Endocrine Abstracts

Background: Mitotane is a strong inducer of hepatic CYP3A4 activity (cortisol metabolism) and increases cortisol-binding globulin (CBG). High hydrocortisone dosages are necessary in patients with adrenocortical cancer (ACC) on mitotane treatment. The newly modified release hydrocortisone has not been used in mitotane-treated ACC patients yet.

Aim: To compare cortisol (serum and saliva), calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with conventional and modified release hydrocortisone.

Design: Nine patients with ACC on mitotane treatment and on stable daily hydrocortisone dose (60 mg) were included. Patients were taking 1 day conventional hydrocortisone (40–20–0 mg) and the next day modified-release hydrocortisone (40–20–0 mg).

Methods: Cortisol and ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by ELISA and RIA. Salivary cortisol was analysed by electrochemiluminescence immunoassay.

Results: Serum cortisol levels varied widely in the supraphysiological range (20–140 μg/dl) after conventional hydrocortisone intake, and showed a more homogenous pattern after modified release hydrocortisone intake. Most of the patients showed suppressed ACTH levels with no differences between the two hydrocortisone preparations. CBG levels were 0.87–3.0 times above the sex-specific upper-limit of the normal range. Calculated free cortisol levels showed more pronounced peaks after tablet intake of conventional hydrocortisone, whereas peaks were blunted after intake of modified release hydrocortisone. Calculated mean free cortisol level showed no peak after modified release hydrocortisone tablet intake resulting in a continuous free cortisol level between 6 and 12 nmol/l. After 40 mg of conventional hydrocortisone intake the mean free cortisol level peaked at 45 nmol/l, and after 20 mg of conventional hydrocortisone intake at 17 nmol/l.

Conclusions: Modified release hydrocortisone results in smoother total and free cortisol levels, but is lacking a morning free cortisol peak. In contrast conventional hydrocortisone provided a similar free cortisol peak as seen in Addison’s patients on conventional hydrocortisone therapy on a 10–10 mg dose regimen.