Abiraterone acetate treatment lowers 11-oxygenated androgens

in European Journal of Endocrinology

Correspondence should be addressed to R J Auchus; Email: rauchus@med.umich.edu
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Context

The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens.

Objective

To test the hypothesis that AA therapy decreases 11-oxygenated androgens.

Design

Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.

Methods

We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively.

Results

In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1–0.3 nmol/L), equivalent to 64–94% reductions from baseline. In 21OHD patients, administration of AA (100–250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56–77% from baseline.

Conclusions

We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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  • 1

    AuchusRJLeeTCMillerWL. Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron transfer. Journal of Biological Chemistry 1998 273 31583165. (https://doi.org/10.1074/jbc.273.6.3158)

    • Search Google Scholar
    • Export Citation
  • 2

    RegeJNakamuraYSatohFMorimotoRKennedyMRLaymanLCHonmaSSasanoHRaineyWE. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. Journal of Clinical Endocrinology and Metabolism 2013 98 11821188. (https://doi.org/10.1210/jc.2012-2912)

    • Search Google Scholar
    • Export Citation
  • 3

    AuchusRJRaineyWE. Adrenarche – physiology, biochemistry and human disease. Clinical Endocrinology 2004 60 288296. (https://doi.org/10.1046/j.1365-2265.2003.01858.x)

    • Search Google Scholar
    • Export Citation
  • 4

    AuchusRJ. The classic and nonclassic concenital adrenal hyperplasias. Endocrine Practice 2015 21 383389. (https://doi.org/10.4158/EP14474.RA)

    • Search Google Scholar
    • Export Citation
  • 5

    SharifiNGulleyJLDahutWL. An update on androgen deprivation therapy for prostate cancer. Endocrine-Related Cancer 2010 17 R305R315. (https://doi.org/10.1677/ERC-10-0187)

    • Search Google Scholar
    • Export Citation
  • 6

    SharifiN. Mechanisms of androgen receptor activation in castration-resistant prostate cancer. Endocrinology 2013 154 40104017. (https://doi.org/10.1210/en.2013-1466)

    • Search Google Scholar
    • Export Citation
  • 7

    SpeiserPWArltWAuchusRJBaskinLSConwayGSMerkeDPMeyer-BahlburgHFLMillerWLMuradMHOberfieldSE Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2018 103 40434088. (https://doi.org/10.1210/jc.2018-01865)

    • Search Google Scholar
    • Export Citation
  • 8

    AuchusRJSharifiN. Sex hormones and prostate cancer. Annual Review of Medicine 2020 71 3345. (https://doi.org/10.1146/annurev-med-051418-060357)

    • Search Google Scholar
    • Export Citation
  • 9

    de BonoJSLogothetisCJMolinaAFizaziKNorthSChuLChiKNJonesRJGoodmanOBJrSaadF Abiraterone and increased survival in metastatic prostate cancer. New England Journal of Medicine 2011 364 19952005. (https://doi.org/10.1056/NEJMoa1014618)

    • Search Google Scholar
    • Export Citation
  • 10

    RyanCJSmithMRde BonoJSMolinaALogothetisCJde SouzaPFizaziKMainwaringPPiulatsJMNgS Abiraterone in metastatic prostate cancer without previous chemotherapy. New England Journal of Medicine 2013 368 138148. (https://doi.org/10.1056/NEJMoa1209096)

    • Search Google Scholar
    • Export Citation
  • 11

    FizaziKTranNFeinLMatsubaraNRodriguez-AntolinAAlekseevBYOzgurogluMYeDFeyerabendSProtheroeA Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. New England Journal of Medicine 2017 377 352360. (https://doi.org/10.1056/NEJMoa1704174)

    • Search Google Scholar
    • Export Citation
  • 12

    JamesNDde BonoJSSpearsMRClarkeNWMasonMDDearnaleyDPRitchieAWSAmosCLGilsonCJonesRJ Abiraterone for prostate cancer not previously treated with hormone therapy. New England Journal of Medicine 2017 377 338351. (https://doi.org/10.1056/NEJMoa1702900)

    • Search Google Scholar
    • Export Citation
  • 13

    AttardGReidAHYapTARaynaudFDowsettMSettatreeSBarrettMParkerCMartinsVFolkerdE Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. Journal of Clinical Oncology 2008 26 45634571. (https://doi.org/10.1200/JCO.2007.15.9749)

    • Search Google Scholar
    • Export Citation
  • 14

    AuchusRJBuschurEOChangAYHammerGDRammCMadrigalDWangGGonzalezMXuXSSmitJW Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2014 99 27632770. (https://doi.org/10.1210/jc.2014-1258)

    • Search Google Scholar
    • Export Citation
  • 15

    RegeJTurcuAFKasa-VubuJZLerarioAMAuchusGCAuchusRJSmithJMWhitePCRaineyWE. 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. Journal of Clinical Endocrinology and Metabolism 2018 103 45894598. (https://doi.org/10.1210/jc.2018-00736)

    • Search Google Scholar
    • Export Citation
  • 16

    TurcuAFAuchusRJ. Clinical significance of 11-oxygenated androgens. Current Opinion in Endocrinology Diabetes and Obesity 2017 24 252259. (https://doi.org/10.1097/MED.0000000000000334)

    • Search Google Scholar
    • Export Citation
  • 17

    TurcuAFNanbaATChomicRUpadhyaySKGiordanoTJShieldsJJMerkeDPRaineyWEAuchusRJ. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. European Journal of Endocrinology 2016 174 601609. (https://doi.org/10.1530/EJE-15-1181)

