George P. Chrousos, MD
A 19-year-old man complains of anorexia, fatigue, dizziness, and weight loss of 8 months’ duration. The examining physician discovers postural hypotension and moderate vitiligo (depigmented areas of skin) and obtains routine blood tests. She finds hyponatremia, hyperkalemia, and acidosis and suspects Addison’s disease. She performs a standard ACTH 1–24 stimulation test, which reveals an insufficient plasma cortisol response, compatible with primary adrenal insufficiency. The diagnosis of autoimmune Addison’s disease is made, and the patient must start replacement of the hormones he cannot produce himself. How should this patient be treated? What precautions should he take?
The natural adrenocortical hormones are steroid molecules produced and released by the adrenal cortex. Both natural and synthetic corticosteroids are used for the diagnosis and treatment of disorders of adrenal function. They are also used—more often and in much larger doses—for treatment of a variety of inflammatory and immunologic disorders.
Secretion of adrenocortical steroids is controlled by the pituitary release of corticotropin (ACTH). Secretion of the salt-retaining hormone aldosterone is primarily under the influence of angiotensin. Corticotropin has some actions that do not depend on its effect on adrenocortical secretion. However, its pharmacologic value as an anti-inflammatory agent and its use in testing adrenal function depend on its secretory action. Its pharmacology is discussed in Chapter 37 and is reviewed only briefly here.
Inhibitors of the synthesis or antagonists of the action of the adrenocortical steroids are important in the treatment of several conditions. These agents are described at the end of this chapter.
The adrenal cortex releases a large number of steroids into the circulation. Some have minimal biologic activity and function primarily as precursors, and there are some for which no function has been established. The hormonal steroids may be classified as those having important effects on intermediary metabolism and immune function (glucocorticoids), those having principally salt-retaining activity (mineralocorticoids), and those having androgenic or estrogenic activity (see Chapter 40). In humans, the major glucocorticoid is cortisol and the most important mineralocorticoid is aldosterone. Quantitatively, dehydroepiandrosterone (DHEA) in its sulfated form (DHEAS) is the major adrenal androgen. However, DHEA and two other adrenal androgens, androstenedione and androstenediol, are weak androgens and androstenediol is a potent estrogen. Androstenedione can be converted to testosterone and estradiol in extra-adrenal tissues (Figure 39–1). Adrenal androgens constitute the major endogenous precursors of estrogen in women after menopause and in younger patients in whom ovarian function is deficient or absent.
THE NATURALLY OCCURRING GLUCOCORTICOIDS; CORTISOL (HYDROCORTISONE)
Cortisol (also called hydrocortisone, compound F) exerts a wide range of physiologic effects, including regulation of intermediary metabolism, cardiovascular function, growth, and immunity. Its synthesis and secretion are tightly regulated by the central nervous system, which is very sensitive to negative feedback by the circulating cortisol and exogenous (synthetic) glucocorticoids. Cortisol is synthesized from cholesterol (as shown in Figure 39–1). The mechanisms controlling its secretion are discussed in Chapter 37.
In the normal adult, in the absence of stress, 10–20 mg of cortisol is secreted daily. The rate of secretion follows a circadian rhythm (Figure 39–2) governed by pulses of ACTH that peak in the early morning hours and after meals. In plasma, cortisol is bound to circulating proteins. Corticosteroid-binding globulin (CBG), an α2 globulin synthesized by the liver, binds about 90% of the circulating hormone under normal circumstances. The remainder is free (about 5–10%) or loosely bound to albumin (about 5%) and is available to exert its effect on target cells. When plasma cortisol levels exceed 20–30 mcg/dL, CBG is saturated, and the concentration of free cortisol rises rapidly. CBG is increased in pregnancy and with estrogen administration and in hyperthyroidism. It is decreased by hypothyroidism, genetic defects in synthesis, and protein deficiency states. Albumin has a large capacity but low affinity for cortisol, and for practical purposes albumin-bound cortisol should be considered free. Synthetic corticosteroids such as dexamethasone are largely bound to albumin rather than CBG.
FIGURE 39–2 Circadian variation in plasma cortisol throughout the 24-hour day (upper panel). The sensitivity of tissues to glucocorticoids is also circadian but inverse to that of cortisol, with low sensitivity in the late morning and high sensitivity in the evening and early night (lower panel). The sensitivity of tissues to glucocorticoids is inversely related to that of glucocorticoid receptor (GR) acetylation by the transcription factor CLOCK; the acetylated receptor has decreased transcriptional activity. (Adapted, with permission, from Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 2010;21:277. Copyright Elsevier.)
The half-life of cortisol in the circulation is normally about 60–90 minutes; it may be increased when hydrocortisone (the pharmaceutical preparation of cortisol) is administered in large amounts or when stress, hypothyroidism, or liver disease is present. Only 1% of cortisol is excreted unchanged in the urine as free cortisol; about 20% of cortisol is converted to cortisone by 11-hydroxysteroid dehydrogenase in the kidney and other tissues with mineralocorticoid receptors (see below) before reaching the liver. Most cortisol is metabolized in the liver. About one third of the cortisol produced daily is excreted in the urine as dihydroxy ketone metabolites and is measured as 17-hydroxysteroids (see Figure 39–3 for carbon numbering). Many cortisol metabolites are conjugated with glucuronic acid or sulfate at the C3 and C21hydroxyls, respectively, in the liver; they are then excreted in the urine.
FIGURE 39–3 Chemical structures of several glucocorticoids. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the methyl group at C16: in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha.
In some species (eg, the rat), corticosterone is the major glucocorticoid. It is less firmly bound to protein and therefore metabolized more rapidly. The pathways of its degradation are similar to those of cortisol.
A. Mechanism of Action
Most of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors. These proteins are members of the superfamily of nuclear receptors, which includes steroid, sterol (vitamin D), thyroid, retinoic acid, and many other receptors with unknown or nonexistent ligands (orphan receptors). All these receptors interact with the promoters of—and regulate the transcription of—target genes (Figure 39–4). In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic, in oligomeric complexes with chaperone heat-shock proteins (hsp). The most important of these are two molecules of hsp90, although other proteins (eg, hsp40, hsp70, FKBP5) are certainly involved. Free hormone from the plasma and interstitial fluid enters the cell and binds to the receptor, inducing conformational changes that allow it to dissociate from the heat shock proteins. The dimeric ligand-bound receptor complex then is actively transported into the nucleus, where it interacts with DNA and nuclear proteins. As a homodimer, it binds to glucocorticoid receptor elements (GREs) in the promoters of responsive genes. The GRE is composed of two palindromic sequences that bind to the hormone receptor dimer.
