Devra K. Dang, Judy T. Chen, Frank Pucino Jr., and Karim Anton Calis
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the regulation and physiologic roles of hormones produced by the adrenal glands.
2. Recognize the clinical presentation of patients with adrenal insufficiency.
3. Describe the pharmacologic management of patients with acute and chronic adrenal insufficiency.
4. Recommend therapy monitoring parameters for patients with adrenal insufficiency.
5. Recognize the clinical presentation of Cushing’s syndrome and the physiologic consequences of cortisol excess.
6. Describe the pharmacologic and nonpharmacologic management of patients with Cushing’s syndrome.
7. Recommend strategies to prevent the development of Cushing’s syndrome associated with exogeneous glucocorticoid administration.
8. Recommend therapy monitoring parameters for patients with Cushing’s syndrome.
KEY CONCEPTS
Signs and symptoms of adrenal insufficiency reflect the disturbance of normal physiologic carbohydrate, fat, and protein homeostasis caused by inadequate cortisol production and inadequate cortisol action.
Lifelong glucocorticoid replacement therapy may be necessary for patients with adrenal insufficiency, and mineralocorticoid replacement therapy is usually required for those with Addison’s disease.
During an acute adrenal crisis, the immediate treatment goals are to correct volume depletion, manage hypoglycemia, and provide glucocorticoid replacement.
Patients with known adrenal insufficiency should be educated regarding the need for additional glucocorticoid replacement and prompt medical attention during periods of excessive physiologic stress.
Patients with Cushing’s syndrome due to endogenous or exogenous glucocorticoid excess typically present with similar clinical manifestations.
Surgical resection is considered the treatment of choice for Cushing’s syndrome from endogenous causes if the tumor can be localized and if there are no contraindications.
Pharmacotherapy is generally reserved for patients: (a) in whom the ectopic adrenocorticotropic hormone (ACTH)-secreting tumor cannot be localized, (b) who are not surgical candidates, (c) who have failed surgery, (d) who have had a relapse after surgery, or (e) in whom adjunctive therapy is required to achieve complete remission.
In drug-induced Cushing’s syndrome, discontinuation of the offending agent is the best management option. However, abrupt withdrawal of the glucocorticoid can result in adrenal insufficiency or exacerbation of the underlying disease.
Glucocorticoid doses less than 7.5 mg/day of prednisone or its equivalent for less than 3 weeks generally would not be expected to lead to suppression of the hypothalamic–pituitary–adrenal (HPA) axis.
INTRODUCTION
The adrenal glands are important in the synthesis and regulation of key human hormones. They play a crucial role in water and electrolyte homeostasis, as well as regulation of blood pressure, carbohydrate and fat metabolism, physiologic response to stress, and sexual development and differentiation. This chapter focuses on pharmacologic and nonpharmacologic management of the two most common conditions associated with adrenal gland dysfunction: glucocorticoid insufficiency (e.g., Addison’s disease) and glucocorticoid excess (Cushing’s syndrome). Other adrenal disorders such as congenital adrenal hyperplasia, pheochromocytoma, hypoaldosteronism, and hyperaldosteronism are beyond the scope of this chapter.
PHYSIOLOGY, ANATOMY, AND BIOCHEMISTRY OF THE ADRENAL GLAND
The adrenal gland is located on the upper segment of the kidney (Fig. 45–1).1 It consists of an outer cortex and an inner medulla. The adrenal medulla secretes the catecholamines epinephrine (also called adrenaline) and norepinephrine (also called noradrenaline), which are involved in the regulation of the sympathetic nervous system. The adrenal cortex consists of three histologically distinct zones: the zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones (Fig. 45–2).
The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and potassium excretion. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system.
The zona fasciculata produces the glucocorticoid hormone cortisol. Cortisol is responsible for maintaining homeostasis of carbohydrate, protein, and fat metabolism. Its secretion follows a circadian rhythm, generally beginning to rise at approximately 4 am and peaking around 6 to 8 am. Thereafter, cortisol levels decrease throughout the day, approach 50% of the peak value by 4 pm, and reach their nadir around midnight.2 The normal rate of cortisol production is approximately 8 to 15 mg/day.3 Cortisol plays a key role in the body’s response to stress. Its production increases markedly during physiologic stress such as during acute illness, surgery, or trauma. In addition, certain conditions such as alcoholism, depression, anxiety disorder, obsessive-compulsive disorder, poorly controlled diabetes, morbid obesity, starvation, anorexia nervosa, and chronic renal failure are associated with increased cortisol levels. High total cortisol levels are also observed in the presence of increased cortisol binding globulin (the carrier protein for 80% of circulating cortisol molecules), which is seen in pregnancy or other high-estrogen states (e.g., exogenous estrogen administration).2 Cortisol is converted in the liver to an inactive metabolite known as cortisone.
FIGURE 45–1. Anatomy of the adrenal gland. (From Ref. 23.)
The zona reticularis produces the androgens andro-stenedione, dehydroepiandrosterone (DHEA), and the sulfated form of dehydroepiandrosterone (DHEA-S). Only a small amount of testosterone and estrogen are produced in the adrenal glands. Androstenedione and DHEA are converted in the periphery, largely to testosterone and estrogen.
Adrenal hormone production is controlled by the hypothalamus and pituitary. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus and stimulates secretion of adrenocorticotropic hormone(ACTH; also known as corticotropin) from the anterior pituitary. ACTH in turn stimulates the adrenal cortex to produce cortisol. When sufficient or excessive cortisol levels are reached, a negative feedback is exerted on the secretion of CRH and ACTH, thereby decreasing overall cortisol production. The control of adrenal androgen synthesis also follows a similar negative feedback mechanism. Figure 46–1 in the Pituitary Gland Disorders chapter depicts the hormonal regulation with the hypothalamic–pituitary–adrenal axis.
