One of Thyroid Patients Canada’s values is to bring to light little-known aspects of the history of thyroid therapy so that it can open minds about future possibilities.
The history of L-T3 (Liothyronine) monotherapy brings to light the flexibility and diversity of our thyroid pharmaceuticals to adapt to the unique metabolic needs of the individual.
I offer here a full transcription of Dr. Rita Finkler’s 1959 clinical study of “Liothyronine as a replacement for [gold-standard desiccated] thyroid therapy,” now available in the public domain.
Rita Finkler’s study examined treatment with L-T3 in 166 patients with hypothyroidism over a period of approximately 3 years of clinical experience. She provided graphs of in-depth data on 11 patients as well as descriptions of the cases of two women.
In my analysis below the article, I provide:
- more understanding of the historic thyroid laboratory measurements Finkler used, such as BMR, BPI, and total cholesterol
- later scientific data regarding FT3 and TSH levels and physiological response during T3 monotherapy
- a critique of some of her article’s shortcomings,
- a view of contemporary myths and ignorance regarding long-term T3 monotherapy,
- a brief overview of the other fragments of T3 therapy history that can still be found, and
- a call to remain openminded about the future of T3 monotherapy for those who may benefit from it or truly need it after other thyroid therapies have failed them.
Liothyronine as a replacement for thyroid therapy.
Rita Finkler, M. D.,
Desiccated thyroid and thyroxine sometimes prove ineffective. Synthetic thyroidal hormone, liothyronine, on the other hand, is found to be potent and well tolerated under the conditions specified in Dr. Finkler’s study.
Studies by Gross and Pitt-Rivers (1) indicate that liothyronine is the thyroid factor ultimately responsible for cellular metabolic activity. Subsequent studies (2, 3) by others show that the drug is often effective when desiccated thyroid and L-thyroxine proved ineffective.
To evaluate its clinical usefulness relative to that of thyroid preparations, liothyronine was administered to 166 patients showing characteristic signs and symptoms of hypothyroidism. The report summarizes the results of an evaluation conducted during the past three years.
Patients were selected on the basis of their having a subnormal metabolic rate (BMR) in addition to one or more of the following: dry skin, dry hair, obesity with easy weight gain, menstrual irregularities, easy fatigability, and general lassitude. All were seen in private practice. Of the group, 71 had been receiving desiccated thyroid or thyroglobulin; all discontinued these preparations for a week or longer before they began liothyronine therapy. The remaining 95 patients had not previously been given thyroid preparations.
BMR and serum cholesterol levels were determined for all patients before, during, and after therapy. Initial protein bound iodine (PBI) tests were carried out in 30 per cent of patients. Patients in whom normal values were found were not rechecked; others failed to return for further study. Two patients had initial radioactive iodine uptakes which were not repeated since they yielded normal results.
Eleven representative patients who were cooperative (followed dosage instructions, kept appointments) and who had some power of self observation, were selected for special study. Determinations of BMR, protein bound iodine (PBI), and serum cholesterol levels were made on them before, and periodically during, liothyronine therapy. Four of these patients had previously received desiccated thyroid.
Liothyronine dosage was established on an individual basis and adjusted in accordance to patient response. Initially, patients were given 25 micrograms (one tablet) daily for one week. Those who benefited without experiencing side effects were maintained on this dosage. In those who tolerated the drug without showing clinical improvement, the dosage was raised gradually until response was obtained or side-effects supervened. Most patients could be maintained on 50 to 75 micrograms daily without discomfort.
The charts summarize the effects of liothyronine therapy on BMR, on PBI and on serum cholesterol levels, respectively, in the eleven patients selected for special study.
Figure 1: BMR data
Figure 2: Cholesterol and PBI
In general, low BMRs were elevated; PBIs remained essentially unchanged; and high cholesterol levels were lowered. Changes in the latter were often marked, especially in patients whose pretreatment levels were 300 milligrams per cent or over. In these patients, decreases ranged from 32 to 200 milligrams per cent. Provocative as these findings may be, it should be noted that liothyronine (since it is physiologically related to thyroxine) should be used with extreme care in patients with cardiovascular disorders.
These findings, for the most part, parallel those of other investigators (2, 4); they differ slightly from findings by Selenkow and Asper (5) who report that liothyronine decreases PBI levels.
Patients who have been treated previously with thyroid preparations were, when placed on liothyronine, adequately maintained. There were no unfavorable reactions, nor any decrease in clinical response. (Our findings indicate that 25 micrograms of liothyronine proved equivalent to to about one grain of desiccated thyroid”). Fifteen [of the 71] patients who had had incomplete symptomatic relief on thyroid preparations obtained beneficial results with liothyronine.
[Example 1: A 17-year-old girl]
Typical of the response seen in these patients was that of a 17-year old girl whose complaints included amenorrhea, obesity, dry hair and skin, chronic fatigue, constipation, and sensitivity to cold. Previous therapy had been desiccated thyroid (1/2 grain daily), estrogens (Premarin 0.625 milligrams twice a day) and vitamin A (25,000 units, twice a day) with incomplete symptomatic relief. Laboratory tests, one week after desiccated thyroid was discontinued, showed PBI and serum cholesterol levels to be within normal limits (4.9 micrograms per cent and 218 milligrams percent, respectively) while the BMR was minus 26. On liothyronine, she became less lethargic, and more energetic within two weeks. There was a loss of weight and an increase of mental alertness. Gradually, her menstrual cycle became more regular, in contrast to her pre-treatment amenorrhea. After three months’ therapy, symptomatic improvement was complete. Laboratory studies at that time showed that the BMR was raised to plus 2 was PBI and serum cholesterol levels remained within normal limits.
