Here I bring thyroid science into a discussion of effectively adapting and managing the most flexible form of thyroid therapy, T4-T3 combination therapy.
This is a model capable of adapting to an individual’s unique thyroid disability and response to thyroid medication.
Finding an individual’s optimal combination therapy is medically necessary when T4 monotherapy fails due to poor T4-T3 conversion and when T3 monotherapy would be too extreme.
One T3:T4 ratio in medication won’t work for everyone.
In real life thyroid therapy, there’s more than one model of combination therapy.
Knowledge of the science behind what we’re doing helps us adapt our ratio, dose, and even the timing of our doses.
THE PRINCIPLE OF THE FLEXIBLE T3:T4 RATIO
Even in health, thyroid secretion ratios are diverse from person to person. (Wiersinga, 1979).
Elsewhere I’ve critiqued the limited-ratio 1:14 dosing model that some thyroid scientists have been testing in clinical trials since the 1990s — I ridicule it by calling it what it is — a “mini-T3-mono-combination” therapy — because it isn’t that different from T4 monotherapy, and it’s no surprise that results of randomized clinical trials show not much difference.
If diverse people have diverse T3:T4 secretion ratios in health (and they do), and if people respond in diverse ways to T4 monotherapy (and they certainly do), then of course a range of human beings is going to respond differently to any specific dose ratio.
Poor GI health generally interferes more with T4 absorption than with T3 (Wiersinga et al, 2012).
Adjustment of ratio and dose to the individual is the key to combination therapy dosing.
There’s more than one T3:T4 ratio in dosing that is safe, effective and therapeutic. It’s simply and clearly because there’s more than one kind of thyroid patient, especially when it concerns our thyroid hormone metabolism — the likelihood of a person’s deiodinases (thyroid hormone converting enzymes) becoming imbalanced and fighting against their current mode of thyroid therapy.
ARE YOU A GOOD T4-T3 CONVERTER?
Thyroid hormone conversion rates also fall in a wide range, as you see in Wiersinga’s image above.
Our metabolism of T4 and T3 works differently when we have different degrees of thyroid gland loss, generally moving toward poorer T4-T3 conversion when you have less living thyroid tissue (Ito et al, 2015, Kawasaki et al, 2019)
Consider whether a person is a “good converter,” “moderate converter” or “poor converter” of T4 hormone — when you lack thyroid tissue, a thyroid metabolism handicap becomes much more evident, as proven by Midgley et al, 2015.
They examined the FT3 levels, FT4 levels, and TSH levels in people with no thyroid due to carcinoma (thyroid cancer, total thyroidectomy) and people with a range of thyroid gland function (AIT = Autoimmune Thyroiditis, such as Hashimoto’s).
In this graph below, the size of the box and length of line shows the degree of human variation in each group of patients.
When you are permitted to dose thyroid medication to suppress TSH, as you are in thyroid cancer therapy, the patient has a higher chance of getting more T3, unsurprisingly. But it’s a roll of the dice. Not everybody gains the same amount of T3 out of their T4 dosing because the diversity in T4-T3 conversion rates shows up more starkly in people without thyroids.
The red colored boxes are the poor converters in this graph.
If this is the diversity you see even on one limited mode of thyroid therapy, T4 monotherapy, you can reasonably predict that the diversity of human response to ANY thyroid therapy is going to be huger than the range of diversity seen in “normo-thyroid” healthy people.
The dosing ratio that works is the one that yields a healthy ratio and combination of Free T3 and Free T4 in blood for you. A “healthy ratio” means that it’s working with your individual thyroid hormone metabolism — the way your T4-T3-converting deiodinases work given your genetics and current health status.
There’s currently a myth going around on the Internet among patients that you can’t combine desiccated thyroid (NDT) with synthetic T4 because it will be “too much” T4 for the patient. Which individual patient would it be too much for? What are their current FT4 and FT3 and symptoms?
The opposite fear circulates among many doctors — “no one must ever add T3 to therapy to the extent of equaling or exceeding the ratio of desiccated thyroid, because that would always be too much T3.” Of course a person would need a higher T3:T4 ratio in dosing if they are a poor converter of T4.
Trying to fit yourself into a prescribed optimal box can be very counterproductive, like forcing yourself to wear a size 5 shoe when you need a size 8.
Flexibility should be the rule, as well as an understanding that the pituitary’s TSH and other tissues in your body can respond differently as you customize FT3 and FT4 levels.
