During therapy for hypothyroidism, dose adjustments may include changing thyroid hormone pharmaceuticals or combining them in a certain ratio.

To prevent overdose or underdose at the new total dosage, a physician will need to estimate the substitution, and later adjust the dose to the individual’s response. The initial calculation needs to be physiologically accurate.

Is 100 mcg of levothyroxine roughly metabolically equivalent to 25 mcg liothyronine? or is the appropriate substitution closer to 100 mcg to 35 mcg lioithyronine?

The three main thyroid hormone pharmaceuticals and their abbreviations are:

• LT3 (Liothyronine sodium, L-triiodothyronine), brand names such as Cytomel, TEVA
• LT4 (Levothyroxine sodium, L-thyroxine), brand names such as Synthroid, Eltroxin
• DTE (desiccated thyroid extract, porcine), historically called “thyroid” and also known as NDT (natural desiccated thyroid), brand names such as “Thyroid” by ERFA Canada, Armour Thyroid. Each tablet usually provides approximately 38 mcg LT4 for every 9 mcg LT3, or a dose ratio of 4.21:1

What would motivate the integration of LT3 into therapy? For instance, here’s a sample clinical situation:

• The patient is symptomatically hypothyroid, even though their TSH is low-normal at 1.0 mU/L.
• To investigate, the physician orders TSH, FT4 and FT3 tests and discovers the following:
  • FT3 4.0 pmol/L (3.5-6.5) = 16.7% of reference width
  • FT4 20 pmol/L (10-25) = 66.7% of reference width
  • TSH 1.1 mU/L (0.2-4.00)
• The FT3 level is significantly below the population median of approximately 50% of reference, and the FT4 is significantly above the population median of approximately 35-45% of reference.
• The FT3:FT4 ratio in blood (4.0 divided by 20) is 0.20. The ratio is lower than 0.25 (GD of 23 nmol/s), indicating they are a “poor converter.”
• The patient is currently taking 150 mcg LT4.
• A physician would like to integrate 10 micrograms (mcg) of LT3 per day into the patient’s therapy.

Here is the question:

• If the physician wishes to maintain roughly the equivalent potency, how many mcg of LT4 should be substituted (taken away) to prevent mild thyrotoxicosis when adding 10 mcg LT3?

How does one estimate the substitution of one dosage for the other to achieve an overall equal potency?

• 1:5 substitution = add 10 mcg LT3 and remove 50 mcg LT4
• 1:4 substitution = add 10 mcg LT3 and remove 40 mcg LT4
• 1:3 substitution = add 10 mcg LT3 and remove 30 mcg LT4
• 1:2 substitution = add 10 mcg LT3 and remove 20 mcg LT4

A clinical trial made a mistake. Saravanan et al, 2007 performed a 1:5 substitution and once-a-day dosing, which resulted in underdose in their population. The mean TSH was within range 1-12 hours but above reference range between 12-24 hours after a single 10 mcg dose.

But the result of Saravanan’s experiment was reported as a statistical average with standard error or standard deviation. On an individual level, some people were significantly more hypothyroid, and others were significantly more euthyroid.

Today, pharmaceutical equivalency statements are provided in the product monographs for Pfizer Canada’s Cytomel and for ERFA Canada’s “Thyroid” (DTE/NDT) both 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 dose substitutions.

They imply that a simple mathematical calculation can estimate dosages of each pharmaceutical in any ratio, either as a combination, or as monotherapies.

• They do not say if the estimate is based on TSH, FT3 or FT4 biochemistry measured a certain number of hours after an LT3 dose, or clinical response (symptoms, health outcomes).
• They give no room for differential LT3/LT4 variation in absorption, binding/transport, metabolism, or clearance.

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 before 1980 disagreed with substituting LT3 with LT4 at a 1:4 ratio. That will overestimate the potency of LT3 for people switching between full-replacement monotherapies.