FIGURE 39–4 A model of the interaction of a steroid, S (eg, cortisol), and its receptor, R, and the subsequent events in a target cell. The steroid is present in the blood in bound form on the corticosteroid-binding globulin (CBG) but enters the cell as the free molecule. The intracellular receptor is bound to stabilizing proteins, including two molecules of heat-shock protein 90 (hsp90) and several others including FKBP5, denoted as “X” in the figure. This receptor complex is incapable of activating transcription. When the complex binds a molecule of cortisol, an unstable complex is created and the hsp90 and associated molecules are released. The steroid-receptor complex is now able to dimerize, enter the nucleus, bind to a glucocorticoid response element (GRE) on the regulatory region of the gene, and regulate transcription by RNA polymerase II and associated transcription factors. A variety of regulatory factors (not shown) may participate in facilitating (coactivators) or inhibiting (corepressors) the steroid response. The resulting mRNA is edited and exported to the cytoplasm for the production of protein that brings about the final hormone response. An alternative to the steroid-receptor complex interaction with a GRE is an interaction with and altering the function of other transcription factors, such as NF-κB in the nucleus of cells.
In addition to binding to GREs, the ligand-bound receptor also forms complexes with and influences the function of other transcription factors, such as AP1 and nuclear factor kappa-B (NF-κB), which act on non-GRE-containing promoters, to contribute to the regulation of transcription of their responsive genes. These transcription factors have broad actions on the regulation of growth factors, proinflammatory cytokines, etc, and to a great extent mediate the anti-growth, anti-inflammatory, and immunosuppressive effects of glucocorticoids.
Two genes for the corticoid receptor have been identified: one encoding the classic glucocorticoid receptor (GR) and the other encoding the mineralocorticoid receptor (MR). Alternative splicing of human glucocorticoid receptor pre-mRNA generates two highly homologous isoforms, termed hGRα and hGRβ. Human GRα is the classic ligand-activated glucocorticoid receptor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes. In contrast, hGRβ does not bind glucocorticoids and is transcriptionally inactive. However, hGRβ is able to inhibit the effects of hormone-activated hGRα on glucocorticoid-responsive genes, playing the role of a physiologically relevant endogenous inhibitor of glucocorticoid action. It was recently shown that the two hGR alternative transcripts have eight distinct translation initiation sites; ie, in a human cell there may be up to 16 GRα and GRβ isoforms, which may form up to 256 homodimers and heterodimers with different transcriptional and possibly nontranscriptional activities. This variability suggests that this important class of steroid receptors has complex stochastic activities. In addition, rare mutations in hGR may result in partial glucocorticoid resistance. Affected individuals have increased ACTH secretion because of reduced pituitary feedback and additional endocrine abnormalities (see below).
The prototype GR isoform is composed of about 800 amino acids and can be divided into three functional domains (see Figure 2–6). The glucocorticoid-binding domain is located at the carboxyl terminal of the molecule. The DNA-binding domain is located in the middle of the protein and contains nine cysteine residues. This region folds into a “two-finger” structure stabilized by zinc ions connected to cysteines to form two tetrahedrons. This part of the molecule binds to the GREs that regulate glucocorticoid action on glucocorticoid-regulated genes. The zinc fingers represent the basic structure by which the DNA-binding domain recognizes specific nucleic acid sequences. The amino-terminal domain is involved in the transactivation activity of the receptor and increases its specificity.
The interaction of glucocorticoid receptors with GREs or other transcription factors is facilitated or inhibited by several families of proteins called steroid receptor coregulators, divided into coactivators and corepressors. The coregulators do this by serving as bridges between the receptors and other nuclear proteins and by expressing enzymatic activities such as histone acetylase or deacetylase, which alter the conformation of nucleosomes and the transcribability of genes.
Between 10% and 20% of expressed genes in a cell are regulated by glucocorticoids. The number and affinity of receptors for the hormone, the complement of transcription factors and coregulators, and post-transcription events determine the relative specificity of these hormones’ actions in various cells. The effects of glucocorticoids are mainly due to proteins synthesized from mRNA transcribed from their target genes.
Some of the effects of glucocorticoids can be attributed to their binding to mineralocorticoid receptors. Indeed, MRs bind aldosterone and cortisol with similar affinity. A mineralocorticoid effect of the higher levels of cortisol is avoided in some tissues (eg, kidney, colon, salivary glands) by expression of 11β-hydroxysteroid dehydrogenase type 2, the enzyme responsible for biotransformation to its 11-keto derivative (cortisone), which has minimal action on aldosterone receptors.
The GR also interacts with other regulators of cell function. One such molecule is CLOCK/BMAL-1, a transcription factor dimer expressed in all tissues and generating the circadian rhythm of cortisol secretion (Figure 39–2) at the suprachiasmatic nucleus of the hypothalamus. CLOCK is an acetyltransferase that acetylates the hinge region of the GR, neutralizing its transcriptional activity and thus rendering target tissues resistant to glucocorticoids. As shown in Figure 39–2, lower panel, the glucocorticoid target tissue sensitivity rhythm generated is in reverse phase to that of circulating cortisol concentrations, explaining the increased sensitivity of the organism to evening administration of glucocorticoids. The GR also interacts with NF-κB, a regulator of production of cytokines and other molecules involved in inflammation.
Prompt effects such as initial feedback suppression of pituitary ACTH occur in minutes and are too rapid to be explained on the basis of gene transcription and protein synthesis. It is not known how these effects are mediated. Among the proposed mechanisms are direct effects on cell membrane receptors for the hormone or nongenomic effects of the classic hormone-bound glucocorticoid receptor. The putative membrane receptors might be entirely different from the known intracellular receptors. For example, recent studies implicate G protein-coupled membrane receptors in the response of glutamatergic neurons to glucocorticoids in rats. Furthermore, all steroid receptors (except the MRs) have been shown to have palmitoylation motifs that allow enzymatic addition of palmitate and increased localization of the receptors in the vicinity of plasma membranes. Such receptors are available for direct interactions with and effects on various membrane-associated or cytoplasmic proteins without the need for entry into the nucleus and induction of transcriptional actions.
B. Physiologic Effects
The glucocorticoids have widespread effects because they influence the function of most cells in the body. The major metabolic consequences of glucocorticoid secretion or administration are due to direct actions of these hormones in the cell. However, some important effects are the result of homeostatic responses by insulin and glucagon. Although many of the effects of glucocorticoids are dose-related and become magnified when large amounts are administered for therapeutic purposes, there are also other effects—called permissive effects—without which many normal functions become deficient. For example, the response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amounts of this glucocorticoid. Similarly, the lipolytic responses of fat cells to catecholamines, ACTH, and growth hormone are attenuated in the absence of glucocorticoids.
C. Metabolic Effects
The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. The same effects are responsible for some of the serious adverse effects associated with their use in therapeutic doses. Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism.
Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation.
The net results of these actions are most apparent in the fasting state, when the supply of glucose from gluconeogenesis, the release of amino acids from muscle catabolism, the inhibition of peripheral glucose uptake, and the stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain.
D. Catabolic and Antianabolic Effects
Although glucocorticoids stimulate RNA and protein synthesis in the liver, they have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, peripheral fat, and skin. Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness and thinning of the skin. Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing’s syndrome and impose a major limitation in the long-term therapeutic use of glucocorticoids. In children, glucocorticoids reduce growth. This effect may be partially prevented by administration of growth hormone in high doses, but this use of growth hormone is not recommended.
