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Cushing's Syndrome

Aug 24, 20255 min read

IM

H M ABDELRAHIM

Cushing’s Syndrome

Adrenal Gland

The adrenal cortex secretes three main categories of steroids: * Mineralocorticoids (Salt): Primarily Aldosterone, regulated by the renin-angiotensin-aldosterone system. * Glucocorticoids (Sugar): Primarily Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis. * Androgens (Sex Hormones): Contribute to the development of secondary sexual characteristics.

The adrenal cortex is divided into three zones:

  • Zona Glomerulosa (G): Outermost layer, produces Aldosterone.

  • Zona Fasciculata (F): Middle layer, produces Cortisol.

  • Zona Reticularis (R): Innermost layer, produces Androgens.

    The adrenal medulla secretes catecholamines (epinephrine and norepinephrine), which are involved in the “fight-or-flight” response.

Hypercortisolism

Cushing’s Disease: Hypercortisolism specifically caused by an ACTH-producing pituitary adenoma.

Cushing’s Syndrome: A broader term encompassing hypercortisolism from any cause, including:

  • Pituitary adenoma (Cushing’s Disease)
  • Adrenal adenoma or carcinoma
  • Ectopic ACTH production (e.g., from a lung tumor)
  • Administration of exogenous glucocorticoids (e.g., prednisone)

Clinical Presentation

  • Hypertension: High blood pressure.

  • Central Obesity: Accumulation of fat around the abdomen and trunk.

  • Moon Facies: Round, full face.

  • Dorsal Fat Pad (Buffalo Hump): Fat accumulation between the shoulders.

  • Purple Striae: Stretch marks on the skin, often purplish or reddish.

  • Muscle Weakness: Proximal myopathy; muscle weakness, making it difficult to climb stairs or rise from a chair.

  • Other Symptoms:

    • Psychiatric symptoms (e.g., depression, anxiety)
    • Secondary amenorrhea (absence of menstrual periods) in women
    • Hirsutism (excess hair growth) or other signs of masculinization in women
    • Osteoporosis (weakened bones) in both men and women
    • Glucose intolerance or diabetes
    • Metabolic alkalosis with hypokalemia (in severe cases)

Diagnosis

  • Initial Screening:

    • 24-hour Urine Free Cortisol (UFC): Measures the amount of cortisol excreted in the urine over a 24-hour period.
    • Bedtime Salivary Cortisol: Measures cortisol levels in saliva collected at bedtime.
    • 1-mg Overnight Dexamethasone Suppression Test: A low dose of dexamethasone is given at night, and cortisol levels are measured in the morning. Suppression of cortisol indicates a normal response.

  • Differentiating the Cause:

    • Plasma ACTH Levels:
      • High or Normal ACTH: Suggests ACTH-dependent Cushing’s Syndrome (e.g., pituitary adenoma, ectopic ACTH production).
      • Low ACTH (less than 10 pg/mL): Suggests ACTH-independent Cushing’s Syndrome (e.g., adrenal adenoma).

  • Further Investigations:

    • ACTH-Independent: Adrenal imaging (CT or MRI) is necessary to locate the source of excess cortisol production.
    • ACTH-Dependent: Further testing is required to differentiate between pituitary and ectopic ACTH production:
      • High-Dose Dexamethasone Suppression Test (8mg): Less commonly used now due to poor test characteristics.
      • Inferior Petrosal Sinus Sampling (IPSS): The gold standard for differentiating pituitary from ectopic ACTH secretion.
      • MRI of the Pituitary: To visualize the pituitary gland and identify potential adenomas.

Inferior Petrosal Sinus Sampling (IPSS)

  • Gold Standard: For differentiating pituitary (Cushing’s Disease) from ectopic ACTH secretion.
  • Procedure: Catheters are placed in the inferior petrosal sinuses (which drain the pituitary gland) and a peripheral vein. ACTH levels are measured in both locations after administering corticotropin-releasing factor (CRF).
  • Interpretation: A central-to-peripheral ACTH ratio helps determine the source of ACTH.
  • Invasive: Only performed at specialized centers.

