Perspectives in Biology and Medicine

CORTISONE THERAPY: A CHALLENGE TO ACADEMIC MEDICINE IN 1949-1952 G. HETENYI, JR.,* and J. KARSHt On September 21, 1948, at the Mayo Clinic in Rochester, Minnesota, Charles Slocumb and Philip Hench injected 50 mg of a "new" steroid— Compound E, first isolated by their biochemist colleague Edward Kendall from adrenal glands 12 years ago—into a young woman suffering from acute rheumatoid arthritis. The injection was repeated in the afternoon and twice again on the 22nd. By the 23rd the patient conspicuously improved and within a week the remission was near complete [I]. A Discovery in the Post-World War II Era The circumstances of the discovery reflect the era in which it was made [2] . In the years following the second World War, medicine and in particular medical science were imbued with postwar optimism. The thrill created by advances in cell biology, biochemistry, immunology, and physiology inspired physicians to put the new knowledge into practice and stimulated patient-oriented clinical research more than ever before or since. Academic physicians studied their patients on the ward and tried to account for their clinical observations and discover a therapy. This close link between the wards and the laboratory raised potential dilemmas. Obviously, the wellbeing of the patient was the supreme concern. But attempts to learn more about the disease and the search for a cure were sometimes "audacious" [2]. There were no formal institutional ethics committees to advise. Ethical problems were considered at rounds and discussions by staff, often including the patient. This atmosphere encouraged research, and real breakthroughs were achieved. What was the rationale for the new therapeutic trial? Today, a half cen- * Department of Physiology, University of Ottawa tDepartment of Medicine, University of Ottawa Correspondence: 417 Crestview Road, Ottawa, KlH 5G7 Canada.© 1997 by The University of Chicago. All rights reserved. 0031-5982/97/4002-0995101.00 426 G. Hetenyi andJ. Karsh ¦ Cortisone Therapy tury later, it may appear to be tenuous. Hench observed in 1929 that rheumatoid arthritis often improved during pregnancy or in patients withjaundice . He concluded that rheumatoid arthritis is a reversible condition and "may represent some basic biological disturbance, which is transiently corrected by some incidental biological change common to a number of apparently unrelated events" [3]. He thought that pregnancy or jaundice were nonspecific stimuli for the release ofsome hypothetical antirheumatic substance X. After several disappointing trials to identify substance X, by transfusion ofblood from pregnant women or patients withjaundice, iatrogenically induced icterus and female gonadal hormones (steroids!) among others, his attention was turned to the adrenal gland, because it was found that arthritis may improve after surgery or anesthesia, both known to stimulate the secretion of adrenocortical steroid hormones. Compound E had been considered to be substance X in 1941, but was not available in any clinically useful amount. Why was there any interest at all in Compound E? During World War II there was a rumor that German scientists had isolated an adrenal cortical hormone that increased the tolerance of combat pilots to low ambient oxygen pressure and was also useful in the treatment of traumatic shock [1, 4, 5] . Some even believed that German submarines carried large amounts of beef adrenal glands from Argentina to Germany [1] . By the end of the war the military in the United States had supported nine major contracts dealing with adrenal steroids, six of these specifically with respect to Compound E [6] , which had been isolated by Kendall and also by Reichstein in Switzerland, from the adrenal in 1936. It was one of the 28 steroids isolated from the adrenals [7]. After the war Merck and Co. decided to continue work on Compound E because of its potency in preserving the life of adrenalectomized animals. Partial synthesis from desoxycholic acid was achieved in 1946 by L. H. Sarett in the laboratories of Merck and Co. It was the most complicated synthetic process of any steroid known, mainly because of the difficulty in achieving the hydroxylation at the eleventh Catom of the steroid molecule. The yield was low, even after improvements had been introduced by Sarrett early in 1948 [4]. By this time Merck had already invested some $14 million in Compound E and became...