Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 39 Adrenocorticosteroids




Therapeutic Overview

Cortisol is the primary endogenous glucocorticoid in humans. It is synthesized in the adrenal cortex and exerts a wide range of physiological effects. It is involved in the regulation of intermediary metabolism, the stress response, some aspects of central nervous system function, and regulation of immunity. Because of its biological importance, its synthesis and secretion must be tightly regulated. The hypothalamic-pituitary-adrenal (HPA) axis is very sensitive to negative feedback by circulating cortisol or synthetic glucocorticoids. High plasma concentrations of glucocorticoids will suppress HPA axis activity, progressively leading to considerable loss of adrenocorticotropic hormone (ACTH), adrenal cortex size, cortisol biosynthesis, and ultimately circulating cortisol. The effects of chronic exposure to pharmacological levels of glucocorticoids and the ability to recover such effects are directly correlated to the duration of therapy or exposure to cortisol-secreting tumors. It is mandatory that when terminating the chronic administration of excessive levels of



Adrenocorticotropic hormone


Arginine vasopressin


Cyclic adenosine monophosphate


Corticotropin-releasing hormone


Deoxyribonucleic acid


Glucocorticoid receptor






Mineralocorticoid receptor


Melanocyte-stimulating hormone




Steroidogenic acute regulatory protein



Therapeutic Overview


Replacement therapy in adrenal insufficiencies

Antiinflammatory and immunosuppressive action

Myeloproliferative diseases


Replacement therapy in primary adrenal insufficiencies


Steroid Synthesis Inhibitors

Adrenocortical hyperfunction

Steroid Receptor Blockers

Glucocorticoid excess

Mineralocorticoid excess

glucocorticoids, a withdrawal plan must be instituted, or serious morbidity and even mortality may occur. Safe removal from dependence on exogenous glucocorticoids requires systematic and gradual lowering of the administered dosage, which may require up to a year for the natural secretion of cortisol to recover. Also, during periods of emotional or physiological stress, such patients may require glucocorticoid supplementation.

Aldosterone is the major mineralocorticoid in humans. It is synthesized in the adrenal cortex and is regulated primarily by the renin-angiotensin system, K+ and ACTH. Aldosterone contributes to the regulation of Na+ and K+ concentrations in the extracellular fluid.

The main therapeutic uses of the glucocorticoids are: (1) replacement therapy for patients exhibiting inadequate endogenous cortisol production; (2) as antiinflammatory or immunosuppressantagents; and (3) as adjuvants in the treatment of myeloproliferative diseases and other malignant conditions. The major therapeutic use of the synthetic mineralocorticoids is aldosterone replacement for patients with primary adrenal insufficiency or isolated aldosterone deficiency. See the Therapeutic Overview Box for a summary of therapeutic issues.

Mechanisms of Action

The biosynthetic pathways and structures for cortisol and aldosterone are shown in Figures 38-1 and 38-2.


Regulation by ACTH

Cortisol synthesis and secretion are regulated physiologically by ACTH synthesized in the anterior pituitary. ACTH is synthesized in the corticotrope cells of the anterior pituitary as part of the large precursor molecule proopiomelanocorticotropin (POMC), which is proteolytically cleaved to form ACTH, β-endorphin, and melanocyte-stimulating hormone (MSH). β-Endorphin has opioid effects that reduce pain perception (see Chapter 36), whereas MSH acts on the melanocytes that confer skin pigmentation. The hyperpigmentation that is associated with overproduction of ACTH is thought to be associated with overproduction of MSH. The POMC gene is also transcribed in the posterior pituitary, where the POMC precursor is differentially cleaved into endorphins and MSH, but not ACTH. ACTH is secreted episodically from the anterior pituitary, and these pulses can contribute to the larger ACTH fluctuations regulated by circadian rhythms. Generally, the ACTH pulses exhibit greater frequency and magnitude in the early morning compared with the early afternoon. There is a close correlation of ACTH and cortisol secretion, which is characterized by a sharp rise in plasma concentrations followed by a slower decline, with approximately 8 to 10 major bursts of cortisol secretion occurring daily (Fig. 39-1).


FIGURE 39–1 Serum cortisol concentrations in a healthy man. Serial blood samples collected at 10-minute intervals were assayed for cortisol. A, Concentrations plotted, with the continuous line calculated using a multiple parameter model of combined secretion and clearance of cortisol. B, Calculated rates of cortisol secretion as a function of time. Zero time represents 8 am, the beginning of the experimental period.

