Multiple Salivary Cortisol Measurements Are a Useful Tool to Optimize Metyrapone Treatment in Patients with Cushing’s Syndromes Treatment: Case Presentations

Abstract

Measuring salivary cortisol is both convenient and non-invasive for patients; however, its usefulness as a marker for monitoring medical therapy has not yet been established. The aim of this study was to assess the utility of multiple salivary cortisol measurements in patients with Cushing’s syndrome (CS) during medical therapy. Six patients with CS (three with cortisol-secreting adrenocortical adenoma and three with ACTH-secreting pituitary adenoma) were recruited. Samples for morning serum cortisol, urinary free cortisol (UFC), and multiple salivary cortisol levels were collected before and during metyrapone treatment. The area under the curve (AUC) and mean value (MV) of daily salivary cortisol levels were calculated. In five out of six patients, UFC were normalized; however, multiple salivary cortisol measurements revealed an impaired diurnal cortisol rhythm in these patients. To verify the usefulness of multiple salivary cortisol measurements, we performed a prospective case study of a patient in whom the excess secretion of cortisol was not controlled (UFC 211 μg/day) with 2,250 mg/day in four divided doses of metyrapone. Multiple measurements of salivary cortisol revealed that cortisol levels elevated before the next administration. Accordingly, we shortened the interval by increasing the number of administration from four to five times per day, with a slight increment of daily dose of 2,500 mg. These optimizations resulted in a drastic improvement of diurnal pattern as well as UFC level (101 μg/day). Changes in both the MV and AUC of salivary cortisol levels were more correlated with those in UFC levels (Correlation coefficient 0.75, p = 0.007, and 0.70, p = 0.017) than those in the morning serum cortisol levels (0.42, p = 0.200), indicating that multiple salivary cortisol measurements reflect more precisely the excess secretion of cortisol. Our preliminary data suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone during the treatment in patients with CS.

Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

“…While LNSC has an established role in the diagnosis of Cushing's disease and prediction of recurrence risk after surgery, its usefulness as a biomarker of medical treatment response is not yet known (5,6,16,17). The current analysis, which included a large subset of patients enrolled in a Phase III study, provides further evidence supporting a role for LNSC in monitoring patients with active Cushing's disease who are receiving medical treatment.…”

“…In our study, elevated mLNSC in patients with normal mUFC may have resulted from suboptimal recovery of normal circadian cortisol rhythm -characterized by an earlymorning cortisol peak and a gradual decrease during the day to low midnight levels (3) -despite an overall reduction in daily cortisol secretion. Indeed, dysregulation of cortisol circadian rhythm has been shown to persist in some patients during medical therapy even after normalization of mUFC (6,14,16). However, additional salivary cortisol assessments within a single day, including early in the morning and late at night, may be required to confirm the effects of medical therapy on circadian rhythm of cortisol secretion (6), which was not planned in the present study.…”

“…Indeed, dysregulation of cortisol circadian rhythm has been shown to persist in some patients during medical therapy even after normalization of mUFC (6,14,16). However, additional salivary cortisol assessments within a single day, including early in the morning and late at night, may be required to confirm the effects of medical therapy on circadian rhythm of cortisol secretion (6), which was not planned in the present study.…”

“…Assessment of 24-h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC) levels has an established role in the initial screening for hypercortisolism and in the detection of disease recurrence after surgery (4). LNSC has also been used in combination with morning salivary cortisol levels to assess cortisol diurnal rhythm, which is frequently disrupted in patients with Cushing's disease (5,6). Despite this, there remains a lack of guidance on the most appropriate way to monitor disease activity during medical treatment.…”

“…Collection of late-night salivary samples is both simple and convenient for patients to carry out in their own homes, with samples being stable at room temperature for up to 2 weeks and easy to store (12,13). Few studies have examined the role of LNSC in monitoring response to pharmacotherapy in patients with Cushing's disease (6,14).…”