In the Journals

Elevated late-night salivary cortisol may indicate recurrent Cushing’s disease

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July 14, 2016

Elevated late-night salivary cortisol may serve as an early biochemical marker of recurrent Cushing’s disease, and prompt intervention may result in clinical benefits for people with Cushing’s disease, according to recent study findings.

According to the researchers, late-night salivary cortisol level is more sensitive for detecting Cushing’s disease recurrence compared with urinary free cortisol or a dexamethasone suppression test.

“Two important implications are that urine free cortisol should not be used as a screening tool for the detection of recurrent Cushing’s disease and that patients with Cushing’s disease should be screened with late-night salivary cortisol,” Ty B. Carroll, MD, assistant professor at the Medical College of Wisconsin Endocrinology Center and Clinics in Menomonee Falls, told Endocrine Today. “If the late-night salivary cortisol is abnormal therapy should be considered if the patient has clinical features that may be related to cortisol excess.”

Ty Carroll

Ty B. Carroll

Carroll and colleagues evaluated 15 patients (14 women; mean age, 49.1 years) with postsurgical recurrent Cushing’s disease (mean time to recurrence, 3.3 years) after initial remission to determine the performance of urinary free cortisol and late-night salivary cortisol measurements for detecting recurrent Cushing’s disease.

Participants were identified as having Cushing’s disease between 2008 and 2013; there was no standard for follow-up, but after remission confirmation participants were followed at least every 6 months after surgery for 2 years and then annually thereafter. Late-night salivary cortisol was the primary biochemical test to screen for recurrence, and follow-up tests with a dexamethasone suppression test, urinary free cortisol or other tests were performed if late-night salivary results were abnormal or if suspicion of recurrence was high.

Of the cohort, 80% had normal urinary free cortisol (< 45 µg/24 hours) at recurrence. Primary transphenoidal adenoma resection was performed in all participants. Evidence of pituitary adenoma on MRI at the time of recurrence was present in seven of 12 participants with normal urinary free cortisol and two of three participants with abnormal urinary free cortisol. Normal renal function was present in all participants, and 14 underwent testing with late-night salivary cortisol, dexamethasone suppression test and urinary free cortisol.

Of participants with normal urinary free cortisol at recurrence, nine had an abnormal dexamethasone suppression test (cortisol 1.8 µg/dL), and all had at least one elevated late-night salivary cortisol measurement (> 4.3 nmol/L). Mean late-night salivary cortisol was 10.2 nmol/L, and mean urinary free cortisol was 19.9 µg/24 hours.

Therapy for recurrent Cushing’s disease was administered in 11 of the 12 participants with abnormal urinary free cortisol. Adrenocorticotropic hormone (ACTH)-staining pituitary adenoma was confirmed in three participants who underwent repeat transphenoidal adenoma resection. Pharmacotherapy was administered to seven participants with normal urinary free cortisol, and two additional participants underwent bilateral adrenalectomy.

Abnormal dexamethasone suppression test was found in two participants with elevated urinary free cortisol at the time of recurrence, and two participants had confirmed abnormal late-night salivary cortisol. All three participants with elevated urinary free cortisol at the time of recurrence underwent therapy.

“This study highlights two separate but important issues,” Carroll told Endocrine Today. “The first has been described previously and here confirmed that urinary free cortisol is a very insensitive tool for the detection of recurrent Cushing’s disease. The second and more novel message is that patients with recurrent Cushing’s disease, as defined by elevations in late-night salivary cortisol, may have significant clinical benefit from treatment. This benefit occurs even in the absence of elevations of urine free cortisol.” – by Amber Cox

Disclosure: Carroll reports being a consultant for Corcept Therapeutics. Please see the full study for a list of all other authors’ relevant financial disclosures.

itj+ Perspective

Maria Fleseriu

Maria Fleseriu

New studies show recurrence rate of Cushing’s disease to be up to 30% during lifetime, and frequently diagnosis of recurrence is even more difficult than the initial one. While urinary free cortisol has been for quite some time the main screening test for diagnosis of Cushing’s syndrome, recent data have clearly shown that there is a delay of sometime years for the urinary free cortisol to become abnormal in cases of recurrence. Consequences of untreated severe hypercortisolemia are well-known; however, mild disease in the context of early recurrence is less studied. Furthermore, the optimal treatment for early recurrence is not known.

This excellent retrospective, single-center study analyzed outcomes in patients with proven Cushing’s disease recurrence and normal urinary free cortisol. These patients had been treated with a combination of surgeries (pituitary surgery and/or bilateral adrenalectomy) and medical therapy and had sustained various clinical benefits. 

The Endocrine Society guideline recommends yearly late-nighttime salivary cortisol to detect possible early recurrence in all patients with Cushing’s disease. Further prospective outcome data in patients with Cushing’s disease recurrence diagnosed by a variety of methods, especially late-nighttime salivary cortisol, are long awaited. The clinical improvement needs to be better quantified, and likewise, all patients should be optimized on all other medications used to treat their cardiovascular and diabetes comorbidities. However, this study offers insight into the clinical real-life management of patients with Cushing’s disease recurrence and the major challenges associated with it.

Maria Fleseriu, MD, FACE
Professor of Medicine and Neurosurgery
Director, Pituitary Center
Oregon Health and Science University
Portland, Oregon

Disclosure: Fleseriu reports consulting fees and research funding from Ipsen, Novartis Pharmaceuticals and Strongbridge Biopharma.