Chapter 42: ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex

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 of ACTH and the determination of its chemical structure. ACTH was further shown to be essential for maintaining the structural integrity and steroidogenic capacity of the inner cortical zones. Harris established the role of the hypothalamus in pituitary control and postulated that a soluble factor produced by the hypothalamus activated ACTH release. These investigations culminated with the determination of the structure of corticotropin-releasing hormone (CRH), a hypothalamic peptide that, together with arginine vasopressin, regulates secretion of ACTH from the pituitary.

Shortly after synthetic cortisone became available, Hench and colleagues demonstrated its dramatic effect in the treatment of rheumatoid arthritis. These studies set the stage for the clinical use of corticosteroids in a wide variety of diseases, as discussed in this chapter.

The actions of ACTH and the other melanocortins liberated from POMC are mediated by their specific interactions with five melanocortin receptor (MC1-5R) subtypes comprising a distinct subfamily of G protein-coupled receptors. The well-known effects of MSH on pigmentation result from interactions with the MC1R on melanocytes. MC1Rs also are found on cells of the immune system and are thought to mediate the anti-inflammatory effects of α-MSH in experimental models of inflammation. ACTH, which is identical to α-MSH in its first 13 amino acids (Ser-Tyr-Ser-Met-Glu-His-Phe-ArgTrp-Gly-Lys-Pro-Val), exerts its effects on the adrenal cortex through the MC2R. The affinity of ACTH for the MC1R is much lower than for the MC2R; however, under pathological conditions in which ACTH levels are persistently elevated, such as primary adrenal insufficiency, ACTH also can signal through the MC1R and cause hyperpigmentation. Recent studies have defined key roles for β-MSH (Lee et al., 2006) and possibly other melanocortins acting via the MC4R (Farooki et al., 2003) and MC3R (Mencarelli et al., 2008) in the hypothalamic regulation of appetite and body weight, and they therefore are the subject of considerable investigation as possible targets for drugs that affect appetite. The role of MC5R is less well defined, but studies in rodents suggest that MSH triggers aggressive, pheromone-related behavior via the MC5R (Morgan and Cone, 2006).

Cells of the outer zone have receptors for angiotensin II and express aldosterone synthase (CYP11B2), an enzyme that catalyzes the terminal reactions in mineralocorticoid biosynthesis. Although ACTH acutely stimulates mineralocorticoid production by the zona glomerulosa, this zone is regulated predominantly by angiotensin II and extracellular K⁺ (Chapter 25) and does not undergo atrophy in the absence of ongoing stimulation by the pituitary gland. In the setting of persistently elevated ACTH, mineralocorticoid levels initially increase and then return to normal (a phenomenon termed ACTH escape).

In contrast, cells of the zona fasciculata have fewer receptors for angiotensin II and express two enzymes, steroid 17α-hydroxylase (CYP17) and 11β-hydroxylase (CYP11B1), that catalyze the production of glucocorticoids. In the zona reticularis, CYP17 carries out an additional C17-20 lyase reaction that converts C21 corticosteroids to C19 androgen precursors.

In the absence of the anterior pituitary, the inner zones of the cortex atrophy, and the production of glucocorticoids and adrenal androgens is markedly impaired.

Persistently elevated levels of ACTH, due either to repeated administration of large doses of ACTH or to excessive endogenous production, induce hypertrophy and hyperplasia of the inner zones of the adrenal cortex, with overproduction of cortisol and adrenal androgens. Adrenal hyperplasia is most marked in congenital disorders of steroidogenesis, in which ACTH levels are continuously elevated as a secondary response to impaired cortisol biosynthesis. There is some debate regarding the relative roles of ACTH versus other POMC-derived peptides in stimulating adrenal growth, but the essential role of the anterior pituitary in maintaining the integrity of the zona fasciculata is indisputable.

ACTH, binding to MC2R (a GPCR), activates the G_s-adenylyl cyclase-cyclic AMP-PKA pathway. Cyclic AMP is an obligatory second messenger for most, if not all, effects of ACTH on steroidogenesis. Mutations in MC2R account for ∼25% of the cases of familial glucocorticoid deficiency, a rare syndrome of familial resistance to ACTH (Clark et al., 2005).

Temporally, the response of adrenocortical cells to ACTH has two phases. The acute phase, which occurs within seconds to minutes, largely reflects increased supply of cholesterol substrate to the steroidogenic enzymes. The chronic phase, which occurs over hours to days, results largely from increased transcription of the steroidogenic enzymes. A summary of the pathways of adrenal steroid biosynthesis and the structures of the major steroid intermediates and products of the human adrenal cortex are shown in Figure 42–3. The rate-limiting step in steroid hormone production is the conversion of cholesterol to pregnenolone, a reaction catalyzed by CYP11A1, the cholesterol side-chain cleavage enzyme. Most of the enzymes required for steroid hormone biosynthesis, including CYP11A1, are members of the cytochrome P450 superfamily of mixed-function oxidases that play important roles in the metabolism of xenobiotics such as drugs and environmental pollutants, as well as in the biosynthesis of such endogenous compounds as steroid hormones, vitamin D, bile acids, fatty acids, prostaglandins, and biogenic amines (Chapter 6). The rate-limiting components in this reaction regulate the mobilization of substrate cholesterol and its delivery to CYP11A1 in the inner mitochondrial matrix.

To ensure an adequate supply of substrate for steroidogenesis, the adrenal cortex uses multiple sources of cholesterol (Kraemer, 2007), including:

• circulating cholesterol and cholesterol esters taken up via the low-density lipoprotein and high-density lipoprotein receptor pathways

• endogenous cholesterol liberated from cholesterol ester stores via activation of cholesterol esterase

• endogenous cholesterol from de novo biosynthesis.

The mechanisms by which ACTH stimulates the translocation of cholesterol to the inner mitochondrial matrix are not fully defined. A 37,000-Da phosphoprotein—designated the steroidogenic acute regulatory protein—clearly plays essential roles in cholesterol delivery. Mutations in the gene encoding this phosphoprotein are found in patients with congenital lipoid adrenal hyperplasia, a rare congenital disorder in which adrenal cells become engorged with cholesterol deposits secondary to an inability to synthesize any steroid hormones (Stocco, 2002). An important component of the trophic effect of ACTH is the enhanced transcription of genes that encode the individual steroidogenic enzymes, with associated increases in the steroidogenic capacity of the gland. Myriad transcriptional regulators participate in the induction of steroid hydroxylases by ACTH. Among these is the nuclear receptor NR5A1 (steroidogenic factor 1), a transcription factor required for the development of the adrenal cortex and for the expression of most of the steroidogenic enzymes (Parker et al., 2002).

Following release into the hypophyseal plexus, CRH is transported via this portal system to the anterior pituitary, where it binds to specific membrane receptors on corticotropes. Upon CRH binding, the CRH receptor activates the G_s-adenylyl cyclase–cyclic AMP pathway within corticotropes, ultimately stimulating both ACTH biosynthesis and secretion. CRH and CRH-related peptides called urocortins also are produced at other sites, including the amygdala and hindbrain, gut, skin, adrenal gland, adipose tissue, placenta, and additional sites in the periphery. The classical CRH receptor, now designated CRF₁ receptor, belongs to the class II family of G protein-coupled receptors that includes receptors for calcitonin, parathyroid hormone, growth hormone-releasing hormone, secretin, glucagon, and glucagon-like peptide. A second CRH receptor, designated CRF₂ receptor, shares 70% homology at the amino acid level and is distinguished from the CRF₁ receptor in its binding specificities for CRH and the urocortins. In mice, the CRF₂ receptor opposes those effects mediated by the CRF₁ receptor thereby, providing a highly complex neural network that modulates the adaptive response to stress (Bale and Vale, 2004). The finding that the HPA axis often is altered in patients suffering from major depressive disorders illustrates the complex relationships between stress and mood and has stimulated considerable interest in the possible use of CRH antagonists in disorders such as anxiety and depression (Holsboer and Ising, 2008).

Assays for ACTH. Initially, ACTH levels were assessed by bioassays that measured induced steroid production or the depletion of adrenal ascorbic acid. Immunochemiluminescent assays that use two separate antibodies directed at distinct epitopes on the ACTH molecule now are widely available. These assays increase considerably the ability to differentiate patients with primary hypoadrenalism due to intrinsic adrenal disease, who have high ACTH levels due to the loss of normal glucocorticoid feedback inhibition, from those with secondary forms of hypoadrenalism, due to low ACTH levels resulting from hypothalamic or pituitary disorders. The immunochemiluminescent ACTH assays also are useful in differentiating between ACTH-dependent and ACTH-independent forms of hypercorticism: High ACTH levels are seen when the hypercorticism results from pituitary adenomas (e.g., Cushing's disease) or nonpituitary tumors that secrete ACTH (e.g., the syndrome of ectopic ACTH), whereas low ACTH levels are seen in patients with excessive glucocorticoid production due to primary adrenal disorders. Despite their considerable utility, one problem with the immunoassays for ACTH is that their specificity for intact ACTH can lead to falsely low values in patients with ectopic ACTH secretion; these tumors can secrete aberrantly processed forms of ACTH that have biological activity but do not react in the antibody assays.

Therapeutic Uses and Diagnostic Applications of ACTH. There are anecdotal reports that selected conditions respond better to ACTH than to corticosteroids (e.g., multiple sclerosis), and some clinicians continue to advocate therapy with ACTH. Despite this, ACTH currently has only limited utility as a therapeutic agent. Therapy with ACTH is less predictable and less convenient than therapy with corticosteroids. In addition, ACTH stimulates mineralocorticoid and adrenal androgen secretion and may therefore cause acute retention of salt and water, as well as virilization. Although ACTH and the corticosteroids are not pharmacologically equivalent, all proven therapeutic effects of ACTH can be achieved with appropriate doses of corticosteroids with a lower risk of side effects.

