The foundations of synthetic T3-T4 therapy in the 1990s

A trend in thyroid therapy, sparked by a 1995 rat study, attempted to mimic a narrowly estimated T3:T4 ratio secreted by human thyroid glands.

This trend was based on a theory of pharmaceutical mimicry of “the” thyroid gland.

Its proponents chose to represent every human being’s thyroid gland by the narrow statistical average secretion ratio of 14 people’s thyroid glands estimated in a classic study by Pilo and colleagues in 1990.

In my recent post, I introduced you to Pilo’s Subject #7, the only man in the study whose thyroidal secretion ratio was close to Pilo’s estimated average among nine men and five women with a TSH of 1-2 mU/L. I profiled the demographics and biochemistry of Subject #7, with a 1 to 14.5 ratio (T3 to T4). I compared him with Subject #3, with a T3-rich 1 to 6.5 ratio, and Subject #14, with a low 1 to 71.5 ratio. I summarized how doctors and scientists wrote lies, wrote prescriptions, and then wrote prohibitions based on beliefs about static T3:T4 ratios.

In this post I provide more in-depth history and criticism of the medical philosophy behind this tradition and the language it employs to persuade.

This is going to be a two-part visual feast.

Here, I’ll quote and critique articles by Escobar-Morreale and team (mainly 1995, with a sprinkling from 1996 and 1997). They propelled a series of clinical trials that rested on shaky scientific foundations.

As I go into part two, 2004 to 2014, you’ll see that the tradition of research returned to the fundamental assumptions that Escobar-Morreale’s work so eloquently articulated and tested and proved to be questionable.

That’s why it’s worth pondering what went wrong, historically.

Do you think this beginning could have propelled a more fruitful series of clinical trials and guidelines?

Back to Escobar-Morreale et al, in 1995

The study that inspired all the T3:T4 secretion ratio mimicry madness was a 1995 study of thyroid therapy in … Rats.

Escobar-Morreale performed quite an original, deep, insightful, and courageous study that articulated the widespread assumptions and justifications of LT4 monotherapy and investigated them.

Overall, what was the guiding philosophy of endocrine therapy for the failure or loss of a hormone-secreting gland?

“The aim of a hormonal replacement therapy is to ensure an adequate supply of the missing hormone in a manner which mimics the normal supply as closely as possible, and results in normal biological effects, both qualitatively and quantitatively.”

Mimicry at the supply level, therefore, is part of Escobar-Morreale’s philosophy.

The second component, however, is normal biological effects (plural, not singular effect, TSH). People now like to omit this part.

Qualitative effects would have to include freedom from hypothyroid symptoms, quality of life, and health outcomes not easily rated on numeric scales, and quantitative effects may include pituitary TSH responses as well as other measurable biomarkers of euthyroid T3 hormone signalling throughout the body.

The assumptions of the TSH-T4 therapy paradigm

Escobar-Morreale’s team articulated the widespread assumptions implicit in Levothyroxine (LT4) monotherapy and attempted to test them in rats without thyroid glands (athyreotic / athyrotic, with no thyroid).

#1. The idea that peripheral T4-T3 conversion can always compensate for loss of thyroidal T3 secretion.

“An athyrotic rat receiving T4 alone in amounts sufficient to ensure normal circulating levels of both iodothyronines [T4 and T3] ought to be able to compensate for the absence of thyroidal secretion of T3, a relatively minor source of T3 available to tissues.”

Let’s take this quote apart to see the errors in the standard thyroid therapy paradigm that Escobar-Morreale is summarizing.

a) Minimizing rat thyroidal T3 secretion so you can minimize human T3 secretion even more

Notice that they minimized the importance of the rat’s thyroidal T3 secretion by saying:

In “the athyrotic rat,” … “thyroidal secretion of T3 [is] a relatively minor source of T3 available to tissues.”

This minimization is very strange. Rat thyroid glands maximize T3 compared to ours.

As seen in the quote below, rat thyroids secrete on average a T4:T3 ratio of 6.5 to 1, a far more T3-rich average than the 14:1 molar ratio estimated average in human thyroids.

This rhetorical choice to minimize rat thyroidal T3 works to amplify the minimization of human thyroidal T3.

The standard paradigm has defended LT4 monotherapy on the false basis that if rat-thyroid T3 is (on average) “relatively minor” contribution to rat T3 in blood, then human-thyroid T3 must be hardly worth a blink, like a footnote on a footnote.

One of Pilo’s patients, Subject #3, secreted T3 at the rate of a rat. His ratio was approximately 6.5 to 1 (T4 45.3 mcg/d/m2 divided by T3 7.05 = 6.425). But by this reasoning, if rat secretion is minimal, so was this man’s.

