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History of Cortisone at Mayo Clinic
Mayo Clinic evolved from the Rochester, Minnesota, frontier practice of Dr. William Worrall Mayo (1819-1911) and his two sons Dr. William James Mayo (1865-1939) and Dr. Charles Horace Mayo (1865-1939). Mayo Clinic established its research and diagnostic laboratories in 1907 at the urging of Dr. Henry Stanley Plummer (1874-1936), a “many-sided genius” and Mayo Clinic partner since 1901 who was interested, like the Mayo brothers, in diseases and pathophysiology of the thyroid gland. (1)
Dr. Louis B. Wilson, previously assistant director of the bacteriology laboratories at the Minnesota State Board of Health, joined Mayo in 1904. Dr. Wilson “worked out a method for staining fresh tissues that permitted him to do an analysis quickly enough to report to the Mayos while an operation was in progress. This was one of the key breakthroughs in the emergence of clinical pathology—that is, the use of pathology in medical practice rather than strictly for teaching and research.” (2) Dr. Wilson oversaw development of laboratories for clinical pathology, gastric analysis, general pathology, bacteriology, experimental surgery, biochemistry, photography, and necropsy. (3)
On February 1, 1914, Dr. Wilson invited 28-year-old Columbia University-trained biochemist Edward C. Kendall, PhD (1886-1972) to join the staff at Mayo to help isolate the hormone of the thyroid gland, among other projects. Near the end of the 19th century, Professor Eugen Baumann (1846-1896), a physiological chemist at the University of Freiburg, Germany, had prepared iodine-containing extracts of thyroid glands that were useful in treating clinical hypothyroidism. Baumann named his partially purified active principle “iodothyrin.” (4) By 1913, Dr. Kendall, a superb extractionist, purified the active principle about a hundredfold. By the end of 1914, Dr. Kendall successfully precipitated crystals of a pure compound named “thyroxin” (named by Dr. Arnold E. Osterberg, first research associate of Dr. Kendall) and later, “thyroxine,” because biochemists determined that thyroxin was an amino acid with an amine group (hence, the added “e”). (1) In 1926, Mayo Clinic closed its research on the chemistry of the thyroid hormone. (5)
As the Mayo Clinic biochemistry lab was wrapping up its thyroid hormone investigations, Dr. Philip Showalter Hench, MD (1896-1965) began his association with Mayo Clinic (1923) as assistant and three years later as head of its department of rheumatic diseases. Dr. Hench specialized in arthritic diseases and became deeply interested in why some of his patients with rheumatoid arthritis experienced remissions when they developed jaundice or became pregnant. (6) In fall 1929, the brilliant Hungarian physiologist-physician Dr. Albert Szent-Gyorgyi joined the biochemistry lab at Mayo Clinic for eight months as a visiting scientist. In Hungary, he had isolated small amounts of a compound, which he named “hexuronic acid,” found in the cortex of beef adrenal glands. Dr. Kendall provided Dr. Szent-Gyorgi with fresh beef adrenal glands from which Dr. Szent-Gyorgyi isolated large amounts of the same compound. Later researchers renamed hexuronic acid “vitamin C” and “ascorbic acid.” (7-9)
Dr. Szent-Gyorgyi initiated research on adrenal glands in Mayo Clinic biochemistry laboratories at about the same time Frank A. Hartman, PhD and Katherine A. Brownell, PhD at the University of Buffalo (10-12) and WW Swingle, PhD and JJ Pfiffner, PhD at Princeton University (13-15) were publishing their exciting findings on the life-restoring properties of adrenal cortical extracts in adrenalectomized cats. Indeed, Hartman and Brownell had named their extract “cortin” in 1927. (11) Mayo Clinic’s own Dr. Leonard G. Rowntree (he joined in 1920 as the second chief of medicine, Dr. Plummer was the first chief of medicine—there were two chiefs of medicine) obtained some of the Pfiffner-Swingle extract to treat a 39-year-old Mayo patient in Addisonian crisis on May 31, 1930. (16) The short case history follows: The patient was a farmer, aged thirty-nine years, and first came to the clinic in January, 1930. He had had pleurisy with effusion eleven years previously and symptoms of Addison’s disease had been present for eight months. He was in a critical state when admitted; he was in collapse, the systolic blood pressure was 78 mm of mercury, and the blood urea 48 mg for each 100 cc. Treatment was given with solutions of sodium chloride and glucose intravenously, and the Muirhead regimen* was instituted. The patient improved slowly; he was dismissed from the hospital thirty-nine days after admission. Progress at home on the Muirhead regimen was satisfactory for a while, but the patient was brought back to the clinic in a state of collapse, May 31. Treatment with solutions of sodium chloride and glucose was instituted again, with only partial success. The extract of the suprarenal cortex sent by Drs. Swingle and Pfiffner arrived on the sixth day after the patient’s admission to the hospital and treatment was begun with daily doses of 20 cc given subcutaneously. Within thirty-six hours a marked effect on appetite and strength was apparent. The patient, who had been so nauseated as to retain water with difficulty, now asked for wieners and sauerkraut and in lieu of the latter ate a double order of beefsteak with relish. This extract produced considerable local irritation at the site of injection and because of the content of epinephrine could not be given intravenously in therapeutic doses. A further supply of the extract was not available at that time; therefore the patient was put back on the Muirhead regimen. He did well for a few weeks, but gradually failed and again went into collapse, from which the timely arrival of a fresh supply of extract sufficed to insure temporary recovery. This cycle has been repeated three times in this