Modified from Veldhuis JD, Iranmanesh A, Lizarralde G, et al: Am J Physiol 1989; 257:E6.

ACTH acts through membrane receptors, leading to activation of adenylyl cyclase, enhanced formation of intracellular 3’-5’ cyclic adenosine monophosphate (cAMP), and increased phosphorylation by protein kinase type A, which ultimately stimulates cortisol synthesis and secretion. Cholesterol is stored esterified to long-chain fatty acids, which must be cleaved and transported to the inner mitochondrial membrane, where the enzymatic processes leading to steroid synthesis reside. This transport step through the outer mitochondrial membrane is the actual rate-limiting process in overall steroid synthesis and requires the participation of the steroidogenic acute regulatory protein (StAR). ACTH rapidly stimulates StAR synthesis in the adrenals (as the gonadotropins do in the testes and ovaries), which facilitates cholesterol transport through the mitochondria, leading to initiation of steroid synthesis. Mutations in StAR have been associated with congenital lipoid adrenal hyperplasia, an autosomal recessive disorder that leads to deficiencies of adrenal and gonadal hormones and life-compromising pathology associated with salt loss, hyperkalemic acidosis, and dehydration, unless treated with adrenal steroids.

The rate-limiting enzyme in steroid synthesis converts cholesterol to pregnenolone by the P450 cholesterol side-chain cleavage enzyme (see Fig. 38-1), desmolase, located on the inner mitochondrial membrane. ACTH-stimulated increases in cAMP accelerate transcription rates of the gene coding for this enzyme and most other enzymes in the cortisol biosynthetic pathway.

In addition to its role in stimulating adrenocorticosteroid metabolism, ACTH is a tropic hormone that directly controls the size of the adrenal cortex in a concentration-dependent manner. Specifically, low plasma ACTH concentrations lead to adrenal cortex atrophy, whereas elevated levels, such as occur during primary adrenal insufficiency, promote adrenal cortex hyperplasia.

Modulation of ACTH Release

Serum concentrations of ACTH are modulated by integrated stimulatory signals from hypothalamic releasing peptides and by inhibitory feedback from circulating cortisol (Fig. 39-2). Physiologically, serum ACTH concentrations are increased in response to metabolic stresses such as severe trauma, illness, burns, hypoglycemia, hemorrhage, fever, exercise, and psychological stresses such as anxiety and depression. These stresses are believed to induce physiological changes by altering the release of hypothalamic factors. Two hypothalamic peptides, corticotropin-releasing hormone (CRH) and to a lesser extent arginine vasopressin (AVP or antidiuretic hormone), both act to stimulate ACTH release. These peptides bind to distinct membrane receptors on the corticotrope. CRH exerts its effect primarily via cAMP-dependent pathways, whereas AVP stimulates phosphatidylinositol hydrolysis and activates protein kinase C. CRH is the most important physiological stimulating factor and can be used pharmacologically to screen for appropriate corticotrope function. CRH may also increase POMC gene transcription and processing, thus increasing available peptide stores for subsequent release.


FIGURE 39–2 Regulatory feedback mechanisms in the HPA. ACTH, Adrenocorticotrophic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone.

Feedback Control Mechanisms

Pituitary production of ACTH is extremely sensitive to suppression by cortisol at both the pituitary and hypothalamus. Cortisol acts directly on the pituitary to decrease POMC gene transcription and ACTH secretion and to suppress the pituitary response to CRH. It also acts on the hypothalamus to suppress CRH release. Results of this negative feedback can endure for weeks after cessation of glucocorticoid therapy. Thus glucocorticoid therapy and its cessation must be approached cautiously. High concentrations of ACTH may also suppress CRH release from the hypothalamus.


