Adrenal Cortical Adenoma

An adrenal cortical adenoma is a benign neoplasm arising from the adrenal cortex that may be hormonally silent or secrete cortisol, aldosterone, androgens, or, rarely, estrogens.

Also Called

• Adrenocortical adenoma
• Adrenal adenoma
• Cortical adenoma
• Nonfunctioning adrenal adenoma (NFAA)
• Aldosterone-producing adenoma (APA; Conn adenoma)
• Cortisol-secreting adenoma (CSA)
• Androgen-secreting adenoma (very rare)

Key Definitions

• Nonfunctioning adrenal adenoma: a benign tumor that does not secrete active hormones in quantities sufficient to cause a clinical syndrome; often detected incidentally on imaging ^[4]B2b.
• Functioning adrenal adenoma: a tumor that produces excess cortisol (Cushing syndrome), aldosterone (primary hyperaldosteronism), or androgens (virilization).
• Cushing syndrome: the clinical manifestation of chronic glucocorticoid excess; when caused by an adrenal adenoma, it is ACTH-independent ^[10]C4.
• Primary hyperaldosteronism: autonomous aldosterone secretion leading to hypertension and often hypokalemia; the most common surgically correctable cause is an APA ^[12]C4.
• Adrenal incidentaloma: an adrenal mass >1 cm discovered incidentally on imaging; up to 4.4% of patients undergoing CT harbor one, and most prove to be adrenal cortical adenomas ^[5]C4.

Classification by Hormonal Activity

Axis Nomenclature

Adrenal cortical adenomas disrupt specific endocrine axes. Cortisol-secreting adenomas suppress the hypothalamic-pituitary-adrenal (HPA) axis via negative feedback, rendering the contralateral adrenal atrophic. Aldosterone-producing adenomas activate the renin-angiotensin-aldosterone system (RAAS) independently of renin, leading to volume expansion and hypertension. Understanding these axis perturbations is essential for interpreting diagnostic tests and planning perioperative management.

Pearl: A nonfunctioning adrenal adenoma is defined by the absence of overt hormonal excess, but up to 62% of bilateral incidentalomas show evidence of hypercortisolism on dynamic testing ^[8]B3b; always perform a 1-mg dexamethasone suppression test and measure plasma aldosterone and renin in every patient with an adrenal mass.

Building on the classification framework, the pathophysiology of adrenal cortical adenomas is best understood through the endocrine axes they disrupt. Normal adrenal steroidogenesis is orchestrated by the transcription factor steroidogenic factor-1 (SF-1), an orphan nuclear receptor expressed in 100% of normal adrenal cortex and adrenal cortical adenomas ^[21]C4. SF-1 drives the expression of enzymes required for cortisol, aldosterone, and sex hormone synthesis. In the intact hypothalamic-pituitary-adrenal (HPA) axis, corticotropin-releasing hormone (CRH) stimulates pituitary ACTH release, which in turn drives adrenal cortisol production; cortisol then feeds back to suppress CRH and ACTH. Similarly, the renin-angiotensin-aldosterone system (RAAS) responds to volume status: renin release triggers angiotensin II formation, which stimulates aldosterone secretion, and aldosterone acts on the kidney to retain sodium, suppressing renin.

Pathophysiology of Functioning Adenomas

Functioning adrenal cortical adenomas acquire somatic mutations that confer autonomous hormone secretion, uncoupling steroid output from physiologic feedback. In cortisol-secreting adenomas, sustained cortisol production suppresses pituitary ACTH, leading to low or undetectable ACTH levels. In aldosterone-secreting adenomas, autonomous aldosterone secretion suppresses renin activity. Sex hormone-secreting adenomas (androgens or estrogens) suppress pituitary gonadotropins (LH, FSH) via negative feedback. Non-functioning adenomas, by contrast, produce negligible hormones and do not perturb these axes.

A clinically important variant is pheochromocytoma with synchronous ipsilateral adrenal cortical adenoma (PSCA), identified in 4% of patients undergoing adrenalectomy for pheochromocytoma ^[23]C4. Among these patients, 38% had clinically important cortical hormone secretion: 25% had glucocorticoid secretory autonomy and 13% had primary aldosteronism ^[23]C4. This co-occurrence can produce mixed biochemical and imaging features, mimicking a single functioning neoplasm and posing a diagnostic pitfall.

Biochemical Signature and Diagnostic Patterns

The hallmark of a functioning adrenal cortical adenoma is a discordant paired hormone pattern that localizes the lesion to the adrenal gland:

• Cortisol excess: Elevated 24-hour urinary free cortisol or >1.8 mcg/dL after 1 mg dexamethasone suppression, with suppressed ACTH (<10 pg/mL).
• Aldosterone excess: Elevated plasma aldosterone concentration with suppressed plasma renin activity (aldosterone-to-renin ratio >30).
• Androgen excess: Elevated dehydroepiandrosterone sulfate (DHEAS) or testosterone with suppressed LH/FSH.

These patterns distinguish adrenal adenoma from pituitary or ectopic sources. For example, a cortisol-secreting adenoma shows low ACTH, whereas Cushing disease shows high ACTH. Similarly, an aldosterone-secreting adenoma shows low renin, whereas secondary hyperaldosteronism shows high renin.

Mechanism Flowchart

Pearl: When evaluating an adrenal mass, always obtain paired hormone levels (ACTH with cortisol, renin with aldosterone), a discordant pattern (high hormone with suppressed regulator) confirms adrenal autonomy and guides surgical planning.

The biochemical signatures of cortisol, aldosterone, and androgen excess arise from a surprisingly common substrate: adrenal cortical adenomas are found in approximately one-tenth of the general population ^[32]D5. Adrenal incidentalomas, most of which are adenomas, are detected in up to 4.4% of patients undergoing CT scanning, and their detection is rising with increased imaging utilization ^[5]C4.

Demographic Distribution

Sexual dimorphism is pronounced. Non-aldosterone-producing adenomas (NAPACA) and cortisol-secreting adenomas (CSA) are more common in females, with female-to-male ratios ranging from 1.1:1 to 3.8:1 ^[1]B2c. In contrast, aldosterone-producing adenomas (APA) show a slight male predominance (female-to-male ratio 0.8:1) ^[1]B2c. Most adenomas occur in the left adrenal gland, with left-to-right ratios of 1.1:1 to 1.8:1 for NAPACA, CSA, and APA ^[1]B2c. This lateralization may relate to the larger size of the left adrenal in both sexes ^[1]B2c.

