Adrenal Adenoma: Causes, Diagnosis, and Treatment

What Exactly Is an Adrenal Adenoma?

An adrenal adenoma is a benign, usually solitary mass arising from the cortex of the adrenal gland. It is not cancer. The adrenal cortex has three zones, each producing distinct hormones: the zona glomerulosa makes aldosterone, the zona fasciculata makes cortisol, and the zona reticularis makes androgens. An adenoma can originate in any zone, and its zone of origin determines which, if any, hormone it overproduces.

The term "adrenal incidentaloma" applies to any adrenal mass larger than 1 cm discovered on imaging ordered for an unrelated reason. Adrenal adenomas account for the large majority of incidentalomas. Population autopsy data suggest a prevalence of approximately 3% in adults under 50, rising to roughly 10% in adults over 70. [1] A 2020 meta-analysis in the Journal of Clinical Endocrinology and Metabolism estimated that 82% of incidentally found adrenal masses are benign adenomas. [2]

The adrenal glands sit atop each kidney and measure only 4 to 6 cm in their longest dimension. Despite their small size, they regulate blood pressure, the stress response, electrolyte balance, and aspects of immune function. An adenoma that silently secretes even modest amounts of extra cortisol can raise cardiovascular risk over years.

How Common Are Adrenal Adenomas?

Population prevalence is higher than most clinicians expect. Cross-sectional CT series consistently place incidentaloma prevalence at 4 to 7% of all abdominal scans. [3] Because abdominal CT use has grown sharply over the past two decades, detection rates have climbed with it.

Age is the strongest demographic predictor. Data from a Danish registry of 1,004 patients with adrenal incidentalomas showed median age at discovery of 62 years, with fewer than 8% of cases occurring before age 40. [4] Obesity, hypertension, and type 2 diabetes are all associated with higher rates of autonomous cortisol secretion from otherwise "non-functioning" adenomas, a finding that changes management for a large proportion of primary care patients.

Functioning vs. Non-Functioning Adenomas

Adenomas are classified as non-functioning or functioning.

Non-functioning adenomas produce no measurable excess hormone. They require periodic imaging surveillance and repeat biochemical testing rather than surgery. The 2016 Endocrine Society Clinical Practice Guideline on adrenal incidentalomas recommends biochemical reassessment at 1 year for non-functioning lesions, with imaging follow-up at 6 to 12 months if the initial CT is indeterminate. [5]

Functioning adenomas are subdivided by hormone excess:

Autonomous cortisol secretion (ACS). ACS exists on a spectrum. Overt Cushing syndrome requires an 8 mg/dL overnight dexamethasone suppression test (DST) cortisol above 50 nmol/L plus signs of cortisol excess. Mild autonomous cortisol secretion (MACS), formerly called "subclinical Cushing syndrome," is defined by a 1 mg overnight DST cortisol between 51 and 138 nmol/L without classic Cushingoid features. MACS carries real metabolic consequences: a 2022 study in JAMA Internal Medicine (N=4,085 patients from 14 Italian centers) found that patients with MACS had a 2.2-fold higher rate of major adverse cardiovascular events compared with non-functioning adenoma patients over a median 7.4-year follow-up. [6]

Primary aldosteronism (Conn syndrome). An aldosterone-producing adenoma drives autonomous aldosterone secretion independent of renin, producing hypertension and hypokalemia. The Endocrine Society recommends screening with an aldosterone-to-renin ratio (ARR) in all patients with an adrenal adenoma who have hypertension or hypokalemia. [7] An ARR above 30 (with aldosterone above 15 ng/dL) warrants confirmatory testing.