All natural and synthetic glucocorticoids act by binding to specific receptors that are members of the nuclear receptor superfamily. Glucocorticoids bind to both glucocorticoid receptors (GR, also known as NR3C1) and mineralocorticoid receptors (MR, also known as NR3C2). These receptors are closely related in their overall DNA sequence but differ considerably in the N-terminal antigenic region of the ligand-binding domains. Both receptors have similar binding affinities for glucocorticoids and are expressed in many cell types including liver, muscle, adipose tissue, bone, lymphocytes, and pituitary. The receptors are proteins consisting of approximately 800 amino acids, which can be divided into functional domains similar to those for other steroid receptors (see Chapter 1). The structure of the steroid receptor is characterized by zinc finger domains formed by stabilization of protein folds by zinc interaction with cysteine residues. In the cytoplasm the inactive steroid receptor exists as a heteromer associated with cytoplasmic proteins (e.g., heat shock protein 90). The interaction of this complex with a steroid leads to dissociation of the accessory protein-receptor complex. This sequence of events is generally called glucocorticoid receptor activation. Phosphorylation of the receptor stabilizes a configuration, the nuclear location signal that interacts with importin at nuclear pores and initiates translocation of the hormone-receptor complex across the nuclear membrane. Once inside the nuclear membrane, the steroid-receptor complex interacts at specific palindromic sites on deoxyribonucleic acid (DNA), termed glucocorticoid-responsive elements. The binding to DNA is stabilized by the interaction of the zinc finger structures with the major groove of DNA, and specificity is partially conferred by the sequence of the palindromic sites. Specificity among different steroids appears to be conferred by the structure of the steroid-occupied receptor, amino acid sequence of the DNA binding region of the receptor protein, especially the Zn fingers, nucleotide sequence of the DNA binding motif and space between half sites, and chromatin architecture of the gene promoter at sites of interaction of bound receptor protein and DNA. The presence of the specific glucocorticoid response elements in the promoter region of specific genes allows steroids to alter transcription (see Chapter 1).

Metabolic Effects

Glucocorticoids have several metabolic effects including increased hepatic gluconeogenesis as a consequence of stimulating the synthesis of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and increased amino acid degradation as a consequence of stimulating the synthesis of tyrosine aminotransferase and tryptophan oxygenase. In striated muscle, glucocorticoids act in concert with other hormones to influence protein synthesis and degradation. Cortisol has little or no effect on protein turnover in the presence of insulin and in well-fed people. However, during fasting or when the insulin concentration is low, cortisol stimulates the breakdown of muscle protein and decreases the uptake of amino acids. Thus the presence of high concentrations of circulating glucocorticoids for long periods can lead to muscle wasting. In adipose tissue, cortisol stimulates lipolysis, resulting in the release of free fatty acids and glycerol. Other lipogenic hormones are required for the full lipolytic response to occur. Overall, cortisol stimulates both protein and lipid catabolism. Glucocorticoids also regulate growth and development, particularly in fetal tissues. One critical action on the fetus is induction of surfactant synthesis in the lungs before birth. Cortisol can be administered to lessen the severity of respiratory distress syndrome resulting from a failure of sufficient surfactant secretion.


Aldosterone is the major mineralocorticoid produced by the adrenal cortex and acts primarily at the distal portion of the convoluted renal tubule to promote reabsorption of Na+ and the excretion of K+ (seeChapter 21). Adrenal secretion of aldosterone is controlled by the renin-angiotensin system and the circulating concentration of K+. ACTH stimulates aldosterone formation but plays a secondary role in the regulation of aldosterone secretion.

Receptors for mineralocorticoids are expressed both in epithelial tissue such as distal nephrons and in nonepithelial cells including the hippocampus, hypothalamus, cardiomyocytes, adipocytes, and vasculature. Interestingly, both aldosterone and cortisol have a similar affinity for these receptors. Because the level of aldosterone in the circulation is much lower than cortisol, one might expect that the MR would be saturated with cortisol and that it would be difficult for aldosterone to compete for receptor binding. In mineralocorticoid-responsive tissues such as the kidney and vasculature, receptor occupation by cortisol is obviated by the presence of 11β-hydroxysteroid dehydrogenase 2, which converts cortisol to the inactive metabolite cortisone; cortisone has a much lower affinity for the MR, permitting aldosterone to compete effectively for MR activation. It is important to note that licorice or related compounds such as carbenoxolone inhibit 11β-hydroxysteroid dehydrogenase 2 and can result in inappropriate cortisol activation of the MR, resulting in hypertension. Similarly, a rare genetic syndrome, Apparent Mineralocorticoid Excess, associated with failure of the enzyme complex to function properly leads to salt retention, hypokalemia, and hypertension.

The structures of the principal synthetic glucocorticoids and mineralocorticoids are shown in Figure 38-2 Figure 39-3.


