Adrenal Incidentaloma

An adrenal incidentaloma is an adrenal mass ≥1 cm in diameter discovered incidentally on imaging performed for indications unrelated to suspected adrenal disease ^[1]A1c[15]D5. Synonyms include incidental adrenal mass, adrenal nodule and incidental adrenal lesion. The term ‘incidentaloma’ applies only when the patient has no current or prior extra‑adrenal malignancy and no clinically suspected adrenal disorder ^[15]D5.

Adrenal incidentalomas are detected in 4-5 % of CT examinations ^[15]D5; prevalence rises from 3 % in individuals over 50 to 10 % in those over 80 ^[2]C4. Most are non‑functioning adrenocortical adenomas, but the differential includes hormonally active adenomas, pheochromocytoma, adrenocortical carcinoma (ACC), metastasis and other benign entities such as myelolipoma or cyst ^[1]A1c.

Classification by Function and Imaging

Biochemical evaluation begins with the 1 mg overnight dexamethasone suppression test (DST). A serum cortisol ≤50 nmol/L (1.8 µg/dL) defines a non‑functioning adrenal incidentaloma (NFAI) ^[1]A1c[2]C4. Cortisol >50 nmol/L without overt Cushing features is termed mild autonomous cortisol secretion (MACS) ^[2]C4; values >138 nmol/L (>5 µg/dL) are designated autonomous cortisol secretion ^[1]A1c. Overt Cushing syndrome, primary aldosteronism (aldosterone‑producing adenoma) and pheochromocytoma represent other functional categories.

Axis Nomenclature

An adrenal incidentaloma is a structural lesion; its hormonal activity defines the axis perturbation. ACTH‑independent cortisol excess (from MACS, autonomous cortisol secretion or overt Cushing) suppresses pituitary ACTH, causing ipsilateral and contralateral adrenal cortical atrophy. Renin‑independent aldosterone excess (primary aldosteronism) suppresses renin. Catecholamine excess (pheochromocytoma) is independent of the hypothalamic‑pituitary axis. The terms primary (adrenal origin) versus secondary (pituitary/hypothalamic) are reserved for the underlying cause of hormone excess, not the incidentaloma itself.

Pearl: The 1 mg overnight DST with a cutoff of 50 nmol/L (1.8 µg/dL) is the single most important test to distinguish non‑functioning from functioning adrenal incidentalomas; every incidentaloma requires this assessment ^[1]A1c[2]C4.

The hypothalamic-pituitary-adrenal (HPA) axis maintains cortisol secretion within a narrow physiological range through classic negative feedback; disruption at any node produces a characteristic biochemical signature that fingerprints the underlying lesion. The renin-angiotensin-aldosterone system (RAAS) and the sympathoadrenal axis similarly operate under tight regulatory control, and each adrenal incidentaloma subtype perturbs a specific feedback loop, yielding a predictable paired-hormone pattern.

Normal Feedback Architecture

Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates pituitary adrenocorticotropic hormone (ACTH) secretion, which drives adrenal cortisol production. Cortisol then suppresses CRH and ACTH via negative feedback at the pituitary and hypothalamus ^[38]D5. In the RAAS, renal renin release responds to volume status and potassium; renin cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II, stimulating aldosterone secretion from the zona glomerulosa. Aldosterone promotes sodium retention and potassium excretion, and in turn suppresses renin ^[19]D5. The adrenal medulla secretes catecholamines (epinephrine, norepinephrine) in response to sympathetic activation; these are metabolized to metanephrines and normetanephrines ^[26]C4.

Pathophysiology by Lesion Type

Autonomous cortisol secretion (ACS), The most common functional abnormality in adrenal incidentalomas. A benign adrenocortical adenoma acquires somatic mutations (e.g., in PRKACA, GNAS, or CTNNB1) that constitutively activate steroidogenesis, independent of ACTH ^[35]D5. Cortisol is secreted autonomously, suppressing pituitary ACTH via negative feedback. The resulting biochemical signature is: low or undetectable ACTH (<10 pg/mL) with cortisol >50 nmol/L after 1-mg overnight dexamethasone suppression test (F-1mgDST) ^[22]A1b. When F-1mgDST is between 50 and 138 nmol/L without overt cushingoid features, the condition is termed possible autonomous cortisol secretion (PACS) ^[22]A1b. Even this mild excess confers substantial cardiometabolic risk: in a randomized trial, adrenalectomy improved blood pressure control in 68% of PACS patients vs 13% with conservative management (OR 3.0, 95% CI 3.8-108.3) ^[22]A1b. The F-1mgDST cutoff of 75 nmol/L best predicted BP improvement (sensitivity 77%, specificity 75%) ^[22]A1b.

Primary aldosteronism (PA), Aldosterone-producing adenomas (APAs) harbor mutations in ion channels (KCNJ5, CACNA1D, CACNA1H, ATP1A1, ATP2B3) that depolarize zona glomerulosa cells and drive aldosterone synthase (CYP11B2) overexpression ^[35]D5. Autonomous aldosterone secretion suppresses renal renin release. The hallmark biochemical pattern is: suppressed renin (PRA <1.0 ng/mL/h or DRC <10 µIU/mL) with elevated aldosterone-to-renin ratio (ARR) ^[24]B2b. In a prospective study of hypertensive patients with adrenal adenomas, 47% (138/290) had suppressed renin; across aldosterone categories (5-10, 10-15, >15 ng/dL), aldosterone-targeted therapy reduced systolic BP by 18-30 mmHg (all p<0.001) ^[24]B2b. Hypokalemia is present in only a minority, so normokalemia does not exclude PA ^[19]D5.

Pheochromocytoma, Catecholamine-secreting tumors arise from chromaffin cells of the adrenal medulla. Driver mutations occur in RET, VHL, NF1, MAX, or SDHx genes, leading to constitutive activation of tyrosine kinase signaling or pseudohypoxia pathways ^[35]D5. Excess catecholamines cause hypertension , palpitations, and sweating. The biochemical signature is: elevated plasma or urinary metanephrines and normetanephrines ^[21]A1c. Notably, pheochromocytoma patients exhibit a low aldosterone-to-renin ratio (ARR <95.4) due to renin activation from reduced plasma volume and β1-adrenergic stimulation, with sensitivity 83.3% and specificity 86.7% for differentiating from non-functioning adenomas ^[26]C4. Catecholamines also drive muscle wasting via β-adrenergic suppression of ERK signaling, linking high-normal catecholamine levels to sarcopenia ^[28]B3b.

