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Updated: Dec 28, 2025
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic
M Alyamani1, J Li2, M Patel1
1Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
Background:
Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences.
Patients And Methods:
Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median.
Results:
Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed.
Conclusion:
Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.
Insights
Next-generation androgen receptor antagonists like enzalutamide and apalutamide increase active glucocorticoid exposure by suppressing 11β-HSD2. These changes in cortisol levels are linked to clinical outcomes in prostate cancer patients.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Next-generation androgen receptor (AR) antagonists, enzalutamide and apalutamide, are used for prostate cancer.
- The metabolic, hormonal, and immunologic effects of deep AR suppression are not fully understood.
- This study investigates the hypothesis that these drugs suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), increasing active glucocorticoids.
Purpose of the Study:
- To examine the effects of enzalutamide and apalutamide on glucocorticoid metabolism.
- To determine if changes in glucocorticoids correlate with clinical outcomes in prostate cancer.
- To assess the impact of AR antagonists on 11β-HSD2 activity.
Main Methods:
- Human kidney tissues were analyzed for AR and 11β-HSD2 expression.
- Patients in three clinical trials received enzalutamide or apalutamide.
- Cortisol and its metabolites were measured using liquid chromatography-mass spectrometry (LC-MS/MS).
Main Results:
- AR and 11β-HSD2 co-expression was observed exclusively in male kidney tissues.
- AR antagonist treatment led to a significant increase in cortisol concentration and cortisol/cortisone ratios across all trials.
- A high cortisol/cortisone ratio correlated with improved progression-free survival in metastatic CRPC patients treated with enzalutamide alone.
Conclusions:
- Enzalutamide and apalutamide treatments alter renal 11β-HSD2 activity.
- These drugs significantly increase markers of active glucocorticoid exposure.
- Elevated active glucocorticoid exposure is associated with specific clinical outcomes in prostate cancer.
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