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Chapter 42: ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex
Bernard P. Schimmer; John W. Funder
Schimmer BP, Funder JW. Schimmer B.P., & Funder J.W. Schimmer, Bernard P., and John W. Funder.ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex. In: Brunton LL, Chabner BA, Knollmann BC. Brunton L.L., & Chabner B.A., & Knollmann B.C.(Eds.),Eds. Laurence L. Brunton, et al.eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. McGraw Hill; 2015. Accessed January 28, 2023. https://accessmedicine.mhmedical.com/content.aspx?bookid=1613&sectionid=102162158
Schimmer BP, Funder JW. Schimmer B.P., & Funder J.W. Schimmer, Bernard P., and John W. Funder. (2015). Acth, adrenal steroids, and pharmacology of the adrenal cortex. Brunton LL, Chabner BA, Knollmann BC. Brunton L.L., & Chabner B.A., & Knollmann B.C.(Eds.),Eds. Laurence L. Brunton, et al. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1613&sectionid=102162158
Schimmer BP, Funder JW. Schimmer B.P., & Funder J.W. Schimmer, Bernard P., and John W. Funder. "ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex." Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e Brunton LL, Chabner BA, Knollmann BC. Brunton L.L., & Chabner B.A., & Knollmann B.C.(Eds.),Eds. Laurence L. Brunton, et al. McGraw Hill, 2015, https://accessmedicine.mhmedical.com/content.aspx?bookid=1613&sectionid=102162158.
ADRENOCORTICOTROPIC HORMONE (ACTH; CORTICOTROPIN)
ADRENOCORTICAL STEROIDS
INHIBITORS OF THE BIOSYNTHESIS AND ACTION OF ADRENOCORTICAL STEROIDS
ANTIGLUCOCORTICOIDS
CLINICAL SUMMARY
Adrenocorticotropic hormone (ACTH, corticotropin) and the steroid hormone products of the adrenal cortex are considered together because the major physiological and pharmacological effects of ACTH 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 all known therapeutic effects of ACTH can be achieved with corticosteroids, synthetic steroid hormones 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. In addition, glucocorticoids potently suppress inflammation, and their use in a variety of 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, some of which are life threatening. Therefore, the decision to institute therapy with systemic corticosteroids always requires careful consideration of the relative risks and benefits in each patient.
Agents that inhibit steps in the steroidogenic pathway and thus alter the biosynthesis of adrenocortical steroids are discussed in this chapter, as are synthetic steroids that inhibit glucocorticoid action. Agents that inhibit the action of aldosterone are presented in Chapter 25; agents used to inhibit growth of steroid-dependent tumors are discussed in Chapters 60,61,62.
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.
As summarized in Figure 42–1, ACTH is synthesized as part of a larger precursor protein, pro-opiomelanocortin (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). The importance of this enzyme in POMC processing is best illustrated in a rare group of patients with prohormone convertase 1 mutations who present with impaired POMC processing, secondary hypocortisolism, childhood obesity, hypogonadotropic hypogonadism, diabetes, and neonatal onset enteropathy (Farooqi et al., 2007). A number of other biologically important peptides, including endorphins, lipotropins, and the melanocyte-stimulating hormones (MSH), also are produced by proteolytic processing of the same POMC precursor (Chapter 18).
Processing of pro-opiomelanocortin to adrenocorticotropic hormone and the sequence of adrenocorticotropic hormone. The pathway by which pro-opiomelanocortin (POMC) is converted to adrenocorticotropic hormone (ACTH) and other peptides in the anterior pituitary is depicted. The amino acid sequence of human ACTH is shown. The light blue boxes behind the ACTH structure indicate regions identified as 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.
Human ACTH is a peptide of 39 amino acids (Figure 42–1). Whereas removal of a single amino acid at the amino terminus considerably impairs biological activity, a number of amino acids can be removed from the carboxyl-terminal end without a marked effect. The structure–activity relationships of ACTH have been studied extensively, and it is believed that a stretch of four basic amino acids at positions 15-18 is an important determinant of high-affinity binding to the ACTH receptor, whereas amino acids 6-10 are important for receptor activation.
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).
