Cushing’s Syndrome - Management of Patients With Adrenal Disorders

CUSHING’S SYNDROME

Cushing’s syndrome results from excessive, rather than deficient, adrenocortical activity. The syndrome may result from excessive administration of corticosteroids or ACTH or from hyperplasia of the adrenal cortex.

Pathophysiology

Cushing’s syndrome is commonly caused by use of corticosteroid medications and is infrequently due to excessive corticosteroid pro-duction by the adrenal cortex (Tierney et al., 2001). However, overproduction of endogenous corticosteroids may be caused by several mechanisms, including a tumor of the pituitary gland that produces ACTH and stimulates the adrenal cortex to increase its hormone secretion despite adequate amounts being produced. Primary hyperplasia of the adrenal glands in the absence of a pi-tuitary tumor is less common. Another less common cause of Cushing’s syndrome is the ectopic production of ACTH by ma-lignancies; bronchogenic carcinoma is the most common type of these malignancies. Regardless of the cause, the normal feedback mechanisms that control the function of the adrenal cortex be-come ineffective, and the usual diurnal pattern of cortisol is lost.

The signs and symptoms of Cushing’s syndrome are primarily a result of oversecretion of glucocorticoids and androgens (sex hor-mones), although mineralocorticoid secretion also may be affected.

Clinical Manifestations

When overproduction of the adrenal cortical hormone occurs, ar-rest of growth, obesity, and musculoskeletal changes occur along with glucose intolerance. The classic picture of Cushing’s syn-drome in the adult is that of central-type obesity, with a fatty “buffalo hump” in the neck and supraclavicular areas, a heavy trunk, and relatively thin extremities. The skin is thin, fragile, and easily traumatized; ecchymoses (bruises) and striae develop. The patient complains of weakness and lassitude. Sleep is disturbed because of altered diurnal secretion of cortisol.

Excessive protein catabolism occurs, producing muscle wast-ing and osteoporosis. Kyphosis, backache, and compression frac-tures of the vertebrae may result. Retention of sodium and water occurs as a result of increased mineralocorticoid activity, produc-ing hypertension and heart failure.

The patient develops a “moon-faced” appearance and may ex-perience increased oiliness of the skin and acne. There is increased susceptibility to infection. Hyperglycemia or overt diabetes may develop. The patient may also report weight gain, slow healing of minor cuts, and bruises.

Women ages 20 to 40 years are five times more likely than men to develop Cushing’s syndrome. In females of all ages, viril-ization may occur as a result of excess androgens. Virilization is characterized by the appearance of masculine traits and the re-cession of feminine traits. There is an excessive growth of hair on the face (hirsutism), the breasts atrophy, menses cease, the clitoris enlarges, and the voice deepens. Libido is lost in men and women.

Changes occur in mood and mental activity; psychosis may develop. Distress and depression are common and are increased by the severity of the physical changes that occur with this syn-drome. If Cushing’s syndrome is a consequence of pituitary tumor, visual disturbances may occur because of pressure of the growing tumor on the optic chiasm. Chart 42-10 summarizes the changes associated with Cushing’s syndrome.

Assessment and Diagnostic Findings

Indicators of Cushing’s syndrome include an increase in serum sodium and blood glucose levels and a decreased serum concen-tration of potassium, a reduction in the number of blood eosinophils, and disappearance of lymphoid tissue. Measure-ments of plasma and urinary cortisol levels are obtained. Several blood samples may be collected to determine whether the normal diurnal variation in plasma levels is present; this variation is fre-quently absent in adrenal dysfunction. If several blood samples are required, they must be collected at the times specified and the time of collection must be noted on the requisition slip.

An overnight dexamethasone suppression test is the most widely used screening test for diagnosis of pituitary and adrenal causes of Cushing’s syndrome. It can be performed on an outpa-tient basis. Dexamethasone (1 mg) is administered orally at 11 pm, and a plasma cortisol level is obtained at 8 the next morn-ing. Suppression of cortisol to less than 5 mg/dL indicates that the hypothalamic-pituitary-adrenal axis is functioning properly. Stress, obesity, depression, and medications such as antiseizure agents, estrogen, and rifampin can falsely elevate cortisol levels. Other diagnostic studies include a 24-hour urinary free cortisol level and a high-dose or low-dose dexamethasone suppression test. High-dose and low-dose suppression tests are similar to the overnight test but vary in dosage and timing.

Measurement of plasma ACTH by radioimmunoassay is used in conjunction with the high-dose suppression test to distinguish pituitary tumors from ectopic sites of ACTH production as the cause of Cushing’s syndrome. Elevation of both ACTH and cor-tisol level indicates pituitary or hypothalamic disease. Low ACTH with a high cortisol level indicates adrenal disease. A CT scan, ultrasound, or MRI may be performed to localize adrenal tissue and detect tumors of the adrenal gland.

Medical Management

If Cushing’s syndrome is caused by pituitary tumors rather than tumors of the adrenal cortex, treatment is directed at the pituitary gland. Surgical removal of the tumor by transsphenoidal hypo-physectomy is the treatment of choice and has a 90% success rate (Rakel & Bope, 2001). Radiation of the pitu-itary gland also has been successful, although it may take several months for control of symptoms. Adrenalectomy is the treatment of choice in patients with primary adrenal hypertrophy.

Postoperatively, symptoms of adrenal insufficiency may begin to appear 12 to 48 hours after surgery because of reduction of the high levels of circulating adrenal hormones. Temporary replace-ment therapy with hydrocortisone may be necessary for several months until the adrenal glands begin to respond normally to the body’s needs. If both adrenal glands have been removed (bilateral adrenalectomy), lifetime replacement of adrenal cortex hormones is necessary.

Adrenal enzyme inhibitors (eg, metyrapone, aminoglutethi-mide, mitotane, ketoconazole) may be used to reduce hyper-adrenalism if the syndrome is caused by ectopic ACTH secretion by a tumor that cannot be eradicated. Close monitoring is neces-sary because symptoms of inadequate adrenal function may result and because of possible side effects of these medications.

If Cushing’s syndrome is a result of the administration of cor-ticosteroids, an attempt is made to reduce or taper the medica-tion to the minimum dosage needed to treat the underlying disease process (eg, autoimmune and allergic diseases and rejec-tion of transplanted organs). Frequently, alternate-day therapy decreases the symptoms of Cushing’s syndrome and allows re-covery of the adrenal glands’ responsiveness to ACTH.