Eric Dietrich, Steven M. Smith, and John G. Gums
KEY CONCEPTS
Glucocorticoid secretion from the adrenal cortex is stimulated by adrenocorticotropic hormone (ACTH) or corticotropin that is released from the anterior pituitary in response to the hypothalamic-mediated release of corticotropin-releasing hormone (CRH).
To ensure the proper treatment of Cushing’s syndrome, diagnostic procedures should (a) establish the presence of hypercortisolism and (b) discover the underlying etiology of the disease.
The rationale for treating Cushing’s syndrome is to reduce the morbidity and mortality resulting from disorders such as diabetes mellitus, cardiovascular disease, and electrolyte abnormalities.
The treatment of choice for both ACTH-dependent and ACTH-independent Cushing’s syndrome is surgery, whereas pharmacologic agents are reserved for adjunctive therapy, refractory cases, or inoperable disease.
Pharmacologic agents that may be used to manage the patient with Cushing’s syndrome include steroidogenesis inhibitors, adrenolytic agents, neuromodulators of ACTH release, and glucocorticoid-receptor blocking agents.
Spironolactone, a competitive aldosterone receptor antagonist, is the drug of choice in bilateral adrenal hyperplasia (BAH)–dependent hyperaldosteronism.
Addison’s disease (primary adrenal insufficiency) is a deficiency in cortisol, aldosterone, and various androgens resulting from the loss of function of all regions of the adrenal cortex.
Secondary adrenal insufficiency usually results from exogenous steroid use, leading to hypothalamic–pituitary–adrenal (HPA)–axis suppression followed by a decrease in ACTH release, and low levels of androgens and cortisol.
Virilism results from the excessive secretion of androgens from the adrenal gland and often manifests as hirsutism in females.
The adrenal glands were first characterized by Eustachius in 1563. After Addison identified a case of adrenal insufficiency in humans, adrenal anatomy and physiology flourished. Most of the work done in the early and mid-1900s centered on the glucocorticoid cortisol. With the discovery of aldosterone by Simpson and Tait in 1952, adrenal pharmacology turned toward the mineralocorticoid. Conn1 followed with his classical description of primary aldosteronism (PA) in 1955, and numerous clinicians and investigators have continued to explore the variety of disease processes promoted through the adrenal gland.
PHYSIOLOGY, ANATOMY, AND BIOCHEMISTRY
The adrenal glands are located extraperitoneally to the upper poles of each kidney (Fig. 59-1). On average, each adrenal gland weighs 4 g and is 2 to 3 cm in width and 4 to 6 cm in length. The gland is fed by small arteries from the abdominal aorta and renal and phrenic arteries. Drainage of the adrenal gland occurs via the renal vein on the left and the inferior vena cava on the right.
FIGURE 59-1 Anatomy of the adrenal gland.
The adrenal medulla occupies 10% of the total gland and is responsible for the secretion of catecholamines. The adrenal cortex accounts for the remaining 90% and is responsible for the secretion of three types of hormones (Fig. 59-2) from three separate zones.
FIGURE 59-2 Hormone synthetic pathways in relation to the zones of the adrenal cortex.
The zona glomerulosa accounts for 15% of the total adrenal cortex and is responsible for mineralocorticoid production, of which aldosterone is the principal end product. Aldosterone maintains electrolyte and volume homeostasis by altering potassium and magnesium secretion and renal tubular sodium reabsorption. The zona fasciculata, the middle zone, makes up 60% of the cortex, is high in cholesterol, and is responsible for basal and stimulated glucocorticoid production. Glucocorticoids, mainly cortisol, are responsible for the regulation of fat, carbohydrate, and protein metabolism. The zona reticularis occupies 25% of the adrenal cortex, and is responsible for adrenal androgen production. The androgens, testosterone and estradiol, are the major end products and influence the reproductive system in addition to modulating primary and secondary sex characteristics.
Hormone Production and Metabolism
Adrenal steroid hormone synthesis begins with the conversion of cholesterol to pregnenolone by cytochrome P450 (CYP) enzymatic side-chain cleavage. Following this rate-limiting step, pregnenolone is converted to various 19- and 21-carbon steroids, depending on the enzymatic capabilities within each zone of the cortex. Androgenic properties predominate in the 19-carbon steroids, whereas mineralocorticoid and glucocorticoid properties manifest in the 21-carbon steroids.
Aldosterone production is initiated by the 21-hydroxylation of progesterone to form deoxycorticosterone. Subsequently, aldosterone synthase converts deoxycorticosterone to aldosterone through the intermediary, corticosterone. The zona glomerulosa preferentially produces aldosterone for three main reasons. First, the zona glomerulosa lacks 17α-hydroxylase activity and therefore can only convert pregnenolone to progesterone. Second, in contrast to the other zones, cells in the zona glomerulosa possess aldosterone synthase activity, which catalyzes the terminal steps in aldosterone synthesis. Lastly, cells of the zona glomerulosa display a greater number of angiotensin II receptors than cells of the other zones. Binding of angiotensin II to these receptors provides the stimulus for initiating the aldosterone biosynthesis cascade. Thus, aldosterone synthesis is a unique feature of the zona glomerulosa, explaining why aldosterone is not affected during disease processes limited to the zona fasciculata and/or reticularis.
Cortisol is produced from pregnenolone via four successive hydroxylations. These hydroxylations occur primarily in the zona fasciculata, although the zona reticularis is also capable of producing glucocorticoids.
Androgens, produced primarily in the zona reticularis and less commonly in the zona fasciculata, have a 19-carbon structure and serve as precursors to more potent analogues produced in the periphery. The adrenal gland can synthesize estradiol and estrone from testosterone and androstenedione, respectively; however, these synthesized quantities are extremely small. The rates of production for the various steroids produced by the adrenal gland are listed in Table 59-1.
TABLE 59-1 Rates of Adrenal Production and Plasma Concentrations of Various Steroids
Glucocorticoid metabolism occurs in the liver and is responsible for converting inactive steroids to active metabolites, as well as modifying active steroids to less active or inactive metabolites. Most pharmaceutical steroid products are active; however, in the case of prednisone and cortisone, metabolism is necessary for conversion to the active prednisolone and cortisol, respectively.
Following metabolic conversion, glomerular filtration is primarily responsible for eliminating endogenously produced glucocorticoids. The half-life of cortisol is 70 to 120 minutes, whereas aldosterone exhibits extremely high intrinsic clearance and a corresponding half-life of only 15 minutes.
Metabolism and conversion of the various steroids can be altered by a variety of disease states and medicinal compounds. Drugs known to enhance steroid clearance include phenytoin, phenobarbital, rifampin, mitotane, and aminoglutethimide. Likewise, diseases such as hyperthyroidism and renal disease (dexamethasone only) can enhance steroid clearance. In contrast, drugs such as estrogens and estrogen-containing oral contraceptives reduce steroid clearance. Similarly, liver disease, age, pregnancy, hypothyroidism, anorexia nervosa, protein–calorie malnutrition, and renal disease (prednisolone only) are associated with reduced steroid clearance.
Plasma glucocorticoids are bound to one of three plasma proteins in varying degrees. Corticosteroid-binding globulin (CBG), albumin, and α1-glycoprotein are capable of binding glucocorticoids, with CBG being the principal binding protein. Steroid binding serves as a reservoir for steroids in their inactive state and ≥95% of cortisol is normally bound in this fashion. This binding prevents glucocorticoid activity at receptor-activating sites. Therefore, a final but important variable in altered plasma concentration of free (active) steroids is concentration of plasma proteins.
Regulation of Hormone Secretion
Glucocorticoid secretion is regulated by the pituitary hormone, adrenocorticotropic hormone (ACTH [also known as corticotropin]). Under normal conditions, ACTH is released from the anterior pituitary in response to corticotropin-releasing hormone (CRH), which is secreted by the median eminence of the hypothalamus (Fig. 59-3). Vasopressin and oxytocin have weak ACTH-releasing activity through binding to the inferior V3 receptor. CRH, in combination with vasopressin and oxytocin, stimulates greater ACTH secretion than each hormone individually.
FIGURE 59-3 Negative feedback system involved in the regulation of cortisol secretion under normal conditions. (ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.)
Additionally, histochemical studies have demonstrated that certain neurotransmitters can stimulate production of CRH or ACTH directly. Specifically, both serotonin and norepinephrine have been shown to increase levels of ACTH. After release, ACTH stimulates the adrenal gland to release cortisol and, to a lesser extent, aldosterone and androgens. The rising cortisol concentration inhibits the secretion of CRH and ACTH through a negative feedback mechanism. In addition, leptin, an adipocyte hormone, can have an inhibitory effect on hypothalamic–pituitary–adrenal (HPA) activity.
Adrenal androgens are regulated in a similar fashion to cortisol. When plasma androgen reaches sufficient concentrations, production is terminated via a negative feedback loop. Androgen release is increased during puberty and in women with hirsutism. Adrenal androgen release decreases with age and in fasting states, including anorexia nervosa.