ADRENAL INSUFFICIENCY
EPIDEMIOLOGY AND ETIOLOGY
Adrenal insufficiency generally refers to the inability of the adrenal glands to produce adequate amounts of cortisol for normal physiologic functioning or in times of stress. The condition is usually classified as primary, secondary, or tertiary, depending on the etiology (Table 45–1).2,4–8 The estimated prevalences of primary adrenal insufficiency and secondary adrenal insufficiency are approximately 60 to 143 and 150 to 280 cases per one million persons, respectively. Primary adrenal insufficiency is usually diagnosed in the third to fifth decade of life, whereas secondary adrenal insufficiency is commonly detected during the sixth decade.2,9 Adrenal insufficiency is more prevalent in women than in men, with a ratio of 2.6:1.2 Chronic adrenal insufficiency is rare.
PATHOPHYSIOLOGY
Primary adrenal insufficiency, also known as Addison’s disease, occurs when the adrenal glands are unable to produce cortisol. It occurs from destruction of the adrenal cortex, usually from an autoimmune process. In general, the clinical manifestations are observed when destruction of the cortex exceeds 90%.4 Signs and symptoms of adrenal insufficiency reflect the disturbance of normal physiologic carbohydrate, fat, and protein homeostasis caused by inadequate cortisol production and inadequate cortisol action. Primary adrenal insufficiency usually develops gradually. Patients may remain asymptomatic in the early stages, with signs and symptoms present only during times of physiologic stress. Persistent signs and symptoms of hypocortisolism typically occur with disease progression. Additionally, primary adrenal insufficiency may be accompanied by a reduction in aldosterone and androgen production. See Clinical Presentation and Diagnosis of Chronic Adrenal Insufficiency and Clinical Presentation and Diagnosis of Acute Adrenal Insufficiency (Adrenal Crisis) textboxes.
FIGURE 45–2. Adrenal steroid synthesis. The adrenal cortex consists of three histologically distinct zones: The zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones. (17, 17-hydroxylase; 3B-HSD, 3β-hydroxysteroid dehydrogenase; 21, 21α-hydroxylase; 17, 20, 17, 20-lyase; 11B, 11β-hydroxylase; AS, aldosterone synthase; DHEA, dehydroepiandrosterone; DHEA-S, sulfated form of dehydroepiandrosterone.)
Secondary adrenal insufficiency occurs as a result of a pituitary gland dysfunction, whereby decreased production and secretion of ACTH leads to a decrease in cortisol synthesis. Tertiary adrenal insufficiency is a disorder of the hypothalamus that results in decreased production and release of CRH, which in turn decreases pituitary ACTH production and release. In contrast to Addison’s disease (i.e., primary adrenal insufficiency), aldosterone production is unaffected in the secondary and tertiary forms of the disease. Chronic adrenal insufficiency often has a good prognosis if diagnosed early and treated appropriately.
Acute adrenal insufficiency (i.e., adrenal crisis) results from the body’s inability to sufficiently increase endogenous cortisol during periods of excessive physiologic stress. Adrenal crisis can occur when patients with chronic adrenal insufficiency do not receive adequate glucocorticoid replacement during stressful conditions such as those experienced during surgery, infection, acute illness, invasive medical procedures, or trauma. Acute adrenal insufficiency can also result from bilateral adrenal infarction due to hemorrhage, embolus, sepsis, or adrenal vein thrombosis. Additionally, abrupt discontinuation or rapid tapering of glucocorticoids, given chronically in supraphysiologic doses, may lead to adrenal crisis. This condition results from prolonged suppression of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent adrenal gland atrophy and hypocortisolemia. Other drugs associated with adrenal insufficiency include those that inhibit production (e.g., ketoconazole) or increase metabolism (e.g., the cytochrome P-450 subfamily IIIA polypeptide 4 [CYP450 3A4] inducer rifampin) of cortisol.4Regardless of etiology, patients experiencing an adrenal crisis require immediate glucocorticoid treatment because manifestations such as circulatory collapse can lead to life-threatening sequelae.