HOW TO OPTIMIZE NET T3 SUPPLY IN BLOOD
There is no single “optimal” place in the hormone reference ranges for all combination therapy patients.
That’s because the population reference ranges for TSH, T4, and T3 are based on statistics that cover a huge range of human diversity. Research has proven that Individual thyroid ranges are 38-68% the size of the lab reference range. One healthy person will reside near the top of range, and another near the bottom.
Our bloodstream concentrations provide unbound (free) thyroid hormones that can be transported into organs and tissues.
In cells, FT4 gets slowly converted into T3 every minute of every day, and T3 has activity in the nuclear receptors in the very core of your cells.
Then tissues’ FT3 and FT4 and other metabolites get exchanged back with the bloodstream supply for recirculation, riding out of cells on the same transporters that brought them into the cells. (Bianco et al, 2019; see their visualization of the cell’s exchange.)
A key concept here is that bloodstream is not just a one-way input.
The amount of T3 and T4 flowing through blood is the reservoir that is exchanged with all tissues in both directions (the idea of a “hidden pool” of T3 in the body was logically dismissed in 1989 by Faber et al).
That means that what’s in your blood is partly based on your input (from medication and any thyroid function), and partly a representation of how your tissues have used and converted those hormones lately.
Think about T4 as mainly a delivery package for future T3 or RT3.
T4 is not a separate hormone, but a father of two potential hormones, and the ratio and amount you get of each (T3, versus RT3) is uncertain and unpredictable.
In contrast, free T3 is instantly active hormone for cells. Humans can live on T3 monotherapy without any T4 in blood because thyroid hormone sufficiency is largely synonymous T3 sufficiency at the cellular level.
This means, in application,
1) everyone needs a minimum level of Free T3 in blood, and it’s nowhere near the lower boundary of the FT3 reference range!
2) permit a higher Free T3 to counterbalance low Free T4. That’s what biology does whenever T4 is lower.
THE FREE T3 BASEMENT
The baseline Free T3 concentration in blood is a foundation of T3 thyroid hormone sufficiency in the body as a whole.
We can learn this powerful lesson from the condition of “low T3 syndrome” or “nonthyroidal illness syndrome” (NTIS).
In this syndrome, when Free T3 is quickly depleted to below-normal levels by a health crisis, your life is at risk, even if you have a healthy thyroid.
When nonthyroidal illness strikes in acute, critical illness, it is temporary. But that doesn’t mean it is benign. It’s temporary because they either die, stay sick, or recover.
The FT3 is not usually kept chronically low, except in some chronic diseases like heart failure, liver failure, and kidney failure, and even in these illnesses, the outcomes are deadly the lower their T3 levels are. (See Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.)
This proves the basic law #1, “everyone needs a minimum level of Free T3 in blood.”
How does one recover from Low T3 syndrome?
At a certain phase in nonthyroidal illness, after not only your FT3 but also your Free T4 levels drop, TSH then has the metabolic permission to rise (why would TSH rise and add T4 from thyroidal secretion when there’s already a lot of T4 floating around?).
Something triggers the body “it’s time to heal now,” and your pituitary saviour TSH rises fast and high, stimulating a healthy thyroid gland to release a higher than average dose of T3 from the “pharmacy in the neck” to fill the FT3 hole in the bucket, supply but not overwhelm a person with FT4, and save that person’s life, and gently help tissues recover. (Peeters et al, 2005; Citterio et al, 2018)
What happens when a person doesn’t have thyroid gland tissue for TSH to overstimulate into hyper-T3 productivity during this low-T3 recovery phase? Abdalla and Bianco (2014) have also wondered! No answer. Silence.
This is awful. I can’t believe it either. I’ve looked and looked for years. Nobody knows how the thyroidless survive FT3 depletion because science has excluded the thyroidless from study of nonthyroidal illness on a mass scale.
There is no excuse for leaving a thyroid-disabled person too vulnerable, too close to their personal FT3 basement, for the rest of their lives, on poorly dosed, poorly adapted thyroid therapy of any type — It can happen on both monotherapies as well as combination therapy. Chronic low T3 can happen even while the TSH is normal or suppressed, because an isolated FT4 can singlehandedly keep TSH low while FT3 is depleted.
We have tissues and organs that depend largely on that direct, bloodstream source of T3. Those organs and tissues would truly suffer if you lowered FT3 too far.
A fallacy has kept too many people T3-starved in thyroid therapy: Doctors saying “look at all that T4 in your blood! Your tissues CAN convert it, so of course they will convert ENOUGH.” No, that’s not fair to the tissues that depend largely on direct FT3 supply from blood.