But what is the point of minimizing T3 at any time when T3 is the hormone with the maximal metabolic potency, which we know has health outcomes?

As you can see, as Escobar-Morreale summarized the assumptions, the numerical and rhetorical minimization of thyroidal T3 is a distortion of evidence that justifies the maximization of LT4 in the ratio of dosage (100:0).

b) Incorrect model of the physiological mechanisms that “compensate” for T3 losses.

Note the theory of compensation articulated in this quotation. I’ve written another post about how Pilo’s article, and others since then, show that thyroid T3 secretion compensates for T4-T3 conversion.

Escobar-Morreale summarized the standard belief. Doctors had justified their preference to use 100% T4 to replace the thyroid gland by believing that the peripheral T4-T3 metabolism of the rat (and by extension the human) “ought to be able to compensate” for such a “minor” loss as a 6.5 to 1 thyroidal T4:T3 secretion.

As of 2020, we now know that the peripheral T4-T3 converting deiodinases are assistants, but Abdalla & Bianco’s and Laurberg’s review of science show that the thyroid gland is our complete T3 shield (see the link to our post). The powerful thyroid can always secrete a T3-enriched ratio to make up for shortfalls in T3 production due to deiodinase problems, but the peripheral deiodinases (the deiodinases located outside the thyroid gland) can’t always compensate for thyroid tissue loss.

Was there any hard empirical evidence, as of 1995, that the human deiodinases which perform T4-T3 metabolism in peripheral tissues were capable of fully compensating for the lack of T3 secretion from the thyroid? No.

Escobar-Morreale’s next sentence is:

This assumption, however, has never been confirmed directly, although it is implicit in substitution therapies using T4 alone.”

“Has never been confirmed directly?” Let’s ponder this lack of assumption-checking in light of the usual progress of clinical trials for experimental therapies.

Histories of thyroid therapy tell us that prescriptions for levothyroxine outpaced prescriptions for desiccated thyroid during the 1970s.

Escobar-Morreale’s team are saying that scientists waited until 1995 to test this fundamental assumption underpinning LT4 monotherapy in experimental rats.

Therefore, T4 monotherapy had already gone ahead in experimental humans worldwide.

We ought to be able to compensate! Why? Because doctors feel better about their therapy choice on vulnerable people’s behalf when they reassure themselves “you can compensate for my imbalanced choice.” And if the patient can’t? …

#2. The idea that “tissue” T3 sufficiency can be predicted by “serum” T3 or serum T4 normalcy.

Escobar-Morreale then articulated the other implicit assumptions about thyroid biochemistry and physiology that were at the foundation of LT4 treatment according to the TSH-T4 paradigm in 1995:

  1. Tissue T3 in FT3-dependent tissues would be normal when serum T3 was normal, and
  2. In the tissues that depended on T4-T3 conversion, tissue T3 would be normal under the following circumstances and assumptions:

“when T4 was normal or somewhat elevated,

provided the physiological responses to changes in thyroid status of the different deiodinases and of other regulatory mechanisms are not impaired.”

You can see that the standard therapy paradigm, which judged by normal ranges, permitted T4 to be elevated. But it was silent on permitting T3 elevation because it would conflict with the normal TSH assumption, articulated next.

In the phrase “provided…” above, we learn that the TSH-T4 paradigm took as a fundamental assumption that deiodinases (the three T4-T3 conversion enzymes D1, D2, and D3) and mechanisms such as transmembrane transport proteins, were not handicapped.

And why should it be reassuring that our peripheral deiodinases are not impaired?

Because all humans are assumed to be “deiodinase rich” people.

To use a monetary metaphor, all humans are assumed to invest T4 hormone in tissues within and beyond the thyroid that yield a sufficient rate of T3 hormone dividends.

The loss of thyroidal deiodinases is presumed to be a minimal loss.

Sure, you’ve had your thyroidal deiodinases removed or killed. But lucky you! You’ve got superconverting peripheral deiodinases everywhere else in your body. They can rise to the occasion of increased demand for T4 conversion. Now you can retire from flexible, customized thyroidal secretion of T3! Now, your doctor can be excused from providing you any T3 replacement! You can rely only on a steady, reliable stream of nonthyroidal T3 investment income (from your global nonthyroidal T4-T3 conversion rate).

This is a fiction of no human diversity in T4 metabolism that reassures doctors and patients about the extent of T3 loss from tissues given “normal T3” and “normal T4” after thyroid gland loss.

#3. The idea that normalization of pituitary TSH confirms tissue T3 throughout the entire body during thyroid disease and therapy.

Next, they identify the master-assumption that arose from the assumed superiority of the master-gland (the pituitary). As they summarize this ruling philosophy, they explain that TSH was established as the primary judge of euthyroidism within the TSH-T4 therapy paradigm:

“Normalization of circulating thyroid-stimulating hormone (TSH) is usually taken as confirmation that this [tissue euthyroid status] has occurred.”

