Adrenocortical Steroids

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The adrenal cortex synthesizes two classes of steroids: the corticosteroids, which have 21 carbon atoms, and the androgens, which have 19 (Figure 59-2). The actions of corticosteroids are classified as glucocorticoid (carbohydrate metabolism-regulating) and mineralocorticoid (electrolyte balance-regulating), reflecting their preferential activities. In humans, cortisol (hydrocortisone) is the main glucocorticoid and aldosterone is the main mineralocorticoid. Typically cortisol is secreted at a rate of 10 mg/day whereas aldosterone is secreted at a rate of 0.125 mg/day. The concentrations of cortisol in peripheral plasma are considerably higher in the morning (16 ,ug/dL at 8 am) than in the late afternoon (4 ,ug/dL at 4 pm) reflecting diurnal regulation, whereas the plasma concentrations of aldosterone are lower and more constant (0.01 ,ug/dL) throughout the day. The daily production of cortisol can rise at least tenfold in the setting of severe stress.

Although adrenal DHEA is an important precursor of testosterone and estradiol synthesis in women, patients with adrenal insufficiency can be restored to normal life expectancy by replacement therapy with glucocorticoids and mineralocorticoids. Nevertheless, some studies suggest that addition of DHEA to the standard replacement regimen in women with adrenal insufficiency improves subjective well-being and sexuality. The finding that the levels of DHEA and its sulfated derivative DHEA-S fall progressively after the third decade of life has prompted speculation that DHEA may at least partly reverse the adverse consequences of aging. This has led to the wide use of DHEA as a nutritional supplement despite the absence of definitive data.

Physiological Functions and Pharmacological Effects

PHYSIOLOGICALACTIONS The effects of corticosteroids are numerous and widespread, and include alterations in carbohydrate, protein, and lipid metabolism; maintenance of fluid and electrolyte balance; and preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system, and the nervous system. In addition, corticosteroids endow the organism with the capacity to resist such stressful circumstances as noxious stimuli and environmental changes. In the absence of the adrenal cortex, survival is made possible only by maintaining an optimal environment, including adequate and regular feedings, ingestion of relatively large amounts of sodium chloride, and maintenance of an appropriate environmental temperature; stresses such as infection and trauma can be life-threatening when adrenal function is impaired.

The actions of corticosteroids are interrelated to those of other hormones. In the absence of glucocorticoids, epinephrine and norepinephrine have only minor effects on lipolysis. Administration of a small dose of glucocorticoid, however, markedly potentiates their lipolytic action. Those effects of corticosteroids that involve concerted actions with other hormonal regulators are termed permissive and most likely reflect steroid-induced changes in protein synthesis that, in turn, modify tissue responsiveness to other hormones.

Corticosteroids traditionally are divided into mineralocorticoids and glucocorticoids according to their relative potencies in Na+ retention and effects on carbohydrate metabolism (i.e., hepatic deposition of glycogen and gluconeogenesis) In general, potencies of steroids to sustain life in adrenalectomized animals closely parallel their mineralocorticoid activity, while potencies as antiinflammatory agents closely parallel their effects on glucose metabolism. The effects on Na+ retention and the carbohydrate/anti-inflammatory actions are not closely related and reflect selective actions at distinct receptors.

Estimates of potencies of representative steroids in these actions are listed in Table 59-1. Some steroids that are classified predominantly as glucocorticoids (e.g., cortisol) also possess modest but significant mineralocorticoid activity and thus may affect fluid and electrolyte handling in the clinical setting. At doses used for replacement therapy in patients with primary adrenal insufficiency (see below), the mineralocorticoid effects of these "glucocorticoids" are insufficient to replace that of aldosterone, and concurrent therapy with a more potent mineralocorticoid generally is needed. In contrast, aldosterone is exceedingly potent with respect to Na+ retention, but has only modest potency for effects on carbohydrate metabolism. At normal rates of secretion by the adrenal cortex or in doses that maximally affect electrolyte balance, aldosterone has no significant glucocorticoid activity and thus acts as a pure mineralocorticoid.

GENERAL MECHANISMS FOR CORTICOSTEROID EFFECTS Corticosteroids interact with specific receptor proteins in target tissues to regulate the expression of corticosteroid-responsive

Table 59-1

Relative Potencies and Equivalent Doses of Representative Corticosteroids

Table 59-1

Relative Potencies and Equivalent Doses of Representative Corticosteroids

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