Imagine a patient is a poor converter of T4 to begin with, perhaps genetically. Their vulnerable FT3-dependent organs can’t possibly develop a higher local efficiency of T4-T3 conversion that would compensate for someone stealing away their precious FT3 supply from blood.
Measure Free T3 in thyroid therapy and you’ll be far more safe from harm both from excess and deficiency of this most vital thyroid hormone.
A HEALTHY RATIO IS T3-DOMINANT
The “lower T4 higher T3” pattern in blood is part of normal thyroid biochemistry among people with healthy thyroids.
Look at FT3 and FT4 average levels and ratios in large population studies to see proof that a mild FT3 dominance over FT4 is nature’s norm. On average, Free T3 is 5 to 10% higher in its range than T4 is within its range.
The contrast with the distorted ratio in LT4 monotherapy (on the right) is stark.
In addition, larger T3-dominant patterns are benignly adaptive in nature (higher T3:T4 ratios, where FT3 dominates over FT4 in blood, in relationship to their respective reference ranges).
This law of the healthy T3-dominant thyroid hormone ratio is what has enabled the human race to survive local iodine deficiencies.
In iodine deficiency, T4 drops low, but a rising TSH saves your body from harm by ramping up T3 synthesis and conversion. People with low T4 and enlarged thyroids (goiter) can actually be euthyroid (Pharaoh et al, 1973). Isn’t nature smart? When you don’t have that many iodine atoms, your body has a way to shift production to more cheaper 3-iodine hormone molecules (T3) than normal, less costlier 4-iodine molecules (T4) than normal, and the T3 is the more direct, essential hormone, anyway.
This is also the basic principle that keeps a person non-symptomatic (without hypothyroid symptoms) while their thyroid gland slowly dies over years and decades, from autoimmune thyroid gland attack — before they pass the tipping point of too much thyroid tissue loss.
In untreated subclinical hypothyroidism, the body’s TSH rises in order to push slightly more T3 than normal out of the dying thyroid and drive up its ability to convert T4-T3 as blood flows through its tissues (Carpi et al, 1979).
This high T3:T4 ratio is naturally induced in subclinical hypo for a good reason. Just as in iodine deficiency, the body is doing everything it can to keep Free T3 afloat, above the Free T3 basement — the body’s metabolic minimum requirement for healthy function in every tissue and organ.
However, there are exceptions to this general principle of the healthy T3:T4 ratio ranging from mildly T3-dominant to highly T3-dominant.
Some people who fare well on T4 monotherapy or very low T3:T4 dosing ratios will get enough FT3 supply even though their blood is still very FT4-dominant.
Rigidity regarding optimal ranges has no place in combination therapy — “one size fits all” is the bane of T4 monotherapy, so let’s not let it creep into combo therapy. When websites like Stop the Thyroid Madness give guides to optimal Free T3 and Free T4 thyroid hormone levels and ratios, they can be very helpful up to a certain point, sure. But all these generalizations can be is a handy guide to where a lot of patients have reported feeling optimal. They are not absolute laws for each person.
ADJUST FT3:FT4 RATIO TO OPTIMIZE
How much “net T3 supply” in blood is going to satisfy all your tissues and organs’ needs? What are your circulating hormone levels saying about your thyroid hormone metabolism?
Each individual patient will manifest a “fingerprint” range for their optimal — each person has a characteristic ratio of FT3 and FT4 in blood, and they and a good thyroid doctor will get to know where they are relatively symptom-free.
The “optimal” locations of FT3 and FT4 within or at the boundaries of reference range are always in relationship to each other, never in isolation.
In thyroid therapy, it is necessary to look at bloodstream levels of thyroid hormone not just from the supply point of view (dosing & thyroid gland secretion), but from the perspective of the tissue consumers of hormone.
As a person’s T3 intake and T3:T4 ratio intake increases, let their FT4 drop, or you will overload them with “net T3 supply” in blood, but be reasonable about how far they drop.
If you lower T3 dosing, you will need more T4 floating around to deliver more T3 to cells within T4 “delivery packages” that provide slow-release tissue T3.