In this way, the TSH was imbued with supraphysiological omniscience regarding tissue euthyroidism throughout the entire body.

This assumption that TSH normalization meant tissue euthyroidism was severely questioned in a 1994 rat study (which likely served as inspiration to Escobar-Morreale). They distinguished between TSH-suppressing activity (TSA) of a thyroid hormone and its metabolic activity (MA):

“Although elements of the TSH regulatory loop and the peripheral metabolic effector loop may be identical, for example, receptor-mediated transcriptional events, there are no obvious biochemical reasons requiring that the effective TSA of a thyroid hormone must be proportional to its MA.”

Barsano et al, 1994

In other words, just because a certain thyroid hormone concentration normalizes pituitary TSH secretion, which has a regulatory role, it does not mean that the T4 and T3 hormone concentration is equally active in tissues beyond the pituitary where it has a primarily metabolic role.

How did this TSH supremacy happen?

If you’re interested in stepping back from Escobar-Morreale for a while, I’ll give you a brief history of how the development of TSH testing changed thyroid therapy around 1990.

Click to reveal TSH supremacy history section

In thyroid therapy practice, TSH gradually rose in significance as an assessment of thyroid hormone supply and thyroid function. But TSH received its final push to preeminence as the primary judge of euthyroidism around 1990 when a more highly sensitive TSH assay was developed that could detect levels below normal reference range.

In 1990, Utiger, a leading thyroid scientist who could be considered “the father of the TSH test” heralded this ultra-sensitive TSH test. However, he gave a strong caution that a low TSH on this new assay did not always mean overtreatment or hyperthyroidism. Nevertheless, Utiger, in love with the “exquisite sensitivity” of the TSH hormone, had faith in this hormone. He guessed that once this TSH test could finally reveal the hormone’s full range of senstivity, a low TSH “probably” meant that an LT4 patient was overtreated. (See our analysis of Utiger’s TSH-T3 relationship insights.) He overstepped himself and revealed his faith in TSH, and many followed in his faith.

Before 1990, doctors using T4 monotherapy knew they often had to provide supraphysiological T4 (yielding an excess T4 above the reference range) if they wanted to produce clinical euthyroidism. They knew that therapeutically raising T4 would lower TSH. (Ingbar et al, 1982).

Leading scientists that measured T3 and the T3:T4 ratio knew that

  • clinically measurable signs and symptoms of euthyroidism appeared to be based on T3 supply (an individual’s optimal T3 within range, not just anywhere in range), and
  • clinical status was not ensured by normal T4 supply, and by extension, euthyroidism was not ensured by normal TSH supply (Ingbar et al, 1982).

(Wang & Volpe agreed, in 1981 — see “In 1981, Canadians argued T3 was the best test in thyroid therapy“)

The metabolic importance of thyroidal T3 was already theorized in Laurberg’s 1984 review, on the basis of science showing TSH-enhanced T3:T4 ratios of secretion from thyroid tissue.

  • Thyroidal T3 Secretion is the sum of both
    • TSH-stimulated T3 synthesis in the thyroid, and
    • TSH-stimulated T4-T3 conversion in the thyroid gland cells as blood flows through the thyroid.

In Laurberg’s review in 1984, this TSH-driven and 2-component view of thyroid secretion explained the significantly lower T3:T4 ratios in thyroidless people on LT4 monotherapy even at a normalized TSH.

Therefore, physicians who retained a pre-1990 therapy paradigm that did not (yet) worship TSH, physicians were quite accepting of supraphysiological T4 dosing and subphysiological TSH suppression if it was necessary to achieve the ultimate goal of true clinical euthyroidism for the individual.

Once the paradigm shifted around 1990 and the therapy goal became keeping TSH within reference, and secondarily T4 within reference, it resulted in more physicians dismissing the patient’s clinical signs and symptoms of hypothyroidism that remained when biochemistry was normalized.

But most doctors were happy to be relieved of the challenging messiness of depending on clinical judgment of euthyroidism by means of assessing multiple indicators (Escobar-Morreale’s goal of achieving qualitative and quantitative indices of therapy response). Therefore, an increasing number of physicians

  • depended on false faith in the peripheral deiodinases (DIO1 and DIO2 beyond the thyroid) to compensate for loss of thyroidal T3 secretion and thyroidal deiodinases, and
  • placed false faith in normal TSH response as a proxy for all tissues’ response to circulating thyroid hormone.

The average LT4 dose dropped from between 200-400 mcg a day to 75-150 mcg a day, mainly to normalize the TSH (Toft, 2017).

