Slater SD (2010). The discovery of thyroid replacement therapy.
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© Dr Stefan Slater, 80 Whitehouse Road, Cramond, Edinburgh EH4 6PD, Scotland. Email: avowood@yahoo.co.uk


Cite as: Slater SD (2010). The discovery of thyroid replacement therapy. JLL Bulletin: Commentaries on the history of treatment evaluation (http://www.jameslindlibrary.org/articles/the-discovery-of-thyroid-replacement-therapy/)


Introduction

There is a poignant before and after photolithograph of a Victorian lady in the 1878 transactions of the Royal Medical and Chirurgical Society of London (Figure 1) (Ord 1878). This is not the usual celebratory image before and after successful treatment. It is a picture of the woman, aged 21 in 1870, and then seven years later, unrecognisably aged by the effects of undiagnosed and untreated thyroid deficiency. It is poignant because she probably dies of the disease, the introduction in 1891 of effective treatment with subcutaneous injections of thyroid extract by George Murray of Newcastle-upon-Tyne coming too late (Murray 1891a).

The images are from a paper by William Ord, physician at St Thomas’s Hospital, entitled: On Myxoedema, a term proposed to be applied to an essential condition in the ‘Cretinoid’ Affection occasionally observed in Middle-Aged Women. In this he described a ‘mucous oedema’ of the skin, finding in it an excess of mucin on microscopy and chemical analysis. From this description he coined the term ‘myxoedema’, a name lastingly synonymous with thyroid deficiency.

A number of steps led to the discovery of thyroid replacement therapy: the slow understanding that this debilitating disease, myxoedema, was in some way linked to the thyroid; the acceptance of the notion that the thyroid elaborated some important factor with an endocrinefunction; the emergence of the principle of replacement therapy: and the introduction of replacement therapy in practice. But, contrary to general belief, Murray was not the first to treat myxoedema effectively.

In the beginning: endemic goitre and iodine

The history of the thyroid gland goes back millennia. Its name derives from the Greek, θυριοs, a shield, because of the shield-like shape of the tracheal cartilage there. Its long history is inseparable from that of goitre – Latin guttur, neck or throat – for there must always have been people with goitrous swollen necks. August Hirsch in his monumental three-volume work, Handbook of Geographical and Historical Pathology, provides many past references worldwide to endemic goitre and endemic cretinism, notably prevalent in mountain valley regions but absent in coastal regions (Hirsch 1885). Amongst these – and suggestive evidence of a general public awareness of goitre – is Juvenal in the early 2nd century CE asking rhetorically: Quis tumidum guttur miratur in Alpibus [Who wonders at a swollen neck in the Alps]. Rolleston quotes a source in 1775 describing an incident involving an English traveller in the Tyrol of whom it was remarked that he would have been quite handsome if only he had had a goitre, such was the almost universal presence of goitre in that region (Rolleston 1936), presumably a long-standing feature. In Britain, we had our own, colloquial, ‘Derbyshire neck’.

Goitres did not escape artistic or literary attention, being painted by Leonardo Da Vinci (A Grotesque Head or Scaramuccia) (Vescia and Basso 1997), amongst others, and referred to by Shakespeare in The Tempest:

Faith, sir, you need not fear. When we were boys,
Who would believe that there were mountaineers
Dew-lapp’d like bulls, whose throats had hanging at ’
Wallets of flesh? (Gonzalo, Act III, Scene 3)

Mark Twain in A Tramp Abroad writes in 1880 of a fellow traveller laconically remarking: ‘Well, I am satisfied, I have seen the principal features of Swiss scenery – Mont Blanc and the goiter – now for home!’ (Twain 1880).

Hirsch, in his forensic analysis of the possible cause of endemic goitre, touches on a ‘short-lived opinion’ that absence of iodine in the drinking water and in the air was responsible. However, he concludes that while iodine ‘in the most minimal quantities [in] air and food’ may protect against endemic goitre and endemic cretinism, these conditions were probably infective in origin. Tantalisingly close to the truth, while he refers to the ‘curative power’ of iodine – though, surprisingly, provides no reference -he thought it ‘very doubtful’whether giving iodine would have any prophylactic value. It was Jean Francois Coindet in Geneva who, in 1820, reported iodine’s efficacy in treating goitre (Coindet 1820a; 1820b).He also, astutely, in light of things to come, recommended it preoperatively to diminish goitre size and vascularity. At the time, he did not know he was treating iodine deficiency, just ‘suspected, from analogy’ that iodine might be the active principle in burnt sponge, which he knew to have been a long-time remedy. He encountered opposition, opponents claiming iodine was poisonous, and it has been suggested that: ‘Coindet would not leave his house for fear of being stoned in the street’! (Zimmerman 2008). Coindet is regarded as the first to try iodine but, in fact, William Prout in London had done so earlier in 1816, five years after iodine was discovered (Prout 1834). However, he appears to have treated only one case and did not publish until 1834, and then only in a short, but informative, footnote, saying he was instrumental in St Thomas’s Hospital adopting the remedy in 1819.

Further historical detail on this aspect is provided by Rolleston and more recently by Medvei in their extensive monographs (Rolleston 1936; Medvei 1993) and by Zimmerman (2008). It is sobering to reflect that, as recounted by Medvei and in particular detail by Zimmermann, it took 100 years after Coindet’s successful treatment of goitre for the safe prophylactic value of iodine to be convincingly established by Marine and Kimball in a controlled trial in schoolgirls in Akron, Ohio (Marine and Kimball 1917; Marine and Kimball 1920). One of the grounds for earlier antagonism was that a goitre exempted young men from military service in the French army! (Zimmerman 2008). Yet, challenges in the delivery and uptake of iodine prophylaxis remain (Miles 1998).