In combination therapy, T3 sufficiency is only obtained by flexibly adapting ratios and not fearing statistically-predetermined boundaries. The current paradigm fears and prohibits the crossing of reference range boundaries that often need to be the most flexible in T3-T4 combination therapy:
Unnecessary Fear #1) The upper boundary of the Free T3 reference range (which is not hyperthyroid if FT4 is considerably lower),
Unnecessary Fear #2) The lower boundary of the Free T4 reference range (which is not necessarily hypothyroid if Free T3 is considerably higher), and
Unnecessary Fear #3) The lower boundary of the TSH range (which is not necessarily hyperthyroid if T3 dominates over T4 in a high T3:T4 ratio and both are within reason).
The abnormal dosing ratios and blood levels are not necessarily maladaptive. Abnormally low TSH and FT4 can also be therapeutically adaptive, as the next sections demonstrate.
KNOW THE FREE T3 DOSING CURVE
When dosing any amount of T3 hormone, it is absolutely essential for both doctors and patients to understand the “curve” of FT3 in blood in relation to blood tests. It’s also useful to know the curve when splitting a dose 2 or 3 times a day for optimal symptom-free living.
The dosing curve strongly influences what your thyroid hormone-converting deiodinases and other metabolic processes are doing to T3 during its FT3 post-dose peak.
Time post-dose also tells you about how long FT3 takes to exchange with various organs and tissues and activate receptors to get a symptomatic response. If you experience a symptom within an hour after a dose, scientists suspect it is likely because of non-genomic FT3 action at the cell-wall receptors, not the more powerful genomic action at receptors in the nucleus.
Here’s a graph from Saravanan et al, 2007 that expresses changes in pmol/L and mU/L units. Notice the shape of the curve and where the average FT3 peak is located. Maybe you don’t want to dose 1x a day because this is quite a steep FT3 hill:
And here’s a graph that expresses it as % change in each hormone.
Figure: from Saravanan et al, 2007, figure 2.
For dose-splitting advice and managing symptoms throughout each 24 hour cycle, learn from people on T3 monotherapy to understand how they live when they are fully exposed to the fluctuations of the fast-release (regular) T3 pharmaceutical. They don’t have T4 converting into T3 every minute of every day, so they feel the doses and the roller coaster, and they know what T3 dosing does to their body. You may find my T3 monotherapy narrative enlightening.
It’s rare for people taking T3 in doses NOT to split doses into 2x a day. If you are a slow metabolizer or are taking a lower dose ratio of T3:T4 you can get away with 1x a day, but as you increase total T3 dose, it will create higher peaks and you might want to dose more frequently to keep the peaks lower.
See the graph below from Ben-Shachar et al showing how you can cut down peaks during which your body responds more dramatically — especially in heart rate — and during which it more quickly clears out FT3. Each peak represents a dose.
As you multi-dose, you are taking less mcg in per dose and you are spreading out your FT3 levels between doses, economizing the $$ per microgram and being less demanding on your cardiovascular system and adrenals, and perhaps also your brain will thank you.
Be very consistent in blood test timing, always waiting the same amount of time after the FT3’s volatile and unpredictable “peak” in blood has faded, otherwise you can’t compare progress between two lab tests three months apart!
Measuring during peak FT3 is pointless, other than doing it once or twice out of curiosity or for research purposes. Even 20 minutes can make a big difference in FT3 levels during its volatile peak. The time it takes for FT3 to rise and fall from that peak is highly individualized and can shift based on D3 conversion activity that will likely be triggered at this time.
Lab testing FT3 consistently 12 hours post dose is a good rule of thumb because it is biased neither to the volatile peak, nor to the hypothyroid trough. Who wants to cause a patient undue suffering by delaying their next T3-containing dose too long? If most of a patient’s combination therapy is in the form of T3, starving the body of T3 for too long can have side effects afterward for days or weeks.
KNOW YOUR CONVERSION ENZYMES: DEIODINASES
The three deiodinases convert our thyroid hormones in our cells. They are at the core of thyroid hormone metabolism.
They are the key to understanding how to help therapy fit an individual.
A doctor and patient dosing any combination of T3 and T4 should understand the basic science on the behavior of the two most prominent deiodinases in therapy, Deiodinase type 2 and type 3 (Learn about D1 further below).
Deiodinase type 2
This deiodinase is the most important for T4-T3 conversion.
It’s the deiodinase that has received by far the most scientific attention for this reason. Many of our articles discuss D2, and we can learn a lot from studying its role in any form of thyroid therapy.
The D2 enzyme is in almost every tissue, but it’s a fragile and vulnerable enzyme, sensitive to how much T4 is available to convert.
Understand ubiquitination — this is the process by which increasing Free T4 even within reference range causes T4 to yield less and less T3 in tissues.
