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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Hormones of the Adrenal Cortex

, PhD and , PhD.

Cortisol and its synthetic analogs have been in widespread clinical use for the treatment of a variety of disorders for more than 50 years. Since their first clinical application, intensive research has expanded our understanding of the physiology, biochemistry, and pharmacology of steroids and has led to a large body of literature addressing the therapeutic use and harmful side effects of corticosteroids. This chapter reviews corticosteroid pharmacology and physiology, discusses the use of these hormonal agents in the treatment of neoplasms, and presents the currently understood mechanism of action of corticosteroids in the context of their therapeutic efficacy.

As early as the mid-nineteenth century, it was observed that a lack of functional adrenal glands is incompatible with life.1,2 Subsequent research categorized the effects of adrenal insufficiency into two distinct groups: those due to electrolyte imbalance and those due to altered carbohydrate metabolism.3,4 Hypercortical syndrome was described by Cushing in 1932,5 and in the 1940s and 1950s, adrenocorticotropic hormone (ACTH) was identified in the anterior pituitary and described as a stimulator of the adrenal cortex.6,7 During this time, several bioactive steroids, including cortisol and aldosterone (the principal active corticosteroids in humans) were isolated from the adrenal cortex and characterized.

In 1949, Hench8 first reported the efficacy of cortisol and ACTH in the treatment of rheumatoid arthritis, an observation that was quickly extended to therapeutic applications in a wide variety of diseases. Intense investigation of these compounds was spurred by this widespread clinical interest, and in the subsequent decade, most of the biochemistry involved in the synthesis and metabolism of adrenocortical steroids was elucidated. During this period, the field of corticosteroid therapy rapidly advanced as the majority of synthetic corticosteroid analogs available today were developed and practical methods of plasma cortisol determination were identified.

In the intervening years, synthetic corticosteroid analogs that separate antiinflammatory and electrolyte balance effects were developed. However, despite continual effort, successful separation of clinical efficacy from deleterious side effects has not been achieved. Consequently, chronic use of these powerful drugs is limited by their slow, cumulative side-effect profile. The damage associated with corticosteroid therapy may not become apparent until the consequences are catastrophic.

Adrenal Anatomy

The adrenal cortex comprises three zones: the zonae glomerulosa, fasciculata, and reticularis. Aldosterone, the major bioactive mineralocorticoid in humans, is synthesized in the outermost zona glomerulosa. This region of the adrenal cortex is regulated by circulating sodium, potassium, and angiotensin. The inner zonae fasciculata and reticularis produce both cortisol and corticosterone. These regions of the adrenal, and to a much lesser extent the zona glomerulosa, are regulated by ACTH released from the anterior pituitary.

Secreted Steroids

Five classes of steroid hormones are produced in the adrenal cortex: glucocorticoids, mineralocorticoids, progestins, androgens, and estrogens. However, the amount of progestin, androgen, and estrogen produced by the adrenal is a minor fraction of the total amount of these steroids produced in the body. By contrast, glucocorticoids and mineralocorticoids are produced almost exclusively in the adrenal cortex. Glucocorticoids have a broad physiologic role that includes both regulation of glucose metabolic pathways and modulation of the immune system. Mineralocorticoids are key regulators of mineral and water balance.

Biosynthetic Pathways

Corticosteroid biosynthesis has been well characterized, and is presented in simplified form in Figure 62-1. Cholesterol, the precursor to all steroid biosynthetic pathways, is converted to a variety of steroid molecules in a series of reactions catalyzed by several cytochrome P450 (cyp 450) enzymes.9 While some cholesterol can be synthesized within the adrenal cortex, the vast majority of cholesterol used in steroid biosynthesis is taken up from a pool of circulating cholesterol bound to low-density lipoproteins in the plasma. After synthesis, corticosteroids are rapidly secreted. Because corticosteroids are not stored in the adrenal cortex, the rate of steroid synthesis is essentially equal to the rate of secretion from the adrenal gland.

Figure 62-1. Principal pathways for the biosynthesis of adrenocorticosteroids.

Figure 62-1

Principal pathways for the biosynthesis of adrenocorticosteroids. (Reproduced with permission from Haynes and Murad.)

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12994

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