case. The last time it was possible to use Swingle and Pfiffner’s newest extract, which is free from epinephrine. This was given intravenously in divided doses in a quantity of 20 cc daily with a total dosage of 50 cc. Before its use the patient was excessively weak, bedridden, depressed, nauseated, losing weight and showed evidence of failing circulation. Within forty-eight hours he had taken a new lease on life, his appetite was excellent, his strength was greatly improved and he appeared to be in a state of perfect health. He gained 9 pounds in weight in the next eight days and has been in good condition since then. (16) *What is the Muirhead regimen? Physician and Addison’s disease sufferer Dr. AL Muirhead, professor of pharmacology at the Creighton University College of Medicine in Omaha, is the namesake for the Muirhead regimen of “forced organotherapy.” (1920). (17) The method involved administration of epinephrine “hypodermically” and by rectum three times a day, and [dried] whole adrenal gland by mouth (or rectum) three times a day “in doses that represented his maximum tolerance.” The results gratified him but unfortunately lasted only a few months. Dr. Muirhead obtained the preparation of dried whole suprarenal gland and a similar preparation of whole pituitary gland from Dr. EM Houghton, director of the research laboratories of Parke, Davis and Company (Detroit, Michigan). (18) In 1933, Dr. Rowntree published a review article titled “Diseases of the suprarenal glands” in which he described twenty-three patients with Addison’s disease that he treated with cortical hormone, even though the hormone was exceedingly difficult to obtain because it was exceeding difficult to produce. Seventeen patients did well, three died at Mayo Clinic and three died in their homes. (19) Dr. Rowntree wrote, The disappearance of anorexia, the return of hunger, and the improvement in digestive functions are striking beyond all belief. The results in Addison’s disease suggest that the cortical hormone exerts a fundamental influence form the standpoints of hunger, of activity of the digestive tract, and of generation of muscular energy. The psychic effects are very marked and constitute new problems. Before the advent of this treatment our patients had not been eager to return to work but many of them under this treatment, have felt a keen desire to return to some occupation. The significant changes in laboratory and metabolic data resulting from the treatment are increase in the basal metabolic rate; gain in weight; improved renal function with disappearance of nitrogen, urca and sulphate retention in the blood; disappearance of creatinuria, and disappearance of achlorhydria [failure of the stomach lining parietal cells to produce hydrochloric acid]. (19-21) The growing Kendall group of investigators at Mayo Clinic needed a source of beef adrenal glands with which to conduct their research. By 1935, Parke Davis and Company provided large quantities of beef adrenal glands to the Kendall group in exchange for epinephrine (adrenalin), which Kendall and his associates separated, purified, and returned to Parke Davis. (22) The Wilson Laboratories of Chicago also supplied beef adrenal glands from the stockyards in exchange for bioassays on the adrenal cortical extract prepared for clinical use by the company. “For at least five years, the laboratory processed 900 pounds of beef adrenal glands every week” [italics added], wrote Ingle. (22) Tadeus Reichstein, PhD (1897-1996) was a German chemist who was working in Zurich, Switzerland, to identify the active compound(s) in adrenal cortex at the same time as the Kendall group in the early 1930s. Reichstein noted that of 1,000 kg (2,200 pounds) of adrenals from cattle, industrial extraction could produce only 1 kg (2.2 pounds) of dry residue. The “activity” of this dry residue extract could be concentrated to about 25 grams by careful distributive operations, without noticeable loss. Dr. Reichstein identified 29 steroids from the adrenal extracts, each closely related to the other. “Of these 29 steroids,” he wrote, “five were already known [i.e., cholesterol, alloprenanolone, progesterone, androstedione and oestrone]; they occur in other natural substances. The rest,” he said, were “characteristic of the adrenals. The difference between them is due mainly to the presence or absence of certain oxygen atoms and to the presence or absence of a double bond. Of these 29 steroids, 6 were biologically active in the sense that they prolong the life of adrenalectomized animals and are able to eliminate one or more of the deficiency symptoms.” (23) The names of the six biologically active adrenal cortex steroids identified by Reichstein are:
Of the six, he learned that DOCA had the strongest effect on the electrolyte and water metabolism (called mineralocorticoid effect) and cortisone and 17-hydroxycorticosterone had the strongest effect on carbohydrate metabolism (called glucocorticoid effect). (23) Reichstein published his findings in the German language in 1936. (24) In 1937, M. Steiger and T. Reichstein prepared 11-desoxycorticosterone by partial synthesis. Ingle noted that Dr. George W. Thorn (1906-2004), a pioneer in Addison’s disease, then of Johns Hopkins Hospital, found this steroid to be highly potent in sustaining the life of adrenalectomized animals and of patients with Addison’s disease. (25) Meanwhile, Mayo biochemists worked furiously in Kendall’s lab to separate 28 different compounds from beef adrenal cortex. (26) Four compounds, A (11-dehydrocorticosterone), B (corticosterone), E (17-hydroxycorticosterone), and F (cortisone or hydrocortisone), were of interest because they possessed glucocorticoid properties, which restored carbohydrate metabolism and the ability of muscles to contract in adrenalectomized animals, while other steroids isolated from adrenal cortex possessed mineralocorticoid properties, which did not.
