Canadian LT3 brands: TEVA vs. Cytomel bioequivalence, fasted vs. fed

Did you know that Canadian TEVA LT3 has a much faster-release effect than Canadian Cytomel LT3 in the fasted state? They are not bioequivalent in all ways, despite Health Canada approval following a bioequivalence study.

In addition, both Canadian brands have a “slower-release” effect when dosed on a full stomach and a lower maximum peak. Mealtime LT3 dosing may be better for some patients who are hypersensitive to fast, high FT3 peaks, despite overall reduced LT3 absorption with meals and the need for a higher prescription to compensate.

These data, when compared with other bioequivalence studies, also urge us to look into the science to understand why higher doses (a single large overdose of 100 mcg was used in the bioequivalency study) result in a paradoxically shorter, not longer, T3 half-life than smaller doses.

The data tables are easily overlooked in the Canadian LT3 product monograph. Who reads the full monographs? Who stops to examine complex data tables? But when the 100 mcg single-dose data is displayed in the graphs I provide, they reveal clinically relevant differences between two LT3 brands, and between dosing any brand of LT3 in fasted vs fed states.

And the data in the tables directly contradict some of the statements in the rest of the monograph regarding LT3 absorption!

These data reinforce the need for updated product monographs, better bioequivalence studies and clinical trials that compare LT3 brands and dose protocols, due caution when substituting one brand with another, better physician education, and mutual learning and decision-making between physicians and patients.

Background & challenges

As many of you know, Liothyronine (LT3) is the synthetic pharmaceutical that provides bioidentical T3 (triiodothyronine), the most active thyroid hormone, to blood. LT3 has been used to safely and effectively treat hypothyroidism since the 1950s (See the 1957 clinical trial by Finkler). LT3 is rarely used as a  monotherapy, although some patients are safely dosing as a complete or partial thyroid replacement. LT3 is most often combined with levothyroxine (LT4) in synthetic LT3-LT4 combination therapy.

Sometime during the past five years, Health Canada permitted the marketing of TEVA brand Liothyronine, a “generic” LT3 alternative that is cheaper than Cytomel LT3. The basis of its approval was a bioequivalence study, whose results are reported in tables on pages 13 and 14 of the Canadian TEVA LT3 product monograph dated November 20, 2019 (this date is likely prior to Health Canada’s approval to “market” of the drug).

But the appearance of TEVA LT3 on the Canadian market was unannounced, and its groundbreaking bioavailability study data has been overlooked.

As a result of this bioequivalence study, but without comparative clinical trials in hypothyroid patients, many health care plans across the country approved the substitution of TEVA LT3 for Cytomel.

Some patients who were on LT3 Cytomel received LT3 TEVA substitutions without being informed by their pharmacists.

The bioequivalence may fit within Health Canada’s parameters, but the effects of chronic dosing of TEVA LT3 hypothyroid patients has had unexpected, and sometimes adverse, effects. In cases of Cytomel > TEVA LT3 switching reported on Canadian thyroid support groups, we saw one patient have a steep rise in TSH and fall in FT3 and another experience the onset of atrial fibrillation. We only knew about a small number of people who posted about it, but their suffering was awful.

The stories of these patients motivated me to look into the TEVA LT3 product monograph by Health Canada. I was very intrigued when I saw the TEVA vs Cytomel data, so I entered the data into Excel, made graphs, and shared my findings with our private thyroid support group community. I’ve applied the findings to my own LT3 treatment with great benefit. Now I’m sharing the findings publicly.

In the absence of published clinical trials using TEVA LT3, I believe there are clues to some patients’ adverse effects on TEVA LT3 in the bioequivalence data published by TEVA.

But this article is about much more than the caution that switching brands could cause adverse effects for some hypersensitive people. Some of their study’s data are clinically very useful.

