title: Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Chortis
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Hughes
authors.forename: Donna M
authors.initials: DM
authors.lastname: O'Neil
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Niki
authors.initials: N
authors.lastname: Karavitaki
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Emilio
authors.initials: E
authors.lastname: Porfiri
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
authors.forename: Mark
authors.initials: M
authors.lastname: Sherlock
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.forename: Peter
authors.initials: P
authors.lastname: Nightingale
authors.forename: Cedric H L
authors.initials: CH
authors.lastname: Shackleton
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hahner
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000008:administration & dosage / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D006301:Health Services Needs and Demand; D020249:Hormone Replacement Therapy / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000009:adverse effects* / Q000627:therapeutic use*; D057285:Precision Medicine / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D008939:Mitotane; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase