Cyclical Cushing’s Syndrome: A Multidisciplinary Approach to Diagnosis and Management

Purpose: Cyclical Cushing’s syndrome is an uncommon disorder, defined by intermittent hypercortisolism, which can be associated with fluctuating clinical signs and symptoms. It is diagnosed after the biochemical demonstration of at least three “peaks” and two “troughs” in the production of cortisol, with similar distance between the peaks. Cyclical Cushing’s syndrome has been reported in patients with pituitary-dependent Cushing’s, adrenal and ectopic ACTH secretion including bronchial and thymic carcinoid tumors as well as ectopic ACTH secreting pituitary adenomas. Confirmation of the diagnosis can be difficult particularly if investigations are performed in the “trough” period where testing can be normal. Furthermore, the duration of cycles has been reported to vary between 12 hours and 85 days. Failure to recognize cyclical Cushing’s syndrome can result in misdiagnosis and delay in definitive treatment.

We present a case to discuss how to approach and diagnose cyclical Cushing’s syndrome.

Case: The patient is a 39-year-old male with Cushing’s syndrome. His complaints included weight gain, easy bruising, headache, fatigue, and muscle weakness that progressively worsened over 3 years. His physical exam demonstrated moon-like facies, abdominal obesity, purple striae, and prominent dorsal cervical fat pad. Workup revealed abnormal 1 mg Dexamethasone suppression test (cortisol 19 µg/dL) with elevated 24-hour free cortisol in urine × 2 (283 µg/24 hour and 119 µg/24 hour, normal <  100) as well as elevated morning ACTH of 61 (normal 6–48). Midnight salivary cortisol level was also elevated at 1,500 ng/dL. Dex-CRH suppression test was high suggestive of Cushing’s syndrome: cortisol was not suppressed at 17.5 µg/dL before CRH and remained within the same range at 15.0 after CRH. High dose of dexamethasone suppressed cortisol by > 50% (7.5 from 25 µg/dL), which suggests a pituitary origin. MRI (pituitary protocol) was negative. Rest of pituitary panel was normal. Inferior petrosal sinus sampling (IPSS) initially could not be interpreted due to lack of hypercortisolism during the time of procedure. Weekly 24-hour urine-free cortisol levels were all normal until 4 months later where it was elevated; at that time, IPSS was repeated and consistent with pituitary origin. He underwent transsphenoidal surgery and was eventually found to have an ectopic ACTH-producing pituitary adenoma located in the sphenoid sinus. His postoperative course was uneventful, and he has since been on hydrocortisone for hypocortisolism.

Conclusion: Since the first description of Cushing’s syndrome by Dr. Harvey Cushing in 1912, the approach to diagnosis and management has significantly advanced yet remain challenging. When suspicious for Cushing’s syndrome, particularly with equivocal laboratory work up, cyclical Cushing’s syndrome should be considered as a possible diagnosis. Repeating testing at various timing intervals and using late night salivary cortisol may increase the diagnostic yield.