Historically, clinicians gave much higher doses and ranges to L-T3 because they were interested in equivalent clinical or metabolic effectiveness at a full replacement dose, not an equivalent TSH response involving an LT3/LT4 combination therapy. Also, they often provided dose ranges.

In this post, I begin by listing the variables that can change the relative potency of oral thyroid hormone dosing, and by doing so, skew the substitution ratio.

I then summarize what five 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.

At the end, I’ll show the misleading dose-equivalency charts found in pharmaceutical monographs today and discuss why they are so misleading.

Part 2, the next post in this series, discusses the more recent thyroid science on LT4-LT3-DTE pharmaceutical equivalency. However, before you go there, it is best to understand the scientific history first, because contemporary thyroid science and therapy has been strongly biased by the TSH-T4 paradigm that arose during the 1980s.

Variables influencing dose potency

The number of micrograms of T3 or T4 you put into your mouth does not predetermine how much of each will contribute to T3 signaling in bodily tissues.

These are some of the major variables that will alter the relative potency of LT4 vs. LT3:

1. The number of divided doses of T3 or DTE per day (i.e. 15 mcg /day LT3 taken as 3 doses of 5 mcg each separated by 5-10 hours)
2. Absorption rate, fasted state — in a healthy person, when the stomach is empty, T3 is usually more quickly and completely absorbed than T4 in the fasted state.
3. Absorption rate, fed state, or with interfering substances — ingesting calcium, iron, etc.are known to hinder LT4 absorption. Dosing T3 in a fed state can also delay its peak (Tmax) and reduce its peak concentration (Cmax) and its total % absorption (AUC).
4. Binding protein availability and affinity — How much Thyroxine binding globulin (TBG), Albumin and Transthyretin are available to bind T4 and T3 in blood?
   • Estrogen will elevate TBG, reducing free thyroid hormone availability in a person dependent on dosing (relatively higher % Bound T4/T3 than Free T4/T3), but slowing down metabolic and urinary clearance rates.
   • Lower albumin can inflate FT3 temporarily after a dose (relatively lower % Bound T4/T3 than % Free T4/T3), but the metabolic and urinary clearance rate will increase.
5. Metabolism: intracellular T4-T3 conversion efficiency via global deiodinase type 1 (D1) and deiodinase type 2 (D2)
   • An increase in FT3 above the population median (50% of the reference range) will be expected to upregulate D1, most abundant in thyroid, liver, and kidney tissue.
   • An increase in FT4 above the population median (35-45% of the reference range) will be expected to reduce D2 activity via the process of ubiquitination.
6. Metabolism: intracellular T4 and T3 losses to less-active metabolites (i.e. RT3, 3,3-T2, Tetrac, Triac, T4S T3S, T4G, T3G).
   • Metabolic clearance rates rise as FT3 and FT4 concentrations rise.
7. Urinary losses of T4 and T3 — FT3 losses are faster than FT4 losses, and the clearance rates rise as concentrations rise.
8. Illnesses — Metabolic losses will increase in severe illness or injury. Relatively more FT3 is lost than FT4.
9. Acute effect on TSH within hours/days of a single dose:
   • After absorption, the peak Free T3 provided an LT3 dose will acutely and significantly reduce TSH within 3 hours and subsequently delay its recovery from 12h to 100h in a dose-dependent manner,
   • After absorption of a single dose, the LT4 dose will have a very subtle effect on TSH.
10. Chronic effect on TSH over weeks of daily stable dosing:
    • A delay of 6-8 weeks after an LT4 dose change for FT4, FT3 and TSH to fully stabilize
    • A delay of 5-7 days (after a daily dose change) and TSH should always be measured the same # of hours post-dose, ideally 12+ h post-dose when FT3 and TSH are more stable, to enable comparison of the TSH across dose changes over time.

Let’s listen to thyroid science history regarding true clinical equivalence!

We pay attention to clinical charts of equivalency from thyroid science history for some other very good reasons.

Sources before 1980 are truly the most recent scientific findings about long-term dosing of all forms of thyroid hormone medication.