[Example 2: A 44-year-old housewife]
Generally speaking, obese patients in the group who had reached a plateau in losing weight on thyroid therapy began to lose weight again when placed on liothyronine. An interesting example is a 44-year old housewife, whose weight gain had been checked and whose somatic complaints diminished slightly on desiccated thyroid (1 grain twice daily). She remained unsatisfied with therapy because of failure to lose more weight. Unable to tolerate desiccated thyroid in higher dosage, she was started on liothyronine (25 micrograms twice daily) after a week’s respite from desiccated thyroid. Laboratory studies just before liothyronine was started showed: BMR minus 26; PBI 4.9 micrograms per cent; and serum cholesterol was 218 milligrams per cent. Within a week the patient reported that she felt better, was not “tired all the time.” On continuing the medication for three months, she lost 12 of her 170 pounds; her hair became soft and glossy in contrast to its pre-treatment coarse, brittle texture. And, in spite of clinical improvement, laboratory studies repeated during liothyronine therapy showed marginal changes: BMR dropped to minus 27; PBI to 3.3 micrograms per cent, and serum cholesterol to 201 milligrams per cent.
Previously untreated patients with hypothyroidism obtained rapid symptomatic relief when given liothyronine. Within a week or so they usually reported that they felt better, of being “less tired” and “more active,” of having interest in tasks that had seemed difficult and monotonous (shopping, attending social and church functions, entertaining house guests). In contrast to psychic changes, such as lessening of psychogenic fatigue and apathy, improvement in physical status occurred gradually, usually over a month’s time or more, although weight loss often became evident within two weeks after therapy was started. In general, results in this group, compared with thyroid therapy in the other group, indicated that the onset of liothyronine’s action occurred more quickly; once established, its action subsided quickly upon withdrawal of the drug.
LIOTHYRONINE, a synthetic thyroidal hormone, was evaluated over a three-year period in 166 patients with hypothyroidism. Laboratory studies showed that it elevated a low metabolic rate, but had little effect on protein bound iodine and generally lowered serum cholesterol level, especially in those whose pretreatment levels were over 300 milligrams per cent. (See the charts).
Liothyronine (25 micrograms) proved a suitable replacement for desiccated thyroid (1 grain) and often provided beneficial results in patients whose response to dedicated thyroid had been incomplete. Moreover, its onset and termination of action is more rapid than that of desiccated thyroid; consequently, it is very easy to manipulate dosage. It seems especially useful in patients intolerant to desiccated thyroid.
- Gross, J. and Pitt-Rivers, R.: Lancet, 1:593 (1952).
- Frawley, T. F., et al.: Journal of the American Medical Ass’n., 160:646 (Feb. 25) 1956.
- Gold, A.: Canadian Services Medical Journal, 12:619 (July) 1956.
- Lerman. J.; Journal of Clinical Endocrinol. & Metab., 13:1341 (Nov.) 1953.
- Selenkow, H. A. and Asper. S. P., Jr.: Journal of Clinical Endocrinol. & Metab., 15:278 (Mar.) 1955.
Thank you to a few fellow patients in the Thyroid Patients Canada Support group who assisted with the transcription.
Commentary on Finkler’s findings
Finkler’s measurements were the gold standard for thyroid status assessment in 1959: Basal Metabolic Rate (BMR), Protein-Bound Iodine (PBI), and Cholesterol.
While the BMR, PBI, and cholesterol were not infallible as a single, independent indicators, together, and in concert with cholesterol and clinical assessment of signs and symptoms, they could produce more agreement regarding the patient’s thyroid status.
For example, in this study conducted in 1959 in Finland by Hortling and Hiisi-Brummer, one can see that PBI and BMR reinforce each other and distinguish the three clinical states:
Each test deserves a little further exporation:
Basal metabolic rate (BMR)
One of the most highly-respected measures for thyroid in the 1950s, which Finkler mentioned early in her methods and placed into her Figure 1, was the BMR.
What is the BMR measurement?
“The basal metabolic rate (BMR), defined as the energy required for performing vital body functions at rest, is the largest contributor to energy expenditure.”[Sabounchi et al, 2013.]
“Historically, basal metabolic rate (BMR) measurement by indirect calorimetry has represented the gold standard for the assessment of TH [thyroid hormone] action  until the advent of immunoassay methods for the direct measurement of TH and TSH.”[Yavuz et al, 2019]
Total energy expenditure (TEE) is composed of approximately 60% REE (resting energy expenditure), which generally correlates with BMR. The remaining 40% is divided among various types of thermogenesis (Yavuz et al, 2019, Figure 1).
During the 1950s and 1960s, various thyroid scientists debated the usefulness and precision of the basal metabolic rate. In defense of the BMR, Keating wrote:
“The basal metabolic rate may be said to reflect primarily the impact of the thyroid hormone upon the organism.
The basal metabolic rate remains particularly useful as the guide to replacement therapy in hypothyroid states.”[Keating, “In defense of the basal metabolic rate,” 1957]
Keating’s stance has been exonerated in recent years. The BMR, and related concepts of Resting Metabolic Rate (RMR) and Resting Energy Expenditure (REE) are key biomarkers in obesity research (Samounchi et al, 2013).
Thyroid scientists and obesity scientists have continued to assess BMR / REE in relation to thyroid hormone biomarkers. Yavuz and colleagues now explain that:
“All TEE [Total Energy Expenditure] components are directly or indirectly modulated by the TH [thyroid hormone] action.”
However, because of the rise of thyroid hormone tests and most of all, the overreliance on TSH, the BMR is no longer a routine test in thyroid diagnosis or treatment.
As for the BMR’s continued relevance to thyroid science, in a 2018 article examining the treatment of Graves’ hyperthyroidism on BMR, the hormone most powerfully related to REE was Free T3, secondarily Total T3, and thirdly, Free T4 (the latter, likely due to its ability to be converted into T3 hormone):
“The REE was positively correlated with the fT3 (r2 = 0.76, p < 0.01), TT3 (r2 = 0.67, p < 0.01), and fT4 (r2 = 0.58, p < 0.01)”[Kim et al, 2018]
In contrast, TSH was very weakly correlated with REE. Strong correlations are close to r2 = +1 or -1 and weak correlations are close to 0 (zero). The correlation to TSH was only -0.27.
Historically, as the BMR became questioned, the PBI rose in importance.
Protein-bound iodine (PBI)
But before T4 tests became widely available, Protein Bound Iodine served as a proxy of Total T4 + Total T3 in circulation.
