What does NEW thyroid science have to say on the topic of thyroid pharmaceutical equivalency?
How many micrograms of L-T3 Liothyronine (i.e. Cytomel) are equivalent to L-T4 Levothyroxine (i.e. Synthroid)?
Thyroid hormone pharmaceutical monographs currently provide very rigid and low-ratio equivalency statements:
- ERFA Canada says “Desiccated thyroid 60 mg is usually considered equivalent to … levothyroxine sodium (T4) 0.1 mg [100 mcg] or liothyronine sodium (T3) 25 mcg.” (p. 8)
- Pfizer Canada says “25 mcg of liothyronine is equivalent to approximately … 0.1 mg [100 mcg] of L-Thyronine [Levothyroxine]” (p. 12)
In my previous post, I uncovered the historical origins of this low 25:100 mcg ratio in the product monographs. I showed that five authoritative publications promoted a higher average of 25 to 35 mcg L-T3 per 100-mcg L-T4.
In this post, I will first review a set of groundbreaking articles from 2010-2013 that discussed this very issue of L-T3 and L-T4 pharmaceutical equivalency by dosing each of them to achieve a target TSH between 0.5 and 1.5 mU/L.
Then I will review principles of thyroid science that prove the futility of trying to determine pharmaceutical equivalency.
Indeed, contemporary thyroid science proves that these are very different pharmaceuticals in their effects on the human body.
One pharmaceutical can never simply “replace” the other.
A ratio of equivalency between the two thyroid pharmaceuticals is impossible to predict in any patient.
However, optimal dosing can be achieved by trial and error and respectful patient-doctor cooperation, just like it was achieved in thyroid therapy history before the TSH and reference ranges overruled us all.
CELI: THE 1:3 EQUIVALENCE TO TSH ALONE
Earlier this decade, Celi and team published three studies that examined what happens when you try to achieve TSH-based equivalency between L-T4 monotherapy on the one hand and L-T3 monotherapy on the other, in people without thyroid tissue (Celi et al, 2010; 2011; Yavuz et al, 2013).
These were rather strong and revealing studies because of their excellent methods.
They knew that science could only test true equivalency if an experiment examined LT3 in isolation from T4 in patients who have almost zero thyroid function and therefore less than 0.3 pmol/L of Free T4 in blood during L-T3 monotherapy.
As soon as an experiment combines L-T3 with a semi-functional thyroid gland and/or another T4-containing medication, it is not really judging L-T3’s intrinsic properties as a pharmaceutical at all. Instead, that experiment is describing how L-T3 interacts with L-T4 at various doses in different types of people.
Whenever you combine the two medications, or when you add T3 to a patient who is producing T4 from their own thyroid gland, the results are far more unpredictable. T4 is the mildly active pro-hormone that can become either T3 or Reverse T3. Therefore, a far wider range of thyroid hormones and TSH concentrations can arise based on the individual’s efficiency at metabolizing the T4 hormone.
Smart researchers such as Celi and team know they have to eliminate this T4 “wild card” from a patient’s body if they are going to test the L-T3 pharmaceutical’s potency on its own.
In their first study (2010), Celi and team used each medication alone to bring the hypothalamus and pituitary tissues to a TSH secretion rate between 0.5 and 1.5 mU/L in 10 people over 30 days. The daily dose was divided into three doses per day.
The dose ranges of mcg / kg / day (micrograms per kilogram of body weight per day) that achieved this narrower target TSH were as follows:
- 0.57 ± 0.08 mcg/kg/day LT-3
- 1.68 ± 0.33 mcg/kg/day LT-4
The L-T3: L-T4 dosage ratio was 0.34 ± 0.05.
This is close to a pharmacological 1:3 ratio of T3 to T4.
Notice the “plus or minus” ranges of doses, and even the range given for the ratio.
This ratio is so close to the ranges given by the five historical thyroid publications’ estimates of equivalency prior to 1980, which I reviewed in my previous post.
The graphs provided with the Celi et al, 2011 article (See Figure 1 below) demonstrate that it takes a significantly higher level of bloodstream Total T3 (NOT Free T3) to achieve an equivalent TSH as a person taking L-T4 monotherapy.
(NOTE: I ethically reproduce the copyrighted image within “Fair use” US Copyright and “Fair Dealing” Canadian copyright for the purposes of criticism and nonprofit education.)
Notice in the graphs that the Total T3 concentration in L-T3 monotherapy varied based on time of day, not just hours since the previous dose.
Individual variation can be seen by the ranges indicated by the vertical lines, showing some people with above-range Total T3 in L-T3 monotherapy.
