I would like to introduce you to Subject #7, the only person in Pilo’s 1990 study who had a thyroid secretion ratio of 14.5 parts T4 to 1 part T3, which was closest to the statistical average of 15.87 to 1.
Why is this individual so important to the history of thyroid science and modern thyroid therapy guidelines?
This person’s estimated thyroidal secretion ratio of T3 and T4 conformed to the 2012 European Thyroid Association’s thyroid treatment guidelines for T4-T3 combination therapy, which claims that 16:1 is the ratio we must target if we are going to use T3 pharmaceuticals at all. (Wiersinga et al, 2012)
Where did they get this idea that 16:1 was a physiologically correct ratio? They cherry-picked the statistical average from Pilo’s 1990 study of 14 people.
No one else in Pilo’s study had a ratio close to 16:1 except … Subject #7.
This person with a 16:1 ratio was almost perfectly mathematically average, so they’ve become a nameless celebrity in thyroid science without knowing it.
He must have been like that beautiful model with the perfect nose, perfect eyebrows, the amazing abdominal muscles, perfect BMI (body mass index).
This perfect thyroid secretion ratio probably yielded an average resting heart rate and average basal body temperature. In fact, all his biochemical indicators must have fit in the middle of the population reference range, right? And he was a he, right?
Subject #7 must have been the perfect model of a human being! Maybe we should imitate him in other ways, too! It will make us all healthier, happier, average people who complain less while our TSH is perfectly normalized.
Let’s get to know this person in Pilo’s 1990 study who, by sheer luck of nature (rather than by mathematically precise dosing), set the standard of ultimate thyroidal averageness.
What was this person like? Their age? sex? body surface area?
More importantly, what were their TSH, FT4 and FT3 levels that they got out of this perfect thyroidally-dosed ratio? Luckily, Pilo told us a lot about this person.
While we’re at it, let’s also get a peek at two of Pilo’s other subjects, Subjects #3 and #14, to understand why they weren’t chosen as ideal models for their secretion ratios, even though they were also supposedly healthy humans with equally healthy thyroids and normal TSH numbers.
If you think Subject #7’s fame is a ridiculous exaggeration, let me explain how this presumption of Subject 7’s representative secretion ratio has led smart medical people to write biological lies over and over again, and then write thyroid prescriptions and therapy guidelines, and then write T3 therapy prohibitions.
Let’s talk about Subject #7.
He was a 27-year-old man. There were no women this young in Pilo’s study.
His thyroid secretion ratio was estimated at 1 part T3 to 14.5 parts T4 over 8 days.
He weighed 82 kilograms. The average weight of an adult man is 88 kg in the United states, but only 68kg in Korea.
His TSH was the highest in the study, at 2.0 µU/ml. The TSH range goes up to 4 now, but Pilo didn’t recruit anyone whose thyroid was being pushed hard to secrete a T3-richer T3:T4 ratio.
Maybe that’s why he recruited only people with TSH no higher than 2.0. Since TSH inevitably skews T3:T4 ratios as it rises, recruiting people with higher TSH levels could bias the average T3:T4 secretion ratio higher, and the statistical averages would not fit those found in all the prior kinetic studies. (See T3 is not always converted from T4: De novo T3 synthesis.)
During the 8 day study, Subject #7 was overdosed with daily iodine drops at 56x the FDA recommended maximum, just to prevent the re-uptake of radioactive iodine-tagged T3 and T4 molecules they injected him with. Those who trust in Pilo’s thyroid secretion estimates don’t want to ponder the possible acute effects on thyroidal secretion too deeply.
His baseline FT3 before the 8 day experiment was 4.1 pg/mL and FT4 was 10.2 pg/mL.
What did those results mean in 1990 in that part of the world? This was measured by immunoassays whose reference ranges and technical specifications are not mentioned and which I cannot trace back to the prior publications by Pilo’s research team. Therefore, we do not know what ranges of FT3 or FT4 are “normal” according to their chosen assay technology, but this certainly matters today.
If you translate his baseline FT3 and FT4 levels into pmol/L using the standard conversion rate, they would be FT3 6.3 and FT4 13.13. Most 50-something female thyroid patients treated with a dosing ratio equalling his thyroidal secretion ratio will likely have a Free T3 a lot lower than his.