Once Total T4 (TT4) tests became available, the correlation between PBI and TT4 became clear.
Ten years later, in Farmer and team’s early study of synthetic T4-T3 combination therapy in 1969, the scientists discovered that adding increasing doses of T3 to a stable dose of T4 (thus increasing the T3/T4 dosing ratio) created a parallel decline in both TT4 and PBI:
The graph shows how TT4 generally follows PBI, though not always precisely.
During the era when physicians relied on PBI, all three major thyroid pharmaceutical types were in use. They had to acknowledge that each type of thyroid treatment would achieve euthyroid status at different levels of PBI.
Tables like Sisson’s in 1965 outlined the levels that physicians should expect to see when different thyroid preparations rendered a hypothyroid person euthyroid:
- Desiccated thyroid, listed first in three brands because it was still the dominant therapy, would achieve normal or slightly subnormal PBI.
- T4 monotherapy, listed next, would achieve high-normal or higher than normal PBI.
- In T3 monotherapy, one would achieve lower than normal PBI because T4 levels were absent or very low, and Total T3 only comprises a small percentage of PBI.
Therefore, mere imitation of “normal range” PBI could not be, and was not, the rational therapy target.
A person on T3 monotherapy was not hypothyroid (despite low PBI), while a person on T4 monotherapy was not hyperthyroid (despite high normal to high PBI).
The target of thyroid therapy at that time was to maintain an euthyroid metabolic rate via appropriate levels of T3 signaling in tissues.
If only physicians could be educated today about where T4 (like PBI) and T3 fall in very different locations within, below, or above the reference range, when a patient is truly clinically euthyroid on hormone replacement!
The descriptive biochemical features found in people with healthy thyroids was not the goal of therapy, but the “reference range” merely provided an index one could compare with successfully treated patients on a similar T3:T4 dosing ratio of thyroid medication.
No thyroid therapy is “natural,” despite the fact that all three preparations provide bioidentical hormones (our bodies recognize and use even the synthetic hormones as identical to our own).
How different is natural T3:T4 secretion from thyroid hormone dosing?
At the core of the unnaturalness of oral thyroid hormone therapy is the fact that hormones are not released 24/7 into blood from a TSH-guided thyroid gland that customizes its T3:T4 secretion ratio to each individual’s unique metabolic needs.
In Pilo’s 1990 landmark historic study of 14 euthyroid people, one person had a T3:T4 secretion ratio closer to desiccated thyroid (1:6.5), while another had a ratio closer to that of T4 monotherapy (1:72).
No one secretes a ratio like T4 monotherapy (0:100 T3 to T4) or T3 monotherapy (100:0 T3 to T4), which makes it clear that both monotherapies are equally unnatural at the point of their supply to the bloodstream.
Yet both of these very unnatural thyroid monotherapies may (if a patient metabolizes T4 and/or T3 appropriately) achieve euthyroid status, if dosed appropriately.
In addition, only a living thyroid gland can shift its T3 secretion and T4-T3 conversion rate to achieve higher night-time FT3 levels in blood, as stimulated by a very wide circadian fluctuation in TSH.
In contrast to the healthy TSH-regulated circadian rhythm, T4 monotherapy completely flattens the FT3 level so that there is no healthy circadian rhythm at all.
In contrast, T3 monotherapy creates dose-dependent FT3 peaks and valleys in blood with very predictable clearance rate profiles.
In 1980, Busnardo and team, who were very experienced with T3 monotherapy dosing in thyroidectomized patients, outlined how three doses spread out the peaks and valleys. This method achieved euthyroidism and avoided all “signs and symptoms of hyperthyroidism,” so that “no electrochardiographic abnormalities were observed” even at the higher-than-normal T3 levels required to compensate for no T4 in blood:
As shown in Busnardo’s graph and table, during full-replacement T3 monotherapy, dosing at least 3 times a day is necessary if the individual has little to no thyroid tissue or T4 secretion, since there will be no baseline T4-T3 conversion rate to cushion their swift fall in FT3 levels 3-8 hours post-dose.
Three daily doses spaced 4-6 hours apart can create a single “T3 valley” per day to roughly imitate a circadian rhythm in this hormone (See “Q&A. Dosing T3 in light of circadian rhythm.” However, in the natural circadian rhythm induced by TSH, the T3 peak in blood occurs after a steep rise during the late evening and achieves its apex during sleeping hours. (T3 hormone is not equivalent to stimulants like caffeine.)
Thyroid scientists who were also clinicians experienced with the metabolic effects of T3 monotherapy were not frightened, as some are today, by the T3 “excursions” above the normal reference range and the “fluctuations” over 24 hours (Jonklaas & Burman, 2016; Jonklaas et al, 2015).
These T3 excursions and fluctuations were well known by early T3 scientists and did not result in undue panic. They knew that these peaks and valleys could be harmless to health over the short term and long term.
As explained by Robert Utiger, the thyroid scientist considered the “father of the TSH test,” the sharp post-dose T3 peaks in blood are “attenuated” (reduced) in their effect on the human body, including his observation of their effect on pituitary TSH (and TRH-stimulated TSH, which enabled detection of subnormal TSH during the era when basal TRH testing was not accurate enough to discern subclinical hyperthyroid levels).
“These fluctuations in serum T3 levels must be sufficiently attenuated at the tissue level that such a sensitive indicator of tissue thyroid hormone action as TSH secretion is constant despite the widely varying T3 concentrations which follow once daily T3 administration.”[Saberi & Utiger, 1974]
In other words, Saberi and Utiger noticed that during maintenance therapy with T3 alone, the TSH neither falls swiftly after a dose creates a high peak T3, nor does TSH rise swiftly during deep valleys in T3 between doses, when administered only 1x / day.
In fact, Saberi and Utiger’s hypothyroid patients who were underdosed for many weeks on 50 mcg/day maintained a hypothyroid TSH (on their old-technology TSH test) despite their supra-physiological temporary Total T3 peaks.
