What is the best course of action for a 37-year-old woman with persistent anxiety, significant unintentional weight loss, paresthesias, and cognitive impairment, with elevated morning cortisol (29 mcg/dL) and normal adrenocorticotropic hormone (ACTH) levels, despite a complex psychiatric and medical history?

Evaluation and Management of Suspected ACTH-Independent Cushing Syndrome

This patient requires urgent adrenal imaging with CT or MRI to evaluate for an adrenal source of hypercortisolism, followed by confirmatory testing with 24-hour urinary free cortisol, as the combination of elevated morning cortisol (29 mcg/dL) with normal ACTH indicates ACTH-independent Cushing syndrome, most likely from an adrenal adenoma or carcinoma. 1

Diagnostic Interpretation

The biochemical pattern is highly suggestive of an adrenal source:

• Elevated cortisol (29 mcg/dL) with normal/non-elevated ACTH indicates ACTH-independent Cushing syndrome, where excessive cortisol secretion originates from the adrenal gland itself rather than being driven by pituitary or ectopic ACTH 1
• This pattern points to adrenal adenoma, adrenal carcinoma, or bilateral adrenal hyperplasia as the most likely diagnoses 2, 1
• The patient's constellation of symptoms—anxiety, cognitive impairment, significant weight loss, and paresthesias—are consistent with hypercortisolism, as neuropsychiatric disturbances occur in 89% of Cushing syndrome patients and correlate with cortisol levels 3

Immediate Diagnostic Workup

Confirmatory Testing for Hypercortisolism

• Obtain at least two 24-hour urinary free cortisol (UFC) collections to confirm Cushing syndrome and account for intra-patient variability, which can be as high as 50% 2
• UFC is advantageous because it measures overall cortisol production independent of cortisol-binding globulin changes 2
• Late-night salivary cortisol (LNSC) can be added if UFC collection is unreliable, though UFC is preferred for suspected adrenal sources 2

Adrenal Imaging Protocol

• Obtain CT scan of the adrenals with adrenal protocol to determine tumor size, unilateral versus bilateral involvement, and features suggesting malignancy 1
• On unenhanced CT, Hounsfield units >10 suggest malignancy; if >10, obtain enhanced CT with 15-minute washout imaging 2
• Enhancement washout <60% at 15 minutes raises concern for malignancy 2
• Suspect adrenal carcinoma if the tumor is >4-5 cm, has irregular margins, is internally heterogeneous, or shows local invasion 2, 1

Risk Stratification Based on Imaging

Features Suggesting Benign Adrenal Adenoma

• Tumor <4 cm with homogeneous appearance and smooth margins 2
• Hounsfield units <10 on unenhanced CT 2
• Enhancement washout >60% at 15 minutes 2

Features Suggesting Adrenal Carcinoma

• Tumor >5 cm with irregular margins or inhomogeneous appearance 2
• Local invasion or adjacent lymph node involvement 2
• Lipid-poor appearance with poor contrast washout 2
• Secretion of multiple hormones 2

Treatment Algorithm

For Benign Adrenal Adenoma

• Laparoscopic adrenalectomy is the definitive treatment for unilateral benign adrenal tumors causing Cushing syndrome 2, 1
• Mandatory postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal (HPA) axis, which has been suppressed by chronic hypercortisolism 2, 1
• Start hydrocortisone 15-25 mg daily in divided doses immediately postoperatively 4

For Suspected Adrenal Carcinoma

• Open adrenalectomy with en bloc resection is required, as laparoscopic approach risks tumor rupture and seeding 2, 1
• Obtain chest, abdomen, and pelvis imaging to evaluate for metastases before surgery 2
• Adjacent lymph nodes and involved structures should be removed for complete resection 1

For Bilateral Adrenal Hyperplasia (Rare)

• If imaging shows bilateral abnormalities, adrenal vein sampling of cortisol production determines lateralization 2
• If asymmetric production, perform laparoscopic unilateral adrenalectomy of the most active side 2
• If symmetric production, medical management is indicated 2

Medical Management Options

Preoperative or Bridge Therapy

• Ketoconazole 400-1200 mg/day is the most commonly used adrenostatic agent due to easy availability and relatively tolerable toxicity profile 2
• Ketoconazole is favored for ease of dose titration but requires monitoring of liver enzymes for hepatotoxicity 2
• Drug-drug interactions must be considered, and hypogonadism may occur in men 2
• Consider preoperative medical therapy if surgery is delayed or if the patient has severe, potentially life-threatening metabolic, psychiatric, infectious, or cardiovascular/thromboembolic complications 2

Alternative Agents

• Osilodrostat achieves high rates of cortisol normalization with convenient dosing but is not limited by hypogonadism 2
• Metyrapone is another option without hypogonadism risk 2
• Mitotane is rarely used as monotherapy in Cushing disease but may be considered for adrenal carcinoma 2

Monitoring Treatment Response

Clinical Endpoints

• Response should be defined by both clinical improvement (weight stabilization, improved hypertension and glucose metabolism, resolution of psychiatric symptoms, quality of life) and biochemical normalization 2
• Monitor UFC levels (except when using mifepristone, which interferes with cortisol assays) 2
• Change treatment if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses 2

Tumor Surveillance on Medical Therapy

• Obtain MRI 6-12 months after initiating medical treatment and repeat every few years 2
• Monitor ACTH levels, as progressive elevations may signal tumor growth, though ACTH has a short half-life and levels fluctuate 2
• If progressive tumor growth occurs, suspend medical treatment and reassess the management plan 2

Critical Pitfalls to Avoid

Diagnostic Errors

• Do not rely on a single cortisol measurement—obtain multiple UFC collections to account for variability 2
• Consider that psychiatric medications (fluoxetine, cimetidine, diltiazem) can affect dexamethasone metabolism and interfere with suppression testing 2
• Oral estrogens increase cortisol-binding globulin and may falsely elevate total cortisol levels 2

Surgical Considerations

• Never perform laparoscopic adrenalectomy for suspected malignancy due to rupture risk 2
• Always plan for postoperative glucocorticoid replacement, as the contralateral adrenal will be suppressed 2, 1
• Ensure endocrine consultation for perioperative stress-dose planning 4

Medical Management Errors

• Avoid under-dosing ketoconazole due to hepatotoxicity concerns—this leads to inadequate cortisol control 2
• Monitor for drug-drug interactions with all adrenostatic agents 2
• Do not use mifepristone if cortisol monitoring is needed, as it blocks cortisol assays and adrenal insufficiency cannot be detected 2

Addressing the Psychiatric and Neurological Symptoms

• The patient's anxiety, cognitive impairment, and paresthesias are likely manifestations of hypercortisolism rather than primary psychiatric disease 3
• Neuropsychiatric disability correlates significantly with cortisol levels and typically improves with successful treatment of Cushing syndrome 3
• Patients with adrenal adenomas (high cortisol, low ACTH) may have less severe neuropsychiatric disability than those with ACTH-dependent disease 3
• Weight loss in Cushing syndrome, while less common than weight gain, can occur and reflects the catabolic effects of chronic hypercortisolism 2