By today’s assays, you can’t easily attain a bloodstream FT3:FT4 ratio like that on LT4 monotherapy or a 1:16 dosing ratio unless you have a disorder like Graves’ disease antibodies or a hypersecreting thyroid nodule, but then your TSH would be low or suppressed.
His extremely high FT3:FT4 ratio of 0.48 pmol/L of FT3 per unit of FT4 is far higher than the average found in contemporary studies. For example, large cohorts of healthy controls (Gullo et al, 2011 and 2017) had an average ratio of 0.32 pmol/L, with a 95% reference range from 0.20 to 0.50.
His ratio of 0.48 is not very average — how could his ratio be at the top of reference if his secretion ratio is only average?
Ah — because Pilo showed that “Thyroid T3 secretion compensates for T4-T3 conversion” and this man’s conversion rate didn’t need as much compensation as your uncle’s, or your mother’s.
This is the man with the “magic” formula.
Wartofsky in 2004 told us that this secretion ratio fits the “magic” formula, the physiological dose ratio that, if dosed with slow-release T3 preparations, might quell all thyroid patients’ psychological complaints within the normal TSH range.
This young man’s secretion ratio is now the basis of the European Thyroid Association 2012 guidelines for T3-T4 combination therapy for all adults without thyroid glands,
- Regardless of DIO1 and DIO2 polymorphisms that we become more vulnerable to after losing thyroidal compensation for them,
- Regardless of the presence of critical or chronic illnesses such as heart failure or kidney failure or liver cirrhosis that can lower FT3:FT4 ratios.
But why didn’t anyone pay attention to the equally “healthy” estimated ratio of secretion of Subject #3?
This is Subject #3.
- 1:6.4 estimated T3:T4 secretion ratio
- a 31-year-old man (4 years older)
- weighing 83 kilograms (1 kilogram more)
- also overdosed with iodine to the same level during the 8-day study
- his TSH was the lowest in the study, at 1.0 µU/ml and yet his thyroid miraculously synthesized more T3 compared to T4 than the other 13 individuals.
- his baseline FT3 was 4.3 pg/mL and FT4 was 8.8 pg/mL (the FT4 was lower)
- If you translate his levels to pmol/L, they would be FT3 6.6 and FT4 11.3 pmol/L, like a super-T4-converter dosed on desiccated thyroid hormone.
- He had an FT3/FT4 ratio of 0.58 pmol/L, which was not the highest ratio in the cohort (the highest was 0.65, in subject #2 and the second-highest was 0.61 in subject #14)
Why isn’t his secretion ratio not the model?
Ah, because Subject #3 had a very T3-heavy ratio. It’s too close to 1:4.2, the ratio of porcine desiccated thyroid (NDT) preparations.
Some people fear what it would look like to recommend anything close to the T3:T4 dosing ratio that they ridiculed and demonized in the 1970s and 1980s.
Some think that would be a thyroidal sin. They think nobody should ever use ratios that are richer in T3, such as 10:1, or this man’s 6.5:1. It’s dangerous.
Yet this man was supposedly an equally healthy human being. (But we don’t really know what standards were used to judge anyone’s health in this study; we are asked to take that on faith.)
And only fourteen people were in the study.
Meet Subject #14
Why can’t the model ratio be one that is owned by a woman?
Oh. Because some women’s ratios are too close to 0:100, the ratio of levothyroxine monotherapy. Well, you might think that is embarrassing to people who champion T3’s role in therapy.
But let’s examine what this Low-T3-secretion end of the ratio looks like in the context of concentrations of T3 and T4 in blood.
She was a 59-year-old woman (The oldest of only 5 females in Pilo’s study), weighing 60 kilograms.
She had a dismally low 1:71.5 estimated T3:T4 secretion ratio. Wow!
How could she live on only 1.4 mcg of T3 secreted from her gland per day?
She was a super-converter! She was estimated to have obtained 93.5% of her daily T3 supply from T4-T3 conversion.
When she was overdosed with iodine, her gland decided to almost turn off the T3 faucet. Is this a normal everyday state?
Her TSH was 1.2 µU/ml, at least at the time of the baseline test.
Her baseline FT3 was 4.3 pg/mL, just like Subject #3 who had the largest amount of T3 secreted from his gland.
Her baseline FT4 was 8.4 pg/mL, so she wasn’t oversecreting a lot of extra T4 to obtain this FT4 level.
If you translate her levels to pmol/L, they would be FT3 6.62 and FT4 10.81 pmol/L. This is a FT3 higher than the top of my lab’s reference range (3.5-6.5) and a FT4 way near the bottom of my lab’s range (10-25). How did Pilo’s skewed laboratory assays bias his estimates? Baseline numbers were in his calculations.
She had an FT3/FT4 ratio of 0.51 pmol/L, which is an astounding metabolic accomplishment. Did this lady have a genetic polymorphism that enriched her Deiodinase type 1?
Some people won’t find her high T4-T3 conversion rate astounding — many people are already biased to believe that the mighty T4-T3 metabolism is far more powerful than what they imagine to be a tiny T3 secretion of a thyroid gland. These are the people who shed no tears for the T3-ectomy they are performing along with the total thyroidectomy in a person with a supposedly “good” cancer — a mere thyroid cancer.
It’s truly frightening to imagine this female T4 superconverter being held up as an excuse for the suffering of a T3-starved thyroid patient on T4 monotherapy.
NO! You LT4 monotherapy-worshippers. You don’t have the right to use her secretion ratio as an excuse to minimize our T3 doses down to zero just because her secretions were estimated to be so low. Biology doesn’t permit that logic. Why?
She needed all her intact deiodinases to convert that much T4 into that much T3.
Where are most of our T4-converting deiodinases located? Pilo didn’t know the answer to this question in 1990; he thought the 5′ deiodinase (only one deiodinase, in the science of his day) was mainly located in organs beyond the thyroid gland. But no.
Our DIO1 and DIO2 deiodinases are mostly located in the thyroid gland, according to the 2020 consensus on RNA expression of DIO1 and DIO2.
So, in 2020 how can you take away our deiodinase-rich thyroids and think we can all equal this female superconverter?
Why are people worshipping Pilo’s average?
There were many grand insights and serious flaws in Pilo’s study, but people are overlooking his insights while making a greater flaw than he ever did.
They are utterly misunderstanding the statistical average secretion ratio cherry-picked from this study.
In the scatterplot below, Subjects 3, 7, and 14 are noted in red with their ratios.
Do you think this constellation of dots has a central tendency, a cluster in the middle around #7?
Does that dotted “trendline” make sense to the position of subject / case #3? how about #14? or #9?
Yeah, some dots are pretty far from the trendline, making it rather a pointless trendline.
Imagining that thyroidal T3 secretion generally decreases as its secretion of T4 increases is as unphysiological as imagining a mathematical average closest to Subject #7 is a prescription for dosing.
We can’t take Pilo’s division of “thyroidal” versus “peripheral” (extrathyroidal?) conversion too seriously today, other than to notice that he recorded human thyroidal diversity for all to see.
Yet almost all the smart thyroid researchers citing Pilo in more than 100 scientific articles didn’t see it. They saw only the average, utterly blind to human diversity.
The 2012 ETA guidelines cite Pilo’s study as their reference #1.
To help doctors mimic Pilo’s perfectly average secretion ratio, Wiersinga’s 2012 ETA guidelines prescribed this perfectly average dosing ratio, as if a living gland can be replaced with two pills. To make precise adjustments for other scientists’ range of human absorption rates of “65-75%” for LT4 and “69-99%” for LT3 pharmaceuticals, Wiersinga’s team even suggested dosing ratios from 13:1 to 20:1 that might achieve a ratio close to 16:1 as the hormones entered the blood from the upper intestine. Woo! What mathematical wizards!
Pilo’s study was based on a very complex and outdated model of thyroid function and hormone metabolism. Thyroid hormone reductionism is the mistake of people who exalted statistical averages over ranges and then built even more complex calculations on this model.
How can we rely on the accuracy of Pilo’s calculations today? Their team did not understand all three deiodinases or where they were located in physiological “compartments” they imagined. Their team didn’t bother to measure Reverse T3, Tetrac, Triac, or consider the “pre-t3” column in the Sephadex gel chromatography results — other scientists knew that was T2.
