Complete History of Thyroid Treatment

The Chinese used burnt sponge and seaweed to treat goiter over many millennia. In 150 AD, Hippocrates and Plato recognised this treatment and thought that the thyroid gland lubricated the larynx.

Thomas Wharton, anatomist in 1656, wrote about the anatomy of the gland that he thought it was there to heat the larynx. He named it ‘thyroid’ after the ancient Greek shield with a similar pronunciation. In German, the thyroid is ‘die Schilddrüse’, the shield gland.

Two other anatomists, from Holland Frederik Ruysch in the 17th century, from Switzerland Albrecht Von Haller in the 18th century and British Thomas Wilkinson King who was a physiologist in the early 19th century, each wondered whether the thyroid elaborated a secretion which was carried away by the veins.

In 1786, Caleb Hillier Parry recorded the first case of Parry’s disease, a malady ‘which had not been noticed by medical writers’. Parry certainly noticed it, describing it as an ‘Enlargement of the Thyroid Gland with Enlargement or Palpitation of the Heart.’ He was thr first to describe exophthalmic goiter.

Thyroid history in the 19th century, however, was a tale of three streams which converged as knowledge of its function emerged. These streams were Iodine, Goitre and Cretinism or hypothyroidism. Each chemist separately identified a new chemical element which they agreed to call “iode”, or iodine, from the Greek word for violet. It is not clear why iodine then became the focus for the treatment of thyroid enlargement.

Initially suggested by Dr William Prout in London, 1816, it was John Elliotson from St Thomas’ Hospital who used it for goitre in 1819.

In 1811, the French chemist Bernard Courtois was extracting soda from burnt seaweed because of a shortage of the usual woodash. He tried to clear the deposit on the bottom of his copper extraction vessels with sulphuric acid and immediately noticed an intense violet vapour which condensed in the form of crystals. By circuitous routes, the crystals eventually reached both the French chemist Joseph Louis Gay-Lussac and, with the permission of Napoleon, Sir Humphrey Davy.

In 1820, the Swiss physician Jean Francois Coindet  used a tincture of iodine more widely with initial success. His treatment was questioned and fell into disrepute when some individuals developed hyperthyroidism (Jod-Basedow syndrome).

In 1825, David Scott used iodine to treat goitre in Assam, India and in 1831, the French chemist Jean-Baptiste Boussingault used iodised salt in present day Columbia for the same condition.

In 1835 Robert James Graves (1797-1853), an astute clinician keenly interested in fevers, published a paper “a newly observed affection of the thyroid gland in females”, since known as Graves’ disease, although as we know today, this condition was first described by Caleb Hillier Parry in 1786.

In 1835, Caleb H Parry followed by Robert James Graves from Ireland described hyperthyroidism with goitre and noted an ophthalmopathy.

The German physician Karl Adolph vonBasedow independently reported similar cases in 1840 and firmly linked hyperthyroidism with the associated ophthalmopathy.

John Simon published his first article on the neck (1842). Two years later in 1844 he won a financial prize for a physiological essay on the thymus gland. Following another paper on the comparative anatomy of the thyroid. He confirmed the 17th century theory of Frederik Ruysch.

In 1850, Thomas Blizzard Curling correlated the absence of thyroid tissue at autopsy in two children with cretinism.

In 1851, the French physician Caspar-Adolphe Chatin discovered that certain goitrous areas of Europe were associated with a low environmental iodine. While the national scientific community in France remained sceptical about Chatin’s evidence, iodine prophylaxis for goitre began in earnest.

The life sustaining property of thyroid was confirmed by the experiments of Moritz Schiff

(1823-1896) in 1856, who showed that in experimental animals, extirpation of thyroid led to their death.

In 1860, Bilroth introduced thyroidectomy as treatment of goiter, and his pupil Emil Theodor Kocher (1841-1917) improved on Bilroth’s technique. Working in the alpine mountain region provided him with innumerable patients.

He performed more than 7000 thyroidectomies in his life; and was awarded with Nobel prize in the year 1909 for his contributions to thyroid surgery. Kocher in a follow-up of his patients noted that a third of his operated patients developed the features described by Gull (he called it cachexia strumipriva), and inferred that myxedema was caused by thyroid deficiency.