Pheochromocytoma. Strictly speaking, a pheochromocytoma is not an adenoma but a catecholamine-secreting tumor of chromaffin cells. Every adrenal mass workup must exclude it with plasma free metanephrines or 24-hour urine fractionated metanephrines before any invasive procedure. [5]

The Hormonal Workup: Step by Step

Every patient with a newly discovered adrenal mass larger than 1 cm needs a structured biochemical evaluation regardless of symptoms. The Endocrine Society 2016 guideline specifies the following minimum panel. [5]

1. 1 mg overnight dexamethasone suppression test to screen for cortisol autonomy. The patient takes 1 mg dexamethasone at 11 p.m. and has serum cortisol drawn at 8 a.m. A result above 50 nmol/L (1.8 mcg/dL) is abnormal.
2. Plasma free metanephrines or 24-hour urine fractionated metanephrines to exclude pheochromocytoma.
3. Aldosterone-to-renin ratio in any patient with hypertension or unprovoked hypokalemia.

If the DST cortisol is between 51 and 138 nmol/L, the diagnosis of MACS is likely. Confirmatory testing with late-night salivary cortisol, 24-hour urinary free cortisol, and/or a 2-day low-dose DST clarifies borderline cases. [8] A cortisol above 138 nmol/L after the 1 mg DST, combined with clinical features, supports overt Cushing syndrome and prompts referral to endocrinology.

Adrenal Adenoma and Cushing Syndrome

Cushing syndrome describes the constellation of signs and symptoms caused by prolonged excess glucocorticoid exposure. ACTH-independent Cushing syndrome, where the adenoma itself drives cortisol independently of pituitary ACTH, accounts for roughly 15 to 20% of all endogenous Cushing syndrome cases. [9]

Clinical features include central obesity, facial rounding ("moon face"), supraclavicular fat pads, wide purple striae (greater than 1 cm), easy bruising, proximal muscle weakness, and hypertension. Not all patients show all features. Bone loss is common: a meta-analysis in Osteoporosis International (N=3,286) found vertebral fracture prevalence of 50% in patients with overt Cushing syndrome vs. 23% in age-matched controls. [10]

Biochemical confirmation follows a three-test approach recommended by the Endocrine Society's 2008 Cushing syndrome guideline: two of three positive results from (a) 24-hour urinary free cortisol above the upper limit of normal on two separate collections, (b) late-night salivary cortisol elevated on two separate collections, or (c) 1 mg overnight DST cortisol above 138 nmol/L (5 mcg/dL). [11]

Once cortisol excess is confirmed, plasma ACTH distinguishes adrenal from pituitary or ectopic sources. A suppressed ACTH (below 10 pg/mL) with a unilateral adrenal adenoma points to ACTH-independent disease. A normal or elevated ACTH directs attention to the pituitary gland.

Cushing Disease: When the Pituitary Drives the Adenoma Workup

Cushing disease refers specifically to pituitary corticotroph adenoma causing ACTH-dependent cortisol excess. The adrenal glands in Cushing disease are typically bilaterally hyperplastic rather than adenomatous, but small adrenal nodules can co-exist and create diagnostic confusion. [12]

Distinguishing Cushing disease from an adrenal adenoma matters because the treatments differ entirely. Cushing disease is treated with transsphenoidal pituitary surgery, with remission rates of 65 to 90% in experienced centers. [13] An adrenal adenoma causing ACTH-independent Cushing syndrome is treated with laparoscopic unilateral adrenalectomy.

The high-dose DST (8 mg overnight) exploits the relative preservation of ACTH responsiveness in Cushing disease. Cortisol suppression by more than 50% suggests pituitary-driven disease; failure to suppress favors an adrenal or ectopic source. Bilateral inferior petrosal sinus sampling (BIPSS) with corticotropin-releasing hormone stimulation remains the gold standard for confirming pituitary ACTH excess when imaging is equivocal. [14]

Adrenal Adenoma and Primary Aldosteronism

Primary aldosteronism (PA) is the most common surgically correctable cause of hypertension. The Endocrine Society estimates PA affects 5 to 10% of all hypertensive patients. [7] Among patients with an adrenal adenoma and coexisting hypertension, PA prevalence rises to approximately 3 to 4%.

