Dr. Ron’s Research Review – March 13, 2014

© 2014

This week’s research review focuses on the androgen hypothesis of prostate cancer.

In the journal European Urology, Muller et al provide the final nail in the coffin for what had been a guiding principle of uro-oncology for over 70 years: the androgen hypothesis of prostate cancer (PCa). (Muller, Gerber et al. 2012) (Morgentaler 2012)

The androgen hypothesis originated with the Nobel-winning work of Charles Huggins, who, together with coauthor Clarence Hodges, reported in 1941 that castration caused PCa regression in men with metastatic disease, and that testosterone (T) administration caused PCa progression. They concluded that T activates PCa, producing an enhanced rate of growth. Medical trainees were taught that the relationship between T and PCa was like food for a hungry tumor or like pouring gasoline on a fire.

Muller, however, found that baseline serum testosterone and DHT levels were unrelated to prostate cancer detection or grade.

The results suggest a saturation model: Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels.

Prostate tissue requires androgens for optimal growth. However, it can only use a relatively small amount, beyond which additional androgen is merely excess. The saturation point is well below physiologic concentrations, which explains why manipulation of serum T into or out of the castrate range produces large changes in prostate biology, whereas normal prostate and PCa appear completely indifferent to variations in serum T from the near-physiologic to supra-physiologic range. (Morgentaler and Traish 2009)

Dr. Ron


Articles

Goodbye androgen hypothesis, hello saturation model

         (Morgentaler 2012) Download

Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial

         (Muller, Gerber et al. 2012) Download

BACKGROUND: Findings of studies on the association between androgens and prostate cancer (PCa) are mixed. Androgens may affect prostate-specific antigen (PSA) levels, thereby influencing biopsy recommendations. Also, androgens may stimulate prostate growth at very low levels with no additional effects at higher levels (saturation model). OBJECTIVE: To test whether androgens were associated with PCa risk in the placebo arm of a prospective study in which biopsies were performed regardless of PSA level. DESIGN, SETTING, AND PARTICIPANTS: Of 8122 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, 4073 men (50.1%) received placebo. Key entry criteria were PSA 2.5-10 ng/ml and one prior negative biopsy. INTERVENTION: Per-protocol biopsies at 2 and 4 yr; for-cause biopsies at physician discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic regression was used to test the association between baseline log-transformed testosterone and dihydrotestosterone (DHT) levels and the risk of detecting either PCa or low-grade PCa (Gleason score <6) compared with high-grade PCa (Gleason score >7). In secondary analysis, we stratified the analysis by low baseline androgen levels (testosterone <10 nmol/l; DHT <0.76 nmol/l) compared with normal baseline androgen levels. RESULTS AND LIMITATIONS: Of 4073 men, 3255 (79.9%) had at least one biopsy after randomization and were analyzed. Androgen levels tested continuously or by quintiles were generally unrelated to PCa detection or grade. PCa detection was similar among men with low compared with normal baseline testosterone levels (25.5% and 25.1%; p=0.831). In secondary analysis, higher testosterone levels at baseline were associated with higher PCa detection (odds ratio: 1.23; 95% confidence interval, 1.06-1.43; p=0.006) only if men had low baseline testosterone (<10nmol/l). For men with normal baseline testosterone (>/=10 nmol/l), higher testosterone levels at baseline were unrelated to PCa risk (p=0.33). No association was found for DHT and PCa (all p>0.85). CONCLUSIONS: Baseline serum testosterone and DHT levels were unrelated to PCa detection or grade. Our findings of the lowest testosterone levels being associated with the lowest PCa risk with no further changes with higher testosterone support a saturation model but must be confirmed in future studies using an a priori defined hypothesis. CLINICALTRIALS.GOV IDENTIFIER: NCT00056407.

Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth

            (Morgentaler and Traish 2009) Download

CONTEXT: The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men. OBJECTIVE: To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate. EVIDENCE ACQUISITION: A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines. EVIDENCE SYNTHESIS: Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect. CONCLUSIONS: The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.


References

Morgentaler, A. (2012). "Goodbye androgen hypothesis, hello saturation model." Eur Urol 62(5): 765-7. [PMID: 22728116]

Morgentaler, A. and A. M. Traish (2009). "Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth." Eur Urol 55(2): 310-20. [PMID: 18838208]

Muller, R. L., L. Gerber, et al. (2012). "Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial." Eur Urol 62(5): 757-64. [PMID: 22658758]