Risk Factors and Etiology

Beyond sex and laterality, genetic syndromes confer substantial risk. In Carney triad , a rare disorder of unknown etiology affecting predominantly young women (85% female, mean onset 20 years), adrenocortical adenomas occur in 20% of patients ^[26]C4. Ectopic adrenocortical adenomas, though rare (incidence of ectopic adrenal tissue ~1%), are typically nonfunctional and diagnosed postoperatively ^[35]C4. Childhood adrenal cortical neoplasms are exceedingly rare, with an annual incidence of 0.3-0.38 per 1 million children under 15 years ^[36]C4.

At the molecular level, adrenal cortical adenomas are driven by somatic mutations in ion channels (in aldosterone-producing adenomas) and the protein kinase A signaling pathway (in cortisol-producing adenomas), linking histopathology to translational genomics ^[32]D5.

These epidemiological patterns set the stage for the clinical presentation, which varies by hormonal activity.

Pearl: The left adrenal predominance and female sex bias for non-aldosterone-producing adenomas are consistent findings that should be considered when interpreting adrenal imaging and planning biopsy or surgery.

The clinical presentation of adrenal cortical adenoma is determined entirely by its secretory profile and size, ranging from an incidental imaging finding to life-threatening endocrine crises. Most adenomas are nonfunctioning and discovered incidentally during abdominal imaging for unrelated indications ^[2]C4. However, even these so-called nonfunctioning tumors may secrete hormones in quantities too small to cause overt syndromes but sufficient to exert subtle metabolic effects, a phenomenon increasingly recognized as a potential cardiovascular risk ^[2]C4.

Presenting Symptoms

Nonfunctioning adenomas are asymptomatic by definition. They are detected on cross-sectional imaging performed for other reasons, and the diagnosis is confirmed by the absence of clinical or biochemical evidence of hormone excess ^[2]C4.

Cortisol-secreting adenomas (Cushing syndrome) present with a classic constellation: hypertension , moon face, buffalo hump, violaceous striae over the abdomen and thighs, trunkal obesity, and hirsutism ^[2]C4. Importantly, hypercortisolism can also precipitate non-atherosclerotic myocardial infarction and heart failure with reduced ejection fraction, a rare but critical presentation ^[11]C4.

Aldosterone-secreting adenomas (primary hyperaldosteronism) manifest with hypertension and fatigue, often accompanied by hypokalemia ^[2]C4. The hypertension may be resistant to standard therapy, and hypokalemia can cause muscle weakness, cramps, and polyuria ^[12]C4.

Androgen-secreting adenomas are rare. A 17-hydroxyprogesterone (17-OHP)-secreting adenoma has been reported in a 33-year-old woman with recurrent miscarriage, highlighting that elevated 17-OHP should not be assumed to represent congenital adrenal hyperplasia ^[43]C4.

Mass effect from large adenomas (typically >4-5 cm) can cause abdominal or flank pain, early satiety, or a palpable mass. Hemorrhage into the tumor is an uncommon but acute complication presenting with sudden severe pain and hemodynamic instability ^[27]D5.

Phenotypic Variants

Red Flags

• Hypertensive crisis with headache, palpitations, and diaphoresis suggests pheochromocytoma (or an adenoma mimicking it) and requires urgent alpha-blockade ^[2]C4[40]C4.
• Severe hypokalemia (serum K+ < 3.0 mmol/L) in a hypertensive patient mandates evaluation for primary hyperaldosteronism ^[2]C4[12]C4.
• Acute chest pain or heart failure in a patient with cushingoid features may indicate hypercortisolism-induced myocardial infarction ^[11]C4.
• Sudden abdominal pain with hypotension raises concern for hemorrhage into a large adenoma ^[27]D5.

Atypical Presentations

Adrenal cortical adenoma can masquerade as other conditions. An oncocytoma variant presented with a near tenfold elevation of urinary vanillylmandelic acid and metanephrines, clinically indistinguishable from pheochromocytoma ^[40]C4. Ectopic adenomas in the renal sinus or gastric wall are typically nonfunctioning and mistaken for renal or gastric stromal tumors on imaging ^{[35]C4[38]C4[41]C4}. A 17-OHP-secreting adenoma mimicked non-classical 21-hydroxylase deficiency, requiring adrenal venous sampling for correct localization ^[43]C4. Dopamine-secreting ganglioneuroma, though not an adenoma, is a key differential for functional adrenal masses and may present with flank pain, weight loss, fatigue, and hypomania ^[42]C4.

Pearl: A patient with hypertension, hypokalemia, and an adrenal mass has primary hyperaldosteronism until proven otherwise; a patient with cushingoid features and chest pain may be having a hypercortisolism-driven myocardial infarction, check cortisol before assuming atherosclerotic etiology.

Once clinical suspicion is raised by the constellation of symptoms and signs described above, the diagnostic workup proceeds in two parallel tracks: biochemical confirmation of hormonal excess and anatomic localization of the adrenal lesion. The goal is to establish whether the adenoma is functioning (cortisol, aldosterone, or androgen excess) and, if so, to lateralize the source to guide surgical planning. Non-functioning adenomas require surveillance rather than intervention, making accurate biochemical phenotyping essential.

Biochemical Evaluation

Screening tests are selected based on the clinical presentation. For suspected Cushing's syndrome, the 1-mg overnight dexamethasone suppression test (DST) is the first-line screen: a post-dexamethasone serum cortisol >1.8 µg/dL (50 nmol/L) indicates failed suppression and warrants further evaluation ^[10]C4. Additional screening includes 24-hour urinary free cortisol (UFC) and late-night salivary cortisol ^[10]C4. For primary hyperaldosteronism, the aldosterone-to-renin ratio (ARR) is the screening test; a ratio >20-30 (depending on assay) with plasma aldosterone >20 ng/dL and renin <2.5 mU/L is suggestive ^[2]C4. For androgen excess, serum 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S) are measured; a cosyntropin stimulation test may unmask subtle elevations ^[15]C4.

Dynamic testing confirms hormonal autonomy. In ACTH-dependent Cushing's, the high-dose dexamethasone suppression test (HDDST) (2 mg every 6 hours for 48 hours) is used: ≥50% suppression of serum cortisol or UFC suggests a pituitary source, while lack of suppression points to ectopic ACTH/CRH production ^[10]C4. The desmopressin stimulation test (8 µg IV) measures ACTH and cortisol response; a ≥50% rise in ACTH or ≥20% rise in cortisol is considered positive ^[10]C4. The overnight metyrapone test (1500 mg at 2200 h) can supplement evaluation: marked cortisol suppression with no ACTH rise suggests an ectopic source ^[10]C4. For primary hyperaldosteronism, confirmatory tests include saline infusion test, captopril suppression, or irbesartan suppression ^[12]C4.