Testing the Integrity of the HPA Axis. The major clinical use of ACTH is in testing the integrity of the HPA axis. Other tests used to assess the HPA axis include the insulin tolerance test (Chapter 38) and the metyrapone test (discussed later in this chapter). Cosyntropin (cortrosyn, synacthen) is a synthetic peptide that corresponds to residues 1-24 of human ACTH. At the considerably supraphysiological dose of 250 μg, cosyntropin maximally stimulates adrenocortical steroidogenesis. In the standard cosyntropin stimulation test, 250 μg of cosyntropin is administered either intramuscularly or intravenously, with cortisol measured just before administration (baseline) and 30-60 minutes after cosyntropin administration. An increase in the circulating cortisol to a level greater than 18-20 μg/dL indicates a normal response. Some accept an increase of 9 μg/dL over the baseline value as a positive response. In patients with pituitary or hypothalamic disease of recent onset or shortly after surgery for pituitary tumors, the standard cosyntropin stimulation test may be misleading because the duration of ACTH deficiency may have been insufficient to cause significant adrenal atrophy with frank loss of steroidogenic capacity. For these patients, some experts advocate a "low-dose" cosyntropin stimulation test, in which 1 μg of cosyntropin is administered intravenously, and cortisol is measured just before and 30 minutes after cosyntropin administration; the cutoff for a normal response is the same as that for the standard test. Care must be taken to avoid adsorption of the cosyntropin to plastic tubing and to measure the plasma cortisol precisely at 30 minutes after the cosyntropin injection. Although some studies indicate that the low-dose test is more sensitive than the standard 250-μg test, others report that this test also may fail to detect secondary adrenal insufficiency.

As already noted, primary adrenocortical insufficiency and secondary adrenocortical insufficiency are reliably distinguished by available sensitive assays for ACTH. More protracted ACTH stimulation tests rarely are used to differentiate between these disorders.

CRH Stimulation Test. Ovine CRH (corticorelin [acthrel]) and human CRH are available for diagnostic testing of the HPA axis, with the former used in the U.S. and the latter preferred in Europe. In patients with documented ACTH-dependent hypercorticism, CRH testing may help differentiate between a pituitary source (i.e., Cushing's disease) and an ectopic source of ACTH. After two baseline blood samples are obtained 15 minutes apart, CRH (1μg/kg) is administered intravenously over a 30- to 60-second interval, and peripheral blood samples are obtained at 15, 30, and 60 minutes for ACTH measurement. It is important that the blood samples be handled as recommended for the ACTH assay. At the recommended dose, CRH generally is well tolerated, although flushing may occur, particularly if the dose is administered as a bolus. Patients with Cushing's disease respond to CRH with either a normal or an exaggerated increase in ACTH, whereas ACTH levels generally do not increase in patients with ectopic sources of ACTH. This test is not perfect: ACTH levels are induced by CRH in occasional patients with ectopic ACTH, and ∼5-10% of patients with Cushing's disease fail to respond.

To improve the diagnostic accuracy of the CRH stimulation test, many authorities advocate sampling of blood from the inferior petrosal sinuses and the peripheral circulation after peripheral administration of CRH. In this test, an inferior petrosal/peripheral ratio of >2.5 supports a pituitary source of ACTH. When performed by a skilled neuroradiologist, this procedure increases diagnostic accuracy with a tolerable risk of complications from the catheterization procedure (Arnaldi et al., 2003).

Absorption and Fate. ACTH is readily absorbed from parenteral sites. The hormone rapidly disappears from the circulation after intravenous administration; in humans, the t_1/2 in plasma is ∼15 minutes, primarily due to rapid enzymatic hydrolysis.

Toxicity of ACTH. Aside from rare hypersensitivity reactions, the toxicity of ACTH is primarily attributable to the increased secretion of corticosteroids. Cosyntropin generally is less antigenic than native ACTH; thus, cosyntropin is the preferred agent for clinical use.

Although the adrenal cortex is an important source of androgen precursors in women, patients with adrenal insufficiency can be restored to normal life expectancy by replacement therapy with glucocorticoids and mineralocorticoids. Adrenal androgens are not essential for survival. The levels of dehydroepiandrosterone (DHEA) and its sulfated derivative DHEA-S peak in the third decade of life and decline progressively thereafter. Moreover, patients with a number of chronic diseases have very low DHEA levels, leading some to propose that DHEA treatment might at least partly alleviate the loss of libido, the decline in cognitive function, the decreased sense of well-being, and other adverse physiological consequences of aging. Whereas some studies have shown that addition of DHEA to the standard replacement regimen in women with adrenal insufficiency improved subjective well-being and sexuality, others have failed to show any benefit of DHEA replacement in either men or women (Chang et al., 2008). Nevertheless, DHEA is widely used as an over-the-counter nutritional supplement for its alleged health benefits, despite the absence of definitive data.

Traditionally, the effects of administered corticosteroids have been viewed as physiological (reflecting actions of corticosteroids at doses corresponding to normal daily production levels) or pharmacological (representing effects seen only at doses exceeding the normal daily production of corticosteroids). More recent concepts suggest that the anti-inflammatory and immunosuppressive actions of corticosteroids—one of the major "pharmacological" uses of this class of drugs—also provide a protective mechanism in the physiological setting. Many of the immune mediators associated with the inflammatory response decrease vascular tone and could lead to cardiovascular collapse if unopposed by the adrenal corticosteroids. This hypothesis is supported by the fact that the daily production rate of cortisol can rise at least 10-fold in the setting of severe stress. In addition, the pharmacological actions of corticosteroids in different tissues and the physiological effects are mediated by the same receptor. Thus the various glucocorticoid derivatives used as pharmacological agents generally have side effects on physiological processes that parallel their therapeutic effectiveness.

The actions of corticosteroids are related to those of other hormones. For example, in the absence of lipolytic hormones, cortisol has virtually no effect on the rate of lipolysis by adipocytes. Likewise, in the absence of glucocorticoids, epinephrine and norepinephrine have only minor effects on lipolysis. Administration of a small dose of glucocorticoid, however, markedly potentiates the lipolytic action of these catecholamines. 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.

Glucocorticoid Receptors. The receptors for corticosteroids are members of the nuclear receptor family of transcription factors that transduce the effects of a diverse array of small hydrophobic ligands, including the steroid hormones, thyroid hormone, vitamin D, and retinoids. These receptors share two highly conserved domains: a region of ∼70 amino acids forming two zinc-binding domains, called zinc fingers, that are essential for the interaction of the receptor with specific DNA sequences, and a region at the carboxyl terminus that interacts with ligand (the ligand-binding domain). The GR resides predominantly in the cytoplasm in an inactive form until it binds glucocorticoids (Figure 42–5). Steroid binding results in receptor activation and translocation to the nucleus. The inactive GR is complexed with other proteins, including heat-shock protein (HSP) 90, a member of the heat-shock family of stress-induced proteins; HSP70; and a 56,000-Da immunophilin, one of the group of intracellular proteins that bind the immunosuppressive agents cyclosporine and tacrolimus (see Chapter 35). HSP90, through interactions with the steroid-binding domain, may facilitate folding of the GR into an appropriate conformation that permits ligand binding.

The gene encoding the GR is located on human chromosome 5 and gives rise to several receptor isoforms as the result of alternative RNA splicing. Of these, GRα is the prototypical glucocorticoid-responsive isoform already discussed and is the best studied. A second major GR isoform, GRβ, is a truncated dominant negative variant that lacks 35 amino acids at the C-terminus and is unable to bind glucocorticoids or activate gene expression. GRβ expression is enhanced by tumor necrosis factor α and other pro-inflammatory cytokines and its relative abundance is thought to contribute to glucocorticoid resistance in some patients. Other splice variants have been identified that retain their ligand-binding activity but have amino acid insertions or deletions of the DNA-binding domain that reduce their transcriptional activity (Gross and Cidlowski, 2008). Finally, polymorphisms have been identified in the human GR that are associated with differences in GR function and have been linked to glucocorticoid insensitivity (Derijk et al., 2008).

Although complete loss of GR function apparently is lethal, mutations leading to partial loss of GR function occur in rare patients with generalized glucocorticoid resistance (Charmandari et al., 2008). These patients harbor mutations in the GR, most of which impair glucocorticoid binding and decrease transcriptional activation. As a consequence of these mutations, cortisol levels that normally mediate feedback inhibition fail to suppress the HPA axis completely. In this setting of partial loss of GR function, the HPA axis resets to a higher level to provide compensatory increases in ACTH and cortisol secretion. Because the GR defect is partial, adequate compensation for the end-organ insensitivity can result from the elevated cortisol level, but the excess ACTH secretion also stimulates the production of mineralocorticoids and adrenal androgens. Because the mineralocorticoid receptor (MR) and the androgen receptor are intact, these subjects present with manifestations of mineralocorticoid excess (hypertension and hypokalemic alkalosis) and/or of increased androgen levels (acne, hirsutism, male pattern baldness, menstrual irregularities, anovulation, and infertility). In children, the excess adrenal androgens can cause precocious sexual development.

Regulation of Gene Expression by Glucocorticoids. After ligand binding, the GR dissociates from its associated proteins and translocates to the nucleus. There, it interacts with specific DNA sequences within the regulatory regions of affected genes. The short DNA sequences that are recognized by the activated GR are called glucocorticoid responsive elements (GREs) and provide specificity to the induction of gene transcription by glucocorticoids. The consensus GRE sequence is an imperfect palindrome (GGTACAnnnTGTTCT, where n is any nucleotide) to which the GR binds as a receptor dimer. The mechanisms by which GR activates transcription are complex and not completely understood, but they involve the interaction of the GR with transcriptional coactivators and with proteins that make up the basal transcription apparatus. Genes that are negatively regulated by glucocorticoids also have been identified. One well-characterized example is the pro-opiomelanocortin gene. In this case, the GR appears to inhibit transcription by a direct interaction with a GRE in the POMC promoter, thereby contributing to the negative feedback regulation of the HPA axis. Other genes negatively regulated by glucocorticoids include genes for cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (NOS2), and inflammatory cytokines.

