In July, 1891, George R. Murray (1865–1939), then a young physician 26 years of age in Newcastle-upon-Tyne without a hospital or medical school appointment, reported his successful treatment of a single case of a woman with myxoedema, a previously incurable disorder, to the British Medical Association assembled in Bournemouth, England. He told them of what was to them a revolutionary new approach, the injection of sheep thyroid extract, and of the conspicuously clear-cut improvement in the patient’s condition (Murray, 1891).
Murray had good reason to try this apparently odd therapy—the injection into a human of a glycerine-phenol extract of a common farm animal. His mentor, Victor Horsley (1857–1916), had helped show that it was the lack of the thyroid gland that produced the myxoedematous condition—we now, of course, call it hypothyroidism—and that the condition was common to patients with cretinism, those who had had thyroidectomy, and patients with spontaneous myxoedema with an atrophic, fibrotic thyroid gland.
Horsley had investigated the problem of the causation of myxoedema through much of the 1880s and had done the first experimental thyroidectomies to show that clinical hypothyroidism follows upon the removal of the thyroid gland. His work then was done as part of a multi-faceted investigation instigated by the Clinical Society of London. The result of the investigation, done by a committee whose work took 5 years to complete, became the famous Myxoedema Report (more properly, chaired by William Ord (1834–1902), the Report is entitled the Report of a Committee of the Clinical Society of London nominated December 14, 1883, to Investigate the Subject of Myxoedema) (Ord, 1888).
The Committee’s findings were presented on Friday, May 25, 1888, to the Society at its last meeting of that academic year. Usually sparsely attended, there was a crowd as the results had been suspected for some time by those who were following the problem. The interest the cause of myxoedema was not just local. This peculiar adult disease, though clinically rare, aroused interest not just because it resembled in some ways the ancient disease, cretinism, but also because its understanding might shed some light on the role of the thyroid gland, heretofore an organ with no known function. The results had even been bruited in the United States 3 years before when William Osler (1849–1919), the preeminent diagnostician of his time, wrote anonymously in the Medical News that “It seems reasonable to attribute these various conditions—cretinism, myxoedema…, and cachexia strumipriva [the name that had been given to the clinical state following thyroidectomy]—to disturbance or arrest of the functions of this gland.” ([Osler], 1885). There was further interest from the United States: present in the audience on that day in 1888 was Fordyce Barker (1818–1891), a peripatetic New York gynecologist who travelled to Europe every year to learn the latest in medicine and surgery.
The Committee’s final conclusions stand today: “a general review of symptoms and pathology leads to the belief that the disease described under the name of myxoedema, as observed in adults, is practically the same disease as that named sporadic cretinism when affecting children; that myxoedema is probably identical with cachexia strumipriva; and that a very close affinity exists between myxoedema and endemic cretinism.” The Committee also noted that “while these several conditions appear…to depend on…destruction or loss of the function of the thyroid gland, the ultimate cause of such destruction or loss is at present not evident,” a comment that is largely true even today.
The Committee’s results were rapidly picked up in the United States. Notes, abstracts, or editorials commenting on the Committee’s work appeared in medical journals published in New York City, Philadelphia, Cincinnati, and Indianapolis, some within a month of the Committee’s final presentation. However, the Committee, despite its modern-sounding and ultimately accurate conclusions, offered nothing substantial in the way of therapy; they specifically did not connect thyroid deficiency with any suggestion of thyroid replacement. Nor did any of the commentators.
Some in the 1880s had tried implantations of thyroid tissue in animals or humans in an attempt to overcome the deleterious effects of the gland’s removal. Moritz Schiff (1823–1896), an Italian and Swiss physiologist, tried to prevent death in dogs after thyroidectomy by implanting part of a dog’s own thyroid gland into its abdomen. And Theodor Kocher (1841–1917), the famous Swiss surgeon and the only person to win a Nobel Prize for studying the thyroid gland, also tried the same in man after thyroidectomy with little success. Neither had any real understanding of what the gland did and their procedures were really “shots in the dark.”
The year after the Myxoedema Committee’s report, in 1889, the Parisian physiologist and physician, Charles-Édouard Brown-Séquard (1817–1894), who was then in his 70s, startled the medical world with his announcement that testicular extracts from dogs and guinea pigs, injected into an older man with failing powers, i.e., himself, brought about a reversal of some of these deficiencies (Brown-Séquard, 1889). In a matter of months, this therapy—now called organotherapy—was extended to extracts of other organs for the treatment of manifold diseases. As it happens, Brown-Séquard never did try thyroid extracts for myxoedema and we now know that his organotherapy’s effects were largely those of a placebo. But at that time organotherapy, though it was viewed with suspicion by some, was well-regarded and accepted by many respectable physicians, including practitioners in the United Kingdom and the United States. The therapy spread through the Western medical world from the United States to Russia.
At the same time in 1889 and 1890, after the Committee’s Report, there were further efforts at transplantation—we would call them implants—of thyroid glands from sheep or monkeys into patients with hypothyroidism, now with a clearer rationale. Although by 1890 Horsley himself was a strong advocate of this approach to therapy for hypothyroidism, he seems not to have tried it himself but urged others to do so (perhaps the rarity of the disease or his burgeoning interest in neurosurgery got in the way). In any case, such implants were tried in France, the United Kingdom, and Switzerland with varying success. there were occasional claims of true vascular connections after these implants but overall the results were sketchy at best. Sometimes there was a transient effect, the disappearance of which was put down to the disintegration of the implant.
