The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer
Open accessAbstract
The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor (AR), as well as the availability of endogenous AR agonists. Originating from the gonads, testosterone is released into circulation and is converted by steroid-5α-reductase in prostate cancer to 5α-dihydrotestosterone (DHT), potently activating AR and driving tumor progression. Advanced prostate cancer is initially treated with gonadal testosterone depletion, which suppresses this cascade of events and typically leads to a treatment response. Eventually, resistance to testosterone deprivation occurs with "castration-resistant" prostate cancer (CRPC) and is driven by the intratumoral synthesis of DHT. The generation of DHT occurs in large part from adrenal 19-carbon precursor steroids, which are dependent on expression of CYP17A1. Although the path from adrenal precursor steroids to DHT was generally thought to require 5α-reduction of testosterone, recent data suggest that it instead involves conversion from Δ-androstenedione by steroid-5α-reductase isoenzyme-1 to 5α-androstanedione, followed by subsequent conversion to DHT. The 5α-androstanedione pathway to DHT therefore bypasses testosterone entirely. Abiraterone acetate effectively inhibits CYP17A1, blocks the synthesis of androgens, and extends the survival of men with CRPC. Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate.
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A4 can also be 5α-reduced to 5α-androstanedione prior to conversion to DHT by AKR1C3, thereby bypassing testosterone.
“A4 can also be 5α-reduced to 5α-androstanedione prior to conversion to DHT by AKR1C3, thereby bypassing testosterone (Fig. 3) [45,55].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [55]
Alternate 5α-androstanedione pathway is favored in tissues with predominant SRD5A1 expression and in conditions such as castration-resistant prostate cancer in which SRD5A1 is upregulated and SRD5A2 is downregulated.
“This so called “alternate 5α-androstanedione” pathway is favored in tissues with predominant SRD5A1 expression and in conditions such as castration-resistant prostate cancer in which the expression of SRD5A1 is upregulated and that of SRD5A2 is downregulated [55,58].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [55]
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- Authors
- Sharifi, N.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Sharifi, Nima
- ORCID
- Sharifi, Nima
- Venue
- Journal of Investigative Medicine
- Publisher
- SAGE Publications
- Published
- 2012-02
- Volume
- 60
- Issue
- 2
- Pages
- 504-507
- ISSN
- 1081-5589 (ISSN-L)
- 1708-8267
- PMC
- PMC3262939
- OpenAlex
- W1601645816
- Cited by
- 52
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 2 · 2013: 8 · 2012: 3
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Investigative Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (L30 CA135719)
- National Center for Research Resources (R13RR023236)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- castration-resistant prostate cancer, dihydrotestosterone, CYP17A1, adrenal androgen synthesis, androgen receptor, abiraterone, androgen deprivation resistance
- MeSH terms
- Abiraterone Acetate, Androstadienes, Etiocholanolone, Humans, Male, Orchiectomy, Prostatic Neoplasms, Dihydrotestosterone, Biosynthetic Pathways
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