• Until TEVA Canada published its bioavailability study data, scientists, physicians and patients have been completely unaware of just how much less LT3 is absorbed with meals when LT3 dosed at specific strengths. The study didn’t say which ingredients caused poorer absorption, but it quantified it.
• No published scientific experiment has ever compared the dynamics of fasted or fed absorption of LT3 over time. We have all been uncertain about the degree to which taking LT3 with a meal could be beneficial by significantly slowing down its absorption, making it behave more like a slow-release LT3 formulation. Now we finally have some data that quantifies just how delayed LT3 absorption is, at least at one particular dose strength.

In fact, this enlightening study has the potential to make LT3 dosing more effective, more stable, and symptoms during LT3 treatment less puzzling. It should inform prescribers’ and pharmacists’ advice to patients, patient support groups’ peer advice … and the design of future LT3 clinical trials.

So let’s examine these data in detail.

Summary of findings

Fasted vs Fed LT3:

• In the fed state, the data show that both TEVA and Cytomel behave more like a slow-release liothyronine product.
  • PRO: This is good for patients and physicians who prefer a slower-release and longer-lasting effect when dosing LT3.
  • CON: they both attain this property at the expense of a relatively lower potency — a smaller percentage is absorbed — as measured by a lower “area under the curve” (AUC), lower time to maximum concentration (Tmax), and a slightly shorter half-life.
  • CAUTION: At the same prescribed dose of LT3, moving from “fasted” to “fed” dosing by overlapping mealtimes and dosing may result in underdose as a patient absorbs relatively less of their LT3 with a meal.
  • FOR FUTURE STUDY: If the new “poly-zinc LT3” slow-release product (currently in development, not yet marketed) is very expensive when marketed, dosing LT3 with meals may achieve a close approximation to a slow-release effect.
• In the fasted state, both TEVA and Cytomel have faster-release properties. But TEVA has an extremely fast and higher T3 peak in blood compared to Cytomel. The fast release is likely followed by a much swifter “crash” — a faster clearance rate in the first hours after a dose (given the science on clearance rates, which I will explain below).
  • CON: Some patients who are hypersensitive to the fast “peak” FT3 within hours after a of liothyronine — such as those who have mild to severe adrenal insufficiency (low cortisol) — may have more extreme acute reactions to TEVA LT3 dosed in the fasted state. This may also apply to patients with POTS (postural orthostatic tachycardia syndrome), whose condition is not necessarily caused by high T3 but can be worsened by high peaks in FT3.
  • CON: Patients dosing any brand of LT3 in the fasted state may experience a more significant “roller-coaster” clinical effect over 24 hours as their FT3 levels rise quickly and likely fall a little more quickly.
  • TIP: If patients ingest LT3 on an empty stomach, it may be advisable to take smaller divided doses (i.e. 15 mcg divided into doses of 5, 5, and 5 mcg) to maintain FT3 levels above the minimum required for the prevention of certain hypothyroid symptoms that may be caused by a faster time to peak.

Cytomel vs TEVA LT3:

• Cytomel is slightly more bioavailable than TEVA in the fed state within the first 12 hours after a dose, largely because of its 10% higher Cmax in the fed state. Treatment with LT3 Cytomel can better withstand occasional dosing with meals, especially if the patient is wisely dividing a daily dose of LT3 into two or three smaller doses to maintain FT3 above levels that induce hypothyroid symptoms. Many would consider Cytomel LT3 to be a more favorable pharmacokinetic profile than TEVA LT3 because the timing of meals and LT3 doses may not always be easy for a patient to control (i.e. if they perform shift work).
• TEVA is significantly more faster-acting than Cytomel in the fasted state as seen by its 33% faster time to maximum concentration (Tmax) (TEVA’s median fasted peak is at 2 hrs vs. 2.67 hours for Cytomel). This means that most of its total bioavailability is squeezed into the first few hours after a dose, when it may result in thyrotoxic symptoms in the fraction of patients who are hypersensitive. Patients report that TEVA tablets are more quickly dissolved in the mouth before swallowing, and this may contribute to its faster-acting properties.
• These two differences between brands were not prioritized by Health Canada because over 48 hours, both Cytomel and Teva have the same AUC and 10% different Cmax in the fed state, and their policy on bioequivalence studies prioritize only AUC and Cmax, allowing more leeway for variance on Cmax. However, dosing LT3 is unlike dosing LT4 and most other slow-acting drugs. Studying the prevalence of side effects is not the aim of a bioequivalence study. This is why LT3 brand comparative clinical trials are needed, not just bioequivalence studies.