Some patients were fine (probably those with some thyroid tissue remaining and/or strong deiodinase genes), but others suffered tremendously from their TSH normalization, and the complaints were often dismissed.

Only people like Escobar-Morreale who tested the T3:T4 ratio in LT4-treated people (or LT4-treated rats) remained aware of the questionable assumptions of this therapy paradigm.

What these courageous researchers did

Escobar-Morreale’s research articulated these common assumptions so that they could poke holes in them.

Then their research results broke down the simpleminded faith in a 1-1 connection between TSH and T3 tissue levels in thyroidless LT4-treated rats (and implicitly, in humans).

Research goals & results

The goal of Escobar-Morreale’s study, therefore, was to investigate tissue euthyroidism in LT4 monotherapy in thyroidless rats:

“It therefore appeared of interest to clarify directly whether, or not, using T4 alone a euthyroid status is ensured simultaneously for all tissues.

They tested treatment with 10 different dose levels of LT4 from underdose to thyrotoxic.

They tested (total) T3, (total) T4, and TSH in 10 different tissues — pituitary, cerebral cortex, cerebellum, brown adipose tissue, liver, kidney, lung, heart, muscle (leg), and spleen

What did they find out from the poor rats?

“As will be seen, none of the 10 doses of T4 which we tested was adequate to ensure simultaneously a normal thyroid status of all the tissues studied.”

Indeed, it often required “supraphysiological” levels of T4 “in most tissues,” and sometimes supraphysiological T3 (in lung tissue and brown adipose tissue), to achieve tissue T3 in the normal range.

We see the word supraphysiological in Escobar-Morreale’s 1995 article, about 8 times referring to T4 concentrations, once to T3 concentrations, in relationship to a normal physiological response at the tissue level.

The following set of graphs from their article shows the ranges of T3 and T4 values in plasma compared to blood.

The most striking results are:

  • Graph A shows that when rat T4 was normal, rat tissue T3 concentrations often fell low, especially in heart, kidney and liver.
  • Graph B shows that often plasma T4, and sometimes T3, had to be elevated in blood to achieve T3 euthyroid status in tissues.
  • Heart, liver, lung and BAT (brown adipose tissue) often required more of both T3 and T4 in blood to normalize tissue T3.

Comparing both A and B graphs, you can see the range of variation among the rats is sometimes narrower, sometimes wider.

  • The gray bar expressing “normal” does not mean optimal for an individual rat, but the 95% confidence intervals for healthy control rats. We do not know which rats had handicapped deiodinases or any impaired signalling from receptors. It simply means statistically normal.
  • The estimated range of doses is wider than the tissue response because different thyroid hormone transporters carry hormone into each tissue, and all three deiodinases may play a role in locally adjusting the tissue levels of T3.

(What about the TSH? In these rats, TSH remained elevated until T4 was elevated in blood.)

What are the broader implications for LT4 therapy in thyroidless rats?

infusion of T4 alone, even at doses which were not tested in the present study, is inadequate to normalize tissue T4 and T3.”

Oh that’s so tragic! Poor rats!

And by extension, perhaps there are some T3-poor men and women whose doses were inadequate!

And having a normalized TSH in these rats did not ensure normal tissue T3!

A lot of intelligent people missed this point about normal TSH not ensuring tissue T3 normalcy. That’s because it challenged one of the deepest assumptions about TSH being the absolute indicator of euthyroidism. It’s like telling a person who believes the earth is flat that they took a trip around the world. It goes against their fundamental world view. It does not compute. They’ll say it does not necessarily apply to human TSH – tissue T3 relationships.

Overall the principle is that thyroid loss plus LT4 monotherapy altered the rat’s tissue metabolism of T4 hormone.

The rat’s metabolism of hormone shifted and skewed in response to these two impacts of

  • Type of thyroid disability (total thyroidectomy), and
  • Type of thyroid therapy chosen (LT4 monotherapy).

If having enough TSH and enough T4 didn’t make these thyroidless rats euthyroid in T3 in all tissues, what then is the solution, at least for thyroidless rats?

“preliminary data show that the combined infusion of T4 and T3, in a molar ratio similar to that of the thyroidal production, does ensure both normal T4 and T3 in all tissues (58).”

This claim was partly based on their 1994 conference presentation in which they had tested T4 monotherapy, T3 monotherapy and T4-T3 combination therapy in rats (item 58 was their conference abstract).

What is that magic molar ratio?

Escobar-Morreale’s prescription

The estimated molar ratio was based on the statistical average from their source #1, which was … Pilo, et al, 1990.

(Do you see why we make Pilo the subject of so many articles? It’s because this seminal work in thyroidology, with all its glorious insights and flaws, has been so badly misused.)

The research team assured us that humans would not need as much T3 as rats because our thyroids don’t secrete as much T3.

