ArticleThe Journal of steroid biochemistry and molecular biology2018
11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer.
Article in The Journal of steroid biochemistry and molecular biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 69 citations in OpenAlex.
- Society for Endocrinology Clinical Practice Guideline for the Evaluation of Androgen Excess in Women.Clinical endocrinology · 2025Guideline
- Novel aldo-keto reductase 1C3 inhibitor affects androgen metabolism but not ovarian function in healthy women: a phase 1 study.European journal of endocrinology · 2023Trial
- AKR1C2 and AKR1C3 expression in adipose tissue: Association with body fat distribution and regulatory variants.Molecular and cellular endocrinology · 2021Trial
- The urinary tract commensalApplied and environmental microbiology · 2026Article
- Approach to the patient: investigation of postmenopausal androgen excess.The Journal of clinical endocrinology and metabolism · 2026Review
- Adrenal AKR1C3-mediated androgen activation contributes to hyperandrogenism in prepubertal ovariectomized rats.Translational pediatrics · 2026Article
- Characterization of an NADPH-dependent 17β-hydroxysteroid dehydrogenase from a urinary tract bacterial isolate.The Journal of steroid biochemistry and molecular biology · 2026Article
- The Expression of Placental 17β-Hydroxysteroid Dehydrogenase Genes Is Associated with the Elevation of Active Androgens and Estrogens in Pregnant Women, but Does Not Affect 11-Oxygenated C19 Steroids.International journal of molecular sciences · 2026Article
- The Urinary Tract commensalbioRxiv : the preprint server for biology · 2026Article
- Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.Research (Washington, D.C.) · 2026Review
- Article
- Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Kidney Disease Disrupts 11-Oxygenated Androgen Biosynthesis.The Journal of clinical endocrinology and metabolism · 2025Observational
- An expanded metabolic pathway for androgen production by commensal bacteria.Nature microbiology · 2025Article
- Human Gonads Do Not Contribute to the Circulating Pool of 11-Oxygenated Androgens.The Journal of clinical endocrinology and metabolism · 2025Article
- Targeting sex steroid biosynthesis for breast and prostate cancer therapy.Nature reviews. Cancer · 2023Review
- Interpretation of Steroid Biomarkers in 21-Hydroxylase Deficiency and Their Use in Disease Management.The Journal of clinical endocrinology and metabolism · 2023Review
- Preoperative Circulating 11-Oxygenated Androgens Are Associated With Metastasis-free Survival in Localized Prostate Cancer.The Journal of urology · 2023Article
- Circulating adrenal 11-oxygenated androgens are associated with clinical outcome in endometrial cancer.Frontiers in endocrinology · 2023Article
- The role of 11-oxygenated androgens in prostate cancer.Endocrine oncology (Bristol, England) · 2023Review
- Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level.The Journal of urology · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 4 countries.
Funding
Abstract
The progression of castration resistant prostate cancer (CRPC) is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. The oxidation of androgens to their inactive form is catalysed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2), but little attention is given to the expression levels of this enzyme. In this study, we show that the 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3. In particular we show that the enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. Using three independent experimental systems and a computational model we subsequently show that increased ratios of AKR1C3:17βHSD2 significantly favours the flux through the 11-oxygenated androgen pathway as compared to the classical or 5α-androstanedione pathways. Our findings reveal that the flux through the classical and 5α-androstanedione pathways are limited by the low catalytic efficiently of AKR1C3 towards classical androgens combined with the high catalytic efficiency of 17βHSD2, and that the expression of the oxidative enzyme therefore plays a vital role in determining the steady state concentration of active androgens. Using microarray data from prostate tissue we confirm that the AKR1C3:17βHSD2 ratio is significantly increased in patients undergoing androgen deprivation therapy as compared to benign tissue, and further increased in patients with CRPC. Taken together this study therefore demonstrates that the ratio of AKR1C3:17βHSD2 is more important than AKR1C3 expression alone in determining intratumoral androgen levels and that 11-oxygenated androgens may play a bigger role in CRPC than previously anticipated.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.