The major physiological and pharmacological effects of adrenocorticotropic hormone (ACTH, corticotropin) result from its action to increase the circulating levels of adrenocortical steroids. Synthetic derivatives of ACTH are used principally in the diagnostic assessment of adrenocortical function. Because corticosteroids mimic the therapeutic effects of ACTH, synthetic steroids generally are used therapeutically instead of ACTH.
Corticosteroids and their biologically active synthetic derivatives differ in their metabolic (glucocorticoid) and electrolyte-regulating (mineralocorticoid) activities. These agents are employed at physiological doses for replacement therapy when endogenous production is impaired. Glucocorticoids potently suppress inflammation, and their use in inflammatory and autoimmune diseases makes them among the most frequently prescribed classes of drugs. Because glucocorticoids exert effects on almost every organ system, the clinical use of and withdrawal from corticosteroids are complicated by a number of serious side effects. Therefore, the decision to institute therapy with systemic corticosteroids always requires careful consideration of the relative risks and benefits in each patient.
Human ACTH, a peptide of 39 amino acids, is synthesized as part of a larger precursor protein, proopiomelanocortin (POMC), and is liberated from the precursor through proteolytic cleavage at dibasic residues by the serine endoprotease, prohormone convertase 1 (also known as prohormone convertase 3) (Figure 42–1). Other biologically important peptides, including endorphins, lipotropins, and the melanocyte-stimulating hormones (MSHs), also are produced by proteolytic processing of the same POMC precursor (see Chapter 18).
Figure 42–1 Processing of proopiomelanocortin POMC to ACTH. Proopiomelanocortin (POMC) is converted to adrenocorticotropic hormone (ACTH) and other peptides in the anterior pituitary. The boxes within the ACTH structure indicate regions important for steroidogenic activity (residues 6-10) and binding to the ACTH receptor (15-18). α-Melanocyte-stimulating hormone also derives from the POMC precursor and contains the first 13 residues of ACTH. LPH, lipotropin; MSH, melanocyte-stimulating hormone.
The actions of ACTH and the other melanocortins liberated from POMC are mediated by their specific interactions with 5 melanocortin receptor (MCR) subtypes (MC1R-MC5R) comprising a subfamily of G protein-coupled receptors (GPCRs). The well-known effects of MSH on pigmentation result from interactions with the MC1R on melanocytes. ACTH, which is identical to α-MSH in its first 13 amino acids, 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. β-MSH and possibly other melanocortins, acting via the MC4R and MC3R in the hypothalamus, play a role in regulating appetite and body weight. The role of MC5R is less well defined.
ACTIONS ON THE ADRENAL CORTEX. Acting via MC2R, ACTH stimulates the adrenal cortex to secrete glucocorticoids, mineralocorticoids, and the androgen precursordehydroepiandrosterone (DHEA). The adrenal cortex histologically and functionally can be separated into 3 zones (Figure 42–2) that produce different steroid products under different regulatory influences:
Figure 42–2 The three anatomically and functionally distinct compartments of the adrenal cortex. The major functional compartments of the adrenal cortex are shown, along with the steroidogenic enzymes that determine the unique profiles of corticosteroid products. Also shown are the predominant physiological regulators of steroid production: angiotensin II (AngII) and K+ for the zona glomerulosa and ACTH for the zona fasciculata. The physiological regulator(s) of dehydroepiandrosterone (DHEA) production by the zona reticularis are not known, although ACTH acutely increases DHEA biosynthesis.
• The outer zona glomerulosa secretes the mineralocorticoid aldosterone.
• The middle zona fasciculata secretes the glucocorticoid cortisol.
• The inner zona reticularis secretes DHEA and its sulfated derivative DHEAS (plasma concentration 1000× that of DHEA). DHEA sulfatase converts DHEAS to DHEA in the periphery.
Cells of the outer zone have receptors for angiotensin II (AngII) 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 AngII and extracellular K+ (see Chapter 25) and does not undergo atrophy in the absence of ongoing stimulation by the pituitary gland. With persistently elevated ACTH, mineralocorticoid levels initially increase and then return to normal (a phenomenon termed ACTH escape). Cells of the zona fasciculata have fewer receptors for AngII and express steroid 17α-hydroxylase (CYP17) and 11β-hydroxylase (CYP11B1) enzymes 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 and ACTH stimulation, 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.
MECHANISM OF ACTION. ACTH stimulates the synthesis and release of adrenocortical hormones by increasing de novo biosynthesis. ACTH, binding to MC2R, activates the Gs-adenylyl cyclase-cyclic AMP-PKA pathway. Cyclic AMP is the second messenger for most effects of ACTH on steroidogenesis. Temporally, the response of adrenocortical cells to ACTH has 2 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. 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 (see Chapter 6).