“The relative importance of thyroidal T3 secretion versus T3 generation from T4 is likely to be greater in rats than humans,

as the molar ratio of T4 to T3 in the respective thyroidal secretion is ~ 6:1 (2-5), and 14:1 (1).”

What were the possibilities, then, for thyroid therapy in humans?

“If our results are shown to be pertinent in humans, the current replacement therapy of hypothyroidism should no longer be considered adequate, and might possibly lead to the development of new strategies of therapy combining administration of both T4 and T3,

albeit at a much higher T4 to T3 molar ratio (possibly 14:1) than previously used clinically (4:1) (60)”

Therefore, Escobar-Morreale threw down the gauntlet.

What courage! The stakes were high, as proving this theory could potentially put all LT4 monotherapy into the dustbin of history!

  • A person reading this in 1995 might think “Watch out Synthroid, here comes Cytomel!”
  • … but this revolutionary ratiometric solution will only permit you a limited amount of Cytomel per microgram of Synthroid, because of the largest mistake in their study: relying on Pilo’s average secretion ratio.

Relying on the average T3 when the average is misleading.

This is a basic scientific error, the misinterpretation of statistics.

You can’t rely on an average to represent all of humanity whenever the range among human subjects is huge, and there is no central tendency (no midpoint clustering) in the data set.

Consider also the problems of relying on a statistical average when

  • the data set is small (14 thyroid glands), and
  • the data is based on unnatural experimental conditions (like iodine overdose in Pilo’s study)
  • and unconfirmed physiological models (incomplete understanding of all three deiodinases in 1990, no mention of deiodinases in the thyroid gland).
[Note that while Pilo’s Subject #7 had the “T3:T4 thyroidal secretion ratio” that was closest to average, Subject #8 had the “thyroidal T3 as percent of total daily T3 supply” that was closest to the statistical average among the 14 people.]

Therefore, Escobar-Morreale and his contemporaries were not reading Pilo’s article as carefully as they should. They were overrelying on the average without being respectful of the wide variation in human thyroidal T3 secretion and T4-T3 conversion rates.

There’s a silver lining in Pilo’s research. The wide range of empirical measurements expresses a physiological principle — that of wide human diversity.

This is the principle Pilo uncovered — Humans vary in overall T3 supply, and their thyroidal T3 secretion adjusts to compensate for T4-T3 conversion efficiency.

Why, then, can’t thyroid therapy’s T3 content also, like a real thyroid, compensate for shortfalls in T4-T3 conversion efficiency?

A statistical interpretation error becomes an ethical error when it results in T3 prescription recommendations that treat an average as if it were a limit that must not be surpassed.

Escobar-Morreale’s final prohibition

In the quotation above, this research team drew an arbitrary line in the sand — NO ratios were to be permitted that came close to the thyroid preparation “previously used clinically” — porcine desiccated thyroid (NDT) at a ratio of 4:1.

  • Ah, a reader in 1995 may have snickered, “Don’t get your hopes up, desiccated thyroid. You’re way too rich in T3 for our current generation of doctors to accept.”

Why not a ratio of 4:1? No explanation is offered here. That is the final sentence in their article. It’s taken as a given. The end.

The lack of comment on the 4:1 prohibition is like a family’s inside joke: “Don’t invite uncle Bob to the party. Because you know, Bob …” wink wink.

Oh… But citation #60 is technically the final word, and that’s Hershman’s 1986 textbook chapter.

Escobar-Morreale’s silence on 4:1 ratio prohibition and their citation of Hershman must not remain unanalyzed, or unanswered. As a representative of patients who thrive on this dosing ratio (though I do not myself), I have the moral right to interrogate you and point out the scientific flaws in your implied reasoning, because what you and Hershman say and fail to say about 4:1 ratios is harmful.

However, it’s technically a digression to expound at length upon the offensive final sentence of this otherwise grand study, and to talk back to Hershman when he is merely being cited. So this “post within a post” is optional reading unless you have the appetite for it.

Click to reveal my rebuttal of this desiccated thyroid 4:1 ratio prohibition

To justify their 4:1 ratio prohibition, Escobar-Morreale’s team cited Hershman’s chapter in an older edition of an endocrine textbook. The 2009 edition I have access to claims this:

desiccated thyroid “contains a T4/T3 ratio of about 4:1. Approximately 4 to 8 hours after ingestion, T3 levels may rise to the supranormal range.”

Um, excuse me Mr. Hershman, but what is the intrinsic problem with having a supranormal T3 level if your overall revised metabolic and glandular context makes it suitable? If a person’s T3 is supranormal, where is their T4 level at the same time?

