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.
Highlights
Cushing’s syndrome (CS) is associated with high mortality and serious morbidities such as infections, cardiovascular disease, stroke, and thromboembolism [1, 2]
The present data suggested that multiple measurements of salivary cortisol levels may be useful for optimization of metyrapone treatment by visualization of diurnal cortisol levels
We clearly demonstrated that measurements of multiple salivary cortisol levels revealed the impaired diurnal cortisol rhythm in patients even after normalization of urinary free cortisol (UFC)
Summary
Cushing’s syndrome (CS) is associated with high mortality and serious morbidities such as infections, cardiovascular disease, stroke, and thromboembolism [1, 2]. To control the excess of cortisol, adrenal steroidogenesis inhibitors such as metyrapone and ketoconazole have commonly been used [3, 4]. The novel steroidogenesis inhibitor LCI699, an inhibitor of 11β-hydroxylase, has been developed [5, 6]. Using these drugs, it is important to suppress cortisol secretion and avoid adrenal insufficiency and reconstitute the circadian rhythm. While undergoing treatment with steroidogenesis inhibitors, early morning serum cortisol, average daily serum cortisol, and daily urinary free cortisol (UFC) have each been suggested as markers for treatment monitoring [7, 8]. Adjusting the dose and timing of drug administration remains challenging
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