If you refuse to replicate Pilo’s study today because it involves radioactive iodine injections and administering overdoses of iodine, at least go back to the drawing board and understand what the data set shows: Thyroid T3 secretion compensates for T4-T3 conversion.
No, we are not Subject #7.
Your average thyroid patient is definitely not Pilo’s Subject #7.
If you believe that the statistical average thyroid secretion ratio in Pilo’s study, 1:16 T3 to T4, is the ideal ratio for T3-T4 combination therapy, you may be prescribing the equivalent ratio of Subject #7 Desiccated Thyroid Powder.
You might as well market your perfect pharmaceutical ratio as a single pill and call it “Subject #7” as if it’s Chanel #7.
The statistical average of 14 healthy people in Pilo’s study do not represent the vast majority of thyroid patients, who are women over the age of 35.
Even if you put age and sex aside, Pilo’s 27-year-old male subject #7 was not a thyroidless human being who was dosing a hormone pharmaceutical instead of secreting from a living gland.
The healthy ratios of Pilo’s Subject #7 are not necessarily the ratios that will induce health in Subject #3 or Subject #14, or thyroid-disabled subject #307994 sitting in a doctor’s office in 2020.
Why do some smart people think that by offering all or any thyroid patient a “physiologically correct” ratio of 1:14 T3 to T4 in medication, while normalizing the TSH, the FT3 and the FT4 and the Free T3:T4 ratio, the person will be “physiologically corrected” in their thyroid hormone health? That’s exactly what Wiersinga’s ETA guidelines paraphrase as the philosophy underpinning this approach to T3-T4 combination therapy.
Well, maybe these smart people don’t think clearly. They are taught, and they believe, and they follow. Many people haven’t seen how ridiculous this secretion ratio-worship is and what it can do to people when it becomes misapplied to dosing ratios.
Many don’t truly care enough to question it by fact-checking it. Instead, all they have to read is their current-day medical textbooks, thyroid test-cancellation tool kits that claim to “understand the gland,” and the venerated thyroid flowcharts and guidelines that build on these fundamental historical mistakes and misrepresentations.
There’s no accountability in our medical systems to achieve thyroid health outcomes at any dose ratio. If the patient dosed with the pharmaceutical combination ratio of 1:16 fails to achieve the health outcomes of true euthyroidism, then the doctor can always blame the patient’s obesity, depression, hair loss, fatigue, and other health problems on the patient herself, or any other health conditions that could also possibly cause them. The doctor will offer her an antidepressant and exercise plan and feel good about doing his job according to the rules.
The patient pays the full price of this medical system’s idiocy, and the doctor loses nothing by his or her guideline-obedient failure.
The doctor and the medical system has written the lie “thyroid function physiologically corrected” on our thyroidally-abnormal bodies.
How did this situation arise?
People wrote lies.
Scientists have written again and again that “the thyroid gland,” based on Pilo’s study, secretes a 1:16 T3 to T4 ratio. That’s not just a white lie. It highlights only the average and it omits the range. It’s a harmful one because it misrepresents the truth of human diversity. It harms those who are vulnerable to suboptimal T4-T3 peripheral conversion rates, the people who truly need a T3-enriched T3:T4 secretion ratio from their thyroid.
Some scientists also claim, based on Pilo’s averages, that “the thyroid” secretes an average 20% of our total daily T3 supply. I’ve even seen some august thyroidologists (who should know better) claim <20% (less than, not average). There is no 20% “cap” on the maximum percent or amount of T3 that a healthy thyroid can secrete under rising TSH stimulation. This is a living gland that shifts both secretion ratio and rate in response to TSH.
Some people don’t even know they are alluding to Pilo’s averages. They just repeat these ratios without crediting anyone. It’s just become a commonplace pseudo-fact, like it was once believed that women’s wombs wandered around their bodies.
Then, they wrote prescriptions.
While presuming these ratios to be true of all healthy people with a normal TSH, by some strange twisted thinking, people have then written guidelines that presume all thyroid-disabled people can be healthy without any T3 dosage at all, as long as it normalizes their TSH.