Figure 42–3 Pathways of corticosteroid biosynthesis. The steroidogenic pathways used in the biosynthesis of the corticosteroids are shown, along with the structures of the intermediates and products. The pathways unique to the zona glomerulosa are shown in the orange box; those that occur in the inner zona fasciculata and zona reticularis are shown in the gray box. The zona reticularis does not express 3β-HSD and thus preferentially synthesizes DHEA; see Figure 42–2. CYP11A1, cholesterol side-chain cleavage enzyme; 3β-HSD, 3β-hydroxysteroid dehydrogenase; CYP17, steroid 17α-hydroxylase; CYP21, steroid 21-hydroxylase; CYP11B2, aldosterone synthase; CYP11B1, steroid 11β-hydroxylase.
REGULATION OF ACTH SECRETION
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. The rate of glucocorticoid secretion is determined by fluctuations in the release of ACTH by the pituitary corticotropes. These corticotropes are regulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), peptide hormones released by specialized neurons of the endocrine hypothalamus. This hypothalamic-pituitary-adrenal (HPA) axis forms an integrated system that maintains appropriate levels of glucocorticoids (Figure 42–4). The 3 characteristic modes of regulation of the HPA axis are diurnal rhythm in basal steroidogenesis, negative feedback regulation by adrenal corticosteroids, and marked increases in steroidogenesis in response to stress.
Figure 42–4 The hypothalamic-pituitary-adrenal (HPA) axis and the immune inflammatory network. Also shown are inputs from higher neuronal centers that regulate CRH secretion. + indicates a positive regulator, – indicates a negative regulator, + and – indicates a mixed effect, as for NE (norepinephrine). In addition, arginine vasopressin stimulates release of ACTH from corticotropes.
The diurnal rhythm is entrained by higher neuronal centers in response to sleep-wake cycles, such that levels of ACTH peak in the early morning hours, causing the circulating glucocorticoid levels to peak at ~8 A.M. Negative feedback regulation occurs at multiple levels of the HPA axis and is the major mechanism that maintains circulating glucocorticoid levels in the appropriate range. Stress can override the normal negative feedback control mechanisms, leading to marked increases in plasma concentrations of glucocorticoids.
ARGININE VASOPRESSIN. AVP also acts as a secretagogue for corticotropes, significantly potentiating the effects of CRH. AVP is produced in the paraventricular nucleus and secreted into the pituitary plexus from the median eminence. AVP binds to V1b receptor and activates the Gq-PLC-IP3-Ca2+ pathway to enhance the release of ACTH. In contrast to CRH, AVP does not increase ACTH synthesis.
NEGATIVE FEEDBACK OF GLUCOCORTICOIDS. Glucocorticoids inhibit ACTH secretion via direct and indirect actions on CRH neurons to decrease CRH mRNA levels and CRH release and via direct effects on corticotropes. The indirect inhibitory effects on CRH neurons appear to be mediated by specific corticosteroid receptors in the hippocampus. At lower cortisol levels, the mineralocorticoid receptor (MR), which has a higher affinity for glucocorticoids than classical glucocorticoid receptors (GRs), is the major receptor species occupied. As glucocorticoid concentrations rise and saturate the MR, the GR becomes increasingly occupied. Both the MR and GR apparently control the basal activity of the HPA axis, whereas feedback inhibition by glucocorticoids predominantly involves the GR. In the pituitary, glucocorticoids act through the GR to inhibit the release of ACTH from corticotropes and the expression of POMC. These effects are both rapid (occurring within seconds to minutes) and delayed (requiring hours and involving changes in gene transcription mediated through the GR).
THE STRESS RESPONSE. Stress overcomes negative feedback regulation of the HPA axis, leading to a marked rise in corticosteroid production. Examples of stress signals include injury, hemorrhage, severe infection, major surgery, hypoglycemia, cold, pain, and fear. Although the precise mechanisms that underlie this stress response and the essential actions played by corticosteroids are not fully defined, increased corticosteroid secretion is vital to maintain homeostasis in these stressful settings. As discussed later, complex interactions between the HPA axis and the immune system may be a fundamental physiological component of this stress response.
ASSAYS FOR ACTH. Immunochemiluminescent assays that use 2 separate antibodies directed at distinct epitopes on the ACTH molecule now are widely available. These assays increase 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 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. 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. ACTH has limited utility therapeutically. All proven therapeutic effects of ACTH can be achieved with appropriate doses of corticosteroids with a lower risk of side effects. Moreover, therapy with ACTH is less predictable and less convenient than therapy with corticosteroids. ACTH stimulates mineralocorticoid and adrenal androgen secretion and may therefore cause acute retention of salt and water, as well as virilization. Cosyntropin (CORTROSYN, SYNACTHEN), a synthetic peptide that corresponds to residues 1-24 of human ACTH, is used testing the integrity of the HPA axis. At the considerably supraphysiological dose of 250 μg, cosyntropin maximally stimulates adrenocortical steroidogenesis. An increase in the circulating cortisol to a level greater than 18-20 μg/dL indicates a normal response.