About this time, in 1890, Murray advanced his mentor’s (Horsley’s) idea of treatment by implant by suggesting that injection of a thyroid extract could accomplish the same thing, i.e., remission of the symptoms of hypothyroidism. Admittedly, injections would have to be more or less continual as opposed to a single permanent therapy. Horsley was not too supportive but told Murray that it was worth a try. Murray was ridiculed by his own local medical society in Newcastle but went ahead after his father, a respected local practitioner, referred to him a patient with myxoedema. In the spring of 1891, he made his crude extract by simply mincing a sheep’ thyroid gland in glycerine, adding a few drops of phenol (as a disinfectant), letting the mixture sit for a it, straining the result through cloth. He then injected the pinkish liquid under the patient’s skin with a hypodermic syringe. Benefit was apparent in a few weeks. There was a cure for the incurable.
Murray knew that, with single case, he had to be cautious. However, probably in the late spring of 1891, Horsley had read of another case treated by sheep thyroid implant. The difference in this case was that the authors had concluded that, because the transient benefit had had such a rapid onset, the benefit must have been due to resorption of thyroid juice from the implant and not from the generation of true vascular connections. The authors, Antonio-Maria Bettencourt-Rodrigues (1854–?) and José-Antonio Serrano (1851–1904) of Lisbon had presented their patient almost a year before in August, 1890, at the annual meeting of the French Association for the Advancement of Sciences in Limoges. One can assume an influence of Brown-Séquard in the authors interpretation of their results. Horsley read only the French abstract (Bettencourt et al., 1890)—after Murray’s success but before Murray had either presented it to an audience or published—and quickly wrote to Murray that he should “publish at once.” And so Murray published. Murray was widely and justifiable credited with a major advance in therapy, one that put Brown-Séquard’s organotherapy on a much firmer footing (most had not yet realized that organotherapy as then practiced was mostly placebo).
What Horsley had not done was read Bettencourt and Serrano’s complete paper which was published in early 1891 in the proceedings of the Association’s meeting. There they not only noted that benefit was likely due to absorption of thyroid juice but also stated that, when they returned home to Lisbon, they planned to treat their next patient hospitalized with this disease with hypodermic injections of glandular juice (“…chez une autre malade, atteinte aussi de myxoedème et actuellement à la ‘Maison de santé,’ nous nous proposons d’essayer les injections hypodermiques de suc glandulaire.”) (BettencourtRodrigues, et al., 1891). Their presentation in Limoges in the summer of 1890 was only a proposal but the proposal was exactly the same as Murray’s, conceived later that same year (1890) but unknown to him or, apparently, to anyone else in England.
Bettencourt and Serrano did in fact find a patient after they returned to Lisbon and proposed the therapy. She initially refused to have this strange treatment but, after she became worse a few weeks later, she agreed. Bettencourt reported their results to the Lisbon Society of Medical Sciences on November 15, 1890 (“…after four or five injections…the patient…experienced notable improvement; the sensation of cold in the dorsal region disappeared, her movements are easier, and she sleeps well. The menstrual periods are now regular, and the areas of alopecia have disappeared.”) (Bettencourt-Rodrigues, 1890).
However, there was little notice of their report; it was published only as a note in the proceeding of the Society and, as it was in Portuguese, few outside Portugal saw it. Murray’s report, also of a single patient, was, as Horsley suggested, published at once; acclaim arose and Murray’s reputation was made for the rest of his life. It is clear that, whatever might be the issue of priority, so dear to competitive scientists, the idea of how one might treat hypothyroidism was “in the air” as a result of the confluence of the Myxoedema Report and Brown-Séquard’s therapy in the minds of European clinicians. Treatment of hypothyroidism with thyroid extract, bizarre though it may have seemed at the time, was in fact the first successful endocrine therapy and helped establish endocrinology as a discipline.
Bettencourt A-M, Serrano J-A: Un cas de myxoedème traité par la greffe hypodermique du corps thyroïde d’un mouton. Sem Medicale 1890; 10:294.
Bettencourt-Rodrigues A-M, Serrano J-A: Un cas de myxoedème (cachexie pachydermique) traité par la greffe hypodermique du corps thyroïde d’un mouton. Comptes Rendus de l’Association Française pour l’Avancement des Sciences. Compte Rendu de la 19me Session, Limoges, 1890. 1891; part 2: 683.
Bettencourt-Rodrigues A-M; Communicaçöes scientificas. J Soc Sci Med Lisboa 1890; 15:114.
Brown-Séquard C.-É: Des effets produits chez l’homme par les injections souscutaneés d’un liquide retiré des testicules frais de cobaye et de chien. C R Soc Biol 1889; 41:415.
Merklen P: Sur un cas de myxoedème amelioré par la greffe thyroïdienne. Bull Mém Soc Méd Hôp Paris 1890; 7:859.
Murray GR: Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. BMJ 1891; 2:796.
Ord WM, et al.: Report of a committee of the Clinical Society of London nominated December 14, 1883, to investigate the subject of myxoedema. Trans Clin Soc Lond 1888; 21(Suppl.).
[ Osler, W. ] The thyroid gland and myxoedema. Med News 1885; 46:381.