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The endogenous corticosteroids are produced by the adrenal cortex and are essential for life. As with the gonadal steroid hormones discussed in Chapter 22, corticosteroids are synthesized from cholesterol. They comprise two major physiologic and pharmacologic groups, glucocorticoids and mineralocorticoids (Figure 23–1). Glucocorticoids have important effects on intermediary metabolism, catabolism, immune responses, and inflammation. Mineralocorticoids regulate sodium and potassium transport in the collecting tubules of the kidney. A third group, the adrenal androgens (dehydroepiandrosterone [DHEA] and androstenedione) constitute the major endogenous precursors of estrogen in females in whom ovarian function is deficient or absent (e.g., postmenopausal) and in preadolescent males. Drugs that modulate the physiologic effects of endogenous corticosteroids either mimic the corticosteroids or inhibit corticosteroid synthesis or receptor interactions.

Figure 23–1.

Classification of drugs that mimic or block the effects of endogenous corticosteroids.

Like other hormones under the control of the hypothalamic and pituitary endocrine system, glucocorticoids provide feedback inhibition of their own production by acting in the hypothalamus and pituitary. Glucocorticoids inhibit the production of corticotropin-releasing factor (CRF) within the hypothalamus and adrenocorticotropic hormone (ACTH) within the pituitary. CRF controls the release of ACTH, which in turn regulates corticosteroid production within the adrenal cortex. A key action of exogenous glucocorticoids is activation of this feedback inhibition system with subsequent suppression of endogenous adrenal steroid production. After chronic treatment with exogenous glucocorticoids, recovery of the endogenous system takes weeks to months.

A large number of synthetic glucocorticoids are available. They can be delivered by a variety of routes, including oral, intravenous, intra-articular, and topical.

Mechanism of Action

Steroid hormones enter the cell and bind to cytosolic receptors. The complex of the receptor and its bound steroid translocates to the nucleus where it alters gene expression by binding to glucocorticoid response elements (GREs) (Figure 23–2). Tissue-specific responses to steroids are made possible by the presence of different protein regulators in each tissue that control the interaction between the hormone-receptor complex, other transcription factors, and particular response elements.

Figure 23–2.

Mechanism of glucocorticoid action. This figure models the interaction of a steroid (S), with its receptor (R) and the subsequent events in a target cell. The steroid is present in the blood—bound to the corticosteroid-binding globulin (CBG)—but it enters the cell as the free form. The intracellular receptor (R) is bound to stabilizing proteins, including heat shock protein 90 (Hsp90) and several others. When the complex binds a molecule of steroid, the Hsp90 and associated molecules are released. The steroid-receptor complex enters the nucleus as a dimer, binds to the glucocorticoid response element (GRE), and thereby regulates gene transcription by RNA polymerase II and associated transcription factors. The resulting mRNA is edited and exported to the cytoplasm ...

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