Can Cushing's syndrome have a mixed adrenal (adrenal gland)/pituitary etiology?

Mixed Adrenal and Pituitary Etiology in Cushing's Syndrome

Cushing's syndrome can rarely have a mixed adrenal and pituitary etiology, though most cases have a single primary cause. The diagnostic approach should focus on identifying the predominant source of hypercortisolism to guide appropriate treatment.

Etiology of Cushing's Syndrome

• Cushing's syndrome is primarily caused by a single source of hypercortisolism, with pituitary adenomas (Cushing's disease) accounting for 75-80% of cases in children/adolescents and 49-71% in adults 1
• Adrenal causes (adenomas, carcinomas, or hyperplasia) represent approximately 20-30% of Cushing's syndrome cases 2
• The classification is typically divided into ACTH-dependent (pituitary or ectopic sources) and ACTH-independent (adrenal) causes 3

Potential Mechanisms for Mixed Etiology

• Primary adrenal causes of Cushing's syndrome are characterized by low or undetectable ACTH levels (ACTH-independent), while pituitary causes show normal or elevated ACTH (ACTH-dependent) 2, 4
• In rare cases, patients may have bilateral adrenal hyperplasia or nodular disease that can coexist with pituitary abnormalities 4
• Genetic syndromes can potentially affect both pituitary and adrenal function simultaneously:
  • Multiple endocrine neoplasia type 1 (MEN1) can rarely present with both pituitary and adrenal involvement 5
  • Carney complex due to PRKAR1A mutations is associated with Cushing's syndrome primarily through bilateral adrenal hyperplasia but can have pituitary involvement 5

Diagnostic Approach for Suspected Mixed Etiology

• Initial testing should focus on confirming hypercortisolism with 24-hour urinary free cortisol, late-night salivary cortisol, and/or overnight dexamethasone suppression test 3, 1
• Measurement of plasma ACTH is crucial to differentiate between ACTH-dependent and ACTH-independent causes 3
• When results are equivocal or suggest possible mixed etiology:
  • High-resolution pituitary MRI to identify potential adenomas 6
  • Adrenal CT or MRI to evaluate for adrenal nodules, hyperplasia, or asymmetry 6
  • Inferior petrosal sinus sampling (IPSS) may be necessary to confirm central ACTH production 1

Clinical Implications

• Treatment approach must target the predominant source of hypercortisolism 7
• For mixed etiology cases, a stepwise approach may be needed:
  • Addressing the primary source first (typically pituitary if ACTH-dependent)
  • Monitoring for persistent hypercortisolism after initial treatment
  • Considering bilateral adrenalectomy if hypercortisolism persists despite pituitary-directed therapy 4

Follow-up Considerations

• Long-term monitoring is essential as recurrence rates after treatment of Cushing's disease vary from 6% to 40% 3
• Patients should receive 6-monthly clinical examinations, 24-hour urinary free cortisol measurements, electrolytes, and morning serum cortisol for at least 2 years, followed by lifelong annual clinical assessment 3
• Monitoring for pituitary hormone deficiencies is important, as they are common after surgical or radiotherapeutic cure of Cushing's disease 3

While mixed adrenal and pituitary etiology in Cushing's syndrome is uncommon, careful biochemical testing and imaging can help identify these complex cases and guide appropriate management strategies.