How should I interpret a patient's lab results showing normal dexamethasone suppression (Cortisol level = 1.5) with low-normal Adrenocorticotropic hormone (ACTH) level (result = 7), but elevated 24-hour urine cortisol (Hypercortisolism) and normal creatinine level, and what are the implications for psychiatric treatment?

Interpretation of Laboratory Results

Your patient's results show a discordant pattern: appropriate cortisol suppression on dexamethasone testing (1.5 μg/dL) but markedly elevated 24-hour urinary free cortisol (62.2 μg/24h), which suggests either cyclic Cushing's syndrome, pseudo-Cushing's state related to psychiatric illness, or significant intra-patient variability in cortisol excretion. 1, 2

Understanding the Discordance

The key issue here is that your patient has passed the overnight dexamethasone suppression test (cortisol 1.5 μg/dL is well below the 1.8 μg/dL cutoff for normal suppression) 2, 3, yet has elevated 24-hour urinary free cortisol. This creates diagnostic uncertainty that requires systematic evaluation.

Why This Pattern Occurs

• Intra-patient variability in 24-hour urinary free cortisol can be substantial—up to 50% between collections—which is why 2-3 collections are recommended before making diagnostic decisions 3

• Cyclic Cushing's syndrome produces weeks to months of normal cortisol secretion interspersed with episodes of excess, leading to inconsistent test results depending on when sampling occurs 1, 3

• Pseudo-Cushing's states (psychiatric disorders, severe obesity, alcohol use) can activate the HPA axis, causing mildly elevated cortisol that mimics true hypercortisolism while maintaining some degree of dexamethasone suppressibility 3, 4

• The ACTH level of 7 pg/mL is detectable and low-normal, which is somewhat unusual—in true ACTH-independent Cushing's syndrome, ACTH should be suppressed to undetectable levels, while in ACTH-dependent disease it should be clearly elevated 1

Recommended Diagnostic Algorithm

Immediate Next Steps

• Obtain 2-3 additional 24-hour urinary free cortisol collections to establish whether the elevation is consistent or represents random variability 3

• Repeat the overnight 1-mg dexamethasone suppression test and measure dexamethasone levels concomitantly with cortisol to exclude false-negative results from abnormal drug metabolism 3

• Obtain late-night salivary cortisol measurements (2-3 samples) as an additional screening modality that may be less affected by psychiatric illness than other tests 3

Excluding Interfering Factors

• Review all medications, particularly:

  • Oral contraceptives or estrogen therapy (increases cortisol-binding globulin, falsely elevating total cortisol) 3
  • CYP3A4 inducers (accelerate dexamethasone metabolism, causing false-positive suppression tests) 3
  • Topical hydrocortisone or fluticasone inhalers (can interfere with cortisol measurements) 3

• Assess for alcohol use disorder, as this is a common cause of pseudo-Cushing's state in psychiatric patients 5, 4

• Evaluate severity of psychiatric illness, as severe depression and stress can cause incomplete dexamethasone suppression and mild hypercortisolism 6, 4

If Discordance Persists

• Consider the Dex-CRH test (dexamethasone-corticotropin releasing hormone test) to distinguish true Cushing's syndrome from pseudo-Cushing's states—this has 90% sensitivity and 95% specificity for Cushing's disease 1

• Extended monitoring for cyclic disease may be necessary, with repeated testing during symptomatic periods to capture episodes of cortisol excess 1, 3

Clinical Interpretation of Current Results

What the Results Suggest

• The cortisol suppression to 1.5 μg/dL argues AGAINST overt Cushing's syndrome, as this demonstrates intact negative feedback of the HPA axis 2, 3

• The elevated 24-hour urinary cortisol (62.2 μg/24h) is concerning if the reference range upper limit is around 40-50 μg/24h, but a single elevated value has limited specificity 3

• The low-normal ACTH (7 pg/mL) is somewhat paradoxical—if this were true ACTH-independent Cushing's, ACTH should be undetectable (<5 pg/mL), and if ACTH-dependent, it should be elevated (>29 pg/mL for high specificity) 1

Most Likely Scenarios

1. Pseudo-Cushing's state related to psychiatric illness with one spuriously elevated urinary cortisol collection 4

2. Cyclic Cushing's syndrome where the dexamethasone test was performed during a quiescent phase but urinary collection captured an active phase 1, 3

3. Mild/early Cushing's syndrome with preserved partial suppressibility—though this would be unusual with such good suppression to 1.5 μg/dL 7

Psychiatric Implications and Treatment Considerations

Impact on Psychiatric Diagnosis

• Hypercortisolism can cause or exacerbate depression, anxiety, cognitive impairment, and psychosis, making it essential to definitively exclude Cushing's syndrome before attributing symptoms solely to primary psychiatric illness 4

• Conversely, severe psychiatric disorders (especially major depression) can activate the HPA axis, creating a bidirectional diagnostic challenge 4

• If true Cushing's syndrome is present, psychiatric symptoms may improve or resolve with treatment of the underlying endocrine disorder 4

Treatment Implications

• Do not initiate or escalate psychiatric medications until the endocrine evaluation is complete, as treating pseudo-Cushing's from psychiatric illness may normalize cortisol levels, while missing true Cushing's will leave psychiatric symptoms refractory to treatment 4

• If the patient is on oral contraceptives, consider switching to non-oral contraception to eliminate CBG elevation that can confound cortisol measurements 3

• Avoid medications that induce CYP3A4 (carbamazepine, phenytoin, rifampin) as these will interfere with dexamethasone testing 3

Monitoring Strategy

• Serial testing over 3-6 months with clinical correlation is often necessary when results are equivocal and clinical suspicion is moderate 3

• Document timing of psychiatric symptoms relative to any documented hypercortisolism to assess causality 4

Critical Pitfalls to Avoid

• Do not rely on a single elevated 24-hour urinary cortisol to diagnose Cushing's syndrome—the 50% random variability makes this unreliable 3

• Do not assume normal dexamethasone suppression completely excludes Cushing's syndrome—18% of patients with Cushing's disease can suppress to <5 μg/dL, and 8% to <2 μg/dL on the 1-mg overnight test 7

• Do not measure ACTH during the overnight dexamethasone suppression test—this is not part of standard protocol and leads to misinterpretation 2

• Do not pursue extensive imaging or invasive testing (BIPSS, pituitary MRI) until biochemical hypercortisolism is definitively established with multiple concordant abnormal tests 1

Summary of Recommended Actions

1. Repeat 24-hour urinary free cortisol (2-3 additional collections) 3
2. Repeat overnight dexamethasone suppression test with dexamethasone level measurement 3
3. Obtain late-night salivary cortisol (2-3 samples) 3
4. Review and optimize medications (discontinue oral contraceptives, avoid CYP3A4 inducers) 3
5. Assess for alcohol use and optimize psychiatric treatment 4
6. If discordance persists, perform Dex-CRH test 1
7. Consider extended monitoring for cyclic disease if clinical suspicion remains high 1, 3