If that person’s circulating T4 is significantly lower in reference than the T3 is in reference (as it often is in desiccated thyroid therapy), then they are not contributing a lot of T4-T3 conversion in cells, and they are not flooding their cells with additional T3 while having circulating T3 peak temporarily in the supranormal range for a few hours per day. And you have to think about what deiodinase type 3 does, and T3 conversion to triac, during the peak T3.

(These dose-dependent T3 peaks can be very predictable and manageable: See scientific reviews in “Free T3 peaks and valleys in T3 and NDT therapy“)

Too often, anti-NDT (desiccated thyroid) attacks are based on the simpleminded belief that a T3-rich pharmaceutical dosing ratio by itself, rather than an overdose of thyroid hormone at any ratio, can “cause” thyrotoxicosis. Eyeroll.

Think about the therapy ratio. Desiccated thyroid therapy is not equivalent to a full dose of LT4 therapy “plus” an overdose of T3 hormone. The lower T4 accommodates the higher T3.

Think about the hormone levels. Look at the T3/T4 ratio and the combined level of thyroid hormone in blood. Use that level and ratio now to judge the degree that the TSH will be unreasonably biased lower by T3 dosing.

Think about the biochemical context of the hormone levels. You can’t judge desiccated thyroid (NDT) or 4:1 synthetic dosing ratios by T3 levels alone, nor by T4 levels alone, and especially not by TSH, because of the principles revealed in this study.

Let’s think about supranormal T3 in the context of Escobar-Morreale’s study. In rat lungs and BAT, T3 had to be supraphysiological in rat blood to lift tissue T3 into normal range in rat tissue. But this was no overall benefit to the rats, because other tissues had excess T3 at the same time that BAT tissue T3 was normalized. And why? Because this was T4 therapy, not 4:1 hormone therapy, and T4 levels in blood were also high when T3 was high.

Do the endocrine math. Less T4 in blood always requires more T3 to compensate metabolically for the lower amount of T4 converting to T3 in cells.

The pituitary gland doesn’t need T3 to compensate as much, but our body is more complex. We are not one huge pituitary gland.

But a powerful paradigm can overrule ethical and scientific thinking.

People reading Hershman’s 2009 edition who are inexperienced in (or rabidly prejudiced against) NDT therapy or T3-rich synthetic therapies can be very naive (or biased) about how these therapies differ from LT4 monotherapy.

As of 2013, Hershman’s response to Hoang et al’s NDT (DTE) clinical trial showed that he was conditionally welcoming to desiccated thyroid therapy, considering NDT “not so dangerous” as long as it fit into his therapy paradigm’s biochemical prison. He still imagined its T3 content to be merely like “adding some additional L-T3” to the T4, not integrative in the therapy. He disparagingly implied the patient’s “hypothyroid” symptoms as imaginary when TSH is normal on LT4, using quotation marks around “hypothyroid.” Gah.

How many Escobar-Morreale studies do you need to break down such a cemented belief system?

  • In thyroidless rats (or humans) dosing thyroid hormones, there’s not the easy 1-1 correspondence between blood concentrations of high T3, low TSH and tissue thyrotoxicosis.
  • If rat metabolism is that far disturbed between healthy control rats and dosed thyroidless rats, don’t you think our metabolism undergoes a two-degree separation from normality, first, gland loss and second, dosing?

Naive or prejudiced people who think we’re untransformed by disease and dosing will tend to freak out needlessly over an isolated transient high T3 in the context of lower T4, or an isolated low T4 in the context of compensatory higher T3 in non-thyrotoxic people on NDT.

(See my review of Penny and Frasier, 1980’s classic anti-NDT study, dredged up from the graveyard of bad thyroid science by Biondi and Wartofsky, 2014.)

These types of fearmongerers tend to point to the T3 nose sticking out too far past the biochemical range, as Hershman did in 2009, as if it’s always and obviously a bad thing to have a T3 enhancement beyond other humans when you’ve chosen a medication that gives you a T4 handicap in exchange for it… and when you’re not getting the extra T3 from constant cellular conversion or thyroidal secretion, but by transient dosing via the GI tract.

Such people’s biochemical bigotry and metabolic ignorance is proven if they would merely shrug over the inverse ratio with a low T3 and higher T4 in a person whose T3 nose has been cruelly chopped off by falling below range.

In light of the metabolic transformations Escobar-Morreale and team uncovered, how dare you say to the T3-destitute on LT4 monotherapy, “But look on the bright side! You have some extra T4.” How dare you put their “hypothyroid” symptoms in quotation marks.

And how dare you say to the underdosed thyroid patient on NDT, “But look, your thyroidless, T3-dosed TSH oracle says you have enough thyroid hormone!” You claim the TSH is so exquisitely sensitive, and yet you are sure it is easily duped into thinking the random waves of T3 hormone from a pill is the same as TSH-driven circadian T3 rhythm through a living thyroid gland?

