The Fascinating Discoveries Leading to Thyroid Treatment Over the Ages

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By Alan Wong, MD
History of Thyroid Treatment Collage

While thyroidology, the study of the thyroid gland, may be perceived as a relatively new area of endocrinology specialty, references to the thyroid can be found as far back as the literature of the ancient Greeks.

Thus, the long history of thyroid disease and its treatment is also central to the history of much of the practice of endocrinology in general, particularly in early initial descriptions of its anatomy, physiology and associated pathologies, as well as the more recent identification of its molecular mechanisms of action, which have resulted in the identification and purification of thyroid replacement hormone.

We begin with goiter (enlarged thyroid), named after gutter, which is Latin for “throat.” Goiter has been long identified in iodine-deficient regions such as the mountainous regions of Europe and China and northern India (where it was known as galaganda) and subsequently by various writers including Hippocrates, Pliny and Galen. As early as 1600 BCE, Chinese writers described goiter treatment using burnt seaweed and sponge, as did European physicians, including Roger of Palermo and Arnold of Villanova in the 12th and 13th centuries, respectively. Goiter was not linked specifically to the thyroid gland, however, until Fabricius did so in the 17th century. Earlier writers had used various terms for goiter, including struma, scrofula, and bronchocele, without necessarily differentiating between tumors of the thyroid and those of other neck structures.

Picture of Galen
Aelius/Claudius Galenus, or Galen of Pergamon, was a Roman Empire physician considered the first to describe the thyroid gland.

Galen, in the first century AD, was the first to describe the thyroid gland, but it wasn’t until the late Middle Ages that more complete descriptions of the thyroid gland itself emerged, first in China by Wang Hei, around 1475, and Vesalius in 1543. Vesalius, in fact, described the thyroid gland as two glands, one on either side of the larynx, but Eustachius a decade later noted that the thyroid was, in fact, a singular gland with the two lobes connected by an “isthmus.” The term “thyroid” (referring to the Greek for an oblong shield, thyreos) was first used by Thomas Wharton in 1675.

To these medical pioneers, the function of the thyroid was unclear. Various functions were ascribed to the thyroid, including a lymphatic function (the transportation of lymph, a fluid containing infection-fighting white blood cells, throughout the body), detoxification, a holder for worms, filling free spaces around the larynx, and guarding “the female system from the influence of the more numerous cases of irritation and vexation of mind to which they are exposed than the male sex (Rush, 1820).”

However, the predominant theory for many years was from Roman Empire physician and philosopher Galen, who described the thyroid as a source of laryngeal lubrication fluid. Subsequently, the thyroid was thought to function as a “vascular shunt,” whereby the thyroid was thought to hold excess blood from the brain and thus prevent adverse consequences to neurologic tissue.

In the mid-to-late 19th century, physiologists such as Berthold, Bernard and Brown-Sequard identified the concept of the bloodborne “chemical messenger” enabling regulation of the functions of distant organs as well as general metabolic effects. In doing so, they established the foundation of modern endocrinology. “Organotherapy,” the identification of deficiencies of unknown “internal secretions” produced by “ductless” glands, coupled with treatment of these conditions by extracts of the corresponding gland, became more popular. The use of thyroid extract for hypothyroidism in the late 1800s was one of the earliest successful applications of this concept.

In 1905, British physiologist Ernest Starling described the term “hormone,” first used by his colleague Sir William B. Hardy and derived from the Greek for “to set in motion,” to describe such bloodborne chemical messengers.

Thyroid physiology, function, and hypothyroidism treatment

In the 17th and 18th centuries, observers such as Dutch anatomists Frederik Ruysch and Albrecht Von Haller, noting the lack of evident ducts but high vascularity of the thyroid gland, suggested that it produced a fluid that was secreted into the bloodstream. Even as early as 1836, Sir Astley Paston Cooper noted the possibility of a substance that “is slowly formed and partially formed and kept in reserve, and that this principle is also supplementary, when poured into the descending cava, to important functions in the course of the circulation...the influence which it exerts upon the circulating fluid may be more or less needful for the healthy subsistence of the entire animal.” Sir Sir John Simon (1844) noted that the structure of the thyroid suggested a secretory function.

