Abiraterone Acetate Treatment Lowers 11-oxygenated Androgens

Overview

Journal Eur J Endocrinol

Publisher Oxford University Press

Specialty Endocrinology

Date 2020 Feb 12

PMID 32045360

Citations 33

Authors

Connor Wright

Patrick ODay

Mohammed Alyamani

Nima Sharifi

Richard J Auchus

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Future Directions in the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Sarafoglou K, Auchus R J Clin Endocrinol Metab. 2025; 110(Supplement_1):S74-S87.

PMID: 39836617 PMC: 11749912. DOI: 10.1210/clinem/dgae759.

Exploring the Predictive Role of 11-Oxyandrogens in Diagnosing Polycystic Ovary Syndrome.

Mody A, Lodish M, Auchus R, Turcu A, Jiang F, Huddleston H Endocrinol Diabetes Metab. 2025; 8(1):e70022.

PMID: 39815717 PMC: 11735743. DOI: 10.1002/edm2.70022.

Treatment and Follow-up of Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency in Childhood and Adolescence.

Peltek Kendirci H, Unal E, Dundar I, Bulus A, Odabasi Gunes S, Siklar Z J Clin Res Pediatr Endocrinol. 2024; 17(Suppl 1):12-22.

PMID: 39713876 PMC: 11730096. DOI: 10.4274/jcrpe.galenos.2024.2024-6-26-S.

Abiraterone and Galeterone, Powerful Tools Against Prostate Cancer: Present and Perspective.

Kuzminac I, Nikolic A, Savic M, Ajdukovic J Pharmaceutics. 2024; 16(11).

PMID: 39598525 PMC: 11597628. DOI: 10.3390/pharmaceutics16111401.

Cardiometabolic Aspects of Congenital Adrenal Hyperplasia.

Krysiak R, Claahsen-van der Grinten H, Reisch N, Touraine P, Falhammar H Endocr Rev. 2024; 46(1):80-148.

PMID: 39240753 PMC: 11720181. DOI: 10.1210/endrev/bnae026.

References

Ryan C, Smith M, de Bono J, Molina A, Logothetis C, de Souza P . Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2012; 368(2):138-48. PMC: 3683570. DOI: 10.1056/NEJMoa1209096. View

Turcu A, Nanba A, Chomic R, Upadhyay S, Giordano T, Shields J . Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol. 2016; 174(5):601-9. PMC: 4874183. DOI: 10.1530/EJE-15-1181. View

OReilly M, Kempegowda P, Jenkinson C, Taylor A, Quanson J, Storbeck K . 11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2016; 102(3):840-848. PMC: 5460696. DOI: 10.1210/jc.2016-3285. View

Auchus R, Rainey W . Adrenarche - physiology, biochemistry and human disease. Clin Endocrinol (Oxf). 2004; 60(3):288-96. DOI: 10.1046/j.1365-2265.2003.01858.x. View

CASEY M, Winkel C, MACDONALD P . Conversion of progesterone to deoxycorticosterone in the human fetus: steroid 21-hydroxylase activity in fetal tissues. J Steroid Biochem. 1983; 18(4):449-52. DOI: 10.1016/0022-4731(83)90064-x. View

Auchus R, Buschur E, Chang A, Hammer G, Ramm C, Madrigal D . Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014; 99(8):2763-70. PMC: 4121028. DOI: 10.1210/jc.2014-1258. View

Nella A, Mallappa A, Perritt A, Gounden V, Kumar P, Sinaii N . A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2016; 101(12):4690-4698. PMC: 5155681. DOI: 10.1210/jc.2016-1916. View

Garrido M, Peng H, Yoshimoto F, Upadhyay S, Bratoeff E, Auchus R . A-ring modified steroidal azoles retaining similar potent and slowly reversible CYP17A1 inhibition as abiraterone. J Steroid Biochem Mol Biol. 2014; 143:1-10. PMC: 4272579. DOI: 10.1016/j.jsbmb.2014.01.013. View

Barnard M, Quanson J, Mostaghel E, Pretorius E, Snoep J, Storbeck K . 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer. J Steroid Biochem Mol Biol. 2018; 183:192-201. PMC: 6283102. DOI: 10.1016/j.jsbmb.2018.06.013. View

10.

Yoshimoto F, Zhou Y, Peng H, Stidd D, Yoshimoto J, Sharma K . 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(36):7064-77. PMC: 3471366. DOI: 10.1021/bi300895w. View

11.

Pretorius E, Africander D, Vlok M, Perkins M, Quanson J, Storbeck K . 11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored. PLoS One. 2016; 11(7):e0159867. PMC: 4956299. DOI: 10.1371/journal.pone.0159867. View

12.

Turcu A, Spencer-Segal J, Farber R, Luo R, Grigoriadis D, Ramm C . Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2016; 101(3):1174-80. PMC: 4803170. DOI: 10.1210/jc.2015-3574. View

13.

Nanba A, Rege J, Ren J, Auchus R, Rainey W, Turcu A . 11-Oxygenated C19 Steroids Do Not Decline With Age in Women. J Clin Endocrinol Metab. 2019; 104(7):2615-2622. PMC: 6525564. DOI: 10.1210/jc.2018-02527. View

14.

Costa-Barbosa F, Carvalho V, Nakamura O, Bachega T, Vieira J, Kater C . Zona fasciculata 21-hydroxysteroids and precursor-to-product ratios in 21-hydroxylase deficiency: further characterization of classic and non-classic patients and heterozygote carriers. J Endocrinol Invest. 2010; 34(8):587-92. DOI: 10.3275/7273. View

15.

Auchus R, Sharifi N . Sex Hormones and Prostate Cancer. Annu Rev Med. 2019; 71:33-45. DOI: 10.1146/annurev-med-051418-060357. View

16.

Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev B . Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017; 377(4):352-360. DOI: 10.1056/NEJMoa1704174. View

17.

Gomes L, Huang N, Agrawal V, Mendonca B, Bachega T, Miller W . Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2008; 94(1):89-95. PMC: 2630875. DOI: 10.1210/jc.2008-1174. View

18.

du Toit T, Bloem L, Quanson J, Ehlers R, Serafin A, Swart A . Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone. J Steroid Biochem Mol Biol. 2016; 166:54-67. DOI: 10.1016/j.jsbmb.2016.06.009. View

19.

Auchus R, Yu M, Nguyen S, Mundle S . Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer. Oncologist. 2014; 19(12):1231-40. PMC: 4257741. DOI: 10.1634/theoncologist.2014-0167. View

20.

Speiser P, Arlt W, Auchus R, Baskin L, Conway G, Merke D . Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018; 103(11):4043-4088. PMC: 6456929. DOI: 10.1210/jc.2018-01865. View