In suspected Adrenocorticotropic hormone (ACTH)-dependent cyclic Cushing's syndrome, is demonstrating three peaks and two troughs of cortisol levels still necessary and should a Magnetic Resonance Imaging (MRI) of the pituitary gland be followed by Bilateral Inferior Petrosal Sinus Sampling (BIPSS) if MRI findings are negative?

Diagnosis and Management of Cyclic ACTH-Dependent Cushing's Syndrome

In suspected cyclic ACTH-dependent Cushing's syndrome, formal diagnosis requires demonstrating three peaks and two troughs of cortisol production, followed by pituitary MRI and bilateral inferior petrosal sinus sampling (BIPSS) if the MRI is negative. 1, 2

Diagnostic Approach for Cyclic Cushing's Syndrome

• Cyclic Cushing's syndrome is characterized by repeated episodes of cortisol excess interspersed with periods of normal cortisol secretion, making diagnosis challenging 1
• To formally diagnose cyclic Cushing's syndrome, three peaks and two troughs of cortisol production should be demonstrated through frequent measurements of urinary or salivary cortisol levels 1
• Frequent measurements of urinary cortisol or salivary cortisol levels are reliable and convenient screening tools for suspected cyclic Cushing's syndrome 1
• Cortisol stimulation or suppression tests may give spurious results due to spontaneous fluctuations in serum cortisol at the time of testing 1

Confirming ACTH Dependency

• ACTH-dependent Cushing's syndrome accounts for 80-85% of cases, with pituitary adenomas (Cushing's disease) being the most common cause (54% of cyclic cases) 3, 1
• Measuring basal morning (08:00-09:00h) plasma ACTH is essential to confirm ACTH dependency 2
• In all patients with Cushing's disease, ACTH is detectable (>5 ng/l) 2
• Using a cut-off value of 29 ng/l, ACTH has a 70% sensitivity and 100% specificity for diagnosing Cushing's disease 2, 4

Imaging and Further Testing

• Pituitary MRI should be performed first to identify a potential adenoma 4, 5
• If the MRI shows an unequivocal pituitary adenoma that is unlikely to be an incidentaloma, BIPSS may not be necessary 2
• If no pituitary adenoma is identified on MRI, BIPSS is strongly recommended to confirm a central source of ACTH excess 2, 6

BIPSS Protocol for Cyclic Cushing's Syndrome

• BIPSS should only be performed in a specialized center with expertise and by an experienced interventional radiologist 2
• For patients with cyclic Cushing's disease, hypercortisolemia should be confirmed immediately prior to BIPSS to ensure the patient is in an active disease phase 2
• During BIPSS, a pituitary source of ACTH excess is confirmed by a ≥2:1 ratio of central-to-peripheral ACTH before CRH or desmopressin stimulation and ≥3:1 ratio after stimulation 2
• BIPSS can also provide information on tumor lateralization if the inter-petrosal sinus ACTH gradient after stimulation is ≥1.4 between the two sides 2
• Medical therapy for Cushing's disease (steroidogenesis inhibitors) must be stopped before undertaking BIPSS 2

Special Considerations for Cyclic Cushing's Syndrome

• The fluctuating clinical picture and discrepant biochemical findings make cyclic Cushing's syndrome extremely difficult to diagnose 1
• Patients may present with fluctuating or permanent clinical signs of Cushing's syndrome, or in some cases, no clinical signs at all 1
• Paradoxical responses to dexamethasone may occur in some cases of cyclic Cushing's disease 7
• When cyclic Cushing's is biochemically confirmed, further imaging and laboratory studies are guided by the presence or absence of ACTH dependency 1

Clinical Presentation and Differential Diagnosis

• Cyclic Cushing's syndrome should be considered in patients with recurrent episodes of idiopathic edema, hypokalemia, or unexplained cardiac arrhythmia 7
• The pituitary-adrenal axis should be tested during the acute phase of the disease or using dexamethasone suppression tests during asymptomatic intervals 7
• In mild cases, distinction from pseudo-Cushing states may be difficult and may require close monitoring for a few months 6