madman
Super Moderator
Two heavy weights in the field drop a big one!
* Sixty-five years after the landmark publication by Huggins and Hodges, it was discovered that their principal conclusion that T injections “activated” PCa even in hormonally intact men was based on erratic acid phosphatase results in a single patient treated for only 18 days. 18
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* In 2009, we presented the Saturation Model 8 as a new paradigm that resolved the paradox in which androgen deprivation therapy (ADT) provided clinical benefits in metastatic PCa, yet TTh failed to demonstrate adverse PCa outcomes. The evidence showed that maximal androgen-stimulated prostate activity was reached at the relatively low T concentration of approximately 250 ng/dL (8.7 nmol/L), termed the saturation point, 8 with some interindividual variability. PSA was shown to increase with TTh if baseline serum T was below the saturation point but not above it. 9 Supraphysiologic T concentrations were shown to cause no greater PSA increase than physiologic concentrations in medically castrated subjects. 10 Another contributing factor may be the resistance of intraprostatic androgen concentrations to changes in serum T levels. 11 Saturation provided the conceptual framework that transformed the use of TTh, especially following treatment of localized PCa.
---
The persistence of the AH fallacy transcends typical scientific inertia. While historical dogma, groupthink, and regulatory caution play a role here, the tenacity of AH stems from perpetuation of false narratives and half-truths that distort the relationship between T and PCa. In this article, we review the evidence, address these false narratives, and provide a refinement of the Saturation Model to provide a high-level, evidence-based, biologically accurate picture of the role of androgens and the prostate. The new proposed framework of androgen adequacy vs inadequacy is disarmingly simple yet has profound implications for research and clinical practice.
==========
Persistence of the AH
The AH continues to inform regulatory warnings, guidelines, and everyday clinical practice. The Food and Drug Administration label for T products still asserts TTh is contraindicated in men with “known or suspected carcinoma of the prostate” and warns that TTh may worsen BPH or increase PCa risk. 19 All published guidelines agreed with this contraindication until 2018 when the AUA guidelines allowed an exception for men with low-risk PCa following successful radical prostatectomy (RP), but not for other men with PCa. 20 In most of the world, any history of PCa is still considered an absolute contraindication to TTh.
=====
Evidence
The relationship of serum androgens with PCa has been extensively studied. Below, we present highlights from key categories.
- RCTs, Meta-Analyses, and Observational Trials
- Endogenous Androgen Concentrations and PCa Risk
- Cancer Grade and Aggressive Disease
- Testosterone Therapy in Men With PCa
- Testosterone and BPH
- Evidence in Support of the AH
=========
False Narratives
Several false narratives have distorted the medical community’s understanding of the nature of the androgen-PC relationship.
=====
Reframing the Relationship of Testosterone and PCa
It is imperative that clinicians and researchers adopt an evidence-based view of androgens and PCa. The 5 concepts below define this new framework.
-----
5. The key concept: adequate versus inadequate androgen concentrations (Figure 3).
With an adequate supply of androgens, prostate tissue -- malignant and benign -- functions normally and growth is unaffected by T concentrations within this normal range. When T concentrations fall below a critical threshold, the deficiency of androgens becomes a rate-limiting step in cellular metabolism and growth. The degree of androgen insufficiency determines the magnitude and character of altered prostatic biology.
=======
A NEW FRAMEWORK: ADEQUACY VS INADEQUACY
The saturation model 8 has served as a powerful framework to understand why androgen deprivation causes PCa regression and growth inhibition, yet TTh does not cause PCa progression nor a rise in PSA for men with baseline T above the saturation point. 9,93 We here wish to refine the saturation model to provide an overarching framework to understand the relationship of T and PCa.
----
* To illustrate the concept of testosterone adequacy vs inadequacy, we have flipped the classic saturation curve 8 in Figure 3 so that serum T concentrations descend from left to right. This makes the following point clear: “PCa growth is unchanged across the entire normal T range but becomes inhibited once T declines below a critical threshold.”
Recognition that TTh or high-dose T administration may have beneficial PCa effects offers exciting new research possibilities. We would like to see RCTs of normal or high-dose TTh before RP and continuing through the recovery period; TTh vs placebo for men with adverse pathology who are not yet candidates for additional treatment; TTh vs placebo for men on active surveillance; normal or high-dose TTh for men with BCR or early stage metastatic disease; continuous high-dose TTh vs cycling bipolar treatment; and confirmation of a modified BAT protocol 65 in men with metastatic PCa that provide extended periods of time with robust T levels. These studies offer the potential not only for improved cancer outcomes but also greater quality of life. Additional TTh studies to consider at physiological or supraphysiological concentrations include men and women in catabolic states, such as patients in shock or with extensive burns, in ICUs, or following major surgeries such as radical cystectomy. We look forward to a new era of research and clinical practice based on evidence and biology, leaving behind a nearly century-long episode in medical history based on a false belief.