In some cases, the inhibitory effects of glucocorticoids on gene expression have been linked to protein–protein interactions between the GR and other transcription factors rather than to negative effects of the GR at specific GREs. Indeed, protein–protein interactions have been observed between the GR and the transcription factors NF-κB and AP-1, which regulate the expression of a number of components of the immune system (De Bosscher et al., 2003). Such interactions repress the expression of genes encoding a number of cytokines—regulatory molecules that play key roles in the immune and inflammatory networks—and enzymes, such as collagenase and stromelysin, that are proposed to play key roles in the joint destruction seen in inflammatory arthritis. Thus, these protein–protein interactions and their consequent negative effects on gene expression appear to contribute significantly to the anti-inflammatory and immunosuppressive effects of the glucocorticoids.

The recognition that the metabolic effects of glucocorticoids generally are mediated by transcriptional activation, whereas the anti-inflammatory effects largely are mediated by transrepression, suggests that selective GR ligands may maintain the anti-inflammatory actions while lessening the metabolic side effects (McMaster and Ray, 2008). Recent reports describing steroidal and nonsteroidal compounds that exhibit anti-inflammatory actions but have little effect on blood glucose suggest that such selective glucocorticoid agonists may emerge from ongoing research.

Regulation of Gene Expression by Mineralocorticoids. Like the GR, the MR also is a ligand-activated transcription factor and binds to a very similar, if not identical, hormone-responsive element. Although its actions have been studied in less detail than the GR, the basic principles of action appear to be similar; in particular, the MR also associates with HSP90 and activates the transcription of discrete sets of genes within target tissues. Studies have not yet identified differences in the DNA recognition motifs for the GR and the MR that would explain their differential capacities to activate discrete sets of target genes. The GR and MR differ in their ability to inhibit AP-1–mediated gene activation, suggesting that differential interactions with other transcription factors may underlie their distinct effects on cell function. The MR has a restricted expression: it is expressed in epithelial tissues involved in electrolyte transport (i.e., the kidney, colon, salivary glands, and sweat glands) and in nonepithelial tissues (e.g., hippocampus, heart, vasculature and adipose tissue) where its functions are less well understood.

Aldosterone exerts its effects on Na⁺ and K⁺ homeostasis primarily via its actions on the principal cells of the distal renal tubules and collecting ducts, whereas the effects on H⁺ secretion largely are exerted in the intercalated cells. The binding of aldosterone to the MR in the kidney initiates a sequence of events that includes the rapid induction of serum- and glucocorticoid-regulated kinase, which in turn phosphorylates and activates amiloride-sensitive epithelial Na⁺ channels in the apical membrane. Thereafter, increased Na⁺ influx stimulates the Na⁺, K⁺-ATPase in the basolateral membrane. In addition to these rapid genomic actions, aldosterone also increases the synthesis of the individual components of these membrane proteins as part of a more delayed effect.

Receptor-Independent Mechanism for Corticosteroid Specificity. The availability of cloned genes encoding the GR and MR led to the surprising finding that aldosterone (a classic mineralocorticoid) and cortisol (generally viewed as predominantly glucocorticoid) bind the MR with equal affinity. This raised the question of how the apparent specificity of the MR for aldosterone was maintained in the face of much higher circulating levels of glucocorticoids. We now know that the type 2 isozyme of 11β-hydroxysteroid dehydrogenase (11βHSD2) plays a key role in corticosteroid specificity, particularly in the kidney, colon, and salivary glands (Hammer and Stewart, 2006). This enzyme metabolizes glucocorticoids such as cortisol to receptor-inactive 11-keto derivatives such as cortisone (Figure 42–6). Because its predominant form in physiological settings is the hemiacetal derivative (Figure 42–7), which is resistant to 11βHSD action, aldosterone escapes this inactivation and maintains mineralocorticoid activity. In the absence of 11βHSD2, as occurs in an inherited disease called the syndrome of apparent mineralocorticoid excess, the MR is activated by cortisol, leading to severe hypokalemia and mineralocorticoid-related hypertension. A state of mineralocorticoid excess also can be induced by inhibiting 11βHSD with glycyrrhizic acid, a component of licorice implicated in licorice-induced hypertension.

The mechanisms whereby glucocorticoids inhibit glucose utilization in peripheral tissues are not fully understood. Glucocorticoids decrease glucose uptake in adipose tissue, skin, fibroblasts, thymocytes, and polymorphonuclear leukocytes; these effects are postulated to result from translocation of the glucose transporters from the plasma membrane to an intracellular location. These peripheral effects are associated with a number of catabolic actions, including atrophy of lymphoid tissue, decreased muscle mass, negative nitrogen balance, and thinning of the skin.

Similarly, the mechanisms by which the glucocorticoids promote gluconeogenesis are not fully defined. Amino acids mobilized from a number of tissues in response to glucocorticoids reach the liver and provide substrate for the production of glucose and glycogen. In the liver, glucocorticoids induce the transcription of a number of enzymes involved in gluconeogenesis and amino acid metabolism, including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, and the bifunctional enzyme fructose-2,6-bisphosphatase. Analyses of the molecular basis for regulation of PEPCK gene expression have identified complex regulatory influences involving an interplay among glucocorticoids, insulin, glucagon, and catecholamines. The effects of these hormones and amines on PEPCK gene expression mirror the complex regulation of gluconeogenesis in the intact organism.

One hypothesis for the redistribution of body fat is that peripheral and truncal adipocytes differ in their relative sensitivities to insulin and to glucocorticoid-facilitated lipolytic effects. Truncal adipocytes respond predominantly to elevated levels of insulin resulting from glucocorticoid-induced hyperglycemia, whereas peripheral adipocytes are less sensitive to insulin and respond mostly to the glucocorticoid-facilitated effects of other lipolytic hormones. This differential sensitivity may reflect differences in the expression of 11βHSD1 that converts inactive cortisone into active cortisol in target tissues (Figure 42–6). Consistent with this idea, overexpression of 11βHSD1 in adipocytes causes obesity in a transgenic mouse model. The potential role of this enzyme in adipocyte function has prompted speculation that 11βHSD1 inhibitors may have a role in the treatment of obesity.

Further insights into the roles of aldosterone target genes in fluid and electrolyte balance have emerged from analyses of patients with rare genetic disorders of mineralocorticoid action, such as pseudohypoaldosteronism and pseudoaldosteronism. Despite elevated levels of mineralocorticoids, patients with classical pseudohypoaldosteronism (i.e., type 1 disease) present with clinical manifestations suggestive of deficient mineralocorticoid action (i.e., volume depletion, hypotension, hyperkalemia, and metabolic acidosis). Molecular analyses have defined discrete subpopulations of patients with this disorder. One form of the disease is caused by autosomal dominant mutations in the MR that impair its activity. A second, autosomal recessive form results from loss-of-function mutations in genes encoding subunits of the amiloride-sensitive epithelial Na⁺ channel. A nonclassical pseudohypoaldosteronism (type 2, also known as Gordon's syndrome) presents with hyperkalemia, mild metabolic acidosis, and familial hypertension. In some of these patients, the disease is caused by autosomal dominant mutations in the protein kinase genes WNK1 and WNK4 that inhibit the sodium chloride cotransporter. Pseudoaldosteronism, also termed Liddle's syndrome, is an autosomal dominant disease that results from mutations in subunits of the amiloride-sensitive Na⁺ channel that interfere with its downregulation. The constitutive activity of this channel leads to hypertension, hypokalemia, and metabolic alkalosis, despite low levels of plasma renin and aldosterone.

Glucocorticoids also exert effects on fluid and electrolyte balance, largely due to permissive effects on tubular function and actions that maintain glomerular filtration rate. Glucocorticoids play a permissive role in the renal excretion of free water. In part, the inability of patients with glucocorticoid deficiency to excrete free water results from the increased secretion of AVP, which stimulates water reabsorption in the kidney.

In addition to their effects on monovalent cations and water, glucocorticoids also exert multiple effects on Ca²⁺ metabolism. Steroids lower Ca²⁺ uptake from the gut and increase Ca²⁺ excretion by the kidney. These effects collectively lead to decreased total body Ca²⁺ stores.

Patients with adrenal insufficiency exhibit a diverse array of neurological manifestations, including apathy, depression, and irritability; some patients are frankly psychotic. Appropriate replacement therapy corrects these abnormalities. Conversely, glucocorticoid administration can induce multiple CNS reactions. Most patients respond with mood elevation, which may impart a sense of well-being despite the persistence of underlying disease. Some patients exhibit more pronounced behavioral changes, such as mania, insomnia, restlessness, and increased motor activity. A smaller but significant percentage of patients treated with glucocorticoids become anxious, depressed, or overtly psychotic. A high incidence of neuroses and psychoses is seen in patients with Cushing's syndrome. These abnormalities usually disappear after cessation of glucocorticoid therapy or treatment of the Cushing's syndrome.

The mechanisms whereby corticosteroids affect neuronal activity are unknown, but it has been proposed that steroids produced locally in the brain (termed neurosteroids) may regulate neuronal excitability. In rodent models, very high doses of glucocorticoids decrease survival and function of hippocampal neurons; in association with these changes, memory also is diminished. In one study in human subjects, basal cortisol levels correlated directly with hippocampal atrophy and memory deficits. To the extent that these results are confirmed, they may have important prognostic implications for age-related memory decline, and for therapeutic approaches directed at diminishing the negative effects of glucocorticoids on hippocampal neurons with aging.

Corticosteroids also affect circulating white blood cells. Addison's disease is associated with an increased mass of lymphoid tissue and lymphocytosis. In contrast, Cushing's syndrome is characterized by lymphocytopenia and decreased mass of lymphoid tissue. The administration of glucocorticoids leads to a decreased number of circulating lymphocytes, eosinophils, monocytes, and basophils. A single dose of hydrocortisone leads to a decline of these circulating cells within 4-6 hours; this effect persists for 24 hours and results from the redistribution of cells away from the periphery rather than from increased destruction. In contrast, glucocorticoids increase circulating polymorphonuclear leukocytes as a result of increased release from the marrow, diminished rate of removal from the circulation, and decreased adherence to vascular walls. Finally, certain lymphoid malignancies are destroyed by glucocorticoid treatment, an effect that may relate to the ability of glucocorticoids to activate programmed cell death.