In contrast to cortisol and adrenal androgens, regulation of aldosterone secretion is considerably more complex. The renin–angiotensin system regulates aldosterone secretion through both intrarenal and extrarenal mechanisms. Renin production and subsequent aldosterone secretion is stimulated by blood pressure lowering (due to volume depletion), erect posture, salt depletion, β-adrenergic stimulation, and CNS excitation (see Chap. 15). Renin production is inhibited by salt loading, angiotensin II, vasopressin, potassium, calcium, blood pressure increases, and a variety of drugs. The renin-mediated production of angiotensin II is the initial stimulus for aldosterone synthesis. Additionally, angiotensin II can be acted on by aminopeptidase and converted to angiotensin III. Both angiotensin II and III are capable of stimulating the zona glomerulosa to secrete aldosterone. Following aldosterone secretion, increases in renal sodium and water retention as well as blood pressure occur, thereby turning off the stimulus for renin release.
HYPERFUNCTION OF THE ADRENAL GLAND
Adrenal disorders can be categorized as hyperfunction or hypofunction of the adrenal gland. Hyperfunction of the adrenal gland generally involves excess production of adrenal hormones, most notably cortisol, resulting in Cushing’s syndrome, or aldosterone, resulting in hyperaldosteronism.
Cushing’s Syndrome
In 1932, Cushing first described a syndrome of pituitary basophilism that attracted national attention. Until this time, no definitive diagnosis existed for patients with unexplained central obesity, cutaneous striae, osteoporosis, weakness, hypertension, diabetes mellitus, and congestion. Cushing emphasized that the disease was of a pituitary origin. Ten years later, Albright focused his attention on the sugar hormone, which he believed originated from the adrenal cortex.2
After the development of a method for measuring urinary steroids, Daughaday discovered elevated steroids in the urine of patients with Cushing’s syndrome. Finally, the end product was identified, and Cushing’s syndrome was correctly explained as an excess of cortisol in the plasma (hypercortisolism).
Etiology
Cushing’s syndrome results from the effects of supraphysiologic levels of glucocorticoids originating either from exogenous administration or, less commonly, from endogenous overproduction by the adrenal glands. Excess glucocorticoids are produced in response to overproduction of ACTH (ACTH-dependent) or by abnormal adrenocortical tissues regardless of ACTH stimulation (ACTH-independent). ACTH-dependent Cushing’s syndrome (≈80% of all Cushing’s syndrome cases) usually originates from overproduction of ACTH by the pituitary gland, which chronically stimulates the adrenal glands causing bilateral adrenal hyperplasia (BAH). Approximately 85% of these cases are caused by pituitary adenomas (Cushing’s disease). Ectopic ACTH-secreting tumors and nonneoplastic corticotropin hypersecretion, possibly secondary to excess CRH production, account for the remainder of ACTH-dependent causes.3 Ectopic ACTH syndrome refers to excessive ACTH production resulting from an endocrine or nonendocrine tumor, usually of the pancreas, thyroid, or lung. Small-cell carcinoma of the lung will lead to ectopic ACTH secretion in 0.5% to 2% of cases, whereas bronchial carcinoid tumors are usually the most common.4 Distinguishing between the various etiologies requires a careful history and pertinent laboratory work (Table 59-2).
TABLE 59-2 Various Etiologies of Cushing’s Syndrome and Their Respective Differences
The remaining 20% of Cushing’s syndrome cases are ACTH-independent and divided almost equally between adrenal adenomas and adrenal carcinomas, with rare cases caused by macronodular hyperplasia, primary pigmented nodular adrenal disease, and McCune-Albright syndrome.3,5 The majority of adrenal cortex tumors are benign adenomas. Adrenal carcinoma is found more often in children than in adults with Cushing’s syndrome.
Clinical Presentation
Patients with Cushing’s syndrome commonly present (>90% of patients) with central obesity and facial rounding. In addition, approximately 50% of patients will exhibit some peripheral obesity and fat accumulation. Fat accumulation in the dorsocervical area (buffalo hump) can be associated with any major weight gain, whereas increased supraclavicular fat pads are more specific for Cushing’s syndrome. Striae usually are present along the lower abdomen and take on a red to purple color. Traditionally, hypertensive complications have been major contributors to the morbidity and mortality of Cushing’s syndrome. Hypertension is diagnosed in 75% to 85% of patients, with diastolic blood pressures greater than 119 mm Hg noted in over 20% of patients.6 In addition, glucose intolerance is present in 60% of patients. Thus, many patients meet diagnostic criteria for the metabolic syndrome and have a corresponding increased risk of coronary heart disease (CHD) and stroke. Screening for Cushing’s syndrome in this population and in patients with uncontrolled diabetes mellitus has been suggested,7,8 particularly when these conditions surface at an unusually early age.9 However, screening all patients with type 2 diabetes is likely not cost-effective.10
Diagnosis
The diagnosis of Cushing’s syndrome involves two steps: (a) establishing the presence of hypercortisolism, which is relatively easy, and (b) differentiating between etiologies, which can be challenging (Fig. 59-4).5,8,11 The presence of hypercortisolism can be established via the following tests: 24-hour UFC, midnight plasma cortisol, late-night salivary cortisol, and/or the low-dose DST (using 1 mg dexamethasone for the overnight test or 0.5 mg/6 hours for the classic 2-day study). However, because these tests cannot determine the etiology of Cushing’s syndrome, other tests and procedures will be subsequently employed. Such tests can include any of the following: plasma ACTH via immunoradiometric assay (IRMA) or radioimmunoassay (RIA); adrenal vein catheterization; metyrapone stimulation test; adrenal, chest, or abdominal computed tomography (CT); CRH stimulation test; IPSS; jugular venous sampling (JVS); cavernous sinus sampling; and pituitary magnetic resonance imaging (MRI). High-dose DST has been used in the past, but is no longer recommended due to its poor specificity and limited diagnostic value. Other possible tests and procedures include insulin-induced hypoglycemia, somatostatin receptor scintigraphy, the desmopressin stimulation test, the naloxone CRH stimulation test, the loperamide test, the hexarelin stimulation test, and radionuclide imaging.5,6,8,11–16 Table 59-3summarizes some of the tests used to diagnose Cushing’s syndrome.
TABLE 59-3 Summary of Tests Used to Diagnose Cushing’s Syndrome
FIGURE 59-4 Algorithm for diagnosing Cushing’s syndrome. (ACTH, adrenocorticotropic hormone.)
CLINICAL PRESENTATION Cushing’s Syndrome
General
• The most common findings, which are present in 90% of patients, are central obesity and facial rounding.
Symptoms
• Approximately 65% and 58% of patients complain of myopathies and muscular weakness, respectively.
Signs
• Peripheral obesity and fat accumulation is found in 50% of patients.
• Facial plethora is caused by an underlying atrophy of the skin and connective tissue and is seen in approximately 84% of patients.
• Patients often are described as having moon faces with a buffalo hump.
• Hypertension is seen in 75% to 85% of patients.
• Psychiatric changes can occur in as many as 55% of patients.
• Approximately 50% to 60% of patients will develop Cushing’s syndrome–induced osteoporosis. Of these, 40% will present with back pain and 20% will progress to compression fractures of the spine.
• Gonadal dysfunction is common with amenorrhea seen in up to 75% of females.
• Excess adrenal and ovary androgen secretion is responsible for 80% of females presenting with hirsutism.
Laboratory Tests
• A midnight plasma cortisol, late-night salivary cortisol, 24-hour urinary free cortisol (UFC), and/or low-dose dexamethasone suppression test (DST) will establish the presence of hypercortisolism.
Other Diagnostic Tests
• The plasma ACTH test, metyrapone stimulation test, CRH stimulation test, or inferior petrosal sinus sampling (IPSS) will help determine the etiology.
