Abiraterone acetate treatment lowers 11-oxygenated androgens

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.

Figure 1.

Abbreviated pathways of adrenal steroid biosynthesis. DHEA is primarily sulfated by sulfotransferase 2A1 (SULT2A1) to DHEAS, but a fraction is converted to A4. A4 is a good substrate for CYP11B1, yielding 11OHA4, and 11OHA4 is metabolized primarily in peripheral tissues to 11KT. Abbreviations not in text: 11βHSD2, 11β-hydroxysteroid dehydrogenase type 2; AKR1C3, aldo-keto reductase 1C3 (17βHSD5); Cyt b₅, cytochrome b₅; StAR, steroidogenic acute regulatory protein.

Figure 2.

Reductions in conventional and 11-oxygenated androgens in CRPC patients with AAP treatment. Symbols show individual patient data from baseline (BL) and after at least 4 weeks of AAP therapy. The dotted lines indicate LLOQ for each steroid, and values

Figure 3.

Changes in conventional and 11-oxygenated androgens with AA in patients with 21OHD. Symbols show individual patient data from baseline (day 1) and days 6-8 for 6 days of AA therapy at 100 mg/d (Period 1) or 250 mg/d (Period 2). Dotted lines indicate upper limit of normal ranges for premenopausal women (18). Conversion factors from nmol/L to ng/dL: multiply value by 28.64 for A4, 28.84 for T, 30.24 for 11OHA4 and 11KT, 30.04 for 11KA4, and 30.44 for 11OHT.

Figure 4.

Changes in progesterone, DOC, and progesterone/DOC (Prog/DOC) ratio in 21OHD patients with AA treatment. Symbols show individual patient data from baseline and after 6 days of AA therapy at 100 mg/d (Period 1) or 250 mg/d (Period 2). Conversion factors for ng/dL: multiply value by 31.45 for progesterone and 33.05 for DOC.

Figure 5.

Changes in adrenal 21-carbon steroids from CRPC patients at baseline and with AAP treatment. Symbols show individual patient data from baseline and after at least 4 weeks of AAP therapy. Conversion factors for ng/dL: multiply by 36.25 for cortisol, 34.65 for corticosterone, 31.45 for progesterone, and 33.05 for DOC.