Dr. Weeks’ Comment: Science is never a matter of majority opinion. Science is a methodology. Read about the scientific relationship of testosterone and prostate cancer and share with your oncologist.
Eur Urol. 2006 Nov;50(5):935-9. Epub 2006 Jul 27.
Testosterone and prostate cancer: an historical perspective on a modern myth.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. email@example.com
To review the historical origins and current evidence for the belief that testosterone (T) causes prostate cancer (pCA) growth.
Review of the historical literature regarding T administration and pCA, as well as more recent studies investigating the relationship of T and pCA.
In 1941 Huggins and Hodges reported that marked reductions in T by castration or estrogen treatment caused metastatic pCA to regress, and administration of exogenous T caused pCA to grow. Remarkably, this latter conclusion was based on results from only one patient. Multiple subsequent reports revealed no pCA progression with T administration, and some men even experienced subjective improvement, such as resolution of bone pain. More recent data have shown no apparent increase in pCA rates in clinical trials of T supplementation in normal men or men at increased risk for pCA, no relationship of pCA risk with serum T levels in multiple longitudinal studies, and no reduced risk of pCA in men with low T. The apparent paradox in which castration causes pCA to regress yet higher T fails to cause pCA to grow is resolved by a saturation model, in which maximal stimulation of pCA is reached at relatively low levels of T.
This historical perspective reveals that there is not now-nor has there ever been-a scientific basis for the belief that T causes pCA to grow. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship of T and pCA that may be clinically and scientifically rewarding.
J Sex Med. 2008 Aug;5(8):1834-40. Epub 2008 Jun 10.
Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancer.
Men’s Health Boston, Harvard Medical School, Boston, MA 02445, USA. firstname.lastname@example.org
A long-standing belief is that higher testosterone (T) will increase the risk of prostate cancer (PCa), yet recent studies do not support this view.
To identify the key historical and scientific events leading to the establishment and persistence of the belief in a T-dependent model of PCa growth, despite evidence to the contrary.
Review of key historical scientific articles regarding T and PCa.
The T-dependent model of PCa growth arose from the work of Huggins and coworkers, who in 1941 demonstrated dramatic responses to castration among men with advanced PCa. These authors and others also reported a rapid clinical progression with T administration. This led to the concept that T was like “food for a hungry tumor” for men with PCa. Fowler and Whitmore recognized in 1981 that the negative effect of T administration did not occur unless men had been previously castrated. However, this critical observation was either forgotten or dismissed amid major changes in PCa diagnosis and management during the 1980s. More recent studies have failed to provide clinical evidence supporting the belief that higher T represents a risk for PCa. Factors contributing to the persistence of the T-dependent model included dramatic effects of castration, continued use of androgen deprivation for treatment of PCa, an influential spokesperson (Huggins), groupthink (failure to acknowledge evidence inconsistent with the prevalent ideology), and an imprecise formulation of the model (“more T, more cancer growth”), making refutation difficult.
The fear that higher T will increase PCa growth stems from a theory of T-dependent PCa growth that originated with observations in a special population (castrated men) that is not particularly relevant to T therapy in hypogonadal men. The negative view of T with regard to PCa should be recognized for what it is–guilt by association.
Eur Urol. 2009 Feb;55(2):310-20. Epub 2008 Sep 24.
Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth.
Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. email@example.com
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.
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.
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.
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.
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.
Urol Clin North Am. 2011 May;38(2):119-24. Epub 2011 Apr 13.
Testosterone and prostate cancer: what are the risks for middle-aged men?
Men’s Health Boston, One Brookline Place, Suite 624, Brookline, MA 02445, USA. firstname.lastname@example.org
With increased recognition of the benefits of testosterone (T) therapy for middle-aged men, there has been a concomitant reexamination of the historical fear that raising T will result in more prostate cancer (PCa). Studies have failed to show increased risk of PCa in men with higher serum T, and supraphysiologic T fails to increase prostate volume or prostate-specific antigen in healthy men. This apparent paradox is explained by the Saturation Model, which posits a finite capacity of androgen to stimulate PCa growth. Modern studies indicate no increased risk of PCa among men with serum T in the therapeutic range.
Curr Treat Options Oncol. 2006 Sep;7(5):363-9.
Testosterone therapy for men at risk for or with history of prostate cancer.
Men’s Health Boston Harvard Medical School, One Brookline Place, Suite #624, Brookline, MA 02445, USA. email@example.com
Since the early 1940s when Huggins showed that severe reductions in serum testosterone by castration or estrogen therapy caused regression of prostate cancer (PCa), it has been assumed that higher testosterone levels cause enhanced growth of PCa. For this reason, it has been considered taboo to offer testosterone replacement therapy (TRT) to any man with a prior history of PCa, even if all objective evidence suggests he has been cured. The fear has been that higher testosterone levels would “awaken” dormant cells and cause a recurrence. Thus, US Food and Drug Administration-mandated language in all testosterone package inserts states that testosterone is contraindicated in men with a history of, or suspected of having, PCa. Although there is little modern experience with administration of testosterone in men with known history of PCa, there is a varied and extensive literature indicating that TRT does not pose any increased risk of PCa growth in men with or without prior treatment. For instance, the cancer rate in TRT trials is only approximately 1%, similar to detection rates in screening programs, yet biopsy-detectable PCa is found in one of seven hypogonadal men. Moreover, PCa is almost never seen in the peak testosterone years of the early 20s, despite autopsy evidence that men in this age group already harbor microfoci of PCa in substantial numbers. The growing number of PCa survivors who happen to be hypogonadal and request treatment has spurred a change in attitude toward this topic, with increasing numbers of physicians now offering TRT to men who appear cured of their disease. Publications have now reported no prostate-specific antigen (PSA) recurrence with TRT in small numbers of men who had undetectable PSA values after radical prostatectomy. Although still controversial, there appears to be little reason to withhold TRT from men with favorable outcomes after definitive treatment for PCa. Monitoring with PSA and digital rectal examination at regular intervals is recommended.