What are the diagnosis and treatment options for hypercortisolism (Cushing's syndrome)?

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Diagnosis and Treatment of Hypercortisolism (Cushing's Syndrome)

The diagnosis of hypercortisolism requires a stepwise approach starting with screening tests followed by confirmatory testing, while treatment must be directed at the underlying cause, with surgical resection of the responsible tumor being the first-line therapy for most forms of Cushing's syndrome. 1

Clinical Manifestations

Key Clinical Features

  • Weight gain with central obesity
  • Facial plethora (moon facies)
  • Supraclavicular and dorsocervical fat pads ("buffalo hump")
  • Purple striae (>1 cm wide)
  • Proximal muscle weakness
  • Easy bruising
  • Hirsutism and menstrual irregularities in women
  • Decreased libido and erectile dysfunction in men
  • Psychiatric disturbances (depression, anxiety, cognitive impairment)

High-Specificity Features

  • Growth deceleration with weight gain in children - this combination has high sensitivity and specificity for Cushing's syndrome in pediatric patients 1
  • Wide (>1 cm) purple striae
  • Proximal myopathy
  • Facial plethora
  • Spontaneous ecchymoses

Comorbidities

  • Hypertension
  • Glucose intolerance/diabetes mellitus
  • Osteoporosis/pathologic fractures
  • Thromboembolic events
  • Recurrent infections
  • Cardiovascular disease

Diagnostic Approach

Step 1: Rule Out Exogenous Causes

  • Confirm patient is not taking exogenous glucocorticoids (oral, injections, topical, inhaled)

Step 2: Initial Screening Tests (perform at least two)

  1. Late-night salivary cortisol (LNSC) - collect at 22:00-23:00 hours (≥2 samples on separate days)
  2. 24-hour urinary free cortisol (UFC) - collect 2-3 samples
  3. 1mg overnight dexamethasone suppression test (DST) - failure to suppress morning cortisol to <50 nmol/L (<1.8 μg/dL)

Step 3: Determine ACTH Dependency

  • Measure plasma ACTH level
    • Low/suppressed ACTH (<5-10 pg/mL): ACTH-independent (adrenal cause)
    • Normal/elevated ACTH: ACTH-dependent (pituitary or ectopic source)

Step 4: Localization Studies

  • For ACTH-independent causes: Adrenal CT or MRI
  • For ACTH-dependent causes: Pituitary MRI
    • If pituitary MRI negative or equivocal: Inferior petrosal sinus sampling (IPSS)
    • If IPSS negative for central source: CT chest/abdomen/pelvis to locate ectopic source

Treatment Algorithm

1. Cushing's Disease (Pituitary ACTH-Secreting Adenoma)

  • First-line: Transsphenoidal surgery (TSS)
    • Success rates: 65-90% for microadenomas, lower for macroadenomas
  • For persistent/recurrent disease:
    • Second TSS
    • Radiation therapy (conventional or stereotactic radiosurgery)
    • Medical therapy
    • Bilateral adrenalectomy

2. Adrenal Causes (Adenoma, Carcinoma, Bilateral Hyperplasia)

  • First-line: Surgical resection
    • Unilateral adrenalectomy for adenoma/carcinoma
    • Bilateral adrenalectomy for bilateral disease

3. Ectopic ACTH Syndrome

  • First-line: Surgical resection of the ACTH-producing tumor
  • If tumor unidentified or unresectable: Medical therapy

4. Medical Therapy Options

  • Adrenal enzyme inhibitors:

    • Ketoconazole: 400-1200 mg/day (divided doses)
      • Monitor liver function tests regularly
      • Avoid in patients on PPIs (requires gastric acid for absorption)
    • Metyrapone: 500-6000 mg/day (divided doses)
      • Monitor for hirsutism and hypertension
    • Osilodrostat: 2-7 mg twice daily (FDA-approved for Cushing's disease)
      • Monitor for hirsutism, hypertension, hypokalemia

  • Pituitary-directed:

    • Pasireotide: 0.6-0.9 mg twice daily subcutaneously
      • Monitor for hyperglycemia

Special Considerations

Diagnostic Pitfalls

  • Pseudo-Cushing's states can cause mild hypercortisolism:
    • Severe obesity
    • Depression
    • Alcoholism
    • Poorly controlled diabetes
    • Polycystic ovary syndrome
    • Consider monitoring for 3-6 months if mild hypercortisolism present

Pediatric Considerations

  • Different clinical presentation with growth failure and weight gain being key features 1
  • Male predominance in prepubertal children (unlike adult female predominance)
  • Microadenomas account for 98% of pediatric Cushing's disease cases
  • Thromboprophylaxis should not be routinely used in pediatric patients undergoing surgery

Post-treatment Monitoring

  • All patients require lifelong monitoring for:
    • Recurrence of hypercortisolism
    • Adrenal insufficiency (after successful treatment)
    • Persistent comorbidities (hypertension, diabetes, osteoporosis)

Treatment Outcomes

  • Mortality is significantly reduced with successful treatment
  • Some comorbidities may persist despite biochemical cure
  • Quality of life improves but may not normalize completely
  • Early diagnosis and treatment leads to better outcomes

Remember that early diagnosis and expert management are critical given the potential for long-term adverse health outcomes from prolonged hypercortisolism 1. Patients should be referred to centers with expertise in managing pituitary and adrenal disorders.

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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