Pharmacokinetic parameters for clinically useful glucocorticoids and mineralocorticoids are summarized in Table 39-1. Most glucocorticoids are absorbed rapidly and readily from the gastrointestinal (GI) tract as a result of their lipophilic character. Glucocorticoids are also absorbed readily from the synovial and conjunctival spaces but are absorbed very slowly through the skin. The long-term use of steroids by nasal spray for the control of seasonal rhinitis can lead to nasal and pulmonary epithelial atrophy. Topical administration of glucocorticoids is often used briefly to produce a local action. However, excessive and prolonged local application may result in sufficient absorption to cause systemic effects. The presence of the hydroxyl group at position 11 (see Fig. 38-2) confers glucocorticoid activity on both cortisol and prednisolone. Cortisone and prednisone are 11-ketocorticoids and must be hydroxylated by 11β-hydroxylase to be activated, a reaction that takes place primarily in the liver. Thus the topical application of 11-ketocorticoids on the skin is ineffective, and administration of 11-ketocorticoids should be avoided in patients with abnormal liver function.

TABLE 39–1 Pharmacokinetic Parameters


Route of Administration



Cortisol (Hydrocortisone)

IM, IV, oral



IM, IV, Oral









IM, IV, oral



IM, oral, topical, IV



Oral, topical, inhaled



Intraarticular, topical, inhaled






Aldosterone (for reference)



Desoxycorticosterone acetate



Principal metabolites of adrenocorticosteroids are steroid glucuronides, which undergo hepatic metabolism and renal excretion.

* Short, 10-90 minutes; intermediate, several hours; long, 5 hours or more.

 Intralesional, intraarticular, nasal, and inhaled; collectively this is referred to as compartmentalized administration.

Most circulating cortisol is bound to plasma proteins; 80% to 90% is bound with high affinity to cortisol-binding globulin (also called transcortin), and 5% to 10% is loosely bound to albumin. The free (bioactive) fraction represents approximately 3% to 10%. Cortisol-binding globulin can also bind synthetic glucocorticoids such as prednisone and prednisolone, but not dexamethasone. As a consequence, almost 100% of plasma dexamethasone is in the bioactive form; thus circulating dexamethasone concentrations lower than those of the natural glucocorticoids can have similar biological effects. Because estrogens increase biosynthesis of cortisol-binding globulin in the liver in conditions where estrogen is elevated, such as during contraception or pregnancy, the concentration of cortisol-binding globulin is elevated, resulting in increased plasma cortisol concentrations.

Addition of a fluorine atom at position 9 and a methyl group at position 16, as present in betamethasone and dexamethasone (see Fig. 39-3), enhances glucocorticoid receptor activation and increases the duration of action of these compounds.


FIGURE 39–3 Structures of representative glucocorticoids and mineralocorticoids.

The liver and kidney are the major sites of glucocorticoid inactivation. Pathways leading to inactivation include reduction of the double bond at position 4/5; reduction of the keto group at position 3; hydroxylation at position 6; and side-chain cleavage. Approximately 30% of inactivated cortisol is metabolized to tetrahydrocortisol-glucuronide and tetrahydrodeoxycortisol-glucuronide and excreted in the urine.

Established inducers of hepatic drug metabolism such as rifampin, phenobarbital, and phenytoin may accelerate the hepatic biotransformation of glucocorticoids. Administration of these drugs may necessitate an increase in the dose of glucocorticoids. Hypothyroidism may decrease glucocorticoid metabolism.

Aldosterone does not bind to a specific plasma protein but binds weakly to several different plasma proteins from which it dissociates rapidly. The half-life of aldosterone is very short (a few minutes), and without ongoing secretion from the adrenals, its rapid clearance from plasma effectively limits its biological effects.

Relationship of Mechanisms of Action to Clinical Response


Glucocorticoids affect glucose, protein, and bone metabolism and possess antiinflammatory and immunosuppressant actions. Glucocorticoids influence the immune system at multiple levels, affecting leukocyte movement, antigen processing, eosinophils, and lymphatic tissues (Box 39-1).

BOX 39–1 Effects of Glucocorticoids


Increased glycogenolysis and gluconeogenesis

Increased protein catabolism and decreased protein synthesis

Decreased osteoblast formation and activity

Decreased Ca++ absorption from the gastrointestinal tract

Decreased thyroid-stimulating hormone secretion


Local and systemic effects, including:

Decreased production of prostaglandins, cytokines, and interleukins

Decreased proliferation and migration of lymphocytes and macrophages

Within hours after administration of glucocorticoids, the number of circulating neutrophils increases. This neutrophilia may result from a glucocorticoid-induced decrease in neutrophil adherence to the vascular endothelium and the inability of neutrophils to egress toward bone marrow or inflammatory sites. In addition, glucocorticoids inhibit antigen processing by macrophages, suppress T-cell helper function, inhibit synthesis of mediators of the inflammatory response (i.e., interleukins, other cytokines, and prostanoids), and inhibit phagocytosis. Glucocorticoids also induce eosinopenia and lymphopenia. The latter may be attributable to a modification in cell production, distribution, or lysis and is more profound on T lymphocytes than on B lymphocytes. This explains the beneficial effect of glucocorticoids for treatment of certain leukemias, such as acute lymphoblastic leukemia of childhood.