TREATMENT AND OUTCOME EVALUATION
Chronic Adrenal Insufficiency
The general goals of treatment are to manage symptoms and prevent development of adrenal crisis. Lifelong glucocorticoid replacement therapy may be necessary for patients with adrenal insufficiency, and mineralocorticoid replacement therapy is usually required for those with Addison’s disease. Glucocorticoids with sufficient mineralocorticoid activity are generally required. However, the addition of a potent mineralocorticoid such as fludrocortisone, along with adequate salt intake, is sometimes needed to prevent sodium loss, hyperkalemia, and intravascular volume depletion. Mineralocorticoid supplementation typically is not indicated for the treatment of secondary or tertiary adrenal insufficiency because aldosterone production is often unaffected. Moreover, patients with secondary or tertiary adrenal insufficiency may only require replacement therapy until the HPA axis recovers. Hydrocortisone is often prescribed because it most closely resembles endogenous cortisol with its relatively high mineralocorticoid activity and short half-life, and allows the design of regimens that simulate the normal circadian cycle.5 Other glucocorticoids, however, can be used. The pharmacologic characteristics of commonly used glucocorticoids are presented in Table 45–3.4 Since patients with primary adrenal insufficiency can experience DHEA deficiency, DHEA replacement also has been tried. Several small clinical studies, consisting mostly of women, suggest that treatment with DHEA can improve mood and fatigue and provide a general sense of well-being.10–13 Nonetheless, use of DHEA remains controversial and requires further study. The specific management strategies for chronic adrenal insufficiency are as follows2,5,9:
• For the treatment of primary adrenal insufficiency (Addison’s disease), oral hydrocortisone 12 to 15 mg/m2 is typically administered in two divided doses, with two-thirds of the dose given in the morning upon awakening to mimic the early morning rise in endogenous cortisol, and the remaining one-third of the dose given in the late afternoon to avoid insomnia and allow for the lowest concentration in the blood at around midnight. Hydrocortisone may also be given in three doses but this may decrease adherence. The longer-acting glucocorticoids (e.g., prednisone, dexamethasone) may provide a more prolonged clinical response thereby avoiding symptom recurrence that can occur at the end of the dosing interval with short-acting agents such as hydrocortisone. Longer-acting agents also may improve adherence in some patients. Patients should be monitored for weight, blood pressure, serum electrolytes, and symptom resolution and feeling of general well-being, and dosages should be adjusted accordingly. Doses of hydrocortisone, dexamethasone, prednisone, and other glucocorticoids may need to be increased or decreased in patients taking CYP450 3A4 inducers (e.g., phenytoin, rifampin, barbiturates) or inhibitors (e.g., protease inhibitors), respectively. Adverse drug reactions from glucocorticoid administration should be monitored. Glucocorticoid therapy at physiologic replacement doses should not lead to the development of Cushing’s syndrome; however, careful monitoring should still be performed, and the smallest effective dose used. Patients should receive education regarding the need for increased glucocorticoid dosage during excessive physiologic stress. In addition, oral fludrocortisone at a daily dose of approximately 0.05 mg to 0.2 mg in the morning should be administered. Monitoring for resolution of hypotension, dizziness, dehydration, hyponatremia, and hyperkalemia should occur, and the dose can be increased if needed. Conversely, consider decreasing the dose if adverse reactions from mineralocorticoid administration such as hypertension, hypokalemia, fluid retention and other significant adverse events occur. In patients receiving hydrocortisone, it should be kept in mind that this drug also possesses mineralocorticoid activity. All patients with primary adrenal insufficiency should also maintain an adequate sodium intake (about 3–4 g/day). Lastly, although controversial, consider giving DHEA 50 mg/day (in the morning) to female patients who do not experience an improvement in mood and well-being even with adequate glucocorticoid and mineralocorticoid replacement. In these patients, monitor serum DHEA-S (aim for the middle range of normal levels in healthy young people) and free testosterone level.
Table 45–1 Etiologies of Adrenal Insufficiency
Primary Adrenal Insufficiency (Addison’s Disease)
• Autoimmune—accounts for 70-90% of all cases of primary adrenal insufficiency
• Infectious or granulomatous diseases
• Cytomegalovirus
• Fungal (histoplasmosis, coccidioidomycosis, cryptococcosis, Blastomyces dermatitidis infection)
• HIV, AIDS
• Mycobacterial, cytomegaloviral, Pneumocystic jiroveci, and Toxoplasma gondii infection
• Sarcoidosis
• Tuberculosis
• Medications—inhibitors of steroidogenesis (etomidate, ketoconazole, metyrapone, mitotane)
• Hemorrhagic
• Bilateral adrenal hemorrhage or infarction—usually due to anticoagulant therapy, coagulopathy, thromboembolic disease, or meningococcal infection. Causes acute adrenal insufficiency
• Adrenalectomy
• Adrenoleukodystrophy (in males)
• Adrenomyeloneuropathy
• Infiltrative disorders—amyloidosis, hemochromatosis
• Genetic causes
• Congenital adrenal hyperplasia
• Familial glucocorticoid deficiency and hypoplasia
• Metastatic malignancy
Secondary Adrenal Insufficiency
• Drug-induced (most common cause of secondary adrenal insufficiency)
• Chronic glucocorticoid administration at supraphysiologic doses
• Megestrol acetate—has glucocorticoid-like activity
• Mifepristone (RU 486)—antagonizes glucocorticoid receptors
• Cushing’s syndrome
• Panhypopituitarism
• Pituitary tumor
• Transsphenoidal pituitary microsurgery
• Pituitary irradiation
• Traumatic brain injury
Tertiary Adrenal Insufficiency
• Hypothalamic failure
• Drug-induced—chronic glucocorticoid administration at supraphysiologic doses
From Refs. 1, 4–8.
Clinical Presentation and Diagnosis of Chronic Adrenal Insufficiency
General
• The symptoms develop gradually (especially in the early stages), may be vague, and may mimic those of other medical conditions.
• The cardinal symptoms and signs are weakness and fatigue requiring rest periods, GI symptoms, weight loss, and hypotension. These symptoms are due to cortisol deficiency.
• Patients with autoimmune adrenal insufficiency may have other autoimmune disorders such as type 1 diabetes mellitus and autoimmune thyroiditis.
Symptoms (Percentage Prevalence)
• Weakness and fatigue are the most common (99%).
• Anorexia, nausea, and diarrhea (56-90%). These may range from mild to severe with vomiting and abdominal pain.
• Hypoglycemia may occur in some patients.
• Amenorrhea may occur in some women.
• Salt craving may occur in some (approximately 22%) patients with primary adrenal insufficiency due to aldosterone deficiency.
Signs
• Weight loss (97%)
• Hypotension (less than 110/70 mm Hg) and orthostasis (87%)
• Dehydration, hypovolemia, and hyperkalemia (in primary adrenal insufficiency only) due to aldosterone deficiency.
• Decreased serum sodium and chloride levels due to aldosterone deficiency. Hyponatremia can also be present in secondary adrenal insufficiency due to cortisol deficiency and increased antidiuretic hormone secretion leading to subsequent water retention.
• Increased serum blood urea nitrogen and creatinine due to dehydration.