Multiple mechanisms are involved in the suppression of inflammation by glucocorticoids. Glucocorticoids inhibit the production by multiple cells of factors that are critical in generating the inflammatory response. As a result, there is decreased release of vasoactive and chemoattractive factors, diminished secretion of lipolytic and proteolytic enzymes, decreased extravasation of leukocytes to areas of injury, and ultimately, decreased fibrosis. Glucocorticoids can also reduce expression of pro-inflammatory cytokines, as well as COX-2 and NOS2. Some of the cell types and mediators that are inhibited by glucocorticoids are summarized in Table 42–3. The net effect of these actions on various cell types is to diminish markedly the inflammatory response.

The influence of stressful conditions on immune defense mechanisms is well documented, as is the contribution of the HPA axis to the stress response (Elenkov and Chrousos, 2006). This has led to a growing appreciation of the importance of glucocorticoids as physiological modulators of the immune system, where glucocorticoids appear to protect the organism against life-threatening consequences of a full-blown inflammatory response (Chrousos, 1995).

Stresses such as injury, infection, and disease result in the increased production of cytokines, a network of signaling molecules that integrate actions of macrophages/monocytes, T lymphocytes, and B lymphocytes in mounting immune responses. Among these cytokines, interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNF-α) stimulate the HPA axis, with IL-1 having the broadest range of actions. IL-1 stimulates the release of CRH by hypothalamic neurons, interacts directly with the pituitary to increase the release of ACTH, and may directly stimulate the adrenal gland to produce glucocorticoids. As detailed earlier, the increased production of glucocorticoids, in turn, profoundly inhibits the immune system at multiple sites. Factors that are inhibited include components of the cytokine network, including interferon γ (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukins (IL-1, IL-2, IL-3, IL-6, IL-8, and IL-12), and TNF-α. Thus, the HPA axis and the immune system are capable of bidirectional interactions in response to stress, and these interactions appear to be important for homeostasis (Chrousos, 1995).

All of the biologically active adrenocortical steroids and their synthetic congeners have a double bond in the 4,5 position and a ketone group at C3 (Figure 42–7). As a general rule, the metabolism of steroid hormones involves sequential additions of oxygen or hydrogen atoms, followed by conjugation to form water-soluble derivatives. Reduction of the 4,5 double bond occurs at both hepatic and extrahepatic sites, yielding inactive compounds. Subsequent reduction of the 3-ketone substituent to the 3-hydroxyl derivative, forming tetrahydrocortisol, occurs only in the liver. Most of these A ring–reduced steroids are conjugated through the 3-hydroxyl group with sulfate or glucuronide by enzymatic reactions that take place in the liver and, to a lesser extent, in the kidney. The resultant sulfate esters and glucuronides are water soluble and the predominant forms excreted in urine. Neither biliary nor fecal excretion is of quantitative importance in humans.

Synthetic steroids with an 11-keto group, such as cortisone and prednisone, must be enzymatically reduced to the corresponding 11β-hydroxy derivative before they are biologically active. The type 1 isozyme of 11β-hydroxysteroid dehydrogenase (11βHSD1) catalyzes this reduction, predominantly in the liver, but also in specialized sites such as adipocytes, bone, eye, and skin. In settings in which this enzymatic activity is impaired, it is prudent to use steroids that do not require enzymatic activation (e.g., hydrocortisone or prednisolone rather than cortisone or prednisone). Such settings include severe hepatic failure and patients with the rare condition of cortisone reductase deficiency, who are unable to activate the 11-keto steroids because of a defect in the enzyme hexose-6-phosphate dehydrogenase, which regulates the activity of 11β-hydroxysteroid dehydrogenase by supplying required reducing equivalents (Lavery et al., 2008).

Structure–Activity Relationships

Chemical modifications to the cortisol molecule have generated derivatives with greater separations of glucocorticoid and mineralocorticoid activity; for a number of synthetic glucocorticoids, the effects on electrolytes are minimal even at the highest doses used (Table 42–2). In addition, these modifications have led to derivatives with greater potencies and with longer durations of action. A vast array of steroid preparations is available for oral, parenteral, and topical use. Some of these agents are summarized in Table 42–4. None of these currently available derivatives effectively separates anti-inflammatory effects from effects on carbohydrate, protein, and fat metabolism, or from suppressive effects on the HPA axis.

The structures of hydrocortisone (cortisol) and some of its major derivatives are shown in Figure 42–7. Changes in chemical structure may alter the specificity and/or potency due to changes in affinity and intrinsic activity at corticosteroid receptors, and alterations in absorption, protein binding, rate of metabolic transformation, rate of excretion, or membrane permeability. The effects of various substitutions on glucocorticoid and mineralocorticoid activity and on duration of action are summarized in Table 42–2. The 4,5 double bond and the 3-keto group on ring A are essential for glucocorticoid and mineralocorticoid activity; an 11β-hydroxyl group on ring C is required for glucocorticoid activity but not mineralocorticoid activity; a hydroxyl group at C21 on ring D is present on all natural corticosteroids and on most of the active synthetic analogs, and seems to be an absolute requirement for mineralocorticoid but not glucocorticoid activity. The 17α-hydroxyl group on ring D is a substituent on cortisol and on all of the currently used synthetic glucocorticoids. Although steroids without the 17α hydroxyl group (e.g., corticosterone) have appreciable glucocorticoid activity, the 17α-hydroxyl group gives optimal potency.

Introduction of an additional double bond in the 1,2 position of ring A, as in prednisolone or prednisone, selectively increases glucocorticoid activity, and results in an enhanced glucocorticoid/ mineralocorticoid potency ratio. This modification also results in compounds that are metabolized more slowly than hydrocortisone.

Fluorination at the 9α position on ring B enhances both glucocorticoid and mineralocorticoid activity, possibly related to an electron-withdrawing effect on the nearby 11β-hydroxyl group. Fludrocortisone (9α-fluorocortisol) has enhanced activity at the GR (10 times relative to cortisol) but even greater activity at the MR (125 times relative to cortisol). It is used in mineralocorticoid replacement therapy and has no appreciable glucocorticoid effect at usual daily doses of 0.05-0.2 mg. When combined with the 1,2 double bond in ring A plus other substitutions at C16 on ring D (Figure 42–7), the 9α-fluoro derivatives formed (e.g., triamcinolone, dexamethasone, and betamethasone) have marked glucocorticoid activity—the substitutions at C16 virtually eliminate mineralocorticoid activity.

Other Substitutions. 6α Substitution on ring B has somewhat unpredictable effects. 6α-Methylcortisol has increased glucocorticoid and mineralocorticoid activity, whereas 6α-methylprednisolone has somewhat greater glucocorticoid activity and somewhat less mineralocorticoid activity than prednisolone. A number of modifications convert the glucocorticoids to more lipophilic molecules with enhanced topical/systemic potency ratios. Examples include the introduction of an acetonide between hydroxyl groups at C16 and C17, esterification of the hydroxyl group with valerate at C17, esterification of hydroxyl groups with propionate at C17 and C21, and substitution of the hydroxyl group at C21 with chlorine. Other approaches to achieve local glucocorticoid activity while minimizing systemic effects involve the formation of analogs that are rapidly inactivated after absorption (e.g., C21 carboxylate or carbothioate glucocorticoid esters, which are rapidly metabolized to inactive 21-carboxylic acids) or the formation of inactive analogs that are selectively activated at their site of action (e.g., glucocorticoid C21 isobutyryl or propionyl esters that are hydrolyzed to active C21 alcohols by airway-specific esterases).

In an effort to diminish the risk of iatrogenic acute adrenal insufficiency, protocols for discontinuing corticosteroid therapy in patients receiving long-term treatment with corticosteroids have been proposed, generally without rigorous documentation of their efficacy. Patients who have received supraphysiological doses of glucocorticoids for a period of 2-4 weeks within the preceding year should be considered to have some degree of HPA impairment in settings of acute stress and should be treated accordingly.

In addition to this most severe form of withdrawal, a characteristic glucocorticoid withdrawal syndrome consists of fever, myalgia, arthralgia, and malaise, which may be difficult to differentiate from some of the underlying diseases for which steroid therapy was instituted (Hochberg et al., 2003). Finally, pseudotumor cerebri, a clinical syndrome that includes increased intracranial pressure with papilledema, is a rare condition that sometimes is associated with reduction or withdrawal of corticosteroid therapy.

Fluid and Electrolyte Handling. Alterations in fluid and electrolyte handling can cause hypokalemic alkalosis and hypertension, particularly in patients with primary hyperaldosteronism secondary to an adrenal adenoma or in patients treated with potent mineralocorticoids. Similarly, hypertension is a relatively common manifestation of glucocorticoid excess, even in patients treated with glucocorticoids lacking appreciable mineralocorticoid activity.

Metabolic Changes. The effects of glucocorticoids on intermediary metabolism have already been described. Hyperglycemia with glycosuria usually can be managed with diet and/or insulin, and its occurrence should not be a major factor in the decision to continue corticosteroid therapy or to initiate therapy in diabetic patients.

Immune Responses. Because of their multiple effects to inhibit the immune system and the inflammatory response, glucocorticoid use is associated with an increased susceptibility to infection and a risk for reactivation of latent tuberculosis. In the presence of known infections of some consequence, glucocorticoids should be administered only if absolutely necessary and concomitantly with appropriate and effective antimicrobial or antifungal therapy.

Possible Risk of Peptic Ulcers. There is considerable debate about the association between peptic ulcers and glucocorticoid therapy. The possible onset of hemorrhage and perforation in these ulcers and their insidious onset make peptic ulcers a serious therapeutic problem (Chapter 45); estimating the degree of risk from corticosteroids has received much study. Most patients who develop gastrointestinal bleeding while receiving corticosteroids also receive nonsteroidal anti-inflammatory agents, which are known to promote ulceration, such that the pathogenic role of corticosteroids remains open to debate. Nonetheless, it is prudent to be especially vigilant for peptic ulcer formation in patients receiving therapy with corticosteroids, especially if administered concomitantly with nonsteroidal anti-inflammatory drugs.