Actions on the Adrenal Cortex. Acting via MC2R, ACTH stimulates the adrenal cortex to secrete glucocorticoids, mineralocorticoids, and the androgen precursor dehydroepiandrosterone (DHEA) that can be converted peripherally into more potent androgens. The adrenal cortex histologically and functionally can be separated into three zones that produce different steroid products under different regulatory influences. The outer zona glomerulosa secretes the mineralocorticoid aldosterone, the middle zona fasciculata secretes the glucocorticoid cortisol, and the inner zona reticularis secretes DHEA (Figure 42–2) and its sulfated derivative DHEAS, which circulates at concentrations 1000 times greater than DHEA. DHEAS can be converted to DHEA in the periphery by DHEA sulfatase.
The adrenal cortex contains three anatomically and functionally distinct compartments. 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 (Ang II) 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.
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.
Mechanism of Action. ACTH stimulates the synthesis and release of adrenocortical hormones. Because specific mechanisms for steroid hormone secretion have not been defined and steroids do not accumulate appreciably in the gland, it is believed that the actions of ACTH to increase steroid hormone production are mediated predominantly at the level of de novo biosynthesis.
ACTH, binding to MC2R (a GPCR), activates the Gs-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).
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 orange box, whereas those that occur in the inner zona fasciculata and zona reticularis are shown in gray box. The zona reticularis does not express 3β-HSD and thus preferentially synthesizes DHEA. 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.
Extra-Adrenal Effects of ACTH. In large doses, ACTH causes a number of metabolic changes in adrenalectomized animals, including ketosis, lipolysis, hypoglycemia (immediately after treatment), and resistance to insulin (later after treatment). Given the large doses of ACTH required, the physiological significance of these extra-adrenal effects is questionable. ACTH also reportedly improves learning in experimental animals, an effect postulated to be mediated via distinct receptors in the CNS.
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, which, in turn, are regulated by several neurotransmitters from the CNS. These three organs collectively are referred to as the hypothalamic-pituitary-adrenal (HPA) axis, an integrated system that maintains appropriate levels of glucocorticoids (Figure 42–4). The three 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. 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. As discussed later, 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.
Overview of 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.
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 Gs-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).
Arginine Vasopressin. Arginine vasopressin (AVP) also acts as a secretagogue for corticotropes, significantly potentiating the effects of CRH. Animal studies suggest that the potentiation of CRH action by AVP probably contributes to the full magnitude of the stress response in vivo. Like CRH, AVP is produced in the parvocellular neurons of the paraventricular nucleus and secreted into the pituitary plexus from the median eminence. After binding to V1b receptors, AVP activates the Gq-PLC-IP3-Ca2+ pathway to enhance the release of ACTH. In contrast to CRH, AVP apparently does not increase ACTH synthesis (Surget and Belzung, 2008).
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 (GR), 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, it is clear that their increased 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 (Elenkov and Chrousos, 2006).
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 t1/2 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.
The adrenal cortex synthesizes two classes of steroids: the corticosteroids (glucocorticoids and mineralocorticoids), which have 21 carbon atoms, and the androgens, which have 19 carbons (Figure 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 shows typical rates of secretion of cortisol and aldosterone, as well as their normal circulating concentrations.
Table 42-1Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids
Table 42-1 Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids
ALDOSTERONE
Rate of secretion under optimal conditions 10 mg/day 0.125 mg/day
Concentration in peripheral plasma:
8 a.m. 16 μg/100 mL 0.01 μg/100 mL
4 a.m. 4 μg/100 mL 0.01 μg/100 mL
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.
Physiological Functions and Pharmacological Effects
Physiological Actions. Corticosteroids have numerous and widespread 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 such stressful circumstances as noxious stimuli and environmental changes. In the absence of the adrenal cortex, survival is made possible only by maintaining an optimal environment, including adequate and regular feeding, ingestion of relatively large amounts of sodium chloride, and maintenance of an appropriate environmental temperature; stresses such as infection, trauma, and extremes in temperature in this setting can be life threatening.
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.
Corticosteroids are grouped 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.
Based on these differential potencies, the corticosteroids traditionally are divided into mineralocorticoids and glucocorticoids. Estimates of potencies of representative steroids in these actions are listed in Table 42–2. 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.