The Chinese contribution

One thing missing in Hirsch’s 1883 account is the Chinese contribution. Missing, because China was then largely a closed book to the West, otherwise it is likely there would have been earlier progress on the thyroid and in several other scientific and technical matters. For the Chinese were not just well aware of an environmental influence on goitre, they looked on it as an anomaly and were treating it. In a work dating from 239 BCE – Master Lu’s Spring and Autumn Annals – it is recorded that: ‘In places where there is too much light water there is much baldness and goitre’ (Needham 1970; Temple 2007). In 610 CE, Chao Yuan Fang, in Discussion of the Origin of Symptoms in Diseases, observed: ‘Do not live long in mountainous regions with black earth and spring water. Drinking such water for a long time may cause goitre’ (Maciocia 2008). There is reference to treating goitre with burnt sponge and seaweed in 1600 BCE (Iason 1946). But any possibility of the use of algae dating from around 2700 BCE, as has been hinted at (Morse 1934; Rolleston 1936) – many traditional Chinese medicines being attributed to the cultural hero and divine, Shen Nong, who is supposed to have lived then – is based on mythology. Powdered shells of molluscs are reported to have been used in the 5th century CE from the Goitre Prescriptions of the Abbot Shen (Needham 1970).

Even more remarkable is that the Chinese are said to have been treating cretins with sheep’s thyroid in the 6th century CE (Hume 1924). This is presumably insofar as they distinguished cretinism – by whatever name they called it – from other forms of childhood mal-development. It is also most likely to have been in the context of goitrous cretinism, for there is reference to this as well as to the treatment of goitre per se with sheep or deer thyroid in the wonderfully titled Thousand Gold Remedies or Thousand Golden Ducats Prescriptions (Wong and Lien-The 1936; Maciocia 2008). This is the Beiji qianjin yaofang by Sun Simiao, literally translated as Essential Prescriptions worth a Thousand Gold Pieces for Every Emergency, completed around 652 CE (Wilms 2007). Although Chinese medicine did not really have a theory of thyroid problems without goitre, and what we know as myxoedema may have corresponded to ‘exhaustion’ or ‘oedema’ and been treated differently (Maciocia 2008), the Chinese are bound to have come across non goitrous cretinism and may have treated it, too, with animal thyroid. The Chinese also recognised then that there were different kinds of goitre: solid neck swellings – malignant tumours – that could not be cured, and movable ones that could (Needham 1970). The extent to which they distinguished and how they managed thyrotoxic goitres is not clear. Remarks in a recent paper on traditional Chinese medicine suggest they may have been aware of a difference and a difficulty in treatment with seaweed (Xixiao 1997).

Robert Temple (2007), in The Genius of China, a useful distillation of Joseph Needham’s monumental, multi-volume work, Science and Civilisation in China,lists a number of thyroid prescriptions for goitre in the 7th century CE. One of these recommended taking 100 thyroid glands from gelded rams, washing them in warm water, removing the fat, then drying them and chopping them up and mixing with jujubes (Chinese dates) – no doubt to try to disguise the taste – to make into pills. Another advised a single thyroid gland be removed from a sheep, the fat taken off, and the raw gland sucked by the patient until all the juice had been extracted and swallowed and the gland itself then eaten. Yet another involved air-drying various animal thyroids to powder, to be taken every night in cold wine. Two of these prescriptions are from Old and New Tried and Tested Prescriptions (Gujin lu yanfang), attributed to Zhen Quan, written about 640 CE. Medical Secrets of an Official (Waitai Miyao)by Wang Tao, 752 CE,recommended steeping sheep’s thyroids in wine and afterwards roasting them to take one daily (Wong and Lien-The 1936). It seemed not to matter which animal was used, whether pigs, sheep, water buffalo or deer; all seem to have been judged effective. One seaweed prescription may have consisted of baking seaweed and sea grass to dryness, then grinding the mixture into a powder that was to be taken in warm water daily (Lu 2005).

It seems improbable that these apparently routine therapeutic interventions of long ago were not the result of astute observation and experience. While their origin may have lain in serendipity or in some instinctive idea of treating like with like, a diseased thyroid with a healthy one – the Chinese thung lei (identity of categories) principle (Needham 1970) – their firm incorporation into Chinese pharmacopoeic texts is most likely to have been because they were seen to work. These texts included The Great Pharmacopoeia – the Pen-ts’ao kang mu or Bencao gangmu (Systematic compendium of materia medica) – by Li Shizhen, published in 1593 or 1596 (Barrett 2007; Temple 2007).It has not proved possible to consult directly any of the original Chinese writings mentioned, but several references to the use of thyroid () and of seaweed (haizao) – or both together – in treating goitre (ying) have been located in modern edited editions (Gao Wenzhu 1993; Zhang Zuoji et al 1995; Xie Pangen 1996; Liu Hengru and Liu Shanyong 1998). 

China might not have been the only ancient civilisation to use seaweed for goitre. For in a paper on the role of algae as a food in antiquity in Central and South America, evidence is presented that dried seaweed was imported into the Andean highlands, an endemic goitrous area (Aaronson 1986).