A quick view of their next two rat studies

In 1995, Escobar-Morreale hadn’t yet proven that T4-T3 combo therapy could fix these rats’ tissue T3 levels.

But we soon found out in 1996. And then we found out more about why in 1997.

In 1996, one year later, Escobar-Morreale’s team published a follow-up article that trumpeted its conclusion in the title:

“Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.”

The 1996 study tested not only the same 10 tissues they did before, but also expanded the study by examining 2 more tissues: ovaries and adrenals.

  • Adrenals required either T3-T4 combination therapy or supraphysiological doses of T4 in the thyroidless rat.
  • Ovaries had subnormal tissue T3 on all but two of the T3-richer T3-T4 combination therapies (90 T4 + 10 T3 and 90+15 mcg/100g/d) in the thyroidless rat.

The philosophy of mimicry quoted above was stated again verbatim at the head of the discussion section. Although some additional data were analyzed, much of the reasoning is the same.

The chart below shows the comparison of average values in the treated rats vs. healthy control rats.

Escobar-Morreale preferred the rat dosage of 90 mcg + 15 mcg dose per 100g because the average values were equal to healthy, undosed rats.

Based on their favorite rat prescription, the conclusion of their 1996 article was a recommended prescription for humans AFTER absorption into blood:

assuming similar absorption rates of T4 and T3,

the preparation should contain t4 and T3 in a molar proportion of approximately 14:1 and deliver into the bloodstream 101 mcg T4 and 6 mcg T3/day, thus mimicking human thyroid secretion.”

(NOTE: Because T4 is more poorly absorbed via GI tract than T3, future T3-T4 therapy recommendations by Wiersinga and the European Thyroid Association would make adjustments for the skew in average absorption rates to ensure the doses had the desired ratio when absorbed into blood.)

Escobar-Morreale also recommended “sustained enteric release forms of T3.” This slow-release recommendation would come up again and again in subsequent discussions of synthetic T3-T4 combo therapy limitations.

Then in 1997, the same team published an article “Regulation of Iodothyronine Deiodinase Activity as Studied in Thyroidectomized Rats Infused with Thyroxine or Triiodothyronine,” a very enlightening study cited only 68 times. This study investigated how rats used their tissue D1, D2 and D3 enzymes to metabolize T4 monotherapy or T3 monotherapy. If you’re going to treat someone with a combo of T3 and T4, you really do need to respect how each operate in isolation: in rats’ tissues, and in humans. A review of that deiodinase study in light of T3 monotherapy studies in humans will have to wait for another post.


Escobar-Morreale’s team’s studies have had a major influence. As of 2020, according to the Scopus database, Escobar-Morreale’s 1995 study has been cited 185 times; the 1996 study has been cited 192 times.

Escobar-Morreale, the lead author, was still in his first decade of scientific publication in the 1990s. He would go on to make even larger contributions to another area of endocrinology: polycystic ovary syndrome. What is the citation count on PCOS articles and guidelines coauthored by him and others? In the thousands.

Consider how even the most brilliant people may briefly skim what they cite and cherry-pick, as people like Escobar-Morreale did with Pilo’s average ratios.

A foundational mistake by such intelligent people can have such a far reach.

And yet look at how this study questioned and investigated foundational beliefs at the tissue level and learned how deiodinases work in rats on LT4 monotherapy.

Therefore, I think we still have more to learn by re-reading these excellent studies of these poor LT4-treated rats–these creatures who gave their lives for the sake of our knowledge–and by pondering their precious data set while carefully following the reasoning of these thoughtful scientists, flaws and all. We need both rat studies and clinical studies to connect the dots between what happens in unseen cells/ tissues and what happens in bloodstream, symptoms, and health outcomes.

Without rat studies testing foundational beliefs at the tissue level, humans have free reign to make up therapy-justifying fantasies like “a normalized TSH means generalized euthyroidism” and “a low TSH always means thyrotoxicosis” — endocrine fantasies that rarely get questioned by the average doctor.

Such unchecked fantasies then went on to harm potentially millions of thyroid-disabled people who are judged by their TSH above all, in comparison to the healthy person’s TSH reference range, as if they still had a healthy thyroid and weren’t dependent on TSH-T3-warping hormone therapy.

Experimental LT4-treated humans would have to wait until later science proved that our deiodinases are certainly not “normalized” after thyroid loss. We know this is partly because thyroid tissue expresses most of our body’s DIO1 and DIO2 mRNA and the thyroid is a flexible and powerful T4-T3 metabolizing engine, not just a hormone synthesis machine.

Unexamined assumptions about TSH-T3 relationships in human thyroid therapy would have to wait for the bold team of scientists Hoermann, Midgley, Larisch and Dietrich to give insight into the “TSH-T3 shunt” in thyroid health versus the TSH-T3 disjoint in thyroid-disabled people on LT4 monotherapy, in their revolutionary research since 2010.