Studies of thyroidectomies in animals in the mid-to-late 1800s supported the vital role of the thyroid for sustaining life. Emil Theodor Kocher (1883), in work that won him the 1909 Nobel Prize in Physiology and Medicine, noted poor outcomes in patients who had undergone thyroidectomies for goiters in Alpine areas of Switzerland. Conditions such as cretinism – consisting of bone growth delay and small bones, dwarfism, mental deficiency (congenital cretinism), and goiter (with endemic cretinism); myxedema – a condition characterized by an increase in mucous in connective tissues and edema, first described by William Gull in 1874; and cachexia strumipriva, noted by dry skin, decreased mental abilities, decreased energy, facial and extremity edema, and muscle weakness, were increasingly thought to have a common cause.

Anatomy drawing by Leonardo da Vinci which includes the thyroid gland
This anatomy drawing by Leonardo da Vinci in 1510 is considered the first drawing of the thyroid gland.

In the 1880s, a trio of physicians linked the loss of the thyroid gland as the common underlying cause of these conditions based on anatomical studies and the effects of thyroidectomies in animals such as monkeys, sheep and dogs. However, thyroid hormone deficiency as the underlying cause was not yet known.

Improvements in the treatment of hypothyroidism followed. After studies in the late 1890s attempting grafting of thyroid tissue after thyroidectomy had produced temporary improvements, English physician George Redmayne Murray demonstrated in 1891 sustained and significant clinical improvement in a myxedematous woman injected with sheep thyroid extract, as did Portugese investigators Bettencourt and Serrano in 1890. After oral thyroid extract was also noted to be effective by H. W. G. MacKenzie and E. L. Fox in 1892, oral treatments became the predominant form of thyroid extract administration.

The essential link between iodine and thyroid disease also became increasingly evident with time. Swiss physician Jean-François Coindet identified iodine as the probable agent in sponge that could treat goiters and started using it for this purpose in 1820. French chemist Jean Baptiste Boussingault, based on his experience in Columbia where he observed locals preventing goiter with salt iodized from a nearby mine, in 1833 suggested iodized salt as a goiter preventative. Unfortunately, initial attempts using iodine to prevent goiter were complicated by adverse effects such as Jod-Basedow phenomenon (high thyroid levels in persons with goiter using excess doses of iodine).

In 1853, French physician Gaspard Adolphe Chatin linked the lack of environmental iodine content with goiter, although his findings were initially disregarded. At that time, goiter was thought to originate from water-related causes or excess dietary magnesium. The iodine-dependent biochemistry of thyroid function also became clearer about this time. In the late 19th century, German chemist Eugene Baumann noted high iodine levels in the thyroid gland, and, in 1896, identified “thyreo-iodin” as the active agent in thyroid. In 1907, Dr. David Marine identified the requirement of iodine for normal thyroid function. The use of iodine was first demonstrated for goiter treatment in animals in 1913 and for greatly decreasing goiter incidence in schoolgirls living in an iodine-deficient region in 1917. The subsequent introduction of iodized salt, initially in Switzerland in 1920 and in the U.S. in 1924, greatly reduced iodine deficiency and the subsequent incidence of iodine deficiency-associated goiters.

In terms of thyroid hormones themselves, crystallized thyroxine (T4) – the main hormone produced by the thyroid gland – was isolated by American physicist Edward Calvin Kendall of the Mayo Foundation in 1914. And in 1927, chemist Charles Robert Harrington characterized the molecular structure of T4. The following year he and colleague George Barger synthesized T4, after which it became more widely available both in quantity and cost. It was observed, however, that T4 alone did not fully explain thyroid activity. In 1928, Kendall, noting that desiccated thyroid extract, which is pig or cow thyroid glands, dried and powdered for therapeutic use – had more effect than thyroxine, suggested the possibility that a more “active” form existed. This agent, T3, with much higher biologic activity than T4, was identified by biochemist Rosalind Pitt-Rivers and endocrinologist Jack Gross in London and Dr. Jean Roche in Paris in 1952.