Screening Tests for Hypercortisolism

  • Confirmation of Cushing’s Syndrome requires 2 out of 3 positive screening tests:
    • 1-mg Dexamethasone Suppression Test: Cortisol >140 nmol/L after dexamethasone administration is considered positive.
    • 24-hour Urine Free Cortisol (UFC): Abnormal on two separate collections.
    • Late-Night Salivary Cortisol: Abnormal on two separate collections.

Cushing’s Syndrome – Don’t pick 8mg Dex! *A note on the high dose (8mg Dex) suppression test: Classic teaching *

High-Dose Dexamethasone Suppression Test (8mg) - Important Note

  • Outdated: While historically used, the 8mg dexamethasone suppression test is no longer recommended due to its poor sensitivity and specificity.

  • Current Practice: MRI of the pituitary and/or IPSS are preferred for differentiating pituitary from ectopic ACTH secretion.

    • If 8mg Dexametazone HS suppresses am cortisol =
      Cushing’s disease due to pituitary cause ⇒ Order MRI Sella
    • If 8mg Dex does not suppress cortisol ⇒ Ectopic ACTH (e.g. neuroendocrine carcinoma) ⇒ CT the chest for malignancy

Poor test characteristics, thus 8mg Dex no longer recommended by newer guidelines; MRI +/- IPSS is used instead

Treatment

  • Pituitary Source (Cushing’s Disease): Transsphenoidal surgery to remove the pituitary adenoma.
  • Adrenal Source: Laparoscopic Adrenalectomy (surgical removal of the affected adrenal gland). best treatment

When Surgical Cure is Not Possible (or in the interim):

  • Medical Therapy: Medications can be used to:

    • Inhibit ACTH secretion (e.g., pasireotide)
    • Inhibit cortisol secretion by the adrenal glands (e.g., ketoconazole, metyrapone, mitotane)
    • Block cortisol effects (e.g., mifepristone)

  • Other Options:

    • Pituitary radiation
    • Bilateral adrenalectomy (in severe cases)

Summary

  • Cushing’s Syndrome is a serious condition caused by prolonged exposure to high levels of cortisol.
  • Early diagnosis and treatment are essential to prevent complications.
  • Treatment options depend on the underlying cause of the hypercortisolism.

Surgery

Cushing’s syndrome

Secretion of cortisol from adrenal cortex

  • 4 times more frequent in females
  • Usually occurs at 35-50 years of age

Causes:

  • Endogenous
    • Adrenal tumor
    • Tumor of the anterior pituitary gland (Cushing’s disease)
    • Hyperplasia (NAH)
    • Ectopic ACTH
      • Secreting tumor (e.g., lung, pancreas)
  • Exogenous
    • Excessive cortisone intake

DIAGNOSIS:

  • High Serum cortisol levels
  • URINARY LEVELS OF STEROID METABOLITES
    • 17-OHCS (hydroxycorticosteroid) (High)
    • 17-KS (ketosteroid) (High)

Hematology:

  • WBCs (Decreased)
  • Lymphocytes (Increased)
  • Eosinophils (Decreased

TREATMENT:

  • Primary:
    • Adrenalectomy (unilateral or bilateral)
    • if bilateral, need hormone replacement for life
  • Secondary
    • Trans-sphenoidal removal of pituitary tumor
  • Ectopic:
    • Try to remove the source of ACTH secretion
    • Radiation to tumors
    • Palliative drugs:
      • MITOTANE (destroys tissue in the adrenal cortex)

Clinical Medicine

  • Mental retardation; Stunted growth
  • Moon Face
  • Inter scapular pad of fat
  • Stretch marks
  • Thin extremities, central Obesity
  • Risk of infections

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