Androgen Receptor Saturation Point in Prostate Tissue
The saturation point for androgen receptors in prostate tissue occurs at serum testosterone levels of approximately 200-250 ng/dL (7-8.7 nmol/L), well below the normal physiologic range, with maximal androgen-receptor binding achieved at castrate or near-castrate levels. 1
The Saturation Model Framework
The relationship between serum testosterone and prostate tissue androgen receptor activation follows a saturation curve, not a linear relationship 1:
- Below 200-250 ng/dL: Prostate growth and androgen receptor activation are exquisitely sensitive to even small changes in testosterone levels 1
- Above 200-250 ng/dL: Additional testosterone produces minimal further effect on androgen receptor binding or prostate tissue stimulation 1
- Clinical implication: This explains why castration (reducing testosterone to <50 ng/dL) dramatically affects prostate cancer, while testosterone administration in eugonadal men has minimal impact 1
Intraprostatic Androgen Levels
The critical factor is tissue-level androgens, not serum levels 2, 3:
Testosterone in Prostate Tissue
- Benign prostate tissue: 2.75-3.26 pmol/g tissue 2, 3
- Recurrent prostate cancer during androgen deprivation: 2.78-3.75 pmol/g tissue (surprisingly similar to benign tissue) 2, 3
- Key finding: Intraprostatic testosterone remains sufficient for androgen receptor activation even during systemic androgen deprivation 2, 3
Dihydrotestosterone (DHT) in Prostate Tissue
- Benign prostate tissue: 13.7 pmol/g tissue (4.97 ng/g) 2, 4
- Recurrent prostate cancer: 1.25-1.45 pmol/g tissue (91% reduction from benign tissue) 2, 3
- Critical threshold: DHT levels as low as 1.45 nM in tissue remain sufficient to activate androgen receptors 3
- DHT has higher affinity: DHT binds androgen receptors more avidly than testosterone, making it the more potent androgenic hormone 5
Mechanism of 5-Alpha Reductase Inhibitors
Understanding the saturation point explains why 5-ARIs work differently than expected 5:
- Finasteride: Reduces serum DHT by ~70%, intraprostatic DHT by ~80% (inhibits type II 5-AR only) 5
- Dutasteride: Reduces serum DHT by ~95%, intraprostatic DHT by ~94% (inhibits both type I and II 5-AR) 5
- Clinical effect: Despite these dramatic reductions, residual DHT levels still permit some androgen receptor activation, which is why 5-ARIs reduce but don't eliminate prostate growth 5
Critical Clinical Caveats
The Saturation Model Has Limitations
A 2020 critical review found that the original Saturation Model evidence was "troublingly taken out of context in many cases" and applied where "it would be unwise to do so." 6 The model's application to prostate cancer treatment decisions should be approached with caution 6.
Intracrine Androgen Production
Recurrent prostate cancer tissue may develop capacity to biosynthesize testicular androgens from adrenal precursors or cholesterol 2:
- This "intracrine" production explains why castrate-resistant prostate cancer maintains androgen receptor activation despite castrate serum levels 2
- Intratumoral testosterone levels of 250-300 ng/dL have been measured even when serum levels are <20 ng/dL 2
- Treatment implication: Novel therapies must target androgen receptor directly and prevent intratumoral androgen formation, not just reduce serum levels 3
Practical Monitoring Parameters
For patients on testosterone therapy or androgen deprivation 5, 7:
- Castrate status definition: Serum testosterone <50 ng/dL (1.7 nmol/L), though this may not reflect intratumoral levels 5
- Recovery threshold for clinical trials: Testosterone ≥150 ng/dL suggests adequate recovery from prior hormonal therapy 7
- Testosterone stability requirement: Maintain ≤10% variation when calculating PSA kinetics 5