The discovery of iodine in 1811, millennia after the Chinese and perhaps other ancient civilisations were using seaweed empirically, was serendipitous and the circumstances are interesting. A French chemist, Bernard Courtois, noticed violet fumes while washing seaweed ash with sulphuric acid in the manufacture of saltpetre. The gas was condensed into crystalline flakes and its properties investigated by Louis Gay-Lussac and Sir Humphry Davy who proposed the name iodine for the new substance, from the Greek, ιωδηs, violaceous (Davy 1814).Davy, assisted by Michael Faraday, worked on it in Paris, visiting the city in 1813 under special permission from Napoleon, having gone there to collect a prize and medal Napoleon had awarded him in 1807 for his electro-chemical work (Williams 1965; Knight 1998; Lamont-Brown 2004). Napoleon’s own affairs had by then taken a fateful turn, but the circumstance of honouring an enemy alien in this way must be very unusual, if not unique. Indeed, French chemists calling on Davy for help in identifying a new substance connected with saltpetre (potassium nitrate), a key component of gunpowder, is also remarkable for it might have proven of military importance. It is evident from Davy’s account that they were already aware it formed a detonating compound with ammonia!

Conceptualising the link between the thyroid and myxoedema

Up to the middle of the 19th century there appears to have been no knowledge of thyroid biology but much speculation. That the thyroid must have some important function was suggested by its very generous blood supply. Some wondered whether it functioned as a vascular shunt to prevent sudden rushes of blood to the brain – a neat idea! Others thought it was involved in voice production by some facilitating, perhaps lubricating, action on the larynx. Indeed, the two thyroid lobes had originally been called the laryngeal glands. But Frederik Ruysch, anatomist in Leyden around 1690, adopted, according to Albrecht von Haller in 1766, the ‘only possible remaining opinion, namely, that a peculiar fluid was elaborated in the gland and poured into the veins’ (Rolleston 1936; Singer and Underwood 1962). The 19th century thus began with thyroidology at best in embryo; but during that century endocrinology was born and the thyroid was its standard bearer.

In 1836, Thomas Wilkinson King of Guys Hospital, regarded by some as the ‘Father of Endocrinology’, anticipated on the basis of observation and experiment the internal secretion of the thyroid. In a meticulous paper on its anatomy, he wondered at the thyroid’s disproportionately large vascular supply in the absence of any evident mechanical or other local function and also at what he described as its ‘peculiar’ fluid (King 1836). He wrote: ‘The most important novel fact concerning the thyroid gland is doubtless this, that its absorbent vessels carry its peculiar secretion to the great veins of the body’. This language is almost identical to that of Ruysch and Haller more than a century earlier. Indeed, King notes that his view ‘has been indirectly surmised by Morgagni [probably in 1761] and others’, usefully acknowledging a continuum in thinking. He goes on to say: ‘Yet we may one day be able to shew [sic], that a particular material principle is slowly formed [in it], and partially kept in reserve [for]important subsequent functions in the course of the circulation.’ King’s experiments included squeezing the gland and observing its lymphatics fill. He proposed that the thyroid is naturally subjected to an analogous periodic kneading or compression during chewing and swallowing from movements of the oesophagus and larynx and adjacent neck muscles, and inferred that the thyroid’s secretion must therefore vary through the day. He also noted an association between pathological findings and clinical features, describing in one case ‘the site of the gland occupied entirely by condensed cellular tissue, with the exception of two pea-sized portions of true gland situated on one side within this tissue. In this case, the peculiarities of the individual were fully sufficient to indicate the importance of the defective part.’ One can only speculate on the clinical findings because King, frustratingly, gives no information, and nothing further appears to have come of this impressive paper. It is not even cited in any of the following seminal papers – no joined-up thinking for King.

In 1850, at a meeting of the Royal Medical and Chirurgical Society of London, chaired by Thomas Addison,Thomas Blizzard Curling, surgeon at the London Hospital, provided a clear clinico-pathological correlate in a paper entitled: Two cases of absence of the thyroid body and symmetrical swellings of fat tissue at the sides of the neck, connected with defective cerebral development (Curling 1850). Curling’s patients were 10 years old and 6 months old and both were regarded as cretins. Post mortem examination in each revealed no trace of thyroid tissue and that the swellings consisted only of fat. Curling concluded that: ‘…it is highly probable, that this fat was dependent on the absence of those changes which result from the action of the thyroid’.

Curling’s important observation was not pursued until 1871 when, at another meeting of the Society, Curling himself then in the chair, Charles Hilton Fagge, a physician at Guy’s Hospital, presented a paper on sporadic cretinism (Fagge 1871). He described four living cases, aged from 8 to 20 years. He noted particularly that none of them had a goitre and that one had been well up to the age of eight and, although now physically cretinous, aged 16, she remained very intelligent. He referred to Curling’s paper and reached essentially the same conclusion from his own observations, that: ‘…the healthy thyroid body is capable of exerting a counteracting influence [on cretinism]’. Perceptively, he felt that these cases deserved a ‘distinct appellation’ to distinguish them from endemic cretinism. He also presciently and accurately speculated on what would be the clinical features of this disease were it to arise in adult life and the possibility then of the thyroid being ‘wasted’. Interestingly, he mentioned what he regarded as a similar case of arrested physical and mental development brought to his attention by a Dr Langdon Down (of Down’s syndrome). The appearances of Fagge’s own four patients in photolithographs do not suggest mongolism.