Therapeutically, the most important effect of the glucocorticoids is inhibition of accumulation of neutrophils and monocytes at sites of inflammation and suppression of the phagocytic, bactericidal, and antigen-processing activity of these cells. However, these effects compromise the immune system and predispose the patient to infection by several common and uncommon pathogens and to saprophytic sepsis. This condition represents the single most dangerous complication of long-term glucocorticoid treatment.


Aldosterone is not used therapeutically to replace a loss of mineralocorticoid activity because of its short duration of action. Synthetic fludrocortisone (9α-fluorohydrocortisone) is the drug of choice for the treatment of primary adrenocortical insufficiency, aldosterone insufficiency, salt-losing congenital adrenal hyperplasia, and idiopathic orthostatic hypotension.

Selection of Drugs

Cortisol and cortisone are used primarily for replacement therapy in patients with adrenal insufficiency, that is, diminished production of endogenous glucocorticoids. Neither compound is used in chronic antiinflammatory therapeutic regimens, because the high levels required would exert significant mineralocorticoid activity.

Prednisone, prednisolone, and methylprednisolone have considerable antiinflammatory activity, intermediate plasma half-lives (allowing easy withdrawal), and relatively low mineralocorticoid activity. These characteristics are ideal for long-term antiinflammatory and immunosuppressant regimens, and prednisone and its derivatives are the most commonly used glucocorticoids for treatment of several autoimmune diseases including collagen diseases (systemic lupus erythematosus and polymyositis-dermatomyositis), vasculitis syndromes (polyarteritis nodosa, giant cell arteritis, and Wegener’s granulomatosis), GI inflammatory diseases (Crohn’s disease and ulcerative colitis), and renal autoimmune diseases (glomerulonephritis and the nephrotic syndromes). Intermediate-acting glucocorticoids are also used for treatment of bronchial asthma and chronic obstructive pulmonary disease (see Chapter 16).

Dexamethasone and betamethasone are long-acting analogs that have minimal mineralocorticoid activity and maximal antiinflammatory activity. Their primary use is to induce strong antiinflammatory therapy acutely (e.g., septic shock or brain edema). Because of their extended duration of action and growth suppression in children and potent bone demineralization properties, these agents are not first-choice drugs for long-term immunosuppressive therapy.

Alternate-day therapy glucocorticoid administration was developed to reduce the untoward effects of the glucocorticoids. This protocol involves administration of double the normal daily dose of an intermediate-acting corticosteroid such as prednisone every other day. The antiinflammatory effects of glucocorticoids with an intermediate action persist longer than suppressive effects on the HPA axis and bone growth rate. However, the use of alternate-day therapy can become problematic as the levels of the adrenocorticosteroid and its clinical effects decrease. Some patients may exhibit unacceptable control of inflammation. In addition, symptoms of clinical hypocortisolism (i.e., a sense of being tired, nausea, vomiting, hypotension) may be precipitated when switching patients from a daily to an alternate-day dosing regimen.

Pharmacovigilance: Clinical Problems, Side Effects, and Toxicity

Clinical syndromes associated with excessive glucocorticoid and mineralocorticoid production include those resulting from lesions in the adrenal (primary) or pituitary (secondary) gland and some instances of ectopic (inappropriate) ACTH production. Clinical problems most commonly encompass congential adrenal enzyme deficiencies, autoimmune diseases, and unregulated ectopic ACTH secretion from tumors and are summarized in the Clinical Problems Box.

