Chapter 42

### INTRODUCTION

Adrenocorticotropic hormone (ACTH, corticotropin) and the steroid hormone products of the adrenal cortex are considered together because the major physiological and pharmacological effects of ACTH result from its action to increase the circulating levels of adrenocortical steroids. Synthetic derivatives of ACTH are used principally in the diagnostic assessment of adrenocortical function. Because all known therapeutic effects of ACTH can be achieved with corticosteroids, synthetic steroid hormones generally are used therapeutically instead of ACTH.

Corticosteroids and their biologically active synthetic derivatives differ in their metabolic (glucocorticoid) and electrolyte-regulating (mineralocorticoid) activities. These agents are employed at physiological doses for replacement therapy when endogenous production is impaired. In addition, glucocorticoids potently suppress inflammation, and their use in a variety of inflammatory and autoimmune diseases makes them among the most frequently prescribed classes of drugs. Because glucocorticoids exert effects on almost every organ system, the clinical use of and withdrawal from corticosteroids are complicated by a number of serious side effects, some of which are life threatening. Therefore, the decision to institute therapy with systemic corticosteroids always requires careful consideration of the relative risks and benefits in each patient.

Agents that inhibit steps in the steroidogenic pathway and thus alter the biosynthesis of adrenocortical steroids are discussed in this chapter, as are synthetic steroids that inhibit glucocorticoid action. Agents that inhibit the action of aldosterone are presented in Chapter 25; agents used to inhibit growth of steroid-dependent tumors are discussed in Chapters 60,61,62.

History. Addison described fatal outcomes in patients with adrenal destruction in a presentation to the South London Medical Society in 1849. These studies were soon extended when Brown-Séquard demonstrated that bilateral adrenalectomy was fatal in laboratory animals. It later was shown that the adrenal cortex, rather than the medulla, was essential for survival in these ablation experiments and that the adrenal cortex regulated both carbohydrate metabolism and fluid and electrolyte balance. The isolation and identification of the adrenal steroids by Reichstein and Kendall and the effects of these compounds on carbohydrate metabolism (hence the term glucocorticoids) culminated with the synthesis of cortisone, the first pharmacologically effective glucocorticoid to become readily available. Subsequently, Tait and colleagues isolated and characterized a distinct corticosteroid, aldosterone, which potently affected fluid and electrolyte balance and therefore was termed a mineralocorticoid. The isolation of distinct corticosteroids that regulated carbohydrate metabolism or fluid and electrolyte balance led to the concept that the adrenal cortex comprises two largely independent units: an outer zone that produces mineralocorticoids and an inner region that synthesizes glucocorticoids and androgen precursors.

Studies of adrenocortical steroids also played a key part in delineating the role of the anterior pituitary in endocrine function. As early as 1912, Cushing described patients with hypercorticism, and later he recognized that pituitary basophilism caused the adrenal overactivity, thus establishing the link between the anterior pituitary and adrenal function. These studies led to the purification ...

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