E. Anti-Inflammatory and Immunosuppressive Effects
Glucocorticoids dramatically reduce the manifestations of inflammation. This is due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other mediators of inflammation. Inflammation, regardless of its cause, is characterized by the extravasation and infiltration of leukocytes into the affected tissue. These events are mediated by a complex series of interactions of white cell adhesion molecules with those on endothelial cells and are inhibited by glucocorticoids. After a single dose of a short-acting glucocorticoid, the concentration of neutrophils in the circulation increases while the lymphocytes (T and B cells), monocytes, eosinophils, and basophils decrease. The changes are maximal at 6 hours and are dissipated in 24 hours. The increase in neutrophils is due both to the increased influx into the blood from the bone marrow and to the decreased migration from the blood vessels, leading to a reduction in the number of cells at the site of inflammation. The reduction in circulating lymphocytes, monocytes, eosinophils, and basophils is primarily the result of their movement from the vascular bed to lymphoid tissue.
Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-presenting cells. The ability of these cells to respond to antigens and mitogens is reduced. The effect on macrophages is particularly marked and limits their ability to phagocytose and kill microorganisms and to produce tumor necrosis factor-α, interleukin-1, metalloproteinases, and plasminogen activator. Both macrophages and lymphocytes produce less interleukin-12 and interferon-γ, important inducers of TH1 cell activity, and cellular immunity.
In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by inhibiting phospholipase A2 thereby reducing the synthesis of arachidonic acid, the precursor of prostaglandins and leukotrienes, and of platelet-activating factor. Finally, glucocorticoids reduce expression of cyclooxygenase-2, the inducible form of this enzyme, in inflammatory cells, thus reducing the amount of enzyme available to produce prostaglandins (see chapters 18 and 36).
Glucocorticoids cause vasoconstriction when applied directly to the skin, possibly by suppressing mast cell degranulation. They also decrease capillary permeability by reducing the amount of histamine released by basophils and mast cells.
The anti-inflammatory and immunosuppressive effects of glucocorticoids are largely due to the actions described above. In humans, complement activation is unaltered, but its effects are inhibited. Antibody production can be reduced by large doses of steroids, although it is unaffected by moderate doses (eg, 20 mg/d of prednisone).
The anti-inflammatory and immunosuppressive effects of these agents are widely useful therapeutically but are also responsible for some of their most serious adverse effects (see text that follows).
F. Other Effects
Glucocorticoids have important effects on the nervous system. Adrenal insufficiency causes marked slowing of the alpha rhythm of the electroencephalogram and is associated with depression. Increased amounts of glucocorticoids often produce behavioral disturbances in humans: initially insomnia and euphoria and subsequently depression. Large doses of glucocorticoids may increase intracranial pressure (pseudotumor cerebri).
Glucocorticoids given chronically suppress the pituitary release of ACTH, growth hormone, thyroid-stimulating hormone, and luteinizing hormone.
Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobacter pylori. They also promote fat redistribution in the body, with increase of visceral, facial, nuchal, and supraclavicular fat, and they appear to antagonize the effect of vitamin D on calcium absorption. The glucocorticoids also have important effects on the hematopoietic system. In addition to their effects on leukocytes, they increase the number of platelets and red blood cells.
Cortisol deficiency results in impaired renal function (particularly glomerular filtration), augmented vasopressin secretion, and diminished ability to excrete a water load.
Glucocorticoids have important effects on the development of the fetal lungs. Indeed, the structural and functional changes in the lungs near term, including the production of pulmonary surface-active material required for air breathing (surfactant), are stimulated by glucocorticoids.
Glucocorticoids have become important agents for use in the treatment of many inflammatory, immunologic, hematologic, and other disorders. This has stimulated the development of many synthetic steroids with anti-inflammatory and immunosuppressive activity.
Pharmaceutical steroids are usually synthesized from cholic acid obtained from cattle or steroid sapogenins found in plants. Further modifications of these steroids have led to the marketing of a large group of synthetic steroids with special characteristics that are pharmacologically and therapeutically important (Table 39–1; Figure 39–3).
TABLE 39–1 Some commonly used natural and synthetic corticosteroids for general use.
The metabolism of the naturally occurring adrenal steroids has been discussed above. The synthetic corticosteroids (Table 39–1) are in most cases rapidly and completely absorbed when given by mouth. Although they are transported and metabolized in a fashion similar to that of the endogenous steroids, important differences exist.
Alterations in the glucocorticoid molecule influence its affinity for glucocorticoid and mineralocorticoid receptors as well as its protein-binding affinity, side chain stability, rate of elimination, and metabolic products. Halogenation at the 9 position, unsaturation of the δ1–2 bond of the A ring, and methylation at the 2 or 16 position prolong the half-life by more than 50%. The δ1 compounds are excreted in the free form. In some cases, the agent given is a prodrug; for example, prednisone is rapidly converted to the active product prednisolone in the body.
The actions of the synthetic steroids are similar to those of cortisol (see above). They bind to the specific intracellular receptor proteins and produce the same effects but have different ratios of glucocorticoid to mineralocorticoid potency (Table 39–1).
A. Diagnosis and Treatment of Disturbed Adrenal Function
1. Adrenocortical insufficiency
a. Chronic (Addison’s disease)—Chronic adrenocortical insufficiency is characterized by weakness, fatigue, weight loss, hypotension, hyperpigmentation, and inability to maintain the blood glucose level during fasting. In such individuals, minor noxious, traumatic, or infectious stimuli may produce acute adrenal insufficiency with circulatory shock and even death.
In primary adrenal insufficiency, about 20–30 mg of hydrocortisone must be given daily, with increased amounts during periods of stress. Although hydrocortisone has some mineralocorticoid activity, this must be supplemented by an appropriate amount of a salt-retaining hormone such as fludrocortisone. Synthetic glucocorticoids that are long-acting and devoid of salt-retaining activity should not be administered to these patients.
b. Acute—When acute adrenocortical insufficiency is suspected, treatment must be instituted immediately. Therapy consists of large amounts of parenteral hydrocortisone in addition to correction of fluid and electrolyte abnormalities and treatment of precipitating factors.
Hydrocortisone sodium succinate or phosphate in doses of 100 mg intravenously is given every 8 hours until the patient is stable. The dose is then gradually reduced, achieving maintenance dosage within 5 days.
The administration of salt-retaining hormone is resumed when the total hydrocortisone dosage has been reduced to 50 mg/d.
2. Adrenocortical hypo- and hyperfunction
a. Congenital adrenal hyperplasia—This group of disorders is characterized by specific defects in the synthesis of cortisol. In pregnancies at high risk for congenital adrenal hyperplasia, fetuses can be protected from genital abnormalities by administration of dexamethasone to the mother.
