What can be done for a 42-year-old female patient with constant fatigue and early morning waking at 0200, suspected of having high cortisol levels?

Evaluation and Management of Suspected Hypercortisolism

Before assuming high cortisol, you must first biochemically confirm hypercortisolism with appropriate screening tests—early morning awakening and fatigue alone are nonspecific symptoms that could represent numerous conditions including sleep disorders, depression, or paradoxically, adrenal insufficiency.

Initial Diagnostic Approach

The clinical presentation of constant fatigue with early morning awakening at 0200 requires systematic evaluation to distinguish between hypercortisolism (Cushing's syndrome), adrenal insufficiency, sleep disorders, and other causes:

Rule Out Adrenal Insufficiency First

• Adrenal insufficiency presents with fatigue in 90% of cases and must be excluded before pursuing Cushing's syndrome, as both can present with fatigue but require opposite treatments 1.
• Morning cortisol and ACTH levels should be measured as the first-line diagnostic test, with basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH diagnostic of primary adrenal insufficiency 1.
• If morning cortisol is indeterminate (between 5-18 μg/dL), perform a cosyntropin stimulation test with 0.25 mg IV or IM, measuring cortisol at 30 and 60 minutes—peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1.

Screen for Cushing's Syndrome

If adrenal insufficiency is excluded, proceed with Cushing's syndrome screening:

• Measure 24-hour urinary free cortisol (UFC) as the primary screening test—elevated UFC above the upper limit of normal suggests hypercortisolism 2.
• Perform overnight 1 mg dexamethasone suppression test (DST), giving 1 mg dexamethasone at 11 PM and measuring cortisol at 8 AM the next morning—failure to suppress cortisol to <1.8 μg/dL (50 nmol/L) indicates abnormal feedback inhibition consistent with Cushing's syndrome 2.
• Measure late-night salivary cortisol (LNSC) on two separate occasions, as loss of circadian rhythm with elevated midnight cortisol is characteristic of Cushing's syndrome 3.

If Cushing's Syndrome is Confirmed

Determine ACTH Dependency

• Measure morning (08:00-09:00h) plasma ACTH to classify the syndrome as ACTH-dependent or ACTH-independent 2.
• Any ACTH level >5 ng/L indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source), while low or undetectable ACTH indicates ACTH-independent disease (adrenal source) 2.
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease (pituitary adenoma) 2.

For ACTH-Dependent Disease

• Obtain high-quality pituitary MRI with thin slices (3T preferred) to identify a pituitary adenoma 2.
• If adenoma ≥10 mm is found, proceed to transsphenoidal surgery 2.
• If no adenoma or lesion <6 mm is found, perform bilateral inferior petrosal sinus sampling (BIPSS) to distinguish pituitary from ectopic ACTH sources—central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH stimulation confirms pituitary source 2.

For ACTH-Independent Disease

• Obtain adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 2.
• Laparoscopic adrenalectomy is the treatment for unilateral adrenal adenoma 2.

Medical Management of Confirmed Cushing's Disease

If surgery is not immediately feasible or fails to achieve remission:

First-Line Medical Therapy

• Adrenal steroidogenesis inhibitors are the preferred initial medical therapy due to reliable effectiveness and rapid onset 3.
• Osilodrostat (approved in the US) induces rapid cortisol control within hours to days, with highest efficacy among available agents based on prospective trials—typical dosing is twice daily with monitoring for adrenal insufficiency 3.
• Ketoconazole (approved in Europe) provides response within days, with ease of dose titration—monitor liver function tests regularly, though mild stable elevations don't necessarily require discontinuation 3.
• Metyrapone (approved in Europe) induces rapid control within hours, without hepatotoxicity concerns or male hypogonadism 3.

For Severe Hypercortisolism

• Combination therapy with multiple steroidogenesis inhibitors may be necessary for severe disease—common regimens include ketoconazole plus metyrapone, or ketoconazole plus cabergoline 3.
• Consider bilateral adrenalectomy if hypercortisolism is very severe and not responsive to optimized medical therapy, to avoid worsening outcomes 3.

Monitoring Medical Therapy

• Regular monitoring of UFC, morning cortisol, and/or LNSC is required to assess treatment efficacy—patients normalizing both UFC and LNSC show better clinical outcomes than those normalizing UFC alone 3.
• Monitor symptoms and comorbidities including weight, glycemia, and blood pressure 3.
• Higher medication doses at bedtime may help restore circadian rhythm patterns, though rigorous evidence is lacking 3.
• Change treatment if cortisol remains persistently elevated after 2-3 months on maximum tolerated doses 3.

Important Caveats

Common Pitfalls to Avoid

• Do not assume high cortisol based on symptoms alone—early morning awakening and fatigue are nonspecific and can occur with low cortisol (adrenal insufficiency), sleep disorders, depression, or chronic fatigue syndrome 4, 5.
• Research shows that chronic fatigue syndrome patients actually display cortisol hyposecretion with lower evening and morning cortisol compared to healthy controls 4.
• Sleep deprivation itself causes elevated evening cortisol levels and delays the quiescent period of cortisol secretion by at least 1 hour 6.
• Low waking cortisol and flat diurnal slope are associated with fatigue and predict future onset of fatigue 7.

False Positives in Screening

• Severe obesity, uncontrolled diabetes, depression, alcoholism, and PCOS can cause false positive screening results 2.
• Medications that induce CYP3A4 (anticonvulsants, rifampin) or oral estrogens increasing corticosteroid-binding globulin can affect test interpretation 2.

If Screening Tests are Negative

• Consider primary sleep disorder evaluation including polysomnography for sleep apnea or other sleep architecture disturbances.
• Evaluate for depression or anxiety disorders, which commonly present with early morning awakening and fatigue.
• Consider chronic fatigue syndrome if symptoms persist for >6 months with characteristic post-exertional malaise and no other explanation.