11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer?

Area of Science:

• Endocrinology
• Oncology
• Steroid Metabolism

Background:

• Adrenal C19 steroids like dehydroepiandrostenedione (DHEA(S)) and androstenedione (A4) are crucial in castration-resistant prostate cancer (CRPC).
• These steroids are metabolized to dihydrotestosterone (DHT), driving CRPC progression.
• The metabolic fate of 11-hydroxyandrostenedione (11OHA4) in CRPC remains largely unknown.

Purpose of the Study:

• To elucidate the novel metabolic pathway of 11OHA4 in CRPC.
• To identify the metabolites of 11OHA4 and assess their androgenic activity.
• To determine the role of these metabolites in driving CRPC progression.

Main Methods:

• Investigated 11OHA4 metabolism in CRPC.
• Identified novel 5α-reduced C19 steroids using mass spectrometry.
• Validated the metabolic pathway in the LNCaP prostate cancer cell line.
• Performed androgen receptor (AR) transactivation studies.

Main Results:

• A novel pathway for 11OHA4 metabolism in CRPC was identified.
• Metabolites include 11ketoT (11KT), 11keto-5α-androstanedione, 11OHDHT, and 11ketoDHT (11KDHT).
• 11KT and 11OHDHT are partial AR agonists; 11KDHT is a full AR agonist, comparable to DHT.
• 11OHA4 itself has negligible androgenic activity.

Conclusions:

• Metabolism of 11OHA4 generates potent androgens (11KT, 11KDHT) in CRPC.
• These metabolites may contribute to CRPC progression in the absence of testicular androgens.
• Understanding this pathway offers potential therapeutic targets for CRPC.