The most common defect is a decrease in or lack of P450c21 (21α-hydroxylase) activity.* As can be seen in Figure 39–1, this would lead to a reduction in cortisol synthesis and thus produce a compensatory increase in ACTH release. The adrenal becomes hyperplastic and produces abnormally large amounts of precursors such as 17-hydroxyprogesterone that can be diverted to the androgen pathway, which leads to virilization and can result in ambiguous genitalia in the female fetus. Metabolism of this compound in the liver leads to pregnanetriol, which is characteristically excreted into the urine in large amounts in this disorder and can be used to make the diagnosis and to monitor efficacy of glucocorticoid substitution. However, the most reliable method of detecting this disorder is the increased response of plasma 17-hydroxyprogesterone to ACTH stimulation.
FIGURE 39–1 Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 22nd ed. McGraw-Hill, 2005. Copyright © The McGraw-Hill Companies, Inc.)
If the defect is in 11-hydroxylation, large amounts of deoxycorticosterone are produced, and because this steroid has mineralocorticoid activity, hypertension with or without hypokalemic alkalosis ensues. When 17-hydroxylation is defective in the adrenals and gonads, hypogonadism is also present. However, increased amounts of 11-deoxycorticosterone are formed, and the signs and symptoms associated with mineralocorticoid excess—such as hypertension and hypokalemia—are also observed.
When first seen, the infant with congenital adrenal hyperplasia may be in acute adrenal crisis and should be treated as described above, using appropriate electrolyte solutions and an intravenous preparation of hydrocortisone in stress doses. Once the patient is stabilized, oral hydrocortisone, 12–18 mg/m2/d in two unequally divided doses (two thirds in the morning, one third in late afternoon) is begun. The dosage is adjusted to allow normal growth and bone maturation and to prevent androgen excess. Alternate-day therapy with prednisone has also been used to achieve greater ACTH suppression without increasing growth inhibition. Fludrocortisone, 0.05–0.2 mg/d, should also be administered by mouth, with added salt to maintain normal blood pressure, plasma renin activity, and electrolytes.
b. Cushing’s syndrome—Cushing’s syndrome is usually the result of bilateral adrenal hyperplasia secondary to an ACTH-secreting pituitary adenoma (Cushing’s disease) but occasionally is due to tumors or nodular hyperplasia of the adrenal gland or ectopic production of ACTH by other tumors. The manifestations are those associated with the chronic presence of excessive glucocorticoids. When glucocorticoid hypersecretion is marked and prolonged, a rounded, plethoric face and trunk obesity are striking in appearance. Protein loss may be significant and includes muscle wasting; thinning, purple striae, and easy bruising of the skin; poor wound healing; and osteoporosis. Other serious disturbances include mental disorders, hypertension, and diabetes. This disorder is treated by surgical removal of the tumor producing ACTH or cortisol, irradiation of the pituitary tumor, or resection of one or both adrenals. These patients must receive large doses of cortisol during and after the surgical procedure. Doses of up to 300 mg of soluble hydrocortisone may be given as a continuous intravenous infusion on the day of surgery. The dose must be reduced slowly to normal replacement levels, since rapid reduction in dose may produce withdrawal symptoms, including fever and joint pain. If adrenalectomy has been performed, long-term maintenance is similar to that outlined above for adrenal insufficiency.
c. Primary generalized glucocorticoid resistance (Chrousos syndrome)—This rare sporadic or familial genetic condition is usually due to inactivating mutations of the glucocorticoid receptor gene. The hypothalamic-pituitary-adrenal (HPA) axis hyperfunctions in an attempt to compensate for the defect, and the increased production of ACTH leads to high circulating levels of cortisol and cortisol precursors such as corticosterone and 11-deoxycorticosterone with mineralocorticoid activity, as well as of adrenal androgens. These increased levels may result in hypertension with or without hypokalemic alkalosis and hyperandrogenism expressed as virilization and precocious puberty in children and acne, hirsutism, male pattern baldness, and menstrual irregularities (mostly oligo-amenorrhea and hypofertility) in women. The therapy of this syndrome is high doses of synthetic glucocorticoids such as dexamethasone with no inherent mineralocorticoid activity. These doses are titrated to normalize the production of cortisol, cortisol precursors, and adrenal androgens.
d. Aldosteronism—Primary aldosteronism usually results from the excessive production of aldosterone by an adrenal adenoma. However, it may also result from abnormal secretion by hyperplastic glands or from a malignant tumor. The clinical findings of hypertension, weakness, and tetany are related to the continued renal loss of potassium, which leads to hypokalemia, alkalosis, and elevation of serum sodium concentrations. This syndrome can also be produced in disorders of adrenal steroid biosynthesis by excessive secretion of deoxycorticosterone, corticosterone, or 18-hydroxycorticosterone—all compounds with inherent mineralocorticoid activity.
In contrast to patients with secondary aldosteronism (see text that follows), these patients have low (suppressed) levels of plasma renin activity and angiotensin II. When treated with fludrocortisone (0.2 mg twice daily orally for 3 days) or deoxycorticosterone acetate (20 mg/d intramuscularly for 3 days—but not available in the USA), patients fail to retain sodium and the secretion of aldosterone is not significantly reduced. When the disorder is mild, it may escape detection if serum potassium levels are used for screening. However, it may be detected by an increased ratio of plasma aldosterone to renin. Patients generally improve when treated with spironolactone, an aldosterone receptor-blocking agent, and the response to this agent is of diagnostic and therapeutic value.
3.Use of glucocorticoids for diagnostic purposes—It is sometimes necessary to suppress the production of ACTH to identify the source of a particular hormone or to establish whether its production is influenced by the secretion of ACTH. In these circumstances, it is advantageous to use a very potent substance such as dexamethasone because the use of small quantities reduces the possibility of confusion in the interpretation of hormone assays in blood or urine. For example, if complete suppression is achieved by the use of 50 mg of cortisol, the urinary 17-hydroxycorticosteroids will be 15–18 mg/24 h, since one third of the dose given will be recovered in urine as 17-hydroxycorticosteroid. If an equivalent dose of 1.5 mg of dexamethasone is used, the urinary excretion will be only 0.5 mg/24 h and blood levels will be low.
The dexamethasone suppression test is used for the diagnosis of Cushing’s syndrome and has also been used in the differential diagnosis of depressive psychiatric states. As a screening test, 1 mg dexamethasone is given orally at 11 PM, and a plasma sample is obtained the following morning. In normal individuals, the morning cortisol concentration is usually less than 3 mcg/dL, whereas in Cushing’s syndrome the level is usually greater than 5 mcg/dL. The results are not reliable in the patient with depression, anxiety, concurrent illness, and other stressful conditions or in the patient who is receiving a medication that enhances the catabolism of dexamethasone in the liver. To distinguish between hypercortisolism due to anxiety, depression, and alcoholism (pseudo-Cushing syndrome) and bona fide Cushing’s syndrome, a combined test is carried out, consisting of dexamethasone (0.5 mg orally every 6 hours for 2 days) followed by a standard corticotropin-releasing hormone (CRH) test (1 mg/kg given as a bolus intravenous infusion 2 hours after the last dose of dexamethasone).