• Hyperpigmentation of skin and mucous membranes (92%). This is usually observed around creases, pressure areas, areolas, genitalia, and new scars. Dark freckles and patches of vitiligo may be present. Hyperpigmentation, due to increased ACTH levels, occurs in most patients with primary adrenal insufficiency but does not occur in secondary or tertiary adrenal insufficiency.
• Personality changes (irritability and restlessness) due to cortisol deficiency.
• Loss of axillary and pubic hair in women due to decreased androgen production.
• Blood count abnormalities (normocytic, normochromic anemia, relative lymphocytosis, neutrophilia, eosinophilia) due to cortisol and androgen deficiency.
Laboratory Tests (Also See Table 45–2)
• Decreased basal and stress-induced cortisol levels.
• Decreased aldosterone level (in primary adrenal insufficiency only).
• Lack of increase in cortisol and aldosterone levels after ACTH stimulation.
Other Diagnostic Tests (Also See Table 45–2)
• CT or MRI of the adrenal glands, pituitary, and/or hypothalamus can aid in determining the etiology.
• The presence of antiadrenal antibodies is suggestive of an autoimmune etiology.
From Refs. 2, 4, 5, 9.
Clinical Presentation and Diagnosis of Acute Adrenal Insufficiency (Adrenal Crisis)
General
• Onset of symptoms is acute and precipitated by excessive physiologic stress.
Symptoms
• Severe weakness and fatigue
• Abdominal or flank pain
Signs
• Severe dehydration leading to hypotension and shock (circulatory collapse). Hypovolemia may not be responsive to IV hydration and may require the use of vasopressors.
• Tachycardia
• Nausea, vomiting
• Fever
• Confusion
• Hypoglycemia
• Laboratory abnormalities are similar to those observed in chronic adrenal insufficiency.
Laboratory Tests
• The unstimulated serum cortisol and rapid ACTH stimulation tests are useful in the diagnosis of adrenal crisis (Table 45–2). The insulin tolerance test is contraindicated due to pre-existing hypoglycemia. The metyrapone test is also contraindicated since metyrapone inhibits cortisol production.
Note: Due to the life-threatening nature of this condition, empiric treatment should be started before laboratory confirmation in patients who present with the clinical picture of an acute adrenal crisis.
From Refs. 2, 4, 9.
Table 45–2 Tests for Diagnosing Adrenal Insufficiency
Table 45–3 Pharmacologic Characteristics of Commonly Used Glucocorticoids
Patient Encounter 1, Part 1: Presentation and Medical History
AB is a 58-year-old female presenting to the clinic with a chief complaint of fatigue and weakness. She has noticed a gradual increase in symptoms over the past year but attributed this to “old age.” Recently, she has required more frequent rest breaks than before. Upon further questioning, she complained of intermittent nausea leading to decreased appetite and a 4.6-kg (10-lb) weight loss over the past year. She also reported darkening of a recent scar and denies recent or past use of glucocorticoids.
PMH: Type 1 diabetes mellitus since age 5, currently controlled; hypothyroidism, currently controlled; osteoarthritis (knees) for 5 years
FH: Unknown
SH: Retired secretary, denies smoking, alcohol use, or illicit drug use
Current Meds: Insulin glargine 30 units at bedtime; lispro insulin three times daily with meals—practices carbohydrate counting; levothyroxine 75 mcg once daily; acetaminophen 1,000 mg every 8 hours as needed for joint pain; capsaicin 0.075% cream three times a day for joint pain
PE:
VS: Sitting BP 108/70 mm Hg, sitting P 74 bpm, RR 14 breaths/min, standing BP 96/68, standing P 86, wt 68 kg (150 lb), ht 5’5” (165 cm)
Skin: Hyperpigmentation on creases of palms and around breast nipples, darkening of scar of left leg
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
Labs: Serum electrolytes: sodium 132 mEq/L (132 mmol/L), potassium 5.2 mEq/L (5.2 mmol/L), chloride 98 mEq/L (98 mmol/L), bicarb 30 mEq/L (30 mmol/L), blood urea nitrogen (BUN) 25 mg/dL (8.9 mmol/L), creatinine 1.2 mg/dL (106 μmol/L), glucose 120 mg/dL (6.7 mmol/L).
Which signs or symptoms of adrenal insufficiency does AB exhibit?
Does AB’s presentation offer any clues as to the etiology or classification of adrenal insufficiency?
Which tests would be most useful for determining the etiology and confirming the diagnosis of adrenal insufficiency?
• Patients with secondary and tertiary adrenal insufficiency are treated with oral hydrocortisone or a longer-acting glucocorticoid in the same manner as previously described for primary adrenal insufficiency. However, patients with secondary and tertiary adrenal insufficiency may require a lower dose. Some patients will only require glucocorticoid replacement temporarily, which can be discontinued after recovery of the HPA axis (e.g., patients with drug-induced adrenal insufficiency or adrenal insufficiency following treatment for Cushing’s syndrome). Progression of the underlying etiology for the adrenal insufficiency should be monitored. Fludrocortisone therapy is generally not needed.
Acute Adrenal Insufficiency
During an acute adrenal crisis, the immediate treatment goals are to correct volume depletion, manage hypoglycemia, and provide glucocorticoid replacement. Volume depletion and hypoglycemia can be corrected by giving large volumes (approximately 2–3 L) of IV normal saline and 5% dextrose solution.2 Glucocorticoid replacement can be accomplished by administering IV hydrocortisone, starting at a dose of 100 mg every 6 to 8 hours for 24 hours, increasing to 200 mg to 400 mg/day if complications occur, or decreasing to 50 mg every 6 to 8 hours after achieving hemodynamic stability. The hydrocortisone dose can then be tapered to a maintenance dose by the fourth or fifth day and fludrocortisone can be added if needed.2
Patients with known adrenal insufficiency should be educated regarding the need for additional glucocorticoid replacement and prompt medical attention during periods of excessive physiologic stress. Although the dosage of glucocorticoid is generally individualized, a common recommendation is to double the maintenance dose of hydrocortisone if the patient experiences fever, or undergoes invasive dental or diagnostic procedures.5 Patients who experience vomiting or diarrhea may not adequately absorb oral glucocorticoids and may benefit from parenteral therapy until symptoms resolve. Prior to major surgery, additional glucocorticoid replacement (higher dose and parenteral route) must be given to prevent adrenal crisis. A sample protocol is as follows2:
• Correct electrolytes, blood pressure, and fluid status as necessary.