These higher serum T3 levels were necessary in L-T3 therapy to achieve the target TSH on average — and yet some patients had higher-than-target TSH levels in the morning before and after their first L-T3 dose of the day.
The authors were wise to point out that it took 3 divided doses per day of L-T3 to achieve Total T3 levels that didn’t spike too far above the population reference range. A single dose or two doses per day would likely have achieved much higher Total T3 levels four hours post-dose.
In the graphs you will also notice the average and range of TSH was not the same, being higher in L-T3 monotherapy. TSH was also higher in the morning than the evening on both therapies.
The fact that they targeted a 1.0 mu/L- wide range of TSH (between 0.5 and 1.5 mU/L) is interesting in light of these graphs.
It appears that they had to raise the target TSH range to 1.5 mU/L to accommodate L-T3 therapy if they wanted to keep the average Total T3 secretion down within the population reference.
A very different graph would result if they had targeted a narrower 0.5 to 1.0 TSH within L-T3 monotherapy. The Total T3 would have to be higher and may have risen far above the TT3 reference range.
They really tried to achieve TSH equivalency but they didn’t quite make it. The graphs show that it’s an awkward compromise, a square peg in a round hole.
These two pharmaceuticals are definitely not equivalent in terms of their TSH-TT3 ratios.
Clinicians should keep these key differences in mind when looking at lab test results, as well as the even more significant factor discussed next.
“PITUITARY [TSH] EUTHYROIDISM” IS NOT GENERALIZED EUTHYROIDISM
The strongest feature of all three of the studies as a set (Celi et al, 2010, 2011; Yavuz et al, 2013) is that they were very clear in limiting their claims about what they meant by “euthyroidism” when treating someone with L-T3 or L-T4 thyroid hormones while titrating them only to the TSH test.
By 2013 three of the original authors joined new authors, and they had far more precision in their discernment about the same experiment after using a TRH stimulation test to verify the TSH response.
They knew that if they targeted a TSH level, they were comparing only the “pituitary euthyroidism” achieved by L-T3 versus L-T4. They were not necessarily achieving “generalized euthyroidism” in the patient’s body as a whole.
They seriously questioned whether the patients were truly euthyroid when their target TSH was achieved.
They wrote: “In this context, the data suggest that pituitary euthyroidism, both assessed by basal or TRH-stimulated TSH, does not necessarily equate to a state of generalized euthyroidism at the level of the different targets of the hormonal action.”
In instances where a significant difference was achieved, such as weight loss and reduced total cholesterol, the L-T3 monotherapy patients had healthier outcomes.
Nevertheless, the question remains whether they were using an optimal dose of L-T3 and L-T4.
They recommended that “more research must be done to characterize the optimal dosage and the population who may benefit from such intervention.”
It is very odd that this research team did not cite the science already published regarding the “optimal dosage” to achieve body-wide euthyroidism in thyroid patients. In all three articles, they only cite one that I have discussed in the previous post (Saberi & Utiger, 1974), and it was a narrowly focused study on only two doses of L-T3 and two doses of L-T4.
The average L-T3 dose in Celi et al’s TSH-targeted study was only “40.3 ± 11.3 mcg” and their average L-T4 ratio was 115.2 ± 38.5 mcg (Celi et al, 2010).
Neither of these average doses would have achieved euthyroid status in the patients in Saberi & Utiger’s 1974 experiment that they cite. Their doses would have yielded an elevated TSH result on the older-technology TSH test. In clinical practice, true euthyroidism on L-T3 and L-T4 is achieved for most thyroidless patients at higher doses than Celi and team used, and for many it will be achieved at the point of TSH suppression (see the previous post for the scientific proof).
Despite targeting a low-normal TSH, therefore, these three contemporary articles cast more doubt on the policy of “normalized TSH” even in standard L-T4 thyroid therapy.
Is a normalized TSH capable of rendering any thyroid patient’s body fully euthyroid beyond the pituitary gland’s local tissue response?
Other contemporary scientists say “No.”
Clinical studies of L-T4 monotherapy have led some to conclude that a lower-than-reference TSH is required during therapy to relieve signs and symptoms of hypothyroidism in patients without living thyroid tissue (Ito et al, 2012, 107, 2019; Larisch et al, 2018).
The main drawback of titrating L-T4 to TSH is that this hormone is secreted by a set of tissues that have a uniquely high T4-T3 conversion rate (Christoffolete et al, 2006), a rate which is not representative of any other tissue in the human body.