In 1871, Charles Hilton Fagge presented a paper describing four children with sporadic cretinism and wondered whether the thyroid had ‘wasted’.

The first good clinical description of myxedema was provided by William Withey Gull (1816-1890) in the year 1873, of five adult women presenting with cretinoid condition. He described hypothyroidism in adult life as creating a cretinoid appearance with a thick tongue. They were slow, sluggish, obese and puffy in the face.

In 1877, William Ord described ‘mucous oedema’ and proposed the term ‘myxoedema’ for the adult condition. He also described the ‘practical annihilation’ of the thyroid gland at autopsy in these patients.

In 1882, Jaques-Louis Reverdin from Geneva and in 1883, Emil Theodor Kocher from Berne, both Swiss surgeons, noted that after total thyroidectomy, myxoedema was common. Because of this, they each experimented by conserving part of the gland during thyroidectomy, and no further cases of myxoedema occurred.

Although they did not understand what was happening, these surgeons had provided the medical community with the key to understanding the importance of the thyroid gland. Kocher went on to be awarded the Nobel prize for medicine in 1909 for work relating to the surgical and medical treatment of thyroid disease.

In 1883, Felix Semon, a trainee laryngologist, later Sir Felix, suggested, to much ridicule from medical colleagues, that myxoedema and cretinism were one and the same condition, namely the effects of hypothyroidism.

What he managed to do was to encourage his surgical colleagues to survey the experience of thyroid surgeons Europewide.

Also in 1883, the Committee of the Clinical Society of London set it upon itself to investigate the cause of myxoedema. Five years later the Committee announced its verdict: myxoedema was caused by thyroid deficiency. Much of the evidence for that bold statement was based on simple clinical observation. 

For instance, Theodor Kocher (1841-1917), an eminent Swiss surgeon who perfected the art of thyroidectomy, noted that some of his patients who had total thyroidectomies, subsequently developed the typical features of myxoedema.

Following the announcement of the Committee of the Clinical Society of London, progress was rapid even with today’s standards.

Ivar Sandstrőm, Uppsala medical student in 1887, confirmed the existence of the parathyroid glands in 50 autopsies.

1888: A treatise on hypothyroidism was prepared, based on reports from 64 surgeons across Europe, about the deterioration of patients' health when the thyroid gland is removed.

Reporting in 1888 and using experimental work on thyroidectomised monkeys by Sir Victor Horsley, the renowned scientist/surgeon who followed on in neurosurgery from Sir William Macewan, the report vindicated Semon and concluded that myxoedema was almost certainly due to loss of thyroid function and could lead to cretinoid features.

Horsley went on to advocate surgical grafting of sheep thyroid into patients with myxoedema and in 1890, Bettencourt and Serrano of Lisbon had success with resolution of some clinical features in a case grafted under the breast. They then tried hypodermic injections of thyroid juice in 1891 and reported these beneficial too. The function of thyroid was now clear though the mechanism remained a mystery.

Up until 1891: Before a treatment was discovered and became routine, hypothyroidism could progress to severe myxedema: advanced hypothyroidism characterized by swelling, depressed breathing and low oxygen levels, mental slowness, and seizures. Myxedema was usually fatal, typically taking about 10 years from the diagnosis of myxedema to coma, and eventually, death from respiratory and heart failure.

In 1891, Horsely and Professor George Redmayne Murray used hypodermic injections of sheep thyroid extract into a patient with myxoedema and described a dramatic improvement. Murray provided details of his method of preparation and administration of the extract.

1891: First recorded use of thyroid extract in the US. Thyroid extract was not a mass produced drug. Instead, it was produced by apothecaries, also known as chemists or druggists, who custom-prepared medications.

In 1892 Edward Fox showed that thyroid extract did not have to be injected, it worked just as well when taken by mouth. From that point onwards the standard remedy from myxoedema became “half a sheep’s thyroid, lightly fried and taken with currant jelly once a week”, and so oral replacement therapy for glandular hypofunction was born.

In 1893, Walter Bradford Cannon (1871-1945) while studying the effects of autonomic nervous system coined the term ‘homeostasis’ to mean maintenance of constancy in the ‘internal environment’, as proposed by Claude Bernard by means of various chemical substances.

