Effects of mitotane treatment on human steroid metabolism: implications for patient management

Mitotane (o, p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6 beta-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography-mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14-20 mg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6 beta-hydroxycortisol and 6 beta-hydroxy-20-dihydro-cortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35-52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5 alpha-/5 beta-and 20 beta-/20 alpha-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females - mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5 alpha-relative to 5 beta-reduced metabolites were similar to those of patients with 5 alpha-reductase 2 deficiency or on treatment with the 5 alpha-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5 alpha-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6 beta-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20 beta-reduction.