Imaging

Unenhanced CT is the initial imaging modality of choice. Adrenal cortical adenomas typically appear as homogeneous, well-circumscribed masses with low attenuation (<10 Hounsfield units [HU]) on unenhanced CT due to intracellular lipid content ^[31]D5. Lesions >10 HU require further characterization with contrast-enhanced CT and washout calculations: adenomas show >50% absolute washout at 10-15 minutes ^[31]D5. MRI with chemical shift imaging (in-phase/opposed-phase) demonstrates signal drop on opposed-phase sequences in lipid-rich adenomas ^[31]D5.

Functional imaging is reserved for specific scenarios. NP-59 (iodocholesterol) scintigraphy can confirm unilateral aldosterone production when CT findings are equivocal ^[12]C4. Metaiodobenzylguanidine (MIBG) scan is used to rule out pheochromocytoma when catecholamine excess is suspected ^[12]C4. FDG-PET/CT is not routinely indicated for adenoma diagnosis but may be used to differentiate benign from malignant lesions; however, false-positive rates are high (28.2%) because some adenomas exhibit increased FDG uptake ^[33]B3b. Risk factors for true metastasis include a history of lung malignancy and SUVmax >2.65 ^[33]B3b.

Adrenal Venous Sampling

Adrenal venous sampling (AVS) is the gold standard for lateralizing aldosterone excess in primary hyperaldosteronism when CT shows bilateral nodules or normal adrenals ^[12]C4. AVS requires selective catheterization of both adrenal veins and measurement of aldosterone and cortisol. A lateralization index (aldosterone/cortisol ratio on dominant side divided by nondominant side) >2-4 indicates unilateral disease ^[12]C4. AVS is technically challenging and should be performed at experienced centers.

Histopathology and Immunohistochemistry

When surgical resection is performed, histologic examination confirms the diagnosis. Adrenal cortical adenomas are composed of clear cells (lipid-rich) and compact cells, arranged in nests or cords, with no significant nuclear pleomorphism, atypical mitoses, or necrosis ^[10]C4[20]D5. The Ki-67 proliferation index is typically low (<5%) ^[10]C4[20]D5.

Immunohistochemistry (IHC) is essential to confirm adrenocortical origin and exclude pheochromocytoma or metastasis. A panel of markers is recommended:

SF1 is the most reliable marker for confirming adrenocortical origin ^[20]D5. CYP11B2 immunohistochemistry (HISTALDO classification) identifies functional aldosterone-producing sites and helps predict bilateral disease in primary aldosteronism ^[20]D5.

Diagnostic Algorithm

Step 1: Screen for hormonal excess using the appropriate first-line tests based on clinical presentation. Step 2: If screening is positive, perform confirmatory dynamic testing (HDDST, desmopressin, metyrapone for Cushing; saline infusion or captopril for aldosteronism; cosyntropin for androgen excess). Step 3: Localize the lesion with dedicated adrenal CT (unenhanced and washout) or MRI. Step 4: If lateralization is uncertain (bilateral nodules, normal adrenals, or discordant imaging), proceed to AVS for aldosteronism or functional imaging (NP-59, MIBG, FDG-PET/CT) for other scenarios. Step 5: Surgical resection with histopathologic and IHC confirmation.

Diagnostic Test Performance

Note: The PPV of 71.8% corresponds to a false-positive rate of 28.2% in patients with suspected solitary adrenal metastasis ^[33]B3b.

Pearl: The combination of a low-dose dexamethasone suppression test and adrenal CT with unenhanced attenuation <10 HU reliably identifies most cortisol-secreting adenomas, but atypical features (e.g., >10 HU, rapid growth, or bilateral nodules) warrant further evaluation with AVS or NP-59 scintigraphy to avoid unnecessary surgery or missed functional lesions.

Once the diagnosis of an adrenal cortical adenoma is confirmed, the next step is to stratify the lesion by its functional activity, histologic subtype, and risk of malignancy, each tier carries distinct implications for surveillance intensity, surgical urgency, and the likelihood of bilateral disease or recurrence.

Functional Risk Stratification

The functional status of the adenoma determines the immediate clinical urgency. Non-functioning adenomas require surveillance, while functioning adenomas causing Cushing syndrome, primary hyperaldosteronism, or virilization demand surgical management. Autonomous cortisol secretion may be mild and clinically subtle; the 2022 WHO classification notes that in such cases, the non-tumorous adrenal cortex may show intermittent absence of the zona reticularis as the first sign of cortical atrophy ^[20]D5.

In primary aldosteronism , the HISTALDO classification endorsed by the 2022 WHO classification provides a critical risk stratification tool. Classic histology (solitary aldosterone-producing adenoma [APA] or aldosterone-producing nodule [APN]) carries a biochemical recurrence risk of less than 5% after unilateral adrenalectomy , whereas non-classic histology (aldosterone-producing diffuse hyperplasia, multifocal APN, and/or multifocal aldosterone-producing micronodule) is associated with a recurrence risk of approximately 42% due to bilateral disease ^[20]D5. This distinction directly guides postoperative surveillance intensity and the threshold for repeat imaging or biochemical testing.

Histologic Classification of Nodular Disease

The 2022 WHO classification subdivides adrenocortical nodular disease into three categories: (a) sporadic nodular adrenocortical disease, (b) bilateral micronodular adrenocortical disease, and (c) bilateral macronodular adrenocortical disease ^[20]D5. Sporadic nodular disease consists of non-functional, subcentimeter nodules that are typically incidental and require no intervention. In contrast, bilateral micronodular and macronodular disease are usually associated with hypercortisolism and often harbor germline variants in genes regulating the protein kinase A pathway (e.g., PRKAR1A, ARMC5), making genetic counseling and long-term surveillance for recurrence imperative ^[20]D5.

Biomarkers for Malignancy Risk

Preoperative differentiation of adrenal cortical adenoma from adrenal cortical carcinoma (ACC) remains a central challenge. Apolipoprotein A4 (APOA4) has been identified as a consistently downregulated circulating protein in ACC compared with ACA across discovery, targeted, and orthogonal validation platforms, supporting its potential as a serum biomarker for malignancy risk stratification ^[16]B3b. Additionally, metabolic reprogramming markers such as hexokinase 1 (HK1) and pyruvate kinase M2 (PKM2) show significantly higher expression in ACC than in ACA (p < 0.001 and p = 0.014, respectively), further aiding in the risk assessment of an adrenal mass ^[47]B3b.

Imaging and Size-Based Risk

Gross pathological features, tumor size > 5 cm, weight > 100 g, irregular border, and heterogenous cut surface, should alert the clinician to the possibility of malignancy, prompting comprehensive sampling or complete submission of the tumor for histologic evaluation ^[20]D5. These imaging and pathologic features, combined with functional status and biomarker profiles, define the risk tier that selects the appropriate surveillance interval and surgical urgency.

