Metyrapone single administration, as a possible predictive tool of its dosage and timing in Cushing's syndrome

Abstract

Metyrapone is commonly used in the initial management of Cushing's syndrome to reduce hypercortisolemia, but its optimal dosage and timing can vary significantly between patients. Currently, there are limited guidelines on adjustment methods for its administration to individual needs. This study aimed to evaluate responsiveness of each patient to metyrapone and identify the patient characteristics associated with the indices of cortisol responsiveness following a low-dose metyrapone. This single-center retrospective observational study included 15 treatment-naïve patients, 7 of whom had Cushing's disease and 8 had adrenal Cushing's syndrome. Serum cortisol levels were measured hourly from the time of administration of 250 mg of metyrapone up to four hours afterward. Parameters analyzed included the nadir of serum cortisol levels (F_nadir), the difference between basal and nadir serum cortisol levels (_ΔF), the time to nadir, and the characteristics of the patients. As a result, cortisol suppression curves showed significant variability among patients, particularly in the time to nadir. While the median time to nadir was 2 hours, 20% of patients required 4 hours or more, and these responses were not associated with patient characteristics. F_nadir was positively correlated with early-morning serum cortisol levels, serum cortisol levels after low-dose dexamethasone suppression test (LDDST), and urinary free cortisol (UFC) levels, whereas _ΔF was positively correlated with late-night serum cortisol levels, serum cortisol levels after LDDST, and UFC levels. In conclusion, the duration of response to metyrapone appeared unpredictable in patients with Cushing's syndrome and did not correlate with patient characteristics at baseline. Tracking the effect of metyrapone following a single low-dose administration may explain this variability and provide insights for optimizing individual dosing regimens. Further studies are required to validate these findings and guide more personalized treatment adjustments.

Keywords: Cushing’s disease; Cushing’s syndrome; drug responsiveness; hypercortisolemia; metyrapone; monitoring marker.

Figure 1

Items defined as cortisol responsiveness indices after the metyrapone single administration. To illustrate the definition of each item, a scheme for serum cortisol response after a single dose of metyrapone is provided. Vertical axis: serum cortisol levels; horizontal axis: hours after metyrapone administration. For illustrative purposes, this figure shows an example in which the nadir occurs at 3 h. In actual cases, the time to nadir varies among patients. F₀: serum cortisol value at 0 hour; F_nadir: minimum value of serum cortisol after administration; _ΔF: difference between F₀ and F_nadir; F reduction ratio: ratio calculated by dividing _ΔF by F₀; AUC_F: area under the curve plotted with serum cortisol values at each time point.

Figure 2

The cortisol curves for each case after the metyrapone single administration. Solid line: cortisol curves for patients with time to nadir of less than four hours, dotted line: cortisol curve for patients with time to nadir of four hours or more.