Two years later, in 1873, Fagge’s senior colleague at Guy’s, Sir William Withey Gull, presented before the Clinical Society of London two of the five cases he had seen of what he called A Cretinoid State supervening in Adult Life in Women (Gull 1874). He described their cretin-like appearance, drawing particular attention to the broad and thick tongue and the guttural voice and its pronunciation ‘as if the tongue were too large for the mouth’. He acknowledged his remarks were tentative, hence, he said, his use of the word ‘cretinoid’, but he had no doubt this was a ‘substantive’ condition and not one of cardiac or renal origin. In  precise, clear language he wrote: ‘In the [cases] which I have seen, the thyroid was not enlarged; but from the general fulness of the cutaneous tissues, and from the folds of skin about the neck, I am not able to state what the exact condition of it was’.

Gull was an interesting personality with apparently a remarkable presence, resembling Napoleon in face, form and manner (Figure 2) (Rolleston 1936). In the 1970s, 80 years after his death in 1890, he was the subject of a theory, quickly discredited, that he had been ‘Jack the Ripper’, the killer in the still unsolved murders and mutilations of at least five Whitechapel prostitutes in 1888 (Knight 1976). He figured in the 1988 TV film series, Jack the Ripper, starring Michael Caine as the detective.

Gull is credited with the first description of hypothyroidism in adults and his paper was important in defining a recognisable clinical syndrome. Yet many doctors must have come across such patients. The Edinburgh physician, Sir Byrom Bramwell, later in 1893, recounted his general practitioner father showing him a typical case in 1869, and a colleague encountering one in 1854 and recognising it did not conform to any known condition (Bramwell 1893). Others realised in retrospect they had seen similar cases (Duckworth 1880).

Then, in 1877, William Miller Ord, read his paper before the Royal Medical and Chirurgical Society of London and proposed the term ‘myxoedema’ for the adult condition (Ord 1878). He described the non-pitting, ‘mucous oedema’. He also described how the hands of one of his patients went ‘dead’ when she attempted to sew. This was possibly due to carpal tunnel syndrome, a potential complication of hypothyroidism, but then an unknown entity. Ord ended his paper carefully, stating that: ‘… the name [myxoedema] is only intended to represent the condition, and does not profess to involve an explanation of its causes.’ However, he described the ‘practical annihilation’ of the thyroid gland he found at autopsy, and went on to discuss the possible relevance of this, attempting a synthesis of the earlier reports by Curling (1850) and Fagge (1871). He reached the same conclusion: that destruction of the thyroid might relate in some way to the condition of his patients, although he opined there could be some more ultimate cause. He also presented an engaging theory to explain the lethargy, inertia and slow responses associated with the disease. He suggested that these might result from the sheathing and insulation of the body in a ‘jelly-like’, mucin-laden integument that interfered with sensory perceptions and stimulation. It is sobering to read his descriptions of the increasingly wretched life endured by these patients, culminating in death in coma or from almost certain cardiac failure.

Ord deserves more credit than just as the originator of a name, but the term ‘myxoedema’ was certainly an inspired invention. It was a memorable, snappy for the times, single-word label which – notwithstanding some controversy over its appropriateness (Rolleston 1936) – must have helped to focus attention on a condition which, despite its frequency and unifying features, had long gone unidentified. Six years later, he chaired the committee set up by the Clinical Society of London to investigate the whole matter. He also later undertook some of the earliest metabolic studies of the effects of treating myxoedema with thyroid extract, showing the rapid weight loss and rise in temperature and in urinary volume and nitrogen excretion that occurred (Ord and White 1893).

The Swiss key: myxoedème opératoire – precedence and prestige

The key papers, which advanced these English authors observations, were those of the Swiss surgeons, Jaques-Louis Reverdin in Geneva and Emil Theodor Kocher in Bern, Kocher later receiving the Nobel Prize for his work on the thyroid. How fitting it is that it should be two Swiss doctors whose practices unlocked an understanding of the importance of the thyroid. For they each identified the late effects of total ablation (extirpation) of goitres.  Reverdin first presented his findings briefly at a meeting of the Medical Society of Geneva on 13 September 1882 (Reverdin 1882) and then in an extended paper co-authored with his cousin Auguste Reverdin in June 1883 (Reverdin and Reverdin 1883a). In this, they noted the great similarity of Gull’s and Ord’s myxoedema cases with their affected post-operative patients, referring to the comparison as a ‘rapprochement complet’, clearly making the connection. They acknowledged Gull’s primacy in describing the clinical manifestations and Ord’s ‘christening’ the condition ‘myxoedema’, and proposed that surgical cases be known as ‘myxoedème opératoire’. In light of his findings in 1882, Reverdin thereafter sought to conserve a part of the gland during thyroidectomy for goitre, speculating that its complete removal may have been responsible for these late effects. He had noticed that no such problems followed removal of only one lobe of the gland.

Kocher, on the other hand, surprisingly appears to have been either unaware of the reports by Gull and Ord, or omitted to refer to them. He first reported his findings to the Congress of the German Surgical Society on 4 April 1883 and they were published later that year (Kocher 1883). Theexact date of publication is unclear, but it was after the Reverdin paper of June 1883 (Tröhler 2010a). Reverdin had remarked in that paper that he wondered when Kocher would publish his findings. Kocher called the disease picture in his affected cases ‘cachexia strumipriva’ – literally, a bad condition due to the removal of a struma (goitre). He ascribed it to a combination of oxygen insufficiency from tracheal atrophy, consequent on operative interference in the neck, and loss of the thyroid’s role as a safety valve for both the cerebral circulation – the old theory – and, as he saw it, in breathing. Kocher’s biographer, Ulrich Tröhler, goes into this in more detail (Tröhler 1984;)As Halsted put it in his monumental review of goitre surgery: ‘It is interesting to follow the argumentation of a mind so exceptionally keen and sane as Kocher’s in its futile efforts to explain insufficiently illuminated phenomena’(Halsted 1920).

In reading Kocher’s 1909 Nobel Prize Lecture (in English translation) (Kocher 1909), one gets the impression that Kocher was aware in 1883 of Gull’s and Ord’s reports, despite not referring to them, and he dismisses Reverdin’s contribution. He appears to assert that Reverdin only became aware of the connection between the effects of total thyroidectomy and the English cases after his,Kocher’s, oral communication in Berlin, and he firmly refutes Reverdin’s ‘later claim’ to have been the first to discover the ill effects of total thyroidectomy. In support of his denigration of Reverdin, Kocher fastens on a paper Reverdin had published in April 1883 (Reverdin and Reverdin 1883a). Kocher should have noticed the words ‘A suivre’ [to follow] at the end of the paper he was targeting.

This was all intriguing and made more so by Rolleston’s (1936) comment that: ‘A now forgotten controversy arose between J.L. Reverdin and Kocher’. There is no doubt this controversy was an argument over priority and recognition, and this has previously been investigated (Bornhauser 1951; Michler and Benedum 1970; Reverdin 1971; Trőhler 1984). Reverdin was certainly the first to raise a concern at the Geneva meeting in September 1882, and, by then, he had already modified his surgical approach to one of subtotal thyroidectomy because of the possibility that loss of thyroid functionwas responsible for the ‘non encore décrits’ [not yet described] clinical manifestations (Reverdin 1882). The transcription of his presentation is brief and there is no mention at that point of any awareness of Gull or Ord, and it may be he had not yet made the connection. Kocher was present at that meeting. Indeed, he and Reverdin had had a conversation a few days beforehand – on a steamboat! The nature and direction of that conversation was later the subject of a fascinating correspondence, which is recorded in Henri Reverdin’s biography of his father (Reverdin 1971): Kocher claimed he had introduced Reverdin to the ill effects of total thyroidectomy, whereas Reverdin claimed it was he who had advised Kocher. Reading these letters today, Reverdin’s is the more convincing. A full analysis of them is provided by Michler and Benedum (1970).

In Reverdin’s extended, final part, paper published in June 1883, it seems he was aware of Kocher breathing heavily down his neck, because he refers to the possibility of Kocher publishing before him. Kocher’s paper reported the long-term results in a much larger group of patients and is a superb study, but it was disingenuous of him to dismiss Reverdin in his Nobel Prize Lecture years later. There is every indication that it was Reverdin’s prompting in September 1882 that led Kocher to review his thyroidectomised patients. While in his 1883 paper he does acknowledge Reverdin’s influence (Kocher 1883), he concedes it only as having been a spur to investigations allegedly, but unconvincingly, already underway. That Reverdin was the prime mover is the understanding of some latter-day reviewers of the history of thyroid surgery (Zimmerman and Veith 1961; Welbourn 1996; DuBose et al. 2004),while others, in paying homage to Kocher, either fail to mention Reverdin or subordinate his contribution in this particular matter to Kocher’s (Giddings 1998; Andrén-Sandberg and Mai 2001; Rogers-Stevane and Kauffman 2008).

Kocher, in his Nobel Prize Lecture, also maintains that a letter he wrote to the Clinical Society of London about his findings was the ‘impulse’ for the Society’s subsequent investigation into myxoedema. In fact, that letter, while no doubt of some influence, was itself prompted by a letter from Ord drawing Kocher’s attention to his, Ord’s, cases of myxoedema, and was accompanied by some photographs of his patients (Ord 1883). In his reply to Ord, Kocher revealingly wrote he had never seen such a case – presumably because they would be unlikely to come to a surgeon’s attention – but, myxoedema having now been brought to his notice, he agreed it was analogous to his cases of cachexia strumipriva (Ord 1883). It is also obvious that Kocher, like many surgeons of the time, cannot have engaged in routine postoperative outpatient follow-up, for otherwise the ensuing problems in his goitre-operated patients would have been detected years earlier.

None of these observations about Kocher should detract from his contributions. They serve rather to show that Reverdin should be recognised more widely. There can be no doubt of the primacy of Reverdin’s observations, reported in 1882 and fully published during the first half of 1883; of his speculation then that loss of the thyroid may be to blame; and, perhaps most important, of his decision always to retain a portion of the thyroid in operations for goitre (Bornhauser 1951; Michler and Benedum 1970; Reverdin 1971; Tröhler 1984; Tröhler 2010b ). In respect of this key moment in the history of the thyroid, Reverdin could be said to hold the intellectual property. The thought has been expressed that perhaps he should have shared the 1909 Nobel Prize with Kocher (Ellis 2009; Rowley 2010).

However, despite the self-serving tone in Kocher’s Nobel Prize Lecture and his attempts to relegate Reverdin, there is no doubt about his prodigious contribution to the study of the thyroid, which far exceeded Reverdin’s, as well as to surgery in general. He was ‘a surgical maestro’, as one review puts it (Andrén-Sandberg and Mai 2001). But it is interesting to read that Kocher was considered ‘very touchy, he hardly overcame setbacks. Likewise, he insisted on the priority of his work and merits, which he aggressively defended… he had only a few close friends’ (Liebermann-Meffert 2000). Reverdin, in 1927, three days short of his 85th birthday and two years before his death, received a telegram from the International Conference on Goitre in Bern, paying tribute to his pioneering role in myxoedema (Reverdin 1971). It was a nice touch. Kocher, who was from Bern, had died there 10 years earlier, age 76. By coincidence, the telegram arrived on 25 August, Kocher’s birth date.