In patients in whom the diagnosis of Cushing’s syndrome has been established clinically and confirmed by a finding of elevated free cortisol in the urine, suppression with large doses of dexamethasone will help to distinguish patients with Cushing’s disease from those with steroid-producing tumors of the adrenal cortex or with the ectopic ACTH syndrome. Dexamethasone is given in a dosage of 0.5 mg orally every 6 hours for 2 days, followed by 2 mg orally every 6 hours for 2 days, and the urine is then assayed for cortisol or its metabolites (Liddle’s test); or dexamethasone is given as a single dose of 8 mg at 11 PM, and the plasma cortisol is measured at 8 AM the following day. In patients with Cushing’s disease, the suppressant effect of dexamethasone usually produces a 50% reduction in hormone levels. In patients in whom suppression does not occur, the ACTH level will be low in the presence of a cortisol-producing adrenal tumor and elevated in patients with an ectopic ACTH-producing tumor.
B. Corticosteroids and Stimulation of Lung Maturation in the Fetus
Lung maturation in the fetus is regulated by the fetal secretion of cortisol. Treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely. When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone, 12 mg, followed by an additional dose of 12 mg 18–24 hours later, is commonly used. Betamethasone is chosen because maternal protein binding and placental metabolism of this corticosteroid is less than that of cortisol, allowing increased transfer across the placenta to the fetus. A study of over 10,000 infants born at 23 to 25 weeks of gestation indicated that exposure to exogenous corticosteroids before birth reduced the death rate and evidence of neurodevelopmental impairment.
C. Corticosteroids and Nonadrenal Disorders
The synthetic analogs of cortisol are useful in the treatment of a diverse group of diseases unrelated to any known disturbance of adrenal function (Table 39–2). The usefulness of corticosteroids in these disorders is a function of their ability to suppress inflammatory and immune responses and to alter leukocyte function, as previously described (see also Chapter 55). These agents are useful in disorders in which host response is the cause of the major manifestations of the disease. In instances in which the inflammatory or immune response is important in controlling the pathologic process, therapy with corticosteroids may be dangerous but justified to prevent irreparable damage from an inflammatory response—if used in conjunction with specific therapy for the disease process.
TABLE 39–2 Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders.
Since corticosteroids are not usually curative, the pathologic process may progress while clinical manifestations are suppressed. Therefore, chronic therapy with these drugs should be undertaken with great care and only when the seriousness of the disorder warrants their use and when less hazardous measures have been exhausted.
In general, attempts should be made to bring the disease process under control using medium- to intermediate-acting glucocorticoids such as prednisone and prednisolone (Table 39–1), as well as all ancillary measures possible to keep the dose low. Where possible, alternate-day therapy should be used (see the following text). Therapy should not be decreased or stopped abruptly. When prolonged therapy is anticipated, it is helpful to obtain chest X-rays and a tuberculin test, since glucocorticoid therapy can reactivate dormant tuberculosis. The presence of diabetes, peptic ulcer, osteoporosis, and psychological disturbances should be taken into consideration, and cardiovascular function should be assessed.
Treatment for transplant rejection is a very important application of glucocorticoids. The efficacy of these agents is based on their ability to reduce antigen expression from the grafted tissue, delay revascularization, and interfere with the sensitization of cytotoxic T lymphocytes and the generation of primary antibody-forming cells.
The benefits obtained from glucocorticoids vary considerably. Use of these drugs must be carefully weighed in each patient against their widespread effects on every part of the organism. The major undesirable effects of glucocorticoids are the result of their hormonal actions, which lead to the clinical picture of iatrogenic Cushing’s syndrome (see later in text).
When glucocorticoids are used for short periods (< 2 weeks), it is unusual to see serious adverse effects even with moderately large doses. However, insomnia, behavioral changes (primarily hypomania), and acute peptic ulcers are occasionally observed even after only a few days of treatment. Acute pancreatitis is a rare but serious acute adverse effect of high-dose glucocorticoids.
A. Metabolic Effects
Most patients who are given daily doses of 100 mg of hydrocortisone or more (or the equivalent amount of synthetic steroid) for longer than 2 weeks undergo a series of changes that have been termed iatrogenic Cushing’s syndrome. The rate of development is a function of the dosage and the genetic background of the patient. In the face, rounding, puffiness, fat deposition, and plethora usually appear (moon facies). Similarly, fat tends to be redistributed from the extremities to the trunk, the back of the neck, and the supraclavicular fossae. There is an increased growth of fine hair over the face, thighs and trunk. Steroid-induced punctate acne may appear, and insomnia and increased appetite are noted. In the treatment of dangerous or disabling disorders, these changes may not require cessation of therapy. However, the underlying metabolic changes accompanying them can be very serious by the time they become obvious. The continuing breakdown of protein and diversion of amino acids to glucose production increase the need for insulin and over time result in weight gain; visceral fat deposition; myopathy and muscle wasting; thinning of the skin, with striae and bruising; hyperglycemia; and eventually osteoporosis, diabetes, and aseptic necrosis of the hip. Wound healing is also impaired under these circumstances. When diabetes occurs, it is treated with diet and insulin. These patients are often resistant to insulin but rarely develop ketoacidosis. In general, patients treated with corticosteroids should be on high-protein and potassium-enriched diets.
B. Other Complications
Other serious adverse effects of glucocorticoids include peptic ulcers and their consequences. The clinical findings associated with certain disorders, particularly bacterial and mycotic infections, may be masked by the corticosteroids, and patients must be carefully monitored to avoid serious mishap when large doses are used. Severe myopathy is more frequent in patients treated with long-acting glucocorticoids. The administration of such compounds has been associated with nausea, dizziness, and weight loss in some patients. These effects are treated by changing drugs, reducing dosage, and increasing potassium and protein intake.
Hypomania or acute psychosis may occur, particularly in patients receiving very large doses of corticosteroids. Long-term therapy with intermediate- and long-acting steroids is associated with depression and the development of posterior subcapsular cataracts. Psychiatric follow-up and periodic slit-lamp examination is indicated in such patients. Increased intraocular pressure is common, and glaucoma may be induced. Benign intracranial hypertension also occurs. In dosages of 45 mg/m2/d or more of hydrocortisone or its equivalent, growth retardation occurs in children. Medium-, intermediate-, and long-acting glucocorticoids have greater growth-suppressing potency than the natural steroid at equivalent doses.
When given in larger than physiologic amounts, steroids such as cortisone and hydrocortisone, which have mineralocorticoid effects in addition to glucocorticoid effects, cause some sodium and fluid retention and loss of potassium. In patients with normal cardiovascular and renal function, this leads to a hypokalemic, hypochloremic alkalosis and eventually to a rise in blood pressure. In patients with hypoproteinemia, renal disease, or liver disease, edema may also occur. In patients with heart disease, even small degrees of sodium retention may lead to heart failure. These effects can be minimized by using synthetic non-salt-retaining steroids, sodium restriction, and judicious amounts of potassium supplements.