* Sixty-five years after the landmark publication by Huggins and Hodges, it was discovered that their principal conclusion that T injections “activated” PCa even in hormonally intact men was based on erratic acid phosphatase results in a single patient treated for only 18 days. 18
----
* In 2009, we presented the Saturation Model 8 as a new paradigm that resolved the paradox in which androgen deprivation therapy (ADT) provided clinical benefits in metastatic PCa, yet TTh failed to demonstrate adverse PCa outcomes. The evidence showed that maximal androgen-stimulated prostate activity was reached at the relatively low T concentration of approximately 250 ng/dL (8.7 nmol/L), termed the saturation point, 8 with some interindividual variability. PSA was shown to increase with TTh if baseline serum T was below the saturation point but not above it. 9 Supraphysiologic T concentrations were shown to cause no greater PSA increase than physiologic concentrations in medically castrated subjects. 10 Another contributing factor may be the resistance of intraprostatic androgen concentrations to changes in serum T levels. 11 Saturation provided the conceptual framework that transformed the use of TTh, especially following treatment of localized PCa.
---
The persistence of the AH fallacy transcends typical scientific inertia. While historical dogma, groupthink, and regulatory caution play a role here, the tenacity of AH stems from perpetuation of false narratives and half-truths that distort the relationship between T and PCa. In this article, we review the evidence, address these false narratives, and provide a refinement of the Saturation Model to provide a high-level, evidence-based, biologically accurate picture of the role of androgens and the prostate. The new proposed framework of androgen adequacy vs inadequacy is disarmingly simple yet has profound implications for research and clinical practice.
==========
Persistence of the AH
The AH continues to inform regulatory warnings, guidelines, and everyday clinical practice. The Food and Drug Administration label for T products still asserts TTh is contraindicated in men with “known or suspected carcinoma of the prostate” and warns that TTh may worsen BPH or increase PCa risk. 19 All published guidelines agreed with this contraindication until 2018 when the AUA guidelines allowed an exception for men with low-risk PCa following successful radical prostatectomy (RP), but not for other men with PCa. 20 In most of the world, any history of PCa is still considered an absolute contraindication to TTh.
=====
Evidence
The relationship of serum androgens with PCa has been extensively studied. Below, we present highlights from key categories.
- RCTs, Meta-Analyses, and Observational Trials
- Endogenous Androgen Concentrations and PCa Risk
- Cancer Grade and Aggressive Disease
- Testosterone Therapy in Men With PCa
- Testosterone and BPH
- Evidence in Support of the AH
=========
False Narratives
Several false narratives have distorted the medical community’s understanding of the nature of the androgen-PC relationship.
=====
Reframing the Relationship of Testosterone and PCa
It is imperative that clinicians and researchers adopt an evidence-based view of androgens and PCa. The 5 concepts below define this new framework.
-----
5. The key concept: adequate versus inadequate androgen concentrations (Figure 3).
With an adequate supply of androgens, prostate tissue -- malignant and benign -- functions normally and growth is unaffected by T concentrations within this normal range. When T concentrations fall below a critical threshold, the deficiency of androgens becomes a rate-limiting step in cellular metabolism and growth. The degree of androgen insufficiency determines the magnitude and character of altered prostatic biology.
=======
A NEW FRAMEWORK: ADEQUACY VS INADEQUACY
The saturation model 8 has served as a powerful framework to understand why androgen deprivation causes PCa regression and growth inhibition, yet TTh does not cause PCa progression nor a rise in PSA for men with baseline T above the saturation point. 9,93 We here wish to refine the saturation model to provide an overarching framework to understand the relationship of T and PCa.
----
* To illustrate the concept of testosterone adequacy vs inadequacy, we have flipped the classic saturation curve 8 in Figure 3 so that serum T concentrations descend from left to right. This makes the following point clear: “PCa growth is unchanged across the entire normal T range but becomes inhibited once T declines below a critical threshold.”
Recognition that TTh or high-dose T administration may have beneficial PCa effects offers exciting new research possibilities. We would like to see RCTs of normal or high-dose TTh before RP and continuing through the recovery period; TTh vs placebo for men with adverse pathology who are not yet candidates for additional treatment; TTh vs placebo for men on active surveillance; normal or high-dose TTh for men with BCR or early stage metastatic disease; continuous high-dose TTh vs cycling bipolar treatment; and confirmation of a modified BAT protocol 65 in men with metastatic PCa that provide extended periods of time with robust T levels. These studies offer the potential not only for improved cancer outcomes but also greater quality of life. Additional TTh studies to consider at physiological or supraphysiological concentrations include men and women in catabolic states, such as patients in shock or with extensive burns, in ICUs, or following major surgeries such as radical cystectomy. We look forward to a new era of research and clinical practice based on evidence and biology, leaving behind a nearly century-long episode in medical history based on a false belief.