Around 1935-1936, Dr. Kendall began supplying adrenal cortical extract to Mayo Clinic physicians to treat patients with various diseases, according to Ingle. (22) Adrenal cortical extracts “were generally available from commercial sources, but large amounts were required to restore a patient with Addison’s disease to normal vigor; no patient could afford to purchase all of the cortical extract needed,” wrote Ingle. (22) However, Dr. George Thorne (noted above) told JFK biographer Robert Dallek, PhD, in 1991, “We always had adrenal extract for those who could afford it.” (27) Dr. Thorn obtained his steroids from the Mayo group, wrote Ingle. (28) Dr. Philip Hench, the Mayo rheumatologist noted earlier, was one of the clinicians at Mayo Clinic who began to collaborate with Dr. Kendall. He observed that patients with rheumatoid arthritis sometimes went into remission when they became jaundiced or pregnant. “He postulated that some humoral substance formed during jaundice and pregnancy [was] responsible for the remission.” (29) In January 1941, he wanted to test Compound E (cortisone) for a possible effect on rheumatoid arthritis but there was insufficient amount yet available for clinical investigation. Instead, he administered “cortin” (adrenal cortex extract) to three patients with rheumatoid arthritis, “without impressive results,” he wrote. (30) He then “produced in a few arthritis volunteers jaundice induced by the oral use of lactophenin after the method of Hanssen. Temporary remissions were induced but we could not identify the agent,” Dr. Hench continued. Eight years later, in 1948, Merck and Company completed the first large-scale synthesis of cortisone (Kendall lab’s compound F). Dr. Hench obtained a small supply from Drs. Randolph Major, Vice President, and James Carlisle, medical director of Merck & Company in September 1948. On September 21, 1948, Drs Hench, Kendall and Dr. Charles Slocumb administered the crystalline suspension of cortisone acetate in saline solution (100 milligrams, to avoid underdosing) to a woman with rheumatoid arthritis. Within three days the patient was markedly improved and continued to improve until the daily dose was reduced to 25 milligrams. (30) Note that cortisone is about one-fifth the potency of prednisone. Dr. Hench also administered to some of his rheumatoid arthritic patients ACTH (adrenocorticotropic hormone), which he obtained from Dr. John R. Mote, then director of laboratories of Armour & Company.In May 1949, cortisone became available in oral form (Upjohn). (31)
Dr. Hench noted with dismay that patients experienced relief of their symptoms only as long as he gave cortisone or ACTH. When he discontinued the drug, they suffered relapses, usually within one or two months, and occasionally more promptly and severely. (32) He also learned about the undesirable effects of cortisone and ACTH. The doses required to put rheumatoid arthritis patients into remission are relatively high compared with doses required for people with Addison’s disease or “Addison’s insufficiency.” The side effects noted by Dr. Hench among his patients included mild irritability with increased psychomotor activity; an initial retention, generally mild, of sodium chloride and water, producing fluctuant weight with or without visible pretibial edema; mild hypertrichosis [hair growth]; facial acne; and rounding of the face (“moon” facies”). Thus, he recommended that cortisone and ACTH always needed to be used with caution. Indeed, a continued high dosage of cortisone could induce Cushing’s syndrome. In 1950, Drs. Kendall, Hench, and Reichstein shared the Nobel Prize in Physiology or Medicine for “their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.” (33) Notes:
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