Non-functioning adrenal incidentaloma (NFAI), By definition, cortisol after 1-mg DST is ≤50 nmol/L and no other hormone excess is detected ^[2]C4. However, a meta-analysis of 2,059 patients found that NFAI is not metabolically inert: during mean follow-up of 46-59 months, diabetes prevalence increased (RR 1.33, 95% CI 1.07-1.65) and dyslipidemia increased (RR 1.22, 95% CI 1.07-1.38) ^[2]C4. Additionally, 8% (95% CI 5%-14%) of NFAI became functional over 45 months, and 4% grew >10 mm ^[2]C4. These observations suggest subtle, intermittent cortisol secretion below current detection thresholds, possibly mediated by glucocorticoid receptor polymorphisms (e.g., BclI variant) that alter tissue sensitivity ^{[29]B3b[30]C4}. Single-cell transcriptomics reveals that even non-functioning adenomas show dysregulated steroidogenic enzyme expression (CYP11B2, HSD3B2) and upregulation of clusterin (CLU), a potential biomarker ^[35]D5.

Genetic Modifiers of the Biochemical Phenotype

Glucocorticoid receptor (GR) polymorphisms modulate the clinical expression of cortisol excess. The BclI polymorphism (associated with increased GR sensitivity) is linked to smaller adenoma size, more complete DST suppression, and paradoxically lower diabetes risk in women with adrenal incidentalomas ^{[29]B3b[30]C4}. Conversely, rare inactivating GR mutations (e.g., hGRαT556I) cause Chrousos syndrome, generalized glucocorticoid resistance with compensatory ACTH-driven cortisol excess and adrenal hyperplasia ^[33]C4[37]D5.

Biochemical Signature Summary

Pearl: The biochemical fingerprint of an adrenal incidentaloma is defined by the paired relationship between the excess hormone and its suppressed regulator, low ACTH with elevated cortisol points to autonomous cortisol secretion, suppressed renin with elevated aldosterone points to primary aldosteronism, and low ARR with elevated metanephrines points to pheochromocytoma.

From the biochemical axis, we turn to the population burden: adrenal incidentalomas are now among the most common endocrine diagnoses, found in 1% to 5% of abdominal CT scans and up to 8.7% at autopsy ^[56]A1b. A prospective study of unselected outpatients reported a prevalence of 7.3% ^[41]B2b, and the incidence has increased 10-fold over the past two decades ^[48]B3b. This rise reflects both increased imaging utilization and true higher detection.

The typical patient is older (median age 61-63 years) and female (58- of cohorts) ^{[45]B3b[49]B3b}. Geographic patterns differ: primary aldosteronism is more prevalent in Asian cohorts, while autonomous cortisol secretion is more common in Western populations ^[40]B2a.

Risk Factors

Several risk factors for adrenal incidentaloma and its functional subtypes are well-characterized (Table 1).

Table 1. Risk factors for adrenal incidentaloma and associated hormonal activity. MACS = mild autonomous cortisol secretion.

MACS itself is a strong risk factor for adverse outcomes: age-adjusted rate ratio for atrial fibrillation 2.6 ^[44]B3b, all-cause mortality HR 1.54 (1.27-1.81) ^[39]A1a, and cardiovascular events OR 2.46 (1.5-4.1) ^[46]B3b. In women younger than 65, the mortality HR for autonomous cortisol secretion rises to 4.39 ^[49]B3b. Even non-functioning adenomas carry metabolic risk: during follow-up, diabetes increased by 33% (RR 1.33) and lipid disorders by 22% (RR 1.22) ^[2]C4.

Etiology

The etiology spans benign non-functioning adenomas (most common), MACS, primary aldosteronism, pheochromocytoma, Cushing syndrome, and adrenocortical carcinoma . Functioning tumors occur in 27.5% (95% CI 23.0-32.5) of incidentalomas ^[40]B2a. Bilateral disease raises the possibility of ARMC5 mutations, found in 18.8% of patients with MACS and bilateral incidentalomas ^[50]C4.

Pearl: In patients with adrenal incidentaloma, the presence of MACS markedly increases cardiovascular and mortality risk, especially in women under 65; even non-functioning adenomas are associated with metabolic progression, warranting serial cardiometabolic assessment.

Following the epidemiology of adrenal incidentalomas, the clinical presentation spans a wide spectrum, from entirely asymptomatic masses discovered on cross-sectional imaging to overt endocrine syndromes. The mode of presentation critically influences prognosis: ACCs presenting as incidentalomas have prolonged recurrence-free and overall survival compared with symptomatic tumors ^[58]B3b.

Asymptomatic Incidentaloma

Incidental discovery is the most frequent presentation, occurring in 63.7% of patients with adrenal masses in a large tertiary-care cohort ^[59]B3b. Among these, the majority are benign non-functioning adenomas. However, even in asymptomatic patients, biochemical evaluation commonly reveals mild autonomous cortisol secretion (MACS), defined as cortisol excess without the classical features of Cushing's syndrome ^[62]A1b. MACS is present in up to one-third of patients with adrenal incidentalomas and is associated with a worse metabolic phenotype: increased cardiovascular events, mortality, insulin resistance, visceral obesity, and dyslipidemia ^[62]A1b.

Syndrome of Overt Hormone Excess

When adrenal masses produce clinically significant hormone excess, the presentation depends on the specific secretory product:

Cortisol (Cushing's syndrome) - Weight gain, central obesity, facial plethora, easy bruising, proximal myopathy, osteoporosis, hypertension , diabetes, and psychiatric disturbance. In one series, weight gain was reported in 57.4% of women with Cushing's syndrome under age 45 years, but in only 15.8% of women aged ≥65 years, who were more often diagnosed incidentally via screening for an adrenal incidentaloma ^[69]B3b.

Aldosterone ( primary aldosteronism ) - Hypertension (often resistant), hypokalemia (though normokalemic forms are common), and an increased risk of cardiovascular events and chronic kidney disease. MACS co-secretes in a significant proportion of these patients: a meta-analysis of 11 studies found a prevalence of 21.9% (95% CI 18.1-26.2) for MACS among primary aldosteronism patients, and MACS was associated with chronic kidney disease (OR 1.96), diabetes (OR 1.60), and cardiovascular disease (OR 1.37) ^[57]B2a.

Catecholamines (pheochromocytoma) - The classic triad of palpitations, sweating, and headache occurs in only 12% of patients ^[66]B3b. Hypertension is present in 82% of patients with pheochromocytoma or paraganglioma ^[66]B3b. Palpitations (48% vs. 29%) and anxiety (37% vs. 17%) are more common with pheochromocytoma than with paraganglioma ^[66]B3b. Pre-diabetes or diabetes mellitus is also more prevalent (45% vs. 24%) ^[66]B3b. Importantly, 43.4% of pheochromocytomas are detected as incidentalomas, and a significant proportion of these are “silent”, without symptoms or signs of catecholamine excess ^[5]B3b[68]C4. In a series of 130 patients undergoing adrenalectomy for incidentaloma, 6.1% were silent pheochromocytomas, all with tumor size >4 cm, precontrast Hounsfield units >10, and absolute washout <60% ^[68]C4.