Myopathy. Myopathy, characterized by weakness of proximal limb muscles, can occur in patients taking large doses of corticosteroids and also is part of the clinical picture in patients with endogenous Cushing's syndrome. It can be of sufficient severity to impair ambulation and is an indication for withdrawal of therapy. Attention also has focused on steroid myopathy of the respiratory muscles in patients with asthma or chronic obstructive pulmonary disease (Chapter 36); this complication can diminish respiratory function. Recovery from the steroid myopathies may be slow and incomplete.

Behavioral Changes. Behavioral disturbances are common after administration of corticosteroids and in patients who have Cushing's syndrome secondary to endogenous hypercorticism; these disturbances may take many forms, including nervousness, insomnia, changes in mood or psyche, and overt psychosis. Suicidal tendencies are not uncommon. A history of previous psychiatric illness does not preclude the use of steroids in patients for whom they are otherwise indicated. Conversely, the absence of a history of previous psychiatric illness does not guarantee that a given patient will not develop psychiatric disorders while on steroids.

Cataracts. Cataracts are a well-established complication of glucocorticoid therapy and related to dosage and duration of therapy. Children appear to be particularly at risk. Cessation of therapy may not lead to complete resolution of opacities, and the cataracts may progress despite reduction or cessation of therapy. Patients on long-term glucocorticoid therapy at doses of prednisone of ≥10-15 mg/day should receive periodic slit-lamp examinations to detect glucocorticoid-induced posterior subcapsular cataracts.

Osteoporosis. Osteoporosis, a frequent serious complication of glucocorticoid therapy, occurs in patients of all ages and is related to dosage and duration of therapy (Woolf, 2007). A reasonable estimate is that 30-50% of all patients who receive chronic glucocorticoid therapy ultimately will develop osteoporotic fractures. Glucocorticoids preferentially affect trabecular bone and the cortical rim of the vertebral bodies; the ribs and vertebrae are the most frequent sites of fracture. Glucocorticoids decrease bone density by multiple mechanisms, including inhibition of gonadal steroid hormones, diminished gastrointestinal absorption of Ca²⁺, and inhibition of bone formation due to suppressive effects on osteoblasts and stimulation of resorption by osteoclasts via changes in the production of osteoprotegerin and RANK ligand. In addition, glucocorticoid inhibition of intestinal Ca²⁺ uptake may lead to secondary increases in parathyroid hormone, thereby increasing bone resorption.

The considerable morbidity of glucocorticoid-related osteoporosis has led to efforts to identify patients at risk for fractures and to prevent or reverse bone loss in patients requiring chronic glucocorticoid therapy. The initiation of glucocorticoid therapy—that is, ≥5 mg/day prednisone (or its equivalent) for ≥3 months—is considered an indication for bone densitometry to detect abnormalities in trabecular bone. Because bone loss associated with glucocorticoids predominantly occurs within the first 6 months of therapy, densitometric evaluation, preferably with techniques such as dual-energy x-ray absorptiometry of the lumbar spine and hip, along with prophylactic measures should be initiated with therapy or shortly thereafter. Most authorities advocate maintaining a Ca²⁺ intake of 1500 mg/day by diet plus Ca²⁺ supplementation and vitamin D intake of 800 IU/day, assuming that these measures do not increase urinary calcium excretion above the normal range. Although gonadal hormone replacement therapy has been widely used in specific groups of patients receiving chronic glucocorticoid therapy, this is the subject of considerable debate based on recently published results from randomized placebo-controlled trials (Chapter 40). Recombinant parathyroid hormone 1-34 (teriparatide, FORTEO) also has received considerable attention as a potential therapy of glucocorticoid-induced osteoporosis.

The most important advance to date in the prevention of glucocorticoid-related osteoporosis is the successful use of bisphosphonates, which have been shown to decrease the decline in bone density and the incidence of fractures in patients receiving glucocorticoid therapy. Additional discussion of these issues is found in Chapters 40 and 44.

Osteonecrosis. Osteonecrosis (also known as avascular or aseptic necrosis) is a relatively common complication of glucocorticoid therapy. The femoral head is affected most frequently, but this process also may affect the humeral head and distal femur. Joint pain and stiffness usually are the earliest symptoms, and this diagnosis should be considered in patients receiving glucocorticoids who abruptly develop hip, shoulder, or knee pain. Although the risk increases with the duration and dose of glucocorticoid therapy, osteonecrosis also can occur when high doses of glucocorticoids are given for short periods of time. Osteonecrosis generally progresses, and most affected patients ultimately require joint replacement.

Regulation of Growth and Development. Growth retardation in children can result from administration of relatively small doses of glucocorticoids. Although the precise mechanism is unknown, there are reports that collagen synthesis and linear growth in these children can be restored by treatment with growth hormone; further studies are needed to define the role of concurrent treatment with growth hormone in this setting. Further studies also are needed to explore the possible effects of exposure to corticosteroids in utero. In experimental animals, antenatal exposure to glucocorticoids is clearly linked to cleft palate and altered neuronal development, ultimately resulting in complex behavioral abnormalities. Thus, although the actions of glucocorticoids to promote cellular differentiation play important physiological roles in human development in late gestation and in the neonatal period (e.g., production of pulmonary surfactant and induction of hepatic gluconeogenic enzymes), the possibility remains that antenatal steroids can lead to subtle abnormalities in fetal development.

The lack of demonstrated deleterious effects of a single dose of glucocorticoids within the conventional therapeutic range justifies their administration to critically ill patients who may have adrenal insufficiency. If the underlying condition does result from deficiency of glucocorticoids, then a single intravenous injection of a soluble glucocorticoid may prevent immediate death and allow time for a definitive diagnosis to be made. If the underlying disease is not adrenal insufficiency, the single dose will not harm the patient.

In the absence of specific contraindications, short courses of high-dose systemic glucocorticoids also may be given for diseases that are not life threatening, but the general rule is that long courses of therapy at high doses should be reserved for life-threatening disease. In selected settings, as when a patient is threatened with permanent disability, this rule is justifiably violated.

In an attempt to dissociate therapeutic effects from undesirable side effects, various regimens of steroid administration have been used. To diminish HPA axis suppression, the intermediate-acting steroid preparations (e.g., prednisone or prednisolone) should be given in the morning as a single dose. Alternate-day therapy with the same glucocorticoids also has been employed because certain patients obtain adequate therapeutic responses on this regimen. Alternatively, pulse therapy with higher glucocorticoid doses (e.g., doses as high as 1 to 1.5 g/day of methylprednisolone for 3 days) frequently is used to initiate therapy in patients with fulminant, immunologically related disorders such as acute transplantation rejection, necrotizing glomerulonephritis, and lupus nephritis. The benefit of such pulse therapy in long-term maintenance regimens remains to be defined.

The immediate management of patients with acute adrenal insufficiency includes intravenous therapy with isotonic sodium chloride solution supplemented with 5% glucose and corticosteroids and appropriate therapy for precipitating causes such as infection, trauma, or hemorrhage. Because cardiac function often is reduced in the setting of adrenocortical insufficiency, the patient should be monitored for evidence of volume overload such as rising central venous pressure or pulmonary edema. After an initial intravenous bolus of 100 mg, hydrocortisone (cortisol) should be given by continuous infusion at a rate of 50-100 mg every 8 hours. At this dose, which approximates the maximum daily rate of cortisol secretion in response to stress, hydrocortisone alone has sufficient mineralocorticoid activity to meet all requirements. As the patient stabilizes, the hydrocortisone dose may be decreased to 25 mg every 6-8 hours. Thereafter, patients are treated in the same fashion as those with chronic adrenal insufficiency.

For the treatment of suspected but unconfirmed acute adrenal insufficiency, 4 mg of dexamethasone sodium phosphate can be substituted for hydrocortisone because dexamethasone does not cross-react in the cortisol assay and will not interfere with the measurement of cortisol (either basally or in response to the cosyntropin stimulation test). A failure to respond to cosyntropin in this setting is diagnostic of adrenal insufficiency. Often, a sample for the measurement of plasma ACTH also is obtained because it will provide information about the underlying etiology if the diagnosis of adrenocortical insufficiency is established.

Traditional replacement regimens have used hydrocortisone in doses of 20-30 mg/day. Cortisone acetate, which is inactive until converted to cortisol by 11βHSD1, also has been used in doses ranging from 25-37.5 mg/day. In an effort to mimic the normal diurnal rhythm of cortisol secretion, these glucocorticoids generally have been given in divided doses, with two-thirds of the dose given in the morning and one-third given in the afternoon. Based on revised estimates of daily cortisol production and clinical studies showing that subtle degrees of glucocorticoid excess can decrease bone density in patients on conventional replacement regimens, many authorities advocate a lower hydrocortisone dose of 15-20 mg/day divided into either two doses (e.g., 10-15 mg on awakening and 5 mg in late afternoon) or three doses (e.g., 10 mg on awakening, 5 mg at lunch, and 5 mg in late afternoon). Others prefer to use intermediate- (e.g., prednisone) or long-acting (e.g., dexamethasone) glucocorticoids because no regimen employing shorter-acting steroids can reproduce the peak serum glucocorticoid levels that normally occur before awakening in the morning. The superiority of any one of these regimens has not been rigorously demonstrated. Although some patients with primary adrenal insufficiency can be maintained on hydrocortisone and liberal salt intake, most of these patients also require mineralocorticoid replacement; fludrocortisone acetate generally is used in doses of 0.05-0.2 mg/day. For patients with secondary adrenal insufficiency, the administration of a glucocorticoid alone is generally adequate because the zona glomerulosa, which makes mineralocorticoids, is intact. When initiating treatment in patients with panhypopituitarism, it is important to administer glucocorticoids before initiating treatment with thyroid hormone because the administration of thyroid hormone may precipitate acute adrenal insufficiency by increasing the metabolism of cortisol.

The adequacy of corticosteroid replacement therapy is judged by clinical criteria and biochemical measurements. The subjective well-being of the patient is an important clinical parameter in primary and secondary disease. In primary adrenal insufficiency the disappearance of hyperpigmentation and the resolution of electrolyte abnormalities are valuable indicators of adequate replacement. Overtreatment may cause manifestations of Cushing's syndrome in adults and decreased linear growth in children. Plasma ACTH levels may be used to monitor therapy in patients with primary adrenal insufficiency; the early-morning ACTH level should not be suppressed but should be <100 pg/mL (22 pmol/L). Although advocated by some endocrinologists, assessments of daily profiles of cortisol based on multiple blood samples or measurements of urinary free cortisol have been used more frequently as research tools than as a routine part of clinical practice.