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 disease) and an ectopic source of ACTH.
ABSORPTION AND FATE TOXICITY. ACTH is readily absorbed from parenteral sites. The hormone rapidly disappears from the circulation after intravenous administration; in humans, the t1/2 in plasma is ~15 min, primarily due to rapid enzymatic hydrolysis. 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.
The adrenal cortex synthesizes 2 classes of steroids: the corticosteroids (glucocorticoids and mineralocorticoids; see Figure 42–3), which have 21 carbon atoms, and the androgens, which have 19 carbons (see Figures 41–1 and 41–3). The actions of corticosteroids historically were described as glucocorticoid (reflecting their carbohydrate metabolism–regulating activity) and mineralocorticoid (reflecting their electrolyte balance–regulating activity). In humans, cortisol (hydrocortisone) is the main glucocorticoid and aldosterone is the main mineralocorticoid (Table 42–1).
Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids
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 DHEA and 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. However, studies on the benefits of addition of DHEA to the standard replacement regimen in women with adrenal insufficiency have been inconclusive.
PHYSIOLOGICAL FUNCTIONS AND PHARMACOLOGICAL EFFECTS
PHYSIOLOGICAL ACTIONS. Corticosteroids have numerous effects, which include alterations in carbohydrate, protein, and lipid metabolism; maintenance of fluid and electrolyte balance; and preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system, and the nervous system. In addition, corticosteroids endow the organism with the capacity to resist stressful and noxious stimuli and environmental changes. In the absence of the adrenal cortex, survival is made possible only by maintaining an optimal environment, including adequate and regular feeding, ingestion of relatively large amounts of NaCl, and maintenance of an appropriate environmental temperature; stresses such as infection, trauma, and extremes in temperature in this setting can be life threatening.
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. Conversely, in the absence of glucocorticoids, EPI and NE 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.
Corticosteroids are termed mineralocorticoids and glucocorticoids, according to their relative potencies in Na+ retention, effects on carbohydrate metabolism (i.e., hepatic deposition of glycogen and gluconeogenesis), and anti-inflammatory effects. In general, potencies of steroids as judged by their ability to sustain life in adrenalectomized animals closely parallel those determined for Na+ retention, whereas potencies based on effects on glucose metabolism closely parallel those for anti-inflammatory effects. The effects on Na+ retention and the carbohydrate/anti-inflammatory actions are not closely related and reflect selective actions at distinct receptors. As noted below (see structure-activity relationships and Table 42–3), some steroid derivatives provide relative selectivity for effects on Na+ retention or anti-inflammatory effects.
GENERAL MECHANISMS FOR CORTICOSTEROID EFFECTS. Corticosteroids bind to specific receptor proteins in target tissues to regulate the expression of corticosteroid-responsive genes, thereby changing the levels and array of proteins synthesized by the various target tissues (Figure 38–5). Most effects of corticosteroids are not immediate but become apparent after several hours; clinically, one generally sees a delay before beneficial effects of corticosteroid therapy become manifest. Although corticosteroids predominantly act by increasing gene transcription, there are examples in which glucocorticoids decrease gene transcription. In addition, corticosteroids may exert some of their immediate effects by nongenomic mechanisms.
Glucocorticoid Receptors (GRs). The receptors for corticosteroids are members of the nuclear receptor family of transcription factors. The GR resides predominantly in the cytoplasm in an inactive form complexed with other proteins. Steroid binding results in receptor activation and translocation to the nucleus (see Figure 38–5). Several GR isoforms result from alternative RNA splicing. Of these, GRα is the prototypical glucocorticoid-responsive isoform. 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. Polymorphisms have been identified in the human GR that are associated with differences in GR function and have been linked to glucocorticoid insensitivity.
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 called glucocorticoid responsive elements (GREs), which provide specificity to the induction of gene transcription by glucocorticoids. Genes can be activated or inhibited by GR-GRE interactions. 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. In a case of transcriptional inhibition by GR, GR inhibits transcription of POMC 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 NO synthase (NOS2), and inflammatory cytokines. Some inhibitory effects of glucocorticoids such as downregulation of expression of genes encoding a number of cytokines, collagenase, and stromelysin, have been linked to protein–protein interactions between the GR and other transcription factors (e.g., NF-κB and AP-1) rather than to negative effects of the GR at specific GREs. Such 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.
