Corticosteroids, despite their well-recognized adverse effects, are an essential component in the treatment of many types of autoimmune and other inflammatory conditions.
The discovery of cortisone more than sixty years ago inspired a wealth of endocrinologic and immunologic research and indelibly linked, often with a “love-hate” aspect, the study of hormones to the study and treatment of immune-mediated diseases. The most prominent figure in this scientific milestone in early stages of this research was Philip Showalter Hench, a clinician who was widely recognized for his oratory skills and meticulous clinical research. Philip Showalter Hench was born, raised and educated in Pennsylvania. He enlisted in the medical corps of the US Army upon graduation from Lafayette College and went on to receive his MD degree from the University of Pittsburgh in 1922. By 1928, he was head of the Mayo Clinic’s first rheumatic disease center in Rochester, Minnesota. In 1942, Hench reentered military service and was appointed Chief of the Medical Service and Director of the Army’s Rheumatism Center at the Army and Navy General Hospital. He left the medical corps in 1946 and became expert consultant to the Army Surgeon General, holding the position of Professor of Medicine at the Mayo Foundation until his death in 1965. His greatest contribution to modern medicine was the discovery of cortisone as a symptomatic treatment of rheumatoid arthritis (RA) .
Early in his study of patients with RA, Hench pointed out that symptoms of the disease were frequently extraordinarily ameliorated by several conditions. Between 1929 and 1938, Hench studied over thirty cases of RA that improved dramatically with the onset of unrelated jaundice and experimented with various liver compounds in an effort to iatrogenically induce the same anti-inflammatory effects [2,3]. Unfortunately, these efforts failed, and Hench’s attention turned to other possibilities. In the course of his research, he observed that RA symptoms and signs frequently improved impressively during pregnancy, infection, and the postsurgical state [1,3]. Thus, he hypothesized that these conditions altered levels of a common endogenous substance, such as a hormone.
With the advent of new research and therapeutic attempts, Hench came to suspect a role for the adrenal glands. In 1936, Hans Selye began to publish on the subject of the general adaptation syndrome, a reaction to non-specific stressors, culminating in glucocorticoid release from the adrenals and systemic glucocorticoid effects . Hench’s colleague and friend John Glyn remembers, “At the same time, rheumatologists were beginning to appreciate the non-specificity of the treatments they were routinely recommending. Any surgery seemed to result in temporary improvement. Even the giving of anesthetic alone, or the induction of artificial hyperpyrexia, could result in temporary remissions” . Such procedures could represent Selye’s non-specific stressors and lead to glucocorticoid secretion, in turn improving RA symptoms. Furthermore, Addison’s disease, a disease of the adrenal glands, could be treated with an extract of animal adrenals, and Hench had long observed similarities in the clinical presentation of RA and Addison’s disease – marked fatigue and hypotension were common to both [1,3]. Thus, Hench turned to Edward Kendall’s substantial work on adrenal hormones for clues to his mysterious therapeutic agent.
Kendall, a basic scientist, had by 1936 painstakingly isolated several steroid compounds from bovine adrenals, of which Compound E, 17-hydroxy-11-dehydrocorticosterone, was most effective in prolonging the life of adrenalectomized animals . However, production from animal organs was expensive, laborious, and low-yield, and funding for further investigations lagged .
Research into human use of adrenal extracts was propelled into the forefront again when the U.S. entered World War II in 1941. Rumors that German pilots were using the hormones to improve combat effectiveness incited a frantic quest to further characterize the active substance [1,2,7]. Efforts to synthesize dehydrocorticosterone in the laboratory persisted even after the rumor was discredited, and in 1946 Lewis Sarett of Merck published the synthetic pathway from desoxycholic acid .
Finally, compound E, now cortisone, could be produced in sufficient quantities and distributed to researchers, including Hench. September 21, 1948 marked the beginning of a new era of medicine, when the first patient with rheumatoid arthritis was injected with cortisone [1,2,7]. The woman, crippled and wheelchair-bound for over five years, regained full function within four days of treatment. She could now walk, suffering no muscular soreness or stiffness. The following thirteen patients experienced similarly astounding improvements with cortisone injections, and administering corticotropin seemed to work equally well [1,7]. Soon, news spread to the scientific community and the media, and cortisone began to be touted as the new “miracle cure” .
A flurry of research suggested that cortisone was effective in treating asthma, various allergic conditions, eye inflammations, systemic lupus erythematosus, polyarteritis nodosa, and others . In 1950, Hench, Kendall, and Reichstein (who had independently isolated cortisone) were awarded the Nobel Prize for Medicine and Physiology in recognition of their seminal contributions [3,7].
Despite these wide-ranging successes, Hench was aware from the very beginning that cortisone was not a cure but provided symptomatic control. As he said of cortisone and corticotropin, “they appeared to act, not by removing the causes of the diseases responsive thereto, but by suppressing in large measure the reactions of the tissues to the irritating agents. Although the hormones influenced greatly the reversible part of these diseases, the pathologic physiology (the “fire,” the active inflammation which causes symptoms), they exerted no influence on the irreversible part, the pathologic anatomy or residual ‘ashes’” .
It became evident very quickly that patients always suffered relapse when steroid treatment was withdrawn, and numerous dangerous side effects appeared with chronic use. Harvey Cushing had in 1932 described the clinical features of hypercortisolism stemming from a corticotropin-secreting pituitary tumor . The systemic side effects caused by cortisone treatment were identical, and even today, exogenous corticosteroid administration is the most common cause of Cushing’s syndrome. Classic cushingoid features include central obesity, moon facies, weakness, hirsutism, hypertension, glucose intolerance, osteoporosis, neuropsychiatric problems, amenorrhea, striae, and bruising. Thus, not only were the side effects uncomfortable and cosmetically unpalatable, they could lead to severe illness as well.
Over the next decade, various corticosteroid analogs were manufactured in an effort to improve anti-inflammatory properties and reduce undesirable side effects. These drugs, prednisone, prednisolone and dexamethasone, are still in use today. The mechanisms that underlie the potent anti-inflammatory and immunoregulatory effects of the agents continue today to be a focus of intense research, but the undesirable adverse effects of these agents as a therapy is deeply appreciated. Despite the diversity of perspectives on corticosteroids, Phillip Hench was undeniably a critical figure in the history of neuroimmunoendocrinology. Aside from the obvious discovery of cortisone as a pharmacological agent, as noted by Le Fanu, Hench “opened the way to the understanding that many illnesses share the unifying feature of being caused by uncontrolled or excessive inflammation” . Corticosteroids, both endogenously produced and exogenously administered, play a key role in checking dysregulated inflammatory processes.
D Broadway – F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
R Wilder – PAREXEL International, Durham, NC 27713
- Lloyd M. Philip Showalter Hench, 1896-1965. Rheumatology 2002; 41: 582-84.
- Le Fanu J. 1949: Cortisone. In: Le Fanu J, ed, The rise and fall of modern medicine. New York: Carroll & Graff Publishers, Inc. 2000; 16-25.
- Glyn J. The discovery and early use of cortisone. J Royal Soc Med 1998; 91: 513-17.
- Selye H. A syndrome produced by diverse nocuous agents. Nature 1936; 138: 32.
- Hench PS. Cortisone, hydrocortisone and corticotropin; some facts and speculations with special reference to rheumatoid arthritis. Trans Assoc Life Insur Med Dir Am 1951; 35: 5-33.
- Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital 1932; 50: 137-95.
- Hillier SG. Diamonds are forever: the cortisone legacy. J Endocrinol 2007; 195: 1-6.
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