Androgens/estrogens ( adrenocortical carcinoma ) - Androgen excess (e.g., hirsutism, virilization, menstrual irregularities) is a strong predictor of malignancy (OR 27.67) ^[59]B3b. ACC may also present with abdominal pain, unintentional weight loss , or a palpable mass. Rarely, ACC can mimic pheochromocytoma with elevated 3-methoxytyramine excretion ^[73]C4.

Mild Autonomous Cortisol Secretion (MACS)

MACS is the most common hormonal abnormality in adrenal incidentalomas, affecting approximately one-third of patients ^[62]A1b. It is defined as autonomous cortisol secretion without overt Cushing’s stigmata. Clinically, it is associated with a higher prevalence of hypertension, diabetes, dyslipidemia, and cardiovascular events ^[62]A1b. The diagnosis is established biochemically (see Diagnosis and Workup section), but the phenotype is often subtle. Predictive factors for developing MACS during follow-up include adenoma size >28 mm (HR 12.4), bilateral adrenal tumors (HR 5.36), and low/suppressed ACTH (HR 11.2) ^[71]B3b.

Adrenal Hemorrhage

Adrenal hemorrhage presents acutely with unexplained abdominal pain and hemodynamic instability in a patient with a predisposing condition (trauma, sepsis, coagulopathy, COVID-19 , or vaccine-induced immune thrombocytopenia and thrombosis ^[61]D5). Bilateral hemorrhage can lead to adrenal insufficiency and potentially fatal adrenal crisis without timely recognition ^[61]D5.

Red Flags

• Hemodynamic instability with abdominal pain → adrenal hemorrhage
• Hypertensive crisis or paroxysmal symptoms → pheochromocytoma
• Rapidly enlarging mass or new abdominal pain → adrenocortical carcinoma
• Weight loss, virilization, or androgen excess → malignancy
• Any patient with a predisposing condition (anticoagulation, sepsis, recent trauma) and unexplained abdominal pain → consider adrenal hemorrhage

Phenotypic Variants

Pearl: In a patient with an adrenal incidentaloma, the absence of classic Cushing stigmata does not rule out autonomous cortisol secretion, assess for metabolic comorbidities (hypertension, diabetes, cardiovascular disease) as clinical clues to MACS, which is present in up to one-third of cases ^[62]A1b.

[Compilation failed for this section after 2 attempts. Manual review required.]

Once the diagnosis of an adrenal incidentaloma is confirmed and the initial hormonal and imaging workup is complete, the next step is to stratify the lesion by malignant potential and functional status, a process that directly determines surveillance intensity, surgical urgency, and long-term management.

Imaging-Based Malignancy Risk Stratification

Unenhanced CT Hounsfield unit (HU) attenuation is the cornerstone of risk assessment. Homogeneous lesions with HU ≤10 are benign with a 0% malignancy risk and require no additional imaging, regardless of size ^{[75]A1c[56]A1b}. Lesions with HU 10-20 are indeterminate (0.5% risk), while those with HU >20 are suspicious (6.3% risk) and warrant comprehensive evaluation ^[56]A1b. For lesions >4 cm that are inhomogeneous or have HU >20, the risk of malignancy is sufficiently high that surgery is the usual management of choice ^[75]A1c.

Growth rate is another critical predictor: >0.8 cm/year strongly suggests malignancy ^[56]A1b. Among myelolipomas, growth ≥1 cm correlates with larger initial size and hemorrhagic changes, and tumors ≥6 cm are more likely to cause mass effect and require resection ^[98]B3b.

Functional imaging adds further discrimination. 18F-FDG PET/CT has a pooled sensitivity of 87.3% (95% CI 82.5%-90.9%) and specificity of 84.7% (95% CI 79.3%-88.9%) for identifying malignant adrenal tumors, though data in incidentalomas are limited ^[77]B2a. Combined FDG PET and [123I]iodometomidate SPECT classifies adrenocortical adenoma with high specificity (95.7%, 95% CI 85.2%-99.5%) but low sensitivity (48.3%) due to moderate/high FDG uptake in some adenomas ^[8]B3b.

Functional Risk Stratification

Hormonal excess defines a separate axis of risk. Mild autonomous cortisol secretion (MACS) is defined by serum cortisol >50 nmol/L (>1.8 µg/dL) after 1-mg overnight dexamethasone suppression test, without overt Cushing stigmata ^[75]A1c. MACS is present in 5%-30% of incidentalomas and is associated with increased cardiovascular morbidity, metabolic comorbidities, and mortality ^{[56]A1b[75]A1c[90]B3b[91]B3b}. Cortisol secretion does not increase cancer prevalence but is significantly associated with stage IV cancer at diagnosis (OR 2.68, 95% CI 1.19-6.00) and mortality (OR 3.2, 95% CI 1.28-7.97) ^[90]B3b.

Overt Cushing syndrome presents with markedly elevated cortisol, suppressed ACTH, and characteristic clinical features ^[56]A1b. Primary aldosteronism (5%-6% of incidentalomas) is diagnosed by aldosterone-to-renin ratio >30 with confirmatory testing ^{[56]A1b[88]A1c}. Pheochromocytoma (4%-8%) is identified by elevated plasma-free metanephrines ^[56]A1b; incidentally detected pheochromocytomas are common (43.4% of cases in one registry) and are associated with older age and lower rates of hypertension , but similar disease-free survival compared to clinically detected cases ^{[5]B3b[96]B3b}.

Integrating Risk into Management Decisions

Risk stratification directly guides intervention. Surgery is indicated for: (1) lesions with high malignancy risk (size >4 cm, HU >20, inhomogeneous); (2) functioning tumors (overt Cushing, pheochromocytoma, primary aldosteronism); and (3) selected MACS patients with cortisol-related comorbidities, where recent trials show superior cardiovascular and metabolic outcomes compared to medical management alone ^{[75]A1c[56]A1b[21]A1c}. In patients with MACS, surgical treatment should be individualized based on age, comorbidity burden, and patient preference ^[75]A1c.

For nonfunctioning lesions with benign imaging features (HU ≤10), routine scheduled follow-up is not suggested ^{[75]A1c[21]A1c}. Indeterminate or suspicious lesions require repeat imaging at 6-12 months and annual hormonal re-evaluation for 3-5 years ^[75]A1c[6]C4. In cancer patients, an adrenal incidentaloma may represent metastasis; stage migration occurs in 68% of malignant adrenal findings, potentially changing treatment intent from curative to palliative ^[92]B3b.

Pearl: A homogeneous adrenal lesion with HU ≤10 on unenhanced CT is benign; no further imaging or follow-up is needed. All other lesions require multidisciplinary discussion to weigh malignancy risk, functional status, and patient factors before deciding on surgery versus surveillance.