Regulation of Gene Expression by Mineralocorticoids. Like the GR, the mineralocorticoid receptor (MR) also is a ligand-activated transcription factor and binds to a very similar hormone-responsive element. The MR also associates with HSP90 and activates the transcription of discrete sets of genes within target tissues. The selective actions of GR and MR result from differences in their ability to inhibit AP-1–mediated gene activation and differential interactions with other transcription factors. In addition, the MR has 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).
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. Aldosterone (a classic mineralocorticoid) and cortisol (generally viewed as predominantly glucocorticoid) bind the MR with equal affinity. The apparent specificity of the MR for aldosterone is maintained in the face of much higher circulating levels of glucocorticoids by the type 2 isozyme of 11β-hydroxysteroid dehydrogenase (11βHSD2). This enzyme metabolizes glucocorticoids such as cortisol to receptor-inactive 11-keto derivatives such as cortisone (Figure 42–5). Because its predominant physiological form is the hemiacetal derivative that is resistant to 11βHSD action, aldosterone escapes this inactivation and maintains mineralocorticoid activity.
Figure 42–5 11β-hydroxysteroid dehydrogenase confers specificity of corticosteroid action. Type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2) converts cortisol, which binds to both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), to cortisone, which binds to neither MR nor GR, thereby protecting the MR from the high circulating concentrations of cortisol. This inactivation allows specific responses to aldosterone in sites such as the distal nephron. Aldosterone hemiacetal is resistant to 11βHSD. The type 1 isozyme of 11βHSD (11βHSD1) catalyzes the reverse reaction, which converts inactive cortisone to active cortisol in such tissues as liver and fat. Only ring C of the corticosteroid is depicted; see text figures for structures of cortisone and aldosterone hemiacetal.
CARBOHYDRATE AND PROTEIN METABOLISM. Corticosteroids profoundly affect carbohydrate and protein metabolism, which can be viewed as protecting glucose-dependent tissues (e.g., the brain and heart) from starvation. They stimulate the liver to form glucose from amino acids and glycerol and to store glucose as liver glycogen. In the periphery, glucocorticoids diminish glucose utilization, increase protein breakdown and the synthesis of glutamine, and activate lipolysis, thereby providing amino acids and glycerol for gluconeogenesis. The net result is to increase blood glucose levels. Because of their effects on glucose metabolism, glucocorticoids can worsen glycemic control in patients with overt diabetes and can precipitate the onset of hyperglycemia in susceptible patients.
LIPID METABOLISM. Two effects of corticosteroids on lipid metabolism are firmly established. The first is the dramatic redistribution of body fat that occurs in hypercorticism, such as Cushing syndrome. In this setting, there is increased fat in the back of the neck (“buffalo hump”), face (“moon facies”), and supraclavicular area, coupled with a loss of fat in the extremities. The other is the permissive facilitation of the lipolytic effect of other agents, such as growth hormone and β adrenergic receptor agonists, resulting in an increase in free fatty acids after glucocorticoid administration.
ELECTROLYTE AND WATER BALANCE. Aldosterone is by far the most potent endogenous corticosteroid with respect to fluid and electrolyte balance. Mineralocorticoids act on the distal tubules and collecting ducts of the kidney to enhance reabsorption of Na+ from the tubular fluid; they also increase the urinary excretion of K+ and H+. These actions on electrolyte transport, in the kidney and in other tissues (e.g., colon, salivary glands, and sweat glands), appear to account for the physiological and pharmacological activities that are characteristic of mineralocorticoids. Thus, the primary features of hyperaldosteronism are positive Na+ balance with consequent expansion of extracellular fluid volume, normal or slight increases in plasma Na+ concentration, normal or low plasma K+, and alkalosis. Mineralocorticoid deficiency, in contrast, leads to Na+ wasting and contraction of the extracellular fluid volume, hyponatremia, hyperkalemia, and acidosis. Chronically, hyperaldosteronism causes hypertension, whereas aldosterone deficiency can lead to hypotension and vascular collapse.
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.
CARDIOVASCULAR SYSTEM. The most striking effects of corticosteroids on the cardiovascular system result from mineralocorticoid-induced changes in renal Na+, as is evident in primary aldosteronism. MR activation has direct effects on the heart and vessel walls; aldosterone induces hypertension and interstitial cardiac fibrosis in animal models. The increased cardiac fibrosis appears to result from direct mineralocorticoid actions in the heart rather than from the effect of hypertension because treatment with spironolactone, an MR antagonist, blocks the development of fibrosis without altering blood pressure. The second major action of corticosteroids on the cardiovascular system is to enhance vascular reactivity to other vasoactive substances. Hypoadrenalism is associated with reduced responsiveness to vasoconstrictors such as NE and AngII, perhaps due to decreased expression of adrenergic receptors in the vascular wall. Conversely, hypertension is seen in patients with excessive glucocorticoid secretion, occurring in most patients with Cushing syndrome and in a subset of patients treated with synthetic glucocorticoids (even those lacking any significant mineralocorticoid action).