C. Adrenal Suppression
When corticosteroids are administered for more than 2 weeks, adrenal suppression may occur. If treatment extends over weeks to months, the patient should be given appropriate supplementary therapy at times of minor stress (twofold dosage increases for 24–48 hours) or severe stress (up to tenfold dosage increases for 48–72 hours) such as accidental trauma or major surgery. If corticosteroid dosage is to be reduced, it should be tapered slowly. If therapy is to be stopped, the reduction process should be quite slow when the dose reaches replacement levels. It may take 2–12 months for the hypothalamic-pituitary-adrenal axis to function acceptably, and cortisol levels may not return to normal for another 6–9 months. The glucocorticoid-induced suppression is not a pituitary problem, and treatment with ACTH does not reduce the time required for the return of normal function.
If the dosage is reduced too rapidly in patients receiving glucocorticoids for a certain disorder, the symptoms of the disorder may reappear or increase in intensity. However, patients without an underlying disorder (eg, patients cured surgically of Cushing’s disease) also develop symptoms with rapid reductions in corticosteroid levels. These symptoms include anorexia, nausea or vomiting, weight loss, lethargy, headache, fever, joint or muscle pain, and postural hypotension. Although many of these symptoms may reflect true glucocorticoid deficiency, they may also occur in the presence of normal or even elevated plasma cortisol levels, suggesting glucocorticoid dependence.
Contraindications & Cautions
A. Special Precautions
Patients receiving glucocorticoids must be monitored carefully for the development of hyperglycemia, glycosuria, sodium retention with edema or hypertension, hypokalemia, peptic ulcer, osteoporosis, and hidden infections.
The dosage should be kept as low as possible, and intermittent administration (eg, alternate-day) should be used when satisfactory therapeutic results can be obtained on this schedule. Even patients maintained on relatively low doses of corticosteroids may require supplementary therapy at times of stress, such as when surgical procedures are performed or intercurrent illness or accidents occur.
Glucocorticoids must be used with great caution in patients with peptic ulcer, heart disease or hypertension with heart failure, certain infectious illnesses such as varicella and tuberculosis, psychoses, diabetes, osteoporosis, or glaucoma.
Selection of Drug & Dosage Schedule
Glucocorticoid preparations differ with respect to relative anti-inflammatory and mineralocorticoid effect, duration of action, cost, and dosage forms available (Table 39–1), and these factors should be taken into account in selecting the drug to be used.
A. ACTH versus Adrenocortical Steroids
In patients with normal adrenals, ACTH was used in the past to induce the endogenous production of cortisol to obtain similar effects. However, except when an increase in androgens is desirable, the use of ACTH as a therapeutic agent has been abandoned. Instances in which ACTH was claimed to be more effective than glucocorticoids were probably due to the administration of smaller amounts of corticosteroids than were produced by the dosage of ACTH.
In determining the dosage regimen to be used, the physician must consider the seriousness of the disease, the amount of drug likely to be required to obtain the desired effect, and the duration of therapy. In some diseases, the amount required for maintenance of the desired therapeutic effect is less than the dose needed to obtain the initial effect, and the lowest possible dosage for the needed effect should be determined by gradually lowering the dose until a small increase in signs or symptoms is noted.
When it is necessary to maintain continuously elevated plasma corticosteroid levels to suppress ACTH, a slowly absorbed parenteral preparation or small oral doses at frequent intervals are required. The opposite situation exists with respect to the use of corticosteroids in the treatment of inflammatory and allergic disorders. The same total quantity given in a few doses may be more effective than that given in many smaller doses or in a slowly absorbed parenteral form.
Severe autoimmune conditions involving vital organs must be treated aggressively, and undertreatment is as dangerous as overtreatment. To minimize the deposition of immune complexes and the influx of leukocytes and macrophages, 1 mg/kg/d of prednisone in divided doses is required initially. This dosage is maintained until the serious manifestations respond. The dosage can then be gradually reduced.
When large doses are required for prolonged periods of time, alternate-day administration of the compound may be tried after control is achieved. When used in this manner, very large amounts (eg, 100 mg of prednisone) can sometimes be administered with less marked adverse effects because there is a recovery period between each dose. The transition to an alternate-day schedule can be made after the disease process is under control. It should be done gradually and with additional supportive measures between doses.
When selecting a drug for use in large doses, a medium- or intermediate-acting synthetic steroid with little mineralocorticoid effect is advisable. If possible, it should be given as a single morning dose.
C. Special Dosage Forms
Local therapy, such as topical preparations for skin disease, ophthalmic forms for eye disease, intra-articular injections for joint disease, inhaled steroids for asthma, and hydrocortisone enemas for ulcerative colitis, provides a means of delivering large amounts of steroid to the diseased tissue with reduced systemic effects.
Beclomethasone dipropionate, and several other glucocorticoids—primarily budesonide, flunisolide, and mometasone furoate, administered as aerosols—have been found to be extremely useful in the treatment of asthma (see Chapter 20).
Beclomethasone dipropionate, triamcinolone acetonide, budesonide, flunisolide, and others are available as nasal sprays for the topical treatment of allergic rhinitis. They are effective at doses (one or two sprays one, two, or three times daily) that in most patients result in plasma levels that are too low to influence adrenal function or have any other systemic effects.
Corticosteroids incorporated in ointments, creams, lotions, and sprays are used extensively in dermatology. These preparations are discussed in more detail in Chapter 61.
Recently, new timed-release hydrocortisone tablets were developed for the replacement treatment of addisonian and congenital adrenal hyperplasia patients. These tablets produce plasma cortisol levels that are similar to those secreted normally in a circadian fashion.
MINERALOCORTICOIDS (ALDOSTERONE, DEOXYCORTICOSTERONE, FLUDROCORTISONE)
The most important mineralocorticoid in humans is aldosterone. However, small amounts of deoxycorticosterone (DOC) are also formed and released. Although the amount is normally insignificant, DOC was of some importance therapeutically in the past. Its actions, effects, and metabolism are qualitatively similar to those described below for aldosterone. Fludrocortisone, a synthetic corticosteroid, is the most commonly prescribed salt-retaining hormone.
Aldosterone is synthesized mainly in the zona glomerulosa of the adrenal cortex. Its structure and synthesis are illustrated in Figure 39–1. The rate of aldosterone secretion is subject to several influences. ACTH produces a moderate stimulation of its release, but this effect is not sustained for more than a few days in the normal individual. Although aldosterone is no less than one third as effective as cortisol in suppressing ACTH, the quantities of aldosterone produced by the adrenal cortex and its plasma concentrations are insufficient to participate in any significant feedback control of ACTH secretion.
Without ACTH, aldosterone secretion falls to about half the normal rate, indicating that other factors, eg, angiotensin, are able to maintain and perhaps regulate its secretion (see Chapter 17). Independent variations between cortisol and aldosterone secretion can also be demonstrated by means of lesions in the nervous system such as decerebration, which decreases the secretion of cortisol while increasing the secretion of aldosterone.