These scientific sources prior to 1980 were not just doing a short-term 6-week trial of an LT4-LT3 combination, but managing patients for years or decades on each type of therapy.

After about 1980, science history mainly gives us studies of short-term L-T3 monotherapy before radioiodine ablation of remnant thyroid tissue after a total thyroidectomy for thyroid cancer.

Trials of fixed-dose mini-T3 combination therapies of LT3/LT4 began in the mid-1990s. These are all based on a mistaken belief that thyroid hormone combination dosing ought to imitate the narrow statistical average of the secretions of human thyroid glands, estimated by Pilo and team in 1990 in a historic study of 14 men and women. (See “The foundations of synthetic T3-T4 therapy in the 1990s” and “Mimicry: The idol of T3-T4 combo therapy 2004-2014“)

And of course, throughout thyroid science history, we have a lot of studies of rats or mice dosed with T3. But rats metabolize thyroid hormones differently, and rats were not usually taking pills but were often receiving T3 injections. Most importantly, you can’t interview a rat about their thyroid symptoms.

Older historical scientific 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.

These studies were pharmaceutically objective and unbiased.

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 their current “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, older sources do not have their clinical judgment clouded by “in or out” thinking about hormone reference range boundaries.

Their aim was not merely to normalize TSH, T4 or T3 levels in blood to fit within 95% of the untreated population’s range, but to achieve full clinical resolution of hypothyroid symptoms without inducing any hyperthyroid symptoms.

In other words, these sources were not biased toward mere biochemical conformity — forcing the individual thyroid-disabled body to conform to the outer limits of the healthy-thyroid population’s TSH, FT3 or FT4 concentrations in blood.

They were biased instead toward achieving an euthyroid physiological, clinical response to those hormone concentrations in blood.

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 of excess T3 but not as much fear of excess T4.

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 one-sided fear of T3 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.

The older scientists were not overruled by the excessive fear that an isolated mildly high T3 was always harmful and the lack of fear that isolated mildly high T4 was always benign.

The older scientists were not tempted to dismiss “mildly low” T3 or FT3 levels during LT4 therapy as benign, but the ATA 2012 thyroid therapy guidelines did.

This modern scientific bias — thinking that an isolated T3 deficiency could be acceptable and normal during LT4 thyroid therapy — becomes shocking when you realize that decades of thyroid science has already shown that isolated “mildly low” T3 levels can be deadly in people who are not dosing any thyroid hormones! (See “Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.“)

Thyroid science since the 1990s has engaged in “confirmation bias” — the psychological tendency to seek only evidence that confirms your favorite hypothesis while failing to seek disconfirming evidence.

Since 1990 or so, thyroid scientists have defended the hypothesis that TSH-normalized LT4 monotherapy is benign and protective for every thyroid patient and that T3 dosing and desiccated thyroid are unnecessary or harmful.

As part of engaging in self-defensive confirmation bias, thyroid science has turned a blind eye to the death and suffering that occurs when contemporary LT4 therapy policy permits patients’ T3 to fall low for the sake of a normalized TSH. (See “Thyroid patients are routinely excluded from low T3 syndrome (NTIS) research“)

Another aspect of confirmation bias is to ignore thyroid therapy history that showed how dosing was managed to achieve clinical euthyroidism in LT3 monotherapy and desiccated thyroid therapy.

Much of thyroid science history speaks “inconvenient truths” about benign long-term maintenance LT3 and desiccated thyroid 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 historical 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 cited one common mistaken belief:

“The usual equivalence given is 25 mcg daily by mouth of liothyronine being comparable to 60 mg dessicated thyroid, USP,”

— BUT they used scientific, clinical data to refute this belief.  I’ll show how they put this statement into context and continually questioned it.

In their Table 2, they provided the equivalencies based on multiple references, mainly giving them in the form of ranges rather than averages.

The only dosage they gave 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 was being compared to one grain or 65 mg.