What is a bioequivalence study?

To interpret the tables and graphs below, a reader needs a good understanding of what a “bioequivalence study” is for, and the weaknesses and strengths of its methodology. They are not like clinical trials. They involve extremely high doses rarely taken in real clinical practice (like 50-100 mcg LT3 all at once), and they test the drug in human subjects who don’t have any thyroid problems.

Graphs generated from TEVA’s LT3 bioequivalence tables

Screenshots of the original tables are provided below the set of graphs.

Cytomel Vs Teva

AUC — area under the curve, or total concentration absorbed over 48 hours.

Cmax — maximum concentration reached after the dose.

For Tmax, time to maximum concentration, notes are required under the graph to explain the range of variation:

Both brands act more like a slow-release formulation in the fed state because their Tmax is significantly delayed.

Note that there was significant inter-individual variability among research subjects for “Time to maximum concentration” (Tmax):

• TEVA LT3 fasted Tmax, median 2.00 hours (1.33 – 4.00 hours)
• TEVA LT3 fed Tmax, median 4.67 hours (2.00 – 8.00 hours)
• Cytomel LT3 fasted Tmax, 2.67 hours (1.67 – 4.72 hours)
• Cytomel LT3 fed Tmax, 4.67 hours (2.33 – 8.00 hours)

Half-life, the time at which 50% of the circulating dose is achieved.

Why did the LT3 half-life shorten at a larger dose?

In this study of 100 mcg single dose-response, the life is incredibly short at 13-14 hours.

In the 50 mcg single-dose study by Jonklaas and colleagues in 2015, the half life was 22.4 hours.

An inverse T3 half-life correlation according to thyroid status was discovered in the 1970s:

“Studies reported by Nicoloff and colleagues in 1972 calculated a half-life of T3 that varied with thyroid status (8). The mean half-life was 0.63 days in 7 hyperthyroid patients, 1.0 day in 8 euthyroid individuals, and 1.38 days in 9 hypothyroid patients.” (Jonklaas et al, 2015)

Therefore, The half-life of a 100 mcg LT3 dose will be much shorter than for a 50, 25, or 10 mcg dose.

Why is the half-life almost cut in HALF when the dose increases from 50 to 100? Higher peak T3 levels speed up the T3 clearance rate through metabolism (as T3 is converted more quickly to T2, Triac, and other metabolites), and meanwhile urinary T3 losses will at least keep pace with Free T3 in blood:

1. Excess T3 hormone signaling will upregulate D3 enzyme in tissues throughout the body. The DIO3 gene is highly sensitive to T3 and to the effect of intracellular hypoxia caused by excess T3 signaling. This means that higher levels of FT3 will produce higher levels of D3 enzyme, causing a T3-D3 negative feedback loop at an intracellular level. Although healthy euthyroid individuals mainly express D3 enzyme in brain, skin, and placenta, D3 enzyme is expressed in all human tissues during fetal life, and many adult cell types still have the encoding to re-express D3 enzyme. This D3 enzyme performs both T4-RT3 conversion and T3-3,3-T2 conversion (T4 and T3 inactivation), but it is more efficient at T3 inactivation. The net result of this enzyme is intracellular T3 loss, which contributes to plasma T3 loss — unless a person replenishes plasma losses with sufficient LT3 thyroid hormone dosing. D3 enzyme is likely the major driver of the speed of the Total T3 clearance rate. D3 enzyme can have up to a 12-hour half life. (Marsili et al, 2011; Bianco et al, 2019; Köhrle & Frädrich, 2022)
2. T3 hormone also upregulates D1 enzyme. This enzyme also contributes significantly to T3-3,5-T2 conversion whenever there is far more T3 in blood than sulfated thyroid hormones, RT3 or T4, which are preferred substrates (Maia et al, 2011). There certainly is a lot of T3 to be converted by a powerfully-upregulated D1 enzyme when 100 mcg LT3 has just been ingested. NOTE: the subjects in the bioequivalence study had normal levels of FT4 in serum, and so the upregulation of D1 enzyme would have enhanced their T4-T3 conversion as well. It could have boosted the 48-hour AUC data and half-life, making it seem like more T3 had come from the LT3 pharmaceutical than actually did. D1 enzyme also has a 12-hour half life. (Marsili et al, 2011; Maia et al, 2011; Bianco et al, 2019)
3. In 1980, Yoshida found that “urinary T3 values reflect serum free T3 concentrations” in a mixed population of healthy, pregnant, sick, hypothyroid, and hyperthyroid patients. “Excretion of urinary T3 in 45 euthyroid patients was 0.81 +/-0.39 mcg/day (mean +/- SD), ranging from 0.3 to 1.96 mcg/day.” In contrast, “The mean urinary T3 in 18 hyperthyroid patients was 7.48+/-3.32 mcg/day (range, 2.88-14.6 mcg/day).” However, none of the subjects was dosing LT3, so we don’t know whether a transiently high T3 Cmax can trigger accelerated urinary T3 losses per unit of T3 in plasma.

This is one reason why smaller, more frequent divided doses of LT3 are recommended. If a large daily dose is administered in an undivided single dose, the higher, faster peak and more rapid clearance rate causes a potential overdose for <12 hours per day, followed by possible underdose for the next >12 hours every day. Given the half life of the enzymes, T3 will continue to break down in cells at a faster rate even after T3 has fallen close to its trough level. But when each dose is smaller in size, the Cmax is lower, the rate of metabolic T3 losses is reduced, and the half-life of each dose is extended.

Faster T3 clearance explains why, in published case studies of LT3 overdose, relatively healthy people often survive the emergency, and it often quickly resolves. LT3 overdose poses a lower health risk than LT4 overdose, desiccated thyroid overdose, or endogenous hyperthyroidism. Even doses as large as LT3 1200 mcg yielding T3 levels “20- fold higher than the upper limit of normal” are rapidly cleared, although the adverse effects on organs and tissues can be severe during the peak T3 levels, in proportion to the size of the overdose (Sylvia Vela & Dorin, 1991).

TEVA LT3 original tables

The fed state, page 13

The fasted state, page 14

As you can see, the tables on Pages 13 and 14 completely separate the fed data from the fasted data. It is difficult for a reader to compare fasted vs fed states. Doctors cannot be expected to flip back and forth between pages 13 and 14 in the TEVA LT3 product monograph to see the fasted vs. fed data. That’s why I am publishing graphs derived from this data.

TEVA LT3 “Passed” the bioequivalence test. How?

The US FDA applies the 80-125 rule to passing or failing a bioequivalence test when comparing it to the “reference” pharmaceutical (the brand name drug) :

The regulatory limits applied are that the 90% confidence intervals of the geometric means for the ratios (test:reference) of the AUC values and the C-max values must fall between 80% and 125%. (van Gelder et al, 2013)

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In Canada, the rules are more stringent for “critical dose drugs” (similar to “narrow therapeutic index” drugs in the U.S.A.). Given that TEVA conducted a study under both the fasted and fed state, it seems that TEVA LT3 was required to meet the higher standards of Critical dose drugs:

For these drugs: 1) The 90% confidence interval of the relative mean AUC* of the test to reference product should be within 90.0% -112.0% inclusive…. 2) The 90% confidence interval of the relative mean C_max of the test to reference product should be within 80.0% – 125.0% inclusive. (Health Canada, 2012)

In addition, Health Canada’s policy added a third criterion: “These requirements are to be met in both the fasted and fed states.”