Exposure to Excessive Levels of Glucocorticoids

Cushing’s syndrome is associated with excessive exposure to glucocorticoids. Its clinical manifestations include hypertension, truncal obesity, diabetes, hirsutism, acne, ecchymoses, proximal muscle weakness, wide purple stria over the skin, and behavioral abnormalities. The syndrome results most commonly from exogenous administration of glucocorticoids. However, there are also endogenous causes including pituitary ACTH-dependent Cushing’s syndrome, ectopic ACTH syndrome, ectopic corticotropin-releasing hormone syndrome, cortisol-secreting adrenal adenomas, and rarely, adrenal carcinoma (Fig. 39-4). To diagnose Cushing’s syndrome, the presence of increased cortisol production must be confirmed by (1) an increased urinary free cortisol concentration and (2) failure of serum cortisol concentrations to be suppressed to less than 5 µg/dL in response to a low dose of dexamethasone. A patient with an increased cortisol production not suppressed by a low dose of dexamethasone should undergo further testing to distinguish among the different causes of Cushing’s syndrome. In most cases a high-dose dexamethasone suppression test can be used to differentiate between pituitary ACTH-dependent Cushing’s disease and other causes of Cushing’s syndrome. For this test serum cortisol concentrations are determined before and after administration of oral dexamethasone for 3 days. If plasma cortisol concentrations decrease to less than 50% of baseline, a pituitary site is indicated; if not, an adrenal tumor or ectopic ACTH syndrome is indicated.


FIGURE 39–4 Hypercortisolemia and its impact on normal feedback mechanisms in Cushing’s syndrome, ACTH-dependent Cushing’s syndrome, ectopic ACTH syndrome, adrenal adenoma, and exogenous steroid administration. +, Stimulation; –, inhibition.

Many cases of pituitary Cushing’s syndrome result from corticotrophin or ACTH-secreting adenomas that are constantly stimulating the adrenal glands and are only partially responsive to steroid feedback suppression. Successful removal of the adenoma can often relieve the symptoms. However, many of these tumors are microadenomas and are difficult to isolate and remove. To evaluate patients with hypercortisolemia, metyrapone is administered, and plasma ACTH, cortisol, and 11-deoxycortisol concentrations are measured in the plasma and urine the following day. Metyrapone is a competitive inhibitor of the 11-hydroxylase enzyme involved in cortisol synthesis, thus leading to a reduced plasma cortisol concentration and an increased production of 11-deoxycortisol. A decrease in the concentration of cortisol and an increase in the concentrations of 11-deoxycortisol and ACTH after the metyrapone test are indicative of a positive response. Failure to respond to this test indicates a lesion in hypothalamic-pituitary function.

Surgical removal is the best treatment for excess cortisol (or aldosterone) secretion by an adrenal tumor. Treatment with biosynthetic inhibitors such as aminoglutethimide, ketoconazole, mitotane, or steroid receptor antagonists such as mifepristone may be useful in cases in which surgical treatment does not sufficiently reduce elevated steroid concentrations (see New Horizons).

A primary adrenal excess of mineralocorticoids occurs occasionally in patients with adrenal tumors, producing a syndrome of hypertension, hypokalemia and metabolic alkalosis, and mild hypernatremia. Both plasma and urinary aldosterone concentrations are elevated in the patient after high Na+ intake. In the absence of a surgical cure, an important inhibitor is spironolactone, which is also used clinically as a diuretic and an antihypertensive agent (Chapter 21). Spironolactone binds to the MR and acts as a competitive antagonist to aldosterone.

Disorders Associated with Decreased Cortisol Production

Decreased cortisol production is associated with either primary or secondary adrenal insufficiency. Primary adrenal insufficiency is most commonly caused by an autoimmune polyendocrine deficiency syndrome. Other causes are tuberculosis, adrenal hemorrhage, granulomatous diseases, amyloidosis, metastatic neoplasia, and congenital unresponsiveness to corticotropin. The secondary causes of adrenal insufficiency include adrenal suppression occurring after the administration of glucocorticoids (very common) or after treatment of Cushing’s syndrome and diseases of the hypothalamus or pituitary gland leading to ACTH deficiency.

Plasma cortisol concentrations should be measured in patients with suspected acute adrenal insufficiency, and if low, patients should be treated immediately with intravenously administered hydrocortisone. A further test is required to confirm a diagnosis in patients with suspected chronic adrenal insufficiency, in which ACTH is administered intravenously. If the problem lies at the secondary or pituitary level (low ACTH secretion), a response will be obtained; failure to respond indicates a primary adrenal insufficiency. In either case cortisol replacement should be initiated.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia can result from alterations in any of the steps in steroid synthesis leading to diminished cortisol secretion and consequent stimulation of synthesis and release of ACTH. Depending on the site of the abnormality, the steroidogenesis pathway in the adrenal gland is shifted, resulting in an imbalance of specific hormones, such as an excess secretion of androgens. The cornerstone for treatment of patients with congenital adrenal hyperplasia is administration of glucocorticoids to suppress ACTH secretion, thereby decreasing stimulation of the adrenal gland and inappropriate steroid synthesis.

