Remsen Lecture
Cortisone EDWARD C. KENDALL, Division of Biochemistry, Mayo Foundation, Rochester, Minn.
First to isolate cortisone, the author tells its story and predicts it will reveal more secrets of the adrenal cortex τ ÎLE adrenal cortex is the last of the ductless glands to yield its secrets to t h e investigator. I t was shown to b e essential to life before anything was known about t h e chemical nature of its hormones, but even after these had been separated in crystalline form and their chemical structure had been established, t h e role of the adrenal cortex in health and in disease remained obscure. T h e availability of desoxycorticosteronc acetate, made by Steiger and Reichstein, in 1937 provided an answer to t h e problem of control of the metabolism of electrolytes and water, but even after t h e use of this hormone some patients were only partially relieved and others died. It then became evident that something more was furnished by the adrenal cortex, and further study indicated that this agent was one or more of the crystalline hormones which had been isolated from the adrenal cortex. The results of investigation of t h e adrenal cortex by Wintersteiner and Pfifiner, Reichstein and his associates, and by my laboratory furnished no less than 2S crystalline compounds from which to choose, but physiologic investigation on small animals soon reduced the choice to four of these compounds. These were designated in my laboratory by the letters A, B, E, and F . All were dcr' stives of Δ'-pregncne and differed one from t h e other only by the number and position of hydroxy! and ketone groups attached to positions 11 a n d 17. No sharp qualitative difference was found between the physiologic activity of these four compounds on adrenalectomized animals, and it was assumed that any one of them could b e used in substi tution therapy for patients who had Ad dison's disease. Unfortunately, the supply of these four hormones was so limited that it was impossible to carry out an investigation o n t h e h u m a n being. However, i t was clearly evident that there was a m a r k e d qualitative difference between desoxycorticosterone acetate a n d compounds A, B, E, and F . No amount of the former would produce t h e typical effect exerted by a small amount of t h e latter four compounds. T h e most significant physiologic prop erties of compounds A, B, E, a n d F w e r e their strong effect on the metabolism of carbohydrate and protein and their rather 2074
mild influence on the metabolism of water and electrolytes. These two tyrpes of physiologic activity were clearly recog nized and were associated with the chemi cal structure of these hormones some time before 1940. There was speculation that compounds A, B, E, and F would b e of value for substitution therapy in Addison's disease, and there was hope that they would be useful in the treatment of shock, trau matic injuries, burns, and some types of infection; but beyond this there was no place for any product of the adrenal cor tex in clinical medicine. T h e prospect that the hormones of the adrenal cortex would have b u t limited application dis couraged the commercial production of these compounds which would have made them available for study in clinical medi cine. Work Begun in 1941 However, World W a r II furnished a great stimulus to the large-scale produc tion of these hormones, and at the request of the National Research Council a group of chemists who were interested in steroids carried out investigations with t h e hope that these substances could b e produced on a commercial scale. At a conference held in October 1941, it was decided first to make compound A, 11-dehydrocorticosterone. However, merely to make compound A was not the objective; Reich stein and his associates did this in 1943. It was necessary to devise a method which could be used to prepare this hormone on a large scale. This was done in my labo ratory in 1944, and in 1945 Merck & Co., Inc., prepared a large sample by our method. In the first months of 1946 it was tested on laboratory animals and was found to behave exactly as did compound A, sepa rated from t h e adrenal cortex, b u t when given to patients w h o h a d Addison's dis ease it was found to be of little value. Interest in t h e hormones of the adrenal cortex sank to a very low level. In 1946 there was no conclusive evidence that compound Ε was qualitatively different from compound A, a n d there was there fore no assurance t h a t large-scale produc tion of compound Ε was worth while. Under these circumstances Merck & Co., Inc., adopted a course which was a com promise. They decided to make a small CHEMICAL
sample of compound E . A n important reason for this decision was t h e fact that in 1946 L. H. Sarett, working in the re search laboratory of Merck & Co., Inc., had prepared a few milligrams of com pound E, b u t t h e yield was so small that t h e method Dr. Sarett used could not he applied to large-scale production. During the following 18 months im portant improvements of some of the steps in the preparation of compound A were devised in my laboratory, and Dr. Sarett discovered an entirely new pro cedure to convert a product closely re lated to compound A into compound Ε b y introduction of a hydroxyl group at C-17. T h e final yield of compound Ε was raised nearly a hundredfold. In April 1948 a few grams of com pound Ε acetate were at h a n d , and it seemed advisable to Merck & Co., Inc., to hold a conference with a group of clini cians to consider how t h e material should b e used. This conference marks the alltime low point in the fortunes of com p o u n d E. Some confidence in the \'alue of compound Ε in the treatment of Addi son's disease w a s expressed, h u t for the most part it was feared that compound Ε would take a place a m o n g discarded drugs, right beside compound A. Merck & Co., Inc., h a d decided that unless