Elevated UFC concentrations are highly suggestive of Cushing’s syndrome, especially values fourfold greater than the upper limit of normal.3,13 In contrast to plasma measurements of cortisol, UFC measures only unbound cortisol. Consequently, the UFC test is unaffected by conditions and medications that alter CBG levels. Normal reference values for UFC are 20 to 90 mcg per 24-hour period. A twofold to threefold increase in urine cortisol is not uncommon in the patient with hyperfunction of the adrenal gland. Starvation, hydration from water loading (greater than 5 L/day), alcoholism, and acute stress are all capable of elevating urine cortisol concentrations. Likewise, elevated UFC results can occur during therapy with topical steroids, carbamazepine, and fenofibrate depending on the type of UFC test. Conversely, renal impairment (creatinine clearance [CrCl] of less than 60 mL/min) can falsely lower UFC concentrations. Because other pathologic conditions can increase the amount of free cortisol, additional tests may be warranted to confirm the diagnosis, or the diagnostic evaluation should be repeated when the acute stress has resolved. Of all urinary measures, UFC is the most useful assessment for patients with suspected Cushing’s syndrome.8,13,15
In healthy individuals, cortisol release follows a circadian rhythm whereby serum cortisol levels peak around 8:00 AM and thereafter decline by 60% to 80%, reaching a nadir between 3:00 and 4:00 AM. This rhythm is lost in the Cushing’s syndrome patient. Although many patients with Cushing’s syndrome will have serum cortisol values in the high normal range if the serum is assayed in the morning, only 3.4% will have normal values if measured late at night.17 Thus, a midnight serum cortisol greater than 7.5 mcg/dL (>1.8 mcg/dL if the patient is sleeping) is a highly sensitive assay for Cushing’s syndrome. However, this test is cumbersome and rarely recommended because it requires that patients be admitted for more than 48 hours to avoid false-positive responses secondary to the stress of hospitalization. An alternative assay is the measurement of late-night salivary cortisol. Salivary cortisol is highly correlated with free serum cortisol and independent of salivary flow rates. Moreover, salivary cortisol concentrations reflect changes in serum cortisol within minutes. Salivary cortisol can be considered as an acceptable alternative to UFC because of its convenience, stability (1 week), accuracy, and reproducibility. Unfortunately, normal reference ranges are assay-dependent, and cutoff points vary among institutions.18,19
In the overnight DST, 1 mg of dexamethasone is administered at 11:00 PM. The following morning at 8:00 AM fasting plasma cortisol is obtained for analysis. This supraphysiologic dose suppresses ACTH stimulation and cortisol production in healthy individuals. In contrast, the negative feedback loop is ineffective in patients with Cushing’s syndrome who generally exhibit morning cortisol concentrations above 5 mcg/dL. Some patients with Cushing’s syndrome administered the overnight DST can slightly suppress cortisol and using 1.8 mcg/dL as a cutoff can increase sensitivity, but at the expense of reduced specificity.20 Therefore, the overnight DST is useful only as a screening tool for Cushing’s syndrome. Drugs that induce or inhibit CYP3A4 metabolism can significantly alter dexamethasone levels, increasing the number of false-positive and false-negative DST tests. Concurrent measurements of dexamethasone levels with cortisol may improve the accuracy of testing for patients on CYP3A4-modifying drugs, although dexamethasone assays are not widely available. Also noteworthy, pregnancy and estrogen use (including oral contraceptives) increase CBG levels and frequently elicit false-positive results.13Consequently, UFC testing is preferred over DST in these patient populations.
The first test used to determine the etiology of Cushing’s syndrome is the plasma ACTH test. Plasma ACTH concentrations can be measured via RIA or IRMA.12 In ACTH-dependent Cushing’s syndrome, ACTH can be normal or elevated. Very high levels of ACTH favor ectopic production. In contrast, ACTH values generally are low (less than 5 pg/mL) in ACTH-independent (adrenal) Cushing’s syndrome. Furthermore, ACTH levels can appear artificially low in some ectopic ACTH-producing tumors because ACTH can be secreted as an active prohormone that is not detected by the assay.
IPSS offers the highest sensitivity and specificity of any test in differentiating the etiology of Cushing’s syndrome. This technique requires catheterization of both petrosal sinuses with serial measurements of ACTH in each sinus and a peripheral vein after administration of CRH. A central-to-peripheral ACTH gradient is diagnostic for Cushing’s disease, whereas no gradient indicates ectopic ACTH production. Complications, such as venous thromboembolism, brain stem vascular damage, cost, and technical expertise, can limit use of this test.12 JVS uses the same concept as IPSS, is less invasive, and produces fewer complications; however, sensitivity is compromised.
Abnormal adrenal anatomy is effectively identified using high-resolution CT scanning and MRI.21 Nodules as small as 1 to 1.5 cm on the adrenal cortex are easily identified by CT. With the use of thin-section scanning, nodules as small as 3 to 5 mm can be visualized.22 Importantly, adrenal incidentalomas are prevalent in 5% to 10% of the general population. These masses may be functional (secreting), requiring intervention, or nonfunctional (nonsecreting), requiring only periodic observation. For this reason, abnormal imaging results are unable to conclusively diagnose adrenal disease when used alone. Nonadrenal imaging studies may be useful for identifying ectopic sources of ACTH secretion in patients for whom IPSS has ruled out Cushing’s disease.
Differential Diagnosis
Iatrogenic (exogenous) Cushing’s syndrome is the most common form of the disease. Therefore, all patients exhibiting hypercortisolism should undergo a comprehensive history and evaluation assessing medication use before laboratory testing is performed to identify endogenous causes. Iatrogenic Cushing’s syndrome can occur from administration of oral, inhaled, intranasal, intraarticular, and topical glucocorticoids, as well as progestins such as medroxyprogesterone acetate and megestrol acetate.23 Disease severity correlates with exogenous glucocorticoid potency, dose, frequency, route, and treatment duration. Moreover, patients taking CYP3A4 inhibitors concomitantly with a glucocorticoid can be at higher risk of developing iatrogenic Cushing’s syndrome.24,25 If exogenous glucocorticoids are being taken, plasma cortisol levels can increase, while corticosterone levels remain low.17
In the absence of any known exogenous causes, the clinician will need to differentiate the syndrome from other syndromes, such as pseudo-Cushing’s syndrome, that mimic Cushing’s. Patients with obesity, chronic alcoholism, depression, and acute illness of any type can present with certain features of Cushing’s syndrome. However, these patients may lack true Cushing’s syndrome. For example, depressed patients, although mimicking the urinary steroid abnormalities of Cushing’s syndrome, will not resemble a cushingoid patient in appearance. In chronic alcoholics, steroid laboratory panels generally return to baseline after ceasing alcohol intake. And obese patients often will have normal cortisol concentrations on both serum and urinary screening. Thus, identifying true cases of Cushing’s syndrome requires a comprehensive history in combination with laboratory and possibly imaging assessment.
TREATMENT
Desired Outcomes
If left untreated, Cushing’s syndrome is associated with high morbidity and mortality due to associated disorders such as hypertension, diabetes mellitus, cardiovascular disease, and electrolyte abnormalities. These disorders limit the survival of the patient with Cushing’s syndrome to 4 to 5 years following initial diagnosis. The desired outcomes of treatment are to limit such detrimental outcomes and return the patient to a normal functional state by removing the source of hypercortisolism while minimizing pituitary or adrenal deficiencies.
The treatment of choice for both ACTH-dependent and ACTH-independent Cushing’s syndrome is surgical resection of any offending tumors.3,11 However, several secondary pharmacologic treatment plans are available, depending on the etiology of the disease (Table 59-4).26,27 These pharmacologic options are generally used in preoperative patients or as adjunctive therapy in postoperative patients awaiting response. Rarely, monotherapy is used as a palliative treatment when surgery is not indicated.
TABLE 59-4 Possible Treatment Options in Cushing’s Syndrome Based on Etiology
Pharmacologic Therapy
Pharmacotherapy of Cushing’s syndrome (dosing and monitoring parameters can be found in Tables 59-5 and 59-6, respectively)28 can be divided into four categories based on the anatomic site of action of the agent: (a) steroidogenesis inhibitors, (b) adrenolytic agents, (c) neuromodulators of ACTH release, and (d) glucocorticoid-receptor blocking agents.26,27
TABLE 59-5 Drug Dosing in the Treatment of Cushing’s Syndrome
TABLE 59-6 Drug Monitoring in the Treatment of Cushing’s Syndrome
Steroidogenesis Inhibitors
As their name implies, steroidogenesis inhibitors block the production of cortisol. This class includes metyrapone, ketoconazole, etomidate, and aminoglutethimide. Metyrapone inhibits 11β-hydroxylase, the enzyme responsible for converting 11-deoxycortisol to cortisol. Following administration, a sudden decrease in cortisol levels occurs within hours and prompts a compensatory rise in plasma ACTH concentrations. As ACTH increases and blockage of cortisol synthesis persists, adrenal steroidogenesis efforts are shunted toward androgen production. Consequently, metyrapone is associated with significant androgenic side effects, including hirsutism and increased acne, making it less ideal for females. In addition, metyrapone blocks aldosterone synthesis and causes the accumulation of aldosterone precursors, which exhibit weak mineralocorticoid activity. Blood pressure and electrolyte level variations can ensue, depending on the level of circulating 11-deoxycortisol and the degree of aldosterone inhibition. Additional adverse effects, including nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash, have been reported following administration, but are often signs of overtreatment.26,27,29 Metyrapone is currently available through the manufacturer only for compassionate use.
The imidazole derivative antifungal, ketoconazole, effectively inhibits steroidogenesis via multiple mechanisms when used in large doses. In contrast to the quick onset of metyrapone, the benefits of ketoconazole therapy are achieved only after several weeks of therapy. In addition to lowering serum cortisol levels, ketoconazole exhibits antiandrogenic activity attributable to its inhibition of multiple CYP enzymes as well as 11β-hydroxylase and 17α-hydroxylase.26 This activity may be beneficial in female patients with Cushing’s syndrome, but can cause gynecomastia and hypogonadism in males. Sustained therapy with ketoconazole also imparts beneficial effects on serum cholesterol profiles, including lowering total and LDL cholesterol levels. Ketoconazole induces a reversible elevation of hepatic transaminases in approximately 10% of patients.30 Frequent liver function monitoring is recommended, although progression to serious hepatotoxicity is rare. Additional common adverse effects include GI discomfort and dermatologic reactions.
