When cortisone was first reported to produce dramatic beneficial effects in patients with rheumatoid arthritis in 1949(1), its use was welcomed as a major advance in medical therapy. The fact that it was a normal hormone, the only hormone that is absolutely essential for life, and that it also produced similar dramatic beneficial effects in patients with other autoimmune disorders, in those with chronic allergic disorders, and in those with many other illnesses, resulted in its discoverers being awarded the Nobel Prize. Yet within a few years patients receiving cortisone or its derivatives had developed so many serious and sometimes fatal side effects that these medications developed a reputation for being dangerous drugs whose use should be limited to patients with serious illnesses that could not be helped by any other treatment. Meanwhile it became evident that cortisone must be converted to hydrocortisone before having its characteristic physiologic effects and chemists pointed out that cortisol was a more proper term for hydrocortisone, thus adding to the confusion of most physicians and patients.

When serious side effects developed in patients receiving the large dosages of cortisone or hydrocortisone (cortisol) that were thought to be necessary for therapeutic effects, derivatives such as prednisone or triamcinolone were introduced, but except for less tendency to produce retention of salt and water (edema), the derivatives often produced any or all of the undesirable side effects of excessive amounts of the normal hormone. Hence cortisone and cortisol developed a reputation for being dangerous drugs whose use should be confined to patients with serious, life-threatening illnesses that would not improve with any other treatment.

Having trained at the Massachusetts General Hospital under Dr. Fuller Albright, a pioneer in the study of adrenocortical function, I was developing an endocrine clinic and research laboratory at Western Reserve University Hospitals in Cleveland, Ohio and I saw every patient admitted for treatment with cortisone or its derivatives for the first two years that these medications were available. In 1955 I wrote a review article summarizing the problems that existed at that time that was published in the New England Journal of Medicine entitled, "The Present Status of ACTH, Cortisone and Related Steroids in Clinical Medicine" (2). During this time I determined that the duration of effect of a single dose of cortisol was approximately 8 hours and that normal human adrenals produced the equivalent of 35 to 40 mg of cortisol daily when taken as tablets by mouth 4 times daily, before meals and at bedtime in the absence of unusual stress.

Meanwhile I also began to work in an infertility clinic associated with Western Reserve University and found that many of its women patients had evidence of mild disorders of adrenal function that improved when they were given small, subreplacement dosages of cortisone or cortisol (3). During the next twenty years over 200 babies were born to women with mild disorders of ovarian function who took safe, physiologic dosages of cortisone or cortisol not only in order to get pregnant but also throughout their pregnancies to protect against miscarriages, without any evidence or harm to either mothers or babies (4). These dosages therefore appeared to be restoring normal function rather than impairing it.

Some of these women reported that while taking the small, safe dosages of cortisone or cortisol their symptoms of allergies, or unexplained chronic fatigue (the chronic fatigue syndrome), or autoimmune disorders such as rheumatoid arthritis or chronic thyroiditis, also improved. These beneficial effects of safe, physiologic dosages of cortisone or cortisol were reported at the annual meeting of the American College of Physicians in New York City in April, 1966, and in a paper published in the Archives of Internal Medicine in 1967 (5), but by that time patents on the normal hormones, cortisone and cortisol, had expired. Pharmaceutical laws require that when a new use is found for a medication, it must receive all of the relevant tests for its safety, including therapeutic trials, before the new use can be advertised. Because such studies are expensive, pharmaceutical companies have little incentive for performing them when they no longer have the protection for their investment that is provided by a patent. Hence pharmaceutical companies apparently could not even mention in their package inserts or advertisements any of these potential new uses of safe dosages of the normal hormone, cortisol! Further reports of the beneficial effects of safe dosages of cortisone or cortisol were published in endocrine journals and conference proceedings in the 1960's and 1970's, but these were received skeptically by most physicians when no ads or promotional efforts by the pharmaceutical companies marketing the hormones appeared.

I, like most other physicians, did not realize the cause of this problem, so I thought it might be helped by my writing a book reviewing the cortisone story and describing the beneficial effects of safe, physiologic dosages of cortisone or cortisol that had been observed. In 1981, therefore, Safe Uses of Cortisone was published by the Charles C. Thomas Company, a reputable medical publisher that had published much of the earlier work on cortisone and its derivatives.

This book also received little attention until a few patients with chronic allergies and their physicians found that this therapeutic approach was both safe and effective. During the past five years, when it has become evident that the hypothalamus-pituitary-adrenal (HPA) axis plays a major role in immunity and in the response to stress, there has been a return to considering the possibility that autoimmune disorders, especially rheumatoid arthritis, and chronic allergic disorders might be related to mild adrenocortical deficiency, either primary in the adrenal glands or secondary to deficient stimulation by adrenocorticotropic hormone (ACTH) from the pituitary gland. An update on Safe Uses of Cortisone entitled Safe Uses of Cortisol has therefore recently been published, reviewing these developments and the evidence that mild adrenocortical deficiency, a diagnosis that is not mentioned in medical textbooks, is very probably a factor in the development of many, if not all, allergic disorders and autoimmune disorders, and describing a safe treatment of these disorders with physiologic dosages of cortisol (6). Hopefully this book will help to clarify this confusing situation. Cortisol is a normal hormone, the only hormone that is absolutely essential for life, so it must be safe in proper physiologic amounts!

These developments have therefore revealed a serious problem in our pharmaceutical laws that will hopefully be corrected. If a cure for cancer were found tomorrow in a medication whose patent had expired, especially one that had developed a bad reputation like cortisone, it might be extremely difficult to get anyone to pay any attention to it!

1. Hench PS, Kendall EC, Slocumb CH, Polley HF. The effects of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: Compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis; preliminary report. Proc Staff Meet Mayo Clin 1949, 24:181-97.

2. Jefferies, W.McK. The present status of ACTH, cortisone and related steroids in clinical medicine. New Eng J Med 1955, 253:441-6.

3. Jefferies, W.McK. Glucocorticoids and Ovulation. In Greenblatt, R.B.(Ed): Ovulation. Philadelphia, Lippincott,1966. pp 62-74.

4. Jefferies, W.McK. Safe Uses of Cortisol (second edition) Charles C.Thomas, Springfield, 1996, p.86.

5. Jefferies, W.McK. Low dosage glucocorticoid therapy. Arch Intern Med 1967, 119:265-78.

6. Jefferies, W.McK. Safe Uses of Cortisol (second edition) Charles C.Thomas, Springfield, 1996, Chapters 4 through 11.