Scientists now know that there are natural barriers between bloodstream T3 and the nuclear and mitochondrial receptors located inside cells. Rate-limiting mechanisms of transport and metabolism occur before FT3 enters intracellular receptors. More than 99% of Total T3 becomes bound to circulating proteins, and is not Free T3. All three deiodinase enzymes, in addition to liver metabolism to inactive T3 sulfate, will cooperate to quickly redirect transient high FT3 peaks into non-T3 metabolites. All these mechanisms combine to induce the steep fall in FT3 levels seen after achieving a very brief, high T3 peak after its quick absorption.
This is why Busnardo found that in T3 monotherapy,
“When T4 is absent in serum, serum T3 levels would need to increase about twofold to normalize nuclear T3 concentrations in the pituitary.”[Busnardo et al, 1983]
Yet the unnatural ingestion of thyroid hormones to remedy the unnatural loss of thyroid tissue can nevertheless achieve a therapeutic replacement dose, when assessed clinically according to health outcomes, signs and symptoms.
Therefore, the biochemically abnormal conditions of T3 monotherapy can indeed be therapeutic.
Unfortunately, today’s obsession over the enforcement of normal biochemistry limits on thyroid-disabled people has become a form of institutionalized medical prejudice against the very unnatural, yet therapeutic TSH-FT3 relationships and FT3:FT4 ratios obtained during all forms of thyroid therapy (See our research review on “Biochemical bigotry: Enforcing normalized thyroid lab results” and the data showing the TSH-T3 disjoint in T4 monotherapy).
Total cholesterol, age, and thyroid status
The third historic biomarker for thyroid diagnosis, used here by Finkler’s study of Liothyronine, was total cholesterol. As explained by Bartels in 1950,
“In the presence of myxedema [hypothyroidism], the plasma cholesterol is usually elevated and in hyperthyroidism it tends to be low.”[Bartels, 1950]
The benefit of the cholesterol test was its precision of measurement, even in 1950:
“The chance of a laboratory error in determining the plasma cholesterol is less likely than that involved in determining the basal metabolic rate.”[Bartels, 1950]
However, the main challenge is that the normal range is wide.
“Hurxthal and Simpson (13) emphasized this wide normal range and noted an increase in the cholesterol with age, the average at 20 years being 150 mg. per 100 cc. and at 60 years, 220 mg. per 100 cc, with an overall average of 180 mg. per 100 cc.”[Bartels, 1950]
As seen in the image, the literature taught reference ranges sometimes do not apply to the individual hypothyroid person. Some patients may be truly hypothyroid and benefit from treatment even when their total cholesterol is only mildly elevated or normal:
In this era, the percentage of change effected by treatment served to reinforce the patient’s genuine need for thyroid hormone therapy as well as their benefit from it. As explained by Bartels,
“the substantial drop (37 per cent) in the level of the cholesterol followed the administration of desiccated thyroid, indicating that the initial levels were true for these patients and the drop was of the same magnitude as that observed in other patients with myxedema following treatment.
Therefore, should a patient with presumptive myxedema have a normal cholesterol, the diagnosis is still tenable and for confirmation one can resort to changes in the cholesterol which follow thyroid therapy, since nearly a 40 per cent drop in the plasma cholesterol will occur if myxedema is present.”[Bartels, 1950]
It seems as if Finkler had Bartels’ cholesterol graph in mind, including the line at the top showing the 300 mg average for hypothyroid patients, when she wrote that
“Changes in the latter were often marked, especially in patients whose pretreatment levels were 300 milligrams per cent or over. In these patients, decreases ranged from 32 to 200 milligrams per cent.”[Finkler, 1959]
Liothyronine benefits, side effects
Finkler emphasized some benefits to the patients’ symptoms and signs while being completely honest about the little change or even reversals in measurable biomarkers like cholesterol and PBI.
In the estimation of Bartels above, many of Finkler’s 11 patients studied in-depth did not have a significant degree of liver-specific hypothyroidism, since a significantly lower T3 would be needed to hinder the cholesterol clearance rate in liver.
Finkler acknowledged that while some individuals’ drop in cholesterol was not very large and others was significant, Almost everyone’s increase in BMR was significant.
Finkler’s honesty with some of the 11 patients’ lackluster metrics, and her caution about cardiovascular conditions, makes her findings far more credible when she claims that people “benefited” from T3 monotherapy.
The clinical benefit was due to her clinical caution with the titration of dose to the individual patient:
- She was conservative in her dosing approach, stopping at the initial 25 mcg if it benefited patients after one week, and only escalating dose thereafter if necessary, “gradually until response was obtained or side-effects supervened.”
- One can assume that she cut back the dose when side effects supervened. Such an expected side effect from mildly high T3 levels (also an expected effect on T4 monotherapy or desiccated thyroid) must have differed qualitatively from an adverse or “unfavorable” response, since she claimed “There were no unfavorable reactions, nor any decrease in clinical response.”
- Finkler’s note about the lack of “decrease in clinical response” meant that once a stable euthyroid dose of T3 had been achieved, patients did not develop a need for continually escalating doses, as some had feared during the 1950s. (Clearly, some mildly hypothyroid patients dosed on only 25 mcg a day did not experience TSH suppression and the expected loss of any T4 secretion ability, since 25 mcg is not a full replacement dose for a human adult.)
- Even the mild discomfort of patients was avoided when higher doses were necessary in cases of more complete thyroid failure: “Most patients could be maintained on 50 to 75 micrograms daily without discomfort.” Indeed, the average full-replacement dose of T3 monotherapy was later acknowledged to be approximately 75 mcg/day (Chopra et al, 1973).
- Science later explained why variation in euthyroid T3 dosing reflects more than body weight. For example,
- Absorption hindrances can occur not only with T4 monotherapy but also with T3 if one has very poor gastrointestinal health.
- Individuals may have different responses of liver enzymes that convert T3 to inactive “T3 sulfate” and/or a lack of healthy microbiota that can recover a small percentage of T3S back to T3 (LoPresti & Nicoloff, 1974; Rutgers et al, 1989).
