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Cyclic Cushing’s syndrome

The term “cyclic Cushing’s syndrome” has been used to describe the presence of spontaneous, intermittent periods of cortisol excess that do not occur as a consequence of glucocorticoid therapy (such as prednisone, hydrocortisone or dexamethasone) or other medical intervention. “Periodic hormonogenesis”, “intermittent hypercortisolism”, “unpredictable hypersecretion of cortisol” and “fluctuating steroid excretion” are additional terms used to describe this condition. Regardless of the exact name used to describe it, the hallmarks of cyclic Cushing’s syndrome include the transient and recurring occurrence of abnormally high cortisol secretion, interspersed with periods during which cortisol levels are normal (or occasionally below normal).

Cyclic Cushing’s syndrome appears to be more common than originally thought and may occur in patients with a variety of underlying tumors, including pituitary adenomas secreting adrenocorticotropin (ACTH), tumors outside the pituitary secreting ACTH (ectopic ACTH syndrome), and several types of adrenal tumors. Cyclic Cushing’s syndrome caused by a pituitary adenoma has been reported in up to 19% of patients with ACTH-secreting pituitary tumors in case series. In one study, 36% of patients with Cushing’s syndrome of diverse causes showed evidence of cyclic Cushing’s syndrome.

It is not known why cyclic Cushing’s syndrome develops in some patients. Speculation and limited evidence suggests that episodic tumor hemorrhage or cell death and fluctuations in the regulation of hormone secretion may be underlying the presence of intermittent cortisol excess. It is clear that a lot of work remains to be done in order to understand the mechanisms leading to cyclic Cushing’s syndrome.


Cyclic Cushing’s syndrome has been reported in individuals of all ages and both genders. Patients with cyclic Cushing’s syndrome have symptoms that are not different from those experienced by other patients with this condition. Some patients have symptoms that are constant and do not appear to fluctuate over time. In contrast, other patients with cyclic Cushing’s syndrome have symptoms lasting for days or weeks, which appear to remit spontaneously and then recur after variable lengths of time. Weight gain, high blood pressure, muscle weakness, edema (swelling), high blood glucose (“sugar”) and low potassium levels may all come and go.

Regardless of the presence of constant or intermittent symptoms, these patients have intermittently elevated cortisol levels, measured in any one of the standard tests used to diagnose the presence of Cushing’s syndrome (24 hour urine free cortisol, late night salivary cortisol or dexamethasone suppression testing). It is important to consider the possibility of cyclic Cushing’s syndrome in patients with intermittent (albeit typical) symptoms suggestive of cortisol excess as well as those with typical symptoms of Cushing’s syndrome that show normal or inconsistent results on initial testing. The presence of a paradoxical increase in cortisol levels after dexamethasone administration has also been reported in some patients with cyclic Cushing’s syndrome.


As is true of all patients with suspected Cushing’s syndrome, the first step in the evaluation of patients with possible cyclic Cushing’s syndrome is to document the presence of cortisol excess, followed by a search for the underlying tumor.

Taking a thorough history and performing a physical examination are very important and should aim at establishing a symptom timeline and excluding the possibility of glucocorticoid therapy. Unless specifically prompted, some patients may not immediately consider some medications as being glucocorticoids, including some hemorrhoidal suppositories, injections used to treat back pain or inhalers for asthma. The possibility of underlying depression or alcohol excess should be considered, as is true of other patients being evaluated for possible cortisol excess.

Since cortisol excess is by definition intermittent, it is important to choose laboratory tests that can be performed repetitively and conveniently. Some studies have advocated measuring cortisol levels in the blood at several times during the day or measuring cortisol in morning urine specimens (to calculate the urine cortisol to creatinine ratio) repetitively on several days.

