This is the first study showing evidence for an association between changes in testosterone levels within individuals and prostate cancer development. This knowledge may have substantial clinical impact on prostate cancer prevention and provides a critical message for healthcare professionals to start regular monitoring of testosterone levels, even in younger men.
Most previous studies on the link between testosterone levels and prostate cancer measured testosterone levels at a single time point or simply average testosterone levels during the studied time periods. This may explain previous inconsistent findings about the effects of testosterone on the risk of prostate cancer. In contrast, the study reported here conducted serial measurements of testosterone levels for up to 11 years, which allowed for detection of patterns of testosterone levels and their association with incident prostate cancer development.
Different role of testosterone in the onset and progression of prostate cancer
Previous studies and discussions about testosterone and prostate cancer failed to distinguish between prostate cancer development vs. prostate cancer progression. These are two distinct processes that may be differentially impacted by testosterone.
Prostate carcinogenesis (cancer development) is a process where normal prostate cells first adjust themselves to progressively declining testosterone levels at the cellular and receptor levels. As testosterone levels fall below a critical threshold where normal prostate cells are not able to make additional adjustments without mutations, some of the normal prostate cells may turn into cancer cells.4 If testosterone therapy is started before reaching this threshold, prostate cancer development could be prevented.
Implications for testosterone therapy
The dynamic model suggests that testosterone therapy should be started before testosterone levels drop below the threshold beyond which normal prostate cells turn into cancer cells. Even though testosterone therapy does not increase levels of intra-prostatic testosterone and dihydrotestosterone in men with hypogonadism (at least in the short term), intra-prostatic levels of testosterone and dihydrotestosterone decline further in hypogonadal men who are not treated with testosterone therapy.5 This suggests that testosterone therapy maintains intra-prostatic androgen levels while raising serum testosterone levels.
Given the large inter-individual variation in testosterone levels, androgen receptor sensitivity and thresholds, longitudinal monitoring of testosterone levels is necessary to find out an individual man’s healthy baseline and to detect deviations. Monitoring of testosterone levels in the general population may need to start before age 30 since the incidence of prostate cancer in autopsy studies has been reported to be as high as 17% in men younger than 30 years old.6 Knowing a man’s young healthy baseline level of testosterone will also serve as an individualized reference therapeutic target during testosterone treatment.
Racial disparities of prostate cancer
Black men are approximately twice as likely to develop prostate cancer compared to white men.7 The increased risk of prostate cancer for blacks could be due to more rapid reductions in testosterone levels with age when compared to white men.8 During young adulthood, testosterone levels are higher in blacks than in whites, but the difference diminishes with age and completely disappears after 60 years of age.8-10 Thus, black men have a steeper decline in testosterone levels with age, which may explain, their higher risk of prostate cancer.
Comparison with previous studies
The present study confirms the results from a previous study, which found that faster age-related reductions in testosterone levels, rather than absolute testosterone levels captured either as a one-time measure or 5-year average, are significantly associated with the risk of prostate cancer.11 In this study, compared to men with a relatively stable testosterone, those with an annual testosterone reduction of more than 1 nmol/L (30 ng/dL) had 5-fold increased risk of prostate cancer.11 Both studies suggest that preventing the age-related testosterone decline with testosterone therapy may be an effective strategy for prostate cancer prevention.2,11