• Give 100 mg of hydrocortisone sodium phosphate or hydrocortisone sodium succinate intramuscularly (also, make sure this is readily available to the operating room).
• Give 50 mg of hydrocortisone intramuscularly or IV in the recovery room and then every 6 hours for the first 24 hours.
• If the patient is hemodynamically stable, reduce dosage to 25 mg every 6 hours for 24 hours and then taper to maintenance dosage over 3 to 5 days.
• Resume previous fludrocortisone dose when the patient is taking oral medications.
• Maintain or increase hydrocortisone dosage to 200 mg to 400 mg/day if fever, hypotension, or other complications occur.
Patient Encounter 1, Part 2: Treatment
After appropriate laboratory and diagnostic tests are performed, AB is diagnosed with Addison’s disease.
How should her chronic primary adrenal insufficiency be treated?
What monitoring parameters (therapeutic and toxic) should be implemented?
HYPERCORTISOLISM (CUSHING’S SYNDROME)
EPIDEMIOLOGY AND ETIOLOGY
Cushing’s syndrome refers to the pathophysiologic changes associated with exposure to supraphysiologic cortisol concentrations (endogenous hypercortisolism) or pharmacologic doses of glucocorticoids (exogenous hypercortisolism). Cushing’s syndrome from endogenous causes is a rare condition, with an estimated incidence of two to five cases per 1 million persons per year.14 Patients receiving chronic supraphysiologic doses of glucocorticoids, such as those with rheumatologic disorders, are at high risk of developing Cushing’s syndrome.
Patient Care and Monitoring: Adrenal Insufficiency
1. Evaluate patients presenting with the typical clinical manifestations for chronic or acute adrenal insufficiency.
2. Perform initial screening tests to confirm the presence of adrenal insufficiency.
3. Once diagnosis is confirmed, perform further testing to differentiate between primary, secondary, and tertiary adrenal insufficiency.
4. In patients presenting with acute adrenal crisis who have not been previously diagnosed with adrenal insufficiency, immediate treatment with injectable hydrocortisone and IV saline and dextrose solutions should be initiated prior to confirmation of the diagnosis because of the life-threatening nature of this condition. Determine and correct the underlying cause of the acute adrenal crisis (e.g., infection).
5. Glucocorticoid replacement therapy is necessary for patients with adrenal insufficiency, and mineralocorticoid replacement therapy is required for those with Addison’s disease.
6. In patients with chronic adrenal insufficiency, when excessive physiologic stress is anticipated (e.g., pending surgery), devise a strategy to give supplemental doses of glucocorticoid during this period. Monitor the patient for signs of an acute adrenal crisis and develop a plan to treat this emergency condition.
7. Monitor the patient for adequacy of treatment as well as adverse reactions from glucocorticoid and/or mineralocorticoid therapy.
8. Determine the duration of treatment for patients with secondary and tertiary adrenal insufficiency.
9. Provide patient education regarding disease state and its treatment:
• Causes of adrenal insufficiency, including drug-induced etiologies.
• How to recognize the clinical manifestations.
• How to prevent an acute adrenal crisis (adhere to therapy and do not abruptly stop glucocorticoid treatment). There may be a need to increase the dose of glucocorticoid during excessive physiologic stress.
• Administration of parenteral glucocorticoid during an acute adrenal crisis.
• Need to notify all health care providers of condition.
• Encourage wearing or carrying a medical alert (e.g., bracelet, card).
• Counsel on dietary and pharmacologic therapy, including duration of treatment and potential adverse consequences of glucocorticoid and mineralocorticoid replacement.
PATHOPHYSIOLOGY
Cushing’s syndrome can be classified as ACTH-dependent or ACTH-independent (Table 45–4).2,15–17 ACTH-dependent Cushing’s syndrome results from ACTH-secreting (or rarely CRH-secreting) adenomas. ACTH-independent Cushing’s syndrome is due either to excessive cortisol secretion by the adrenal glands (independent of ACTH stimulation) or to exogenous glucocorticoid administration. Patients with Cushing’s syndrome due to endogenous or exogenous glucocorticoid excess typically present with similar clinical manifestations. The term Cushing’s disease refers specifically to Cushing’s syndrome from an ACTH-secreting pituitary adenoma. The plasma ACTH concentration is elevated in ACTH-dependent conditions but not in ACTH-independent causes because elevated cortisol concentrations suppress pituitary ACTH secretion via negative feedback. ACTH and cortisol concentrations are elevated episodically in ACTH-dependent disease due to random hypersecretion of ACTH.4Other major differences among the vast etiologies of Cushing’s syndrome are shown in Table 45–5.
Physiologic cortisol secretion follows a circadian pattern, with cortisol levels rising in the early morning, peaking at approximately 6 to 8 am, and then declining steadily throughout the remainder of the day until they reach a nadir at midnight. This circadian rhythm is lost in most patients with Cushing’s syndrome. As such, detection of elevated midnight cortisol concentrations can be useful in the diagnosis of Cushing’s syndrome.
