Cyclic Cushing's Syndrome: Recurrent Intermittent Cortisol Spikes
Yes, cyclic Cushing's syndrome is a rare disorder characterized by repeated episodes of cortisol excess interspersed with periods of normal cortisol secretion, making it one of the most diagnostically challenging endocrine conditions. 1
Understanding the Condition
Cyclic Cushing's syndrome involves rhythmic fluctuations in ACTH secretion resulting in cyclic variation of adrenal steroid production. 2 The cycles of hypercortisolism can occur regularly or irregularly, with intercyclic phases ranging from days to years. 1 To formally diagnose cyclic Cushing's syndrome, three peaks and two troughs of cortisol production should be demonstrated. 1
Etiology Distribution
The underlying causes break down as follows:
- 54% originate from a pituitary corticotroph adenoma (Cushing's disease) 1
- 26% from ectopic ACTH-producing tumors 1
- 11% from adrenal tumors 1
- Remainder unclassified 1
Clinical Presentation
The majority of patients with cyclic Cushing's syndrome have clinical signs that can be either fluctuating or permanent, though a minority may have absent clinical signs despite biochemical evidence. 1
Key clinical features during hypercortisolemic episodes include:
- Peripheral edema 3
- Hypokalemia 3
- Cardiac arrhythmias 3
- Typical Cushingoid features (facial plethora, easy bruising, purple striae) when present 4
The condition may remain unrecognized for years since typical features of Cushing's disease are usually absent due to the intermittent and brief duration of cortisol hypersecretion. 3
Diagnostic Approach
Multiple, periodic, sequential late-night salivary cortisol (LNSC) measurements are particularly useful for longitudinal surveillance of patients with cyclic Cushing's syndrome who exhibit weeks to months of normal cortisol secretion interspersed with episodes of cortisol excess. 5
Screening Strategy
- Frequent measurements of urinary cortisol or salivary cortisol levels are the most reliable and convenient screening tools for suspected cyclic Cushing's syndrome 1
- 24-hour urinary free cortisol testing should be performed repeatedly to capture peaks and troughs 4
- Cortisol stimulation or suppression tests may give spurious results owing to spontaneous falls or rises in serum cortisol at the time of testing 1
Critical Diagnostic Pitfall
Clinicians should actively search for cyclic Cushing's syndrome in all patients with suspected Cushing's syndrome but normal biochemistry or vice versa. 1 Patients may show paradoxical responses to dexamethasone suppression testing, with increased rather than suppressed ACTH and cortisol levels, which can reflect increasing or decreasing endogenous hormone activity. 3, 2
Dynamic tests are best interpreted if performed during a sustained period of hypercortisolism, and sometimes lengthy periods of observation are necessary to confirm the diagnosis. 2
Localization After Biochemical Confirmation
Once cyclic Cushing's syndrome is biochemically confirmed:
- Measure plasma ACTH levels to distinguish between adrenal causes (suppressed ACTH) and ACTH-dependent forms (mid-normal to elevated ACTH) 4
- For ACTH-dependent disease, obtain pituitary MRI and consider bilateral inferior petrosal sinus sampling 4
- For suspected ectopic ACTH production, perform specific biochemical testing including serotonin in platelets and/or urine, chromogranin A, and calcitonin 1
- For ACTH-independent disease, obtain adrenal imaging with CT or MRI using adrenal protocol 6
Treatment Considerations
For patients with persistent hypercortisolism even during trough periods, adrenal steroidogenesis inhibitors should be used as first-line medical therapy due to their reliable effectiveness. 5
Medical Management Options
- Osilodrostat has the highest efficacy based on prospective clinical trials 7, 5
- Metyrapone has rapid onset of action within hours 5
- Ketoconazole is effective within days 5
When trough cortisol levels remain elevated, combination therapy is strongly recommended to maximize adrenal blockade. 5 Effective combinations include ketoconazole with metyrapone, or a steroidogenesis inhibitor plus a tumor-targeting agent such as ketoconazole plus cabergoline. 5
Monitoring Treatment Response
Responses to treatment must be closely monitored, interpreted, and evaluated with caution because of potential variations in steroidogenesis. 2 Regular monitoring should include:
- Multiple serial tests of both urinary free cortisol and LNSC 5
- Morning cortisol values, especially in patients taking higher medication doses in the evening versus morning 7, 5
- Clinical symptoms and comorbidities, particularly weight, glycemia, and blood pressure 5
A block-and-replace regimen may be particularly useful for patients with cyclic Cushing's syndrome to maintain stable cortisol levels, involving complete blockade of cortisol production with steroidogenesis inhibitors while simultaneously providing glucocorticoid replacement. 5