Ketoconazole may be used concomitantly with metyrapone to achieve synergistic reductions in cortisol levels. Because these drugs differ in their onset of action, coadministration allows for more complete suppression of cortisol synthesis. Moreover, the antiandrogenic actions of ketoconazole therapy may offset the androgenic potential of metyrapone, thus attenuating a major limitation of metyrapone therapy.
The anesthetic etomidate is an imidazole derivative similar to ketoconazole that inhibits 11β-hydroxylase.26 Etomidate is available only in a parenteral formulation and is therefore limited to patients with acute hypercortisolemia requiring emergency treatment.
Initially, aminoglutethimide was used to treat refractory forms of epilepsy, but was later discovered to be a potent inhibitor of adrenal steroid synthesis. Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone early in the steroid biosynthesis pathway, thereby inhibiting the production of cortisol, aldosterone, and androgens. Owing to these broad inhibitory actions, side effects, including severe sedation, nausea, ataxia, and skin rashes, limit the use of aminoglutethimide in many patients.26,27 Moreover, because other steroidogenesis inhibitors offer greater efficacy combined with fewer side effects, aminoglutethimide has fallen out of favor in the treatment of Cushing’s syndrome. If aminoglutethimide is used, it should be coadministered with another steroidogenesis inhibitor, usually metyrapone, secondary to high relapse rates with aminoglutethimide monotherapy.
Adrenolytic Agents
Mitotane is a cytotoxic drug that structurally resembles the insecticide dichlorodiphenyltrichloroethane (DDT). Mitotane inhibits the 11-hydroxylation of 11-desoxycortisol and 11-desoxycorticosterone in the cortex, resulting in a net inhibition of cortisol and corticosterone synthesis. Similar to ketoconazole, mitotane takes weeks to months to exert beneficial effects. Sustained cortisol suppression occurs in most patients and may persist following discontinuation of therapy in up to one third of patients. Because of its cytotoxic nature, mitotane degenerates cells within the zona fasciculata and reticularis, resulting in atrophy of the adrenal cortex. The zona glomerulosa is minimally affected during acute therapy but can become damaged following long-term treatment.28,31
Importantly, mitotane can induce significant neurologic and GI side effects and patients should be monitored carefully or hospitalized when initiating therapy. Nausea and diarrhea are common adverse effects that occur at doses greater than 2 g/day and can be avoided by gradually increasing the dose and/or administering the agent with food. Approximately 80% of patients treated with mitotane develop lethargy and somnolence, and other CNS adverse drug reactions occur in approximately 40% of patients. Furthermore, significant but reversible hypercholesterolemia and prolongation of bleeding times can result from mitotane use.26,27 Mitotane increases production of CBG resulting in artifactually elevated plasma cortisol; thus, UFC and urinary steroid production should be monitored to assess response to therapy.26If necessary, steroid replacement therapy can be given. However, because mitotane also increases extraadrenal metabolism of exogenously administered corticosteroids (especially hydrocortisone), higher steroid replacement doses may be required.
Neuromodulatory Agents
Pituitary secretion of ACTH is normally mediated by various neurotransmitters, including serotonin, GABA, acetylcholine, and the catecholamines. Although ACTH-secreting pituitary tumors (Cushing’s disease) self-regulate ACTH production to some degree, these neurotransmitters are still capable of promoting pituitary ACTH production. Consequently, agents that target these neurotransmitters have been proposed for the treatment of Cushing’s disease. Such agents include cyproheptadine, ritanserin, ketanserin, bromocriptine, cabergoline, valproic acid, octreotide, lanreotide, rosiglitazone, and tretinoin. However, none of these drugs have demonstrated consistent clinical efficacy in the treatment of Cushing’s disease.
Cyproheptadine, a nonselective serotonin receptor antagonist and anticholinergic drug, can decrease ACTH secretion in some Cushing’s disease patients. However, side effects, including sedation and weight gain, significantly limit the use of this drug. Likewise, selective serotonin type 2 receptor antagonists, including ritanserin and ketanserin, have demonstrated limited efficacy. Owing to their poor efficacy and high relapse rates, these drugs should be avoided except in nonsurgical candidates refractory to more conventional treatments.
Dopamine D2 receptor agonists, including bromocriptine and cabergoline, initially reduce ACTH secretion in as many as half of all patients with Cushing’s disease. This action occurs through activation of inhibitory D2 receptors that are expressed in approximately 80% of pituitary adenomas.32 Reductions in ACTH levels are often minor and rarely sustained with long-term bromocriptine therapy. Cabergoline exhibits a higher specificity and affinity for D2receptors as well as a prolonged half-life compared with bromocriptine. These differences may explain the greater response rates observed with cabergoline monotherapy; however, a sustained response occurs in only 30% to 40% of patients.33,34
The somatostatin analogues, octreotide and lanreotide, generally are ineffective in reducing ACTH secretion in Cushing’s disease. These two agents primarily target somatostatin receptor subtype 2 (sst2), whereas pituitary adenomas predominantly express sst5. Pasireotide, a recently approved somatostatin analogue, exhibits a high affinity for sst1, sst2, sst3, and, especially, sst5 receptor subtypes. In a phase 3 study of 162 adults with Cushing’s disease and an elevated UFC level, pasireotide administered at 600 or 900 mcg injected subcutaneously twice daily reduced the median UFC by 50% by month 2; levels remained stable for the duration of the 12-month study. Clinical signs and symptoms of Cushing’s disease were also improved as were blood pressure, weight, LDL cholesterol, and quality of life. Side effects were mostly GI in nature, although 73% of subjects experienced an adverse event related to hyperglycemia; preexisting diabetes mellitus or impaired glucose tolerance increased the risk for these events. Notably, glycated hemoglobin A1c increased by an average of 1.4%. Gallstones were also rarely seen with six subjects undergoing cholecystectomy.35
Glucocorticoid-Receptor Blocking Agents
Mifepristone (RU-486) is a potent progesterone- and glucocorticoid-receptor antagonist that inhibits dexamethasone suppression and increases endogenous cortisol and ACTH levels in normal subjects.26,29Clinical experience and trial data in Cushing’s syndrome suggest that RU-486 is highly effective in reversing the manifestation of hypercortisolism, including hyperglycemia, hypertension, and weight gain.36However, because of its novel site of action, RU-486 induces a compensatory rise in ACTH and cortisol levels. Consequently, efficacy and toxicity monitoring must rely on clinical signs rather than laboratory assessments. Common adverse effects of RU-486 include fatigue, nausea, headache, arthralgia, peripheral edema, endometrial thickening (with or without vaginal bleeding), and significant reductions in serum potassium. Oral potassium supplementation or spironolactone can be effective in mitigating the latter adverse effect, although high doses may be required.36
Close monitoring of 24-hour UFC levels and serum cortisol levels is essential to detect treatment-induced adrenal insufficiency. Steroid secretion should be monitored with all of these drugs except RU-486 and steroid replacement given as needed. Whatever the choice, pharmacologic therapy in pituitary-dependent disease is mainly centered around patient stabilization prior to surgery or in patients waiting for potential response to other therapies.
Clinical Controversy…
The traditional strategy for suppressing hypercortisolism in Cushing’s disease consists of titrating medications to achieve normal cortisol levels. However, some clinicians advocate a “block and replace” strategy, whereby greater doses of medications are used to completely suppress endogenous cortisol production, followed by administration of physiologic doses of glucocorticoids to treat adrenal insufficiency.
Nonpharmacologic Therapy
Surgery
The treatment of choice for Cushing’s disease is transsphenoidal resection of the pituitary tumor.3,11,29,37 The advantages of this procedure include preservation of pituitary function, low complication rate, and high clinical improvement rate. The overall cure rate of histologically proven microadenomas approaches 90%, whereas remission rates for macroadenomas generally do not exceed 65%.
For persistent disease following transsphenoidal surgery or when tumor-specific surgery is not possible, several second-line treatment options are available and should be tailored toward the individual patient. In the case of persistent disease following transsphenoidal surgery, repeat surgery may be performed, although overall remission rates are lower with subsequent procedures. Alternatively, radiotherapy may be preferred for tumors invading the dura or cavernous sinus because these tumors respond poorly to surgical intervention.38 Radiotherapy provides clinical improvement in approximately 50% of patients within 3 to 5 years, but increases the risk for pituitary-dependent hormone deficiencies (hypopituitarism).
Laparoscopic adrenalectomy is often preferred in patients with unilateral adrenal adenomas for whom transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used.3,11,29 Bilateral adrenalectomy rapidly reverses hypercortisolism. However, patients can develop Nelson’s syndrome, an aggressive pituitary tumor that secretes high quantities of ACTH, which causes hyperpigmentation. Because Nelson’s syndrome occurs in as many as 30% of bilateral adrenalectomy cases, patients should undergo regular MRI scans and ACTH level assessments. Additionally, these patients require lifelong glucocorticoid and mineralocorticoid supplementation.