    • Search Google Scholar
    • Export Citation
  • 18

    NanbaATRegeJRenJAuchusRJRaineyWETurcuAF. 11-Oxygenated C19 steroids do not decline With age in women. Journal of Clinical Endocrinology and Metabolism 2019 104 26152622. (https://doi.org/10.1210/jc.2018-02527)

    • Search Google Scholar
    • Export Citation
  • 19

    O’ReillyMWKempegowdaPJenkinsonCTaylorAEQuansonJLStorbeckKHArltW. 11-Oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2017 102 840848. (https://doi.org/10.1210/jc.2016-3285)

    • Search Google Scholar
    • Export Citation
  • 20

    PretoriusEAfricanderDJVlokMPerkinsMSQuansonJStorbeckKH. 11-Ketotestosterone and 11-ketodihydrotestosterone in castration resistant prostate cancer: potent androgens which can no longer be ignored. PLoS ONE 2016 11 e0159867. (https://doi.org/10.1371/journal.pone.0159867)

    • Search Google Scholar
    • Export Citation
  • 21

    AttardGReidAHMAuchusRJHughesBACassidyAMThompsonEOommenNBFolkerdEDowsettMArltW Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. Journal of Clinical Endocrinology and Metabolism 2012 97 507516. (https://doi.org/10.1210/jc.2011-2189)

    • Search Google Scholar
    • Export Citation
  • 22

    AuchusRJYuMKNguyenSMundleSD. Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer. Oncologist 2014 19 12311240. (https://doi.org/10.1634/theoncologist.2014-0167)

    • Search Google Scholar
    • Export Citation
  • 23

    GomesLGHuangNAgrawalVMendonçaBBBachegaTAMillerWL. Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2009 94 8995. (https://doi.org/10.1210/jc.2008-1174)

    • Search Google Scholar
    • Export Citation
  • 24

    MallappaASinaiiNKumarPWhitakerMJDaleyLADigweedDEcklandDJVan RyzinCNiemanLKArltW A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2015 100 11371145. (https://doi.org/10.1210/jc.2014-3809)

    • Search Google Scholar
    • Export Citation
  • 25

    NellaAAMallappaAPerrittAFGoundenVKumarPSinaiiNDaleyLALingALiuCYSoldinSJ A Phase 2 study of continuous subcutaneous hydrocortisone infusion in adults with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2016 101 46904698. (https://doi.org/10.1210/jc.2016-1916)

    • Search Google Scholar
    • Export Citation
  • 26

    TurcuAFSpencer-SegalJLFarberRHLuoRGrigoriadisDERammCAMadrigalDMuthTO’BrienCFAuchusRJ. Single-dose study of a corticotropin-releasing factor receptor-1 antagonist in women with 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2016 101 11741180. (https://doi.org/10.1210/jc.2015-3574)

    • Search Google Scholar
    • Export Citation
  • 27

    GarridoMPengHMYoshimotoFKUpadhyaySKBratoeffEAuchusRJ. A-ring modified steroidal azoles retain similar potent and slowly reversible CYP17A1 inhibition as abiraterone. Journal of Steroid Biochemistry and Molecular Biology 2014 143 110. (https://doi.org/10.1016/j.jsbmb.2014.01.013)

    • Search Google Scholar
    • Export Citation
  • 28

    BarnardMQuansonJLMostaghelEPretoriusESnoepJLStorbeckKH. 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): implications for castration resistant prostate cancer. Journal of Steroid Biochemistry and Molecular Biology 2018 183 192201. (https://doi.org/10.1016/j.jsbmb.2018.06.013)

    • Search Google Scholar
    • Export Citation
  • 29

    du ToitTBloemLMQuansonJLEhlersRSerafinAMSwartAC. Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC(2)-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone. Journal of Steroid Biochemistry and Molecular Biology 2017 166 5467. (https://doi.org/10.1016/j.jsbmb.2016.06.009)

    • Search Google Scholar
    • Export Citation
  • 30

    GentRdu ToitTBloemLMSwart AC. 11β-Hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with 11βHSD2 favouring 11-ketotestosterone. Journal of Steroid Biochemistry and Molecular Biology 2019 189 116126. (https://doi.org/10.1016/10.1016/j.jsbmb.2019.02.013)

    • Search Google Scholar
    • Export Citation
  • 31

    CaseyMLWinkelCAMacDonaldPC. Conversion of progesterone to deoxycorticosterone in the human fetus: steroid 21-hydroxylase activity in fetal tissues. Journal of Steroid Biochemistry 1983 18 449452. (https://doi.org/10.1016/0022-4731(83)90064-x)

    • Search Google Scholar
    • Export Citation
  • 32

    Costa-BarbosaFACarvalhoVMNakamuraOHBachegaTAVieiraJGKaterCE. Zona fasciculata 21-hydroxysteroids and precursor-to-product ratios in 21-hydroxylase deficiency: further characterization of classic and non-classic patients and heterozygote carriers. Journal of Endocrinological Investigation 2011 34 587592. (https://doi.org/10.3275/7273)

    • Search Google Scholar
    • Export Citation
  • 33

    YoshimotoFKZhouYPengHMStiddDYoshimotoJASharmaKKMatthewSAuchusRJ. Minor activities and transition state properties of the human steroid hydroxylases cytochromes P450c17 and P450c21, from reactions observed with deuterium-labeled substrates. Biochemistry 2012 51 70647077. (https://doi.org/10.1021/bi300895w)

    • Search Google Scholar
    • Export Citation