To the same degree, lower Free T4 can optimize T4-T3 conversion — as long as T3 is not concurrently too high and triggering D3.
Few people discuss this fact, but D2 is also involved in converting T3 to one of its forms of T2, a benign and beneficial type.
Deiodinase Type 3
Deiodinase type 3, the fire-fighter enzyme that minimizes or prevents temporary thyrotoxicosis, can resurface within hours or days in any tissue where the body senses “excess” T4 or T3 above the current thyroid hormone homeostatic setpoint. Sometimes D3 goes a bit too far and runs amok de-iodinating more thyroid hormone than it should.
This D3 action is the real phenomenon that “Stop The Thyroid Madness” (STTM) — a valuable patient-driven resource for desiccated thyroid therapy — is talking about when it uses the language of “Reverse T3 dominance.” It’s actually Deiodinase Type 3 dominance, because D3 does more worrisome things than create Reverse T3 — it converts your T3 into T2.
STTM currently propose that RT3 is “blocking” nuclear receptors, something not possible given what we know of thyroid hormone action in cells.
Reverse T3’s more profound effect is that it amplifies Free T4 levels’ action of inhibits Deiodinase Type 2, without increasing TSH secretion (Cettour-Rose et al, 2005; Sabatino et al, 2015).
STTM also propose that the FT3 hormone is “pooling” in blood and unable to enter cells, which is just as highly doubtful in science. True pooling happens if you have an MTC8 deficiency — this occurs in rare males who are mentally retarded from birth because their brains don’t get enough T3 during fetal life (Bernal et al, 2015; van Mullem et al, 2016; Groeneweg et al, 2017). Yes, by describing “pooling,” they are describing a real phenomenon experienced by patients. Yes their tips may work for many people, since it is crowdsourced wisdom.
Understand D3 dominance and you will understand how to manage what is being described as “pooling” and what is really going on with both T3 and T4 when your RT3 levels are rising.
You can’t have any RT3 at all if you don’t have T4 to make it from, so of course RT3 will rise, even in a healthy person with a healthy thyroid, when their FT4 rises in reference. RT3 is not an evil molecule if healthy people make some every day.
Outside of thyroid therapy and fetal life, Deiodinase Type 3 is rather dormant, just operating enough to keep the body converting a flexible baseline percent of T4 into RT3 per day. This D3 enzyme gets powerfully upregulated and “reactivated” as D2 becomes suppressed (Bianco et al, 2019). This can occur when either or both FT4 or FT3 cross the upper boundary of an individual’s homeostatic set point (personal optimal range). The homeostatic ceiling can get lower during illness and this will reawaken D3 — after cardiac surgery, FT3 can plummet within 24 hours due to the quick response of D3, as it lowers the metabolic rate (Engler et al, 1978).
The generation of RT3 from T4 — and the generation of T2 from T3 — are simultaneous activities of the D3 enzyme in cells. It is one enzyme with two roles. There is a row of D3 “soldiers” in cells that express it (Bianco et al, 2019, Figure 1).
The main effect is that an overactive D3 leads to T3 hormone depletion. D3 can both destroy T3 or divert T4 into RT3 before those precious three-iodine molecules can reach the hormone receptor in the nucleus.
In thyroid therapy, there is a point at which D3 starts throwing micrograms of T3 and T4 medication in the metabolic garbage heap. The variant of 3’3′ T2 that is converted from T3 by this enzyme D3 can be thought of as “Reverse T2,” and one rare scientific article has called it that — Colucci et al, 2018.)
Deiodinase type 1
Deiodinase type 1 is a two-faced enzyme.
When FT4 is low and FT3 is below mid-reference, this enzyme can power-up the T4-T3 conversion that D2 enzyme is accomplishing. D1 also plays a role in increasing T3 oversupply in Graves’ hyperthyroidism.
But this enzyme can generate RT3 from T4 as well. Scientists don’t yet understand how or when D1 starts to switch over to remove iodine from the inner ring of the molecule where deactivation occurs, but they believe at normal levels of T3, about half D1 goes to T3 and the other half goes to RT3.
Deiodinase type 1 is powered by T3. It has thyroid response-elements (TREs), parts of thyroid receptors, in it (Gereben et al, 2008). This is one reason why it’s more efficient when T3 is relatively more abundant, and why it overpowers in Graves’ disease.
If you want RT3 to clear out of your body, D1 is your friend, because that’s its main job. If RT3 is building up, it’s not just because a lot of RT3 is being made, but it can be because D1 is downregulated or handicapped by loss of T3, and perhaps D1 is being overwhelmed by RT3 supply and can’t clear it out fast enough.