Cushing’s disease and adrenal carcinomas cause adrenal androgen hypersecretion in high enough concentrations to result in signs of androgen excess such as acne, menstrual irregularities, and hirsutism, and cause virilization in women.4 Drug-induced Cushing’s syndrome from glucocorticoid administration occurs most commonly in patients receiving oral therapy, but other routes such as inhalation, dermal, nasal, and intra-articular have also been implicated.15 Nonprescription products, including dietary supplements, should also be evaluated since they may contain corticosteroids. Drug-induced Cushing’s syndrome has been reported with the use of Chinese herbal products that contain corticosteroids.19,20 The risk of glucocorticoid-induced Cushing’s syndrome appears to increase with higher doses and/or longer treatment durations.15
Left untreated, patients with Cushing’s syndrome may experience severe complications of hypercortisolism, resulting in up to a nearly fourfold increase in mortality.18 Mortality in patients with Cushing’s syndrome is mostly attributed to cardiovascular disease. Hypertension, hyperglycemia, and hyperlipidemia are common findings and can be associated with cardiac hypertrophy, atherosclerosis, and hypercoagulability. Osteopenia, osteoporosis, and increased fractures also have been reported.14 Children may experience linear growth retardation from reduced growth hormone secretion and inhibition of epiphysial cartilage development in long bones.14,18
TREATMENT
The goal of treatment in patients with Cushing’s syndrome is reversal of hypercortisolism and management of the associated comorbidities, including the potential for long-term sequelae such as cardiac hypertrophy. Surgical resection is considered the treatment of choice for Cushing’s syndrome from endogenous causes if the tumor can be localized and if there are no contraindications. The treatment of choice for Cushing’s syndrome from exogenous causes is gradual discontinuation of the offending agent.
Table 45–4 Etiologies of Cushing’s Syndrome
ACTH-Dependent
• ACTH-secreting pituitary tumor (Cushing’s disease)—70% of cases of endogenous Cushing’s syndrome
• ACTH-secreting nonpituitary tumors (ectopic ACTH syndrome)—15% of cases of endogenous Cushing’s syndrome; usually from small cell lung carcinoma, bronchial carcinoids, pheochromocytoma, or from thymus, pancreatic, ovarian, or thyroid tumor. The tumor is usually disseminated (difficult to localize)
• CRH-secreting nonpituitary tumors (ectopic CRH syndrome)—rare
ACTH-Independent—15% of cases of endogenous Cushing’s syndrome
• Unilateral adrenal adenoma
• Adrenal carcinoma
• Bilateral nodular adrenal hyperplasia—rare (less than 1%)
Drug-Induced Cushing’s Syndrome (ACTH-independent)—most common cause of Cushing’s syndrome
• Prescription glucocorticoid preparations (most routes of administration)
• Nonprescription and natural health products with glucocorticoid activity (e.g., nonprescription anti-itch products with hydrocortisone, natural health products with magnolia bark or those claiming to contain adrenal cortex extracts or other by-products)
• Other drugs with glucocorticoid activity (e.g., megestrol acetate, medroxyprogesterone)
ACTH, adrenocorticotropic hormone or corticotropin; CRH, corticotropin-releasing hormone.
From Refs. 2, 15–17.
Table 45–5 Differences Among the Major Etiologies of Cushing’s Syndrome
Nonpharmacologic Therapy
Transsphenoidal pituitary microsurgery is the treatment of choice for Cushing’s disease. Removal of the pituitary tumor can bring about complete remission or cure in 78% to 97% of cases. HPA axis suppression associated with chronic hypercortisolism can result in prolonged adrenal insufficiency lasting for months after surgery and requiring exogenous glucocorticoid administration. Pituitary irradiation or bilateral adrenalectomy is usually reserved for patients who are not surgical candidates or for those who relapse or do not achieve complete remission following pituitary surgery. Because the response to pituitary irradiation can be delayed (several months to years), concomitant treatment with cortisol-lowering medication may be necessary. Bilateral adrenalectomy is also used for the management of adrenal carcinoma and in patients with poorly controlled ectopic Cushing’s disease in whom the ACTH-producing lesion cannot be localized. Bilateral laparoscopic adrenalectomy achieves an immediate and total remission (nearly 100% cure rate), but these patients will require lifelong glucocorticoid and mineralocorticoid supplementation.21,22 Nelson’s syndrome may develop in nearly 20% to 50% of patients who undergo bilateral adrenalectomy without pituitary irradiation. This condition presumably results from persistent hypersecretion of ACTH by the intact pituitary adenoma, which continues to grow because of the loss of feedback inhibition by cortisol. Treatment of Nelson’s syndrome may involve pituitary irradiation or surgery.4
The treatment of choice in patients with adrenal adenomas is unilateral laparoscopic adrenalectomy. These patients require glucocorticoid supplementation during and after surgery due to atrophy of the contralateral adrenal gland and suppression of the HPA axis. Glucocorticoid therapy is continued until recovery of the remaining adrenal gland is achieved. Patients with adrenal carcinomas have a poor prognosis, with a 5-year survival of 20% to 58%, due to the advanced nature of the condition (metastatic disease). Surgical resection to reduce tumor burden and size, pharmacologic therapy, or bilateral laparoscopic adrenalectomy are the treatment options commonly utilized to manage this condition.1,22
Pharmacologic Therapy
Pharmacotherapy is generally reserved for patients: (a) in whom the ectopic ACTH-secreting tumor cannot be localized, (b) who are not surgical candidates, (c) have failed surgery, (d) who have had a relapse after surgery, or (e) in whom adjunctive therapy is required to achieve complete remission.23 The drugs used are classified according to their mechanism and site of action (Table 45–7).21,24–26 The most widely used therapeutic class is the adrenal steroidogenesis inhibitors.17 Agents in this class include ketoconazole, etomidate, and metyrapone. Steroidogenesis inhibitors can treat hypercortisolism by inhibiting enzymes involved in the biosynthesis of cortisol. Because of their potential to cause adrenal suppression, temporary glucocorticoid replacement, and in some cases mineralocorticoid supplementation, may be needed during and after treatment. Centrally-acting neuromodulators of ACTH release such as bromocriptine, cyproheptadine, octreotide, ritanserin, and valproic acid are generally ineffective.