A. Physiologic and Pharmacologic Effects
Aldosterone and other steroids with mineralocorticoid properties promote the reabsorption of sodium from the distal part of the distal convoluted renal tubule and from the cortical collecting tubules, loosely coupled to the excretion of potassium and hydrogen ion. Sodium reabsorption in the sweat and salivary glands, gastrointestinal mucosa, and across cell membranes in general is also increased. Excessive levels of aldosterone produced by tumors or overdosage with synthetic mineralocorticoids lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension.
Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells, especially principal cells of the distal convoluted and collecting tubules of the kidney. The drug-receptor complex activates a series of events similar to those described above for the glucocorticoids and illustrated in Figure 39–4. It is of interest that this receptor has the same affinity for cortisol, which is present in much higher concentrations in the extracellular fluid. The specificity for mineralocorticoids in the kidney appears to be conferred, at least in part, by the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone. The latter has low affinity for the receptor and is inactive as a mineralocorticoid or glucocorticoid in the kidney. The major effect of activation of the aldosterone receptor is increased expression of Na+/K+-ATPase and the epithelial sodium channel (ENaC).
Aldosterone is secreted at the rate of 100–200 mcg/d in normal individuals with a moderate dietary salt intake. The plasma level in men (resting supine) is about 0.007 mcg/dL. The half-life of aldosterone injected in tracer quantities is 15–20 minutes, and it does not appear to be firmly bound to serum proteins.
The metabolism of aldosterone is similar to that of cortisol, about 50 mcg/24 h appearing in the urine as conjugated tetrahydroaldosterone. Approximately 5–15 mcg/24 h is excreted free or as the 3-oxo glucuronide.
DOC, which also serves as a precursor of aldosterone (Figure 39–1), is normally secreted in amounts of about 200 mcg/d. Its half-life when injected into the human circulation is about 70 minutes. Preliminary estimates of its concentration in plasma are approximately 0.03 mcg/dL. The control of its secretion differs from that of aldosterone in that the secretion of DOC is primarily under the control of ACTH. Although the response to ACTH is enhanced by dietary sodium restriction, due to adaptations, a low-salt diet does not increase DOC secretion. The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia with reduced P450c11 or P450c17 activity.
This compound, a potent steroid with both glucocorticoid and mineralocorticoid activity, is the most widely used mineralocorticoid. Oral doses of 0.1 mg two to seven times weekly have potent salt-retaining activity and are used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency. These dosages are too small to have important anti-inflammatory or antigrowth effects.
The adrenal cortex secretes large amounts of DHEA and smaller amounts of androstenedione and testosterone. Although these androgens are thought to contribute to the normal maturation process, they do not stimulate or support major androgen-dependent pubertal changes in humans. Recent studies suggest that DHEA and its sulfate may have other important physiologic actions. If that is correct, these results are probably due to the peripheral conversion of DHEA to more potent androgens or to estrogens and interaction with androgen and estrogen receptors, respectively. Additional effects may be exerted through an interaction with the GABAA and glutamate receptors in the brain or with a nuclear receptor in several central and peripheral sites. The therapeutic use of DHEA in humans has been explored, but the substance has already been adopted with uncritical enthusiasm by members of the sports drug culture and the vitamin and food supplement culture.
The results of a placebo-controlled trial of DHEA in patients with systemic lupus erythematosus have been reported as well as those of a study of DHEA replacement in women with adrenal insufficiency. In both studies a small beneficial effect was seen, with significant improvement of the disease in the former and a clearly added sense of well-being in the latter. The androgenic or estrogenic actions of DHEA could explain the effects of the compound in both situations. In contrast, there is no evidence to support DHEA use to increase muscle strength or improve memory.
ANTAGONISTS OF ADRENOCORTICAL AGENTS
SYNTHESIS INHIBITORS & GLUCOCORTICOID ANTAGONISTS
Inhibitors of steroid synthesis act at several different steps and one glucocorticoid antagonist acts at the receptor level.
Aminoglutethimide (Figure 39–5) blocks the conversion of cholesterol to pregnenolone (see Figure 39–1) and causes a reduction in the synthesis of all hormonally active steroids. It has been used in conjunction with dexamethasone or hydrocortisone to reduce or eliminate estrogen production in patients with carcinoma of the breast. In a dosage of 1 g/d it was well tolerated; however, with higher dosages, lethargy and skin rash were common effects. The use of aminoglutethimide in breast cancer patients has now been supplanted by tamoxifen or by another class of drugs, the aromatase inhibitors (see chapters 40 and 54). Aminoglutethimide can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in patients with Cushing’s syndrome due to adrenocortical cancer who do not respond to mitotane.
FIGURE 39–5 Some adrenocortical blockers. Because of their toxicity, some of these compounds are no longer available in the USA.
Aminoglutethimide also apparently increases the clearance of some steroids. It has been shown to enhance the metabolism of dexamethasone, reducing its half-life from 4–5 hours to 2 hours.
Ketoconazole, an antifungal imidazole derivative (see Chapter 48), is a potent and rather nonselective inhibitor of adrenal and gonadal steroid synthesis. This compound inhibits the cholesterol side-chain cleavage, P450c17, C17,20-lyase, 3β-hydroxysteroid dehydrogenase, and P450c11 enzymes required for steroid hormone synthesis. The sensitivity of the P450 enzymes to this compound in mammalian tissues is much lower than that needed to treat fungal infections, so that its inhibitory effects on steroid biosynthesis are seen only at high doses.
Ketoconazole has been used in the treatment of patients with Cushing’s syndrome due to several causes. Dosages of 200–1200 mg/d have produced a reduction in hormone levels and clinical improvement in some patients. This drug has some hepatotoxicity and should be started at 200 mg/d and slowly increased by 200 mg/d every 2–3 days up to a total daily dose of 1000 mg.
Etomidate [R-1-(1-ethylphenyl)imidazole-5-ethyl ester] is a unique drug used for induction of general anesthesia and sedation. At subhypnotic doses of 0.1 mg/kg/h this drug inhibits adrenal steroidogenesis at the level of 11β-hydroxylase and has been used as the only parenteral medication available in the treatment of severe Cushing’s syndrome.
Metyrapone (Figure 39–5) is a relatively selective inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosterone synthesis. In the presence of a normal pituitary gland, there is a compensatory increase in pituitary ACTH release and adrenal 11-deoxycortisol secretion. This response is a measure of the capacity of the anterior pituitary to produce ACTH and has been adapted for clinical use as a diagnostic test. Although the toxicity of metyrapone is much lower than that of mitotane (see text that follows), the drug may produce transient dizziness and gastrointestinal disturbances. This agent has not been widely used in the treatment of Cushing’s syndrome. However, in doses of 0.25 g twice daily to 1 g four times daily, metyrapone can reduce cortisol production to normal levels in some patients with endogenous Cushing’s syndrome. Thus, it may be useful in the management of severe manifestations of cortisol excess while the cause of this condition is being determined or in conjunction with radiation or surgical treatment. Metyrapone is the only adrenal-inhibiting medication that can be administered to pregnant women with Cushing’s syndrome. The major adverse effects observed are salt and water retention and hirsutism resulting from diversion of the 11-deoxycortisol precursor to DOC and androgen synthesis.