In 1894 the pharmaceutical company Merck started producing commercial quantities of thyroid extract and “Thyroidinum siccatum” (desiccated thyroid) became widely available and could be prescribed until the 1980’s.

1894: Thyroidinum siccatum  Introduction of desiccated sheep thyroid gland (powder, later tablets) in Germany. Available as Thyroidin Merck until 1983.

In 1895 Eugen Baumen found an iodine compound in the thyroid gland, which opened the gate for controlling goiter by addition of iodine to table salt.

1896: Thyroidin Merck (USA) Offered in the price list published in Merck's 1896 Index (New York).

Early 1900s: The Armour Meat Packing company made Armour Thyroid available to apothecaries as an ingredient for thyroid extract

In 1901, the French physiologist Eugene Gley linked the absence of parathyroids after thyroid surgery to tetany which was often a sequel.

1901: Antithyroidin Merck Produced from the serum of thyroidectomized rams (Moebius).

In 1905, Ernest Starling proposed that the substances they worked with were called ‘hormones’ after the Greek ‘ormao’ – to excite, and at this precise point in history, a new speciality called ‘endocrinology‘ emerged. It studied substances produced by one tissue and then transported by the circulation of blood to another tissue, called the target.

Harvey Cushing (1869-1939), an outstanding neurosurgeon of his time, and avid researcher and biographer, described in 1906 relationship between pituitary tumors and sexual infantilism. And in 1932 he described a clinical syndrome named ‘hypophysial basophilism’, since known as Cushing’s disease.

1911: Glandula Thyroideae siccata "Merck" Tabletten  Dessiccated thyroid gland available as tablets.

1912: Research on a standardized thyroid extract product (Annual report Scientific Laboratory 1912).

In 1915 Edward Calvin Kendall isolated and crystallized thyroxine (also

isolated cortisone and was awarded Nobel prize in 1936) the active principle of thyroid extract, and thyroid hormone supplementation became a reality.

1920: Dr. George Redmayne Murray published a description of a patient successfully treated for almost 30 years with thyroid extract.

1921: Thyreoidinum depurat. Notkin Tabletten Thyroid protein extract.

1925: Evaluation of Kendall's Thyroxine  "Obviously thyroxine is not the only active thyroid product".

1925: Thyroidea Opton Introduction of protein-free degradation product of the thyroid gland.

In 1927 the chemical structure of thyroxine was discovered.

1928: Novothyral 

Introduction of water soluble standardized thyroid extract (Axolotl).

1934: Western Research Laboratories was founded by Dr. William McClymonds to manufacture and distribute the first commercially-prepared and distributed natural desiccated thyroid drug, called Westhroid.

1938: The new federal Food, Drug and Cosmetic Act gave the Food and Drug Administration (FDA) oversight over various medications, and established formalized approval processes. As an existing medication, natural desiccated thyroid was “grandfathered,” and not required to go through any approvals.

Broda Barnes' study of over 70,000 of these autopsy reports spanning the war years of 1939-1945, lead Barnes to conclude that atherosclerosis, the underlying cause of heart disease and heart attacks, was not caused by diet and cholesterol as is widely believed, but instead by hypothyroidism.

1941: Thyroidin Merck  Standardized also with Axolotl method.

1942: Broda Barnes' "Barnes Basal Temperature Test" was published in the Journal of the American Medical Association (JAMA).

1948: Methicil  Brand of Methylthiouracil available from Merck in Germany.

1949: Levothyroxine (synthetic thyroxine) became commercially available. New drug application and approval was not required by the FDA at that time.

1950: The medicine Natrium Thyroid came on the market, but was very unstable and unpredictable, and doctors continued with NDT.

1958: The first usable synthetic thyroxine (T4), Synthyroid hit the market. (Knoll Pharma, later acquired by Abbot). NDT is slowly starting to being phased out.

1960: The first commercial tests to measure thyroxine became available. They measured total thyroxine (TT4). Before this, a convenient measurement of thyroid hormones was not possible.

Until this year, clinical assessments and patients' symptoms were dominant in diagnoses of various degrees of hypothyroidism.

However, breakthrough though this was, it was immediately realised that this was insufficient for accurate estimation of thyroid function.