EQUIVALENCE // Daily maintenance dose in mg/day

• Thyroid  USP Armour 65 mg potency // maintenance dose 120-180 mg/day
• … is equivalent to L-T4 Levothyroxine 100-125 mcg potency // maintenance dose 0.15 – 0.40 mg/day
• … is equivalent to L-T3 Liothyronine 25-35 mcg potency // maintenance dose 0.075 – 0.125 mg/day

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.”

(Selenkow & Rose, 1976)

(*NOTE: 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.” It matters whether you are testing long-term maintenance therapy or not.

Selenkow and Rose’s article is objective, fair, and scientific, with abundant scientific citations. 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 their 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.”

(Selenkow & Rose, 1976)

Notice there is no rhetoric of panic or abnormality about the suppression of both T4 and TSH by means of T3 dosing. This is just expected and “normal” in “normal” subjects.

What is the “thyroid suppression test”?

The T3 “thyroid suppression test” was used to diagnose Graves’ autoimmune hyperthyroidism before there were antibody tests available, long before they knew it was an antibody that caused the thyroid gland to continue secreting at a high rate in the absence of circulating TSH. (In fact, they used to call the unknown substance a “long acting thyroid stimulator” or LATS.)

The reasoning of the T3 suppression test goes like this:

1. A “normal maintenance dosage” of T3 effectively stops T4 secretion in normal people, but nevertheless maintained euthyroid status.
2. If this “normal manitenance dosage” of T3 failed to suppress thyroid gland function in the test subject, then something else was stimulating the test subject’s thyroid gland to abnormally continue to secrete T4. (They didn’t yet know this was the TSH-receptor stimulating antibody).

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 minor practical 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.”

(Selenkow & Rose, 1976)

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, and our scientific review of “Free T3 peaks and valleys in T3 and NDT therapy“).

For this very reason, the laboratory test peaks and valleys, 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.”

(Selenkow & Rose, 1976)

Are high T3 fluctuations harmful? No, they didn’t think so! I must repeat this phrase in case you missed it above:

“The calorigenic response to this acute load is well known to be delayed and evanescent”

(Selenkow & Rose, 1976)

— no toxic reaction.

(NOTE: 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.”

(Selenkow & Rose, 1976)

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 rather,

“the clinical well-being of the patient.”

GREEN, 1968

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:

EQUIVALENCY:

• 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.”

(Green, 1968)

Therefore, 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.”

(Green, 1968)

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, 1968)

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.”

(Green, 1968)

Of course, the key difference was that in 1968, the TSH test was not yet refined to reveal TSH levels below the 95% reference range for untreated people. The crude TSH tests available at the time could not distinguish the bottom of reference from full suppression.

By 1990, we had a more highly refined TSH test.

Unfortunately, the mistaken overgeneralization that TSH indicated body-wide T3 signaling made doctors feel justified in lowering people’s doses to fit within the reference range — and to dismiss all clinical signs and symptoms of hypothyroidism that remained within the reference range.

REFETOFF, 1975

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.”

(Refetoff, 1975)

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.”

(Refetoff, 1975)

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.” 

(Saberi & Utiger, 1974)

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.”

(Saberi & Utiger, 1974)

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:

1. 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.
2. 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 likely 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.

TSH-centrism is a scientific handicap. 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).”

(Saberi & Utiger, 1975)

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 et al, 1973)

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.” ….

(Chopra et al, 1973)

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.”

(Chopra et al, 1973)

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.”

(Chopra et al, 1973)

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.”

(Chopra et al, 1973)

Now understand the aim of their argument here.

They were not trying to accuse LT3 monotherapy of abnormality and to say that it should never be used as a form of replacement therapy.

No. Instead, Chopra and team 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!

Yes, they were theorizing that T4 was not just an inactive prohormone, that T4 alone, prior to being converted to T3, must have some effect on the body.

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.”

