Objective: Mitotane (o,pDDD) is an effective adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC). Suppression of cortisol biosynthesis, including inhibition of 11β-hydroxylation, has been described. Decreased cortisol bioavailability 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. Design and method: Following urinary steroid profiling by GC-MS to identify persistence of tumour steroid secretion after surgical excision, we compared steroid metabolite ratios for 6 patients with ACC treated with mitotane and hydrocortisone (M+H) with those for 5 patients with adrenal adenoma receiving hydrocortisone only (H).
Results: The ratios (mean [range]) of 5β/5α tetrahydrocortisol were 2.6 [0.64.9] for H and 499  for M+H (P=0.004), indicating inhibition of 5α-reductase by mitotane. The order of 4 pairs of 5β/5α reduced steroid metabolites matched findings in 5α-reductase II deficiency and finasteride treatment and was different from dutasteride treatment, confirming inhibition was of 5α-reductase II. The ratios of 20α/20β reduced CM were 2.0 [1.02.8] for H and 30  for M+H (P=0.004), indicating inhibition of 20β-reductase by mitotane. Ratios that reflected net 11-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase were not different between groups. There were large increases in 6-hydroxylated metabolites. Two patients receiving mitotane and dexamethasone after unilateral adrenalectomy excreted small amounts of tetrahydro 11-deoxycortisol and showed similar changes in cortisol metabolism.
Conclusions: Mitotane treatment profoundly decreases 5α II- and 20β- reduction, does not affect net 11- or 20- oxidoreduction and enhances 6β-hydroxylation of administered cortisol. Inhibition of adrenal 11β-hydroxylase is confirmed. These findings can inform interpretation of identified steroid markers and assist treatment, explaining the need for increased hydrocortisone. If androgen supplementation is required, a synthetic androgen such as nandrolone would be more effective than testosterone, which would fail to convert to dihydrotestosterone.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.