Three thyroid hormone medications have had a long history of effective use. I discuss them in chronological order, from the earliest thyroid medication to the most recently invented.
No new thyroid medications have been invented since the 1950s, although all three of them have been further refined, and various manufacturers exist for each of them.
1. Animal-derived thyroid hormone
Since the 1800s, animal-derived thyroid hormone was first extracted from the thyroid glands of sheep, and later, from pigs. Some therapies even involved eating raw or cooked fresh sheep’s thyroid gland.
Murray (1920) “described ‘The Life History of the First Case of Myxoedema Treated by Thyroid Extract’. Treatment was continued for 28 years and the patient, Mrs. S., died at the age of 74 years having consumed extracts prepared from the thyroid glands of 870 sheep.” (Ibbertson, 1977)
“the advice of a contemporary author (Fox, 1892) [was] that the optimal preparation was ‘half a thyroid gland lightly fried and minced to be taken with currant jelly over a week.” (Ibbertson, 1977)
Over the 20th century, desiccated thyroid extract (DTE / NDT) was purified and its use as a pharmaceutical more carefully regulated. Concerns over irregular or inconsistent batches of DTE arose in the 1960s and 1970s, but processes have been further refined since then.
In a 2017 survey of over 12,000 patients by the American Thyroid Association, patients gave DTE the highest rating compared with L-T4 monotherapy and T3/T4 combination therapy.
2. T4 hormone medication
Thyroxine (T4) was isolated from pig thyroids in the early 1900s, but it was not in a form that was very useful in therapy until 1949, when a synthetic Levothyroxine (L-Thyroxine) medication was commercially launched by Glaxo.
For the next two decades, the preferred mode was still desiccated thyroid. An early comparative study by McGavack and Reckendorf in 1956 pointed out that L-thyroxine and desiccated thyroid were similar in their effects, with L-thyroxine resulting in an euthyroid state within an average of 19.2 days (at very high doses) and desiccated thyroid achieving this goal in 21 days.
The use of L-T4 grew more widespread as the TSH test became prominent, since T4 has a direct relationship to TSH and it was very satisfying use the drug to “normalize” TSH. As McAninch and Bianco have explained in their 2016 article “The History and Future of Treatment of Hypothyroidism,”
Two major developments in the 1970s led to a transition in clinical practice: 1) The development of the serum thyroid-stimulating hormone (TSH) radioimmunoassay led to the discovery that many patients were overtreated, resulting in a dramatic reduction in thyroid hormone replacement dosage, and 2) the identification of peripheral deiodinase-mediated T4-to-T3 conversion provided a physiologic means to justify l-thyroxine monotherapy, obviating concerns about inconsistencies with desiccated thyroid. Thereafter, l-thyroxine mono-therapy at doses to normalize the serum TSH became the standard of care.
For a brief discussion of this medication’s current foothold, see our separate article, “Why T4 monotherapy has dominated.”
3. T3 hormone medication
Triiodothyronine (T3) was first discovered in 1952, and was synthesized as Liothyronine in the same year. It was found to be far more potent than Levothyroxine in reducing pituitary inflammation, thyroid inflammation, and blood levels of cholesterol, and in raising the depressed basal metabolic rate that characterized hypothyroidism.
Gross and Pitt-rivers (1953) found that “a dose of 80 g. of L-triiodothyronine daily seems to be within the range of normal requirement in man and to have an effect similar to that of a daily oral dose of 100-300 g. of L-thyroxine.”
Gross and Pitt rivers found that L-T3 was 5 times as more potent than L-Thyroxine at inhibiting the release of TSH from the pituitary gland. They also found that when both were delivered orally rather than subcutaneously (by injection), L-T3 was approximately twice as effective as thyroxine.
In McGavack and Reckendorf’s comparative study of the three therapies, Liothyronine (L-T3) was the fastest to achieve an euthyroid state; it took only 5 days (L-T4 = 19.2 days, DTE = 21 days).
However, because the potency and speed of L-T3’s actions on the body are far greater than for DTE and L-T4, more hyperthyroid side-effects have been reported for L-T3 over the years. Guidelines written by those who prefer L-T4 have found its potency a reason to flatly discourage the use of L-T3 entirely, even though L-T4 also can cause harm and symptoms if overdosed. Indeed, most of the so-called “side-effects” of T3, if not due to cortisol/adrenaline issues, are errors in dosing. As with any medication, we are responsible to adapt the dose to the patient’s metabolic state and overall health. Practitioners who use T3 need to be aware of its pharmacokinetic effects, the serum Free T3 “curve” in a graph over time, which is easy to find in the more recent literature (see Jonklaas et al, 2015; Saravanan et al, 2007).
Synthetic Liothyronine has been used either alone or in combination with Levothyroxine since Liothyronine was first discovered.
See our review of a 1957 article that described 100 patients’ safe and effective therapy on L-T3 alone: L-T3 monotherapy in 1957
Currently the use of L-T3 therapy is seeing a revival as part of synthetic “combination therapy” alongside L-T4.
More researchers and clinicians are recognizing that the current L-T4 monotherapy results in potential loss of Free T3 and a certain percentage of patients are still symptomatic. A combination therapy achieves T3 and T4 thyroid hormone levels in serum that are closer to those found in untreated, healthy subjects.
