• Cushing's Syndrome:
  • Primary Cause: iatrogenic administration of steroids
  • Primary Non-iatrogenic Cause:
    • bilateral adrenal hyperplasia due to pituitary adenoma (basophilic tumor)
    • about 20 to 25 percent of Cushing's syndrome patients have adrenal neoplasm
    • ACTH Hypersecretion

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  • Other Causes:
    • adrenal tumors
    • nodular adrenal hyperplasia-- causes:
      • familial autoimmune (children/young adults)-- pigmented multinodular cortical dysplasia
      • hypersensitivity to gastric inhibitory peptide {increased peptide receptor expression in adrenal cortex}
    • ectopic, nonendocrine tumors that produce ACTH
  • Incidence:
    • three times greater in women
    • most frequent age of onset: 30s to 40s

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  • Manifestations:
    • Abnormal fat deposition:
      • truncal obesity-- mesenteric bed
      • rounded face ("moon facies")
      • interscapular area ("buffalo hump")
    • hirsuitism;
    • effects of protein loss --
      1. muscle wasting
      2. skin thinning
      3. striae-- secondary to weakening/rupture of dermal collagen fibers
      4. poor wound healing
      5. bruising
      6. osteoporosis
    • mental disorders--
      • irritability/emotional lability
      • severe depression, confusion, psychosis
    • diabetes
      • frequency < 20%
      • impaired glucose tolerance:
        1. increased hepatic gluconeogenesis
        2. insulin resistance
    • hypertension-- common

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  • Short-termTreatment:
    • Surgical pituitary tumor removal
    • Irradiation/removal of pituitary adenomas (ACTH producing)
      •  microadenoma surgical resection is associated with recurrence rate that may be greater than 20 percent
    • About 20% -- 25% of Cushing's patients have an adrenal neoplasm.
      • usually unilateral;  about 50%, malignant
      •  Adrenal carcinoma diagnosis: approximate three-year post-diagnosis survival time
        • associated with liver and lung metastasis
        • primary chemotherapeutic agent: mitotane which suppresses cortisol production, decreasing plasma and urine steroid levels
        • Mitotane: -- relatively selective for glucocorticoid-secreting adrenal cortex zone; extra-adrenal cortisol metabolism may also be affected
          1. one-third of patients: tumor and metastasis regress
          2. in many patients:
             • steroidogenesis -- inhibited
             • no regression of tumor metastases
    • resection of hyperplastic adrenals -- if source of ACTH is apparent
      • cure rate approximates 100%
      •  adverse effects:
        • lifelong glucocorticoid and mineralocorticoid replacement
        • 10% to 20% probability of developing pituitary tumor over following ten year period (Nelson's syndrome)
    • in surgical approach not feasible, "medical" adrenalectomy may be required:
      • "Medical" adrenalectomy:
        • high-dose ketoconazole (Nizoral) (inhibit steroidogenesis)
        • mitotane (Lysodren) and/or aminoglutethimide (blocks steroid synthesis) and metyrapone

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  • Patient management:(surgical intevention)
    1. Before surgery: large doses of cortisol
    2. During and immediately after surgery: large doses of cortisol
    3. Tapered cortisol to normal replacement doses (long-term maintenance)

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  • Diagnosis: Dexamethasone suppression testing
    • Initial Screening
      1. demonstration of increased cortisol production (8 a.m. plasma cortisol > 140 nmol/L (5 microgram/dL);
      2. cortisol > , following 1 mg dexamethasone (Decadron) at midnight
    • Definitive diagnosis:
      1. failure of urinary cortisol to fall to less than 80 nmol/d (30 microgram/d) or
      2. plasma cortisol to fall to less than 140 nmol/L (5 microgram/dL) following standard low-dose dexamethasone (Decadron) suppression testing (0.5 mg every six hours for 48 hours)

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