Adrenal Adenoma
Surgical resection of benign adrenal adenoma is associated with relatively few side effects and a high cure rate (95%). The contralateral gland in the patient with adrenal adenoma is usually atrophic; therefore, steroid replacement is needed both perioperatively and postoperatively. Table 59-7 outlines an approach to steroid replacement for three separate routes of hydrocortisone. Therapy should be continued for 6 to 12 months following surgery. Before replacement therapy is discontinued, recovery of the adrenal axis can be assessed by measuring the morning (8 AM) cortisol level. Cortisol levels should exceed 20 mcg/dL before discontinuing exogenous steroids.23
TABLE 59-7 Alternative Steroid Replacement Regimens in the Adrenal Adenoma Patient
Adrenal Carcinoma
Unlike the benign adenoma patient, those with adrenal carcinoma have an unfavorable outcome with surgical resection.11 Often the complete tumor cannot be excised, leaving the patient with some degree of symptomatology and extraadrenal involvement. Radiotherapy can be used if metastases are discovered. In the patient with adrenal carcinoma who is not a surgical candidate, the focus of treatment is on palliative pharmacologic intervention.
Mitotane may be used in inoperable functional and nonfunctional adrenal carcinoma or as adjuvant therapy in surgical patients with a high risk of relapse. However, mitotane induces tumor regression in less than 20% of patients.39 Metyrapone and ketoconazole can be given to attempt control of steroid hypersecretion; aminoglutethemide is considered a third-line treatment option. 5-Fluorouracil also has been used in combination therapy.
Ectopic ACTH Syndrome
In ectopic ACTH syndrome, ACTH-secreting tumors may exist in a variety of sites, including thymic, pulmonary, appendiceal, pancreatic, and thyroid tissues. Locating these sites is often difficult, but essential for determining an appropriate treatment strategy. Surgical resection is the most effective treatment option for these patients, but only approximately 10% to 30% of patients are cured following surgery due to high rates of metastatic disease or occult tumors. The remaining 70% to 90% receive postoperative medication.
Pharmacologic management with steroidogenesis inhibitors is effective in patients with ectopic ACTH syndrome. Mitotane has been used in this setting; however, its side effect profile generally limits its use. RU-486 and somatostatin analogues also have been reported to reduce the clinical signs of ectopic ACTH syndrome.40
Additional tumor-directed therapy can include systemic chemotherapy, interferon α, chemoembolization, radio-frequency ablation, and radiation therapy.38 If all else fails, bilateral adrenalectomy can prevent the downstream effects (e.g., steroidogenesis) of high levels of tumor ACTH secretion.
Personalized Pharmacotherapy
Unfortunately, several factors limit the ability to personalize pharmacotherapy in patients with Cushing’s syndrome. First, few rigorous studies have compared the various pharmacologic options used in Cushing’s syndrome. Consequently, data are limited in terms of clinical predictors of disease response to these agents. Second, virtually nothing is known of the pharmacogenomic predictors of individual patient response in these disease states. Finally, because most agents are used off-label, scarce data exist on agent-specific pharmacokinetic parameters in this patient population.
With these limitations in mind, drug selection is determined primarily according to the etiology of Cushing’s syndrome, as described previously. Once the etiology has been correctly identified, gender should be considered since some pharmacologic options (steroidogenesis inhibitors in particular) used in Cushing’s syndrome affect the sex hormones. Specifically, metyrapone is a clear second choice in women due to a high incidence of hirsutism, whereas ketoconazole may be a secondary choice in men due to drug-induced gynecomastia and hypogonadism. During pregnancy, metyrapone is commonly used, while RU-486 must be avoided. Additionally, women desiring pregnancy within the next 5 years should avoid mitotane as this agent is stored in adipose tissue for up to several years following discontinuation. Preexisting medication profiles should be considered also, since many of the pharmacologic options can inhibit (e.g., ketoconazole) or induce (e.g., metyrapone) important CYP isoenzymes such as 3A4.
Ultimately, pharmacotherapy is guided by patient response and several agents may need to be tried sequentially to elicit a substantial response. Combination therapy may be more effective and better tolerated than monotherapy in some patients, but studies on what constitutes the most appropriate drug regimens are lacking.
Hyperaldosteronism
Excess aldosterone secretion is categorized as either primary or secondary hyperaldosteronism.41–45 In PA, the stimulation for aldosterone secretion arises from within the adrenal gland. Conversely, extraadrenal stimulation is classified as secondary aldosteronism.
Primary Aldosteronism
Etiology The most common causes of PA include BAH (65%) and aldosterone-producing adenoma (APA; otherwise known as Conn’s syndrome) (30%). Other rare causes include unilateral (primary) adrenal hyperplasia, adrenal cortex carcinoma, renin-responsive adrenocortical adenoma, and two forms of familial hyperaldosteronism (FH): FH type 1, also known as glucocorticoid-remediable aldosteronism (GRA), and FH type II.41,42,44
Clinical Presentation PA is present in approximately 10% of the general hypertensive population and is the leading cause of secondary hypertension. The disease is more common in women than in men, and diagnosis usually occurs between the third and sixth decades of life. Signs and symptoms can include arterial hypertension, which is often moderate to severe and resistant to pharmacologic intervention, as well as hypokalemia (10% to 40% of PA patients), muscle weakness, fatigue, and headache. These features are nonspecific for PA and many patients are asymptomatic. Historically, hypokalemia was considered a requisite feature for PA diagnosis; however, normokalemia exists frequently in patients and should not obviate concern for PA.
CLINICAL PRESENTATION Primary Aldosteronism
Symptoms
• Patients may complain of muscle weakness, fatigue, paresthesias, and headache.
Signs
• Hypertension
• Tetany/paralysis
• Polydipsia/nocturnal polyuria
Laboratory Tests
• A plasma-aldosterone-concentration–to–plasma-renin-activity (PAC–to–PRA) ratio, or aldosterone-to-renin ratio (ARR) greater than 20 is suggestive of PA.
• Common laboratory findings include suppressed renin activity, elevated plasma aldosterone concentrations (PACs), hypernatremia (>142 mEq/L), hypokalemia, hypomagnesemia, elevated bicarbonate concentration (>31 mEq/L), and glucose intolerance.
Confirmatory Tests
• Oral or IV saline loading, fludrocortisone suppression test (FST), and genetic testing
Diagnosis Diagnostic confirmation of PA is obtainable through screening, confirmatory tests, and subtype differentiation. As in Cushing’s syndrome, discovery of the underlying etiology ensures proper treatment. Table 59-8 lists the various abnormalities that must be ruled out when suspicion of hyperaldosteronism is high.
TABLE 59-8 Differential Diagnosis of Primary Aldosteronism
Initial diagnosis is made through proper screening of patients with suspected PA. Such patients include those with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) stage two hypertension—appreciating that the prevalence of PA increases with hypertensive severity—and resistant hypertensives. Screening for PA is most often done by using the plasma-aldosterone-concentration–to–plasma-renin-activity (PAC-to-PRA) ratio, otherwise known as the ARR. An elevated ARR is highly suggestive of PA; however, an optimal cutoff level remains undefined because testing conditions (posture, time, current drug therapy, recent dietary salt intake), patient characteristics, and variable levels of specificity and sensitivity among assays can significantly alter test results.46 ARR cutoffs of 20 to 40 or 20 with an aldosterone level greater than 15 ng/dL are used most often.43,47,48
Following a positive ARR screening test, confirmatory testing must be performed to exclude any false-positive cases. Confirmatory tests include the oral sodium loading test, saline infusion test, FST, and the captopril challenge test. Although individual tests can vary in sensitivity, specificity, and reliability, any test can be used depending on patient- and institution-specific considerations. FST generally is considered the most reliable, but requires hospitalization. Prior to performing these tests, potassium levels must be normalized and renin–angiotensin–aldosterone system (RAAS) inhibitors should be temporarily discontinued, if possible. Positive tests indicate autonomous aldosterone secretion under inhibitory pressures and are diagnostic for PA. After diagnosis, patients with confirmed PA before age 20 or with a family history of PA or strokes before age 40 should undergo genetic testing to properly identify GRA.46
Differentiating between an APA and BAH is imperative to formulate a proper treatment plan. Most adenomas are singular and small (<1 cm) and occur more often in the left adrenal gland than the right. Patients with APA generally have more severe hypertension, more profound hypokalemia, and higher plasma and urinary aldosterone levels compared with patients with BAH. Adrenal venous sampling (AVS) provides the most accurate means of differentiating unilateral from bilateral forms of PA. However, AVS is expensive, invasive, and frequently unavailable. CT scanning can detect most adenomas, although an incidentaloma can occasionally cause confusion. If CT scanning is inconclusive, AVS is performed to characterize lateralization.43,49–51
The underlying abnormality in BAH remains a mystery, but some investigators believe that a hormone factor stimulates the zona glomerulosa, resulting in increased sensitivity to angiotensin II. In contrast to those with an APA, patients with BAH are able to maintain control of the renin–angiotensin system, with little effect following doses of ACTH.