- During T3 monotherapy, there can be expected a far higher rate of metabolism of T3 to “Reverse T2” (relatively inactive 3,3′-T2 or 3′,5′-T2) instead of active 3,5-T2, especially during the brief post-dose T3 peaks, since DIO3 can be upregulated by peak T3.
As for T4-T3 pharmaceutical equivalency, Finkler’s estimate that “25 micrograms of liothyronine proved equivalent to to about one grain [60-65 mg] of desiccated thyroid” is on track with other dosage tables during the era, which often included average daily doses and ranges of equivalency for T3 monotherapy, T4 monotherapy, and desiccated thyroid, such as Selenkow & Rose’s extensive review of many scientific sources in 1976:
Note that the “Relative potency” of 25-35 mcg to 65 mg of desiccated thyroid in Selenkow & Rose’s chart is in relation to “Average maintenance dose,” i.e. a person maintained long-term on T3 monotherapy. The physiological potency of L-T3 Liothyronine will be higher when a person is combining T4 dosing (or desiccated thyroid dosing, or natural thyroid secretion) with 5-25 mcg of L-T3.
Finkler’s study’s shortcomings
Finkler’s report was not complete; it left some things to be desired:
- The main data that is lacking is more characterization of the large group of 166 patients. Saying that “most” benefited begs the question of “how many?”
- When Finkler mentions that “Fifteen patients who had had incomplete symptomatic relief on thyroid preparations obtained beneficial results with liothyronine,” the rate of success requires the reader to do the math themselves. One has to recall or re-read the Dose (methods) section to discover how many patients had previously been on desiccated thyroid extract (DTE/NDT) or thyroglobulin, which is stated as 71 of the 166 patients. Dividing 15 by 71 yields a relatively low success rate of 21%. This demonstrates that T3 monotherapy according to Finkler’s clinical model was helpful, but only to a minority, of those who had struggled to optimize their thyroid status on DTE.
- The success rate of the “95 patients had not previously been given thyroid preparations” is not given at all.
- It would have been helpful not just to have the 11 whose data was featured in graphs and the 2 women whose cases were featured in verbal descriptions. There were apparently 30 patients whose PBI was measured, but their data set is not provided, only the 11 whose BMR and cholesterol is also shown in graphs.
- A reader would normally want to know more about the patients’ range and average length of treatment on T3 monotherapy at the time of writing, and at the time of measurement. The study’s duration was 3 years, but some patients may have been on T3 monotherapy only during the final 3 months of the study.
- How about their specific doses, and dose per kg body weight? No specific data.
- What about their sexes and ages? No specific data.
- How many had which positive symptoms/outcomes? No symptom / signs tables.
We encourage future studies of long-term T3 monotherapy to give the details omitted by Finkler.
Nevertheless, we can be grateful for the research data she provided on the 11 patients. The 11 subjects were clearly not cherry-picked for their empirical biomarkers of “success,” since some of the 11 had data that reveal they were likely only mildly hypothyroid and may have been maintained on Finkler’s starting dose of 25 mcg.
Contemporary ignorance of T3 monotherapy
Several histories of thyroid therapy entirely omit mention of successful maintenance T3 monotherapy:
- Chiovato, L., Magri, F., & Carlé, A. (2019). Hypothyroidism in Context: Where We’ve Been and Where We’re Going. Advances in Therapy, 36(Suppl 2), 47–58. https://doi.org/10.1007/s12325-019-01080-8
- Hennessey, J. V. (2017). The emergence of levothyroxine as a treatment for hypothyroidism. Endocrine, 55(1), 6–18. https://doi.org/10.1007/s12020-016-1199-8
- Lindholm, J., & Laurberg, P. (2011). Hypothyroidism and Thyroid Substitution: Historical Aspects. Journal of Thyroid Research, 2011. https://doi.org/10.4061/2011/809341
Another article on “Triiodothyronine” falsely claims that
“Like thyroxine, [L-T3] can be used in treating hypothyroidism but offers no advantages, except in myxedema coma, where it has a more rapid onset of action.”[Furman, 2016]
It’s too easy for endocrinologists to imagine that T3 monotherapy simply has not been used in long term therapy. But it’s a present-opinion based claim, not an evidence-based claim. It’s largely a historical-ignorance-based claim that has been reinforced by absence of inclusion in some histories.
Once there was an era of thyroid therapy when all thyroid pharmaceuticals were on the table to treat hypothyroidism, and yet some of them, and sometimes diverse combinations of them, were still found to be more advantageous for a given patient than thyroxine (L-T4) alone.
One of the most recent clinical trials of T3 monotherapy was performed by Celi and team. They studied TSH-normalized T3 monotherapy in patients post-thyroidectomy, with articles published in 2010 and 2011, with a third article under the lead authorship of their colleague Yavuz, in 2013. None of their three articles acknowledged that T3 monotherapy was ever used outside the context of a short 6-week phase prior to radioactive iodine ablation of thyroid gland fragments.
In 2014, Biondi and Wartofsky reviewed Celi’s team’s work. They seemed amazed that no adverse effects had occurred on T3 monotherapy and remarked upon the advantages that exceeded those of LT4:
“Patients receiving T3 achieved reduced body weight and an improved lipid profile after 6 weeks of treatment with T3 with no significant adverse effects on cardiac function, insulin sensitivity, or QOL [Quality of Life].”
However, the next thing they did was defer its clinical application. They called on researchers to conduct larger long-term studies, apparently unaware that prior studies, such as Finkler’s and a couple of others, had been conducted over many years, not just 6 weeks:
“Additional prospective double-blind randomized and controlled larger studies will be necessary to determine whether potential beneficial effects of L-T3 therapy may be achieved without accompanying adverse effects.[Biondi & Wartofsky, 2014)
Consider the mismatch between their proposed research method and their proposed research goal. If even one person achieved “beneficial effects” of T3 monotherapy without “adverse effects” long term, then the question of “whether” it is possible to achieve them (“may be achieved”) has already been answered. Larger studies are not needed to prove it 166 times or more.