Fortunately, because Health Canada’s policy was applied to LT3, this is the only known “fasted vs. fed” bioequivalence study of LT3. Currently, the US FDA only requires bioequivalence testing of immediate-release drugs in the fasted state:

“For IR [immediate release] products, FDA indicates that single dose fasting study is required, while limited food effect study may be required when needed. For CR [controlled release] products, the current FDA guidance recommends single-dose non-replicate fasting and food-effect studies be conducted.” (Chow et al, 2014)

If you know of another published study of fasted vs. fed oral LT3 administration, whether it was a clinical trial or a bioequivalence study or a rat/animal study, please put a link or reference in a comment!

What do doctors and patients need?

First of all, we need to disseminate the findings about the differences between LT3 formulations and fasted/fed conditions that can affect patient safety and can inform the adjustment of LT3 divided dose timing for improved therapeutic effectiveness.

1. TEVA LT3 did NOT have to pass any bioequivalence standards for time to maximum concentration (Tmax), which showed that TEVA LT3 was 33% faster acting than Cytomel LT3. TEVA’s tables did not provide the mean and 90% confidence interval for those data. This is relevant to clinical response because T3 has fast-acting non-genomic effects hours before it genomic signaling in the nucleus has its effect. If doctors and patients were provided with the knowledge of TEVA LT3’s Tmax being 2 hours in the fasted state vs. 4.67 hours in the fed state, some patients on TEVA LT3 would prefer to have the delayed-release effect and lower Cmax of dosing TEVA LT3 with food.
2. TEVA LT3’s 10% lower Cmax in the fed state (% ratio of geometric means = 90.27% [CI = 87.04 to 93.62]) could have added up over days, weeks, or months and caused underdose when switching from Cytomel to TEVA under the conditions of dosing with food. TEVA’s reduced bioavailability at Cmax was acceptable to Health Canada because their tolerance for Cmax was wider (80-125%) than it was for AUC (90-112%).
3. Both TEVA LT3 and Cytomel LT3 product monographs FAIL to caution patients and health care providers about the significant fasted vs. fed differences within each single brand. Both the Cytomel LT3 product monograph (rev. 2017) and the TEVA LT3 (despite the tables included) say “Drug-Food Interactions: interactions with food products have not been established.” The data reveal a clear interaction with “food.” Other bioidentical hormone medications like Promerium (progesterone) include a general notice that absorption changes in the fed vs fasted states. When divided doses of LT3 coincide more or less often with meals as patients’ divided dosing schedules change, this can cause puzzling therapeutic instability over weeks, months, or years.

Currently, both LT3 product monographs give descriptions of LT3 absorption that conceal the huge degree of variability in the fasted vs fed states:

“Liothyronine is the synthetic levo form of triiodothyronine, with all pharmacologic activities of the natural substance. Its onset of action is rapid, occurring within a few hours. … Following oral administration, about 95% of the dose of thyronine is absorbed from the gastrointestinal tract in four hours. Liothyronine, not firmly bound to serum protein, is readily available to body tissues. Its biologic half-life is about 2 ½ days.” (TEVA product monograph, p. 12)

The Cytomel product monograph statement is verbatim (p. 12) except for inclusion of the Cytomel brand name in the statement.

As one can see in the quotation above:

• The concept that “95% … is absorbed … in four hours” does NOT provide sufficient clinical information about the time to maximum concentration (Tmax) in plasma, which may vary from 1.33 hours in the fasted state to as long as 8 hours in the fed state (for a single 100 mcg dose).
• “Its biologic half-life is about 2 1/2 days” likely refers to T3 concentrations in the UNtreated state, NOT the half life of the pharmacologic dose. The comparison of Jonklaas et al 2015 with the TEVA LT3 study data shows that the half-life can be shorter after high doses (100 mcg) and longer in smaller doses (10, 25, 50 mcg).