Pearl: In primary aldosteronism, the HISTALDO classification is the single most actionable risk-stratification tool: classic histology predicts a < 5% recurrence risk, while non-classic histology carries a ~ 42% risk, mandating longer postoperative biochemical surveillance.

Once a functioning adrenal cortical adenoma is identified, the clinician must be prepared for life-threatening decompensations that can arise from cortisol or aldosterone excess. These emergencies, acute pulmonary edema, hypertensive crisis, hypokalemic paralysis, and perioperative adrenal crisis, demand a time-critical, drug-specific pathway. The evidence base is limited to case reports (Level 4), but the patterns are consistent and actionable.

Step 1: Initial Assessment and Severity Classification

Classify the emergency by the dominant syndrome:

• Cushing’s crisis: acute pulmonary edema, hypertensive crisis, heart failure with preserved or reduced ejection fraction, hypokalemia, hyperglycemia. In pregnancy, overlapping features with pre-eclampsia ( hypertension , edema, proteinuria) require a high index of suspicion ^[51]C4.
• Hyperaldosteronism crisis: severe hypertension, hypokalemia (potassium <3.0 mmol/L), muscle weakness, periodic paralysis , cardiac arrhythmias.
• Postoperative adrenal crisis: hypotension, hyponatremia, hyperkalemia, hypoglycemia, shock, occurs after unilateral adrenalectomy for cortisol-producing adenoma due to contralateral adrenal suppression ^[52]C4.

Disposition: ICU admission for any patient with acute pulmonary edema, hypertensive emergency, or hemodynamic instability. Non-invasive ventilation or intubation may be required ^[11]C4[51]C4.

Step 2: First-Line Interventions

For acute pulmonary edema / heart failure in Cushing’s syndrome:

• Diuretics: intravenous furosemide (dose per renal function) to reduce preload ^[51]C4.
• Blood pressure control: intravenous magnesium sulphate (e.g., 4 g bolus then 1 g/hour) for hypertensive crisis, especially in pregnancy ^[51]C4. Add oral antihypertensives (e.g., nifedipine, labetalol) as tolerated.
• Cortisol-lowering therapy:
• Mifepristone (glucocorticoid receptor antagonist) 300-600 mg orally daily, as used in a case of Cushing’s syndrome with non-atherosclerotic myocardial infarction and heart failure; the patient’s ejection fraction improved from 33% to 52.5% after addition ^[11]C4.
• Metyrapone (11β-hydroxylase inhibitor) 250-500 mg orally three times daily, titrated to serum cortisol, used preoperatively in a pregnant patient with recurrent acute pulmonary edema ^[51]C4.
• Supportive care: aspirin , statin, beta-blocker ( metoprolol ), sacubitril/ valsartan for heart failure with reduced ejection fraction ^[11]C4.

For hyperaldosteronism crisis:

• Potassium replacement: intravenous potassium chloride (10-20 mmol/hour) with cardiac monitoring.
• Mineralocorticoid receptor antagonist: spironolactone 25-100 mg orally daily (or eplerenone ) to block aldosterone effects.
• Blood pressure control: calcium channel blockers (e.g., amlodipine ) or alpha-blockers (e.g., doxazosin) as first-line; avoid ACE inhibitors/ARBs until volume status is optimized.

For postoperative adrenal crisis:

• Hydrocortisone : 100 mg IV bolus, then 50-100 mg IV every 6 hours, or continuous infusion (e.g., 200 mg/24 hours). Taper to oral replacement (e.g., hydrocortisone 15-20 mg daily in divided doses) once stable ^[52]C4.
• Fluid resuscitation: 0.9% saline or balanced crystalloid (e.g., lactated Ringer’s) for hypotension.
• Correct electrolytes: treat hyperkalemia with insulin + glucose if needed.

Step 3: Second-Line and Escalation

• If pulmonary edema persists despite diuretics and cortisol-lowering therapy, consider emergency delivery (if pregnant) after 28 weeks gestation, or earlier if maternal instability ^[51]C4. Cesarean section is often required.
• For refractory hypertension, add intravenous nicardipine or nitroprusside (with caution in pregnancy).
• If adrenal crisis is suspected but not confirmed, draw random cortisol and ACTH before giving hydrocortisone; do not delay treatment.

Step 4: Monitoring and Titration

• Hemodynamics: continuous blood pressure, heart rate, oxygen saturation; central venous pressure if available.
• Electrolytes: serum potassium, sodium, glucose every 4-6 hours.
• Cardiac function: bedside echocardiogram to assess ejection fraction, pericardial effusion, regional wall motion ^[51]C4.
• Cortisol levels: if using metyrapone, monitor serum cortisol (target 150-300 nmol/L) to avoid adrenal insufficiency.
• Fetal monitoring (if pregnant): continuous cardiotocography, ultrasound for growth and amniotic fluid.

Step 5: Resolution and Transition to Definitive Therapy

• Once the acute crisis is controlled (e.g., pulmonary edema resolved, blood pressure <140/90 mmHg, potassium >3.5 mmol/L), plan for definitive adrenalectomy.
• In pregnancy, surgery is safest between 6-28 weeks gestation; after 28 weeks, delay until postpartum if possible ^[51]C4.
• Preoperatively, continue cortisol-lowering therapy (mifepristone or metyrapone) to reduce surgical risk.
• Postoperatively, anticipate hypocortisolism in patients with cortisol-producing adenomas; start hydrocortisone replacement and educate on sick-day rules ^[52]C4.
• For hyperaldosteronism, unilateral adrenalectomy often cures hypertension and hypokalemia; continue spironolactone until surgery.

Drug / Modality Comparison Table

What NOT to Do

• Do not delay cortisol-lowering therapy in Cushing’s crisis while awaiting confirmatory tests, start mifepristone or metyrapone empirically if clinical suspicion is high ^[11]C4[51]C4.
• Do not use ACE inhibitors or ARBs as first-line for hypertensive crisis in hyperaldosteronism without volume repletion; they may worsen hypotension.
• Do not discharge a patient after adrenalectomy without a clear plan for glucocorticoid replacement and sick-day dose escalation ^[52]C4.

Pearl: Acute pulmonary edema and hypertensive crisis in Cushing’s syndrome require immediate ICU-level care with diuretics, antihypertensives, and cortisol-lowering therapy (mifepristone or metyrapone); definitive adrenalectomy should follow stabilization, and postoperative hypocortisolism must be anticipated and managed with hydrocortisone replacement ^{[11]C4[51]C4[52]C4}.