Standard doses of glucocorticoids often must be adjusted upward in patients who also are taking drugs that increase their metabolic clearance (e.g., phenytoin, barbiturates, or rifampin). Dosage adjustments also are needed to compensate for the stress of intercurrent illness, and proper patient education is essential for the execution of these adjustments. All patients with adrenal insufficiency should wear a medical alert bracelet or tag that lists their diagnosis and carries information about their steroid regimen. During minor illness, the glucocorticoid dose should be doubled. Patients should be instructed to contact their physician if nausea and vomiting preclude the retention of oral medications. The patient and family members should also be trained to administer parenteral dexamethasone (4 mg subcutaneously or intramuscularly) in the event that severe nausea or vomiting precludes the oral administration of medications; they then should seek medical attention immediately. Based largely on empirical data, glucocorticoid doses also are adjusted when patients with adrenal insufficiency undergo either elective or emergency surgery (Axelrod, 2003). In this setting, the doses are designed to approximate or exceed the maximal cortisol secretory rate of 200 mg/day; a standard regimen is hydrocortisone, 100 mg parenterally every 8 hours. Following surgery, the dose is halved each day until it is reduced to routine maintenance levels. Although some data suggest that increases in dose to this degree are not essential for survival even in major surgery, this approach remains the standard clinical practice.

In ∼90% of patients, CAH results from mutations in CYP21, the enzyme that carries out the 21-hydroxylation reaction (Figure 42–3). Clinically, patients are divided into those with classic CAH, who have severe defects in enzymatic activity and first present during childhood, and those with nonclassic CAH, who present after puberty with signs and symptoms of mild androgen excess such as hirsutism, amenorrhea, infertility, and acne. Female patients with classic CAH, if not treated in utero with glucocorticoids, frequently are born with virilized external genitalia (female pseudohermaphroditism), which results from elevated production of adrenal androgen precursors at critical stages of sexual differentiation in utero. Males appear normal at birth and later may have precocious development of secondary sexual characteristics (isosexual precocious puberty). In both sexes, linear growth is accelerated in childhood, but the adult height is reduced by premature closure of the epiphyses.

A subset of patients with classical CAH are unable to conserve Na⁺ normally and thus are called "salt wasters." These patients can present with cardiovascular collapse secondary to volume depletion. In an effort to prevent such life-threatening events, especially in males who appear normal at birth, many centers routinely screen all newborn babies for elevated levels of 17-hydroxyprogesterone, the immediate steroid precursor to the enzymatic block.

All patients with classical CAH require replacement therapy with hydrocortisone or a suitable congener, and those with salt wasting also require mineralocorticoid replacement. The goals of therapy are to restore levels of physiological steroid hormones to the normal range and to suppress ACTH and thereby abrogate the effects of overproduction of adrenal androgens. The typical oral dose of hydrocortisone is ∼0.6 mg/kg daily in two or three divided doses. The mineralocorticoid used is fludrocortisone acetate (0.05-0.2 mg/day). Many experts also administer table salt to infants (one-fifth of a teaspoon dissolved in formula daily) until the child is eating solid food. Therapy is guided by gain in weight and height, by plasma levels of 17-hydroxyprogesterone, and by blood pressure. Elevated plasma renin activity suggests that the patient is receiving an inadequate dose of mineralocorticoid. Sudden spurts in linear growth often indicate inadequate pituitary suppression and excessive androgen secretion, whereas growth failure suggests overtreatment with glucocorticoid.

The ability to detect classical CAH (21-hydroxylase deficiency) prenatally has made possible the treatment of affected females with glucocorticoids in utero, potentially eliminating the need for genital surgery to correct the virilization of the external genitalia. To suppress fetal adrenal androgen production effectively and consequent virilization, glucocorticoid therapy (e.g., dexamethasone, 20 μg/kg taken daily orally by mothers at risk) must be initiated before 10 weeks of gestation, before a definitive diagnosis of CAH can be made. The genotype and sex of the fetus then are determined, and steroid therapy is stopped if the sex is male or there is at least one wild-type allele for 21-hydroxylase. If genotyping reveals an affected female, steroid therapy is continued until delivery. A large-scale study currently is in progress to determine if exposure to glucocorticoids in utero has developmental consequences. To date, no adverse effects on developmental milestones and cognitive development have been noted; however, increased shyness and internalization behavior have been observed in small pilot study and will need to be reevaluated in the larger trial. Potential maternal side effects include hypertension, weight gain, edema, and mood changes.

Rheumatic Disorders. Glucocorticoids are used widely in the treatment of a variety of rheumatic disorders and are a mainstay in the treatment of the more serious inflammatory rheumatic diseases, such as systemic lupus erythematosus, and a variety of vasculitic disorders, such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, and giant cell arteritis. For these more serious disorders, the starting dose of glucocorticoids should be sufficient to suppress the disease rapidly and minimize resultant tissue damage. Initially, prednisone (1 mg/kg per day in divided doses) often is used, generally followed by consolidation to a single daily dose, with subsequent tapering to a minimal effective dose as determined by the clinical picture.

Although they are an important component of treatment of rheumatic diseases, glucocorticoids are often used in conjunction with other immunosuppressive agents such as cyclophosphamide and methotrexate, which offer better long-term control than steroids alone. The exception is giant cell arteritis, for which glucocorticoids remain superior to other agents. Caution should be exercised in the use of glucocorticoids in some forms of vasculitis (e.g., polyarteritis nodosa), for which underlying infections with hepatitis viruses may play a pathogenetic role. Although glucocorticoids are indicated in these cases, there is at least a theoretical concern that glucocorticoids may complicate the course of the viral infection by suppressing the immune system. To facilitate drug tapering and/or conversion to alternate-day treatment regimens, the intermediate-acting glucocorticoids such as prednisone and methylprednisolone are generally preferred over longer-acting steroids such as dexamethasone.

In rheumatoid arthritis, because of the serious and debilitating side effects associated with chronic use, glucocorticoids are used as stabilizing agents for progressive disease that fails to respond to first-line treatments such as physiotherapy and nonsteroidal anti-inflammatory agents. In this case, glucocorticoids provide relief until other, slower-acting antirheumatic drugs, such as methotrexate or agents targeted at tumor necrosis factor, take effect. A typical starting dose is 5-10 mg of prednisone per day. In the setting of an acute exacerbation, higher doses of glucocorticoids may be employed (typically 20-40 mg/day of prednisone or equivalent), with rapid taper thereafter. Complete relief of symptoms is not sought, and the symptomatic effect of small reductions in dose (decreases of perhaps 1 mg/day of prednisone every 2-3 weeks) should be tested frequently while concurrent therapy with other measures is continued, to maintain the lowest possible prednisone dose. Alternatively, patients with major symptomatology confined to one or a few joints may be treated with intra-articular steroid injections. Depending on joint size, typical doses are 5-20 mg of triamcinolone acetonide or its equivalent.

In noninflammatory degenerative joint diseases (e.g., osteoarthritis) or in a variety of regional pain syndromes (e.g., tendinitis or bursitis), glucocorticoids may be administered by local injection for the treatment of episodic disease flare-up. It is important to use a glucocorticoid that does not require bioactivation (e.g., prednisolone rather than prednisone) and to minimize the frequency of local steroid administration whenever possible. In the case of repeated intra-articular injection of steroids, there is a significant incidence of painless joint destruction, resembling Charcot's arthropathy. It is recommended that intra-articular injections be performed with intervals of at least 3 months to minimize complications.

Renal Diseases. Patients with nephrotic syndrome secondary to minimal change disease generally respond well to steroid therapy, and glucocorticoids clearly are the first-line treatment in both adults and children. Initial daily doses of prednisone are 1-2 mg/kg for 6 weeks, followed by a gradual tapering of the dose over 6-8 weeks, although some nephrologists advocate alternate-day therapy. Objective evidence of response, such as diminished proteinuria, is seen within 2-3 weeks in 85% of patients, and >95% of patients have remission within 3 months. Cessation of steroid therapy frequently is complicated by disease relapse, as manifested by recurrent proteinuria. Patients who relapse repeatedly are termed steroid-resistant and often are treated with other immunosuppressive drugs such as azathioprine or cyclophosphamide. Patients with renal disease secondary to systemic lupus erythematosus also are generally given a therapeutic trial of glucocorticoids.

Studies with other forms of renal disease, such as membranous and membranoproliferative glomerulonephritis and focal sclerosis, have provided conflicting data on the role of glucocorticoids. In clinical practice, patients with these disorders often are given a therapeutic trial of glucocorticoids with careful monitoring of laboratory indices of response. In the case of membranous glomerulonephritis, many nephrologists recommend a trial of alternate-day glucocorticoids for 8-10 weeks (e.g., prednisone, 120 mg every other day), followed by a 1- to 2-month period of tapering.

Allergic Disease. The onset of action of glucocorticoids in allergic diseases is delayed, and patients with severe allergic reactions such as anaphylaxis require immediate therapy with epinephrine. The manifestations of allergic diseases of limited duration—such as hay fever, serum sickness, urticaria, contact dermatitis, drug reactions, bee stings, and angioneurotic edema—can be suppressed by adequate doses of glucocorticoids given as supplements to the primary therapy. In severe disease, intravenous glucocorticoids (methylprednisolone, 125 mg intravenously every 6 hours, or equivalent) are appropriate. In less severe disease, antihistamines are the drugs of first choice. In allergic rhinitis, intranasal steroids are now viewed as the drug of choice by many experts.

