Exogenous Cushing Syndrome

A 52 year old female with long-standing rheumatoid arthritis presents with progressive weight gain, proximal muscle weakness, irregular menstruation, and fatigue over the past year. She has been taking high-dose oral prednisone for severe rheumatoid arthritis flares for many months. On examination, she has central obesity, moon facies, supraclavicular fat pads, purple abdominal striae, thin extremities, proximal muscle wasting, and easy bruising. Blood pressure is 156/94 mmHg. Laboratory investigations reveal hyperglycemia, low ACTH levels, and suppressed endogenous cortisol production due to chronic glucocorticoid therapy. Diagnosis?

Diagnosis is exogenous Cushing syndrome due to chronic glucocorticoid use.

1. Definition

Exogenous Cushing syndrome is hypercortisolism caused by prolonged administration of glucocorticoids.

It is the most common cause of Cushing syndrome overall

2. Etiology

Common Causes

Systemic Glucocorticoids

  1. Prednisone
  2. Dexamethasone
  3. Hydrocortisone
  4. Methylprednisolone

Other Sources

  1. Inhaled corticosteroids
  2. Topical corticosteroids
  3. Intra-articular steroid injections
  4. Chronic ophthalmic steroid use

Risk increases with:

  1. High doses
  2. Long duration of therapy
  3. Potent glucocorticoids

3. Pathophysiology

  1. Chronic glucocorticoid exposure suppresses hypothalamic CRH secretion
  2. ACTH secretion decreases due to negative feedback
  3. Bilateral adrenal cortical atrophy develops
  4. Excess glucocorticoid activity produces metabolic and catabolic effects

Effects of Excess Glucocorticoids

Metabolic Effects

  1. Increased gluconeogenesis causing hyperglycemia
  2. Insulin resistance
  3. Dyslipidemia

Catabolic Effects

  1. Protein breakdown causing muscle wasting
  2. Skin thinning and easy bruising
  3. Osteoporosis

Mineralocorticoid Effects

  1. Sodium retention
  2. Hypertension
  3. Hypokalemia may occur in severe cases

4. Clinical Features

4.1 Fat Redistribution

  1. Central obesity
  2. Moon facies
  3. Buffalo hump
  4. Supraclavicular fat pads
  5. Thin extremities due to muscle wasting

4.2 Skin Changes

  1. Purple abdominal striae
  2. Skin thinning
  3. Easy bruising
  4. Poor wound healing
  5. Acne

4.3 Musculoskeletal Manifestations

  1. Proximal muscle weakness
  2. Osteoporosis
  3. Vertebral compression fractures

4.4 Metabolic Features

  1. Hyperglycemia or diabetes mellitus
  2. Hypertension
  3. Weight gain

4.5 Endocrine and Reproductive Features

  1. Amenorrhea or oligomenorrhea
  2. Decreased libido
  3. Hirsutism may occur

4.6 Neuropsychiatric Features

  1. Depression
  2. Anxiety
  3. Insomnia
  4. Cognitive dysfunction

4.7 Immune Effects

  1. Increased infection risk
  2. Impaired inflammatory response

5. Diagnosis

Key Principle

Diagnosis is primarily clinical and based on history of chronic glucocorticoid exposure

Laboratory Findings

  1. Low ACTH due to pituitary suppression
  2. Suppressed endogenous cortisol production
  3. Hyperglycemia may be present
  4. Electrolyte abnormalities may occur

Important Diagnostic Point

Standard hypercortisolism screening tests:

  1. 24 hour urinary free cortisol
  2. Late-night salivary cortisol
  3. Dexamethasone suppression testing

are generally not useful in patients with known exogenous glucocorticoid exposure

Imaging

  1. Adrenal glands may appear bilaterally atrophic due to chronic ACTH suppression
  2. Pituitary imaging is not indicated unless endogenous Cushing syndrome is suspected

6. Differential Diagnosis

  1. Cushing disease (pituitary ACTH adenoma)
  2. Ectopic ACTH syndrome
  3. Adrenal adenoma or carcinoma
  4. Pseudo-Cushing states:
    • Alcohol use disorder
    • Major depression
    • Severe obesity

7. Management

7.1 Glucocorticoid Reduction

  1. Gradual tapering of glucocorticoids is essential
  2. Abrupt withdrawal may precipitate adrenal crisis

7.2 Steroid-Sparing Therapy

Use alternative therapies when possible for underlying disease:

  1. DMARDs in autoimmune disease
  2. Biologic agents
  3. Nonsteroidal therapies when appropriate

7.3 Monitor for Adrenal Insufficiency

Symptoms during taper:

  1. Fatigue
  2. Weakness
  3. Hypotension
  4. Nausea
  5. Hypoglycemia

Recovery of HPA axis suppression may take months

7.4 Management of Complications

  1. Control hypertension
  2. Treat diabetes mellitus
  3. Calcium and vitamin D supplementation
  4. Bisphosphonates for osteoporosis prevention
  5. Vaccination and infection prevention strategies

8. Complications

  1. Osteoporosis
  2. Diabetes mellitus
  3. Hypertension
  4. Opportunistic infections
  5. Muscle wasting
  6. Psychiatric disorders
  7. Adrenal insufficiency after withdrawal

9. Prognosis

  1. Many features improve after glucocorticoid reduction
  2. Recovery may take months to years
  3. Osteoporosis and metabolic complications may persist
  4. Long-term adrenal suppression may occur

10. Key Clinical Insight

Patient with central obesity, proximal muscle weakness, purple striae, hypertension, and chronic glucocorticoid use strongly suggests exogenous Cushing syndrome

11. Key Exam Points

  1. Exogenous glucocorticoid use is the most common cause of Cushing syndrome overall
  2. ACTH is suppressed due to negative feedback
  3. Chronic ACTH suppression causes bilateral adrenal atrophy
  4. Proximal muscle weakness and purple striae are classic findings
  5. Osteoporosis is a major complication
  6. Hyperglycemia and hypertension are common
  7. Abrupt steroid withdrawal may cause adrenal crisis
  8. Gradual tapering is essential
  9. Endogenous cortisol production may remain suppressed for months
  10. Pituitary imaging is not indicated unless endogenous Cushing syndrome is suspected
By Prabin Duwadee at

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