Clinical Presentation and Diagnosis of Cushing’s Syndrome
General
• Patients with Cushing’s syndrome due either to endogenous or exogenous glucocorticoid excess typically present with similar clinical manifestations.
• Differential diagnoses include diabetes mellitus and the metabolic syndrome, as patients with these conditions share several similar characteristics with Cushing’s syndrome patients (e.g., obesity, hypertension, hyperlipidemia, hyperglycemia, and insulin resistance). In women, the presentations of hirsutism, menstrual abnormalities, and insulin resistance are similar to those of polycystic ovary syndrome. Cushing’s syndrome can be differentiated from these conditions by identifying the classic signs and symptoms of truncal obesity, “moon facies” with facial plethora, a “buffalo hump” and supraclavicular fat pads, red-purple skin striae, and proximal muscle weakness.
• True Cushing’s syndrome also must be distinguished from other conditions that share some clinical presentations (as well as elevated plasma cortisol concentrations) such as depression, alcoholism, obesity, and chronic illness—the so-called pseudo-Cushing’s states.
Signs and Symptoms (Percentage Prevalence)
General Appearance
• Weight gain and obesity, manifesting as truncal obesity (90%)
• A rounded and puffy face (“moon facies”) (75%)
• Dorsocervical (“buffalo hump”) and supraclavicular fat accumulation
• Hirsutism (excessive hair growth) (75%)
Skin Changes—From Atrophy of Dermis and Connective Tissue
• Thin skin
• Facial plethora (70%)
• Skin striae (“stretch marks” that are usually red or purple in appearance and greater than 1 cm) (50%)
• Acne (35%)
• Easy bruising (40%)
• Hyperpigmentation
Metabolic
• Hyperglycemia that can range from impaired glucose tolerance (75%) to diabetes mellitus (20-50%)
• Hyperlipidemia (70%)
• Polyuria (30%)
• Kidney stones (15-50%)
• Hypokalemic alkalosis (from mineralocorticoid effect of cortisol)
Cardiovascular
• Hypertension (from mineralocorticoid effect of cortisol) (85%)
• Patients are at risk of the cardiovascular complications of hypertension, hyperlipidemia, and hyperglycemia
• Peripheral edema
Genitourinary
• Menstrual irregularities (the most typical presentation is amenorrhea) (70%)
• Erectile dysfunction (85%)
Other
• Psychiatric changes such as depression, emotional lability, psychosis, euphoria, anxiety, and decreased cognition (85%)
• Sleep disturbances
• Osteopenia (80%) and osteoporosis—usually affecting trabecular bone
• Linear growth impairment in children
• Proximal muscle weakness (65%)
• Avascular necrosis—more common in iatrogenic cases
• Glaucoma and cataracts
• Impaired wound healing and susceptibility to opportunistic infections
• Hypothyroidism
Laboratory Tests
• The diagnosis of Cushing’s syndrome and its etiology is often complex and generally requires the involvement of endocrinologists and specialized testing centers.
• Initial screening tests to confirm the presence of hypercortisolism and differentiate Cushing’s syndrome from conditions with similar presentations include 24-hour urinary free cortisol and overnight low-dose dexamethasone suppression test (DST; Table 45–6).
• The midnight plasma cortisol or combined dexamethasone suppression plus CRH test are less commonly used.
• Typically, a combination of at least two screening tests is used to establish the preliminary diagnosis.
• Once the diagnosis is confirmed, additional tests can be performed to determine the etiology.
Other Diagnostic Tests
• Imaging studies may be used to distinguish among pituitary, ectopic, and adrenal tumors (Table 45–5).
From Refs. 2, 14, 15.
Table 45–6 First-Line Screening Tests in Patients With Characteristics of Cushing’s Syndrome
In drug-induced Cushing’s syndrome, discontinuation of the offending agent is the best management option. However, abrupt withdrawal of the glucocorticoid can result in adrenal insufficiency or exacerbation of the underlying disease.15 Glucocorticoid doses less than 7.5 mg/day of prednisone or its equivalent for less than 3 weeks generally would not be expected to lead to suppression of the HPA axis.2,22 However, in patients receiving pharmacologic doses of glucocorticoids for prolonged periods, gradual tapering to near physiologic levels (5–7.5 mg/day of prednisone or its equivalent) should precede drug discontinuation. Administration of a short-acting glucocorticoid in the morning and use of alternate-day dosing may reduce the risk of adrenal suppression. Testing of the HPA axis may be useful in assessing adrenal reserve. In some cases, supplemental glucocorticoid administration during excessive physiologic stress may be needed for up to 1 year after glucocorticoid discontinuation.15 Table 45–8 lists strategies to prevent the development of hypercortisolism and hypocortisolism.
Table 45–7 Pharmacologic Treatments for Cushing’s Syndrome
Table 45–8 Principles of Glucocorticoid Administration to Avoid Hypercortisolism or Hypocortisolism
To Prevent Hypercortisolism and Development of Cushing’s Syndrome:
• Give the lowest glucocorticoid dose that will manage the disease being treated and for the shortest possible duration
• If feasible, give glucocorticoid via administration routes that minimize systemic absorption (such as inhalation or dermal)
• If feasible, administer glucocorticoid treatment every other day (calculate the total 48-hour dose and give as a single dose of intermediate-acting glucocorticoid in the morning)4
• Avoid concurrent administration of drugs that can inhibit glucocorticoid metabolism
To Prevent Hypocortisolism and Development of Adrenal Insufficiency or Adrenal Crisis:
• Assess patients at risk for adrenal insufficiency with screening tests (serum cortisol, plasma ACTH stimulation, etc.)