SKELETAL MUSCLE. Permissive concentrations of corticosteroids are required for the normal function of skeletal muscle, and diminished work capacity is a prominent sign of adrenocortical insufficiency. In patients with Addison disease, weakness and fatigue are frequent symptoms. Excessive amounts of either glucocorticoids or mineralocorticoids also impair muscle function. In primary aldosteronism, muscle weakness results primarily from hypokalemia rather than from direct effects of mineralocorticoids on skeletal muscle. In contrast, glucocorticoid excess over prolonged periods, either secondary to glucocorticoid therapy or endogenous hypercorticism, causes skeletal muscle wasting. This effect, steroid myopathy, accounts in part for weakness and fatigue in patients with glucocorticoid excess.
CNS. Corticosteroids exert a number of indirect effects on the CNS, through maintenance of blood pressure, plasma glucose concentrations, and electrolyte concentrations. Increasingly, direct effects of corticosteroids on the CNS have been recognized, including effects on mood, behavior, and brain excitability. Patients with adrenal insufficiency exhibit a diverse array of neurological manifestations, including apathy, depression, and irritability, even psychosis. 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 syndrome. These abnormalities usually disappear after cessation of glucocorticoid therapy or treatment of the Cushing syndrome.
FORMED ELEMENTS OF BLOOD. Glucocorticoids exert minor effects on hemoglobin and erythrocyte content of blood, as evidenced by the frequent occurrence of polycythemia in Cushing syndrome and of normochromic, normocytic anemia in adrenal insufficiency. More profound effects are seen in the setting of autoimmune hemolytic anemia, in which the immunosuppressive effects of glucocorticoids can diminish erythrocytes destruction. Corticosteroids also affect circulating white blood cells. Addison disease is associated with an increased mass of lymphoid tissue and lymphocytosis. In contrast, Cushing 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 h; this effect persists for 24 h 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 capacity of glucocorticoids to activate apoptosis.
ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE ACTIONS. In addition to their effects on lymphocyte number, corticosteroids profoundly alter the immune responses of lymphocytes. These effects are an important facet of the anti-inflammatory and immunosuppressive actions of the glucocorticoids. Although the use of glucocorticoids as anti-inflammatory agents does not address the underlying cause of the disease, the suppression of inflammation is of enormous clinical utility and has made these drugs among the most frequently prescribed agents. Similarly, glucocorticoids are of immense valuable in treating diseases that result from undesirable immune reactions. These diseases range from conditions that predominantly result from humoral immunity, such as urticaria (see Chapter 65), to those that are mediated by cellular immune mechanisms, such as transplantation rejection (see Chapter 35). The immunosuppressive and anti-inflammatory actions of glucocorticoids are inextricably linked, perhaps because they both involve inhibition of leukocyte functions.
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 42–2.
Inhibitory Effects of Glucocorticoids on Inflammatory/Immune Responses
ABSORPTION. Hydrocortisone and numerous congeners, including the synthetic analogs, are orally effective. Certain water-soluble esters of hydrocortisone and its synthetic congeners are administered intravenously to achieve high concentrations of drug rapidly in body fluids. More prolonged effects are obtained by intramuscular injection of suspensions of hydrocortisone, its esters, and congeners. Minor changes in chemical structure may markedly alter the rate of absorption, time of onset of effect, and duration of action. Glucocorticoids also are absorbed systemically from sites of local administration, such as synovial spaces, the conjunctival sac, skin, and respiratory tract. When administration is prolonged, when the site of application is covered with an occlusive dressing, or when large areas of skin are involved, absorption may be sufficient to cause systemic effects, including suppression of the HPA axis.
