Testosterone Replacement Therapy and Prostate Cancer Risk

A review of research on the use of testosterone replacement therapy in men with a history of prostate cancer and in men with elevated prostate cancer risk found no evidence of statistically significant associations between such treatment and cancer progression.

The finding supports the conclusion of several other recent studies that have attempted to evaluate replacement therapy in such populations and failed to find evidence of danger.

Such work has begun to overturn the longstanding assumption that testosterone supplements would prove deadly to many men with elevated prostate-cancer risk, but the authors of the new review say that large, randomized trials will be needed to justify sweeping changes to treatment strategies.

“The historical basis for concern originated in 1941 when Huggins and Hodges demonstrated that reducing testosterone to castrate levels caused regression of prostate cancer while administration of exogenous testosterone stimulated its growth,” the authors of the review wrote in the Asian Journal of Andrology.

“While there is now definitive evidence regarding the effect of castration, the latter finding was based on evidence from one single patient and the validity has been called into question by numerous more recent studies.”

The authors of the new paper, who all hail from the University of Texas Medical School at Houston, begin by noting that trials of testosterone replacement therapy in hypogonadal men with healthy prostate tissue have found little evidence of any activity inside the organ.

A number of trials have found that prostate volume and prostate specific antigen (PSA) remain unchanged, regardless of whether patients are using normal supplement doses designed to restore normal testosterone levels or massive dosed used to elevate testosterone levels far beyond normal bounds.

Another trial found that testosterone replacement therapy, even when it raises testosterone levels in the rest of the body, does not raise testosterone levels inside prostate tissues.

“A model to describe these findings is the prostate saturation theory,” the authors wrote. “When the level of circulating androgen is below normal, some androgen receptors are inactive, and the secondary downstream effects are decreased. Once androgen receptors within the prostate are saturated, however, increasing testosterone will no longer have an effect.”

A very low saturation point — low enough that even hypogonadal men rarely fell below it —would explain both why androgen deprivation therapy works as a prostate cancer treatment and why research has yet to find that testosterone replacement spurs prostate cancer (or even raises PSA) in other men.

The authors of the new paper cited 11 randomized and controlled trials, along with another 29 trials with no control arms, that all measured prostate health in men who used testosterone therapy. None of those studies demonstrated any increased risk of prostate cancer or increased disease severity among patients who did develop prostate cancer.

Among those studies were 4 that specifically concentrated on men prostate cancer survivors and, again, found no negative effects from testosterone replacement.

The largest such study to date was a retrospective analysis by Pastuszak et al of 103 hypogonadal men and 49 non-hypogonadal men who all underwent prostatectomy for cancer. The hypogonadal men were all treated with testosterone and men in both groups were followed for an average of 27.5 months. Over that time, cancer recurred in 4 treatment-group members and 8 control-group members.

Published research, according to the review authors, has also found that testosterone therapy does not increase prostate cancer risk in men who are under active surveillance or men with prostatic intraepithelial neoplasia (PIN). That said, the total number of active-surveillance and PIN patients studied to date has been very small.

“Over the past 15 years, a significant shift has occurred in the understanding of the relationship between testosterone and prostate cancer,” the authors concluded.

“While these retrospective observational studies provide somewhat limited evidence, they each suggest that testosterone replacement in symptomatic men with prostate cancer warrants further investigation.

“Currently, there are several randomized control trials examining the effect of testosterone replacement in the setting of prostate cancer… Further investigation with randomized control trials may lead to a major revision of the traditional standard.”