Table 42-2Relative Potencies and Equivalent Doses of Representative Corticosteroids
Table 42-2 Relative Potencies and Equivalent Doses of Representative Corticosteroids
COMPOUND ANTI-INFLAMMATORY POTENCY Na+-RETAINING POTENCY DURATION OF ACTIONa EQUIVALENT DOSE (mg)b
Cortisol 1 1 S 20
Cortisone 0.8 0.8 S 25
Fludrocortisone 10 125 I c
Prednisone 4 0.8 I 5
Prednisolone 4 0.8 I 5
6α-Methylprednisolone 5 0.5 I 4
Triamcinolone 5 0 I 4
Betamethasone 25 0 L 0.75
Dexamethasone 25 0 L 0.75
aS, short (i.e., 8-12 hour biological t1/2); I, intermediate (i.e., 12-36 hour biological t1/2); L, long (i.e., 36-72 hour biological t1/2).
bThese dose relationships apply only to oral or intravenous administration, as glucocorticoid potencies may differ greatly following intramuscular or intraarticular administration.
cThis agent is not used for glucocorticoid 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 42–5). As a consequence of the time required to modulate gene expression and protein synthesis, most effects of corticosteroids are not immediate but become apparent after several hours. This fact is of clinical significance because a delay generally is seen before beneficial effects of corticosteroid therapy become manifest. Although corticosteroids predominantly act by increasing gene transcription, there are well-documented examples in which glucocorticoids decrease gene transcription, as discussed later. In addition, corticosteroids may exert some of their immediate effects by nongenomic mechanisms (Stahn and Buttgereit, 2008).
Intracellular mechanism of action of the glucocorticoid receptor. The figure shows the molecular pathway by which cortisol (labeled S) enters cells and interacts with the glucocorticoid receptor (GR) to change GR conformation (indicated by the change in shape of the GR), induce GR nuclear translocation, and activate transcription of target genes. The example shown is one in which glucocorticoids activate expression of target genes; the expression of certain genes, including pro-opiomelanocortin (POMC) expression by corticotropes, is inhibited by glucocorticoid treatment. CBG, corticosteroid-binding globulin; GR, glucocorticoid receptor; S, steroid hormone; HSP90, the 90-kd heat-shock protein; HSP70, the 70-kd heat-shock protein; IP, the 56-kd immunophilin; GRE, glucocorticoid-response elements in the DNA that are bound by GR, thus providing specificity to induction of gene transcription by glucocorticoids. Within the gene are introns (gray) and exons (red); transcription and mRNA processing leads to splicing and removal of introns and assembly of exons into mRNA.
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.
Receptor-independent mechanism by which 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. The type 1 isozyme of 11β-HSD (11β-HSD1) 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 Figure 42–7 for complete structure.
Structure and nomenclature of corticosteroid products and selected synthetic derivatives. The structure of hydrocortisone is represented in two dimensions. Note that the steroid ring system is not completely planar and the orientation of the groups attached to the steroid rings is an important determinant of the biological activity. The methyl groups at C18 and C19 and the hydroxyl group at C11 project upward (forward in the two-dimensional representation and shown by a solid line connecting the atoms) and are designated β. The hydroxyl at C17 projects below the plane (behind in the two-dimensional representation, and represented by the dashed line connecting the atoms) and is designated α.
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.
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.
Lipid Metabolism. Two effects of corticosteroids on lipid metabolism are firmly established. The first is the dramatic redistribution of body fat that occurs in settings of endogenous or pharmacologically induced hypercorticism, such as Cushing's 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.
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.
Electrolyte and Water Balance. Aldosterone is by far the most potent endogenous corticosteroid with respect to fluid and electrolyte balance. Thus, electrolyte balance is relatively normal in patients with adrenal insufficiency due to pituitary disease, despite the loss of glucocorticoid production by the inner cortical zones. 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+. Conceptually, it is useful to think of aldosterone as stimulating a renal exchange between Na+ and K+ or H+, although this does not involve a simple 1:1 exchange of cations in the renal tubule.
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. Indeed, mineralocorticoid-deficient patients are especially predisposed to Na+ loss and volume depletion through excessive sweating in hot environments. Chronically, hyperaldosteronism causes hypertension, whereas aldosterone deficiency can lead to hypotension and vascular collapse.
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.