Therapeutic Management
BAH-Dependent Aldosteronism Aldosterone receptor antagonists are the treatment of choice in bilateral cases of PA (drug dosing and monitoring parameters can be found in Tables 59-9 and 59-10, respectively). Spironolactone, a nonselective aldosterone receptor antagonist, competes with aldosterone for binding at the aldosterone receptor, thus preventing the negative downstream effects of aldosterone receptor activation. Additionally, spironolactone is capable of inhibiting aldosterone synthesis within the adrenal gland; however, the magnitude of this inhibition is relatively small and the effect only occurs at doses above those recommended in the clinical setting.52Spironolactone is available in oral form, with most patients responding to doses between 25 and 400 mg/day. The clinician should wait 4 to 8 weeks before reassessing the patient for urinary electrolytes and blood pressure control. Adverse effects of spironolactone are dose-dependent and include GI discomfort, impotence, gynecomastia, menstrual irregularities, and hyperkalemia. Gynecomastia and menstrual irregularities observed with spironolactone therapy arise from activity at androgen and progesterone receptors and inhibition of testosterone biosynthesis. Additionally, because salicylates increase the renal secretion of canrenone, the active metabolite, patients should be advised to avoid concomitant therapy with salicylates. In patients intolerant of spironolactone, alternative options include eplerenone and amiloride.43,53–55
TABLE 59-9 Drug Dosing in the Treatment of Hyperaldosteronism
TABLE 59-10 Drug Monitoring in the Treatment of Hyperaldosteronism
Eplerenone is a selective aldosterone receptor antagonist with high affinity for the aldosterone receptor and low affinity for androgen and progesterone receptors. Consequently, eplerenone elicits fewer sex steroid–dependent effects while ostensibly maintaining similar efficacy to spironolactone; however, no significant comparative data exist between these two agents in this setting. Dosing starts at 50 mg daily, with titration to 50 mg twice a day.53Titration should occur at 4- to 8-week intervals. In addition, eplerenone is a substrate of CYP3A4 and should not be taken with potent CYP3A4 inhibitors. Eplerenone has been proven effective in primary essential hypertension; however, its role in the management of hyperaldosteronism has not been established.56
Amiloride, a potassium-sparing diuretic, is dosed at 5 mg twice a day up to 30 mg/day if necessary. It is less effective than spironolactone and often requires additional therapy to adequately control blood pressure. Additional second-line options include the calcium channel blockers, ACE inhibitors, and diuretics such as chlorthalidone, although all lack outcome data evaluation in PA.51,54 However, some agents (e.g., diuretics, calcium channel blockers) can promote a reactive rise in PRA, ultimately leading to increased aldosterone levels and potentially worsening PA. A prudent strategy would be to use these agents only in combination with RAAS inhibitors to mitigate the downstream aldosterone effects of any increase in PRA.
Aldosterone synthase inhibitors, currently under development, may offer additional therapeutic options in the future.
APA-Dependent Aldosteronism The treatment of choice for APA-dependent aldosteronism remains laparoscopic resection of the adenoma.57 Nearly 100% of patients show blood pressure improvement while 30% to 72% are permanently cured.55,58 Because APAs are small and often occur in multiples, resection should target the entire adrenal gland. In successful cases, blood pressure control is achieved in 1 to 3 months. Medical management can be efficacious in this population if surgery is contraindicated. However, medical management may be significantly more expensive than unilateral resection.
Glucocorticoid-Remediable Aldosteronism Glucocorticoids are very effective in treating GRA.42 Low doses are used (0.125 to 0.5 mg/day of dexamethasone or 2.5 to 5 mg/day of prednisone) because complete suppression of ACTH-stimulated aldosterone release is unnecessary. Spironolactone, eplerenone, and amiloride are alternative treatment options.43
Summary The diagnosis of PA is made through proper screening of suspected patients followed by confirmatory testing. Subsequent differentiation between the various etiologies ensures appropriate treatment (Fig. 59-5). Patients with APA can be distinguished from patients with BAH by CT scan, but AVS provides increased sensitivity and specificity. Treatment depends on the etiology with surgical resection in adenomas, and spironolactone, eplerenone, or amiloride plus second-line agents in patients with bilateral hyperplasia.
FIGURE 59-5 Algorithm for the diagnosis of primary aldosteronism. (ARR, aldosterone-to-renin ratio; APA, aldosterone-producing adenoma; AVS, adrenal venous sampling; BAH, bilateral adrenal hyperplasia; FH-1, familial hyperaldosteronism type 1; FST, fludrocortisone suppression test; PAC, plasma aldosterone concentration.)
Secondary Aldosteronism
Secondary aldosteronism results from an appropriate response to excessive stimulation of the zona glomerulosa by an extraadrenal factor, usually the renin–angiotensin system. Excessive potassium intake can promote aldosterone secretion, as can oral contraceptive use, pregnancy (aldosterone secretion 10 times normal by the third trimester), and menses. Congestive heart failure, cirrhosis, renal artery stenosis, and Bartter’s syndrome also can lead to elevated aldosterone concentrations.
Treatment of secondary aldosteronism is dictated by etiology. Control or correction of the extraadrenal stimulation of aldosterone secretion should resolve the disorder. Medical therapy with spironolactone is the mainstay of treatment until an exact etiology can be located.
HYPOFUNCTION OF THE ADRENAL GLAND
Hypofunction of the adrenal gland can affect any or all adrenal hormones, depending on the etiology of the disorder. However, hypofunction does not always lead to insufficient production of adrenal hormones as might be expected. As described below, some types of adrenal hypofunction can lead to excess production of certain hormones.
Addison’s Disease
Primary adrenal insufficiency, or Addison’s disease, most often involves the destruction of all regions of the adrenal cortex. Deficiencies arise in cortisol, aldosterone, and the various androgens and levels of CRH and ACTH increase in a compensatory manner. In developed countries, autoimmune dysfunction is responsible for most cases (80% to 90%), whereas tuberculosis predominates as the cause in developing countries. Approximately 50% of patients with autoimmune etiologies present with one or more concomitant autoimmune disorders, usually involving other endocrine organs. Autoimmune thyroid disorders (e.g., Hashimoto’s thyroiditis or Graves’ disease) are the most common, but the ovaries, pancreas, parathyroid gland, and organs of the GI system can also be affected. This polyglandular failure syndrome, termed autoimmune polyendocrine syndrome (APS), is associated with the idiopathic etiology only and has not been seen with adrenal insufficiency associated with tuberculosis or other invasive diseases. Medications that inhibit cortisol synthesis (ketoconazole) or accelerate cortisol metabolism (phenytoin, rifampin, phenobarbital) can also cause primary adrenal insufficiency.59
Secondary insufficiency is characterized by reduced glucocorticoid production secondary to decreased ACTH levels. Low levels of ACTH most commonly result from exogenous steroid use, leading to suppression of the HPA axis and decreased release of ACTH, resulting in impaired androgen and cortisol production. These effects occur with oral, inhaled, intranasal, and topical glucocorticoid administration.60–62 Moreover, mirtazapine and progestins, such as medroxyprogesterone acetate and megestrol acetate, have been reported to induce secondary adrenal insufficiency.63,64 Chronic suppression also can result in atrophy of the anterior pituitary and hypothalamus, impairing recovery of function if the exogenous steroid is reduced. Endogenous secondary insufficiency can occur with tumor development in the hypothalamic–pituitary region. Secondary disease classically presents with normal concentrations of mineralocorticoids since the zona glomerulosa is controlled by the renin–angiotensin system rather than ACTH levels.
Approximately 90% of the adrenal cortex must be destroyed before adrenal insufficiency symptoms will occur.65 Specific etiologies for both primary and secondary insufficiency are listed in Table 59-11. Adrenal hemorrhage can result from multiple etiologies including traumatic shock, coagulopathies, ischemic disorders, and other situations of severe stress, but septicemia is the most common. Symptoms include truncal pain, fever, shaking, chills, hypotension preceding shock, anorexia, headache, vertigo, vomiting, rash, psychiatric symptoms, abdominal rigidity or rebound, and death in 6 to 48 hours if not treated. The most common organisms found on autopsy are Neisseria meningitidis, Pseudomonas aeruginosa, Streptococcus pneumoniae, Group A Streptococcus, and Haemophilus influenzae.65,66
TABLE 59-11 Etiologies of Primary and Secondary Adrenal Insufficiency
Diagnosis
Distinguishing Addison’s disease from secondary insufficiency is difficult; however, the following guidelines may be helpful:
1. Hyperpigmentation, commonly found in areas of skin exposed to increased friction, is seen only in Addison’s disease because of excess secretion of ACTH and other proopiomelanocortin (POMC) peptides that induce melanocyte-stimulating hormone production. Secondary adrenal insufficiency is fundamentally characterized by deficient ACTH and POMC peptide secretion and a corresponding low level of melanocyte-stimulating hormone production. In fact, some patients with secondary insufficiency may exhibit pale-colored skin secondary to hypopigmentation.
2. Aldosterone secretion usually is preserved in secondary insufficiency.
3. Weight loss, dehydration, hyponatremia, hyperkalemia, and elevated blood urea nitrogen are common in Addison’s disease.
4. Addison’s disease will have an abnormal response to the short corticotropin stimulation test. Plasma ACTH levels are usually 400 to 2,000 pg/mL in primary insufficiency, versus low to normal (5 to 50 pg/mL; see Table 59-3) in secondary insufficiency. A normal corticotropin stimulation test does not rule out secondary adrenal insufficiency, particularly in mild cases.