• If the patient requires discontinuation from chronic treatment with supraphysiologic doses of glucocorticoid, the following discontinuation protocol can be used4:
• Gradually taper the dose to approximately 20 mg of prednisone or equivalent per day, given in the morning, then
• Change glucocorticoid to every other day administration, in the morning
• Stop the glucocorticoid when the equivalent physiologic dose is reached (20 mg/day of hydrocortisone or 5–7.5 mg/day of prednisone or equivalent)
• Understand that recovery of the HPA axis may take up to a year after glucocorticoid discontinuation during which the patient may require supplementation therapy during periods of physiologic stress
• Evaluate patients at risk for adrenal insufficiency as a result of treatment(s) of Cushing’s syndrome and initiate glucocorticoid and mineralocorticoid replacement therapy as appropriate
• Avoid concurrent administration of drugs that can induce glucocorticoid metabolism
• Educate patients about:
• The need for replacement or supplemental glucocorticoid and mineralocorticoid therapy
• How to administer parenteral glucocorticoid if unable to immediately access medical care during an emergency
• Need to wear or carry medical identification regarding their condition (e.g., card, bracelet)
ACTH, adrenocorticotropic hormone or corticotropin; HPA, hypothalamic–pituitary–adrenal.
Patient Encounter 2
EF is a 45-year-old woman who presents to the dermatologist for evaluation of facial acne. She has a history of a 11.4-kg (25-lb) weight gain, irregular menses, and frequent vaginal yeast infections over the past 2 years. During the review of systems, she also complains of increased facial hair growth and lower extremity muscle weakness. Physical exam reveals facial acne, facial hirsutism, truncal obesity, thin skin, and purple abdominal striae. Her past medical history is significant for hypertension, type 2 diabetes mellitus, hyperlipidemia, and lupus.
Which findings are suggestive of Cushing’s syndrome?
Is there anything in the patient’s history that would suggest an exogenous cause of the patient’s presumed Cushing’s syndrome?
Outcome Evaluation
• Monitor patients receiving surgical, medical, or radiation therapy for resolution of the clinical manifestations of hypercortisolism. Symptoms often improve immediately after surgery and soon after initiation of drug therapy. However, it may take months for symptoms to resolve following radiation therapy.
• Monitor for normalization of serum cortisol concentrations.
• The Patient Care and Monitoring textbox discusses additional evaluation strategies.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
Patient Care and Monitoring: Cushing’s Syndrome
1. Patient evaluation should include a thorough history of all medications and herbal or dietary supplements.
2. Perform initial screening tests to confirm Cushing’s syndrome and rule out those with pseudo-Cushing’s conditions.
3. Once diagnosis is confirmed, perform further testing to determine etiology of Cushing’s syndrome.
4. Attempt to taper glucocorticoid if Cushing’s syndrome is from exogenous administration.
5. If endogenous Cushing’s syndrome, determine if patient is an appropriate candidate for surgical resection of the tumor. Does the patient have any conditions that contraindicate surgical resection such as advanced disease (metastatic adrenal carcinoma)?
6. Develop a formal plan to assess the response and complications associated with surgery21:
• Measure plasma cortisol post surgery to determine if the patient displays persistent hypercortisolism (surgical treatment failure) or hypocortisolism (adrenal insufficiency requiring steroid replacement therapy).
• In patients demonstrating hypocortisolism:
• Monitor for signs and symptoms of glucocorticoid withdrawal (headache, fatigue, malaise, myalgia).
• Monitor for signs and symptoms of adrenal insufficiency.
• Monitor morning cortisol or response to ACTH stimulation every 3 to 6 months to assess for HPA axis recovery. Discontinue glucocorticoid replacement therapy when cortisol concentrations are greater than 19 mcg/dL (524 nmol/L) on either test.
• Monitor cortisol, ACTH, low-dose dexamethasone suppression, or other tests to assess for risk of relapse of hypercortisolism.
• Monitor for development of pituitary hormone deficiency
7. If surgical resection does not achieve satisfactory disease control or is not indicated, evaluate patient for pituitary radiation or bilateral adrenalectomy with concomitant pituitary radiation.
• Monitor patients treated with pituitary radiation for development of pituitary hormone deficiency.
8. Evaluate patients with adrenal adenomas for unilateral adrenalectomy.
9. Give glucocorticoid and mineralocorticoid replacement to patients who undergo adrenalectomy (permanently in the case of bilateral adrenalectomy).
10. Evaluate patient for appropriateness of pharmacologic therapy depending on etiology of Cushing’s syndrome.
11. Monitor patient for response to therapy, need for dose adjustments, and presence of adverse drug reactions.
12. Once disease control is achieved, continue to monitor biochemical markers and patient for development of complications of Cushing’s syndrome, as relapse may occur.
13. Provide patient education regarding disease state and treatment:
• Causes of Cushing’s syndrome, including drug-induced etiologies.
• How to recognize the clinical manifestations of Cushing’s syndrome.
• Possible sequelae of Cushing’s syndrome.
• How to reduce modifiable cardiovascular and metabolic complications.
• Advantages and disadvantages of potential treatment options.
• Possible adverse consequences of treatment.
• Need for glucocorticoid and mineralocorticoid replacement after treatment, if appropriate.
• Importance of adherence to therapy.
REFERENCES
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