The dismissal of T3 secretion and thus all T3 dosage is based on this line of reasoning:
“the majority of circulating T3 comes from peripheral conversion of T4 to T3 and not secretion of T3 from the thyroid , hence a T4:T3 secretion ratio of approximately 14:1 appears average in humans, suggesting only a small role for secreted T3.”(Dayan and Panicker, 2018)
On the basis of minimizing the role of secreted T3, endocrinologists have then written thyroid therapy guidelines that strongly recommend a 0:100 dosing ratio for everyone without a healthy thyroid to normalize our TSH, while even permitting T3 to fall below range. (Garber et al, 2012 ATA guidelines; Jonklaas et al, 2014 ATA guidelines). None of Pilo’s subjects had a T3 below range.
Only the ETA 2012 guidelines propose that some few and rare patients who complain enough of hypothyroid symptoms despite normalized TSH might be permitted a 1:16 ratio like Pilo’s Subject #7 but only if it normalizes our TSH, FT3 and FT4.
Then, they wrote T3 prohibitions.
Building on such T3-dismissal and minimization, these and many other thyroid treatment guidelines around the world “do not recommend,” or even outright forbid, T3-richer dosing ratios of T4 and T3 hormone lower than 1:13 even if it would normalize our TSH.
The prohibition is made on the basis that these T3-richer dosing ratios contain “supraphysiological” ratios of T3 and T4, ignoring ratios such as Subject #3’s 1:6.5 ratio.
Prohibitors often write such fearful sentences as “The inappropriate use of thyroid extracts [desiccated thyroid; NDT] in euthyroid and hypothyroid patients can result in thyrotoxic symptoms and severe adverse effects (135)” (Biondi & Wartofsky, 2014). But these prohibitors are citing articles that found no thyrotoxicosis or severe adverse effects at all, just doctors who feared they might occur. (See a further analysis of this article and its cited sources: “Biondi and Wartofsky’s 2014 dismissal of desiccated thyroid“.)
Wiser historians of thyroid therapy point out that the T3-richer T3:T4 dose ratio in desiccated thyroid is not responsible for inducing thyrotoxic symptoms. When desiccated thyroid was the gold standard of therapy, “thyrotoxic adverse effects were typically remediable by simple dose reduction, so desiccated thyroid remained the preparation of choice” until the mid 1970s (McAninch and Bianco, 2016).
Clear contradictions arise in prohibitions of T3-inclusive therapies that could resolve LT4 treatment risks in ischemic heart disease:
- First, Biondi and Wartofsky note the increased risk of “morbidity for circulatory diseases and ischemic heart disease despite apparently adequate treatment with L-T4.”
- Then, they then mention their belief that “The physiological L-T4 to L-T3 ratio in humans is about 13:1 to 15:1,” citing their own 2012 article on T3-T4 combination therapy that used Pilo, 1990 to argue we ought to “mimic a more perfect thyroid hormone replacement therapy.”
- But ultimately, they conclude by reiterating the fact that the AACE, ATA, and ETA guidelines forbid any T3 to vulnerable cardiac patients: they all “suggest avoiding treatment with T3 in pregnant women and in patients with a history of arrhythmias or chronic ischemic heart disease.”
(See our review of 2019 research, “The impact of thyroid hormone dysfunction on ischemic heart disease, and how T3 therapy may help.”)
In summary, a population of LT4 monotherapy patients are known to be at significant health risk without T3 dosing, and physiology provides T3 from the thyroid. Nevertheless, Biondi and Wartofsky and three associations “suggest avoiding” (which in practice often means prohibiting) giving any T3 to these very same people at risk, even at this idealized ratio.
Let’s write the undistorted truth.
Write an email to everyone you see who cites Pilo’s secretion ratio as “the” secretion ratio of “the” healthy thyroid, and send them a link to this article or even just the scatterplot graph in the middle of it.
Ask them to acknowledge that the healthy human thyroid gland may also secrete at a ratio of 1 to 6.5 parts T3 to T4 at a TSH of 2.0, in the same study by Pilo that they used to justify a narrow secretion ratio.
Ask them what they predict the full range of healthy human secretion ratios would be if someone did a study of more than 14 people and included people with TSH levels higher than 2.0.
You will do thyroid patients everywhere a service by getting people to check their thyroid science facts, investigate the basis of theories of thyroidal secretion ratios and variable peripheral conversion rates, and reconsider the presumptions underlying their therapy guidelines and T3 prohibitions.