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Updated: Aug 22, 2025
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
Steroidogenesis in castration-resistant prostate cancer
Masaki Shiota1, Satoshi Endo2, Leandro Blas1
1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract:
Castration resistance is in part attributable to aberrant activation of androgen receptor (AR) signaling by the intracrine activation of androgen precursors derived from adrenal glands. To overcome this, novel AR pathway inhibitors (ARPIs) that suppress androgen synthesis by CYP17 inhibition or AR activation by antiandrogen effects have been developed. However, primary or acquired resistance to these ARPIs occurs; in turn attributable, at least in part, to the maintained androgen milieu despite intensive suppression of AR signaling similar to castration resistance. In addition to the classical pathway to produce potent androgens such as testosterone and dihydrotestosterone, the alternative pathway and the backdoor pathway which bypasses testosterone to produce dihydrotestosterone have been shown to play a role in intratumor steroidogenesis. Furthermore, the 11β-hydroxyandrostenedione pathway to produce the potent oxygenated androgens 11-ketotestosterone and 11-ketodihydrotestosterone has been suggested to be functional in prostate cancer. These steroidogenesis pathways produce potent androgens that promote tumor resistance to endocrine therapy including novel ARPIs. Here, we overview the current evidence on the pathological androgen milieu by altered metabolism and transport in prostate cancer, leading to resistance to endocrine therapy.
Insights
Prostate cancer resistance to therapies stems from altered androgen production pathways. Understanding these pathways is key to developing more effective treatments for advanced prostate cancer.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Castration-resistant prostate cancer (CRPC) often involves aberrant androgen receptor (AR) signaling.
- Adrenal gland-derived androgen precursors contribute to intracrine AR activation.
- Novel androgen pathway inhibitors (ARPIs) aim to suppress androgen synthesis and AR activation.
Purpose of the Study:
- To review evidence on pathological androgen milieu in prostate cancer.
- To explore how altered steroidogenesis and transport contribute to endocrine therapy resistance.
- To highlight alternative and backdoor androgen synthesis pathways in prostate cancer.
Main Methods:
- Literature review of current evidence on androgen metabolism and transport in prostate cancer.
- Analysis of steroidogenesis pathways, including classical, alternative, backdoor, and 11β-hydroxyandrostenedione pathways.
- Examination of AR signaling and its resistance mechanisms in the context of endocrine therapy.
Main Results:
- Resistance to ARPIs is linked to a persistent androgen milieu.
- Alternative, backdoor, and 11β-hydroxyandrostenedione pathways generate potent androgens (e.g., dihydrotestosterone, 11-ketotestosterone).
- These pathways contribute to intratumoral steroidogenesis, promoting resistance to endocrine therapy.
Conclusions:
- Altered androgen metabolism and transport create a pathological milieu in prostate cancer.
- This milieu drives resistance to endocrine therapies, including novel ARPIs.
- Targeting these specific steroidogenesis pathways may offer new therapeutic strategies for advanced prostate cancer.
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