From the preceding staging and risk stratification framework, the clinician must now recognize that a subset of patients with adrenal incidentaloma will present with, or evolve into, a life-threatening endocrine emergency. The two principal crises are adrenal crisis (most often from bilateral adrenal hemorrhage) and pheochromocytoma crisis (catecholaminergic crisis, frequently triggered by glucocorticoids). Both demand a time-critical, drug-specific pathway.

Step 1: Recognition of Endocrine Emergency

Adrenal crisis should be suspected in any patient with an adrenal incidentaloma and unexplained hypotension or shock, confusion, anorexia, nausea, vomiting, or abdominal pain. In a large series of patients with bilateral adrenal hemorrhage, hypotension or shock occurred in 83%, confusion in 79%, and anorexia/nausea/vomiting in 55% ^[61]D5. Low-grade fever is present in about 50% of patients ^[61]D5. Electrolyte disturbances (hyponatremia, hyperkalemia, hypoglycemia, hypercalcemia ) occur in less than 20% but support the diagnosis when present ^[61]D5. The diagnosis is confirmed by a low early morning serum cortisol (<140 nmol/L [5 µg/dL]) with an elevated ACTH (more than two-fold above the upper reference range) ^[61]D5. However, treatment should not be delayed for laboratory confirmation if the clinical suspicion is high.

Pheochromocytoma crisis presents with paroxysmal hypertension , headache, palpitations, diaphoresis, chest pain, and cardiac failure. It can be unmasked by exogenous glucocorticoids, including high-dose dexamethasone suppression testing (DST) ^{[99]C4[111]C4}. In a review of 25 case reports, three patients with an adrenal incidentaloma suffered a catecholaminergic crisis following high-dose DST; one was fatal ^[111]C4. Importantly, no crisis has been reported with a low-dose (1 mg) DST ^[111]C4. Pheochromocytoma crisis may also present as tako-tsubo cardiomyopathy ^[107]C4 or acute pancreatitis ^[113]C4.

Step 2: Immediate Interventions

For adrenal crisis:

• Administer hydrocortisone 100-200 mg intravenously immediately, followed by 200 mg per 24 hours as a continuous infusion or 50 mg every 6 hours ^[61]D5.
• Simultaneously, begin intravenous fluid resuscitation with normal saline or balanced crystalloids.
• At high doses, hydrocortisone provides adequate mineralocorticoid activity; do not delay glucocorticoid administration to add fludrocortisone ^[61]D5.
• If adrenal hemorrhage is suspected as the cause, proceed to CT imaging to confirm the diagnosis: an acute adrenal mass with high attenuation (50-90 Hounsfield units) and surrounding soft tissue stranding is characteristic ^[61]D5.

For pheochromocytoma crisis:

• First-line therapy is alpha-adrenergic blockade. Phenoxybenzamine 10 mg twice daily, titrated to blood pressure control, is the traditional agent; doxazosin is an alternative.
• Do not administer beta-blockers before adequate alpha-blockade; this can precipitate unopposed alpha-receptor stimulation and worsen hypertension ^[107]C4.
• For dopamine-secreting pheochromocytomas (rare, often asymptomatic), alpha-blockers are not indicated and may cause hypotension and cardiovascular failure; calcium channel blockers or metyrosine may be better alternatives ^[112]C4.
• If the crisis is triggered by glucocorticoid administration, discontinue the steroid immediately and manage the hypertensive emergency with alpha-blockers and intravenous fluids as needed ^[99]C4.

Step 3: Monitoring and Support

Adrenal crisis:

• Monitor vital signs, serum electrolytes, and glucose every 4-6 hours initially.
• Taper the hydrocortisone dose as the acute stress resolves: once the patient is stable, reduce to 15-25 mg per day in 2-3 divided doses (two-thirds in the morning) ^[61]D5.
• Add fludrocortisone 100-150 µg daily when the hydrocortisone dose is less than 50 mg/day ^[61]D5.
• Assess for mineralocorticoid deficiency: a high renin with low aldosterone confirms the need for fludrocortisone ^[61]D5.

Pheochromocytoma crisis:

• Monitor blood pressure continuously in an intensive care setting.
• Once the crisis is controlled, prepare for definitive management with laparoscopic adrenalectomy after at least 10-14 days of preoperative alpha-blockade ^[108]D5.
• In patients with ongoing hemorrhage from a ruptured pheochromocytoma, endovascular embolization of the adrenal arteries is preferred over emergency surgery, which carries a mortality risk close to 50% ^[61]D5.

Step 4: Transition to Definitive Management

Adrenal hemorrhage: Most cases are managed conservatively. If the patient is hemodynamically stable and the imaging shows a shrinking hematoma, follow-up imaging at 3 months is appropriate ^[61]D5. If an underlying adrenal tumor is suspected (e.g., pheochromocytoma, adrenocortical carcinoma ), plan elective surgical resection after full hormonal evaluation. In patients with bilateral adrenal hemorrhage, adrenal insufficiency is usually permanent; lifelong glucocorticoid (and often mineralocorticoid) replacement is required ^[61]D5. Recovery of glucocorticoid function is infrequent but may occur; check early morning cortisol 3-6 monthly for the first 1-2 years ^[61]D5.

Pheochromocytoma: Once the catecholaminergic crisis is controlled, proceed to biochemical confirmation (plasma or urinary metanephrines) and imaging (MRI or CT). Laparoscopic adrenalectomy is the standard approach for adrenal pheochromocytomas ^[108]D5. Postoperatively, continue monitoring for adrenal insufficiency if the contralateral gland is compromised.

Drug / Modality Comparison Table

What NOT to Do

• Do not administer glucocorticoids (including high-dose DST) to a patient with an adrenal incidentaloma until pheochromocytoma has been excluded by biochemical testing ^{[99]C4[111]C4}. Exogenous glucocorticoids can unpredictably trigger a fatal catecholaminergic crisis ^[99]C4.
• Do not give beta-blockers before alpha-blockade in a patient with suspected pheochromocytoma crisis ^[107]C4.
• Do not delay hydrocortisone administration in suspected adrenal crisis while waiting for laboratory confirmation ^[61]D5.

Controversies and Guideline Disagreement

Treatment Failure Protocol

If the patient with adrenal crisis does not respond to hydrocortisone and fluid resuscitation (persistent hypotension >1 hour), consider:

• Additional stress-dose hydrocortisone (repeat 100 mg IV) and search for an alternate cause of shock (e.g., sepsis, hemorrhage).
• If the patient with pheochromocytoma crisis remains hypertensive despite alpha-blockade, consider adding intravenous phentolamine or sodium nitroprusside for acute blood pressure control.