However, there are serious problems with most combinatinon therapy studies. We call on researchers to rethink their unreasonable limitations on T3:T4 ratio in dosage, their fears of FT3 serum fluctuations, and their refusal to allow TSH to benignly fall below reference, all of which result in failure of these studies to enable patients achieve Free T3 in the upper part of reference range, and from a patient’s perspective this constitutes a failure to achieve the MAIN PURPOSE of including T3 within therapy.
Because of these serious blinders and limitations, these studies unsuprisingly end up with comparative results that show no net benefit over LT4 monotherapy. In essence, the trials are “rigged” by dogma, against any innovation.
Research since 2008 has theorized that more optimal levels of T3 hormone in serum could help thyroid patients with genetic polymorphisms in T4 conversion (DIO1 and DIO2) and thyroid hormone transport (MCT8, MCT10). Several of our blog posts have reviewed articles on these polymorphisms and combination therapies.
In future, we may hope to see improved methods of delivery for both synthetic and natural T3-based therapies. The short half-life of T3 is cited as an inconvenience to patients, yet the “trouble” of taking several doses per day is a ridiculous obstacle to place in the way of improved health. Compounded slow-release L-T3 varies in its absorption through the gut and will therefore vary in its potency as gut health improves or worsens. Perhaps a dermal patch or subdermal implant could assist patients with T3 dosing in a way that would not suppress the TSH as much as oral dosing does. Gross and Pitt Rivers found in the 1950s that injection vs. oral dosing made a difference in effectiveness (injection being far more effective for both L-T4 and L-T3).
See more discussion of all three of these therapies in our Campaign Statement pages.
Other sources consulted
- Bryan, J. (2013, July 18). Levothyroxine: from sheep thyroid injections to synthetic formulations. Retrieved July 25, 2018, from https://www.pharmaceutical-journal.com/news-and-analysis/levothyroxine-from-sheep-thyroid-injections-to-synthetic-formulations/11123454.article
- Gross, J., & Pitt-Rivers, R. (1953). 3:5:3’-triiodothyronine. 2. Physiological activity. The Biochemical Journal, 53(4), 652–657.
- Gross, J., Pitt-Rivers, R., & Trotter, W. R. (1952). Effect of 3:5:3’-L-triiodothyronine in myxoedema. Lancet (London, England), 1(6717), 1044–1045.
- Ibbertson, H. K. (1977). Hypothyroidism. Pharmacology & Therapeutics. Part C: Clinical Pharmacology and Therapeutics, 2(2), 177–196. https://doi.org/10.1016/S0362-5486(77)80004-6
McAninch, E. A., & Bianco, A. C. (2016). The History and Future of Treatment of Hypothyroidism. Annals of Internal Medicine, 164(1), 50–56. https://doi.org/10.7326/M15-1799
- McGavack, T. H., & Reckendorf, H. K. (1956). Therapeutic activity of desiccated thyroid substance, sodium L-thyroxine and D,L-triiodothyronine: A comparative study. The American Journal of Medicine, 20(5), 774–777. https://doi.org/10.1016/0002-9343(56)90159-0
2 thoughts on “History of the three thyroid medications”
Have been looking through some very old papers about thyroid and found one co-authored by Charles Harington, who was very much to the fore in efficient isolation of thyroxine from animal thyroid, and co-inventor of a method of synthesising thyroxine.
The irony from today’s’ perspective lies in this paragraph:
CLXXIX. SOME DERIVATIVES OF THYROXINE.
BY JULIUS NICHOLSON ASHLEY
AND CHARLES ROBERT HARINGTON.
From the Department of Pathological Chemistry, University College Hospital Medical School, London.
(Received October 31st, 1928.)
SINCE thyroxine has been available in the pure condition its therapeutic use has been limited by the fact that it is only possible to elicit with certainty the full physiological activity of the substance when it is administered intravenously. When thyroxine or its sodium salt is administered by the mouth absorption appears to be irregular, and scarcely ever is the full effect of a given dose obtained. Except, therefore, in hospital practice where the intravenous injection offers no difficulties, thyroxine compares unfavourably with crude desiccated thyroid gland as a therapeutic agent. In our opinion thyroxine fails to be absorbed after oral administration owing to its extreme insolubility when in the free condition.
anyonefort, Thanks so much for sharing that quotation. I’ve downloaded and added their article to my bibliography. What a juicy quotation.
Yes isn’t it interesting to ponder that this was the state of medicine from the time of thyroxine’s formulation until it was conveniently made into pharmaceutical tablets in 1949. Even then, it took until the mid-1970s for levothyroxine sodium (the sodium salt) to achieve the majority of prescriptions in the US (according to McAninch and Bianco’s history). It’s rational that so many physicians preferred desiccated thyroid because it was clinically so successful and included both hormones. One of the major drawbacks with levothyroxine is indeed its poor absorption, which requires good gut health plus a fasted state for optimal and steady-state absorption from day to day.
The other drawback rarely discussed today in the science is people’s variable metabolic response to LT4 monotherapy. Harington could not see that. Only with the advent of Free T3 and Free T4 tests have scientists been able to see the fact that some people have severely low T4-T3 conversion rates and low FT3:FT4 ratios while on LT4 monotherapy, regardless of their level of LT4 absorption into blood. – Tania