Bronchial Asthma and Other Pulmonary Conditions. Corticosteroids frequently are used in bronchial asthma (Chapter 36). Although they sometimes are employed in chronic obstructive pulmonary disease (COPD), particularly when there is some evidence of reversible obstructive disease, data supporting the efficacy of corticosteroids are much less convincing than for bronchial asthma. The increased use of corticosteroids in asthma reflects an increased appreciation of the role of inflammation in the immunopathogenesis of this disorder. In severe asthma attacks requiring hospitalization, treatment with high-dose parenteral glucocorticoids is essential. Symptomatic relief sometimes is very rapid; however, the onset of a maintained response may take up to 6-12 hours. Intravenous administration of 60-120 mg methylprednisolone (or equivalent) every 6 hours is used initially, followed by daily oral doses of prednisone (30-60 mg) as the acute attack resolves. The dose then is tapered gradually, with withdrawal planned for 10 days to 2 weeks after initiation of steroid therapy. In general, patients subsequently can be managed on their prior medical regimen.

Less severe acute exacerbations of asthma (as well as acute flares of COPD) often are treated with brief courses of oral glucocorticoids. In adult patients, 30-60 mg prednisone is administered daily for 5 days; an additional week of therapy at lower doses also may be required. Upon resolution of the acute exacerbation, the glucocorticoids generally can be rapidly tapered without significant deleterious effects. Any suppression of adrenal function usually dissipates within 1-2 weeks. In the treatment of severe chronic bronchial asthma (or, less frequently, COPD) that is not controlled by other measures, the long-term administration of glucocorticoids may be necessary. As with other long-term uses of these agents, the lowest effective dose is used, and care must be exercised when withdrawal is attempted. Given the risks of long-term treatment with glucocorticoids, it is especially important to document objective evidence of a response (e.g., an improvement in pulmonary function tests). In addition, these risks dictate that long-term glucocorticoid therapy be reserved for those patients who have failed to respond to adequate regimens of other medications (Chapter 36).

In many patients, inhaled steroids (see Table 42–4) can either reduce the need for oral corticosteroids or replace them entirely. Many physicians prefer inhaled glucocorticoids over previously recommended oral theophylline in the treatment of children with moderately severe asthma, in part because of the behavioral toxicity associated with chronic theophylline administration. The oral bioavailability of inhaled corticosteroids varies considerably; however, when used as recommended, inhaled glucocorticoids are effective in reducing bronchial hyperreactivity and are less likely to suppress adrenal function than are the oral glucocorticoids. Dysphonia or oropharyngeal candidiasis may develop, but the incidence of such side effects can be reduced substantially by maneuvers that reduce drug deposition in the oral cavity, such as spacers and mouth rinsing or by using corticosteroids with low oral bioavailability. For example, ciclesonide (alvesco, omnaris) and beclomethasone dipropionate (beconase aq, qvar), are inactive compounds that are activated on site by lung esterases; therefore they are less likely to adversely affect the oral cavity (Derendorf et al., 2006). The status of glucocorticoids in asthma therapy is discussed in Chapter 36.

Antenatal glucocorticoids are used frequently in the setting of premature labor, decreasing the incidence of respiratory distress syndrome, intraventricular hemorrhage, and death in infants delivered prematurely. Betamethasone (12 mg intramuscularly every 24 hours for two doses) or dexamethasone (6 mg intramuscularly every 12 hours for four doses) is administered to women with definitive signs of premature labor between 26 and 34 weeks of gestation (Roberts and Dalziel, 2006). Due to evidence of decreased birthweight and adrenal suppression in infants whose mothers were given repeated courses of glucocorticoids, only a single course of glucocorticoids should be administered.

Infectious Diseases. Although the use of immunosuppressive glucocorticoids in infectious diseases may seem paradoxical, there are a limited number of settings in which they are indicated in the therapy of specific infectious pathogens. One dramatic example of such beneficial effects is seen in AIDS patients with Pneumocystis carinii pneumonia and moderate to severe hypoxia; addition of glucocorticoids to the antibiotic regimen increases oxygenation and lowers the incidence of respiratory failure and mortality. Similarly, glucocorticoids clearly decrease the incidence of long-term neurological impairment associated with Haemophilus influenzae type b meningitis in infants and children ≥2 months of age.

A long-standing controversy in medicine is the use of glucocorticoids in septic shock (Sprung et al., 2008). Supraphysiological doses of glucocorticoids had been used routinely as adjunctive therapy in subjects with septic shock associated with gram-negative bacteremia until it was recognized that glucocorticoid therapy in supraphysiologic doses actually increased mortality. Subsequent studies then examined the benefit of somewhat lower doses of glucocorticoids (e.g., 100 mg hydrocortisone every 8 hours) administered to patients early in the course of their disease. In one multicenter randomized placebo-controlled trial, beneficial effects of hydrocortisone plus fludrocortisone were seen only in subjects with adrenal insufficiency as determined by the rapid cosyntropin stimulation test. Although a second large study using hydrocortisone alone failed to demonstrate a beneficial effect regardless of adrenal status, current guidelines suggest that hydrocortisone be used in adult patients with septic shock whose blood pressure fails to respond adequately to fluids and vasopressors (Dellinger et al., 2008).

Ocular Diseases. Ocular pharmacology, including some consideration of the use of glucocorticoids, is discussed in Chapter 64. Glucocorticoids frequently are used to suppress inflammation in the eye and can preserve sight when used properly. They are administered topically for diseases of the outer eye and anterior segment and attain therapeutic concentrations in the aqueous humor after instillation into the conjunctival sac. For diseases of the posterior segment, intraocular injection or systemic administration is required. Generally, ocular use of glucocorticoids should be supervised by an ophthalmologist.

A typical prescription is 0.1% dexamethasone sodium phosphate solution (ophthalmic), 2 drops in the conjunctival sac every 4 hours while awake, and 0.05% dexamethasone sodium phosphate ointment (ophthalmic) at bedtime. For inflammation of the posterior segment, typical doses are 30 mg of prednisone or equivalent per day, administered orally in divided doses.

Topical glucocorticoid therapy frequently increases intraocular pressure in normal eyes and exacerbates intraocular hypertension in patients with antecedent glaucoma. The glaucoma is not always reversible on cessation of glucocorticoid therapy. Intraocular pressure should be monitored when glucocorticoids are applied to the eye for >2 weeks.

Topical administration of glucocorticoids to patients with bacterial, viral, or fungal conjunctivitis can mask evidence of progression of the infection until sight is irreversibly lost. Glucocorticoids are contraindicated in herpes simplex keratitis because progression of the disease may lead to irreversible clouding of the cornea. Topical steroids should not be used in treating mechanical lacerations and abrasions of the eye because they delay healing and promote the development and spread of infection.

Skin Diseases. Glucocorticoids are remarkably efficacious in the treatment of a wide variety of inflammatory dermatoses. As a result, a large number of different preparations and concentrations of topical glucocorticoids of varying potencies are available. A typical regimen for an eczematous eruption is 1% hydrocortisone ointment applied locally twice daily. Effectiveness is enhanced by application of the topical steroid under an occlusive film, such as plastic wrap; unfortunately, the risk of systemic absorption also is increased by occlusive dressings, and this can be a significant problem when the more potent glucocorticoids are applied to inflamed skin. Glucocorticoids are administered systemically for severe episodes of acute dermatological disorders and for exacerbations of chronic disorders. The dose in these settings is usually 40 mg/day of prednisone. Systemic steroid administration can be lifesaving in pemphigus, which may require daily doses of up to 120 mg of prednisone. Further discussion of the treatment of skin diseases is presented in Chapter 65.

Gastrointestinal Diseases. Glucocorticoid therapy is indicated in selected patients with inflammatory bowel disease (chronic ulcerative colitis and Crohn's disease; Chapter 47). Patients who fail to respond to more conservative management (i.e., rest, diet, and sulfasalazine) may benefit from glucocorticoids; steroids are most useful for acute exacerbations. In mild ulcerative colitis, hydrocortisone (100 mg) can be administered as a retention enema with beneficial effects. In more severe acute exacerbations, oral prednisone (10-30 mg/day) frequently is employed. For severely ill patients—with fever, anorexia, anemia, and impaired nutritional status—larger doses should be used (40-60 mg prednisone per day). Major complications of ulcerative colitis or Crohn's disease may occur despite glucocorticoid therapy, and glucocorticoids may mask signs and symptoms of complications such as intestinal perforation and peritonitis.

Budesonide, a highly potent synthetic glucocorticoid that is inactivated by first-pass hepatic metabolism, reportedly exhibits diminished systemic side effects commonly associated with glucocorticoids. Oral administration of budesonide in delayed-release capsules (entocort, 9 mg/day) facilitates drug delivery to the ileum and ascending colon; the drug also has been used as a retention enema in the treatment of ulcerative colitis.

Hepatic Diseases. The use of corticosteroids in hepatic disease has been highly controversial. Glucocorticoids clearly are of benefit in autoimmune hepatitis, where as many as 80% of patients show histological remission when treated with prednisone (40-60 mg daily initially, with tapering to a maintenance dose of 7.5-10 mg daily after serum transaminase levels fall). The role of corticosteroids in alcoholic liver disease is not fully defined; the most recent meta-analysis of previously published reports failed to establish a beneficial role of corticosteroids, even in patients with severe disease (Rambaldi et al., 2008). Further studies are needed to confirm or refute the role of steroids in this setting. In the setting of severe hepatic disease, prednisolone should be used instead of prednisone, which requires hepatic conversion to be active.

Malignancies. Glucocorticoids are used in the chemotherapy of acute lymphocytic leukemia and lymphomas because of their antilymphocytic effects. Most commonly, glucocorticoids are one component of combination chemotherapy administered under scheduled protocols. Glucocorticoids once were frequently employed in the setting of hypercalcemia of malignancy, but more effective agents, such as the bisphosphonates, now are the preferred therapy.

Cerebral Edema. Corticosteroids are of value in the reduction or prevention of cerebral edema associated with parasites and neoplasms, especially those that are metastatic. Although corticosteroids are frequently used for the treatment of cerebral edema caused by trauma or cerebrovascular accidents, controlled clinical trials do not support their use in these settings.