some wide demand for compound Ε developed, they would not make more of this hor mone. T h e months from April to October 1948 are perhaps the most interesting period in t h e development of the clinical applica tion of compound E—not because of w h a t was done b u t because of w h a t was not done. T h e situation during that period furnishes good evidence for our lack of information concerning the function of t h e adrenal cortex. At that time, had any one suggested that compound Ε should b e administered to patients who had rheumatoid arthritis, he would have been asked to state the rationale for such a seemingly irrational proposal. I know this to be true from actual experience, and I also know that w h e n Philip S. Hench a n d I attempted to state a rationale, t h e re sult was not too impressive. Nevertheless, there was at least a theoretical basis for t h e suggestion that compound Ε might relieve the symptoms of rheumatoid arth ritis. This disease has been considered to b e AND
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relentless and progressive, with death t h e only avenue of escape from pain and d e formity, b u t in 1929 and 1931 Dr. Hench m a d e two observations which led him to believe that it is potentially reversible. T h e first was that during a n attack of jaundice the painful symptoms of r h e u matoid arthritis frequently are relieved for a period which varies from a few weeks to several months or even years. T h e second observation was that during t h e months of pregnancy women w h o have arthritis frequently are relieved of symptoms of the disease. Dr. H e n c h a n d I have had many con ferences on the probable cause and treat ment of rheumatoid arthritis, and at such a meeting in January 1941 we reached the decision that compound Ε should be employed for patients wbo had rheuma toid arthritis. T h e reasons why we be lieved that compound Ε should be tried have been given elsewhere, and I shall not repeat them here. It is not an exaggeration to say that the successful investigation of compound Ε was assured w h e n we decided to grind t h e crystals to a fine powder, to use 100 mg. for the daily dose, and to inject the material intramuscularly. Intramuscular injection ensured a slow absorption con tinued over many hours, a condition which simulated the m o d e of release of the hormone from t h e gland. On Sept. 21, 1948, C. H. Slocumb of the Mayo Clinie injected 100 m g . of compound Ε intra muscularly into a patient who h a d rheu matoid arthritis. Throughout t h e winter
of 1948-49, 1 5 more patients received t h e hormone, a n d in the spring five patients who h a d r h e u m a t i c fever w e r e given compound E . T h e effect of c o m p o u n d Ε on r h e u m a toid arthritis a n d rheumatic fever has been widely publicized. Most of you already k n o w that the effect w a s obvious in all patients w h o h a d either disease. I have not heard of a single exception. These results in t u r n suggested that compound Ε might influence t h e so-called collagen diseases. Prominent among these are lupus erythematosus, psoriasis, p e m phigus, and conditions associated with allergy, such as asthma and hay fever. When c o m p o u n d Ε was given t o patients who h a d these diseases, encouraging re sults were obtained. Confusion with Vitamin Ε I n t h e minds of some people c o m p o u n d Ε and vitamin Ε seemed to b e closely related, and for this reason it was desir able to assign a distinctive n a m e to com pound E. Dr. H e n c h a n d 1 therefore chose t h e w o r d "cortisone," w h i c h was derived by deletion of certain letters from 17-hydroxy-11 -dehydrocorticosterone. T h e first s a m p l e of cortisone w h i c h was used in rheumatoid arthritis was m a d e by a m e t h o d not devised in any one labo ratory. T h e conversion of desoxycholic acid into cortisone requires five altera tions. One of these was devised b y Miescher a n d his associates in t h e labora tories of Ciba a n d Co., Basel, Switzerland. Three of t h e alterations were developed
Κι Λ! J» « Ί . Ι Ι
COMPOUND S
in my laboratory and the r e m a i n i n g o n e introduction of a hydroxyl group a t C-17 —was discovered by Dr. Sarett in t h e research laboratories of Merck & Co., I n c . Dr. Sarett's m e t h o d for t h e introduction of a hydroxyl group at C-17 was discov ered in the summer of 1947, and of sev eral essential contributions t h i s was t h e most important one w h i c h m a d e cortisone available for use in clinical medicine in 1948. T h e method is satisfactory from the standpoint of yield a n d is free of technical difficulties; however, it does reciuire osmium tetroxide i n stoichiometric, not catalytic, amounts, a n d this is an objectionable feature. A l l traces of t h e expensive r e a g e n t must b e recovered, a n d although this c a n b e d o n e i n small-scale production, t h e r e comes a time w h e n recovery of osmium will set a limit to t h e rate of production of cortisone. Osmium is not only expensive; it is also scarce. For this reason, a n d i n t h e h o p e t h a t still higher yields could be obtained by some other p r o c e d u r e w h i c h did not use osmium, a study of m e t h o d s for intro duction of the hydroxyl group a t C-17, which was b e g u n in 1 9 4 6 i n my labora tory, has b e e n continued. Recently we have m a d e substantial progress, HIKI al though this is not t h e occasion o n which to present n e w work in d e t a i l , I shall out line t h e s e q u e n c e of steps (Figs. 2 and 3 ) . T h e ultimate usefulness of the method must await m u c h further investigation. Cortisone is a powerful tool with which it is possible t o study p r o b l e m s related both to etiology a n d t o treatment of a
DESOXYCORTIXOSTERONE (DCA)
AMORPHOUS FRACTION H 2 C-OH C=0
V O L U M E
2 8,
NO.
25
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» JUNE
19,
1950
2075
H2Ç-OAC