Once acute endocrine emergencies are controlled, the long-term management of adrenal cortical adenoma follows a treat-to-target framework: definitive surgical resection of the functioning adenoma, perioperative glucocorticoid replacement to prevent adrenal insufficiency, and medical suppression of hormone excess when surgery must be delayed or is contraindicated.

Step 1: Selecting the Management Strategy

Functioning adenomas causing Cushing's syndrome, primary hyperaldosteronism, or virilization warrant definitive adrenalectomy . Non-functioning adenomas require surveillance unless they are large (>4 cm) or have suspicious imaging features. For patients with severe hypercortisolism, marked by hypokalemia, hyperglycemia, or opportunistic infection, preoperative medical therapy reduces surgical risk ^[10]C4.

Step 2: Preoperative Medical Suppression

For Cushing's syndrome, metyrapone 750 mg daily combined with octreotide 400 µg daily and a single intramuscular injection of lanreotide 120 mg can rapidly lower cortisol levels and stabilize the patient ^[10]C4. In primary hyperaldosteronism, spironolactone up to 400 mg daily (or eplerenone ) controls hypertension and corrects hypokalemia ^[10]C4[29]C4. The preoperative targets are fasting serum glucose <200 mg/dL, serum potassium >3.5 mmol/L, and morning serum cortisol <12-15 µg/dL ^[10]C4.

Step 3: Definitive Surgical Resection

Laparoscopic adrenalectomy is the standard of care for most adrenal adenomas. Both transperitoneal and posterior retroperitoneoscopic approaches are safe and effective, with mean operative times of 99-103 minutes and hospital stays of 1.4-1.5 days in experienced centers ^[34]C4[54]C4. Robotic adrenalectomy, including single-port posterior retroperitoneoscopic techniques, is feasible for small tumors (<2 cm) and offers enhanced dexterity, though operative times are longer (mean 159 minutes) ^[6]C4[58]C4. In pregnant patients with Cushing's syndrome secondary to adrenal adenoma, surgery is recommended during the third trimester if an experienced surgeon is available ^[55]C4. Ectopic adrenal adenomas, reported in the renal sinus, gastric wall, and spinal region, require complete resection; laparoscopic or open approaches are chosen based on location and surgeon experience ^{[35]C4[38]C4[41]C4[60]C4}.

Step 4: Perioperative Glucocorticoid Replacement

Patients with cortisol-secreting adenomas are at risk of adrenal insufficiency after tumor removal because the contralateral gland is suppressed. On the day of surgery, administer hydrocortisone 100 mg intravenously every 12 hours ^[10]C4. Over the next 2-4 days, transition to oral hydrocortisone: 20 mg at 8 AM, 20 mg at 1 PM, and 10 mg at 6 PM, then taper to 20-10-10 mg based on clinical assessment ^[10]C4. Discontinue replacement when morning serum cortisol exceeds 15 µg/dL; in one case, cortisol rose to 20.8 µg/dL with preserved circadian rhythm by postoperative day 6 ^[10]C4.

For patients undergoing adrenalectomy for non-cortisol-secreting adenomas (e.g., primary hyperaldosteronism or non-functional tumors), routine glucocorticoid replacement is not required. However, postoperative hypocortisolism occurs in a subset, 7 of 35 patients (20%) in one cohort, and is predicted by lower morning cortisol and ACTH levels ^[4]B2b. Monitor for symptoms of adrenal insufficiency (fatigue, nausea, hypotension, hyponatremia, eosinophilia) and initiate replacement only if cortisol is low or symptoms develop ^[4]B2b.

Step 5: Postoperative Monitoring and Long-term Follow-up

After adrenalectomy for functioning adenomas, biochemical remission is expected. In primary hyperaldosteronism, systolic blood pressure falls significantly (mean 158 to 125 mmHg), but only 76% of patients achieve cure of hypertension; predictors of persistent hypertension include higher ASA physical status and the need for three or more antihypertensive medications before surgery ^[34]C4. For Cushing's syndrome, the hypothalamic-pituitary-adrenal axis may recover rapidly after resection of a CRH-producing adenoma, but prolonged secondary insufficiency is typical after ACTH-dependent cases ^[10]C4. Monitor morning cortisol and ACTH every 1-2 weeks initially, then taper glucocorticoids as the axis recovers. Imaging surveillance (CT or MRI) is indicated for syndromic patients ( Beckwith-Wiedemann syndrome , Carney triad) who are at risk of recurrence or metachronous tumors ^{[37]C4[56]C4[60]C4}.

Drug / Modality Comparison

Controversies and Guideline Disagreement

Pearl: For functioning adrenal adenomas, laparoscopic adrenalectomy is the definitive treatment; preoperative medical suppression with metyrapone and somatostatin analogues can stabilize severe hypercortisolism, and postoperative glucocorticoid replacement should be guided by morning cortisol levels rather than given routinely ^[4]B2b[10]C4.

Building on the treat-to-target framework, the management of adrenal cortical adenoma has been shaped not by large treatment trials but by a series of diagnostic and pathological milestones that refined lesion characterization, surgical planning, and perioperative safety.

Syndromic Recognition

The first syndromic context for adrenal cortical adenoma emerged with the description of Carney triad in the 1970s. Among 77 patients, 85% were women, onset ranged from 7 to 48 years (mean 20 years), and 20% had adrenocortical adenoma(s) ^[26]C4. The triad, paraganglioma, gastric stromal tumor, and pulmonary chondroma, was later recognized as a chronic, indolent disorder with a 20% mortality rate, usually from metastatic gastric stromal tumor ^[26]C4. In multiple endocrine neoplasia type 1 (MEN1), adrenal lesions are frequent, and the coexistence of a small ACA contiguous with a large ACC in one patient suggested possible progression, though comparative whole-exome sequencing did not demonstrate a causal adenoma-to-carcinoma transition driven by MEN1 loss of heterozygosity ^[9]C4.

Pharmacologic and Pathologic Discoveries

Spironolactone , used to treat hyperaldosteronism, produces concentrically laminated electron-dense inclusions within the adrenal gland. In a contemporary cohort of 15 patients treated with aldosterone antagonists, inclusions were identified in 33% of patients, far lower than previously reported ^[29]C4. Among patients treated with spironolactone alone, 50% had inclusions, while none using eplerenone alone had them ^[29]C4. Inclusions persisted in one patient despite prolonged drug discontinuation ^[29]C4. Pathologists should be aware of these infrequently encountered bodies, particularly when clinical history of hyperaldosteronism and pharmacologic treatment is not provided ^[29]C4.