Caption: Figure 1: Acute management algorithm for endocrine emergencies in patients with adrenal incidentaloma (adapted from ^[61]D5 and ^[99]C4).

Pearl: In any patient with an adrenal incidentaloma who develops unexplained hypotension or a hypertensive crisis, immediately suspect adrenal crisis (from hemorrhage) or pheochromocytoma crisis (especially if glucocorticoids have been administered), and initiate the appropriate drug-specific pathway without delay - hydrocortisone 100-200 mg IV for adrenal crisis ^[61]D5, alpha-blockade for pheochromocytoma crisis ^{[99]C4[111]C4}.

[Compilation failed for this section after 2 attempts. Manual review required.]

The treat-to-target framework that organizes current incidentaloma management rests on evidence accumulated over three decades: from the initial recognition that incidentally discovered adrenal masses could harbor malignancy or subtle hormone excess, to landmark randomized trials that now justify surgical intervention for mild autonomous cortisol secretion (MACS).

The Pre-Guideline Era: Size and Overt Hypersecretion

Before the 2000s, management focused almost exclusively on mass size and overt hormone excess. Lesions exceeding 4-6 cm were routinely resected due to concern for adrenocortical carcinoma , while smaller masses were considered benign and left untreated. Hormonal evaluation was limited to excluding overt Cushing's syndrome , pheochromocytoma , and primary aldosteronism . The concept of subclinical hypercortisolism had not yet entered clinical practice ^[120]A1b.

The Recognition of Subclinical Cushing's Syndrome

The 2002 study by Terzolo et al. demonstrated that patients with incidental adrenal adenomas had higher 2-hour postchallenge glucose (7.43 ± 2.49 vs. 6.10 ± 1.44 mmol/L, P = 0.01) and higher systolic blood pressure (135.4 ± 15.5 vs. 125.0 ± 15.6 mm Hg, P = 0.003) compared with matched controls, and that these metabolic abnormalities were most pronounced in those with subclinical Cushing's syndrome ^[121]C4. This landmark observation shifted the focus from size alone to functional assessment. The 2011 AME position statement formalized the use of the 1-mg overnight dexamethasone suppression test (DST) with a threshold of 138 nmol/L (5.0 µg/dL) to define subclinical Cushing's syndrome, and recognized that even cortisol levels between 50 and 138 nmol/L (1.8-5.0 µg/dL) created an area of diagnostic uncertainty ^[76]A1c.

The Shift to Autonomous Cortisol Secretion

The 2016 European Society of Endocrinology (ESE) guideline introduced the term "autonomous cortisol secretion" for post-DST cortisol >138 nmol/L and "possible autonomous cortisol secretion" for values between 50 and 138 nmol/L ^[1]A1c. This nomenclature reflected the recognition that even mild cortisol excess was associated with increased cardiovascular risk. Morelli et al. (2017) showed that a post-DST cortisol ≥1.8 µg/dL (50 nmol/L) was independently associated with cardiovascular events (OR 2.46, 95% CI 1.5-4.1, P = 0.01) ^[46]B3b. The 2023 ESE guideline further refined the terminology to "mild autonomous cortisol secretion" (MACS), defined as post-DST cortisol >50 nmol/L (1.8 µg/dL), and recommended that all patients with MACS be screened for cortisol-related comorbidities ^[75]A1c.

The Landmark RCTs: Evidence for Surgery

Two randomized controlled trials provided the strongest evidence that adrenalectomy improves outcomes in MACS. In the COAR study, Koh et al. (2023) randomized 132 patients with MACS to adrenalectomy or conservative management. After a median follow-up of 48 months, the adrenalectomy group showed significantly higher rates of improved weight control (32.6% vs. 6.5%, P = 0.002), glucose control (45.7% vs. 15.2%, P = 0.002), and blood pressure control (45.7% vs. 23.9%, P = 0.029). Adrenalectomy was an independent predictor of improved glucose control (OR 5.30, 95% CI 1.63-17.25, P = 0.006) ^[124]A1b. Morelli et al. (2022) randomized 62 patients with possible autonomous cortisol secretion (post-DST 50-138 nmol/L) and found that adrenalectomy improved blood pressure control in 68% vs. 13% (P = 0.001) and glycometabolic control in 28% vs. 3.3% (P = 0.02), with a post-DST cutoff of 75 nmol/L best predicting BP improvement (sensitivity 77%, specificity 75%) ^[22]A1b.

Current Paradigm: Risk Stratification and Individualized Approach

Contemporary guidelines integrate these findings into a risk-stratified algorithm. The 2023 ESE guideline recommends adrenalectomy for patients with MACS who have relevant comorbidities ( hypertension , type 2 diabetes) in an individualized approach ^[75]A1c. Surgery is not indicated for asymptomatic, nonfunctioning, benign-appearing masses ^{[1]A1c[75]A1c}. The growth rate cutoff of 2.68 mm/year (sensitivity 87.5%, specificity 88.8%) has been identified as the best predictor of malignancy in atypical adrenal masses ^[80]B3b. The 2025 SEEN guideline reaffirms that adrenalectomy is the gold standard for malignant lesions or overt hormonal syndromes, but emphasizes that multidisciplinary discussion is essential for indeterminate cases ^[55]A1c.

Pearl: The evolution from size-based to hormone-based management culminated in the 2023 ESE guideline, which now defines MACS at a post-DST cortisol >50 nmol/L (1.8 µg/dL), a threshold that both predicts cardiovascular risk and identifies patients likely to benefit from adrenalectomy.

The evolution of surgical and medical management has clarified that adrenal incidentalomas are not isolated endocrine events; they frequently arise within hereditary tumor syndromes and perturb multiple hormonal axes simultaneously.

Hereditary Syndromes and Genetic Predisposition

Pheochromocytoma, detected in 3.8% of adrenal incidentalomas ^[40]B2a, carries a substantial hereditary burden. In a large UK tertiary center series, hereditary predisposition was detected in 20.4% of patients with pheochromocytoma, but the proportion differed markedly by presentation: only 15.3% of incidentally detected tumors were hereditary, compared with 42.9% of those presenting with adrenergic symptoms or uncontrolled hypertension ^[82]B3b. This pattern suggests that incidental pheochromocytomas may represent a distinct, less aggressive tumor biology, yet the absolute risk of an underlying germline mutation remains high enough to warrant genetic counseling and testing in all confirmed cases, particularly those with syndromic features, family history, or bilateral disease. Other hereditary syndromes associated with adrenal masses, such as MEN1, MEN2, VHL, NF1, and Lynch syndrome , are not directly addressed in the current evidence base but should be considered when clinical clues are present.

