In an elderly patient, how should I assess and manage suspected cortisol excess (Cushing’s syndrome) or deficiency (adrenal insufficiency)?

Assessment and Management of Cortisol Disorders in Elderly Patients

Evaluating Suspected Cortisol Excess (Cushing's Syndrome)

Initial Screening Approach

Screen elderly patients with at least two of the following tests, performing 2-3 measurements of each to account for biological variability and cyclic disease patterns 1:

• 24-hour urinary free cortisol (UFC): Values >100 μg/24h on multiple collections are diagnostic; sensitivity >90% but requires complete collection verified by creatinine excretion 1, 2
• Late-night salivary cortisol (LNSC): Collected between 11 PM-midnight; abnormal threshold >3.6 nmol/L with sensitivity 92-100% and specificity 93-100% 1, 2
• 1-mg overnight dexamethasone suppression test (DST): Give 1 mg at 11 PM-midnight, measure cortisol at 8 AM; abnormal if ≥1.8 μg/dL (≥50 nmol/L) 1, 2

Critical Pitfalls in Elderly Patients

Before pursuing any workup, obtain a comprehensive medication history including oral steroids, inhaled corticosteroids (especially fluticasone), topical preparations, intra-articular/epidural injections, and over-the-counter supplements—failure to exclude exogenous glucocorticoids is the most common cause of unnecessary testing 1, 2.

Recognize pseudo-Cushing's states that are more common in elderly: severe obesity, depression, alcoholism, and uncontrolled diabetes can cause mildly elevated cortisol without true Cushing's syndrome 1, 2.

Account for medication interactions: CYP3A4 inducers (phenytoin, carbamazepine, rifampin) accelerate dexamethasone metabolism causing false-positive DST; oral estrogens increase cortisol-binding globulin causing falsely elevated total cortisol 1, 2.

Determining ACTH Dependency

Once hypercortisolism is confirmed with ≥2 abnormal screening tests, measure 9 AM plasma ACTH to distinguish ACTH-dependent from ACTH-independent disease 1:

• ACTH >5 ng/L (>1.1 pmol/L): ACTH-dependent (pituitary or ectopic source)
• ACTH >29 ng/L (>6.4 pmol/L): 70% sensitivity and 100% specificity for pituitary Cushing's disease 1
• ACTH <5 ng/L or undetectable: ACTH-independent (adrenal source) 1

Localizing ACTH-Dependent Disease

For ACTH-dependent Cushing's, obtain high-resolution 3-Tesla pituitary MRI with thin slices and gadolinium contrast 1:

• Adenoma ≥10 mm: Proceed directly to transsphenoidal surgery 1
• Adenoma 6-9 mm: Perform CRH or desmopressin stimulation test; cortisol rise >38 nmol/L at 15 minutes supports pituitary source with >70% sensitivity 1
• No adenoma or <6 mm lesion: Bilateral inferior petrosal sinus sampling (BIPSS) is mandatory—this is the gold standard with 96-100% sensitivity and near-100% specificity 1

BIPSS diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 1. BIPSS must be performed only in specialized centers by experienced interventional radiologists, with confirmation of active hypercortisolism on the morning of the procedure 1.

Consider ectopic ACTH syndrome especially in elderly patients with rapid symptom onset, severe hypokalemia, or very high cortisol levels; obtain neck-to-pelvis thin-slice CT and consider 68Ga-DOTATATE PET imaging if BIPSS indicates peripheral source 1. Pulmonary carcinoid tumors account for up to 40% of ectopic ACTH cases 1.

Management of Confirmed Cushing's Syndrome

For overt Cushing's disease with clinical signs/symptoms: unilateral adrenalectomy of the affected gland via minimally-invasive surgery when feasible 3.

For mild autonomous cortisol secretion (MACS) without overt symptoms: Consider adrenalectomy in younger elderly patients with progressive metabolic comorbidities (diabetes, hypertension, cardiovascular events, vertebral fractures) after shared decision-making; those managed non-surgically require annual clinical screening 3. Note that MACS is associated with increased morbidity and mortality but has low risk of progression to overt Cushing's 3.

