Mitotane Therapy in Adrenocortical Cancer Induces CYP3A4 and Inhibits 5α-Reductase, Explaining the Need for Personalized Glucocorticoid and Androgen Replacement
Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, O'Neil DM, Libé R, Allolio B, Bertagna X, Bertherat J, Beuschlein F, Fassnacht M, Karavitaki N, Mannelli M, Mantero F, Opocher G, Porfiri E, Quinkler M, Sherlock M, Terzolo M, Nightingale P, Shackleton CH, Stewart PM, Hahner S, Arlt W. J Clin Endocrinol Metab. 2012 Nov 16. [Epub ahead of print]

Source

Centre for Endocrinology, Diabetes, and Metabolism (V.C., A.E.T., P.S., J.W.T., B.A.H., D.M.O'N., M.S., C.H.L.S., P.M.S., W.A.), School of Clinical and Experimental Medicine, and School of Cancer Sciences (E.P.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Endocrinology (R.L., J.B., X.B.), Institut National du Cancer Cortico-Medullo Tumeurs Endocrines, Cochin Hospital, Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 1016, René Descartes University, Paris, F-75006 France; Endocrine and Diabetes Unit (S.H., B.A., M.F.), Department of Medicine I, University Hospital, University of Würzburg, D-97080 Würzburg, Germany; Endocrine Research Unit (F.B., M.F.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department of Endocrinology (N.K.), John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; Endocrinology Unit (M.M.), Department of Clinical Pathophysiology, University of Florence and Istituto Toscano Tumori, I-50121 Florence, Italy; Familial Cancer Clinic (G.O.) and Division of Endocrinology (F.M.), Veneto Institute of Oncology Instituto di Ricovero e Cura a Carattere Scientifico and Department of Medical and Surgical Sciences, University of Padova, I-35100 Padova, Italy; Clinical Endocrinology (M.Q.), Charité Campus Mitte, Charité University Medicine Berlin, D-10117 Berlin, Germany; Department of Endocrinology (M.S.), Tallaght Hospital, and Department of Medicine, Trinity College Dublin, Dublin 2, Ireland; Department of Clinical and Biological Sciences (M.T.), Internal Medicine I, University of Turin, I-10124 Turin, Italy; and Wellcome Trust Clinical Research Facility (P.N.), University Hospital Birmingham National Health Service Foundation Trust, Birmingham B15 2TH, United Kingdom.

Abstract

Context:Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane] is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the primary tumor. Mitotane is considered an adrenolytic substance, but there is limited information on distinct effects on steroidogenesis. However, adrenal insufficiency and male hypogonadism are widely recognized side effects of mitotane treatment.Objective:Our objective was to define the impact of mitotane treatment on in vivo steroidogenesis in patients with ACC.Setting and Design:At seven European specialist referral centers for adrenal tumors, we analyzed 24-h urine samples (n = 127) collected from patients with ACC before and during mitotane therapy in the adjuvant setting (n = 23) or for metastatic ACC (n = 104). Urinary steroid metabolite excretion was profiled by gas chromatography/mass spectrometry in comparison with healthy controls (n = 88).Results:We found a sharp increase in the excretion of 6β-hydroxycortisol over cortisol (P < 0.001), indicative of a strong induction of the major drug-metabolizing enzyme cytochrome P450 3A4. The contribution of 6β-hydroxycortisol to total glucocorticoid metabolites increased from 2% (median, interquartile range 1-4%) to 56% (39-71%) during mitotane treatment. Furthermore, we documented strong inhibition of systemic 5α-reductase activity, indicated by a significant decrease in 5α-reduced steroids, including 5α-tetrahydrocortisol, 5α-tetrahydrocorticosterone, and androsterone (all P < 0.001). The degree of inhibition was similar to that in patients with inactivating 5α-reductase type 2 mutations (n = 23) and patients receiving finasteride (n = 5), but cluster analysis of steroid data revealed a pattern of inhibition distinct from these two groups. Longitudinal data showed rapid onset and long-lasting duration of the observed effects.Conclusions:Cytochrome P450 3A4 induction by mitotane results in rapid inactivation of more than 50% of administered hydrocortisone, explaining the need for doubling hydrocortisone replacement in mitotane-treated patients. Strong inhibition of 5α-reductase activity is in line with the clinical observation of relative inefficiency of testosterone replacement in mitotane-treated men, calling for replacement by 5α-reduced androgens.