(Chopra et al, 1973)

So, if you want to know if a patient on LT3 monotherapy is getting enough T3 into their tendons, test their ankle reflex, not just their Free T3 or Total T3 level in blood.

Today’s misleading equivalency statements

Now you have the historical context to understand how far “out of line” are the more recent equivalency charts we see today.

Here are screenshots from Pfizer Canada’s Cytomel monograph and ERFA Canada Thyroid product monographs, available online in PDF format at the time of writing.

Cytomel, sold by Pfizer in Canada

This one shows Pfizer’s misleading statement from their product monograph under the heading “Composition,” 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):

The phrase “is equivalent to approximately” is simply not reasonable considering the diversity of response by real thyroid patients in clinical practice.

You cannot expect to switch a person without any thyroid gland function who is euthyroid on 100 mcg / 0.1mg of L-thyronine (levothyroxine) and expect them to survive on 25 mcg liothyronine per day once there is no T4 circulating in blood!

No, in fact, 50-100 mcg of LT3 is the normal range of dosage to maintain an adult (see scientific tables below). Dosing 100 mcg of LT3 is absolutely not the same as dosing 400 mcg of LT4 in terms of the resulting levels of FT3 and FT4 circulating in blood and signaling in cells.

It is unclear how the chemical “composition” of the contents of three different pharmaceutical tablets could be have “equivalency” outside the human body, while they are sitting on the shelf next to each other.

The product monograph states in a separate section “Dosage and administration” on page 10, something very different, and a lot wiser:

“Switching to Cytomel® from thyroid, L-thyroxine or thyroglobulin medication:

When switching a patient to Cytomel® from thyroid, L-thyroxine or thyroglobulin, discontinue the other medication, initiate Cytomel® at a low dosage, and increase gradually according to the patient’s response.

When selecting a starting dose, bear in mind that this drug has a rapid onset of action, and that residual effects of the other thyroid preparation may persist for the first several weeks of therapy.“

(Cytomel product monograph, July 25, 2017, page 10)

Their language, once again, is misleading to lay readers. What they likely mean by “thyroglobulin” is pharmaceutical grade, prescription-only desiccated thyroid extract containing T4 and T3 hormones.

“Thyroid” by ERFA Canada

ERFA Canada has named their Health Canada regulated prescription-only product “thyroid.”

It is a porcine thyroid formulation that has approximately the same ratio of T3 and T4 found in American desiccated thyroid products like Armour and NatureThroid. 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).”

Here is ERFA Canada’s similar statement of what “is usually considered equivalent”:

This is also quite misleading, because the human body will absorb, transport and metabolize T4 and T3 differently when they are dosed at different combinations, or separately, either in the context of a person’s partly functioning gland or their completely removed or non-functional thyroid gland.

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.

These statements presume a 1:4 ratio between T3 and T4 pharmaceuticals.

• 25 mcg of L-T3 = 100 mcg of L-T4 — No, this is false in the human body.
• 50 mcg of L-T3 = 200 mcg of L-T4 — No, this is false in the human body.
• 75 mcg of L-T3 = 300 mcg of L-T4 — No, this is false in the human body.

Major clinical problems can arise with this limited, oversimplified math.

These equivalency statements are completely out of context of the pharmaceuticals’ ability to yield circulating Total T4 and/or Total T3 in blood, much less Free T4 or Free T3 in blood, in a human being over 24 hours.

The more T3 hormone you take in a given dose, the lower the percentage of T3 hormone binds to receptors in cells. In the absence of circulating T4 in blood, deiodinase enzymes are not occupied by the labor of T4 deiodination. A higher percentage of T3 is converted to T2 hormone by deiodinases D1, D2 and D3 before it can bind to receptors.

The scientists cannot see into cells and determine the amount of T3 that finally binds to receptors in the nuclei of cells under all pharmaceutical treatments, so where do they get these ideas?

What is the unstated basis of these equivalency statements?

It’s a shame that the basis is not stated. Where is the published scientific study or studies that prove it?