The short corticotropin stimulation test, also known as the cosyntropin stimulation test, can be used to assess patients suspected of hypocortisolism. Patients are given 250 mcg of synthetic ACTH IV or intramuscularly, with serum cortisol levels drawn at baseline and 30 to 60 minutes after the injection. A resulting cortisol level ≥18 mcg/dL (500 nmol/L) rules out adrenal insufficiency.67 Because 250 mcg represents a massive supraphysiologic dose, this test can elicit normal, elevated cortisol responses in some cases of mild secondary insufficiency. Thus, some suggest that higher cutoff values (≥22 mcg/dL [≥600 nmol/L]) should be used to prevent false-negative test results.68Alternatively, a low-dose corticotropin stimulation test, using 1 mcg of synthetic ACTH, can achieve equivalent results to the standard test and is more sensitive in establishing the diagnosis of secondary insufficiency.69 Other tests include the insulin hypoglycemia test, the metyrapone test, and the CRH stimulation test.59,67,70
The standard cutoffs described above are of limited use in acutely ill patients.71 Severe infection, trauma, burns, illnesses, or surgery can increase cortisol production by as much as a factor of 6, making the recognition of adrenal insufficiency in this population extremely difficult. In the critically ill, a random cortisol level below 15 mcg/dL (415 nmol/L) is suggestive of adrenal insufficiency, whereas a level greater than 34 mcg/dL (940 nmol/L) suggests that adrenal insufficiency is unlikely.71 For patients who fall between these two values, a poor response to corticotropin (less than 9 mcg/dL [250 nmol/L] increase in plasma cortisol from baseline at 30 or 60 minutes) indicates the possibility of adrenal insufficiency and a need for corticosteroid supplementation.71 A severe hypoproteinemic patient (albumin <2.5 g/L) will have markedly lower CBG, which can falsely underestimate the free fraction of cortisol. These patients can benefit from retesting as an outpatient to prevent indefinite glucocorticoid therapy.59
Treatment of Addison’s disease must include adequate patient education, so that the patient is aware of treatment complications, expected outcome, consequences of missed doses, and drug side effects. The agents of choice are hydrocortisone, cortisone, and prednisone, administered twice daily with the treatment objective being the establishment of the lowest effective dose while mimicking the normal diurnal adrenal rhythm.59 Usually a twice-daily dosing schedule is adequate with the dose depending on the agent used.
Endogenous cortisol production varies between 5 and 10 mg/m2/day.72 Hence, the classic 12 to 15 mg/m2/day rule for cortisol supplementation can be excessive in most patients. Recommended starting doses to properly mimic endogenous cortisol production are 15 to 25 mg of hydrocortisone daily, which is roughly equal to 25 to 37.5 mg of cortisone acetate or 2.5 mg of prednisone.59,70,72 The majority of the dose (67%) is given in the morning, whereas the remainder (33%) is given 6 to 8 hours later to duplicate the normal circadian rhythm of cortisol production. Since no laboratory test adequately determines the appropriateness of dosing, the patient’s symptoms should be monitored every 6 to 8 weeks to assess proper glucocorticoid replacement.
In primary insufficiency, fludrocortisone acetate can be used to supplement mineralocorticoid loss. A dose of 0.05 to 0.2 mg by mouth once a day is adequate. If parenteral therapy is needed, 2 to 5 mg of deoxycorticosterone trimethylacetate in oil intramuscularly every 3 to 4 weeks can be substituted. Mineralocorticoid replacement attenuates the development of hyperkalemia, but may be unnecessary in all primary cases since glucocorticoids also contribute to mineralocorticoid binding. Adverse effects must be monitored closely. Symptoms include gastric upset, edema, hypertension, hypokalemia, insomnia, excitability, and diabetes mellitus. In addition, patient weight, blood pressure, and electrocardiogram should be monitored regularly.70
In women, the primary source of dehydroepiandrosterone (DHEA) and androgens is the adrenal cortex, specifically the zona reticularis. DHEA is converted to more potent androgens and estrogens in the periphery. Consequently, women with adrenal insufficiency can have decreased libido. DHEA, available as a dietary supplement, has been advocated as an option for female patients with adrenal insufficiency complaining of decreased libido and low energy.73 However, clinical trial data for DHEA are conflicting, and a recent meta-analysis suggests no benefit for sexual well-being.74 Given this limited efficacy and a lack of any standardization among the various commercial products, DHEA should not be used routinely in female patients to improve libido. DHEA may improve mood and well-being in select male and female patients who are already receiving optimal glucocorticoid and mineralocorticoid replacement.
Most adrenal crises occur secondary to glucocorticoid dose reduction or lack of stress-related dose adjustments. Patients receiving corticosteroid replacement therapy should receive an additional 5 to 10 mg of hydrocortisone shortly before strenuous activities such as exercise.70 Likewise, during times of severe physical stress such as febrile illnesses or injury, patients should be instructed to double their daily dose until recovery.75,76 For major trauma, surgery, or in critically ill patients, larger doses are required. Parenteral therapy should be used for patients experiencing diarrhea or vomiting. In patients with concomitant, newly diagnosed, or uncontrolled hypothyroidism, thyroid replacement should take place only after adequate glucocorticoid replacement as euthyroidism can trigger an adrenal crisis by accelerating cortisol metabolism.59
The end point of therapy is difficult to assess in most patients, but a reduction in excess pigmentation is a good clinical marker. The development of features of Cushing’s syndrome indicates excessive replacement. Treatment of secondary adrenal insufficiency is identical to primary disease treatment, except that mineralocorticoid replacement usually is unnecessary. Patient education is paramount with emphasis placed on the medication regimen and adrenal crisis prevention.
Acute Adrenal Insufficiency
Adrenal crisis, or Addisonian crisis, is characterized by an acute adrenocortical insufficiency. It represents a true endocrine emergency. Anything that increases adrenal requirements dramatically can precipitate an adrenal crisis. Stressful situations, surgery, infection, and trauma all are potential triggering events, especially in the patient with some underlying adrenal or pituitary insufficiency. The most common cause of adrenal crisis is HPA-axis suppression brought on by chronic use of exogenous glucocorticoids and abrupt withdrawal.
Treatment of adrenal crisis involves the administration of parenteral glucocorticoids. Hydrocortisone is the agent of choice owing to its combined glucocorticoid and mineralocorticoid activity. Hydrocortisone is initially administered at a dose of 100 mg IV through rapid infusion, followed by a continuous infusion (usually 10 mg/h) or intermittent bolus of 100 to 200 mg every 24 hours.77 IV administration is continued for 24 to 48 hours, at which time if the patient is stable, oral hydrocortisone can be administered at a dose of 50 mg every 6 to 8 hours, followed by tapering to the individual’s chronic replacement needs. Fluid replacement often is required and can be accomplished with dextrose 5% in normal saline solution (D5NS) at a rate to support blood pressure. During initial treatment for adrenal crisis, mineralocorticoid replacement generally is unnecessary because of hydrocortisone’s mineralocorticoid activity (hydrocortisone 50 mg ≈ fludrocortisone 0.1 mg). If hyperkalemia is present after the hydrocortisone maintenance phase, additional mineralocorticoid supplementation can be achieved with 0.1 mg of fludrocortisone acetate daily.
Patients with adrenal insufficiency should be instructed to carry a card or wear a bracelet or necklace, such as MedicAlert, that contains information about their condition. Additionally, patients should have easy access to injectable hydrocortisone or glucocorticoid suppositories in case of an emergency or during times of physical stress, such as febrile illness or injury.70
Hypoaldosteronism
Hypoaldosteronism is rare and usually associated with low-renin status (hyporeninemic hypoaldosteronism), diabetes, complete heart block, or severe postural hypotension, or it can occur postoperatively following tumor removal. Hypoaldosteronism can be part of a larger adrenal insufficiency or a stand-alone defect. In nonselective hypoaldosteronism, generalized adrenocortical insufficiency is the most likely etiology (see Addison’s Disease above). In selective hypoaldosteronism, insufficient aldosterone levels are precipitated by a specific defect in the stimulation of adrenal aldosterone secretion, with 21-hydroxylase deficiency being most common. Pseudohypoaldosteronism results from a defect in peripheral aldosterone action, whether from increased peripheral resistance or a reduced number of functional aldosterone receptors.
CLINICAL PRESENTATION Adrenal Insufficiency
Symptoms
• Patients commonly complain of weakness, weight loss, GI symptoms, craving for salt, headaches, memory impairment, depression, and postural dizziness.
• Early symptoms of acute adrenal insufficiency also include myalgias, malaise, and anorexia. As the situation progresses, vomiting, fever, hypotension, and shock will develop.
Signs
• Increased pigmentation
• Hypotension (postural)
• Fever
• Decreased body hair
• Vitiligo
• Features of hypopituitarism (amenorrhea and cold intolerance)
Laboratory Tests
• The short cosyntropin stimulation test can be used to assess patients suspected of hypercortisolism.
Other Diagnostic Tests
• Other tests include the insulin hypoglycemia test, the metyrapone test, and the CRH stimulation test.