TRANSPORT, METABOLISM, AND EXCRETION. After absorption, ≥90% of cortisol in plasma is reversibly bound to protein under normal circumstances. Only the fraction of corticosteroid that is unbound is active and can enter cells. Two plasma proteins account for almost all of the steroid-binding capacity: corticosteroid-binding globulin (CBG; also called transcortin), and albumin. CBG is an α-globulin secreted by the liver that has high affinity for steroids (estimated dissociation constant of ~1.3 × 10–9 M) but relatively low total binding capacity, whereas albumin, also produced by the liver, has a relatively large binding capacity but low affinity (estimated dissociation constant of 1 × 10–3 M). At normal or low concentrations of corticosteroids, most of the hormone is protein bound. At higher steroid concentrations, the capacity of protein binding is exceeded, and a greater fraction of the steroid exists in the free state. CBG has relatively high affinity for cortisol and some of its synthetic congeners and low affinity for aldosterone and glucuronide-conjugated steroid metabolites; thus, greater percentages of these latter steroids are found in the free form. A special state of physiological hypercorticism occurs during pregnancy. The elevated circulating estrogen levels induce CBG production, and CBG and total plasma cortisol increase severalfold. The physiological significance of these changes remains to be established.
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.
STRUCTURE-ACTIVITY RELATIONSHIPS. Chemical modifications to the cortisol molecule have generated derivatives with greater separations of glucocorticoid and mineralocorticoid activity (Table 42–3); for a number of synthetic glucocorticoids, the effects on electrolytes are minimal even at the highest doses used. 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. 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.
Relative Potencies and Equivalent Doses of Representative Corticosteroids
Estimates of Na+-retaining and anti-inflammatory potencies of representative steroids are listed in Table 42–3. Some steroids that are classified predominantly as glucocorticoids (e.g., cortisol), also possess modest but significant mineralocorticoid activity and thus may affect fluid and electrolyte handling in the clinical setting. At doses used for replacement therapy in patients with primary adrenal insufficiency, the mineralocorticoid effects of these “glucocorticoids” are insufficient to replace that of aldosterone, and concurrent therapy with a more potent mineralocorticoid generally is needed. In contrast, aldosterone is exceedingly potent with respect to Na+ retention but has only modest potency for effects on carbohydrate metabolism. At normal rates of secretion by the adrenal cortex or in doses that maximally affect electrolyte balance, aldosterone has no significant glucocorticoid activity and thus acts as a pure mineralocorticoid.
TOXICITY OF ADRENOCORTICAL STEROIDS
Two categories of toxic effects result from the therapeutic use of corticosteroids: those resulting from withdrawal of steroid therapy and those resulting from continued use at supraphysiological doses. The side effects from both categories are potentially life threatening and require a careful assessment of the risks and benefits in each patient.
WITHDRAWAL OF THERAPY. The most frequent problem in steroid withdrawal is flare-up of the underlying disease for which steroids were prescribed. Several other complications are associated with steroid withdrawal. The most severe complication of steroid cessation, acute adrenal insufficiency, results from overly rapid withdrawal of corticosteroids after prolonged therapy has suppressed the HPA axis. Many patients recover from glucocorticoid-induced HPA suppression within several weeks to months; however, in some individuals the time to recovery can be a year or longer. Protocols for discontinuing corticosteroid therapy in patients receiving long-term treatment with corticosteroids have been proposed. 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. 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. 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.
CONTINUED USE OF SUPRAPHYSIOLOGICAL GLUCOCORTICOID DOSES. Besides the consequences that result from the suppression of the HPA axis, a number of other complications result from prolonged therapy with corticosteroids. These include fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, possible peptic ulcers, osteoporosis, myopathy, behavioral disturbances, cataracts, growth arrest, and the characteristic habitus of steroid overdose, including fat redistribution, striae, and ecchymoses.
With the exception of replacement therapy in deficiency states, the use of glucocorticoids largely is empirical. Given the number and severity of potential side effects, the decision to institute therapy with glucocorticoids always requires a careful consideration of the relative risks and benefits in each patient. For any disease and in any patient, the appropriate dose to achieve a given therapeutic effect must be determined by trial and error and must be reevaluated periodically as the activity of the underlying disease changes or as complications of therapy arise. A single dose of glucocorticoid, even a large one, is virtually without harmful effects, and a short course of therapy (up to 1 week), in the absence of specific contraindications, is unlikely to be harmful. As the duration of glucocorticoid therapy is increased beyond 1 week, there are time- and dose-related increases in the incidence of disabling and potentially lethal effects. Except in patients receiving replacement therapy, glucocorticoids are neither specific nor curative; rather, they are palliative by virtue of their anti-inflammatory and immunosuppressive actions. Finally, abrupt cessation of glucocorticoids after prolonged therapy is associated with the risk of adrenal insufficiency, which may be fatal.
