doses in T3 monotherapy (25 mcg, 50 mcg).
They found “The elevated basal serum TSH levels indicate that, in these 8 patients as a group, 50 mcg T3 was not adequate replacement.” In contrast, “The mean basal serum TSH concentrations were elevated in the patients receiving 100 μ.g T4 daily and were normal in those receiving 200 μ.g T4 daily.”
Granted, TSH was measured on their old-technology TSH assay, but two reasons make their TSH test a valid measure for the purposes of comparison:
- This TSH test was a single measure applied to both therapies. No matter how imperfect their measuring stick was, it was consistent across the entire experiment.
- Their TSH test was not sensitive enough at lower levels, but it could still reveal higher TSH levels with enough accuracy, which showed a very different TSH response between 50 mcg L-T3 and 200 mcg of L-T4.
Keep in mind that these 8 patients’ concurrent T4 levels in blood were a factor in their study — they still had a T4 supply, even though it was below reference range. In the experiment, 30 days was not long enough for their T4 to clear from their bloodstream. A lot of their T4 supply, although reduced, was likely to convert to T3 in tissues, based on the general scientific principle that more T4 will be converted to T3 via Deiodinase Type 2 when the T4 concentration is low. People without thyroid glands who are not taking any L-T4 will need an increasing dose of L-T3 as their concurrent T4 supply in blood and tissues gradually falls to undetectable levels.
Once-a-day dosing was also a factor in their study. (It was not common practice to dose L-T3 once daily. Three times daily seemed to be the norm.)
And yet the very high peak T3 levels in the 50mcg dose did not decrease TSH sufficiently.
Saberi and Utiger reasoned that “These fluctuations in serum T3 levels must be sufficiently attenuated at the tissue level that such a sensitive indicator of tissue thyroid hormone action as TSH secretion is constant despite the widely varying T3 concentrations which follow once daily T3 administration.”
Notice their wording — the “fluctuations” are “sufficiently attenuated at the tissue level” — attenuated means “reduce the force, effect, or value of.”
In other words, they theorized that the peak T3 above reference was being buffered or weakened within tissues.
The large wave (the peak) was being reduced to a small wave by the time it reached the hypothalamus and pituitary shores — the “shores” are the T3 receptors within the nuclei of cells.
Again, bloodstream T3 fluctuations, even far above reference, were not feared in this mode of therapy.
They were not imagined to be like a damaging L-T3-tsunami as they are today.
They were taken as a matter of course — They mentioned in a very matter-of-fact tone that of course the T3 will rise above reference, because the T3 pool in blood is smaller than the T4 pool. Of course T3 will have a swifter effect because it is far more efficiently absorbed through the GI tract than T4.
Of course the two medications L-T3 and L-T4 will operate differently on the bloodstream concentrations.
But the main question is not just the bloodstream concentration and the sensitivity of the TSH, the pituitary and hypothalamus tissues (something that Utiger was extremely fixated upon), but whether or not the patient’s entire body was in an euthyroid state. As with Celi et al’s articles in 2010-2013, “generalized euthyroidism” was not well answered in this article, while TSH-based pharmacoequivalence was.
At the conclusion of their article, Saberi and Utiger pointed to another article that reported a more effective dose of L-T3: “A similar conclusion was reached by Chopra and coworkers on the basis of their findings in hypothyroid patients receiving 75 μg T3 daily (10).”
This is where Saberi & Utiger’s article ends, and so Chopra and coworkers’ findings will be examined next.
CHOPRA ET AL, 1973
In this 1973 study, Chopra and his colleagues wrote this:
“It is generally held that one must administer 50 to 100 mcg of T3 daily to hypothyroid patients to achieve a euthyroid state. Recent studies, using gradually increasing doses of T3, also indicate that one requires about 100 mcg of T3 a day to suppress elevated serum TSH in hypothyroid patients to within normal range (22).”…
Chopra and team also remarked at length on the height of the T3 mountain range in serum:
“When we examined T3 concentrations in patients taking 75 mcg T3/day, probably a minimal dose to normalize serum TSH (22), it was evident (Figs. 2 and 3) that serum total as well as free T3 concentrations were clearly in the supranormal range during most of the day.” ….
And again: “In four hypothyroid patients given 75 μg T3 per day, serum concentrations of total and free T3 were supranormal [above reference range] during most of the day.”
And again: “Serum T3 concentration may reach as high as 3 times normal before serum TSH is suppressed to normal in hypothyroid patients treated with increasing doses of L-T3.”
All this repeated emphasis pushed their main point — a high L-T3 dose was required to maintain true euthyroid status because they lack T4 in blood:
“Together with previously published information indicating that 75 μg of T3 is no more than necessary to maintain euthyroidism and to suppress elevated serum TSH to normal, our data suggest that maintenance of euthyroidism may require a supranormal concentration of serum T3 because serum T4 is subnormal in this situation.”
They were building up to their main hypothesis — which was not about therapy but about molecular action — they were indicating that because of the relative IMPOTENCY of such high mountains of T3 in the blood, the hormone T4 must have a lot of activity on cells independently of T3!
But that debate would take us off track here. So back to the main point of equivalency.
How did they know these people were truly “euthyroid” if their T3 was above the reference range?
They relied on clinical assessment, not just TSH and T3 levels, to determine an euthyroid dose of T3 monotherapy.
Chopra and team trusted the TSH not for its own sake, but because the test, as rough and imperfect as it was, without prejudicial distinctions at extremely low concentrations, was at that time more consistent with their expert clinical physical examination of the patient.
They say that patients in their group “did not differ clinically or biochemically,” meaning that their clinical status went hand in hand with their biochemical status.
They confirmed their diagnosis of hypothyroidism in patients with insufficient T3 doses by the cheapest and most specific “Tissue-T3-sufficiency” test ever invented:
“The diagnosis of hypothyroidism was also favored by prolongation of Achilles reflex time in the four patients in whom it was measured.”
The historical discussion of pharmaceutical equivalency reveals that it arose out of a rich scientific and clinical debate about real thyroid patients achieving global euthyroid status, versus “mere” biochemical normalcy in terms of TSH and T3 levels in blood.
The dose “equivalencies” were more like an approximate range of effective dosing for each pharmaceutical. They held them lightly because they had to individualize dosing.
Thyroid science history has lessons to teach. It’s a fallacy to dismiss historical thyroid science just because it’s historical. It’s like saying older people are too old to have anything relevant to say about the present.
These were the wise people of their day, guiding therapy based on the wisest thyroid science of their day.
There is no evidence that they were truly overdosing and damaging people’s bodies.
There is no sign of malpractice or of higher levels of disease, frailty, chronic illness, or early death in the treated thyroid patient population before 1980.
What evidence do we have to accuse them with?
Are our thyroid patients today more healthy than theirs were?
Today, we are part of tomorrow’s history. We would be fools to think we know it all better than they did.
People will look back at some of us 50 years from now and laugh heartily at fixed dose equivalency assertions, our rigid-ratio wrangling, our Free T3 fluctuation fears, our thyroid hormone pharmaceutical prejudices and our worship of the sacred TSH secretion.
Contemporary thyroid science has a lot more to say about the degree to which equivalency could be possible at varying doses, given the differences between L-T3 and L-T4 hormone pharmaceuticals, the T3 and T4 concentrations in blood and tissues, and the diversity that exists from patient to patient.
However, that is the topic of another post.
- Tania S. Smith
Link to the separate references page.