Deiodinase Type 1’s expression is localized mainly to the thyroid gland, liver, and kidney. These are the organs that are fast-exchanging with blood and generate a lot of blood FT3 via both deiodinases 1 and 2. A person without a thyroid loses a huge portion of potential D1 conversion activity.
Add to this knowledge of deiodinases an understanding of an individual’s metabolic handicaps so that you know how to optimize T4-T3 conversion in a poor converter on the one hand, and how to keep an eye on overconversion in a highly efficient converter of T4 hormone on the other hand.
The net effect of all three deiodinases
How do you know a person’s baseline conversion efficiency? The best measure of the degree to which a poor converter is truly handicapped is by doing the SPINA-Thyr analysis while they are on T4 monotherapy, not very sick, and FT4 levels are around 30% to mid range, where they would be in a normo-thyroid person.
Now consider how D2 and D3 can shift conversion to be less efficient or more efficient when FT4 and/or FT3 are relatively higher or lower in its range.
Now consider the individual’s metabolic handicaps.
The ultimate judge of the net effect is the person’s full body response to thyroid medication. At some point you have to go beyond blood levels and look at signs and symptoms.
SAFE DOSES OF T3 AND NDT CAN SUPPRESS TSH
The abnormal behaviour of TSH in desiccated thyroid therapy (and other T3-dominant therapy combinations at different ratios) has become the biggest obstacle to its effective dosing and the more widespread application of desiccated thyroid therapy.
Too many doctors have a kneejerk reaction to a low TSH that is not justified by the older scientific literature that is the most informed about desiccated thyroid and synthetic T3.
What does our science say?
It says very clearly that TSH is a local tissue response.
TSH is not a global indicator of T3 sufficiency all cells anywhere outside the hypothalamus and pituitary. TSH is not the secretion of an all-knowing godlike gland (Dietrich et al, 2012).
These two glands can be hypersensitive to factors beyond thyroid hormones because they are designed to drive change and anticipate metabolic needs, not just passively respond in a closed feedback loop, like some oversimplified models naively suggest.
With so many potentially competing inputs into these two glands, it’s not easy to adjust one hormone’s secretion, TSH. Thyroid tissue loss and thyroid therapy break down the natural feed-forward cycle and thyroid therapy interferes in the system’s normal function. (Hoermann et al, 2016)
What does thyroid science history say?
Robert Utiger, the renowned “father of the TSH test” had a few strong cautions against relying on TSH in T3-based therapy. See my “dialogue with Utiger” post for more details on his scientific experiments with T3 dosing, and his bold claim in 1972 that an effective, safe dose is one that is capable of suppressing the TSH.
As the TSH testing technology was developed between 1965 and 1988 and it became more and more sensitive to measuring small concentrations, levels below the normal statistical reference range, Utiger cautioned against the “overzealous” application of this lower TSH boundary to judge everyone below it as always thyrotoxic (Utiger, 1988).
Utiger had a prophetic sense of how the TSH test would grow too powerful and influential. He suspected that its sensitive lower boundary, the TSH innovation in the late 1980s, would be wielded against thyroid patients and could end up making thyroid testing less efficient and more costly in the long run.
Utiger’s own deep scientific research on desiccated thyroid as well as other therapies informed him as he wrote this passage cautioning overreliance on TSH mono-testing.
“Consider the problem of subclinical thyroid disease—that is, patients who are clinically euthyroid and have normal serum T4 and T3 concentrations but abnormal serum TSH concentrations.” … “These patients will likely undergo additional tests. In contrast, had only serum thyroxine [T4] been measured in such patients, the normal result would preclude the need for additional tests.”
Utiger continues: “In practice, much depends on the testing philosophy of those ordering the tests and the physician’s confidence in his clinical judgment…”
Ponder Utiger’s claim that “much depends on the testing philosophy” — it has become tyrannical and fanatical the more people yield their clinical judgment to a single pituitary number, the TSH.
“My conclusion,” Utiger writes, “is that the use of initial serum TSH measurements for evaluation of suspected thyroid disease has both strengths and weaknesses. It is clearly superior for assessment of certain patients, but as a general test in an ambulatory setting” [that is, outside of hospitals], “TSH measurements will identify too many patients in whom the unwary or overzealous may undertake unnecessary further testing and even treatment.”