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. Studies have shown direct effects of MR activation on the heart and vessel wall; aldosterone induces hypertension and interstitial cardiac fibrosis in animal models. The increased cardiac fibrosis is proposed to result from direct mineralocorticoid actions in the heart rather than from the effect of hypertension because treatment with spironolactone, a MR antagonist, blocks the development of fibrosis without altering blood pressure. Indeed, in age-, sex-, and blood pressure-matched hypertensive patients, those with primary aldosteronism have a higher prevalence of atrial fibrillation, stroke, and myocardial infarction, indicating direct effects of increased aldosterone on the cardiovascular system. Similar cardiac effects of MR activation in human beings may explain the beneficial effects of spironolactone in patients with congestive heart failure (Chapter 28).
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 norepinephrine and angiotensin II, 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's syndrome and in a subset of patients treated with synthetic glucocorticoids (even those lacking any significant mineralocorticoid action).
The underlying mechanisms in glucocorticoid-induced hypertension also are unknown; the hypertension related to the endogenous secretion of cortisol, as seen in patients with Cushing's syndrome, likely results from multiple effects mediated by the GR and MR. Unlike hypertension caused by high aldosterone levels, the hypertension secondary to excess glucocorticoids is generally resistant to Na+ restriction (Magiakou et al., 2006).
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's 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, termed steroid myopathy, accounts in part for weakness and fatigue in patients with glucocorticoid excess and is discussed in more detail later.
Central Nervous System. 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; 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.
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's 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 the self-destruction of erythrocytes.
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.
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. Glucocorticoids can prevent or suppress inflammation in response to multiple inciting events, including radiant, mechanical, chemical, infectious, and immunological stimuli. 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 value in treating diseases that result from undesirable immune reactions. These diseases range from conditions that predominantly result from humoral immunity, such as urticaria (Chapter 65), to those that are mediated by cellular immune mechanisms, such as transplantation rejection (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 42–3. 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).
Table 42-3Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
Table 42-3 Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
CELL TYPE FACTOR COMMENTS
Macrophages and monocytes
Arachidonic acid and its metabolites (prostaglandins and leukotrienes)
Cytokines, including: interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α)
Mediated by glucocorticoid inhibition of COX-2 and PLA2.
Production and release are blocked. The cytokines exert multiple effects on inflammation (e.g., activation of T cells, stimulation of fibroblast proliferation).
These include the third component of complement.
ELAM-1 and ICAM-1: critical for leukocyte localization.
Same as above, for macrophages and monocytes.
IgE-dependent release inhibited by glucocorticoids.
Fibroblasts Arachidonic acid metabolites Same as above for macrophages and monocytes. Glucocorticoids also suppress growth factor–induced DNA synthesis and fibroblast proliferation.
Lymphocytes Cytokines (IL-1, IL-2, IL-3, IL-6, TNF-α, GM-CSF, interferon-γ) Same as above for macrophages and monocytes.
ELAM-1, endothelial-leukocyte adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1.
Absorption, Transport, Metabolism, and Excretion
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). Because of its higher dissociation constant, albumin-bound corticosteroid makes a greater contribution to the active corticosteroid fraction in tissues that have a slow capillary transit time (e.g., liver and spleen) than in tissues with rapid capillary transit times (e.g., kidney). 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. Corticosteroids compete with each other for binding sites on CBG. 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.
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).