Measuring late night salivary cortisol can be particularly helpful in patients with suspected cyclic Cushing’s syndrome, since salivary specimen collections can be repeated on multiple nights (at 11 pm) in order to search for the presence of intermittent cortisol excess. This test is quite convenient for patients, who collect the specimens at home and can mail them to the laboratory, since salivary cortisol is stable at room temperature for several days. However, it should be pointed out that the test cannot be relied upon in third shift workers and requires instruction in proper specimen collection in order to avoid contamination by glucocorticoid-containing preparations (including some creams or cosmetics). Measuring cortisol in hair has been proposed in order to detect spontaneous fluctuations in cortisol secretion in these patients, and might facilitate the diagnosis of cyclic Cushing’s syndrome. However, this technique is currently investigational and is not available for routine clinical use.

Patients with intermittent (episodic) symptoms should be tested repeatedly when symptomatic. Patients that have constant symptoms also require repeated testing in order to detect the presence of cortisol excess. In the presence of persistent clinical suspicion for Cushing’s syndrome, repeat testing should be obtained over several days, weeks or months. It is therefore clear that the diagnosis of cyclic Cushing’s syndrome can be challenging and requires a thorough assessment of all available clinical and laboratory data. On the other hand, patients with episodic symptoms and concurrently normal cortisol test results on several occasions are unlikely to have Cushing’s syndrome as the cause of their symptoms.

Once the presence of Cushing’s syndrome has been documented, a search for the underlying tumor is in order. Measuring ACTH levels in the morning during a period of cortisol excess will generally distinguish between patients with ACTH-dependent Cushing’s (reflecting either pituitary or ectopic ACTH secretion) and ACTH-independent Cushing’s (caused by an adrenal tumor or hyperplasia). A pituitary MRI examination should be obtained in patients with ACTH-dependent Cushing’s and a CT examination of the adrenals should be obtained in patients with ACTH-independent causes. If a clear cut pituitary tumor (at least 6-10 mm in diameter) is not identified on MRI, then bilateral inferior petrosal sinus sampling (BIPSS) may often help distinguish between a pituitary and an ectopic source of ACTH excess. However, it should be pointed out that BIPSS will only be reliable during a period of cortisol excess, necessitating documentation of cortisol levels before the procedure in order to be sure that the data obtained through BIPSS is valid.


The primary form of treatment of cyclic Cushing’s syndrome involves the resection of the tumor causing the condition, if possible. An experienced surgeon should be consulted once the underlying tumor has been identified. One study has found that patients with cyclic Cushing’s syndrome of pituitary origin may be somewhat less likely to experience remission after pituitary surgery than other patients with Cushing’s. However, this observation has not been independently verified.

The presence of cyclic cortisol excess may often make it difficult to establish whether remission of cyclic Cushing’s syndrome occurs after surgery, requiring repeated monitoring of cortisol levels in blood (early morning), urine or salivary specimens. In patients who are not in remission after surgery, additional options may include radiation therapy to the pituitary (in patients with a pituitary tumor), medical therapies, or bilateral adrenalectomy. A discussion of these treatments is beyond the scope of this article. It may be noted, however, that assessment of response to therapy can be complicated by the periodic nature of cortisol excess in patients with cyclic Cushing’s syndrome.


Cyclic Cushing’s syndrome is characterized by the presence of intermittent cortisol excess in patients who may have either constant or episodic symptoms that are otherwise typical of the condition. It appears to be more common than originally thought. More research is needed in order to understand why it occurs. The diagnosis of cyclic Cushing’s syndrome requires a high degree of suspicion and repeated testing. The treatment of cyclic Cushing’s syndrome is generally similar to that of other patients with this condition. However, assessment of the outcome of therapy can be hampered by the presence of intermittent cortisol excess.

Author: Dr. Nicholas A. Tritos, Summer, 2015

Editor’s Note: Dr. Tritos is a neuroendocrinologist in the Neuroendocrine and Pituitary Tumor Clinical Center and a faculty member in the Neuroendocrine Unit at the Massachusetts General Hospital. He serves as an Assistant Professor of Medicine at Harvard Medical School and has extensive experience with Cushing’s patients.

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