In today’s context, many will imagine that TSH response is the basis of this supposed equivalency (although this is not stated). Many will mistake that a normalized TSH (a localized hypothalamus & pituitary tissue response to T3 receptor occupancy in those tissues alone) ought to be the sole target of therapy in each and every pharmaceutical modality.

In fact, TSH cannot be used as a judge of equivalency between these three pharmaceutical because of the unnatural response of the hypothalamus and pituitary to T3 dosing.

These tissues simply do not respond normally to fluctuating T3 levels, a fact that was noticed early on by the “father of the TSH test,” Robert Utiger (See A Dialogue with Utiger: T3-based thyroid therapy over-suppresses TSH“). The hypothalamus and pituitary expect T3 to be continually secreted from a thyroid gland or converted from T4. Of course they must respond sensitively to the transient peak in Free T3 levels, because a high level could cause hyperthyroidism if the peak were not just a peak, but a constantly high level.

Therefore, dosed T3 creates peak FT3 levels in blood that artificially over-suppress TSH and can keep it suppressed even during the FT3 “valleys” between T3 doses (Jonklaas et al, 2015; see “Free T3 peaks and valleys in T3 and NDT therapy“).

Clearly, if TSH is the implicit judge of pharmaceutical equivalency, it is faulty. An abnormally lower TSH is a pharmaceutical side effect of T3-inclusive therapy on organs designed to regulate a functioning thyroid gland, not a sign of the effect of dosing on the entire human body.

Because the pituitary responds to T3 dosing in a different way than T4 dosing, the assumptions that establish “normalized TSH” as the target guideline for L-T4 monotherapy cannot fairly set the standards to which the other two pharmaceuticals must conform. 

Overall, these product monographs 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.

In real clinical practice, people occasionally combine thyroid pharmaceuticals, and sometimes T3 is used in isolation as a full thyroid replacement. Therefore, these false approximations could easily lead to underdose when L-T3 is used either alone, or in combination with synthetic T4 or desiccated thyroid. 

On the one hand, a 1:4 “L-T3 = L-T4 pharmaceutical equivalency” is stated in product monographs. This will lead physicians to believe this:

• If you remove 20 mcg of LT4 from a person’s 100 mcg dose, can you “replace” it with 5 mcg of Cytomel and obtain the same clinical effect as 100 mcg of LT4?

NO, one cannot think this way.

Dosing LT3 at a single dose of 20 mcg once a day will upregulate Deiodinase type 3 (D3) enzyme during the post-dose peak in blood. This causes loss of T4 to RT3 and also T3 loss to inactive T2. In addition, T4 and T3 metabolism to glucoronide and sulphate and urinary loss can shift.

But on the other hand, a 1:14 molar ratio (or 1:16 ratio by mcg) is being promoted by modern clinical research trials on T3-T4 combination therapy.

• This “combination dose ratio” is based on the mistaken thinking that combination thyroid hormone therapy must mimic only the average “physiological” ratio of secretion from a human thyroid gland, which is found to secrete an average of 1 part T3 to 14 parts T4.
• The European Thyroid Association (ETA) published a set of guidelines with tables outlining the dose ratios that could be used, given different calculations for T4 and T3 absorption rates — which one cannot control because GI tract health and the consumption of many nutrients and medications that compete with T4 absorption.

The idea that 1:14 ratio is the only “physiologial” combination 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, (one being a replacement ratio, the other a combination dose ratio), and they are sending mixed messages to doctors and patients.

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.

CONCLUSION

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 by giving them an average 75 mcg per day of LT3 (liothyronine) alone.

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? Do we have data proving our thyroid patients today more healthy than theirs were?

Today, we are part of tomorrow’s history. 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, PhD, Thyroid science analyst, thyroid patient, and founder & president of Thyroid Patients Canada

Read Part 2 — New thyroid science

• L-T3 pharmaceutical equivalency, Part 2: New thyroid science

REFERENCES

Link to the separate references page.