Metyrapone is commonly used in tests of adrenal function. The blood levels of 11-deoxycortisol and the urinary excretion of 17-hydroxycorticoids are measured before and after administration of the compound. Normally, there is a twofold or greater increase in the urinary 17-hydroxycorticoid excretion. A dosage of 300–500 mg every 4 hours for six doses is often used, and urine collections are made on the day before and the day after treatment. In patients with Cushing’s syndrome, a normal response to metyrapone indicates that the cortisol excess is not the result of a cortisol-secreting adrenal carcinoma or adenoma, since secretion by such tumors produces suppression of ACTH and atrophy of normal adrenal cortex.
Pituitary function may also be tested by administering metyrapone, 2–3 g orally at midnight and by measuring the level of ACTH or 11-deoxycortisol in blood drawn at 8 AM or by comparing the excretion of 17-hydroxycorticosteroids in the urine during the 24-hour periods preceding and following administration of the drug. In patients with suspected or known lesions of the pituitary, this procedure is a means of estimating the ability of the gland to produce ACTH. Metyrapone has been withdrawn from the market in the USA but is available on a compassionate basis.
Trilostane is a 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones and is comparable to aminoglutethimide. Trilostane’s adverse effects are predominantly gastrointestinal; adverse effects occur in about 50% of patients with both trilostane and aminoglutethimide. There is no cross-resistance or crossover of side effects between these compounds. Trilostane is not available in the USA.
Abiraterone is the newest of the steroid synthesis inhibitors to be approved. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase (Figure 39–1), and predictably reduces synthesis of cortisol in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and is approved for the treatment of refractory prostate cancer.
The search for a glucocorticoid receptor antagonist finally succeeded in the early 1980s with the development of the 11β-aminophenyl-substituted 19-norsteroid called RU-486, later named mifepristone. Unlike the enzyme inhibitors previously discussed, mifepristone is a pharmacologic antagonist at the steroid receptor. This compound has strong antiprogestin activity and initially was proposed as a contraceptive-contragestive agent. High doses of mifepristone exert antiglucocorticoid activity by blocking the glucocorticoid receptor, since mifepristone binds to it with high affinity, causing (1) some stabilization of the hsp-glucocorticoid receptor complex and inhibition of the dissociation of the RU-486–bound glucocorticoid receptor from the hsp chaperone proteins; and (2) alteration of the interaction of the glucocorticoid receptor with coregulators, favoring the formation of a transcriptionally inactive complex in the cell nucleus. The result is inhibition of glucocorticoid receptor activation.
The mean half-life of mifepristone is 20 hours. This is longer than that of many natural and synthetic glucocorticoid agonists (dexamethasone has a half-life of 4–5 hours). Less than 1% of the daily dose is excreted in the urine, suggesting a minor role of kidneys in the clearance of the compound. The long plasma half-life of mifepristone results from extensive and strong binding to plasma proteins. Less than 5% of the compound is found in the free form when plasma is analyzed by equilibrium dialysis. Mifepristone can bind to albumin and α1-acid glycoprotein, but it has no affinity for corticosteroid-binding globulin.
In humans, mifepristone causes generalized glucocorticoid resistance. Given orally to several patients with Cushing’s syndrome due to ectopic ACTH production or adrenal carcinoma, it was able to reverse the cushingoid phenotype, to eliminate carbohydrate intolerance, normalize blood pressure, to correct thyroid and gonadal hormone suppression, and to ameliorate the psychological sequelae of hypercortisolism in these patients. At present, this use of mifepristone can only be recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapeutic manipulations. Its pharmacology and use in women as a progesterone antagonist are discussed in Chapter 40.
Mitotane (Figure 39–5), a drug related to the DDT class of insecticides, has a nonselective cytotoxic action on the adrenal cortex in dogs and to a lesser extent in humans. This drug is administered orally in divided doses up to 12 g daily. About one third of patients with adrenal carcinoma show a reduction in tumor mass. In 80% of patients, the toxic effects are sufficiently severe to require dose reduction. These include diarrhea, nausea, vomiting, depression, somnolence, and skin rashes. The drug has been withdrawn from the market in the USA but is available on a compassionate basis.
In addition to agents that interfere with aldosterone synthesis (see above), there are steroids that compete with aldosterone for its receptor and decrease its effect peripherally. Progesterone is mildly active in this respect.
Spironolactone is a 7α-acetylthiospironolactone. Its onset of action is slow, and the effects last for 2–3 days after the drug is discontinued. It is used in the treatment of primary aldosteronism in dosages of 50–100 mg/d. This agent reverses many of the manifestations of aldosteronism. It has been useful in establishing the diagnosis in some patients and in ameliorating the signs and symptoms when surgical removal of an adenoma is delayed. When used diagnostically for the detection of aldosteronism in hypokalemic patients with hypertension, dosages of 400–500 mg/d for 4–8 days—with an adequate intake of sodium and potassium—restore potassium levels to or toward normal. Spironolactone is also useful in preparing these patients for surgery. Dosages of 300–400 mg/d for 2 weeks are used for this purpose and may reduce the incidence of cardiac arrhythmias.
Spironolactone is also an androgen antagonist and as such is sometimes used in the treatment of hirsutism in women. Dosages of 50–200 mg/d cause a reduction in the density, diameter, and rate of growth of facial hair in patients with idiopathic hirsutism or hirsutism secondary to androgen excess. The effect can usually be seen in 2 months and becomes maximal in about 6 months.
Spironolactone as a diuretic is discussed in Chapter 15. The drug has benefits in heart failure greater than those predicted from its diuretic effects alone (see Chapter 13). Adverse effects reported for spironolactone include hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, gastrointestinal disturbances, and skin rashes.
Eplerenone, another aldosterone antagonist, is approved for the treatment of hypertension (see chapters 11 and 15). Like spironolactone, eplerenone has also been found to reduce mortality in heart failure. This aldosterone receptor antagonist is somewhat more selective than spironolactone and has no reported effects on androgen receptors. The standard dosage in hypertension is 50–100 mg/d. The most common toxicity is hyperkalemia, but this is usually mild.
Drospirenone, a progestin, in an oral contraceptive (see Chapter 40), also antagonizes the effects of aldosterone.
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CASE STUDY ANSWER
The patient should be placed on replacement oral hydrocortisone at 10 mg/m2/d and fludrocortisone at 75 mcg/d. He should be given a MedicAlert bracelet and instructions for minor and major stress glucocorticoid coverage at 2 times and 10 times replacement of hydrocortisone over 24 and 48 hours, respectively.
*Names for the adrenal steroid synthetic enzymes include the following: P450c11 (11b-hydroxylase), P450c17 (17α-hydroxylase), P450c21 (21α-hydroxylase).