Collision tumors, two histologically distinct neoplasms within a single gland, are rare but important. The adrenal cortical adenoma-cavernous hemangioma collision tumor demonstrates a sharp planar interface with a fibrous septum, visible on CT and MRI ^[63]C4. Myelolipoma within a myxoid cortical adenoma associated with Conn syndrome has been reported in only 16 cases worldwide ^[30]C4. An adrenal cortical adenoma arising from an adrenohepatic union has also been described ^[64]C4.

Diagnostic Imaging Advances

18F-FDG PET/CT is a powerful tool but carries a false-positive rate of 28.2% for suspected adrenal metastasis, with most false positives being benign adrenal cortical adenomas ^[33]B3b. Risk factors for true metastasis include a history of primary lung malignancy (OR 20.00, 95% CI 1.01-333.3) and SUVmax > 2.65 (OR 31.606, 95% CI 2.46-405.71) ^[33]B3b. Benign adenomas may accumulate FDG due to chronic inflammation ^[65]C4. Fine-needle aspiration cytology remains important for differentiating benign from metastatic lesions, though cytomorphologic overlap is significant ^[19]D5.

Biochemical and Endocrine Testing Evolution

For hyperandrogenism, a DHEAS level >600 mg/dl indicates an androgen-secreting adrenal cortical adenoma ^[53]D5. When 17-hydroxyprogesterone is elevated, a cosyntropin stimulation test can be misleading: one case showed a 17-OHP of 31.8 ng/mL at 60 minutes, mimicking non-classic congenital adrenal hyperplasia , but genetic testing was negative and a 4.5 × 4.8 cm adrenal adenoma was found ^[15]C4. Postoperative normalization of 17-OHP confirmed the tumor as the source ^[15]C4. Adrenal venous sampling, after preparation with alpha blockade, successfully lateralized an aldosterone-producing adenoma in a patient with coexisting paraganglioma and bilateral adrenal tumors ^[12]C4.

Ectopic and Rare Presentations

Ectopic adrenal cortical adenoma is extremely rare but has been reported in the spinal canal. Only 10 cases had been described as of 2019 ^[62]C4. In one case, the tumor was located at the L2 level and contained high levels of androstenedione without virilizing effects ^[61]C4. Complete surgical removal was curative ^[61]C4. These ectopic tumors have nonspecific MRI features and can be confused with ependymoma, schwannoma, meningioma , or metastasis ^[62]C4.

Although dedicated treatment trials for adrenal cortical adenoma are absent from the literature, the diagnostic and pathological milestones above have directly informed the current approach: selective use of functional imaging, biochemical confirmation with dynamic testing, histopathologic verification of ambiguous lesions, and careful preoperative planning for functioning adenomas.

Pearl: The absence of treatment-specific trials for benign adrenal cortical adenoma does not mean a lack of evidence, the diagnostic and pathological milestones (FDG-PET false-positive rate of 28.2%, spironolactone body incidence of 33%, DHEAS >600 mg/dL threshold) are the evidence base that guides current management decisions.

Beyond the surgical and medical management discussed above, adrenal cortical adenomas frequently arise in the context of inherited tumor syndromes that demand syndromic screening and cross-axis surveillance.

Inherited Tumor Syndromes

Carney triad, the combination of gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma, includes adrenal cortical adenoma as a fourth component ^[26]C4[56]C4. Among 77 patients with the syndrome, 85% were women and 20% had adrenocortical adenoma(s) ^[26]C4. The adrenal neoplasm is usually asymptomatic and a late finding; bilateral lesions occur in 4 of 14 patients ^[56]C4. None of the resected tumors recurred or metastasized, but after excision one patient required glucocorticoid support, suggesting subclinical cortisol excess ^[56]C4.

Multiple endocrine neoplasia type 1 (MEN1) predisposes to adrenal lesions, mostly adrenal cortical adenomas, although the frequency of adrenal cortical carcinomas is higher than in the general population ^[9]C4. Comparative whole-exome sequencing of three tumors from a familial MEN1 patient, a small ACA contiguous with a large ACC and its recurrence, identified a clone characterized by TP53 and NF1 mutations absent in the ACA but present in the ACC and recurrence, suggesting a possible relationship between benign and malignant lesions without demonstrating causal adenoma-to-carcinoma progression driven by MEN1 loss of heterozygosity ^[9]C4.

Beckwith-Wiedemann syndrome (BWS), a pediatric overgrowth disorder, carries a predisposition to embryonal tumors including adrenal cortical adenoma. In a cohort of 47 children with BWS, 6 underwent resection of an embryonal tumor, including two adrenal cortical adenomas ^[37]C4. Ectopic spinal adrenal cortical adenoma has been reported in a 2-year-old boy with BWS; the tumor recurred one year after gross total resection, underscoring the need for tight follow-up ^[60]C4.

Sexual dimorphism and adrenal asymmetry also influence tumorigenesis. In a multicenter study of 8037 patients, adrenal cortical adenomas (cortisol-secreting and nonfunctioning) were more common in females (female-to-male ratio 1.1:1-3.8:1) and occurred more frequently in the left adrenal (left-to-right ratio 1.1:1-1.8:1) ^[1]B2c. The left adrenal is larger than the right in both sexes, and females have smaller adrenals than males; this asymmetry may relate to pathogenesis and should be considered during diagnosis ^[1]B2c.

Genetic Alterations and Clonal Evolution

Molecular profiling has linked benign aldosterone-producing adenomas to ion channel mutations and cortisol-producing adenomas to mutations in the protein kinase A (PKA) signaling pathway ^[32]D5. The 2022 WHO classification emphasizes diagnostic biomarkers: SF1 is the most reliable marker of adrenal cortical origin, while paranuclear IGF2 expression helps distinguish malignancy ^[20]D5. Immunohistochemistry can differentiate adrenal cortical adenoma from pheochromocytoma: Melan-A, inhibin α, and vimentin are significantly higher in cortical adenoma (P<0.05), whereas CgA and S100 are more noticeable in pheochromocytoma (P<0.05) ^[2]C4. However, these markers do not distinguish among Cushing syndrome, primary hyperaldosteronism, and nonfunctioning adenoma ^[2]C4.

Co-Axis Effects and Ectopic Hormone Production

Adrenal cortical adenomas can perturb adjacent endocrine axes through ectopic hormone secretion. The first reported case of ectopic CRH production by an adrenal adenoma caused ACTH-dependent Cushing syndrome with severe hypercortisolemia (morning cortisol 1185 nmol/L, normal 166-507 nmol/L) ^[10]C4. Immunohistochemistry was positive for CRH and negative for ACTH and chromogranin A; after adrenalectomy , the hypothalamic-pituitary-adrenal axis recovered within days ^[10]C4.

