What causes autonomic cortisol secretion?

Causes of Autonomous Cortisol Secretion

Autonomous cortisol secretion is primarily caused by adrenal adenomas, with the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system playing important regulatory roles.

Primary Causes

Adrenal Adenomas

• Non-functioning adrenal adenomas are the most common adrenal incidentalomas (71-84%) 1
• Cortisol-secreting adenomas account for 1-30% of adrenal incidentalomas 1
• These adenomas produce cortisol independent of normal ACTH regulation
• Mild autonomous cortisol secretion (MACS) occurs when there is subtle cortisol excess without overt Cushing's syndrome 1

Other Adrenal Pathologies

• Adrenocortical carcinoma (1.2-12% of adrenal masses) can cause autonomous cortisol secretion 1
• Bilateral adrenal hyperplasia can cause ACTH-independent Cushing syndrome 1
• Myelolipomas, ganglioneuromas, and adrenal cysts rarely cause hormonal dysfunction 1

Physiological Mechanisms

Hypothalamic-Pituitary-Adrenal Axis Dysfunction

• Normal cortisol production is regulated by the HPA axis:
  • Hypothalamus releases corticotropin-releasing factor (CRF)
  • CRF stimulates anterior pituitary to release ACTH
  • ACTH stimulates adrenal cortex to produce cortisol 1
• In autonomous secretion, cortisol is produced without proper regulation by this axis
• Normally, cortisol follows a circadian rhythm with levels highest in morning (140-700 nmol/L at 0900) and lowest at midnight (80-350 nmol/L) 1

Sympathetic Nervous System Contribution

• The sympathetic nervous system can directly stimulate cortisol production via splanchnic nerve innervation of the adrenal cortex 2
• Increased sympathetic tone contributes to elevated basal and rapid glucocorticoid production, particularly following chronic stress 3
• Serotonin in the adrenal cortex acts as a paracrine signal to stimulate cortisol secretion through 5-HT4/5-HT7 receptors 4

Diagnostic Approach

Laboratory Testing

• 1 mg dexamethasone suppression test (DST) is the preferred screening test for autonomous cortisol secretion 1
  • 50 nmol/L excludes cortisol hypersecretion
  • 51-138 nmol/L suggests possible autonomous cortisol secretion

  • 138 nmol/L indicates cortisol hypersecretion

Interpretation of Results

• ACTH independence should be confirmed by measuring plasma ACTH levels 1
• Suppressed ACTH levels indicate autonomous adrenal production
• Additional testing may include 24-hour urinary free cortisol and midnight salivary cortisol 1

Clinical Implications

Associated Comorbidities

• MACS is associated with:
  • Type 2 diabetes
  • Hypertension
  • Cardiovascular events
  • Vertebral fractures
  • Increased mortality 1
• Despite these associations, patients with MACS rarely progress to overt Cushing's syndrome 1

Management Considerations

• Adrenalectomy is recommended for:
  • Patients with unilateral cortisol-secreting adrenal masses and clinically apparent Cushing's syndrome 1
  • Younger patients with MACS who have progressive metabolic comorbidities attributable to cortisol excess 1
• Patients not managed surgically should undergo annual clinical screening for new or worsening associated comorbidities 1

Special Considerations

Stress Response

• Normal stress response increases cortisol production up to five-fold (approximately 100 mg/day) 1
• During critical illness, reduced metabolism and clearance contribute to hypercortisolemia 1
• CRH can stimulate cortisol release even in the absence of pituitary ACTH, suggesting extrapituitary mechanisms 5

Mental Health Connections

• Fluctuations in cortisol secretion often accompany psychiatric disorders 6
• Normalization of cortisol levels correlates with improvement in mental health 6

By understanding these mechanisms, clinicians can better diagnose and manage patients with autonomous cortisol secretion and related conditions.