Co-Axis Effects: Cortisol Excess and Cardiovascular Comorbidity

Mild autonomous cortisol secretion (MACS), the most frequent hormonal alteration in adrenal incidentalomas (prevalence 11.7% ^[40]B2a), exerts systemic effects that extend well beyond the adrenal gland. The CV-CORT-EX study demonstrated that even mild cortisol excess is associated with glucocorticoid-induced cardiac alterations: in MACS, cardiac remodeling was even more pronounced than in individuals with metabolic syndrome ^[127]C4. These structural changes persist despite long-term biochemical remission; patients with cured Cushing's syndrome had worse diastolic function than the general population (LV relaxation velocity e' 0.08 vs 0.10 ms⁻¹, P <.001) ^[127]C4. Atrial fibrillation risk is also amplified: patients with autonomous cortisol secretion had a 2.95-fold higher risk of incident AF compared with those with nonsecreting tumors (HR 2.95, 95% CI 1.27-6.86), independently of traditional risk factors ^[44]B3b. Visceral fat accumulation, a key driver of cardiometabolic risk, is increased in patients with a post- dexamethasone cortisol >1.8 μg/dL and is similar to that found in patients with overt Cushing's syndrome ^[128]C4. Health-related quality of life follows a gradient of burden, with mild impairment in nonfunctioning adenomas, intermediate impairment in MACS and primary aldosteronism , and the most pronounced and persistent deficits in adrenal Cushing's syndrome, pheochromocytoma, and adrenocortical carcinoma ^[79]B2a.

Co-Secretion: MACS in Primary Aldosteronism

Cortisol and aldosterone excess frequently coexist. In a meta-analysis of 2882 patients with primary aldosteronism (PA), the prevalence of MACS among PA patients was 21.9% (95% CI 18.1-26.2) ^[57]B2a. This dual hormonal excess is clinically consequential: MACS in PA was significantly associated with chronic kidney disease (OR 1.96), diabetes mellitus (OR 1.60), and cardiovascular diseases (OR 1.37) ^[57]B2a. Clinical indicators for MACS screening in PA patients include older age, higher plasma aldosterone concentration, lower plasma renin activity, lower eGFR, and larger adrenal tumor size ^[57]B2a. These findings underscore the importance of complete hormonal evaluation, including a 1-mg dexamethasone suppression test, in all patients with adrenal incidentaloma, even when another hormonal excess (e.g., aldosterone) has already been identified.

Pearl: In any patient with an adrenal incidentaloma, consider the possibility of a hereditary syndrome (especially if pheochromocytoma) and always assess for co-existing hormonal excess in other axes, as MACS frequently co-occurs with primary aldosteronism and amplifies cardiovascular risk beyond that of either condition alone.

Beyond the syndromic associations, the chronic hormone excess, even at subclinical levels, drives a cascade of target-organ damage that defines the long-term morbidity of adrenal incidentalomas. The most consequential complications arise from mild autonomous cortisol secretion (MACS), which is present in 5%-30% of incidentalomas and carries a burden that rivals overt Cushing syndrome in frequency, if not in severity ^[56]A1b.

Cardiometabolic Complications

MACS substantially increases the risk of hypertension , type 2 diabetes, and dyslipidemia. In a meta-analysis of 30 cross-sectional and 16 cohort studies (n = 17 156), patients with MACS had a relative risk of 1.24 for hypertension (95% CI 1.16-1.32), 1.44 for diabetes (1.23-1.69), and 1.23 for dyslipidemia (1.13-1.34) compared to patients with nonfunctioning adenomas ^[39]A1a. The cardiac consequences are structural: at baseline, patients with MACS showed a higher prevalence of left ventricular hypertrophy (46% vs 16%) and diastolic dysfunction (34% vs 12%) than those with nonfunctioning adenomas ^[42]C4. In the prospective ITACA study, left ventricular mass index (LVMi) fell by -14.8 g/m² after adrenalectomy but rebounded by 5 years, while patients under surveillance showed progressive hypertrophy over the same period ^[42]C4. Even after biochemical remission of overt Cushing syndrome, diastolic function remains impaired compared to the general population (e′ 0.08 vs 0.10 ms⁻¹), indicating persistent glucocorticoid-induced cardiac injury ^[127]C4.

Cardiovascular events (CVE) are independently associated with MACS. In a cohort of 518 patients, cortisol after 1 mg dexamethasone ≥1.8 µg/dL carried an odds ratio of 2.46 (95% CI 1.5-4.1) for CVE, regardless of traditional risk factors ^[46]B3b. Coagulation abnormalities also cluster with MACS: after adrenalectomy, the prevalence of altered anticoagulant parameters fell from 54.2% to 10.5% ^[54]A1b.

Bone Health and Fracture Risk

Cortisol excess, even at the MACS level, damages trabecular bone. In patients with autonomous cortisol secretion (ACS, defined as 1 mg DST 1.9-5.0 µg/dL), high-resolution peripheral quantitative CT revealed lower trabecular volumetric BMD, reduced bone volume/tissue volume ratio, and thinner trabeculae at the distal radius compared to nonfunctioning adenomas ^[131]B3b. Osteoporosis by DXA was frequent in both groups (75% in ACS, 64.9% in nonfunctioning), but vertebral fracture prevalence trended higher in ACS (73.7% vs 55.6%, P = 0.24) ^[131]B3b.

Infectious Complications

Patients with MACS and overt Cushing syndrome have increased susceptibility to infections. Using the ICARO questionnaire, CS was associated with higher odds of urinary tract infections (OR 5.1, 95% CI 2.3-9.9), mycoses (4.4, 2.1-8.8), and flu (2.9, 1.4-5.8); MACS showed similarly elevated risks for UTIs (3.7, 1.7-8.0) and flu (3.2, 1.5-6.9) ^[52]D5. Post-dexamethasone cortisol levels correlated with infection burden, suggesting a dose-dependent immunosuppressive effect ^[52]D5.

Mortality

Mortality is not increased in patients with nonfunctioning adrenal adenomas (HR 1.13, 95% CI 0.87-1.46) ^[83]B3b. However, MACS carries a graded mortality risk. In the international NAPACA cohort (n = 3656), all-cause mortality was significantly higher with possible autonomous cortisol secretion (cortisol 50-138 nmol/L; HR 1.52, 95% CI 1.19-1.94) and autonomous cortisol secretion (>138 nmol/L; HR 1.77, 1.20-2.62) ^[49]B3b. Women younger than 65 years with autonomous secretion had a striking HR 4.39 (95% CI 1.93-9.96) for death ^[49]B3b. In another cohort, cortisolDST ≥83 nmol/L conferred a mortality HR of 1.99 (1.38-2.88), and ≥138 nmol/L an HR of 4.09 (2.41-6.93) ^[83]B3b.