EQUIVALENCE IS BLIND TO CLINICAL VARIATION
Ultimately, the fallacy of pharmaceutical equivalence is proven by research that shows the wide variation in thyroid patients’ response to thyroid pharmaceuticals — from absorption to receptor activation.
No equivalency statement is capable of accounting for the difference between one thyroid patient and another.
This truth was vividly presented by Midgley and colleagues in 2015, in an aptly-named article “Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency.”
Take two equal Free T4 levels, let’s say 14.5 pmol/L.
At that FT4 level, you will see two different treated thyroid patients achieve a far huger range of concurrent Free T3 levels in blood than you will see between two average healthy people with healthy thyroid glands at a FT4 of 14.5 pmol/L.
Without much thyroid tissue, a person’s thyroid hormone metabolism handicaps become more evident, more exposed.
The less thyroid tissue you have, the higher risk you have of being a “poor converter.”
In poor converters, the higher the FT4, the lower the FT3.
A poor converter and a moderate converter of T4 hormone won’t have as much FT3 as a good converter.
Divide FT3 by FT4 to get a rough ratio, or use the free SPINA-Thyr app to get a precise calculation of global deiodinase efficiency.
Even the best converters among thyroid patients won’t have the high FT3:FT4 ratio above 0.30 pmol/L that you see in the normo-thyroid cohort.
This diverse human response to thyroid therapy amplifies the L-T4 and L-T3 dosing effect. It’s like a domino effect that influences everything from absorption to receptor action.
1) The rates of L-T3 and L-T4 absorption are different, and they vary widely from patient to patient.
These two medications do not get absorbed at the same rates.
The full 32-page pharmaceutical insert for the Levothyroxine brand Synthroid by Mylan (in Canada) states that “absorption varies from 48 to 80 percent of the administered dose” (p. 25).
Within that statement is a 32% variability in the absorption of L-T4. This range directly contradicts any concept of static 1:4 equivalency.
Only part of that variability is due to the long list of substances that can interfere with absorption, including antacids.
The rate of absorption is further influenced by GI tract health in an individual as well as by the choice to ingest the dose close to minerals like iron and calcium.
Take any two patients in a “fasted state,” if one has significantly poorer stomach acids and GI tract health, they are not going to absorb as much as the other.
In contrast, what is the absorption rate of Cytomel L-T3?
“Following oral administration, about 95% of the dose of thyronine is absorbed from the gastrointestinal tract in four hours.” This is now 10% higher than Green’s 1968 estimate of 85% absorption rate for L-T3.
The only absorption-limiting factor listed in the Cytomel monograph is a reduction of bile acids in the stomach, but of course GI tract health will influence absorption of L-T3 as well.
2) These two hormones’ free vs. bound fractions are different, and this affects “loss” of dosed hormone by changing their half-life and clearance rates.
After absorption of L-T3 and/or L-T4 medication into blood, different percentages of T3 and T4 are bound versus free. Each hormone is bound by a different set of serum binding proteins in the bloodstream at a different rate.
This yields a different percentage of each “total” hormone that is “free” and available to be transported across cell membranes.
Percentage bound vs. free differ :
- Approximately 0.03% of total T4
- Approximately 0.3% of total T3 is free = 10x greater per pmol/L
(Feldt-Rasmussen & Rasmussen, 2007)
Strength of binding differ:
- Cytomel’s product monograph says “Liothyronine, not firmly bound to serum protein, is readily available to body tissues” (p. 12).
- Synthroid’s product monograph admits “T4 is more extensively and firmly bound to serum proteins than is T3” (p. 25).
The binding differences result in different clearance rates:
“The ratio of total T4 to T3 in plasma is about 60:1. This is higher than the 20-fold ratio of T4 to T3 that is initially secreted by the thyroid gland because of greater plasma binding of T4 versus T3, resulting in greater clearance rates of T3.” (p. Wondisford, 2016)
Because of differences in binding, T3 and T4 do not have similar half-lives in blood. The half-life of Total T4 is approximately 5-7 days. The half-life of Total T3 is approximately 2.5 days, although reports of T3’s half-life vary, some sources estimating only 1 day.
The differences between these two hormones continue to get larger downstream …
3) The “equivalency” estimates do not account for significant differences in metabolism at different doses.
As T4 and T3 concentrations increase, a human body converts and inactivates them at different rates.
For example, if a person is taking only T4, as Free T4 concentrations rise, less is converted to T3 and more is converted into Reverse T3.
This shift happens whether or not a person is a “good converter” of T4 hormone (Midgley et al, 2015).