---

Evaluating Suspected Cortisol Deficiency (Adrenal Insufficiency)

High-Risk Clinical Scenarios in Elderly

Suspect adrenal insufficiency immediately in elderly patients presenting with 4:

• Unexplained collapse or hypotension (especially if refractory to vasopressors)
• Persistent nausea, vomiting, or diarrhea with weight loss
• Hyponatremia (present in 90% of cases) with or without hyperkalemia (only 50% of cases) 4
• History of ≥20 mg/day prednisone or equivalent for ≥3 weeks 4

Never delay treatment for diagnostic testing in suspected adrenal crisis—give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour if patient is clinically unstable 4.

Diagnostic Algorithm

Step 1: Measure morning (8-9 AM) serum cortisol and plasma ACTH simultaneously 4:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH: Diagnostic of primary adrenal insufficiency 4
• Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH: Strong suspicion of primary adrenal insufficiency 4
• Cortisol >386 nmol/L (>14 μg/dL): Effectively rules out adrenal insufficiency 2
• Cortisol 140-386 nmol/L (5-14 μg/dL): Requires ACTH stimulation testing 4

Step 2: If cortisol is indeterminate, perform cosyntropin stimulation test 4:

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM
• Measure cortisol at baseline, 30 minutes, and 60 minutes
• Peak cortisol <500 nmol/L (<18 μg/dL): Diagnostic of adrenal insufficiency 4
• Peak cortisol >550 nmol/L (>18-20 μg/dL): Excludes adrenal insufficiency 4

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency (high ACTH, low cortisol) 4:

• Often presents with hyperpigmentation, salt craving, hyperkalemia
• Requires both glucocorticoid AND mineralocorticoid replacement
• Measure 21-hydroxylase autoantibodies (positive in ~85% of Western cases) 4
• If antibodies negative, obtain adrenal CT to evaluate for hemorrhage, tumor, tuberculosis 4

Secondary adrenal insufficiency (low/normal ACTH, low cortisol) 4:

• No hyperpigmentation, no hyperkalemia
• Requires only glucocorticoid replacement (renin-angiotensin-aldosterone system intact)
• Evaluate for pituitary pathology with MRI if not iatrogenic 4

Critical Considerations for Elderly Patients

Exogenous steroids confound all testing: Patients on any corticosteroids (including inhaled fluticasone, topical preparations) will have suppressed morning cortisol and ACTH—do not attempt diagnostic testing until adequate washout period after discontinuation 4.

For patients on chronic steroids requiring assessment: Use dexamethasone 4 mg IV for emergency treatment if you still need to perform diagnostic testing later, as dexamethasone does not interfere with cortisol assays 4.

Hyponatremia with hypo-osmolality requires systematic workup: Adrenal insufficiency must be excluded before diagnosing SIADH, as both present with identical laboratory findings (euvolemic hypo-osmolar hyponatremia, inappropriately high urine osmolality, elevated urinary sodium) 4.

Treatment of Confirmed Adrenal Insufficiency

Maintenance glucocorticoid replacement 4:

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) to approximate physiological cortisol secretion
• Alternative: Prednisone 3-5 mg daily or cortisone acetate 25-37.5 mg daily

For primary adrenal insufficiency, add fludrocortisone 50-200 μg daily for mineralocorticoid replacement, adjusted based on blood pressure, salt cravings, and plasma renin activity 4.

Mandatory patient education 4:

• Double or triple dose during illness, fever, or physical stress
• Prescribe hydrocortisone 100 mg IM emergency injection kit with self-injection training
• Wear medical alert bracelet indicating adrenal insufficiency
• Educate on warning signs of adrenal crisis

Stress-dose protocols 4:

• Minor stress: Double usual daily dose for 1-2 days
• Moderate stress: Hydrocortisone 50-75 mg daily
• Major stress/surgery: Hydrocortisone 100-150 mg daily
• Adrenal crisis: 100 mg IV hydrocortisone immediately plus aggressive saline resuscitation

Monitor annually with assessment of health, well-being, weight, blood pressure, serum electrolytes, and screen for new autoimmune disorders (especially hypothyroidism) 4.

Special Situations in Elderly

Persistent hypotension despite hydrocortisone: Optimize fludrocortisone dosing (may need up to 500 μg daily in younger adults); evaluate for drug interactions (diuretics, NSAIDs interfere with fludrocortisone); consider timing adjustments of hydrocortisone doses 4.

Concurrent hypothyroidism: Start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 4.

Nausea and poor appetite: Often indicates under-replacement; consider waking earlier to take first hydrocortisone dose then returning to sleep; adjust timing based on symptom patterns 4.