The major pathways for mineralocorticoid, glucocorticoid, and androgen biosynthesis are shown in Figure 33-1. Also shown is the site of action of drugs that inhibit adrenocorticoid synthesis. In humans, aldosterone is the major mineralocorticoid, cortisol is the major glucocorticoid, and dehydroepiandrosterone (DHEA) is the major adrenal androgen.

FIGURE 33-1 Biosynthetic pathways for adrenal steroids. A, Major pathways for mineralocorticoid, glucocorticoid, and androgen biosynthesis are shown. Important enzymes include 3β-hydroxysteroid dehydrogenase (3β-HSD), steroid 21-hydroxylase (P450₂₁), steroid 11β-hydroxylase (P450_11β), aldosterone synthase (P450_aldo), steroid 17α-hydroxylase (P450_17α), and 17β-hydroxysteroid dehydrogenase (17β-HSD). The structural changes produced by each reaction are unshaded. Aminoglutethimide blocks the synthesis of all adrenal steroids by inhibiting the conversion of cholesterol to pregnenolone. Ketoconazole and metyrapone inhibit P450_11β. The most common defect causing congenital adrenal hyperplasia is P450₂₁ deficiency. B, The structure of dexamethasone is shown in the inset in the lower right corner. In the synthetic steroids, glucocorticoid potency is enhanced by the introduction of a double bond at the 1,2 position or the introduction of a hydroxyl or methyl group at the 16 position. Both glucocorticoid and mineralocorticoid activities are increased by a fluorine substitution at the 9 position.

The regulation of corticosteroid secretion is depicted in Figure 33-2. The secretion of cortisol and adrenal androgens is primarily controlled by corticotropin (ACTH) secreted by the pituitary gland, whereas the secretion of aldosterone is chiefly regulated by the renin-angiotensin system. Various types of physical and mental stress are powerful activators of corticotropin-releasing hormone secretion, leading to increased corticotropin and cortisol production. Cortisol exerts several effects that increase the body’s resistance to stress.

FIGURE 33-2 Regulation of the secretion of cortisol by the adrenal cortex. Stress and other stimuli increase the release of corticotropin-releasing hormone *(CRH)* from hypothalamic paraventricular nuclei, and CRH is carried by hypophysioportal vessels to the anterior pituitary, where it stimulates the release of corticotropin *(ACTH).* Corticotropin acts on the adrenal cortex to increase the release of adrenal steroids, although the release of aldosterone is primarily regulated by the renin-angiotensin system. Cortisol exerts feedback inhibition on the hypothalamus and pituitary to inhibit the release of CRH and corticotropin.

As shown in Figure 33-2, cortisol and other glucocorticoids act as feedback inhibitors of both corticotropin-releasing hormone and corticotropin. This is why exogenously administered glucocorticoids can suppress the hypothalamic-pituitary-adrenal axis and inhibit endogenous cortisol production, leading to adrenal insufficiency when the exogenous glucocorticoid is withdrawn.

Physiologic Effects of Adrenal Steroids

The adrenal steroids act on target tissues by binding to specific cytoplasmic steroid receptors, which are then translocated to the cell nucleus, a common mechanism for all steroid hormones (see Fig. 3-4 in Chapter 3). In the nucleus the activated receptors stimulate the transcription of specific genes and thereby increase the translation of specific proteins. These actions lead to the various metabolic and antiinflammatory effects of glucocorticoids, which are described later. In the renal tubules, activation of the mineralocorticoid receptor stimulates the synthesis of sodium channels and sodium-potassium adenosine triphosphatase, which are needed for sodium reabsorption. This mechanism is responsible for the salt-retaining effects of mineralocorticoids.

The glucocorticoid receptor has a high affinity for cortisol but a much lower affinity for aldosterone, whereas the mineralocorticoid receptor has a high affinity for both aldosterone and cortisol. This enables cortisol to exert both glucocorticoid and mineralocorticoid actions.

Glucocorticoids induce enzymes involved in gluconeogenesis (the formation of glucose from amino acids) and have an antiinsulin effect. For this reason, glucocorticoid insufficiency can lead to hypoglycemia during stress. Glucocorticoids also activate enzymes involved in protein catabolism, thereby increasing the supply of amino acids needed for gluconeogenesis. Glucocorticoids stimulate lipolysis and inhibit the uptake of glucose by adipose tissue. By this mechanism, excessive glucocorticoid levels can lead to abnormal fat distribution and muscle wasting (see later).

Corticosteroid Drugs

A large number of semisynthetic glucocorticoid drugs are available; they are most frequently employed to attain the antiinflammatory effects produced by supraphysiologic doses of these drugs. Less commonly, corticosteroids are used as replacement therapy in the treatment of adrenal insufficiency and in the treatment of adrenogenital syndromes that produce excessive quantities of adrenal androgens and insufficient quantities of other corticosteroids. Mineralocorticoids are primarily used as replacement therapy in persons with adrenal insufficiency. The properties of selected corticosteroids are listed in Table 33-1.

TABLE 33-1

Pharmacologic Properties of Selected Corticosteroids

DRUG*	ROUTE OF ADMINISTRATION	DURATION OF ACTION (HOURS)	MINERALOCORTICOID (SALT-RETAINING) POTENCY	GLUCOCORTICOID (ANTIINFLAMMATORY) POTENCY
Short-Acting Drugs
Hydrocortisone (cortisol)	Oral, parenteral, or topical	8-12	1	1
Cortisone	Oral, parenteral, or topical	8-12	0.8	0.8
Fludrocortisone	Oral	8-12	200	10
Intermediate-Acting Drugs
Methylprednisolone	Oral, parenteral, or topical	12-36	0.5	5
Prednisone	Oral	12-36	0.7	3.5
Triamcinolone	Oral, parenteral, or topical	12-36	0	5
Long-Acting Drugs
Betamethasone	Oral, parenteral, or topical	24-72	0	30
Dexamethasone	Oral, parenteral, or topical	24-72	0	30

^*Fludrocortisone is classified as a mineralocorticoid; the other drugs are classified as glucocorticoids.

Mineralocorticoids

Aldosterone, the major mineralocorticoid in humans, is not suitable for clinical use owing to the potential for electrolyte disturbances. Fludrocortisone is a mineralocorticoid that is used as replacement therapy in patients with primary adrenal insufficiency (Addison disease). The drug’s salt-retaining potency is about 20 times greater than its antiinflammatory potency.

Glucocorticoids

A large number of glucocorticoid preparations are available for oral, parenteral, inhalational, or topical administration for the treatment of a wide range of inflammatory, allergic, autoimmune, and other disorders. Whenever possible, topical or inhalational administration is preferred because it is usually well tolerated and avoids most systemic adverse effects. Topical administration is widely used in the treatment of allergic or inflammatory conditions affecting the skin, mucous membranes, or eyes (see later). For example, topical ocular glucocorticoids are used to treat acute uveitis (inflammation of the iris, ciliary body, or choroid). Glucocorticoids are given by inhalation to treat allergic rhinitis, aspiration pneumonia, asthma, and other respiratory conditions (see Chapter 27).

Classification

The glucocorticoids are usually classified according to their potency and duration of action (see Table 33-1). When given systemically, the duration of action of glucocorticoids is primarily determined by their potency at the glucocorticoid receptor, rather than by their elimination half-life. This is because the highly potent drugs evoke a longer-lasting stimulation of gene transcription than do less-potent glucocorticoids. The potency of specific topical corticosteroids is discussed under the treatment of dermatologic conditions (see later).