Soon, I’ll post Part 2 so you can read about where Wartofsky’s & Wiersinga’s contributions took this tradition 2004-2014. Then you’ll see how the mimicry of the narrow T3:T4 secretion ratio really messed things up for thyroid-disabled humans.


Click to view reference list

Barsano, C. P., Garces, J., & Iqbal, Z. (1994). Metabolic implications of low-dose triiodothyronine administration in rats: Relevance to the adjunctive use of triiodothyronine in the treatment of depression. Biological Psychiatry, 35(10), 814–823.

Escobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G. (1995). Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. The Journal of Clinical Investigation, 96(6), 2828–2838.

Escobar-Morreale, H. F., Del Rey, F. E., Obregón, M. J., & de Escobar, G. M. (1996). Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology, 137(6), 2490–2502.

Escobar-Morreale, H. F., Obregón, M. J., Hernández, A., Escobar del Rey, F., & Morreale de Escobar, G. (1997). Regulation of Iodothyronine Deiodinase Activity as Studied in Thyroidectomized Rats Infused with Thyroxine or Triiodothyronine. Endocrinology, 138(6), 2559–2568.

Hershman, J. M. (2009). Hyperthyroidism and Hypothyroidism. In N. Lavin (Ed.), Manual of endocrinology and metabolism (4th ed., pp. 435–448). Wolters Kluwer/Lippincott Williams & Wilkins Health.

Hershman, J. M. (2013). Patients with Hypothyroidism Taking Desiccated Thyroid Extract Lost Weight As Compared with an Equivalent Dose of Levothyroxine. Clinical Thyroidology, 25, 122–124.

Ingbar, J. C., Borges, M., Iflah, S., Kleinmann, R. E., Braverman, L. E., & Ingbar, S. H. (1982). Elevated serum thyroxine concentration in patients receiving “replacement” doses of levothyroxine. Journal of Endocrinological Investigation, 5(2), 77–85.

Laurberg, P. (1984). Mechanisms governing the relative proportions of thyroxine and 3,5,3’-triiodothyronine in thyroid secretion. Metabolism: Clinical and Experimental, 33(4), 379–392.

Pilo, A., Iervasi, G., Vitek, F., Ferdeghini, M., Cazzuola, F., & Bianchi, R. (1990). Thyroidal and peripheral production of 3,5,3’-triiodothyronine in humans by multicompartmental analysis. The American Journal of Physiology, 258(4 Pt 1), E715-726.

Toft, A. D. (2017). Thyroid hormone replacement – a counterblast to guidelines. Journal of the Royal College of Physicians of Edinburgh, 47(4), 307–309.

5 thoughts on “The foundations of synthetic T3-T4 therapy in the 1990s

  1. I find it interesting that desiccated thyroid effectively disappeared from the UK (as in – no BP preparations – only a few rarely prescribed imported options such as Armour) after this letter:

    SIR, — We write to suggest that thyroid extract (Thyroid, BP) be removed from the British Pharmacopoeia and that its manufacture be abolished.

    We continue to see patients who have been diagnosed as having myxoedema and who are being treated with apparently adequate doses of thyroid extract but who are clinically and biochemically hypothyroid. They have subsequently responded to thyroxine.

    Although it is never to be certain that drugs prescribed are being taken, there is good evidence the potency of thyroid extract is variable and its shelf-life dated. As both active constituents, thyroxine and triiodothyronine, have been available for many years we see no reason for the retention of thyroid extract, which we consider to be dangerous.

    W van’t Hoff G M Besser
    R Hoffenberg J S Staffurth
    D R London David C Anderson
    R Hall J Jenkins
    G F Joplin R L Himsworth
    Peter Sonksen
    1 Martindale: The Extra Pharmacopoeia, ed A Wathe, 27th edn, p1509. London, Pharmaceutical Press 1977.

    Br Med J 1978; 2 doi: (Published 15 July 1978)
    Cite this as: Br Med J 1978;2:200

    Important to note that even this dismal letter predicates the removal of Thyroid, BP on the availability of BOTH thyroxine and triiodothyronine. Despite the assertion that patients were treated with just thyroxine. Which was the reality for the vast majority of patients then and since.

    As I see things, poor quality control of Thyroid, BP should be addressed by improving the product – not removing it from the BP! After all, Armour used to have an animal lab for quality control which probably helped with building their reputation.

    1. Thanks for posting! Yes it is a dismal, abrupt letter, void of evidence, poor in reasoning as you point out, based only on the credibility of the signed persons. This history should be made known. (And, Sorry for the delay in approving this comment which I did not see until today. It was held in queue for approval due to two links.) – TSS

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