The product monograph is misleading. Its generalized statements make it seem like Tmax and Cmax is 100% predictable under fasted and fed conditions and consistent across all doses and brands, when it is not. The differences should influence clinical choices regarding the timing and strength of divided LT3 doses.

Patient-centered solutions for LT3 administration

The following suggestions may address the challenges raised above:

• National drug regulatory bodies, such as Health Canada and the US FDA, should become aware that an LT3 bioequivalence study alone may not be capable of detecting significant clinical differences caused by a different Tmax in the fasted state, and different Cmax in the fed state, between two formulations of LT3. The LT3 pharmaceutical behaves very differently from LT4. Risks may exist when changing formulations despite a narrowly bioequivalent AUC over 48 hours.
• When a country has more than one LT3 brand on the market, scientists should perform clinical trials in diverse hypothyroid patients, not just healthy volunteers in bioequivalency studies. We need studies that compare the effects of different LT3 formulations on clinically realistic LT3 dosing protocols in both fasted and fed states.
• Physicians and pharmacists should be aware of the risks of substituting one LT3 formulation with another without informing the physician and patient and providing cautions about possible side effects when administered in a fasted or fed state. If a patient is at risk from substitution due to the brand differences in Tmax and Cmax, the physician should disallow substitutions.
• Physicians should collaborate with their patients on LT3 divided-dose timing schedules. Within a daily prescribed dose, no expert can predict what LT3 “divided dose schedule” will be realistic, convenient, or effective for the individual. Physicians should equip capable, motivated LT3 patients with the knowledge to micromanage their own split-dose timing. Some LT3 patients are just as competent as Type 1 diabetes patients who diligently take responsibility for micromanaging their insulin dosing. Some LT3 patients have the aptitude and interest to learn about how Tmax and Cmax differ in fasted and fed states. Patients can use this information to experiment with dosing around their own mealtimes, lifestyle, and symptoms. Some may be willing to track their symptoms and vital signs and bring data back to the physician. Mutual learning may enhance patient-physician cooperation and improve health outcomes. Science-based patient groups like Thyroid Patients Canada can support and educate patients between physician visits.
• Patients and physicians could consider both the pros and cons of mealtime LT3 dosing. Not everyone “requires” a slow-release LT3 formulation. A recent study (Chen et al, 2022) found NO cardiovascular effects within 4 hours of an LT3 overdose in healthy subjects. In other patients with hypersensitivity reactions within the first few hours after a dose, taking one or more divided doses of LT3 with a meal may induce a safer, milder, slower-release effect (delayed Tmax and lower Cmax). However, it may require a slightly higher daily dose to compensate for a slightly lower AUC and Cmax for that divided dose.
• Patients and physicians may wish to experiment with placing one of their divided LT3 doses at or close to bedtime to dose it away from food. Physicians often mistakenly imagine LT3 is like caffeine, but the same divided dose strength may have a different effect at 10pm and 10am. Some patients (such as myself) use a bedtime divided LT3 dose as a sleep aid! In untreated, healthy people, FT3 is naturally highest during sleeping hours (Russell et al, 2008), so of course a natural T3 “dose” infused by the thyroid gland itself does not normally cause insomnia. One would need to take an individualized dose strength at a reasonable time after the previous divided dose. Consider the way previous doses during daytime have been influenced by fasted or fed conditions. An accurate, precise fitness tracker’s 24h graph of heart rate can reveal the HR response to a bedtime dose. I find that my heart rate immediately drops after sleep onset despite my LT3 dose. This is likely because norepinephrine levels are lower when supine (Dodt et al, 1997).
• Clinicians and patients need evidence-based guidance on the timing of LT3 withdrawal before thyroid testing. As recommended by international consensus guidelines (Jonklaas et al, 2021), it is more clinically meaningful and practical to measure T3 or FT3 at “trough” levels. The trough predictably begins around 12 hours after LT3 administration, when the fast-clearance “crash” of T3 levels transitions to the much slower-clearance “trickle.” Given the LT3 dose-response curve, neither transitory peak levels nor trough levels are indicative of the average T3 bioavailability level over 24 hours. However, the height of the various divided-dose T3 peaks can be estimated based on a clinician’s familiarity with dose-response graphs by researchers such as Celi et al, 2011, and graphs republished in Jonklaas et al, 2021. Trough levels have the advantages of 1) greater stability over minutes and hours of waiting in the lab, 2) a better correlation with the daily total LT3 dose rather than just the strength of the final divided dose or its administration with or without food, and 3) greater comparability between tests that are weeks or months apart that are also measured X hours after withdrawal, and 4) some time for TSH to perform part of its delayed recovery from the T3 peak.