Thyroid hormones (T4 and T3) leave the thyroid gland and in the bloodstream are bound onto transport proteins that convey the hormones to the tissues. There are three of these transport proteins: thyroxine-binding globulin (TBG), transthyretin and albumin. Of these, TBG is the most important in the average person. It transports about 70% of T4 and 60% of T3.

As the transport proteins and their T4/T3 load pass by the tissues in the bloodstream, very small amounts of hormone are freed as required. These are the free T4 and free T3 fractions. As the tissues remove T4 and T3 for their own use, more is released by the transport proteins for the next tissues to use. The free T4 (FT4) and free T3 (FT3) fractions are a very small percentage of the total circulating hormones.

In the case of FT4 in the average person it is about 2/100 of 1% of the total T4 and for FT3 2/10 of 1% of the total T3. Therefore, it is necessary to measure FT4 and FT3 rather than total T4 or total T3.

The problem is that we are all unique in the makeup and amounts of our transport proteins. In the vast majority of people, the TBG levels can be different by at least a factor of 2; and the same (independently) for the other two proteins. There are people with either no TBG at all or 4 times the normal amount. Their reservoirs of T4 and T3 are therefore hugely different for the same FT4 and FT3. Also, the pregnant woman has twice the TBG and ¾ the amount of albumin she had when not pregnant. We also lose transthyretin and albumin when critically ill or with trauma like burns or septicaemia.

To try to get a measure of FT4, a test was developed in 1963-65 to try to convert the total T4 result to a FT4 result. This was the thyroid hormone uptake test. In conjunction with a total T4 result, the two tests could be amalgamated to produce what was claimed was an estimate of FT4.

This thyroid testing method is still used today; e.g. in certain American private labs and elsewhere. However, it is not based on sound principles and does not work properly, especially for people with extreme differences in TBG from the average. Even the pregnant woman’s results are compromised. In the remainder of the 1960s, commercial firms were set up to provide readymade tests for the clinical chemistry labs to use

By the 1960s, synthetic T4 and T3 could be made. Desiccated thyroid however remained in use as synthetic thyroid hormones were expensive to manufacture.

1960s–1990s: Levothyroxine increasingly replaced the use of natural desiccated thyroid in the UK and US.

1963-1965: The first effective tests to calculate free thyroxine (FT4) arrived. Unfortunately, the first methods for calculating FT4 were not very good and it would take many years before they became reliable.

1965: Kalium jodatum Compretten (100 mg KI) Indicated for prevention of radioactive iodine incorporporation in nuclear accidents.

1966: A peak of 16.6 million prescriptions filled for NDT

1968: Novothyral  Newly introduced as a T4/T3 combination in Germany.

The next landmark in the history of thyroid hormones was the discovery by Dr L Braverman in 1970 that most of the active thyroid hormone T3 was made by tissues such as the liver from thyroxine secreted by the thyroid gland. This discovery formed the basis for the concept that although the tissues in the body only “see” T3, patients with hypothyroidism can be treated with T4 alone.

1970: Armour and Company acquired by bus company Greyhound Corporation.

From the 1970s onwards synthetic T4 could be manufactured cheaply and it replaced the earlier regimens which contained both T3 and T4. In the 1970’s and 1980’s there was also a universal tendency for the replacement dose of thyroxine to be reduced.

Whereas T4 doses in the 1970’s of 300 micrograms per day or more were standard, few patients nowadays are treated with more than 150-200 micrograms of T4 daily. The trend for using lower doses of thyroxine originated from the introduction of sensitive blood tests to monitor thyroxine treatment and the demonstration that the traditionally higher T4 doses resulted in suppressed serum TSH and elevated T4 levels in blood. In many cases features of hyperthyroidism were associated with such treatment.

1973: Euthyrox  Mono T4 tablets introduced in Germany, later in many other countries.

1975: Jodid Merck  Iodide 100 µg tablets (later 200 and 500 µg) introduced in Germany.

1975: The first commercial tests for TSH and T3 hit the market. A few years later, tests for FT3 arrive. The TSH test was the first generation – that is, it could only measure and detect hypothyroidism (the depressed levels in hyperthyroidism were too low to be measured directly).

1978: Greyhound sold Armour (Pharmaceuticals division) to Revlon.

In the late 1970s the shortcomings of the thyroid hormone uptake test, arising from the variation in TBG levels in patients, were very apparent. The demand for properly formulated and soundly developed FT4 and FT3 tests was very great.