When glucocorticoids are to be given over long periods, the dose must be determined by trial and error and must be the lowest that will achieve the desired effect. When the therapeutic goal is relief of painful or distressing symptoms not associated with an immediately life-threatening disease, complete relief is not sought, and the steroid dose is reduced gradually until worsening symptoms indicate that the minimal acceptable dose has been found. Where possible, the substitution of other medications, such as nonsteroidal anti-inflammatory drugs, may facilitate tapering the glucocorticoid dose once the initial benefit of therapy has been achieved. When therapy is directed at a life-threatening disease (e.g., pemphigus or lupus cerebritis), the initial dose should be a large one aimed at achieving rapid control of the crisis. If some benefit is not observed quickly, then the dose should be doubled or tripled. After initial control in a potentially lethal disease, dose reduction should be carried out under conditions that permit frequent accurate observations of the patient.
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. Long courses of therapy at high doses should be reserved for life-threatening disease. 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 1-1.5 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.
REPLACEMENT THERAPY FOR ADRENAL INSUFFICIENCY. Adrenal insufficiency can result from structural or functional lesions of the adrenal cortex (primary adrenal insufficiency or Addison disease) or from structural or functional lesions of the anterior pituitary or hypothalamus (secondary adrenal insufficiency). In developed countries, primary adrenal insufficiency most frequently is secondary to autoimmune adrenal disease, whereas tuberculous adrenalitis is the most frequent etiology in developing countries. Other causes include adrenalectomy, bilateral adrenal hemorrhage, neoplastic infiltration of the adrenal glands, acquired immunodeficiency syndrome, inherited disorders of the steroidogenic enzymes, and X-linked adrenoleukodystrophy. Secondary adrenal insufficiency resulting from pituitary or hypothalamic dysfunction generally presents in a more insidious manner than does the primary disorder, probably because mineralocorticoid biosynthesis is preserved.
ACUTE ADRENAL INSUFFICIENCY. This life-threatening disease is characterized by GI symptoms (nausea, vomiting, and abdominal pain), dehydration, hyponatremia, hyperkalemia, weakness, lethargy, and hypotension. It usually is associated with disorders of the adrenal rather than the pituitary or hypothalamus and sometimes follows abrupt withdrawal of glucocorticoids used at high doses or for prolonged periods.
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 h, a dose that confers sufficient mineralocorticoid activity to meet all requirements. As the patient stabilizes, the hydrocortisone dose may be decreased to 25 mg every 6-8 h. Thereafter, patients are treated in the same fashion as those with chronic adrenal insufficiency. For the treatment of 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.
CHRONIC ADRENAL INSUFFICIENCY. Patients with chronic adrenal insufficiency present with many of the same manifestations seen in adrenal crisis but with lesser severity. These patients require daily treatment with corticosteroids.
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. 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 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).
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) or who suffer the stress of intercurrent illness. 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. 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. Glucocorticoid doses also are adjusted when patients with adrenal insufficiency undergo surgery. 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 h. Following surgery, the dose is halved each day until it is reduced to routine maintenance levels.
CONGENITAL ADRENAL HYPERPLASIA (CAH). This is a group of genetic disorders in which the activity of 1 of the several enzymes required for the biosynthesis of glucocorticoids is deficient. The impaired production of cortisol and the consequent lack of negative feedback inhibition lead to increased release of ACTH. As a result, other hormonally active steroids that are proximal to the enzymatic block in the steroidogenic pathway are produced in excess. CAH includes a spectrum of disorders for which precise clinical presentation, laboratory findings, and treatment depend on which of the steroidogenic enzymes is deficient. In ~90% of patients, CAH results from mutations in CYP21, the enzyme that carries out the 21-hydroxylation reaction (see 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) that 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. Some patients with classical CAH are unable to conserve Na+ normally and thus are called “salt wasters.” 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 2 or 3 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.
THERAPEUTIC USES IN NONENDOCRINE DISEASES. There are important uses of glucocorticoids in diseases that do not directly involve the HPA axis. The disorders discussed below illustrate the principles governing glucocorticoid use in selected diseases for which glucocorticoids are more frequently employed. The dosage of glucocorticoids varies considerably depending on the nature and severity of the underlying disorder. Approximate doses of a representative glucocorticoid (e.g., prednisone) are provided.
Rheumatic Disorders. Glucocorticoids are used widely in the treatment 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 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/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.
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. 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 (e.g., 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. Alternatively, patients with major symptomatology confined to 1 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 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 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. Patients with renal disease secondary to systemic lupus erythematosus also are generally given a therapeutic trial of glucocorticoids. 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 h, or equivalent) are appropriate. In allergic rhinitis, intranasal steroids are viewed as the drug of choice by many experts.
Pulmonary Diseases. The use of glucocorticoids in bronchial asthma and other pulmonary diseases 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 h for 2 doses) or dexamethasone (6 mg intramuscularly every 12 h for 4 doses) is administered to women with definitive signs of premature labor between 26 and 34 weeks of gestation.
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 example of 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 withHaemophilus influenzae type b meningitis in infants and children ≥2 months of age.