Pheochromocytoma Crisis Triggered by Glucocorticoids

A rare but life-threatening complication is the precipitation of pheochromocytoma crisis by exogenous glucocorticoids. Four new cases and seven from the literature document that glucocorticoid administration, including during high-dose dexamethasone suppression testing, can cause hypertensive crisis, cardiac failure, and hemorrhagic pheochromocytoma, with one fatal outcome ^[99]C4. No cases have been reported with the 1 mg dexamethasone dose used for screening, but doses as low as 2 mg may trigger a crisis ^[99]C4. This underscores the importance of ruling out pheochromocytoma before administering glucocorticoids in patients with adrenal masses.

Pearl: In any patient with an adrenal incidentaloma, the presence of MACS, even without overt Cushing stigmata, carries a 1.5- to 4-fold increased risk of death, especially in women under 65; this mortality risk is not seen in patients with truly nonfunctioning adenomas, so the 1 mg dexamethasone suppression test is the single most important prognostic test beyond imaging.

Long-term sequelae of cortisol excess are substantial, but the trajectory of the adrenal mass itself is generally indolent. Understanding the natural history guides surveillance intensity and informs the rationale for screening.

Natural History of Benign and Atypical Masses

Most adrenal incidentalomas are benign, nonfunctional adenomas that remain stable over years. In a prospective cohort of 319 patients, no patient demonstrated a clinically significant increase in tumor size during follow-up, and no changes in metanephrines or renin-aldosterone activity were observed ^[86]C4. Six patients developed subclinical Cushing's syndrome (SCS) while eight with SCS showed biochemical remission, indicating that progression to overt hormone excess is rare ^[86]C4. Among large tumors (≥4 cm), growth occurred in only 4.6% of cases followed for a mean of 30 months, and no malignancy developed in homogeneous lesions with attenuation <10 Hounsfield units (HU) ^[63]C4. The risk of developing mild autonomous cortisol secretion (MACS) among initially nonfunctioning large tumors was 6.7%, with no progression to overt Cushing's syndrome ^[63]C4.

For atypical adrenal masses (AAMs), defined as 10-39 mm with pre-contrast attenuation >10 HU, the median growth rate is 0.3 mm/year (IQR 0-1.8 mm/year) ^[80]B3b. However, malignant potential is significant: of 224 AAMs, 11.2% were adrenocortical carcinoma (ACC) at pathology, with a growth rate of 12.9 mm/year (IQR 3.5-22 mm/year) ^[80]B3b. The best growth rate cutoff for predicting malignancy is 2.68 mm/year (sensitivity 87.5%, specificity 88.8%) ^[80]B3b. Contrast washout is unreliable in this population, absolute washout >60% was present in 71.4% of ACC cases ^[80]B3b.

Prognosis of Specific Lesions

ACC discovered as an incidentaloma carries a better prognosis than symptomatic tumors. In a nationwide Italian cohort of 512 patients, 38.1% were incidentalomas, which showed prolonged recurrence-free survival (RFS) and overall survival (OS) compared with symptomatic presentations ^[58]B3b. After surgical resection, recurrence occurred in 56.2% of patients; cortisol secretion, ENSAT stage III, Ki67%, and Weiss score increased recurrence risk, while margin-free resection, open surgery, and adjuvant mitotane reduced it ^[58]B3b. RFS predicted OS, making it a potential surrogate endpoint ^[58]B3b. Overall 5-year survival for ACC is approximately 50%, falling to <15% if metastatic ^[56]A1b.

Pheochromocytomas are discovered incidentally in the majority of cases (69%), and incidental tumors are smaller (median 42 mm) and present at older age (median 62 years) than those detected due to adrenergic symptoms (60 mm, 42 years) ^[82]B3b. Hereditary predisposition is present in 20.4% of all pheochromocytoma patients but is lower in incidental cases (15.3%) ^[82]B3b, underscoring the need for genetic counseling and cascade screening in all confirmed pheochromocytomas.

Cardiovascular and Metabolic Prognosis

Even mild cortisol excess is associated with persistent cardiac remodeling. In the prospective CV-CORT-EX study, patients with overt Cushing's syndrome (CS) had left ventricular hypertrophy and impaired longitudinal systolic/diastolic function ^[127]C4. After biochemical remission (median 8 months), hypertension and hyperglycemia improved but cardiac alterations only partially recovered ^[127]C4. Patients with prior CS in long-term remission (median 95 months) still had worse diastolic function than the general population (LV relaxation velocity e' 0.08 vs 0.10 ms⁻¹) ^[127]C4. In MACS, cardiac remodeling was more pronounced than in individuals with metabolic syndrome ^[127]C4.

Nonfunctional adrenal tumors (NFATs) are not benign in their systemic effects. A national register-based study of 17,561 NFAT patients found an increased risk of psychiatric and sleep disorders compared with controls (adjusted HR 1.92; 95% CI 1.82-2.01) ^[100]D5. Bilateral nonfunctioning adrenal incidentalomas are independently associated with higher cardiometabolic risk: odds ratio for type 2 diabetes 2.36 (95% CI 1.18-4.72) and for organ damage 2.09 (95% CI 1.00-4.37) compared with unilateral lesions ^[134]B3b.

Prevention: Screening Strategies

Screening for hormone excess is the cornerstone of prevention. The 2008 Endocrine Society guideline recommendations identify three at-risk groups: (A) unusual features for age, (B) multiple (>3) and progressive features, and (C) adrenal incidentaloma compatible with adenoma ^[126]A1c. In a prospective validation of 377 patients, these groups captured 73% of CS cases, and screening within these groups yielded a diagnosis in 39% of patients, compared with 12% in other groups ^[126]A1c. However, 27% of CS patients fell outside the recommended groups, suggesting that clinical judgment should supersede rigid criteria ^[126]A1c. The most powerful predictor of CS was the presence of multiple symptoms (OR 18.0; 95% CI 5.1-63.8), while obesity as a sole complaint decreased the probability (OR 0.11; 95% CI 0.04-0.30) ^[126]A1c.

For all adrenal incidentalomas, the Endocrine Society and ESE guidelines recommend screening for pheochromocytoma and cortisol excess, and for primary aldosteronism in hypertensive or hypokalemic patients ^[76]A1c. The 1-mg overnight dexamethasone suppression test (DST) is recommended, with a threshold of 138 nmol/L to consider subclinical CS; a value <50 nmol/L virtually excludes it ^[76]A1c. In patients with adrenal incidentaloma and MACS, the DST cutoff to differentiate overt CS should be increased to 196 nmol/L ^[60]D5. Late-night salivary cortisol is not suitable as a screening test for subclinical hypercortisolism (sensitivity 22.7% at a cutoff of 5.1 nmol/L) ^[132]D5.