This happens as the two deiodinase enzymes, D2 and D3, reciprocally shift their activity and expression in cells as thyroid hormone concentrations increase, even within reference range (Bianco et al, 2019).
The patient’s Free T4 flowing in blood will always generate T3, RT3, Tetrac and other metabolites — but conversion to RT3 will occur at a higher rate than in healthy normo-thyroid people who are not on L-T4 monotherapy.
In other words, nature deals with an isolated excess T4 by converting it to Reverse T3 while depleting T3 hormone.
In contrast, L-T3 monotherapy has different losses.
During L-T3 monotherapy, the main loss is due to the T3 conversion rate to T2 and metabolites like Triac. This converison likely increases sharply during the spike in post-dose Free T3 concentrations, and at all times is likely higher than in L-T4 monotherapy.
Why is this likely?
It is logical because Deiodinase Type 3 (which converts T4 to Reverse T3) becomes highly active in L-T3 monotherapy, protecting the body from those intermittent high peaks in T3 concentrations. This deiodinase, D3, just loves converting its “preferred substrate” T3 into T2 (Escobar -Morreale, 1997; Gereben et al, 2008). Meanwhile D3 is no longer working part-time converting any T4 or RT3 molecules.
Triac is a potent metabolite of T3 that appears in much greater quantity when T3 is pharmaceutically dosed (Medina-Gomez et al, 2004) compared to when T3 is secreted and converted within the body.
4) The major metabolites — Reverse T3, T3, Tetrac, Triac and two different forms of T2, are different hormones. These metabolites have different actions on cells.
The hormone T4 and its metabolites Reverse T3 and Tetrac bind to receptors on the cell wall rather than the nucleus. These two hormones are not derived from T3.
When T4 and RT3 are too abundant and bind to integrin receptors, they cause certain cancers to proliferate (Davis et al, 2011; 2018).
The two types of T2 have very different effects on the body, as discussed in da Silva Teixeira et al, 2017 (See our summary and review). One of these T2 hormones appears to have activity in the T3 receptor in the nucleus.
Triac powerfully suppresses TSH above a certain concentration, and receptors have a stronger affinity for Triac than they do even to T3 hormone (Groeneweg et al, 2017)
Therefore, Triac’s presence in higher-than-normal levels during T3-dominant therapies must never be dismissed as insignificant to the body.
Triac avoids overexciting alpha thyroid receptors, so it avoids overexciting the heart.
This is why Triac hormone monotherapy is being used successfully in therapy for vulnerable, severely disabled thyroid patients with a MCT8 transport deficiency (Groeneweg et al, 2019).
CONCLUSION: GO BEYOND SIMPLE MATH.
The deceptively “simple math” of any estimated equivalence of L-T3 (i.e. Cytomel) and L-T4 (i.e. Synthroid) per microgram is subject to major adjustments within the human body.
These are very different pharmaceuticals.
They can achieve true euthyroidism by very different methods.
These two methods radically shift the TSH, T4 and T3 levels and ratios.
They result in very different metabolites of T4 and T3 that have different molecular actions on each tissue and organ.
Each thyroid patient will respond differently to them at different doses and combinations.
The higher their doses and the less thyroid tissue a person has, the more impossible it is for these two thyroid pharmaceuticals to be biochemically equivalent to each other at any doses.
As for targeting TSH, this single secretion was never designed to be the ultimate goal or judge of thyroid therapy. This is the role we have decided to attribute to TSH within medicine. It promotes medical convenience at the expense of leaving many individuals’ thyroid hormone levels severely deficient.
Focusing only on TSH is a creates a bias toward the pituitary and a blindness to other organs and tissues that do not respond the same way to thyroid hormone concentrations and pharmaceutical dosing effects.
Even the serum hormone levels of T3 and T4 are a means to an end. The two monotherapies teach us that T4 hormone is fully replaceable by T3, but nobody can live without T3 sufficiency in blood.
What is the minimum T3 concentration required for health? It may vary from person to person, and it always depends on their concurrent T4 levels and their conversion efficiency. “Some” T4 will inevitably convert to T3 in tissues, but nobody can predict how much — or how little.
To require any patient to live with less than their birthright of T3 in serum for the sake of a normalized TSH is a form of medically authorized torture.
The true end of all thyroid therapy is generalized tissue euthyroidism throughout the body.
Give us the freedom to achieve “generalized euthyroid status” by the pharmaceutical method that suits OUR unique bodies the best.
When dosing any type of thyroid hormone, listen to our entire body. We listen to it every day. Listen to us as patients.
- Tania S. Smith
See the separate references page.