Division of Metabolism, Diabetes, and Endocrinology, Department of Internal Medicine.
Genitourinary Malignancies Research Center, Lerner Research Institute.
Eur J Endocrinol. 2020 Apr;182(4):413-421. doi: 10.1530/EJE-19-0905.
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.
To test the hypothesis that AA therapy decreases 11-oxygenated androgens.
Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.
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.
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.
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.
人类肾上腺是去势抵抗性前列腺癌（CRPC）和经典 21-羟化酶缺乏症（21OHD）中雄激素的主要来源。阿比特龙来源于前药阿比特龙醋酸酯（AA），可抑制细胞色素 P450 17-羟化酶/17,20-裂合酶（CYP17A1）的活性，该酶是所有雄激素生物合成所必需的。AA 治疗可有效降低 21OHD 和 CRPC 患者的睾酮和雄烯二酮。11-氧化雄激素是主要的肾上腺源性雄激素，但关于 AA 给药对 11-氧化雄激素的影响知之甚少。
检验 AA 治疗可降低 11-氧化雄激素的假设。
分别从接受 AA 或 AA 加泼尼松（AAP）治疗的 21OHD 或 CRPC 参与者中获得样本。
我们采用液相色谱-串联质谱（LC-MS/MS）法测量了来自 6 例 21OHD 和 6 例 CRPC 患者的血浆或血清样本中四种 11-氧化雄激素（11β-羟基雄烯二酮、11-酮雄烯二酮、11β-羟睾酮和 11-酮睾酮），这些患者分别在接受 AA 或 AAP 治疗前后。
在 CRPC 患者中，AAP（AA 每天 1000mg 加泼尼松和医学去势）治疗可将所有四种 11-氧化雄激素降低至定量下限以下（<0.1-0.3nmol/L），相当于基线水平的 64%-94%的降幅。在 21OHD 患者中，AA 治疗（每天 100-250mg 治疗 6 天）使所有 11-氧化雄激素平均降低了 56%-77%，与基线相比。
我们得出结论，AA 和 AAP 治疗分别显著降低了基线时高（21OHD）或正常（CRPC）11-氧化雄激素患者的肾上腺源性 11-氧化雄激素的产生。11-氧化雄激素的减少是 AA 和 AAP 药理学的一个重要方面。