Ocular Diseases. 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. These uses of glucocorticoids are discussed in Chapter 64.
Skin Diseases. Glucocorticoids are remarkably efficacious in the treatment of a wide variety of inflammatory dermatoses. 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. Chapter 65 presents the dermatologic uses of glucocorticoids.
GI Diseases. Patients with inflammatory bowel disease (chronic ulcerative colitis and Crohn disease) 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 (see Chapter 47).
Hepatic Diseases. The use of corticosteroids in hepatic disease has been highly controversial. Glucocorticoids clearly are of benefit in autoimmune hepatitis; 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-analyses do not support a beneficial role of corticosteroids. 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 as a component of combination therapy (see Chapters 46 and 63).
Cerebral Edema. Corticosteroids are of value in the reduction or prevention of cerebral edema associated with parasites and neoplasms, especially those that are metastatic.
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/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 may be as low as 5 mg/day of prednisone. 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/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 (see 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.
Spinal Cord Injury. Multicenter-controlled trials have demonstrated significant decreases in neurological defects in patients with acute spinal cord injury treated within 8 h of injury with large doses of methylprednisolone sodium succinate (30 mg/kg initially followed by an infusion of 5.4 mg/kg/h for 23 h).
DIAGNOSTIC APPLICATIONS OF DEXAMETHASONE. 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 syndrome. The rationale and procedure are described in detail on page 1233 of the 12th edition of the parent text.
INHIBITORS OF THE BIOSYNTHESIS AND ACTION OF ADRENOCORTICAL STEROIDS
Hypercortisolism with its attendant morbidity and mortality is most frequently caused by corticotroph adenomas that overproduce ACTH (Cushing disease) or by adrenocortical tumors or bilateral hyperplasias that overproduce cortisol (Cushing syndrome). Less frequently, hypercortisolism may result from adrenocortical carcinomas or ectopic ACTH- or CRH-producing tumors. Although surgery is the treatment of choice, it is not always effective, and adjuvant therapy with inhibitors of steroidogenesis becomes necessary. In these settings, ketoconazole, metyrapone, etomidate, and mitotane are clinically useful. Ketoconazole, etomidate, and mitotane are discussed in more detail in other chapters. All of these agents pose the common risk of precipitating acute adrenal insufficiency; thus, they must be used in appropriate doses, and the status of the patient’s HPA axis must be carefully monitored. Agents that act as glucocorticoid receptor antagonists (antiglucocorticoids) are discussed later in this chapter; mineralocorticoid antagonists are discussed in Chapter 25.
Ketoconazole. Ketoconazole (NIZORAL) is an antifungal agent (see 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 (although the FDA has not approved this indication for ketoconazole). In most cases, a dosage regimen of 600-800 mg/day (in 2 divided doses) is required, and some patients may require up to 1200 mg/day (in 2-3 doses). Side effects include hepatic dysfunction. The potential of ketoconazole to interact with CYP isoforms can lead to serious drug interactions (see Chapter 6).
Metyrapone. Metyrapone (METOPIRONE) is a relatively selective inhibitor of CYP11B1 (11β-hydroxylase), which converts 11-deoxycortisol to cortisol, thereby reducing cortisol production and elevating precursor levels (e.g., 11-deoxycortisol). 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.
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 3 or 4 times daily is employed. The use of metyrapone in the treatment of Cushing 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 anesthetic agent and sedative, inhibits cortisol secretion at subhypnotic doses primarily by inhibiting CYP11B1 activity. Etomidate has been used off-label to treat hypercortisolism when rapid control is required in a patient who cannot take medication by the oral route. Etomidate is administered as a bolus of 0.03 mg/kg intravenously, followed by an infusion of 0.1 mg/kg/h to a maximum of 0.3 mg/kg/h.
Mitotane. Mitotane (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. Doses range from 0.5-3 g administered 3 times daily. Its onset of action takes weeks to months, and GI disturbances and ataxia are its major toxicities.
Aminoglutethimide. Aminoglutethimide (CYTADREN) primarily inhibits CYP11A1 (the initial and rate-limiting step in the biosynthesis of all physiological steroids) and also inhibits CYP11B1 and CYP19 (aromatase). Aminoglutethimide recently has been withdrawn from the market by the manufacturer and is no longer available.
The progesterone receptor antagonist mifepristone (MIFEPREX; RU-486) has received considerable attention because of its use as an antiprogestogen that can terminate early pregnancy (see 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 capacity to inhibit glucocorticoid action, mifepristone also has been studied as a potential therapeutic agent in a small number of patients with hypercortisolism. Currently, its use for this purpose is restricted to patients with inoperable causes of cortisol excess that have not responded to other agents.