Adenomas may also secrete 17-hydroxyprogesterone, mimicking non-classic congenital adrenal hyperplasia . In a 36-year-old woman with infertility, elevated 17-OHP (11.3 ng/mL at baseline, 31.8 ng/mL at 60 min after cosyntropin) and poor response to dexamethasone led to imaging that revealed a 4.5 × 4.8 cm adrenal adenoma; postoperative 17-OHP normalized and fertility improved ^[15]C4.

For hyperandrogenism, a DHEAS level over 600 mg/dL indicates an androgen-secreting adrenal cortical adenoma ^[53]D5. Total testosterone assay is first-line; if testosterone is twice the upper limit of normal, DHEAS should be measured ^[53]D5.

Rarely, adrenal cortical adenoma coexists with myelolipoma within the same mass, as reported in a case of Conn syndrome ^[30]C4. Cushing syndrome secondary to adrenal adenoma can present with non-atherosclerotic myocardial infarction and heart failure, highlighting the cardiovascular co-axis effects ^[11]C4. During pregnancy, Cushing syndrome from adrenal adenoma carries significant maternal and fetal complications; surgery is recommended in the third trimester if an experienced surgeon is available ^[55]C4.

Pearl: When an adrenal adenoma is identified, screen for syndromic features (Carney triad, MEN1, BWS) and consider ectopic hormone production (CRH, 17-OHP, androgens) if the biochemical profile is atypical, these cross-axis effects can mimic pituitary or ovarian disease and alter management.

Beyond the genetic syndromes and co-axis effects just discussed, the chronic excess of aldosterone, cortisol, or sex hormones from functioning adrenal cortical adenomas drives target-organ damage that persists even after successful resection. The major complications stem from the hormone itself, not solely from the attendant hypertension or hyperglycemia.

Cardiovascular Remodeling and Arrhythmia in Primary Aldosteronism

Aldosterone exerts direct fibrotic effects on the myocardium. In a case-control study, patients with primary aldosteronism (PA) showed left ventricular hypertrophy (LVH) in 53% compared with 26% of essential hypertensives (p<0.03) ^[66]C4. Left ventricular mass index (LVMi) was significantly higher (50.7±11.4 vs 45.2±10.1 g/m²·⁷, p<0.05) ^[66]C4. Electrical remodeling accompanies the structural change: P-wave duration (108.7±13.7 vs 92.4±12.8 ms, p<0.01) and PR interval (177.9±30.6 vs 152.3±19.5 ms, p<0.02) were significantly prolonged ^[66]C4. First-degree atrioventricular block was present in 16% of PA patients versus only 3.2% of essential hypertensives ^[66]C4. PR duration correlated positively with interventricular septal thickness (r=0.51, p<0.03), suggesting that the conduction delay reflects aldosterone-mediated myocardial fibrosis rather than hypokalemia alone ^[66]C4. QRS duration was also increased (p<0.04) ^[66]C4. These changes likely contribute to the higher rates of atrial fibrillation , myocardial infarction, and stroke reported in PA ^[66]C4.

Cushing's Syndrome: Cardiovascular, Skeletal, and Pregnancy Complications

Cortisol excess can cause non-atherosclerotic myocardial infarction and heart failure with reduced ejection fraction, as reported in a patient with adrenocortical adenoma whose coronary arteries were normal on angiography ^[11]C4. Hypercortisolism also accelerates osteoporosis: a postpartum woman with Cushing's syndrome secondary to adrenal adenoma sustained multiple thoracolumbar compression fractures (T-2,5,8,10,11,12; L-1,2,3,4,5), multiple rib fractures, and a left iliac bone fracture ^[49]C4.

Pregnancy imposes particular risk. Cushing's syndrome during pregnancy may be mistaken for severe pre-eclampsia. One case presented at 31 weeks with uncontrolled hypertension, pulmonary edema, and required emergency cesarean delivery followed by ICU admission for pulmonary hemorrhage, acute renal failure, disseminated intravascular coagulopathy, and congestive heart failure ^[49]C4. The fetus was delivered prematurely; the mother later underwent laparoscopic adrenalectomy for a right adrenal cortical adenoma ^[49]C4. Another case report confirms that surgery in the third trimester can be safely performed by an experienced surgeon ^[55]C4.

Surgical Complications of Adrenalectomy

Minimally invasive adrenalectomy is safe but not without risk. In a 10-year robotic series of 37 patients, four patients (11%) experienced postoperative complications requiring unplanned readmission, and there was one mortality ^[6]C4. In a general-surgeon series of 25 laparoscopic adrenalectomies, intraoperative complications occurred in 3 patients (12%), with one conversion to open surgery (4%) ^[34]C4. No conversions or complications were reported in smaller pediatric series ^[3]C4[54]C4 and in select single-port retroperitoneal cases ^[58]C4[67]C4.

Persistent Hypertension After Surgery

Even after successful removal of a functioning adenoma, hypertension may not resolve. In a series of 25 patients with functional adrenal tumors (76% primary aldosteronism), only 76% achieved cure of hypertension ^[34]C4. Postoperative systolic (125±15 vs 158±18 mmHg, p<0.001) and diastolic (78.5±6.7 vs 95.3±10 mmHg, p=0.013) blood pressures improved significantly ^[34]C4. Independent predictors of persistent hypertension were the patient's American Society of Anesthesiologists physical status (OR 0.66, 95% CI 0.43-1.32, p=0.001) and the need for ≥3 antihypertensive medications before surgery (OR 0.7, 95% CI 0.36-1.2, p=0.002) ^[34]C4.

Other and Mixed-Pathology Complications

Synchronous ipsilateral adrenal cortical adenoma occurs in 4% of patients undergoing adrenalectomy for pheochromocytoma (PSCA) ^[23]C4. In that cohort, 38% had clinically important cortical hormone secretion, 25% glucocorticoid autonomy and 13% primary aldosteronism, meaning that a purely catecholamine-focused workup may miss a second functioning lesion ^[23]C4.

Pearl: In a patient with primary aldosteronism, a PR interval >200 ms on ECG should raise suspicion for aldosterone-mediated cardiac fibrosis and prompt echocardiography to assess for LVH, which is present in over half of these patients ^[66]C4.

Having reviewed the complications that can arise from both the disease and its treatment, the natural history of adrenal cortical adenoma is generally favorable, though surveillance remains essential.