What we need to know from thyroid scientists:

• Studies should explore the mechanisms by which food, supplements, and drugs impair LT3 absorption. One should not expect LT3 to be impaired by iron or calcium to the degree that LT4 is. An enterocyte cell study has shown that T4 hormone is more vulnerable to forming chemical complexes at higher pH levels, causing reduced absorption; but T3 is not as vulnerable at higher pH (Kelderman-Bolk et al, 2015). How do tablet dissolution properties or tablet-crushing speed up Tmax? How much do smaller doses lengthen the T3 half-life?
• Comparative bioavailability studies should test LT3 at both 100 and 50 mcg so that it can be clearly seen that the half-life is shorter with higher doses. It seems like the Tmax also shortens at higher doses. This difference is only seen when the TEVA data is compared with published studies such as Jonklaas et al, 2015. The half-life was almost 2x longer at the lower dose of 50 mcg. One wonders whether any brand-to-brand differences would show up at half the dose that are presently concealed by 100 mcg dosing. A manufacturer could alter the pharmaceutical to pass the minimum requirements of the bioequivalence test rather than to achieve therapeutic equivalence at lower, more realistic doses. Ideally, one should publish a full study as Jonklaas et al did in 2015, describing methods, discussion and with scatterplots and/or line graphs showing TT3 and FT3 dose-response curves, as well as TSH response and delayed recovery.
• It would be relevant to measure active T3 metabolites such as TSH-suppressive Triac hormone and active 2,5-T2 hormone, since these may or may not increase at higher doses, and they have powerful clinical effects. Triac significantly cross-reacts with some T3 immunoassays, amplifying both the FT3 and TT3 concentration as shown in the study by Chan et al, in 2022. A little-known study by Gavin and team in 1980 found that in thyroidless patients rendered euthyroid by dosing synthetic LT3 hormone alone, about 14% of their daily dose turned into Triac. In contrast, among those who dosed only LT4, only about 2.9% of their daily dose converted to Triac (see our review of the science on Triac). In 1995, Everts and colleagues showed that mammalian pituitary TSH-regulating cells cannot defend themselves against T3 or Triac by metabolizing them like other tissues do.
• Studies should examine TSH-FT3-FT4 dissociation over time during acute vs chronic LT3 administration. To what degree does a higher T3-Cmax not only reduce TSH swiftly but also delay TSH recovery so that a TSH measured before X hours is a false indicator of extrapituitary tissues’ thyroid hormone status? Do both urinary T3 and TSH clearance rates increase in a similar, linear manner under different LT3 dose strengths?
• Scientists should always learn about how the conditions and timing of LT3 administration affect health outcomes and quality of life in different ways in diverse patients. Thyroid therapy endpoints encompass health outcomes, not just mere biochemical normalization. One must seek to understand how FT3, FT4 and TSH relationship fluctuations during LT3 therapy affect (or do not affect) multiple biomarkers of tissue T3 signaling beyond the pituitary TSH, as Celi and colleagues did (2011).

References