As a response, companies and individuals produced various forms of thyroid testing claiming to measure these fractions. Many of the offerings were not soundly based, and slowly disappeared into obscurity and obsolescence. Two methods did however prevail and form the basis of FT4 and FT3 testing today.

In the 1980's, Broda Barnes estimated that the prevalence of undiagnosed hypothyroidism had risen to affect more than 40% of the American population.

1981: Dennis Jones/Jones Medical Industries (JMI) acquired Western Research Laboratories from the McClymonds family.

1982: Nature-Throid -- a hypoallergenic version of Westhroid -- was released by Western Research.

In the mid 80s, pressures on the clinical chemistry lab were beginning to be overwhelming. Such was the demand for tests that the disposal of radioactive waste was too great for licencing of disposal. Consequently, non-radioactive detection methods had to be substituted. Two things happened around 1985.

First, second and third-generation TSH tests were developed – now one could directly detect both hypo and hyperthyroidism.

Secondly, the manufacturers produced several solutions to the non-radioactive detection methods and integrated them into dedicated automatic analytical platforms. Now one had machines that took the place of the skilled hands-on technician – it was a case now of loading the machine, programming it and pressing the “start” button.

This led to lab monopoly – having chosen the machine, one was confined to the tests dedicated to that machine. However, the individual solutions of the manufacturers to the method of detection in tests led to problems with FT4 and FT3 test development (uniquely).

Unlike all other tests, FT4 and FT3 tests demand special and essential requirements. They must be run at blood temperature (37 degrees), they must sample only a tiny quantity of the available T4 and T3 so as not to sample the T4 and T3 bound to the transport proteins, they must use the same chemical surroundings (for example, salt content, phosphate content) as is present in the blood, and they must work in the right acidity as present in the blood.

The failure of the development scientists to understand these special requirements, and the compromises needed to make the detection methods work, led to great variation in the performance of the FT4 and especially the FT3 tests between manufacturers offerings. For FT4 this is at present up to 40% difference and for FT3 60%. One would expect no more than a 5% difference as a reasonable variation.

As a result, sensitive TSH tests began to have a paramount position in thyroid function testing. There exists a paradigm of thinking today which closely links FT4 and TSH as a constant relationship over the whole thyroid function spectrum. Therefore, if you do a TSH test, then why do an FT4 test because the TSH value implies an FT4 value – the FT4 test is controversial and inconsistent so why do it? The seeds of TSH only screening had started to sprout.

1985: Revlon sold its drug unit – including Armour Thyroid -- in 1985 to Rorer (later known as Rhône-Poulenc Rorer).

1985: Jodthyrox  T4/Iodide combination introduced in Germany for iodine deficiency goiter.

1988: 4.5 million prescriptions filled for NDT -- Armour Thyroid, Westhroid, and Nature-Throid.

In 1988, John Midgley and his colleagues invented a new test for FT4 and FT3, based on the invention of 1980 but getting rid of the problems at the margins mentioned earlier.

1990: Thyrozol  Thiamazole (Methimazole) introduced in Germany.

1990 - 1997: The FDA reported 10 recalls of levothyroxine, covering 150 different lots of medication, and a total of 100 million tablets.

1991: Forest Laboratories acquired the rights to Armour Thyroid from Rhône-Poulenc Rorer

In 1992, a group of American scientists had begun to analyse and dissect the commercial FT4 tests to understand why they were so inconsistent. They began a series of papers in the peer-reviewed important leading journals which lasted until 2009. Their findings were on the surface devastating – that is, they alleged that however it came about, all FT4 tests were influenced by the levels of transport proteins in the blood – devastating because this meant that they were subject to the T4 and T3 bound by those transport proteins – and the whole point of doing FT4 and FT3 tests is to be independent of these effects. As it turned out, the whole of this work was completely invalid and wrongly conceived from beginning to end – a completely meaningless study programme. John Midgley and a colleague pointed this out but, especially in America, their findings are accepted and further confuse today’s understanding of the FT4 and FT3 tests. Meanwhile, the cheap, easy to understand, rapid, and eminently automatable TSH test was gaining strength as a catch-all screen.

1993: Beginning globalization of Merck KGaA's thyroid business.