The idea of thyroid replacement therapy

At a meeting of the Clinical Society of London in November 1883, Felix Semon drew attention to Kocher’s presentation at the German Surgical Society the previous April, and proposed that myxoedema, cachexia strumipriva and cretinism were all due to the same cause, namely, absence or degeneration of the thyroid (Semon 1883). At the time, Semon was a 34-year-old assistant physician for Diseases of the Throat at St Thomas’s Hospital, London (he would later be knighted as the doyen of British laryngology). According to Rolleston (1936) and Medvei (1993) his remarks ‘excited ridicule’. There is no suggestion of this in the British Medical Journal’s detailed transcription of the proceedings, nor in the exceedingly brief original written minutes of the meeting (an extended account must have been written up at some later point for the BMJ). Ridicule may not, of course, have been minuted. Semon in his autobiography says only that his ‘extremely bold assertion was received with polite scepticism’ (Semon and McIntyre 1926),though he writes of antagonism towards him in his early career. Nonetheless, his very astute idea of the commonality of these conditions caught on, one senior member at the meeting suggesting that British surgeons be canvassed for their experience of thyroidectomy. The following month the Society set up a committee, which included Semon, to investigate the whole matter. He had already advised Ord to write to Kocher, as mentioned above. Indeed, Semon’s role in the unfolding thyroid story deserves much better recognition.

The Society’s survey was a remarkable project, enlisting Europe-wide – including Russian – surgical evidence. One hundred and fifteen surgeons were contacted, including two in Australia. Sixty nine replies were received, 64 of which were usable though to a variable extent. The Committee’s very detailed findings and influential conclusions were published five years later, in 1888, as a supplement volume to the Society’s Transactions (Clinical Society of London 1888). The report fully endorsed Semon’s view, drawing particularly on animal work carried out by Victor Horsley, one of the committee’s members. Horsley had separately reported the effects of total thyroidectomy on monkeys, concluding that myxoedema was almost certainly due to loss of thyroid function and not to ‘chronic asphyxia’, as the Clinical Society’s report summarised Kocher’s explanation (Horsley 1885). He also observed initial tetanic manifestations post-operatively, no doubt due to unwitting removal or operative ischaemia of the parathyroid glands, whose separate identity and function were still unrecognised. The report’s section on treatment, however, had very little to say, surprisingly making no mention of the possibility of any kind of thyroid replacement therapy despite acknowledging that, four years earlier, Moritz Schiff in Geneva had reported some success in transplanting canine thyroid in thyroidectomised dogs (Schiff 1884). Kocher, too, had by then tried thyroid transplantation in one of his patients and would continue experimenting with this till the end of his life (Tröhler 2010b; 2010c).

Horsley went on to advocate a trial of grafting, specifically sheep’s, thyroid to treat myxoedema and cretinism (Horsley 1890). In June 1890, Bettencourt and Serrano of Lisbon did the experiment, inserting half of a sheep’s thyroid subcutaneously into the infra-mammary region on each side of one of their patients (Bettencourt and Serrano 1890; 1891). They found that the graft worked immediately, before it could have vascularised, and concluded that its effect was likely to have been due to simple absorption of juice from the grafted gland, a conclusion of extraordinary importance. They had observed a rise in temperature within 24 hours – not associated with any features suggesting a postoperative febrile reaction – and, over the course of the one month’s follow-up, the patient’s bloating and weight had decreased, bodily movement and speech had improved, sweating had resumed and there was an almost complete resolution of a preoperative anaemia. These findings, and others describing the benefits, albeit transient, of intravenous injection of thyroid extract in thyroidectomised dogs (Gley 1891; Vessale 1891), added to the growing recognition of the thyroid’s endocrine function (although the word ‘endocrine’ was not used until 1904 (Medvei 1993))

In Britain, at a meeting of the Northumberland and Durham Medical Society on 12 February 1891, George Murray, 3 years qualified, having taken advice from Horsley, who had been one of his undergraduate teachers (Paget 1919), presented his idea to treat a case of myxoedema with an extract of sheep’s thyroid given subcutaneously (Murray 1891b). He, too, Medvei (1993) tells us, was ridiculed. While the typed minutes of the meeting contain no trace of ridicule; indeed, to the contrary, what could be interpreted as cautious support, Medvei has sourced a reliable account of one senior member of the Society saying: ‘It would be just as sensible to treat a case of locomotor ataxia with an emulsion of spinal cord’. The medical college at Newcastle refused to help.

The likely reason for this dismissive outburst lay at the feet of that medical colossus, Charles Édouard Brown-Séquard, the French neurologist and physiologist. A kind of scientific Ulysses, he had held university chairs in Richmond, Virginia and in Harvard, Paris, Geneva and Paris again (Rolleston 1936). He declined the chair of physiology in Glasgow because of the weather! The story goes that he once refused a colossal fee of £10,000 to see a wealthy American patient in Italy because he did not think he was the best person to advise and, besides, private practice interfered with research! (Rolleston 1936; Olmsted 1946). In 1889, two years before Murray’s address, Brown-Séquard, aged 72, published a paper on the likely rejuvenating effects on man of injections of animal testicular extracts (Brown-Séquard 1889a) and then presented a paper to the Society of Biology in Paris on the positive effects upon himself of subcutaneous injections of liquid extracts of dog or guinea pig testicles (Brown-Séquard 1889b). His promotion of such ‘organotherapy’, as it came to be called, brought him and his ideas into disrepute, for it spawned every sort of charlatanism and provoked much suspicion amongst ‘respectable’ practitioners. While Brown-Séquard’s research was of the highest order – he had, for example, proven that the adrenals were essential to life – the sensational nature of these later experiments blinded many to the general principle of replacement therapy that was trying to shine through.