Natural History and Disease Trajectory

Most adrenal cortical adenomas (ACAs) are benign, non-functioning lesions that remain stable over years. The risk of malignant transformation is negligible; no provided evidence documents progression of ACA to adrenocortical carcinoma (ACC). Functioning adenomas, those causing Cushing's syndrome, primary hyperaldosteronism, or virilization, follow a trajectory dictated by the severity of hormone excess. In the rare case of ectopic CRH-producing ACA, the clinical course can be severe, with profound hypokalemia (1.77 mmol/L), hyperglycemia (741 mg/dL), and life-threatening infections ^[10]C4. However, surgical resection leads to complete biochemical remission, often with rapid recovery of the hypothalamic-pituitary-adrenal axis; in one case, morning cortisol normalized to 20.8 µg/dL by postoperative day 6 ^[10]C4. This excellent prognosis after adrenalectomy is consistent across functioning adenoma subtypes.

Sexual dimorphism influences tumor prevalence: ACA (non-aldosterone-producing) occurs more frequently in females (female-to-male ratio 1.1:1-3.8:1) and more often in the left adrenal (left-to-right ratio 1.1:1-1.8:1) ^[1]B2c. The left adrenal is larger than the right in both sexes, and females have smaller adrenals than males ^[1]B2c. These anatomic differences may affect detection but do not alter prognosis.

Prognostic Factors

Although ACA itself carries an excellent prognosis, several molecular markers studied across adrenal cortical neoplasms (ACN, including both ACA and ACC) have been associated with overall survival. In univariate analyses of ACN, shorter overall survival correlated with:

• Low MAOA expression in stromal cells (p = 0.008) ^[18]C4
• High EMP1 and EMP3 expression (p = 0.001) ^[17]C4
• GLUT1 positivity in tumor cells (p = 0.017) and CAIX in stromal cells (p = 0.003) ^[68]C4
• PHGDH expression (p = 0.009) ^[68]C4

GLUT1 positivity remained an independent prognostic factor for poor overall survival in multivariate analysis of ACN (p = 0.043) ^[68]C4. These markers are primarily relevant to ACC risk stratification; their utility in predicting progression of benign ACA is not established.

Prevention and Screening

No specific preventive measures exist for sporadic ACA. Environmental exposures may contribute: in a mouse model, maternal ingestion of methylarsonous acid during gestation produced adrenal cortical adenomas in 26% of female and 17-28% of male offspring ^[57]D5. The relevance to human adrenal tumorigenesis remains unclear.

Screening is indicated in syndromes with increased risk of adrenal tumors. In Beckwith-Wiedemann syndrome (BWS), 68% of children required surgery for BWS-related conditions, and 6 of 47 underwent resection of embryonal tumors, including two adrenal cortical adenomas ^[37]C4. Overall survival in this BWS cohort was 100% ^[37]C4. Surveillance protocols for BWS typically include abdominal ultrasound every 3 months until age 8 years, though the provided evidence does not detail specific screening intervals.

Family cascade screening is not addressed in the available literature for ACA. However, when an adrenal adenoma is identified in the context of a familial syndrome (e.g., multiple endocrine neoplasia type 1, familial adenomatous polyposis ), first-degree relatives may benefit from genetic counseling and imaging surveillance.

Pearl: The prognosis of adrenal cortical adenoma is excellent after resection of functioning adenomas, but molecular markers such as GLUT1 and EMP1/3, though studied in adrenal cortical neoplasms, should not alter surveillance of benign, non-functioning adenomas, which require only periodic imaging and hormonal reassessment.

Prognosis after resection of an adrenal cortical adenoma is generally excellent, but the clinical context, pediatric, pregnant, or elderly, can substantially alter presentation, diagnostic evaluation, and management.

Pediatrics

Adrenal cortical adenomas are rare in children, representing only 2 of 16 adrenal masses in a recent pediatric laparoscopic adrenalectomy series ^[3]C4. The median age was 10 years (range eight months to 17.3 years), with a female predominance ^[3]C4. Bilateral micronodular adrenocortical disease, a cause of ACTH-independent Cushing syndrome, occurs mainly in children and young adults, predominantly females ^[20]D5. Ectopic adrenal adenomas, though exceptional, have been reported in the spinal region; one case occurred in a 2-year-old boy with Beckwith-Wiedemann syndrome and recurred one year after gross total resection, underscoring the need for tight surveillance ^[60]C4. A myxoid adrenal cortical adenoma has also been described in a 7-month-old infant ^[69]C4. Laparoscopic adrenalectomy is safe and effective in selected pediatric cases, with no conversions or postoperative complications in the reported series ^[3]C4. Preoperative imaging, particularly assessment of vascular encasement, is critical for determining feasibility of the laparoscopic approach ^[3]C4.

Pregnancy and Fertility

Cushing syndrome during pregnancy is rare but carries significant maternal and fetal complications ^[55]C4. One case initially misdiagnosed as severe pre-eclampsia at 31 weeks gestation resulted in pulmonary hemorrhage, acute renal failure, disseminated intravascular coagulopathy, and multiple osteoporotic fractures ^[49]C4. For Cushing syndrome secondary to an adrenal cortical adenoma, surgery is recommended during the third trimester if an experienced surgeon is available ^[55]C4.

Fertility can be directly impaired by hormone-secreting adenomas. A 36-year-old woman with four years of infertility was found to have a 4.5 cm left adrenal cortical adenoma that autonomously secreted 17-hydroxyprogesterone (17-OHP) and progesterone, mimicking non-classic congenital adrenal hyperplasia ^[15]C4. After laparoscopic adrenalectomy, 17-OHP fell from 11.3 ng/mL to 0.5 ng/mL, progesterone declined from 15.3 ng/mL to 0.1 ng/mL, and the irregular menstrual cycle normalized without medication ^[15]C4. Physicians should check 17-OHP in the infertility workup if persistent high progesterone is detected, and if a 17-OHP-secreting adrenal adenoma is identified, adrenalectomy can restore fertility ^[15]C4.

Elderly

In patients with pheochromocytoma and synchronous ipsilateral adrenal cortical adenoma (PSCA), the median age was 57.7 years ^[23]C4. Among these, 38% had clinically important cortical hormone secretion: 25% had glucocorticoid secretory autonomy and 13% had primary aldosteronism ^[23]C4. This suggests that elderly patients with adrenal adenomas, particularly those presenting with hypertension or metabolic disturbances, should undergo thorough biochemical evaluation for autonomous cortisol and aldosterone secretion, even if the adenoma is discovered incidentally.

Immunocompromised

Data on adrenal cortical adenoma in immunocompromised patients are lacking. Management follows standard principles: biochemical and imaging workup, with surgical resection for functioning adenomas or those with concerning features, adjusted for the patient's overall immune status and surgical risk.

Pearl: In a woman with unexplained infertility and persistently elevated progesterone, always measure 17-hydroxyprogesterone, a 17-OHP-secreting adrenal cortical adenoma is a treatable cause that can be cured by laparoscopic adrenalectomy, restoring normal menstrual cycles and fertility ^[15]C4.