Glucocorticoids and the HPA Axis

Suppression of the HPA axis is the most common side effect of long-term glucocorticoid therapy and can appear within days after initiation of treatment. A suppression of the HPA axis is anticipated with the daily use of an intermediate-acting glucocorticoid at dosages equivalent to 5 mg or more of prednisone for more than 2 weeks. The time needed for recovery depends on the type of glucocorticoid, dosage, frequency of administration (i.e., daily versus alternate days), and the length of treatment. Prolonged administration may take up to a year or longer for recovery, and the patient may need supplementation during stress. The short ACTH test is used to assess recovery.

Glucocorticoids and Bone

A major side effect of glucocorticoids, especially when given for prolonged periods, is their detrimental action on bone. Patients at the highest risk of acquiring glucocorticoid-induced osteoporosis are children and postmenopausal women. Glucocorticoids cause osteoporosis by disrupting the regulation of Ca++ metabolism at several levels: (1) by decreasing intestinal absorption and renal reabsorption of Ca++; (2) by exerting a direct anti-anabolic and catabolic action on bone; and (3) by blocking the protective effect of calcitonin.

Glucocorticoids increase the 1α-hydroxylation of 25-hydroxyvitamin D to its active 1,25-dihydroxyvitamin D form, which facilitates intestinal Ca++ absorption. However, glucocorticoids also block the biological effect of active vitamin D, so the absorption rate of Ca++ decreases despite high concentrations of circulating 1,25-dihydroxyvitamin D. The parathyroid gland responds to the resulting hypocalcemia by secreting more parathyroid hormone, which catabolizes bone in an attempt to increase Ca++ concentrations in the extracellular fluid.

Glucocorticoids also affect bone directly by inhibiting osteoblastic activity. Furthermore glucocorticoids may stimulate osteolysis by accelerating transformation of precursor cells to osteoclasts, resulting in increased bone resorption. This is documented by increased concentrations of hydroxyproline in urine as an index of increased bone collagen catabolism. Finally, glucocorticoids block the bone-sparing effect of calcitonin, a peptide synthesized by the parafollicular cells of the thyroid gland that inhibits osteoclastic bone resorption (see Chapter 44).

Glucocorticoids and Glucose

Glucocorticoids acquired their name from their role in glucose metabolism. They elevate plasma glucose concentration by:

• Increasing gluconeogenesis and glucose secretion by the liver

• Increasing liver sensitivity to the gluconeogenic action of glucagon and catecholamines

• Decreasing glucose uptake and use by peripheral tissues

• Increasing substrates for gluconeogenesis (increasing proteolysis and inhibiting protein synthesis in muscles)

As a consequence, the long-term administration of glucocorticoids may lead to hyperglycemia, diabetes mellitus, osteopenia and osteoporosis in susceptible subjects.

Other Side Effects

Long-term administration of glucocorticoids also increases the risk for developing peptic ulcers. It has been proposed that glucocorticoids cause peptic ulcers by increasing


Most common side effects caused mainly by high concentrations maintained for a long time

Development of cushingoid habitus (truncal obesity, moon facies, buffalo hump), salt retention, and hypertension (i.e., iatrogenic Cushing’s syndrome)

Suppression of the immune system (rendering the patient vulnerable to common and opportunistic infections)

Osteoporosis (rendering the patient vulnerable to fractures)

Peptic ulcers (resulting in gastric hemorrhages or intestinal perforation)

Suppression of growth in children

Behavioral problems

Reproductive problems

Prolonged suppression of the HPA axis

gastric acid output and inhibiting synthesis of mucopolysaccharides that protect the gastric mucosa from acid. Because even short-term treatment (<1 month) with glucocorticoids may cause gastric irritation or ulcers, some physicians prescribe antacids, proton pump inhibitors or H2-histamine receptor blockers with glucocorticoids (see Chapter 18).

In the central nervous system, the primary acute effect of glucocorticoids is promotion of arousal and general euphoria. However, prolonged treatment may cause depression, sleep disturbances, and in some cases, true psychotic ideation.

Glucocorticoids can suppress the synthesis and secretion of gonadotropins and their effects on the gonads. Long-term glucocorticoid treatment in men may cause hypogonadism associated with decreased plasma testosterone concentrations. In women, anovulation, oligomenorrhea, or dysfunctional uterine bleeding may occur.

In most children linear growth rate is impaired with long-term glucocorticoid therapy. Although long-term administration causes a decreased secretion of growth hormone from the anterior pituitary, the inhibitory effect of glucocorticoids on growth is thought to be due to inhibition of the effects of insulin-like growth factor-1 (formerly known as somatomedin C).

