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

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


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.


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.


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.

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