Historical and physiological background

Thomas Addison reported in the mid-1800s on a series of patients who had succumbed to a disease -later named after him - associated with degeneration of the adrenal glands. Foreshadowing a relation between the adrenal cortex and the immune system, he noted that the blood of one patient 'had a considerable excess of white corpuscles'. By the early 1900s patients with Addisons disease, as well as adrenalectomized animals, were known to suffer from low blood glucose and salt loss. These effects were traced in the 1930s to two distinct hormones from the adrenal cortex, each essential for life: glucocorticoids, which influenced blood glucose; and mineralocorticoids, which regulated salt balance. The vital role of mineralocorticoids was well explained by their effects on salt balance, but that of glucocorticoids could not be accounted for by effects on glucose, and remained obscure for many years. By 1940 it was known that glucocorticoids exert numerous other actions, in particular on lymphoid tissue: Addisonian patients and adrenalectomized rats had enlarged thymuses, and glucocorticoids caused atrophy of the thymus and other lymphoid organs.

Harvey Cushing in 1932 described a disease later ascribed to excessive secretion of glucocorticoids. Symptoms such as glucose intolerance, fat redistribution and heightened susceptibility to infection which accompany Cushings syndrome are nowadays most often encountered as undesirable side-effects of glucocorticoid therapy.

Around 1930 it became clear that there is an intimate relationship between glucocorticoids and stress. Stress from almost any source - cold, injury, infection, fright, and other challenges to homeostasis - stimulated glucocorticoid secretion. The resulting high levels of glucocorticoids protected against stress and sustained life, and for a long time were thought to somehow enhance the activity of normal defense mechanisms. A separate protective role for glucocorticoids emerged later from observations that adrenalectomized animals, which died if stressed, could survive moderate - though not severe - stress if maintained on basal levels of glucocorticoids. Such basal levels exert 'permissive' effects essential to maintain a wide range of homeostatic mechanisms, including blood pressure regulation and certain immune reactions.

The principal natural glucocorticoids are Cortisol and corticosterone (Figure 1), the former predominating in humans and the latter in rodents. For many years cortisone, which was isolated in the 1940s, was thought to be the principal glucocorticoid, but it is now known to require conversion to Cortisol for biological activity by reduction of the ketone group at carbon 11 to a hydroxyl group (Figure 1).

Until 1949 the main clinical use of glucocorticoids was for replacement therapy of patients with hormone deficiency. That year the biomedical world was electrified by the totally unexpected discovery that large doses of cortisone exerted powerful antiinflammatory activity, dramatically alleviating the symptoms of rheumatoid arthritis. This development led to a spectacular rise in applications of glucocorticoids - the 'miracle drugs' of the 1950s - and set the stage for much of their current clinical use. Innumerable derivatives of the glucocorticoids were synthesISBN: 0-12-226765-6

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