Indeed the “overzealous” have taken on the job of guarding the lower boundary of the TSH reference range as if they were the holiest guardian angels of the thyroid church, protecting the immutable barrier between health and disease for all but a few exceptions (central hypothyroidism is a noteworthy exception — a handicap in TSH production).
However, it often means patients taking higher T3:T4 doses are forbidden admission to the realms of true euthyroidism.
Yes, when TSH is low or suppressed, that is often where patients find a healthy, optimal dose that produces reasonable net T3 supply in blood, finally satisfying all their tissues and organs (Busnardo, 1980).
A low TSH is the region where a significant percentage of T3-T4 combination therapy patients finally obtain T3 sufficiency and equality with their fellow citizens with healthy thyroids at a normal TSH.
BIASED FEAR OF THYROTOXICOSIS VS. HYPO
Consider the built-in reference range discrimination that currently exists.
In thyroid therapy, one end of the TSH range is defended with more fear and zeal than the other, and it is invariably the lower end that is used to judge hyperthyroidism rather than hypothyroidism. That’s where the witch hunt happens.
How unfair is that?
To what degree is the lower TSH boundary harming patients who medically require a variable dose of T3 from their medication that, as a side effect, lowers or suppresses the TSH for reasons other than thyrotoxicosis (Goluart-Silva et al, 2011)?
To what degree is this ratio-limiting, TSH boundary-defending paradigm holding back understanding of natural human diversity in response to all thyroid therapy modalities, including T4 monotherapy?
Look at what happens at the other end of the TSH range, where overt hypothyroidism occurs. Criminal apathy and blindness to T3 sufficiency in tissues.
The dogmatists of thyroid therapy today are comfortable with allowing people to undergo the tortures of hypothyroidism for the rest of their lives.
They have not yet fully pondered the scientific findings on how unusual the “thyroid disabled” people are.
A thyroid patient’s Free T3 could be anywhere on the map at any level of TSH and Free T4. You can’t predict it!
This graph from Larisch et al (2018) shows the wide-ranging response of people with no thyroid gland to T4 monotherapy. The gray dots show where “healthy controls” are, in a limited region of the right hand side of the graph.
The main point is that we thyroid-disabled people are NOT like “normal” people with healthy thyroid glands.
As you can see, the TSH response to thyroid medication is NOT like the TSH response to hormones secreted by a living gland because it imbalances the hormones to different degrees in different people, and the TSH isn’t wired to interpret these ratio shifts.
With a TSH low or suppressed by medication, we may actually be euthyroid, or even underdosed, depending on our Free T4 and Free T3 levels and ratios in bloodstream.
Larisch and team’s work has been independently confirmed by a different set of researchers, Ito and team, through several experiments and articles (Ito et al, 2015, 2017 and 2019).
The general conclusion of this research tradition — even though it focuses on T4 monotherapy in thyroidless people — is that the TSH lower boundary is absolutely unfair to many thyroid patients.
It’s even more true in T3 therapy, since T3 dosing even at euthyroid, therapeutic doses, is well known to be a TSH-suppressant (Chopra et al, 1978).
The TSH cannot not accurately discern the point at which an individual patient becomes thyrotoxic.
MILD, TEMPORARY THYROTOXICOSIS
As you and your good, safety-minded thyroid doctor work together to discover your optimal FT3-FT4 zone, you might once or twice cross the line into mild thyrotoxicosis.
Occasional mild thyrotoxic effects in lifelong thyroid therapy are not unforgiveable sins. They are part of the trial and error of finding an individual’s true upper boundary for an optimal dose. If you don’t know where your upper ceiling is or how it feels when you get there, you don’t know where in your optimal range you are. This is fine tuning. Your thyroid used to be a self-driving car. Now you’re in the driver’s seat.
One must distinguish between true / overt hyperthyroidism and mild oversupply.
In hyperthyroidism, a patient with Graves’ disease has stimulating antibodies continually pushing a living thyroid gland to oversecrete both T3 and T4. That’s true hyperthyroidism. In Graves’ disease, antibody attack forces on the body a continual oversupply of both thyroid hormones in blood.
True thyrotoxicosis leads to a continually elevated heart rate and continually higher body temp day and night, not levels that fluctuate over 24 hours. (Mathur, 2018; Kalra et al, 2011 – Wayne’s index for hyperthyroidism)
Patients can learn to read their own bodies over weeks, months, and years. Learn from Paul Robinson’s books. Learn from people who live on T3 alone — we know these fluctuations.
