Physiology · Year 1 · from Physiology

Case 1: Cushing Syndrome - Cortisol Excess and Feedback Dysregulation

Clinical Image

Source: Wikimedia Commons - Cushing syndrome - CC BY-SA 4.0

Patient Presentation

A 42-year-old woman presents to her primary care physician with a 6-month history of progressive weight gain, particularly around her abdomen and face, despite no change in diet or activity. She also notes easy bruising, irregular menstrual periods, and new-onset difficulty climbing stairs. Her husband has noticed that she seems more irritable and has been having trouble sleeping.

Demographics

  • Age: 42 years
  • Sex: Female
  • Past Medical History: Hypertension (newly diagnosed 4 months ago), Type 2 diabetes (diagnosed 2 months ago)

Chief Complaint

Progressive central weight gain, easy bruising, and proximal muscle weakness

Physical Examination

  • Blood pressure: 158/96 mmHg
  • Heart rate: 82 bpm
  • BMI: 32 kg/m2
  • General: Moon facies, facial plethora, dorsocervical fat pad ("buffalo hump")
  • Skin: Thin skin with multiple ecchymoses, wide (>1 cm) violaceous striae on abdomen
  • Musculoskeletal: Proximal muscle weakness (difficulty rising from chair)
  • Extremities: Thin arms and legs relative to trunk

Workup

  • 24-hour urine free cortisol: 485 mcg/day (elevated; normal <50 mcg/day)
  • Late-night salivary cortisol: Elevated on two occasions
  • Low-dose dexamethasone suppression test: Cortisol 18 mcg/dL (failed suppression; normal <1.8 mcg/dL)
  • ACTH level: 68 pg/mL (elevated; suggests ACTH-dependent Cushing syndrome)
  • High-dose dexamethasone suppression test: >50% suppression (suggests pituitary source)
  • Pituitary MRI: 6 mm microadenoma in right anterior pituitary

Diagnosis

Cushing Disease (ACTH-secreting pituitary adenoma)

Treatment

  1. Transsphenoidal surgical resection of pituitary adenoma
  2. Perioperative stress-dose glucocorticoids
  3. Postoperative monitoring for adrenal insufficiency
  4. Management of comorbidities (hypertension, diabetes)
  5. Long-term follow-up for recurrence

Physiological Principles Demonstrated

  • Negative feedback failure: The pituitary adenoma secretes ACTH autonomously, not responding to elevated cortisol levels. This demonstrates failure of the normal long-loop negative feedback mechanism where cortisol should suppress CRH and ACTH.
  • Hormone excess effects: Chronic cortisol excess produces the classic phenotype through multiple mechanisms: protein catabolism (muscle weakness, thin skin), altered fat distribution (central obesity, moon facies), hyperglycemia (diabetes), and hypertension.
  • Hypothalamic-pituitary-adrenal axis: This case illustrates the HPA axis hierarchy, where ACTH from the pituitary controls cortisol release from the adrenal cortex.
  • Dynamic testing: The dexamethasone suppression tests exploit the feedback system to differentiate causes of hypercortisolism.

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