Among patients screened for primary aldosteronism, 21% had adrenal imaging after an aldosterone-renin ratio measurement, and the incidence of adrenal mass was 7.2% (median 1.4 cm), yielding a number needed to screen of 14 to detect one mass ^[43]B3b. This suggests that routine adrenal imaging may be considered when PA suspicion is high ^[43]B3b. In PA patients, the prevalence of concurrent MACS is 21.9% (95% CI 18.1-26.2) and is associated with chronic kidney disease (OR 1.96), diabetes (OR 1.60), and cardiovascular disease (OR 1.37) ^[57]B2a.

Quality Improvement and Follow-up

Despite guideline recommendations, appropriate follow-up of incidental adrenal masses is infrequent. A system-wide quality improvement (QI) program incorporating chart-based messages, evidence-based algorithms, standardized radiology recommendations, and access to a multispecialty adrenal clinic increased primary care provider-initiated evaluation from 27.6% to 35.5% (adjusted OR 1.70; 95% CI 1.16-2.50) ^[101]B2b. These data highlight that systematic processes can improve care, but the optimal surveillance interval remains debated. Given the low risk of malignant transformation and hormonal progression in initially benign, nonfunctional masses, routine follow-up for 2-5 years may be excessive, and management should be tailored on an individual basis ^[86]C4.

Family Cascade Screening

When a pheochromocytoma is confirmed, genetic testing for germline pathogenic variants (e.g., RET, VHL, NF1, SDHx) is indicated because hereditary predisposition is present in 20.4% of patients overall ^[82]B3b. Incidental pheochromocytomas have a lower but still substantial rate (15.3%) ^[82]B3b. Confirmation of a pathogenic variant triggers cascade screening of at-risk relatives, with periodic biochemical and imaging surveillance beginning in childhood or early adulthood depending on the gene. For ACC, germline testing for Li-Fraumeni syndrome (TP53) and other predisposition syndromes is recommended in patients with early-onset disease or family history. No formal cascade screening guidelines exist for MACS or primary aldosteronism, though family history of hypertension or endocrine tumors should prompt evaluation.

Pearl: The natural history of most adrenal incidentalomas is benign, but the minority of masses that are malignant or hormonally active drive the need for systematic screening, and the strongest predictor of finding Cushing syndrome is the presence of multiple (>3) typical symptoms, not obesity alone ^[126]A1c.

Prognosis depends on lesion type and hormone status, but these outcomes are further modified by physiologic states that shift the risk-benefit calculus of every diagnostic and therapeutic decision. The following special populations require distinct considerations.

Pediatrics

Adrenal incidentalomas in children are extremely rare ^[135]A1c. The risk of malignancy is much higher than in adults, prompting the 2023 ESE guideline to recommend urgent assessment in children, adolescents, and adults younger than 40 years ^[75]A1c. MRI is the preferred imaging technique to avoid ionizing radiation ^{[75]A1c[135]A1c}. In a single-center series of 55 pediatric patients, neuroblastoma was the most common nonneonatal malignant adrenal incidentaloma (10 of 20 malignant cases) ^[67]C4. In neonates, the rate of spontaneous regression is high, so close observation is feasible if the tumor is small, confined to the adrenal, and without distant metastasis ^[67]C4. Silent pheochromocytoma can occur; in the FRENAR database, 15.2% of patients with pheochromocytoma/paraganglioma were younger than 18 years ^[139]B3b. Preoperative α-blockade is recommended to achieve hemodynamic stability during adrenalectomy ^[68]C4.

Pregnancy

Adrenal masses in pregnancy require urgent evaluation because of the higher likelihood of malignancy ^[75]A1c. MRI is the preferred imaging modality ^[75]A1c. Hormonal workup should include fractionated metanephrines and a 1-mg overnight dexamethasone suppression test, though pregnancy-specific reference ranges for cortisol and aldosterone may confound interpretation. Pheochromocytoma can present with hypertensive crises in pregnancy ^[108]D5; selective α-blockade (e.g., doxazosin) is preferred, and β-blockade should be added only after α-blockade is established. For cortisol-secreting adenomas, surgery is ideally deferred to the second trimester or postpartum. Mifepristone, a glucocorticoid receptor antagonist, has been studied in non-pregnant patients with mild cortisol excess and reduced insulin resistance (lnHOMA-IR decreased from 1.0 to 0.6; p=0.03) ^[141]C4, but it is contraindicated in pregnancy because of its abortifacient effect. Before delivery, a multidisciplinary team (endocrinology, obstetrics, anesthesia) should plan perioperative glucocorticoid coverage for patients with overt Cushing syndrome or mild autonomous cortisol secretion (MACS) ^[21]A1c. Breastfeeding safety data are limited; bisphosphonates such as clodronate are not recommended during lactation, but calcium and vitamin D supplementation is safe. Weekly intramuscular clodronate 100 mg with calcium and vitamin D increased lumbar BMD and prevented new vertebral fractures in premenopausal women with subclinical Cushing syndrome ^[136]A1b.

Elderly

Benign adrenal incidentalomas increase with age, with up to 10% of individuals older than 70 years harboring an adrenal mass ^[135]A1c. The pre-test probability of malignancy is low, so the 2023 ESE guideline recommends that imaging investigations and management be tailored in proportion to the patient's frailty and potential clinical gain ^[75]A1c. For patients with MACS, screening for hypertension and type 2 diabetes is essential ^[75]A1c. Surgery should be considered only if comorbidities are likely cortisol-related and the patient is fit for the procedure. The AAES guideline notes that empirical perioperative glucocorticoid replacement is indicated for overt Cushing syndrome, but for MACS, postoperative day 1 morning cortisol or cosyntropin stimulation testing can guide the need for replacement ^[21]A1c. In elderly patients with poor general health, a conservative approach with surveillance and optimization of cardiovascular risk factors is appropriate.

Immunocompromised

Limited evidence guides management of adrenal incidentalomas in immunocompromised patients. Adrenal masses may represent infection (e.g., tuberculosis, fungal) or lymphoma. The 2023 ESE guideline recommends multidisciplinary expert team discussion for all indeterminate masses ^[75]A1c. Adrenal biopsy may be considered if pheochromocytoma is excluded by biochemical testing and if the result would alter management ^[135]A1c. Immunosuppressed patients have higher surgical risk; underlying comorbidities such as heart failure and respiratory failure independently increase postoperative complications after adrenalectomy (odds ratio 6.3 and 9.9, respectively) ^[20]D5. Perioperative glucocorticoid coverage should be provided if the patient has been on chronic steroid therapy, and stress-dose steroids should be administered during illness or surgery.

Pearl: In patients under 40, especially pregnant women and children, the risk of malignancy is high enough to justify urgent MRI and full hormone testing, whereas in elderly patients over 70 with a small, benign-appearing mass (HU ≤10), further imaging can be safely omitted and management focused on cardiovascular risk factors.