The Conn adenoma (aldosterone-producing adenoma, APA) is typically small, often under 2 cm, and unilateral. Its signature lab pattern is suppressed plasma renin activity alongside elevated aldosterone. After ARR screening and confirmatory testing (oral sodium loading or fludrocortisone suppression test), adrenal venous sampling (AVS) is recommended to confirm lateralization before surgery, because CT alone misidentifies laterality in up to 25% of cases. [7] A 2021 systematic review in Hypertension (N=2,604) found AVS-guided surgical decisions led to biochemical cure in 94% of patients with unilateral APA vs. 54% in those managed by CT alone. [15]

Post-adrenalectomy, blood pressure normalizes completely in 30 to 60% of APA patients; the remainder see significant reductions allowing medication reduction. [16] Factors predicting complete cure include younger age, fewer antihypertensive drugs, absence of renal damage, and shorter hypertension duration.

Adrenal Adenoma, Addison Disease, and Adrenal Insufficiency

Addison disease is primary adrenal insufficiency: the adrenal cortex itself fails to produce adequate cortisol and aldosterone. Adrenal adenomas do not cause Addison disease. The distinction matters because patients and clinicians sometimes conflate low-cortisol states with adrenal tumors.

The most common cause of Addison disease in high-income countries is autoimmune adrenalitis, accounting for roughly 70 to 90% of cases. [17] Classic symptoms include fatigue, weight loss, salt craving, nausea, hyperpigmentation of skin and mucosae (driven by elevated ACTH and melanocyte-stimulating hormone), and postural hypotension. The 250 mcg cosyntropin (synthetic ACTH) stimulation test diagnoses Addison disease: a peak cortisol below 500 nmol/L (18 mcg/dL) at 30 or 60 minutes is abnormal. [17]

Treatment uses oral hydrocortisone 15 to 25 mg/day in divided doses mimicking the diurnal cortisol rhythm, combined with fludrocortisone 0.05 to 0.2 mg/day for mineralocorticoid replacement. [18] Patients need stress dosing instructions: any febrile illness, surgery, or trauma requires doubling or tripling of the hydrocortisone dose. An adrenal crisis (acute severe adrenal insufficiency) is treated with IV hydrocortisone 100 mg bolus followed by 200 mg/24 hours by continuous infusion or 50 mg every 6 hours. [18]

Secondary Adrenal Insufficiency After Adrenalectomy

Secondary adrenal insufficiency (SAI) is caused by inadequate ACTH secretion from the pituitary, not intrinsic adrenal disease. The most common cause globally is exogenous corticosteroid use suppressing the hypothalamic-pituitary-adrenal (HPA) axis. [19] In the context of adrenal adenomas, SAI is a predictable consequence of unilateral adrenalectomy for cortisol-secreting adenomas.

When one adrenal adenoma has been autonomously secreting cortisol, the contralateral adrenal gland is suppressed. After surgery, the remaining gland may take 6 to 18 months to recover full function. [20] During this period, patients need hydrocortisone replacement, typically starting at 20 to 30 mg/day and tapering guided by morning cortisol and cosyntropin stimulation testing every 3 to 6 months.

A 2023 cohort study in The Journal of Clinical Endocrinology and Metabolism (N=312 adrenalectomy patients for MACS) found that 38% had SAI confirmed by cosyntropin testing at 3 months post-operatively, falling to 14% at 12 months. [21] Patients with pre-operative DST cortisol above 138 nmol/L were more likely to experience prolonged SAI.

Clinicians should counsel every patient undergoing adrenalectomy for any cortisol-secreting adenoma that they will need steroid replacement after surgery and must carry a steroid emergency card. [5] Missing this step is a preventable cause of adrenal crisis.

