Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion

Abstract

Context: Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death.

Objective: We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers.

Design, setting, and participants: In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed.

Results: Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment.

Conclusions: In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6.

Copyright © 2017 Endocrine Society

Figures

Figure 1.

Adaptive study design. Figure shows study design highlighting two study phases: baseline analysis (phase 1) and intervention study (phase 2). Interim analysis between phases was organized for research team to analyze data and assess what dose and at what time metyrapone should be administered. At interim analysis 1, all baseline data were analyzed, and based on the results, the decision was taken to administer 500 mg of metyrapone at 6 pm. At interim analysis 2, all data from phase 2 were analyzed, and based on the results, the decision was taken to administer 500 mg of metyrapone at 6 pm and 250 mg at 10 pm.

Figure 2.

Serum cortisol rhythms. (a) Baseline: Concentration time profiles (geometric mean ± standard error of the mean) of cortisol rhythm in groups AI/ACS, AI/NoACS, and HC. Higher nighttime cortisol exposure between 6 pm and 2 am is evident in group AI/ACS. To convert nmol/L to ug/dL, divide by 27.59. (b) Reset rhythm after metyrapone: Concentration time profiles (geometric mean ± standard error of the mean) show that by administering metyrapone 500 mg at 6 pm and 250 mg at 10 pm, one is able to restore the cortisol rhythm to approximate normal physiological concentrations comparable to groups AI/NoACS and HC. After intervention, all 24-hour AUCs of all three concentration time profiles in the three groups of subjects were similar (P = 0.29). Log-transformed AUC between 6 pm and 10 pm (P = 0.85) and between 10 pm and 2 am (P = 0.76) normalized to physiological levels. To convert nmol/L to ug/dL, divide by 27.59.

Figure 3.

Concentration time profile for salivary cortisone in the evening (geometric mean ± standard error of the mean). Patients with AI/ACS have significantly higher salivary cortisone levels than subjects with no ACS (P < 0.001). Levels are restored to normality after administration of metyrapone 500 mg at 6 pm and 250 mg at 10 pm. The measurement of salivary cortisone could hence be considered an alternative means to calculate changes in serum cortisol rhythm.

Figure 4.

Concentration time profiles of serum IL-6 levels before and post administration of metyrapone in patients with AI/ACS (geometric mean ± standard error of the mean). Figure indicates higher IL-6 levels in patients with AI/ACS when compared with patients with no ACS (P = 0.01). Concentrations decrease to normal levels, similar to patients with no ACS after the administration of metyrapone (P = 0.08).