1997: With 37 different manufacturers and repackagers of levothyroxine on the market, and widespread and ongoing problems with content uniformity, sub-potency, and stability, the FDA launched an effort to standardize levothyroxine sodium tablets, and to minimize potency fluctuations. As a result, the FDA declared levothyroxine sodium tablets a “new drug,” and required new drug applications for approval of all levothyroxine drugs. (NDT was not included in this FDA ruling, and remained grandfathered.)

1998: Western Research Laboratories was acquired by the Cox family: Rick, Judy, Lindsay and Riki Cox.

In 1999 Bunevicius and colleagues published a study of patients who were given T4 and T3 in combination and were compared with patients who received T4 alone. They found that patients on T4 and T3 felt and performed psychologically better.

1999 – 2001: Several companies submitted NDAs for levothyroxine, and the first product (Unithroid) was approved in August of 2000. Synthroid filed a citizen's petition to bypass the NDA process, but that was rejected by the FDA, and an NDA was ultimately filed for Synthroid.

The same scientists did another study in 2002, but were unable to confirm their earlier findings. Since then, another five studies exploring the same theme were conducted in various corners of the word. The findings were equally disappointing. No difference between T4 alone and combination of T4 with T3 (although a “placebo” effect was frequently observed). In some of the studies the combination treatment fared worse that T4 alone. The difficulty with all of the above studies is that it is still impossible to reproduce what the normal thyroid does with T4 and T3. In particular T3 has “a short half life”, i.e. after a dose of T3 is taken there is a rapid rise followed by a rapid fall in blood levels. Could these ups and downs be negating the potential benefits of T3 and even be responsible for the observation that in some studies combination was worse that T4 alone? It is possible. What one should use ideally is a slow-release preparation of T3 that provides a similar profile to the normal situation. Sadly, despite the enormous advances in pharmaceutical science and the availability of numerous drugs in “slow-release” preparations, no such alternative exists for T3. On several occasions there have been attempts, but every signle one has failed to stimulate any interest by the pharmaceutical industry in this, although it is technically feasible and potentially profitable if it proves to be effective in the treatment of hypothyroidism. Another reason why the T4 and T3 combination treatment story is not over, is that the ratio of these substances (i.e. relative doses) should be as close to what the normal thyroid produces as possible and not all of the above studies addressed this important issue.

In 2005 a new group of US workers came on the scene with a specialised technique for measuring FT4 and FT3 which they alleged was superior to the commercial thyroid testing in that it more closely correlated FT4 and TSH. In 2009, John Midgley looked into their work and found it had been done at the wrong temperature – this is important because T4/T3 binding to TBG is very temperature sensitive. On advising them of this, they merely obfuscated and blustered, and though henceforward using the right temperature, did not retract their earlier wrong work but actually included it in papers when they used the right temperature as if the wrong work somehow backed them up.

2006: The name of Western Research Laboratories was changed to RLC Laboratories.

2013: A major study from Walter Reed National Military Medical Center found that 49% of patients preferred natural desiccated thyroid, compared to 18% who preferred levothyroxine, and 33% had no preference. That study also found that patients who preferred natural desiccated thyroid had improved general well-being, significant improvement in thyroid symptoms, and lost approximately 4 pounds, compared to no weight loss or improvements in well-being and symptoms in the levothyroxine group.

2013: Acella introduced NP Thyroid as a generic natural desiccated thyroid drug.

2013: WP Thyroid was released. ​

2014: A study published in the Journal of Endocrinology, Diabetes & Obesity found that among patients who didn’t feel well on levothyroxine, 78% who switched to natural desiccated thyroid said they preferred it. ​

2014-2015: Armour Thyroid became an Allergan product with the merger of Forest Laboratories into Allergan.

2017: Natural desiccated thyroid was the 130th most prescribed medication in the United States with around 5.5 million prescriptions per year (levothyroxine was the 3rd most prescribed drug, with almost 102 million prescriptions and refills). ​

2018: An American Thyroid Association survey of more than 12,000 people with hypothyroidism, found that about 30% of patients take natural desiccated thyroid. The same survey found that patients had a higher level of satisfaction taking natural desiccated thyroid compared to levothyroxine. ​

2020: Pharmaceutical company AbbVie acquires Allergan, including Armour Thyroid.