Vital signs can be vital clues. Every thyroid patient who ingests T3 hormone should learn how to measure heart rate and body temperature and track them when making major changes in doses or fiddling with dose timing.
Not all cardiovascular symptoms are thyrotoxicosis signs. When the body falls low in T3 supply, it can give you erratic surges of cortisol and adrenaline that are irregular, like throwing water on a red-hot cast iron pan — these can be signs of the body trying too hard to compensate.
Be a mini-scientist and treat your body as an n=1 experiment. Plot resting heart rate on a chart or table, getting pre- and post-T3 / desiccated dose heart rate, at various times of day keeping in mind things like caffeine, exercise, ambient temperature, and meals. Take note of other symptoms like nervousness and mental health indices like cognition and emotions (Kalra et al, 2011).
Every thyroid patient can take their own body temperature (it’s a slower and more gradual response to T3 than heart rate) and plot it over time of day, and over the a menstrual cycle if they are female and pre-menopausal (body temperature reaches a low mid-month when estrogen rises and more thyroid hormones are bound than free).
Some people find that blood pressure is also an indicator — I personally have not found it relevant at all.
Poor sleep can be caused by running too low on T3 at night or by having too much T3 all night and keeping cortisol high. You don’t know which for sure, unless you get the right kind of cortisol test done. You can try taking a small dose of T3 when you have insomnia at 3am, for example. If it helps you get back to sleep within an hour, you have your answer, you were likely low on T3.
FIXING MILD OVERTREATMENT
If you find yourself mildly thyrotoxic due to dosing, the fix is easy. You can change dosing now.
Usually the effects come from the peak Free T3 and/or Free T4 above a person’s built-in reference range — their own homeostatic set point’s ceiling.
Adjust ratios and doses down when the body speaks! You don’t need a doctor to write a new prescription to lower your dose immediately. What would your doctor want you to do? The answer is obvious. Don’t push your body when it is saying no.
How long does it take for T4 hormone to clear out, compared to T3 dosing?
The half life of T4 is a week at least, so let’s say 2 weeks at least to clear out most of the FT4 peak, but consider that the body hangs on longer to T4 the less it has, so there’s a long tail on the depletion of T4 (and RT3) that could take three months at the lowest end of low as it goes down the drain.
Consider that Total T3 has a half life of a day or two, but peak Free T3 has a far shorter half life, a mere 6-8 hours, after which is another long tail of gradual depletion.
Therefore, T3 dosing mistakes are more temporary in their effects and easier to fix.
How long will these thyrotoxic symptoms last if they occur — a mild tremor, a headache, a faster heart rate, and weak muscles?
Depending on how quickly those organs and tissues exchange 2-way with bloodstream Free T3 and Free T4, these symptoms could be as fleeting as a few hours, days, weeks, or a month until it is recognized and reported by the patient and resolved.
CONCLUSION: THE HUMAN RIGHT TO T3 SUFFICIENCY
Currently, the target of thyroid therapy is a huge range of normalized TSH discovered in people with healthy thyroids. Only the normalized TSH is the judge of effective therapy. This is a TSH secretion profile that is found in those with healthy thyroids who are not dosing any thyroid hormones.
Look in the research by Hoermann, Midgley, Dietrich and Larisch and you will discover that the HPT axis (our TSH, FT4, FT3 relationships) shifts profoundly away from “normal” in thyroid disease and therapy. We are not accommodating for diversity of response to thyroid therapy. There are major flaws in our therapeutic paradigm.
Currently, official guidelines for thyroid therapy for the vast majority of patients limit them either to a nonphysiological rato of 0:100 T4 hormone only, or a tiny ratio of T3 to T4 micrograms in a rigid T3-T4 combination therapy modality.
The freedom to obtain global T3 hormone sufficiency in tissues is the birthright of every human being with a healthy thyroid. Have we lost our birthright with our thyroid function?
Shouldn’t a thyroid disability inspire a claim for for thyroid hormone disability rights and reference range accommodations, just like an ethical claim for the human right to mobility and accessibility aids, like ramps and railings, for those who have a mobility disability?
Why would anyone deny a patient the right to access “optimal net T3 supply” in blood by disallowing them from adapting the ratio of their T4 and T3 dosing, and/or adapting the ratio and levels of their Free T3 and Free T4 in blood, and/or forbidding a lower TSH or the non-secretion of TSH hormone?
Doctors and scientists, expand your door frames to allow disabled people through — expand your medical frameworks and paradigms. Make genuine tissue T3 sufficiency equally accessible to patients who need adaptive thyroid therapy.
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