Admittedly, Finkler’s study of 166 patients was neither randomized nor controlled, but few scientific studies were in the 1950s and 1960s. Scientific standards were different for all scientists back then. They emphasized more rich and diverse, micro-level case data, and it was common to study smaller numbers of patients in depth, which Finkler did.
Today, scientists are more interested in statistical averaging to find statistically significant change in a single variable, such as lower or higher TSH, among all the case subjects as a group and control subjects as a group, and to correlate that with a change in health status or another biomarker on average.
This drive toward a mass-population genre has resulted in harmful mistakes in therapy and policy, such as
- The misapplication of descriptive statistical averages, ranges, odds ratios and correlations in large populations as rigid prescriptions (required treatments and targets) or proscriptions (forbidden treatments and limits) for individuals’ therapy.
- The belief that individuals’ uniqueness does not matter, when they may belong to unique subpopulations of the treatment group, or they may be extreme outliers in comparison with the studied treatment group, or they may belong to a very different population altogether due to their disease etiology, genetics, or concurrent health disorders.
- The belief that the sheer number of studies that employ biomarkers such as TSH and T4 and the sheer size of the studies (large groups of people) justifies a tyrannizing hierarchy among the three thyroid tests (TSH, T4, T3), and by extension, a hierarchy of the hormones they represent. Ironically, the most physiologically potent of the three hormones, T3, is the least performed test among the three hormones in recent research studies. This hormone-testing prejudice appears to justify the appropriateness of limiting L-T3’s use as a hormone pharmaceutical. What a society does not measure, it does not value.
- The belief that only the most frequently studied and frequently prescribed thyroid hormone pharmaceutical (at least in the past 40 years) ought to be used routinely in all patients, until another pharmaceutical or combination can achieve greater fame and be proven to be superior for all patients (and more convenient for doctors) on average. In this unfair game of supremacy, no merely “equally beneficial on average” therapies are permitted to steal a share of the market from the currently most popular therapy.
- The belief that it’s not OK to have in our repertoire a thyroid therapy that only works well for a minority of patients over the long term, (and perhaps L-T3 monotherapy may be that type of therapy). If a therapy is beneficial for a special minority, one has to find the minority that has already benefited and recruit them as part of a retrospective study. Why must a scientist studying a minority therapy recruit a random, large population and pursue a rigid trial in a prospective manner as if one had no idea what to expect? This will inevitably prove that the minority’s therapy fails badly when forced blindly on the majority, so that it will never be prescribed for the minority that needs it.
Ignorance and T3 prejudice are insufficient excuses for prohibition of T3 monotherapy.
More recently, in a video of a presentation by Dr. Claudia Panzer in 2016 on “Thyroid Hormone Medications,” she explains that T3 monotherapy is only used in rare circumstances:
“We do have T3 available. T3 monotherapy, meaning that you’re being treated with only T3, will not really happen. It’s not a beneficial thing to do. We use it only in very rare conditions, for example, when you are getting prepared for radioactive iodine for thyroid cancer. Then you may be on T3 short term, but it’s not treatment for long-term treatment essentially.”[Dr. Claudia Panzer, Rose Medical Center (video), 2016, 01:26]
Speaking from the position of “We” to “you” the patient, Panzer’s is the paternalistic stance and tone of a doctor who forbids pharmaceutical choices on behalf of the individual patient without feeling any need to justify the sweeping judgment of “not beneficial.”
What makes it beneficial enough even in the short term, and how do its short-term benefits translate into a long-term therapy liability? Panzer’s brief explanation focuses more on the “rare” circumstances of post-thyroidectomy preparation than on the benefits or detriments of the therapy. This explanation, along with the vague prohibition “not beneficial,” serves to push T3 monotherapy off the menu for the vast majority of patients.
Panzer’s explanation makes it seem like only patients with thyroidectomies are qualified for even short-term T3 monotherapy. Yet some autoimmune thyroid disease patients have thyroid gland destruction at levels functionally equivalent to that of a total thyroidectomy (such as my atrophied 0.5 mL volume gland).
Of course, Panzer is not solely responsible for this misguided stance and opinion. She is simply voicing a stance reflected in current guidelines and research in the past 10 years. The current stance of prohibiting T3 monotherapy to only rare short-term circumstances is largely based on
- Fearmongering regarding the biochemical T3 excursions (see Jonklaas citations, above, as well as the ATA guidelines by Jonklaas et al, 2014) that are biochemically necessary for body-wide issue euthyroidism in people without T4 in circulation (Yavuz, 2013). There is no demonstration of 3x / day T3 excursions causing harm to human health in people who have little to no concurrent T4 in circulation.
- An irresponsible degree of scholarly ignorance regarding the history of T3 monotherapy.
Panzer and most of her endocrinologist colleagues do not feel compelled to search historical medical archives to verify the benefits and safety profile of long-term T3 monotherapy. Otherwise they would have found and cited articles like Finkler’s by now. (Finkler’s 1959 study has been cited by no other scientific articles, according to the Elsevier Scopus database at the time of writing, despite Rita Finkler’s significant publication history of 53 items. See others.).
Panzer appears to feel professionally justified in treating all patients outside the category of thyroid cancer not as individuals with unique disabilities and unique metabolic needs, but as members of a single homogenous class of thyroid patients.
She feels bold to speak prophetically about the static future of T3 monotherapy. Among all but rare special patients, treatment with humanity’s most potent and essential thyroid hormone alone “will not happen.” Her prohibition covers the future.
The records of long-term T3 monotherapy history
Short-term studies of T3 monotherapy have been published, in the “rare” cases discussed above, of treatment of myxedema and of post-thyroidectomy preparation for radioactive iodine ablation. It has also been used in short term treatment of nonthyroidal illness.