George Murray and sheep’s thyroid

Undeterred, Murray obtained fresh sheep’s thyroid from a slaughterhouse and described carefully his method of preparing and administering the extract. Beginning on 13 April 1891, he injected a 46-year-old woman with most of the characteristic features of myxoedema, with 1.5ml of thyroid extract subcutaneously, twice weekly (one thyroid lobe’s worth) (Murray 1891a). After 3 months his patient was dramatically better, even though (for reasons he did not explain) her treatment had been discontinuous, just 2½ thyroid glands’ – 5 lobes’ – worth of injections having been given. This led Murray to consider that injections every 2-3 weeks would suffice to maintain improvement. Horsley urged him to publish ‘at once’ (Paget 1919), probably because he was aware that others were on the verge of doing the same experiment. Indeed, the 10 October 1891 issue of the BMJ containing Murray’s report also contains a brief report by Fenwick on the diuretic effect of a hypodermic injection of thyroid extract in a case of myxoedema, but Fenwick considered that the primary pathology lay in the kidneys (Fenwick 1891).

Although the BMJ gave no special placement to Murray’s initial paper, a follow-up report published the following August, which included three other treated cases, occupied pride of place on page 1, under proceedings of the 60th annual meeting of the British Medical Association held the previous month (Murray 1892). It included photographs before and after treatment and a temperature chart showing an increase in temperature within days of starting treatment. The particular importance of this second paper lies in the fact that cases 3 and 4, while also showing marked improvement, died suddenly from ‘cardiac failure’ (probably myocardial infarction). Murray writes: ‘[these deaths] show that patients with weak or degenerated hearts may die suddenly after the improvement has taken place, from cardiac failure after exertion to which they have for long been unaccustomed’. This was a telling early alert for the need for caution. Other cases were presented at that BMA meeting, including two who failed to respond to thyroid injections (British Medical Journal 1892). Horsley, who was at the meeting, expressed the hope that cases of non-response would be recorded and that ‘these might be as fully published as the successful cases’, an early plea against publication bias! Years later, Murray learned that the lack of success in these two cases had been because thymus, not thyroid, had been supplied by the butcher! (Murray 1920).

The Portuguese contribution

But Murray, contrary to general understanding, was not the first to try subcutaneous injections of thyroid extract in myxoedema. Portuguese researchers had already done so.

Bettencourt and Serrano’s thyroid graft experiment in the summer of 1890, mentioned above, was initially the subject of a very short communication (Bettencourt and Serrano 1890). Murray had been aware of this and referred to their results in detail in his first BMJ paper. Indeed, he spoke about them when he originally presented his plan of treatment in February, 1891, and it seems very likely they had informed his thinking. But what neither he nor Horsley appear to have been aware of was Bettencourt and Serrano’s full report. This was initially presented at a meeting of L’Association Française pour L’Avancement des Sciences in Limoges in August 1890 and subsequently published the following year (Bettencourt and Serrano 1891) . In it, they intimated their intention to try hypodermic injections of thyroid juice in another myxoedematous patient under their care. And on 15th November, 1890, three months before Murray presented his identical plan to the Northumberland and Durham Medical Society, and almost a year before his first paper in the BMJ, Antonio-Maria Bettencourt-Rodrigues reported beneficial effects from thyroid injections at a meeting of the Lisbon Society of Medical Sciences (Bettencourt 1890).

Previously sharing in the widely held belief in Murray’s priority, the author is indebted for this information to Clark Sawin whose paper has set the record straight (Sawin 2001). Bettencourt’s important results appear to have been published only as a note in the Lisbon Society’s proceedings, so it is perhaps not surprising that they have been overshadowed by Murray’s more accessible papers in the BMJ.

Oral thyroid replacement therapy

Soon after Murray’s 1892 paper, there were reports from others of success with whole sheep thyroid or thyroid extract taken orally. It has a disgusting taste, so attempts were made to disguise this in a sandwich or lightly fried with anchovy paste on toast or taken with current jelly. How reminiscent of the Chinese, centuries earlier – steeping the gland in wine or taking it in jujubes sounds better! One early report is worth quoting in extenso because of the modernity of its language, the appreciation of the importance of controlled conditions, and the finding of a direct correlation between whole thyroid dose and pulse and temperature rise. Hector Mackenzie, a London physician, referring to Murray’s injection method, pointed out its disadvantages (Mackenzie 1892):

 First, it requires the most scrupulous care in the preparation of the extract, the demand for which is never likely to be so great as to enable it to be supplied when manufactured under the ideal conditions at less than an almost prohibitive price, and few medical men have the time to devote to its preparation themselves. Secondly, the application of the remedy sometimes produces alarming immediate symptoms, such as loss of consciousness and tonic spasm; and remoter effects, such as indurated swellings and abscesses at the seat of injection, have followed the use of even the most carefully prepared extract. When it is remembered that these injections have to be personally administered for the remainder of the patient’s life by the medical attendant, these risks, however slight in regard to a single application they may appear, become immensely magnified when a long series has to be taken into account.

Mackenzie went into detail of his patient’s condition during a sequence of pre-treatment hospitalisations ‘In order that it may not be imagined that the effect [of treatment] could be attributed simply to residence in the hospital’. He recognised what he considered as an ‘overdose’ when his patient developed a tachycardia and pyrexia, and provided a nice graph relating dose to pulse and temperature. He gave thyroid with ‘a little brandy.’