Miscellaneous Diseases and Conditions. Sarcoidosis. Corticosteroids are indicated therapy for patients with debilitating symptoms or life-threatening forms of sarcoidosis. Patients with severe pulmonary involvement are treated with 10-20 mg per day of prednisone, or an equivalent dose of alternative steroids, to induce remission. Higher doses may be required for other forms of this disease. Maintenance doses, which often are required for long periods of time, may be as low as 5 mg/day of prednisone. These patients, like all patients who require chronic glucocorticoid therapy at doses exceeding the normal daily production rate, are at increased risk of secondary tuberculosis; therefore, patients with a positive tuberculin reaction or other evidence of tuberculosis should receive prophylactic antituberculosis therapy.

Thrombocytopenia. In thrombocytopenia, prednisone (0.5 mg/kg) is used to decrease the bleeding tendency. In more severe cases, and for initiation of treatment of idiopathic thrombocytopenia, daily doses of prednisone (1-1.5 mg/kg) are employed. Patients with refractory idiopathic thrombocytopenia may respond to pulsed high-dose glucocorticoid therapy.

Autoimmune Destruction of Erythrocytes. Patients with autoimmune destruction of erythrocytes (i.e., hemolytic anemia with a positive Coombs test) are treated with prednisone (1 mg/kg per day). In the setting of severe hemolysis, higher doses may be used, with tapering as the anemia improves. Small maintenance doses may be required for several months in patients who respond.

Organ Transplantation. In organ transplantation, high doses of prednisone (50-100 mg) are given at the time of transplant surgery, in conjunction with other immunosuppressive agents, and most patients are kept on a maintenance regimen that includes lower doses of glucocorticoids (Chapter 35). For some solid organ transplants (e.g., pancreas), protocols that either withdraw corticosteroids early after transplantation or that avoid them completely are becoming more common (Meier-Kriesche et al., 2006).

Spinal Cord Injury. A meta-analysis of several randomized, controlled trials (Bracken, 2002) demonstrated significant decreases in neurological defects in patients with acute spinal cord injury treated within 8 hours of injury with large doses of methylprednisolone sodium succinate (30 mg/kg initially followed by an infusion of 5.4 mg/kg per hour for 23 hours). One trial showed further improvement with an additional 24 hours of treatment. The ability of corticosteroids at these high doses to decrease neurological injury may reflect inhibition of free radical–mediated cellular injury, as occurs following ischemia and reperfusion. Potential side effects include increased susceptibility to infection and other wound complications.

Diagnostic Applications of Adrenocortical Steroids

In addition to its therapeutic uses, dexamethasone is used as a first-line agent to diagnose hypercortisolism and to differentiate among the different causes of Cushing's syndrome (Arnaldi et al., 2003).

To determine if patients with clinical manifestations suggestive of hypercortisolism have biochemical evidence of increased cortisol biosynthesis, an overnight dexamethasone suppression test has been devised. Patients are given 1 mg of dexamethasone orally at 11 p.m., and cortisol is measured at 8 a.m. the following morning. Suppression of plasma cortisol to <1.8 μg/dL suggests strongly that the patient does not have Cushing's syndrome. Drugs such as barbiturates that enhance dexamethasone metabolism or drugs (estrogens) or conditions (pregnancy) that increase the concentrations of corticosteroid binding globulin can interfere with suppression and compromise the test. The formal dexamethasone suppression test is used in the differential diagnosis of biochemically documented Cushing's syndrome. Following determination of baseline cortisol levels for 48 hours, dexamethasone (0.5 mg every 6 hours) is administered orally for 48 hours. This dose markedly suppresses cortisol levels in normal subjects, including those who have nonspecific elevations of cortisol due to obesity or stress, but it does not suppress levels in patients with Cushing's syndrome. In the high-dose phase of the test, dexamethasone is administered orally at 2 mg every 6 hours for 48 hours. Patients with pituitary-dependent Cushing's syndrome (i.e., Cushing's disease) generally respond with decreased cortisol levels. In contrast, patients with ectopic production of ACTH or with adrenocortical tumors generally do not exhibit decreased cortisol levels. Despite these generalities, dexamethasone may suppress cortisol levels in some patients with ectopic ACTH production, particularly with tumors such as bronchial carcinoids, and many experts prefer to use inferior petrosal sinus sampling after CRH administration to make this distinction.

Ketoconazole. Ketoconazole (nizoral) is an antifungal agent, and this remains its most important clinical role (Chapter 57). In doses higher than those employed in antifungal therapy, it is an effective inhibitor of adrenal and gonadal steroidogenesis, primarily because of its inhibition of the activity of CYP17 (17α-hydroxylase). At even higher doses, ketoconazole also inhibits CYP11A1, effectively blocking steroidogenesis in all primary steroidogenic tissues. Ketoconazole is the best tolerated and most effective inhibitor of steroid hormone biosynthesis in patients with hypercortisolism. In most cases, a dosage regimen of 600-800 mg/day (in two divided doses) is required, and some patients may require up to 1200 mg/day given in two to three doses. Side effects include hepatic dysfunction, which ranges from asymptomatic elevations of transaminase levels to severe hepatic injury. The potential of ketoconazole to interact with CYP isoforms can lead to drug interactions of serious consequence (Chapter 6). Further studies are needed to define the precise role of ketoconazole in the medical management of patients with excessive steroid hormonal production, and the FDA has not approved this indication for ketoconazole use.

Metyrapone. Metyrapone (metopirone) is a relatively selective inhibitor of CYP11B1 (11β-hydroxylase), which converts 11-deoxycortisol to cortisol in the terminal reaction of the glucocorticoid biosynthetic pathway. Because of this inhibition, the biosynthesis of cortisol is markedly impaired, and the levels of steroid precursors (e.g., 11-deoxycortisol) are markedly increased. Although the biosynthesis of aldosterone also is impaired, the elevated levels of 11-deoxycortisol sustain mineralocorticoid-dependent functions. In a diagnostic test of the entire HPA axis, metyrapone (30 mg/kg, maximum dose of 3 g) is administered orally with a snack at midnight, and plasma cortisol and 11-deoxycortisol are measured at 8 a.m. the next morning. A plasma cortisol <8 μg/dL validates adequate inhibition of CYP11B1; in this setting, an 11-deoxycortisol level <7 μg/dL is highly suggestive of impaired hypothalamic-pituitary-adrenal function. An abnormal response does not identify the site of the defect; hypothalamic CRH release, ACTH production, or adrenal biosynthetic capacity could be impaired. Some authorities avoid overnight metyrapone testing in outpatients thought to have a reasonable probability of impaired HPA function because there is some risk of precipitating acute adrenal insufficiency. Others believe that the ability to assess the entire HPA axis with a relatively easy test justifies the use of metyrapone testing in outpatients.

Metyrapone also is used to diagnose patients with Cushing's syndrome who respond equivocally to the formal dexamethasone suppression test. Those with pituitary-dependent Cushing's syndrome exhibit a normal response, whereas those patients with ectopic secretion of ACTH exhibit no changes in ACTH or 11-deoxycortisol levels.

Therapeutically, metyrapone has been used to treat the hypercorticism resulting from either adrenal neoplasms or tumors producing ACTH ectopically. Maximal suppression of steroidogenesis requires doses of 4 g/day. More frequently, metyrapone is used as adjunctive therapy in patients who have received pituitary irradiation or in combination with other agents that inhibit steroidogenesis. In this setting, a dose of 500-750 mg three or four times daily is employed. The use of metyrapone in the treatment of Cushing's syndrome secondary to pituitary hypersecretion of ACTH is more controversial. Chronic administration of metyrapone can cause hirsutism, which results from increased synthesis of adrenal androgens upstream from the enzymatic block, and hypertension, which results from elevated levels of 11-deoxycortisol. Other side effects include nausea, headache, sedation, and rash.

Etomidate. Etomidate (amidate), a substituted imidazole used primarily as an anaesthetic agent and sedative, inhibits cortisol secretion at subhypnotic doses primarily by inhibiting CYP11B1 activity. It is administered intravenously and has been used off-label to treat hypercortisolism when rapid control is required in a patient who cannot take medication by the oral route. An international consensus panel recommends that etomidate be administered as a bolus of 0.03 mg/kg intravenously, followed by an infusion of 0.1 mg/kg per hour to a maximum of 0.3 mg/kg per hour (Biller et al., 2008).

Mitotane. Mitotane (o,p'-DDD; lysodren) is an adrenocorticolytic agent used to treat inoperable adrenocortical carcinoma. Its cytolytic action is due to its metabolic conversion to a reactive acyl chloride by adrenal mitochondrial CYPs and subsequent reactivity with cellular proteins. In a few centers, it has been used for long-term control of hypercortisolism. Doses range from 0.5-3 g administered three times daily. Its onset of action takes weeks to months, and GI disturbances and ataxia are its major toxicities.

Aminoglutethimide. Aminoglutethimide (α-ethyl-p-aminophenyl-glutarimide; cytadren) primarily inhibits CYP11A1, which catalyzes the initial and rate-limiting step in the biosynthesis of all physiological steroids and also inhibits CYP11B1 and CYP19 (aromatase). As a result, the production of all classes of steroid hormones is impaired. Although used at one time to treat hypercortisolism and advanced cancer of the breast and prostate, aminoglutethimide recently has been withdrawn from the market by the manufacturer and is no longer available.

Trilostane. Trilostane (4α,5α,17β)-4-5-epoxy-3,17-dihydroxyandrost-2-ene-2-carbonitrile), a competitive inhibitor of the type II 3β-hydroxysteroid dehydrogenase (Figure 42–3), also interferes with the synthesis of both adrenal and gonadal hormones, but it is more effective in dogs than in humans. For this reason, trilostane is not used in humans but still has a place in veterinary medicine.

The progesterone receptor antagonist mifepristone (mifeprex; RU-486; 11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) has received considerable attention because of its use as an antiprogestogen that can terminate early pregnancy (Chapter 66). At higher doses, mifepristone also inhibits the GR, blocking feedback regulation of the HPA axis and secondarily increasing endogenous ACTH and cortisol levels. Because of its ability to inhibit glucocorticoid action, mifepristone also has been studied as a potential therapeutic agent in a small number of patients with hypercortisolism (Johanssen and Allolio, 2007). Currently, its use for this purpose is considered investigational and is restricted to patients with inoperable causes of cortisol excess that have not responded to other agents.