Table 42-4Available Preparations of Adrenocortical Steroids and Their Synthetic Analogs
Table 42-4 Available Preparations of Adrenocortical Steroids and Their Synthetic Analogs
NONPROPRIETARY NAME TRADE NAME TYPE OF PREPARATION
Alclometasone dipropionate aclovate Topical
Amcinonide Topical
Betamethasone acetate and sodium phosphate celestone soluspan Injectable
Beclomethasone dipropionate beconase aq, qvar40, qvar80 Inhaled
diprolene, diproline af Topical
Betamethasone sodium phosphate celestone Oral
Betamethasone valerate beta-val, dermabet, luxiq Topical
Budesonide entocort ec Oral
pulmicort Inhaled
rhinocort Nasal
Ciclesonide alvesco, omnaris Inhaled
Clobetasol propionate clobex, cormax embeline, olux, temovate Topical
Clocortolone pivalate cloderm Topical
Desonide desonate, desowen, verdeso Topical
Desoximetasone topicort Topical
Dexamethasone Oral
Dexamethasone sodium phosphate maxidex Ophthalmic
Diflorasone diacetate psorcon Topical
Fludrocortisone acetate* Oral
Flunisolide aerobid, aerospan hfa Inhaled
nasarel Nasal
Fluocinolone acetonide derma-smoothe/fs, fs, synalar Topical
retisert Intravitreal implant
Fluocinonide lidex, lidex-e, vanos Topical
Fluorometholone fml, fml forte Ophthalmic
Fluorometholone acetate flarex Ophthalmic
Flurandrenolide cordran cordran sp Topical
Halcinonide halog Topical
Hydrocortisone ala-cort, hytone, nutracort, stie-cort, synacort, texacort Topical
cortef Oral
Hydroxycortisone acetate micort-hc Topical
cortifoam Rectal
Hydroxycortisone butyrate locoid Topical
Hydrocortisone cypionate cortef Oral
Hydrocortisone sodium succinate a-hydrocort, solu-cortef Injectable
Hydrocortisone valerate westcort Topical
Methylprednisolone acetate medrol Oral
depo-medrol Injectable
Methylprednisolone sodium succinate a-methapred, solu-medrol Injectable
Mometasone furoate asmanex Inhaled
nasonex Nasal
elocon Topical
Prednisolone Oral
Prednisolone acetate flo-pred Oral
omnipred, pred fort, pred mild Ophthalmic
Prednisolone sodium phosphate orapred, orapred odt, pediapred Oral
Prednisone Oral
Triamcinolone acetonide azmacort Inhaled
nasacort aq Nasal
kenolog Topical
kenolog-10, kenalog-40, triesence, trivaris Injectable
Triamcinolone hexacetonide aristospan Injectable
azmacort Inhaled
*Fludrocortisone acetate is intended for use as a mineralocorticoid.
Note: Topical preparations include agents for application to skin or mucous membranes in creams, solutions, ointments, gels, pastes (for oral lesions), and aerosols; ophthalmic preparations include solutions, suspensions, and ointments; inhalation preparations include agents for nasal or oral inhalation.
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. The therapeutic approach to acute adrenal insufficiency is detailed later. There is significant variation among patients with respect to the degree and duration of adrenal suppression after glucocorticoid therapy, making it difficult to establish the relative risk in any given patient. 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.
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.
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, osteoporosis, myopathy, behavioral disturbances, cataracts, growth arrest, and the characteristic habitus of steroid overdose, including fat redistribution, striae, and ecchymoses.
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.
With the exception of replacement therapy in deficiency states, the use of glucocorticoids largely is empirical. Based on extensive clinical experience, a number of therapeutic principles can be proposed. 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.
These principles have several implications for clinical practice. 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. It is always essential to weigh carefully the relative dangers of therapy and of the disease being treated.
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.
Replacement Therapy. Adrenal insufficiency can result from structural or functional lesions of the adrenal cortex (primary adrenal insufficiency or Addison's 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 (Carey, 1997). 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 it 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 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.
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 (Coursin and Wood, 2002).
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.
Congenital Adrenal Hyperplasia. This term denotes a group of genetic disorders in which the activity of one 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. Congenital adrenal hyperplasia (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 (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.
Therapeutic Uses in Nonendocrine Diseases. Outlined next are important uses of glucocorticoids in diseases that do not directly involve the HPA axis. The disorders discussed are not inclusive; rather, they 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. For convenience, approximate doses of a representative glucocorticoid (generally prednisone) are provided. This choice is not an endorsement of one particular glucocorticoid preparation over other congeners but is made for illustrative purposes only.
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.
Hypercortisolism with its attendant morbidity and mortality is most frequently caused by corticotroph adenomas that overproduce ACTH (Cushing's disease) or by adrenocortical tumors or bilateral hyperplasias that overproduce cortisol (Cushing's 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 (Biller et al., 2008). 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, 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.
Glucocorticoids are administered in multiple formulations (e.g., oral, parenteral, and topical) for disorders that share an inflammatory or immunological basis. Except in patients receiving replacement therapy for adrenal insufficiency, glucocorticoids are neither specific nor curative, but rather are palliative because of their anti-inflammatory and immunosuppressive actions. 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. After therapy is initiated, the minimal dose needed 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) is unlikely to cause harm in the absence of specific contraindications. As the duration of glucocorticoid therapy increases beyond 1 week, adverse effects increase in a time- and dose-related manner. Abrupt cessation of glucocorticoids after prolonged therapy is associated with the risk of adrenal insufficiency due to suppression of the HPA axis, and it may be fatal.
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