Cyclical Cushing's Syndrome: Diagnostic Approach
Understanding the Challenge
Cyclical Cushing's syndrome is characterized by weeks to months of normal cortisol secretion interspersed with episodes of hypercortisolism, making diagnosis extremely difficult when initial screening tests are normal. 1
The phenomenon occurs in approximately 15% of adult Cushing's cases, with even lower prevalence in pediatrics, and requires a high index of suspicion when clinical features suggest Cushing's but biochemistry is discordant. 2, 3
Key Diagnostic Strategy
When cyclical Cushing's is suspected with normal 24-hour urine cortisol, perform serial measurements of late-night salivary cortisol (LNSC) over extended periods to capture episodes of hypercortisolism. 1
Specific Testing Algorithm
Obtain 2-3 additional 24-hour urine free cortisol collections on non-consecutive days to account for the 50% random variability inherent in this test and potentially capture active disease phases. 1
Collect late-night salivary cortisol samples (between 11 PM-midnight) on multiple nights over several weeks, as this has 92-100% sensitivity and 93-100% specificity for Cushing's syndrome and is the most practical method for extended monitoring. 1
Repeat overnight 1-mg dexamethasone suppression tests during symptomatic periods, measuring both cortisol and dexamethasone levels concomitantly to exclude false-negative results from abnormal drug metabolism. 1
Document at least three peaks and two troughs of cortisol production to formally diagnose cyclical Cushing's syndrome, recognizing that intercyclic phases can range from days to years. 3
Critical Pitfalls to Avoid
The most important error is abandoning the diagnostic workup after a single normal screening test when clinical suspicion remains high. 1, 4
Do not rely on single 24-hour urine collections, as patients can have normal values 69% of the time even with proven disease. 4
Avoid performing dexamethasone suppression tests or CRH stimulation during quiescent phases, as these will yield false-negative results. 1
Do not assume normal baseline cortisol excludes Cushing's disease—abnormal control regulation (loss of circadian rhythm, failure to suppress with dexamethasone) may be present even when absolute cortisol levels are normal. 4
Extended Monitoring Protocol
For patients with strong clinical suspicion but persistently normal biochemistry, implement 3-6 months of serial testing during symptomatic periods. 1
Measure late-night salivary cortisol 2-3 times weekly during this monitoring period, as this is the most convenient and reliable screening tool for capturing intermittent hypercortisolism. 3, 5
Instruct patients to collect samples specifically during periods when symptoms worsen (weight gain, facial plethora, proximal weakness, mood changes). 1
Maintain a symptom diary correlating clinical features with biochemical sampling dates to identify patterns. 3
Confirmatory Testing Once Hypercortisolism is Documented
Once active hypercortisolism is biochemically confirmed during a peak phase, immediately proceed to measure 9 AM ACTH to determine ACTH-dependency before cortisol levels spontaneously normalize. 1, 6
If ACTH is normal or elevated (>5 ng/L), perform pituitary MRI to evaluate for corticotroph adenoma, as 54% of cyclical cases originate from pituitary sources. 6, 3
If pituitary MRI is inconclusive or shows lesion <6 mm, proceed directly to bilateral inferior petrosal sinus sampling (BIPSS) during a documented active phase to definitively distinguish pituitary from ectopic sources. 1, 6
Confirm active hypercortisolism immediately prior to BIPSS with same-day LNSC, UFC, or DST, as performing BIPSS during a quiescent phase will yield false-negative results. 1
Etiology-Specific Considerations
The distribution of cyclical Cushing's differs from non-cyclical disease: 3
- Pituitary corticotroph adenoma: 54% of cyclical cases
- Ectopic ACTH-producing tumors: 26% of cyclical cases (particularly carcinoids and neuroendocrine tumors)
- Adrenal tumors: 11% of cyclical cases
For suspected ectopic ACTH production, obtain specific biochemical testing including platelet/urine serotonin, chromogranin A, and calcitonin, followed by neck-to-pelvis thin-slice CT or 68Ga-DOTATATE PET imaging. 6, 3
Management Implications
Surgical resection remains first-line therapy for all etiologies once the source is localized, but timing of surgery should coincide with documented active disease to ensure accurate intraoperative findings. 7
For ACTH-dependent disease with negative imaging, consider medical therapy with steroidogenesis inhibitors (metyrapone) as a temporizing measure during extended diagnostic evaluation. 8, 7
Post-operative monitoring requires extended follow-up with serial cortisol measurements, as recurrence patterns may mirror the pre-operative cyclical nature. 2