Thyroid stimulating hormone (TSH), secreted by the pituitary to regulate thyroid hormone production, was identified in 1935 by J.B. Collip and E.M. Anderson. The presence of a thyrotropic substance (having an influence on thyroid gland secretions) of anterior pituitary gland origin was noted as early in 1916 by two young biologists, Bennet M. Allen and Philip E. Smith, working independently on tadpole models, and in 1929 independently by American physician Leo Loeb and Frenchman Max Aron, who demonstrated thyroid enlargement in guinea pigs given pituitary extract from cattle.

Subsequently, the concept of “feedback control” as applied to biologic systems was described, including the “pituitary-thyroid axis” in the 1940s and the ”thyrostat” as described by R.G. Hoskins, Harvard Medical School Director of Neuro-Endocrine Research, in 1948. This concept of “feedback” inhibition, using TSH to assess the adequacy of thyroid replacement doses, is central to current models of treatment for hypothyroidism resulting from thyroid function deficiency. More recently, TRH (thyrotropin-releasing hormone), originating from the hypothalamus in the brain and which regulates TSH production, was identified by Nobel Prize recipients Andrew V. Schally and Roger Guillemin in 1970.

The most common cause of hypothyroidism in the United States, Hashimoto’s thyroiditis (also known as Hashimoto's disease), was first reported in 1912 by its its eponymous discoverer, Japanese surgeon Hakaru Hashimoto. He described “struma lymphomatosa,” which he identified as goiters infiltrated by lymphocytes, and oftentimes hypothyroidism. His discovery, however, was not fully accredited until 1938, likely due to factors such as the original paper being in German and Hashimoto’s private practice in Japan being outside the confines of academics. We now know that Hashimoto’s thyroiditis is an autoimmune disorder and can be characterized both by enlarged, as well as small, thyroid glands. The identification of Hashimoto’s as an autoimmune disease was first suggested in 1956 when the associated autoantibodies were identified by clinical immunologists Ivan Roitt and Deborah Doniach.

Hyperthyroidism

Mayo Clinic co-founder Dr. Charles Mayo first used the term “hyperthyroidism” in print in 1907, but the distinction between the two major causes of toxic adenoma (a thyroid nodule producing excess thyroid hormone) and Graves’ disease was not clearly made until 1913, by endocrinologist Henry Plummer and Dr. Walter Boothby. Ophthalmopathy (eye protrusion) is a characteristic feature of Graves’ disease, although not always present.

Goiter associated with eye disease has been noted as far back as the 6th century AD. Persian physicians such as Avicenna also described it in the 11th century and Sayyid Ismail Al-Jurjani in the 12th century. Subsequently, the association of goiter, hyperthyroidism and eye disease as a singular disease didn’t occur until the early 1800s when multiple descriptions of goiter and exophthalmos (bulging of the eye out of the orbit) were published.

Caleb Hillier Parry, an English physician in Bath, described a series of thyrotoxic patients in 1786 (but published in 1825) and described the association of goiter, cardiac enlargement, and palpitations, including eye protrusion. Ultimately this disease was called “Graves’ disease” after Robert Graves, an Irish physician who described the condition in 1835. Although both Parry and Graves identified patients with Graves’ disease in their descriptions, neither identified Graves’ disease as a separate entity from other forms of hyperthyroidism. In Germany, Karl Adolph van Basedow described bulging of the eye, goiter, and palpitations in 1840, which he termed the “Merseburg Triad.” In Europe, Basedow’s name is the one associated with this disease. In 1856, Charcot also noted associated tremor. The suggestion of Graves’ disease being caused by excess thyroid production was expressed by Plummer and Boothby in 1924. However, the discovery of the cause, “long-acting thyroid stimulator (LATS)” didn’t occur until the late 1950s (D.D. Adams and J.M. McKenzie). This substance was noted to be an antibody in 1965, and the target of that antibody, the TSH receptor, was identified in 1978.

Early treatment of Graves’ disease mainly utilized iodide treatment or surgery. Iodide use for Graves’ disease was first described in 1820, by Swiss physician Jean-François Coindet. Nine years later, French physician Jean Lugol created the iodine solution that is named for him and still used in modern treatment. In 1948, Drs. Jan Wolff and Israel Lyon Chaikoff at the University of California described the mechanism of iodide exposure leading to inhibited organification of thyroid hormone in abnormal thyroid glands, thereby leading to decreased thyroid production. Subtotal thyroidectomy (surgical removal of the thyroid), sometimes accompanied by the tying off of thyroid arteries (ligature), was also described as early as 1823, although this practice became less common over time, while iodide treatment was increasingly utilized before surgery after Plummer at Mayo started doing so in 1922. In the 1850s and 1860s, cervical sympathetic chain resection was also tried, following the concept that Graves’-related palpitations were associated with increased sympathetic activity.

