What hormone does a functional adrenal incidentaloma most likely produce?

Most Common Hormone Produced by Functional Adrenal Incidentalomas

Cortisol is the most commonly produced hormone by functional adrenal incidentalomas, with subclinical autonomous cortisol secretion (previously called subclinical Cushing's syndrome) being the most frequent hormonal abnormality detected in these tumors.

Epidemiology and Prevalence

All patients with adrenal incidentalomas should be screened for autonomous cortisol secretion using the 1 mg dexamethasone suppression test (DST), as this is the most common functional abnormality. 1

• Subclinical autonomous cortisol secretion occurs in approximately 5-20% of all adrenal incidentalomas 2
• Some studies report that up to 18% of incidentalomas demonstrate autonomous cortisol production when using standard screening criteria 3
• In prospective follow-up studies, subclinical cortisol hypersecretion was the most frequent hormonal abnormality identified 4

Screening Algorithm for Functional Adrenal Incidentalomas

Cortisol Screening (Required for ALL Patients)

The 1 mg overnight dexamethasone suppression test is the preferred screening test for identifying autonomous cortisol secretion. 1

• Interpretation thresholds: 1

  • ≤50 nmol/L (1.8 μg/dL): excludes cortisol hypersecretion
  • 51-138 nmol/L: possible autonomous cortisol secretion

  • 138 nmol/L (5 μg/dL): evidence of cortisol hypersecretion

• Ancillary testing when DST is abnormal: 1

  • Plasma ACTH to confirm ACTH-independent secretion
  • 24-hour urinary free cortisol
  • Midnight salivary cortisol
  • DHEAS levels

Other Hormone Screening (Selective Based on Clinical Context)

Aldosterone screening should be performed only in patients with hypertension and/or hypokalemia. 1

• Aldosterone/renin ratio (ARR) >20 ng/dL per ng/mL/hr has >90% sensitivity and specificity 1
• Testing should be done in the morning after 2 hours upright and 5-15 minutes seated 1

Pheochromocytoma screening is NOT recommended for lesions with <10 HU on unenhanced CT and no symptoms of catecholamine excess. 1

• Screen with plasma free metanephrines if lesion ≥10 HU or symptoms present 1
• Levels >2× upper limit of normal are diagnostic 1

Androgen screening should be performed only when adrenocortical carcinoma is suspected or virilization signs are present. 1

• Initial tests: DHEAS and testosterone 1
• ACC is responsible for >50% of androgen hypersecretion cases 1

Clinical Significance of Subclinical Cortisol Excess

Mild autonomous cortisol secretion (MACS) is associated with significant metabolic comorbidities despite the absence of overt Cushing's syndrome features. 1

Associated Comorbidities

• Type 2 diabetes mellitus 1
• Hypertension 1, 5
• Cardiovascular events 1
• Vertebral fractures 1
• Increased mortality 1

Natural History Considerations

Importantly, patients with failed cortisol suppression rarely progress to overt Cushing's syndrome, but the metabolic complications persist. 1

• Estimated cumulative risk of developing overt Cushing's syndrome is 12.5% after 1 year in patients with subclinical hypercortisolism 6
• Risk of non-secreting incidentalomas developing subclinical hyperfunction is 3.8% at 1 year and 6.6% at 5 years 6
• Intermittent subclinical autonomous cortisol hypersecretion occurs in a significant percentage of cases 4

Management Implications

Younger patients with MACS who have progressive metabolic comorbidities attributable to cortisol excess should be considered for adrenalectomy after shared decision-making. 1

• Minimally-invasive surgery should be performed when feasible 1
• Patients not managed surgically require annual clinical screening for new or worsening comorbidities 1
• Post-adrenalectomy, improvement in hypertension, weight loss, and better metabolic control of diabetes have been documented 5

Critical Pitfall to Avoid

Adrenocortical insufficiency is a major risk after adrenalectomy in patients with autonomous cortisol secretion, even when subclinical. 5, 3

• Temporary adrenal insufficiency occurred in 4 of 7 patients after surgery in one series 5
• Various degrees of HPA axis suppression may be present even when morning cortisol after 1 mg dexamethasone is <140 nmol/L 3
• Perioperative stress-dose glucocorticoid coverage and post-operative monitoring are essential 5, 3