Optimal timing of oral metyrapone intake for the suppression of cold-pressor stress-induced cortisol release

Pharmacological manipulation of cortisol levels is instrumental in elucidating mechanisms underlying acute stress effects and for distinguishing the physiological and behavioral effects of cortisol from those of the adrenergic system. Administration (oral or IV) of hydrocortisone is a direct and efficient method to elevate cortisol, and thus, frequently used in psychobiological stress research. However, lowering of cortisol (i.e. blockade of stress cortisol) requires a more sophisticated approach, such as the administration of the corticostatic compound metyrapone (MET). However, there is insufficient knowledge about the temporal dynamics of MET for the blocking of stress-induced cortisol reactivity. Thus, the present study aimed to build up an experimental protocol suitable to suppress acute behavioral stress-induced cortisol secretion by MET.

50 healthy young men were randomly assigned to one of five treatment groups. They received 750 mg oral MET either 30 (n = 9), 45 (n = 11), or 60 (n = 10) minutes before exposure to a combined cold pressor and mental arithmetic test (stress induction), or were subjected to two different control treatments (placebo 60 min before stress (n = 10) or MET 30 min before non-stressful warm-water condition (n = 10)). Salivary cortisol concentration, hemodynamics, and subjective ratings were assessed.

Suppression of cold stress-induced cortisol release was strongest when MET intake was scheduled 30 min prior to stress onset. Cardiovascular stress-responses and subjective ratings remained unaffected by MET.

In healthy young males, 750 mg of MET efficiently block cold stress-induced cortisol release when oral administration is scheduled 30 min prior to stress onset. This finding may guide future research in improving timing of suppression of stress-induced cortisol secretion.