Laboratory analysis reveals hyponatremia, hyperkalemia, or both. Patients often will present with hyperchloremic metabolic acidosis. In most cases, the deficiency is in mineralocorticoid production and replacement with fludrocortisone in a dose of 0.1 to 0.3 mg is usually effective. Patients should be followed for blood pressure response as well as electrolyte status.
Congenital Adrenal Hyperplasia
Because many enzyme systems are needed to complete the complex cholesterol-to-cortisol pathway, enzyme deficiencies can lead to disruptions of the normal cascade of events (see Fig. 59-2). This group of enzyme disorders is collectively referred to as congenital adrenal hyperplasia because of the resultant chronic adrenal gland stimulation that occurs following enzyme deficiency.78,79 The most frequent cause of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases. Any enzyme deficiency is capable of affecting any one or all three of the steroid pathways. Therefore, treatment focuses on replacement of the deficient hormone, psychological support, and surgical repair of the external genitalia in most female patients.80 Six of the most common enzyme deficiencies are outlined briefly in Table 59-12.
TABLE 59-12 Congenital Adrenal Hyperplasia (CAH)
Adrenal Virilism
Virilism, excessive secretion of androgens from the adrenal gland, commonly occurs as a result of congenital enzyme defects. Depending on the enzyme deficiency, patients accumulate excess levels of a variety of androgens, most notably testosterone. The condition affects females more often than males, with hirsutism being the dominant feature. Additional coexisting features can include voice deepening, acne, increased muscle mass, menstrual abnormalities, clitoral enlargement, redistribution of body fat and loss of female body contour, breast atrophy, and hair recession and crown balding.81
Treatment of virilism centers around suppression of the pituitary–adrenal axis with exogenous glucocorticoids. In adults, the usual steroids used are dexamethasone (0.25 to 0.5 mg), prednisone (2.5 to 5 mg), or hydrocortisone (10 to 20 mg).82
Hirsutism
Women presenting with hirsutism exhibit excess terminal hair growth in an androgen-dependent distribution. Such growth has obvious cosmetic consequences, but also can adversely affect quality of life and psychological well-being.83 Most cases of hirsutism occur in women with some degree of excess androgen production. Androgen excess can be derived from either the ovaries or the adrenal glands, or rarely from pituitary disorders. Polycystic ovarian syndrome (PCOS) is responsible for most cases of ovarian excess and is the most common cause of hirsutism overall.84 Congenital adrenal hyperplasia accounts for 5% of cases while adrenal and ovarian tumors cause hyperandrogenemia in 0.2% of women.
Cosmetic approaches generally are tried first, with repeated photoepilation offering the greatest long-term success.84 If these approaches are unsuccessful, subsequent treatment should include pharmacologic intervention. Oral contraceptives are the treatment of choice in most hirsute women, particularly in those requiring concurrent contraception. If oral contraceptives are used, a progestin with low androgen activity (norethindrone, ethynodiol diacetate) or antiandrogenic activity (drospirenone) should be chosen. Other antiandrogens, including spironolactone and finasteride, can supplement or replace oral contraceptive therapy in women who cannot or choose not to conceive. Antiandrogens can take 6 to 12 months to alleviate hirsutism and treatment should be continued for 2 years, followed by a slow dose reduction.85 Glucocorticoids, such as dexamethasone, can be modestly effective if the androgen source is adrenal, but can induce cushingoid symptoms even in doses of 0.5 mg/day.
Gonadotropin-releasing hormone can be an effective adjunct or alternative to oral contraceptives if the source of androgen is ovarian. However, these products generally are not recommended due to excessive costs, injectable-only routes of administration, and adverse effects resulting from estrogen deficiency. Additionally, insulin sensitizers, such as metformin or thiazolidinediones, can show modest improvement in women with PCOS, but their routine use is not recommended.84
Eflornithine hydrochloride, an irreversible ornithine decarboxylase inhibitor, moderately reduces the rate of hair growth but does not remove hair already present. The drug is available as a topical cream that is applied as a thin layer to the affected area twice daily, at least 8 hours apart. Reduction in unwanted hair can be noted within 6 to 8 weeks with a maximal effect at 8 to 24 weeks; therapy must be continued indefinitely to prevent hair regrowth.82,86Skin irritation can occur that resolves on discontinuation.
PRINCIPLES OF GLUCOCORTICOID ADMINISTRATION
Originally, the term glucocorticoid was given to these agents to describe their glucose-regulating properties. However, carbohydrate metabolism is only one of the myriad effects exhibited by steroids. The activity produced by these drugs is a function of the receptor activated (glucocorticoid vs. mineralocorticoid), the location of the receptor, as well as the agent and dose prescribed.
The mechanism of action of glucocorticoids is complex and not fully known. The glucocorticoid enters the cell through passive diffusion and binds to its specific receptor. Between 5,000 and 100,000 receptors exist in each cell. Steroids exhibit various binding affinities to the vast number of receptors in almost every tissue and therefore elicit a wide variety of biologic effects.
Following receptor binding, a structural change occurs in the receptor, known as activation. After activation, the receptor–steroid complex binds to deoxyribonucleic acid sites in the cell called glucocorticoid response elements(GREs). This binding alters nearby gene expression and stimulates, or in some cases, inhibits transcription of specific mRNAs. Consequently, the resulting protein, which produces the stimulatory or inhibitory glucocorticoid action, varies according to the tissue and cell type in which the glucocorticoid receptor exists.
Pharmacokinetic properties of the glucocorticoids vary by agent and route of administration. In general, most orally administered steroids are well absorbed. Water-soluble agents are more rapidly absorbed following intramuscular injection than are lipid-soluble agents. IV administration is recommended when a quick onset of action is needed. A summary of these agents is provided in Table 59-13.
TABLE 59-13 Relative Potencies of Glucocorticoids
In addition to causing iatrogenic Cushing’s syndrome, systemic steroids can lead to increased susceptibility to infection, osteoporosis, sodium retention with resultant edema, hypokalemia, hypomagnesemia, cataracts, peptic ulcer disease, seizures, and generalized suppression of the HPA axis. Long-term complications tend to be insidious and less likely to respond to steroid withdrawal.
Suppression of the HPA axis is a major concern whenever systemic steroids are tapered or withdrawn. Single doses of glucocorticoids can prevent the axis from responding to major stressors for several hours. In general, steroid administration at a high dose for long periods of time causes suppression of the axis. However, the possibility of suppression occurs any time the patient is exposed to supraphysiologic doses of a steroid.23,87 Symptoms of steroid withdrawal resemble those seen in a patient with adrenocortical deficiency.
A variety of recommendations for steroid tapering are available.23,88–90 In general, patients who have been on long-term steroid therapy will need to be gradually withdrawn toward physiologic doses over months. On average, the normal adult produces approximately 10 to 30 mg of cortisol per day with the peak concentration occurring around 8:00 AM. As the steroid or steroid-equivalent dose approaches the 20- to 30-mg level, the taper should be slowed and the patient checked for axis function. The primary modes to test HPA integrity are the ACTH test, either high or low dose, or a morning (8:00 AM) serum cortisol. A normal morning serum cortisol (>20 mcg/dL) or a normal ACTH test indicates that daily steroid maintenance therapy may be discontinued. If morning serum cortisol is between 3 and 20 mcg/dL, the ACTH or CRH stimulation test can be useful in the assessment of pituitary–adrenal function.23 A morning cortisol less than 3 mcg/dL indicates axis suppression and the need for continued replacement therapy. Suppression can persist for up to a year in some patients. Caution should be used to prevent disease exacerbation during the steroid taper and to avoid the need for rebolusing the patient with another course of high-dose steroids.
Alternate-day therapy (ADT) regimens have been promoted by some as a means to lessen the impact of prolonged steroid administration.23,90 ADT theoretically minimizes the hypothalamic–pituitary suppression as well as some of the adverse effects seen with once-daily therapy. This hypothetical advantage may be especially pertinent in treating children and young adults, in whom growth suppression is a major concern. ADT is not recommended for initial management, but rather in the management of the stabilized patient who needs long-term therapy. The patient is exposed to “on” and “off” days, with the “on” day dose gradually increased corresponding with a dose-reduction in the “off” day dose over a period of 14 days. After 2 weeks, no medication is taken on “off” days. Not all patients will have equivalent disease control on ADT, and it should be avoided in certain indications.23,90
Clinical Controversy…
In an effort to more closely mimic endogenous cortisol secretion, some clinicians advocate thrice-daily dosing of glucocorticoids. Limited comparative data have favored thrice-daily regimens over twice-daily regimens, but serious methodologic flaws make interpretation and application of the study conclusions difficult. If a thrice-daily regimen is selected, the second dose should be administered at noon, followed by a third dose approximately 4 to 6 hours later.
EVALUATION OF THERAPEUTIC OUTCOMES
Successful glucocorticoid therapy involves counseling and monitoring the patient, as well as recognizing complications of therapy (Table 59-14). The risk-to-benefit ratio of glucocorticoid administration should always be considered, especially with concurrent disease states such as hypertension, diabetes mellitus, peptic ulcer disease, and uncontrolled systemic infections.
TABLE 59-14 Factors in Successful Glucocorticoid Therapy
ABBREVIATIONS
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