Endocrine Abstracts

Mitotane (o,p’DDD) is an effective oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC). Inhibition of cortisol biosynthesis has been described. Cortisol metabolic clearance rate is unchanged, but decreased cortisol biovailability is indicated by increased dose requirement for hydrocortisone replacement during mitotane treatment. Urinary excretion of common cortisol metabolites (CM) has been reported to be normal but with increase of 6β-hydroxycortisol and unidentified polar unconjugated metabolites.

Following urinary steroid profiling by GC-MS (USP) to identify persistence of tumour steroid secretion after surgical excision, we compared steroid metabolite ratios for patients with ACC treated with mitotane and hydrocortisone (4M, 25, 42, 47 & 68 years; 2F, 64 & 69 years, 5 clinically silent, 1 Cushing’s) with those for patients with adrenal adenoma receiving hydrocortisone only (3M, 23, 54 & 66 years; 2F, 39 & 62 years). When there was more than one observation per patient, the median value was used.

A high level of excretion of polar unconjugated steroids during mitotane was also confirmed, with 6β-hydroxycortisol and (previously unrecognised) 6β-hydroxy-20-dihydrocortisols predominating. Mitotane treatment thus produces a profound decrease of 5α- vs 5β- and of 20β- vs 20α- reduction, a net decrease of 5-reduction but not of 11- or 20-reduction. No metabolic changes correlated with either dose or blood level of mitotane. Two ACC patients showed relapse during treatment, with increase of previously identified steroid markers, none of which were 5α- or 20β-reduced.

We conclude that mitotane causes consistent, but previously unrecognised, changes in cortisol catabolism, which do not interfere with early detection by USP of relapse in ACC. These indicators of mitotane use are not concentration-dependent. Induction of 6β-hydroxylation probably explains the observed decrease of cortisol bioavailability.