But yet the potential long-term therapy of individuals on T3 monotherapy is something different. It has been documented not only by Rita Finkler, M.D. of Newark, but also by others:
- Read another review, “HISTORY: L-T3 monotherapy in 1957”
- And yet another, “Trials of T3, desiccated thyroid and thyroxine in 1958”
A recent review has listed liothyronine monotherapy trials for treatment-refractory depression:
- Touma, K. T. B., Zoucha, A. M., & Scarff, J. R. (2017). Liothyronine for Depression: A Review and Guidance for Safety Monitoring. Innovations in Clinical Neuroscience, 14(3–4), 24–29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451035/
- Table 1 outlines 9 trials of TCA meds with T3 ranging in dose up to 62.5mcg/d, with 37.5 mcg dose ideal;
- Table 2 shows 6 studies on SSRIs and T3 between 2003 and 2012.
In addition, a retrospective study of patients who were dosed T3 (with or without T4 alongside it, without doses specified) may have included a few on T3 monotherapy:
- Leese, G. P., Soto-Pedre, E., & Donnelly, L. A. (2016). Liothyronine use in a 17 year observational population-based study—The tears study. Clinical Endocrinology, 85(6), 918–925. https://doi.org/10.1111/cen.13052
Two of Finkler’s cited references, Frawley et al, 1956 and Gold, 1956 (the latter not yet located), are ripe for further review.
At least two case studies have been published of women with successful pregnancies on T3 monotherapy whose children had good cognitive health and development (Boix Carreno et al, 2007; Khan & Wheatley, 2016).
A few case studies exist of patients who experienced liver toxicity on levothyroxine and who were thereafter maintained on T3 monotherapy (Kawakami et al, 2007; National Institute of Diabetes and Digestive and Kidney Diseases, 2012; Hlaihel & Al-Khairalla, 2019).
Perhaps other historic studies of T3 monotherapy are still buried in archives, yet to be uncovered. Who will look for them?
These scientific records regarding T3 monotherapy are overlooked and un-cited, buried in archives. As a result of ignorance, the very existence of the minority thyroid patient and her minority thyroid treatment is overlooked. It has become incomprehensible to imagine a patient failed by not only T4 monotherapy but also desiccated thyroid (NDT/DTE) and various T4-T3 combination therapies. Yet such failures have occurred, sometimes followed by success on T3 monotherapy.
Long-term T3 monotherapy is needed as an alternative in cases of T4-inclusive therapy failure.
We need all pharmaceutical options on the table to help accommodate future thyroid patients’ needs, health and safety.
Contrary to the title and intention of Dr. Panzer’s “mythbusting” video presentation, she has propagated a modern endocrinologist’s favorite myth. This treatment option exists. Long term maintenance T3 monotherapy has happened, is happening, and there is a high likelihood that it continually “will happen” among the patients who need it and/or seek it after other thyroid therapy failures.
For some people, their “last resort” of T3 monotherapy will be not only “beneficial” and equal, but superior to all the prior thyroid therapies they have personally experienced.
Click to reveal reference list
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10 thoughts on “Finkler, 1959: Liothyronine as a replacement for thyroid therapy”
I love all of this. I particularly appreciated the comments under Contemporary ignorance of T3 monotherapy. I felt that nowhere in contemporary medical literature is there any acknowledgement that this exists and yet it is still condemned! How can there be such bias, lack of understanding of T3’s power to heal and give health, and total lack of sympathy for the plight of many thousands of people today who would benefit. Thank you so much Tania.
Thanks Linda! The fact is, this article was cited by nobody, according to the Scopus database. Rita Finkler or R. Finkler comes up with 53 medical articles to her name, the most recent one in 1962, “Luteal deficiency in sterility. Therapy with a new hormone.” It appears she was interested in innovative therapies in endocrinology, especially regarding hormones that affected women. She also published a briefer article with a similar name, possibly a summary of this one: “Liothyronine (L-triiodothyronine) as replacement for thyroid hormone. FINKLER, R. 1959, Journal of the American Medical Women’s Association, 14(7), pp. 593-594.
I take 100 mcg of T4 and cant tolerate T3 even in a small dose of 2.5 mcg feeling more fatigue.
This is because now with aded t3 the conversion from the T4 dose doenst happens more and I need an bigger t3 dose or it is lacking of cortisol?
Hello Lucas. Interesting question, and long answer.
First of all I have to say the obvious & recommend working with a doctor who tests your FT3 and FT4 levels regularly when dosing Cytomel. Changes in those levels can sometimes help to explain changes with symptoms. Some T3-effects’ mechanisms are more likely when FT3 and FT4 are both high-normal and others are more likely when they are both low-normal or low. A few things could be going on:
1. T3 does not always act as a stimulant, since it is a hormone that acts in synergy with many other substances and hormones. Its effect truly depends on the circumstances in which it is taken. T3 levels naturally rise at night in synergy with many other hormones that rise at night during their circadian rhythm. Therefore, some patients find that when T3 is taken in the evening, night or early morning when FT3 levels are normally higher, it can make you feel mildly drowsy if your body currently needs sleep. Based on patient experience including my own experience, in some cases of insomnia, even a micro-dose of T3, such as 1.25 to 2.5 mcg, can bring relief within an hour, enabling one to return to sleep.
2. Fatigue could be a symptom of a paradoxical effect that can happen with Cytomel being added or increased. One of the first places patients tend to feel effects post-dose is in their mental status, cognition and fatigue levels, as the MCT8 transporter carries T3 across the blood brain barrier quite readily. In many people, even a small dose can bring relief from anxiety and depression and an improvement of cognitive ability (removal of brain fog). However, both excess and deficiency in thyroid hormones can reduce mental health. And this is how mild excess can do so….
The brain and central nervous system have two deiodinases that counterbalance each other, like a “tug of war,” to keep their T3 levels under very tight control: CNS is rich in D2, the enzyme that makes T4 into T3 and T3 into active T2. CNS is also rich in D3, the enzyme that converts T4 to RT3 and T3 into inactive T2. If you are already near the top of your T4 and T3 supply in CNS tissues, then adding
a little Cytomel may be pushing you mildly over your setpoint in your CNS. Mild excess signaling of T3 in receptors is known to upregulate D3, the enzyme that inactivates hormone, to protect neurons from being flooded with too much T3. It can cause your CNS to get rid of local “excess” T3 at a higher rate, inadvertently causing a temporary deficiency, before it is able to adjust to the dosing effect. It’s as if the firefighter (D3 enzyme) gets a bit too enthusiastic in putting out a fire and floods your home.