New Horizons

Much effort has been expended on identifying drugs for treating symptoms of hypercortisolemia, including specific GR antagonists. The steroid hormone antagonist mifepristone (RU 486) has a high affinity for both human progesterone receptors and GR and weakly binds to androgen receptors. Mifepristone can antagonize the actions of glucocorticoids and suppress the negative feedback of endogenous cortisol. It has been used to treat endometriosis and breast cancer, to interrupt pregnancy through release of prostaglandins and increased uterine contractile sensitivity to prostaglandins, and to initiate labor. In addition, it can be used as a contraceptive drug to inhibit follicle maturation, ovulation, and egg implantation. Currently, mifepristone is approved for the termination of intrauterine pregnancy, not for the management of glucocorticoid excess. Studies with experimental animals suggest the neuropeptides, which appear to reduce an extreme inflammatory response, may prove to be useful to treat autoimmune diseases.


(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Aminoglutethimide (Cytadren)

Betamethasone (Celestone)

Cortisone (Cortone)

Dexamethasone (Decadron, Hexadrol)

Fludrocortisone (Florinef)

Hydrocortisone, Cortisol (Cortef, Hydrocortone)

Ketoconazole (Nizoral)

Methylprednisolone (A-MethaPred, Medrol)

Mifepristone, RU-486 (Mifeprex)

Mitotane (Lysodren)

Prednisolone (Prelone)

Prednisone (Dealtasone, Meticorten, Orasone)

Spironolactone (Aldactone, Spironol)

Triamcinolone (Aristocort, Kenalog)


Anonymous. Fluticasone furoate (Veramyst) for allergic rhinitis. Med Lett. 2007;49:90-92.

Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: A consensus statement. J Clin Endocrinol Metab. 2003;88:5593-5602.

Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711-1723.

Speiser P, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:76-788.

Walsh JP, Dayan CM. Role of biochemical assessment in management of corticosteroid withdrawal. Ann Clin Biochem. 2000;37:279-288.


1. Which of the following measurements is the best way to assess the recovery of the hypothalamus-pituitary-adrenal axis in patients withdrawing from exogenous glucocorticoids?

A. ACTH stimulation test

B. Morning plasma ACTH level

C. Morning serum cortisol level

D. Morning, fasting blood sugar level

E. Postprandial serum cortisol

2. Which of the following moieties on the cortisol molecule must be present for maximal activation of the glucocorticoid receptor?

A. Hydroxyl group at carbon 11

B. Hydroxyl group at carbon 17

C. Hydroxyl group at carbon 21

D. Keto group at carbon 3

E. Keto group at carbon 20

3. Which of the following is the primary advantage of the alternate-day adrenocorticoid therapy?

A. Can be used to directly stimulate growth if used in children

B. Can be used to treat patients who require elevated and sustained immunosuppression

C. Can be used to withdraw patients from chronic glucocorticoid treatment by systematically lowering dosage

D. Minimizes anterior pituitary release of ACTH, which significantly reduces adrenal cortex atrophy

E. Satisfactory replacement of cortisol in the treatment of adrenocortical insufficiency

4. Which of the following is an indication for the clinical use of a mineralocorticoid?

A. Addison’s disease

B. Autoimmune glomerulonephritis

C. Diabetic ketoacidosis

D. Congenital adrenal hyperplasia associated with hyponatremia

E. Vasopressin deficiency

5. Which of the following is the most common cause of Cushing’s syndrome?

A. ACTH-dependent pituitary Cushing’s disease

B. Administration of exogenous steroids

C. Adrenal adenoma

D. Adrenal hyperplasia

E. Ectopic ACTH production

6. Which of the following statements best explains why metyrapone can be used in the diagnosis of the etiology of elevated serum ACTH?

A. It directly blocks the synthesis of cortisol by inhibition of 21β-hydroxylase, which promotes increased ACTH formation from the anterior pituitary but not from ectopic sources.

B. It directly blocks the synthesis of cortisol by inhibition of 11β-hydroxylase, which promotes increased ACTH formation from anterior pituitary but not from ectopic sources.

C. It has a selective cytotoxic effect on tumor cells that produce ACTH, leading to loss of ectopic production of ACTH, suggesting that the increased ACTH arises from an ectopic source.

D. It acts at the anterior pituitary to increase the processing of ACTH from its precursor protein but has no effect on ACTH from ectopic sources.

E. It selectively decreases ACTH formation in pituitary adenomas and has no effect on ectopic production.