By 1940, thyroid surgery techniques had been perfected, including by Dr. William Halsted at Johns Hopkins. Halsted also identified techniques to keep parathyroid glands intact during surgery, noting the complications of postoperative muscular spasms that otherwise resulted due to a deficiency of calcium as a consequence of parathyroid removal. At Mayo, Plummer’s approach of using iodine (Lugol’s) solution preoperatively for Graves’ disease surgery resulted in mortality rates less than 1 percent by 1925. However, surgical approaches were replaced in the 1940s by nonsurgical approaches, including use of radioiodine treatment and thiouracil.

The potential use of radioiodine for hyperthyroidism was first described in 1938 by Dr. Saul Hertz, and MIT physicists Robley Evans and Arthur Roberts, from rabbit studies showing radioiodine was specifically taken up by induced hyperplastic (enlarged by tissue) and goitrous (swollen) thyroid glands. The same year, at the University of California Berkeley, Iodine-131 (I-131), with a longer half-life, was generated by chemist Glenn Seaborg at the behest of friend and colleague Dr. Joseph Hamilton. In 1939, Hamilton and Soley first used I-131 for diagnostic thyroid uptake tests. In 1941, hyperthyroidism treatment with radioiodine using Iodine-130 (I-130) was first described at MIT by Hertz and Roberts, and later that year by Hamilton and Lawrence using I-131. This is the isotope that we use today. Treatment of hyperthyroidism with I-131 became increasingly widespread after 1946, when the substance became available in quantity from the Manhattan Project facility at Oak Ridge, Tennessee.

These nonsurgical approaches revolutionized treatment for Graves’ disease. In the early 1940s, compounds such as thiouracil were also developed as treatments for hyperthyroidism.

Propylthiouracil (PTU) was developed around the same time and, having less side effects than thiouracil, was used widely within a decade. It was soon joined by methimazole and carbimazole, which is used in Europe but not approved in the U.S. PTU and methimazole are the mainstay oral agents of current Graves’ disease treatment.

Thyroid Cancer

As early as the first century AD, Chinese physician Tshui Chih-Thi distinguished non-curable (malignant) from curable (benign) neck masses. Many centuries later, thyroid cancer was first described in 1811. From early on, the differentiated nature of most cases of thyroid cancer was noted. Dr. Humphry Rolleston, in “Endocrine Organs in Health and Disease, (1936), notes thyroid cancer “...may closely resemble normal thyroid tissue, and the metastases may do the same.” Furthermore, “...carcinoma rarely supervenes in the thyroid of toxic goitre.” However, unlike in the modern day, Rolleston noted that the prognosis was “gloomy,” and that “...when the diagnosis is definite, the condition is often beyond the reach of surgery...” However, it is not necessarily true that the cancer cases he was describing were similar to the generally nonaggressive cancers we generally treat nowadays.

The use of radioiodine for treating thyroid cancers was first described in New York in 1941, and subsequently described through the first half of the 1940s, using Iodine-130. Iodine-131 was subsequently available from after 1946. Recent events such as the release of radioiodine from Chernobyl and Fukishima have increased public awareness of thyroid cancer.

More recent approaches to thyroid cancer diagnosis and treatment include the use of fine needle aspirations. Needle biopsy was first described in 1930, by Martin and Ellis, but the technique, by then using finer needle diameters, was not widely adapted in the U.S. until the 1980s. Recent developments in thyroid cancer treatment include the increasing use of ultrasounds for diagnostic purposes, the use of rTSH for treatment and diagnostic purposes in the U.S. (after FDA approval in 1998), as well as the recent development of tyrosine kinase inhibitors for treatment of advanced-stage thyroid cancers. Current “third generation” TSH assays have very high sensitivity for detection of thyroid dysfunction, but also have raised the possibility of detecting subtle changes in thyroid function that are of debatable clinical relevance.