After these reports, Murray changed to oral administration, although he preferred to use an extract whose potency he considered would be more constant, as he was by then preparing it from a pool of sheep’s thyroids. Nearly 30 years later, in a retrospective commentary on his first treated case, he calculated that over the 28 years of her treatment till her death, age 74, his patient had consumed around 5 litres of thyroid extract – initially by injection then orally – derived from some 870 sheep (Murray 1920). In this paper, he also mentions that, back in 1891, he had sought her consent to treatment: ‘The experimental nature of the treatment was explained, and the patient, realizing the otherwise hopeless outlook, promptly consented to its trial’.

Following Murray’s first paper, reviews of larger numbers of treated patients were remarkably quickly assembled, notably by Cecil Beadles and Byrom Bramwell, and the principles of treatment, to which we still adhere, were equally quickly established (Beadles 1893; Bramwell 1895).There was clearly no shortage of cases of myxoedema, underlining how astonishing it is that the condition should have escaped identification as a discrete and homogeneous pathological entity for so long. As the Clinical Society of London’s report put it: ‘For as cretins resemble one another so that they might be taken to be members of one family, so also do the subjects of myxoedema, most approximately in physiognomy, character of voice, and mode of speech’ (Clinical Society of London 1888). Both the efficacy and the risks of treatment with sheep thyroid had become clear without the carefully controlled trials that are needed for reliable detection of less obvious treatment effects. Beadles (1893) wrote that: ‘…this treatment is invariably followed by an improvement, by a rapid change in the appearance of the patient…there is a complete transformation, and the patient has ceased to be a patient, and appears a new individual’. Bramwell (1895) wrote: ‘The effects produced in cases of myxoedema by a relatively minute quantity of thyroid extract, the rapidity with which all the characteristic symptoms disappear, and the extraordinary improvement, both in the physical and mental condition, of sporadic cretins, are very remarkable’. Figure 3 shows photographs of a very advanced case of myxoedema in a 73-year-old woman under Bramwell’s care before treatment, something we never see today. We are told that after 3 months of treatment she looked decidedly better though had been troubled by diarrhoea, but 2 months later she died suddenly. Figure 4 shows photographs before and after only 2 months of treatment in a 4-year-old cretin. The photos were carefully taken to exactly the same scale and the dramatic improvement in appearance and height are obvious.

Bramwell advised that treatment should start with a small dose and, if necessary, be gradually and carefully increased; that too large a dose may be dangerous in the elderly and in patients with heart or arterial disease; and that treatment must be life-long, although he presciently commented that ‘…future observation may show that in some cases…the function of the thyroid gland may be temporarily arrested’. He emphasised that early diagnosis was of great importance in cretinism.

The advent of thyroxine and modern times

Thyroxine was isolated in 1915 (Kendall) (actually, on Christmas Day, 1914), its chemical structure determined in 1926 (Harington), and it was synthesised in 1927 (Harington and Barger). However, it took a long time before it was synthesized on a commercial basis. At first, 3 tons of pigs’ thyroids were needed to isolate just 33 grams of pure thyroxine. Even when thyroxine became commercially available from Glaxo in 1949, tablets of desiccated thyroid extract remained the principle source of treatment for many years.

Tri-iodothyronine (T3) was then identified, isolated and synthesised in 1952/53 (Gross and Pitt-Rivers), but, until relatively recently, used only in the management of myxoedema coma. This life-threatening complication of untreated hypothyroidism is now rarely encountered, but T3 has been advocated for use alongside thyroxine in the routine management of myxoedema. This is, however, controversial, as is the optimum dose of thyroxine and its place in so-called ‘subclinical’ or ‘compensated’  hypothyroidism.

One wonders what Murray and Bettencourt and their colleagues would have made of these nuances in treatment which have arisen since it became possible to assay serum thyroid stimulating hormone levels in 1965 and with ever-increasing sensitivity since then. In Murray’s day – he died in 1939 – the diagnosis of thyroid deficiency was made on purely clinical grounds and very mild cases will have been missed. All these developments since those days merit a more detailed account than lies within the scope of this paper.

Acknowledgements

I would like to acknowledge the indispensable and tireless help of Estela Dukan, library assistant at the Royal College of Physicians of Edinburgh, and Valerie McClure, assistant librarian at the Royal College of Physicians and Surgeons of Glasgow. I am grateful to Mira Gogova, archivist/conservator at the Royal Society of Medicine, for arranging access to the 1883 manuscript minute books of the Clinical Society of London. I am similarly grateful to Jackie Dunn, liaison assistant at the Robinson Library, Newcastle University, for supplying a copy of the minutes of the meeting of the Northumberland and Durham Medical Society on 12 February 1891. I very much appreciate the advice given on the Chinese contribution by Dr Vivienne Lo, senior lecturer, and Penny Barrett, specialist translator and honorary research associate, at the Wellcome Trust Centre for the History of Medicine. Mrs Gesa Walker kindly translated German texts and Tribunal Judge Janice Webster was a great help with the French material. I warmly thank them both. I am grateful to Iain Milne, librarian of the Royal College of Physicians of Edinburgh, who photographed the illustrative material. Finally, I would like to thank professor Ulrich Tröhler for his helpfully detailed critique.

This James Lind Library commentary has been republished in the Journal of the Royal Society of Medicine 2011;104:15-18, 59-63 and 100-106. Print PDF (59-63), print PDF (100-106)

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