3. Alternatively, it could be the known effect of T3 competing with your T4 dose for transport or binding proteins. In this article, the data from Farmer and team shown in one of the graphs reveals that T3 dosing, when added to an unchanged T4 dose, can mildly decrease your T4 levels in blood, especially if you don’t have thyroid function to resupply T4 in response to the reduction. The mildly lower T4 can reduce your local T3 supply in tissues that depend on T4-T3 conversion rate, again causing mild hypothyroidism.
Thank you very much for the long answer.
I am the typical case in which T4 only just reduced my TSH, increased my T4 and left my free t3 smaller than before medication.
I already tried to increase the T4 when introducing the t3 but it also didn’t work. It seems that I am the typical case mentioned that due to low cortisol does not tolerate T3. I’m going to ask my doctor (who is a saint and does everything I ask, lucky me) for a therapeutic test with 5 to 10 mg of hydrocortisone and let’s see what happens.
I was a practicing psychiatric nurse practitioner in Washington State, and had my own clinic for eleven years. During those eleven years I tested all of my clients for low. T4 and low T3 in addition to rigorously assessing symptoms for hypothyroidism. As a result I discovered that one out of five of my clients had Non-Thyroidal Illness Syndrome (NTIS). Treating the NTIS improved their psychiatric symptoms and in many cases I was able to lower or take them off their psychiatric medications.
As a result, the Washington State licencing board investigated my practice for this and other irregularities and in 2012 I lost my nursing license. In the settlement, the Commissioner informed me that I was the second highest prescriber of Liothyronine in medicare patients in the United States. I feel that her statement was made to shame me, but it validated me. I made a difference in the lives of those people I treated, for the time period I was able to treat them.
The down side is that most of those whose lives had been improved could not find practitioners that could, or would, continue their treatment. My case has been used to restrict the scope of Nurse Practitioner practice. In this, I regret that I was unable to protect and improve the contribution Nurse Practitioners could make.
Dear John Vern Billings, thanks so much for your comment, and sorry for not having time to go through comments until today.
I’m so glad that you were able to help people with NTIS and people who were suffering psychiatric difficulty from their chronically low or low-normal T3 levels. So sorry to hear about the investigation and lost license. It is a tragedy, but you’re not alone. It will take time for a collective of informed scientists, physicians and patients to push back against the ways that anti-T3 and T3-blind guidelines are being used to bully health practitioners into compliance to a “low-evidence-based” TSH-T4 paradigm of therapy. The endocrinology establishment won’t beef up its evidence basis while it has the power to ignore patients’ suffering and keep thyroid therapy as simple and cheap as possible for the sake of physicians and health care systems. We must keep up the good fight in public forums where voices can be heard, since the silent suffering of patients over many decades has led to the medical injustices evident today. – Tania S. Smith
Hi there, I switched from NDT/Levo over to T3 monotherapy five days ago. I tried every combo from NDT + T3 and T4/T3 combos with higher and lower amounts of Levo and felt terrible on all of them. I switched right over to 25mcg the very next day and I’m up to 40mcg. I’ve had no negative side effects. In fact, I’ve been sleeping better and I don’t have muscle pain, no heart palps. I’m not nitpicking at things or having Levo rage(hah.) I can already tell that I need more than 40mcg. Taking T3 only feels as natural as taking Levo, without any negative symptoms. I don’t why having T4 in the mix created so many terrible symptoms.
Dear Jrbor, thanks for your comment, and sorry I’ve been to busy to reply until now.
You’re learning that your body responds differently to different thyroid pharmaceuticals. T4 hormone activates a receptor on the cell membrane, and that may be what causes cardiovascular symptoms in sensitive people like you and like me. We don’t have many scientific case studies explaining why this happens, but it does now and then. The literature does talk about cases where raising levothyroxine caused angina.
From Trescoli-Serrano, 1998: “Elderly patients with coronary artery disease and hypothyroidism should be treated cautiously with thyroid hormone replacement to avoid precipitating or exacerbating angina pectoris, precipitating acute myocardial infarction, and precipitating or aggravating ventricular arrhythmias or congestive cardiac failure. However, despite this, 7% will develop angina at the time of starting thyroxine replacement therapy and nearly half of these will not respond to standard antianginal therapy.”
When skimming articles like these, I shake my head and ask “why don’t you measure T3” — Because dosing T4 hormone alone can actually lower a person’s T3 below what it was before T4 therapy was initiated! In 1998 they mainly measured Total T3 not Free T3 like we can now, but they could have done that to diagnose the problem. It is unethical to chronically underdose a person on the standard T4-only regime just because the medical establishment fears the use of T3 hormone based on acquired ignorance of its safe use in clinical history. It’s very sad that people fear using it when the heart may be crying out for T3 hormone. The heart will not explode: this is a natural hormone. T3 dosed safely and properly is a natural vasodilator (it induces nitric oxide) and it can reduce heart rate and high blood pressure caused by individually-insufficient FT3 levels.
When dosing liothyronine (T3 monotherapy) it is extremely rare for an adult to be euthyroid on a dose of only 40 mcg per day, so I’m not surprised you’re not euthyroid yet. I’ve published some dosing tables that show euthyroid doses range from 50 to 100 mcg and average at 75: search this website for “equivalency” to see the older (and more clinically accurate) studies on pharmaceutical equivalency between T3 and T4 pharma.
Hi, I am a thyroidectomized patient (formerly Graves) who, 4 months into mono-levo therapy, felt unwell, despite suppressed TSH, and in-range Ts. I tested reverse T3, and when it came in above max, agreed to change therapy to mono-T3. Can’t say whether I feel better, because it’s been only days thus far. However, I have 2 questions after reading this article, please:
1) On mono-T3 therapy, is the complete lack of T4 in the body of a thyroidectomized patient of no concern? and
2) Given that the main role of the deiodinase enzymes is to convert from T4, how does the absence of T4 impact these enzymes? Thank you.