Imaging Characteristics: How Radiologists Identify Adenomas

Non-contrast CT attenuation is the most reliable single imaging marker. Lipid-rich adenomas, which make up roughly 70% of all adenomas, have CT attenuation values below 10 Hounsfield units (HU) and can be confidently diagnosed without additional workup. [22] Lipid-poor adenomas (10, 30 HU) require contrast-enhanced CT with washout calculation: an absolute washout above 60% or a relative washout above 40% at 15 minutes supports adenoma over malignancy. [23]

MRI chemical shift imaging is an alternative for lipid-rich adenomas when CT is contraindicated. A signal intensity index (SII) drop of more than 16.5% on opposed-phase vs. in-phase imaging confirms lipid content consistent with adenoma. [24]

FDG-PET/CT is reserved for lesions that remain indeterminate after CT and MRI. Adenomas are typically FDG-avid only mildly or not at all; adrenocortical carcinoma and metastases show higher standardized uptake values (SUV). [25]

Size is a secondary but important factor. The 2016 Endocrine Society guideline recommends surgical resection for any adrenal mass above 4 cm regardless of hormonal status, because the risk of adrenocortical carcinoma rises substantially above this threshold. [5] Between 2 and 4 cm, imaging characteristics and hormonal function together guide the decision.

Treatment Options: Surgery, Surveillance, and Medical Management

Laparoscopic adrenalectomy is the standard treatment for all functioning adrenal adenomas and for non-functioning lesions above 4 cm or with indeterminate imaging. Laparoscopic approaches result in shorter hospital stays (median 2 days vs. 5 days open) and lower complication rates. [26] Robotic-assisted adrenalectomy is increasingly used and shows comparable outcomes to standard laparoscopy in experienced centers.

Active surveillance applies to non-functioning adenomas below 4 cm with benign imaging features (attenuation <10 HU or favorable washout). Recommended follow-up is non-contrast CT at 6 to 12 months to assess growth; lesions that grow more than 0.8 cm per year warrant reassessment. Hormonal re-testing at 1 year catches new-onset autonomous secretion in approximately 3 to 5% of initially non-functioning adenomas. [5]

Medical management of autonomous cortisol secretion is an evolving area. Mifepristone (a glucocorticoid receptor antagonist, FDA-approved for Cushing syndrome) at doses of 300, 1 to 200 mg/day may reduce metabolic complications in patients with MACS who are poor surgical candidates. [27] Osilodrostat, a steroidogenesis inhibitor approved by the FDA in March 2020 for Cushing disease, is used off-label in adrenal Cushing syndrome at doses of 2 to 30 mg twice daily. [28]

For primary aldosteronism in patients who refuse or cannot undergo surgery, mineralocorticoid receptor antagonists (spironolactone 25 to 100 mg/day or eplerenone 25 to 50 mg twice daily) control blood pressure and reverse hypokalemia, though they do not cure the underlying adenoma. [7]

Post-Operative Monitoring and Long-Term Follow-Up

Patients who undergo adrenalectomy for cortisol-secreting adenoma need:

• Hydrocortisone replacement starting the morning of surgery.
• Cosyntropin stimulation test at 3 months, 6 months, and 12 months to track HPA axis recovery.
• Morning cortisol above 400 nmol/L on at least two consecutive tests before replacement is withdrawn.
• Annual metabolic panel (blood pressure, fasting glucose, HbA1c, lipid panel) because cardiovascular risk factors take 12 to 24 months to fully improve after cure. [6]

Patients with Conn adenoma need blood pressure monitoring at 1, 3, 6, and 12 months post-operatively. Aldosterone and renin are checked at 1 and 3 months to confirm biochemical cure. Potassium normalizes within days of surgery; antihypertensive medications are tapered as tolerated. [16]

Non-functioning adenomas that remain stable at the 12-month imaging follow-up do not require further routine imaging unless new symptoms develop. Biochemical re-testing is not recommended beyond 4 years if all prior testing has been normal. [5]

The Endocrine Society guideline states: "We recommend that all patients with adrenal incidentalomas undergo a hormonal evaluation to exclude subclinical hormone excess and a radiological evaluation to exclude malignancy." [5] That single sentence defines the floor of care for every adenoma discovered on imaging.