What this study adds
To investigate whether intra-individual variations of testosterone levels contribute to risk of prostate cancer development, 376 untreated men with hypogonadism (testosterone 12.1 nmol/L or less), 45 to 74 years old, were recruited from a urology office in Germany. Age at study entry served as a surrogate for age at the first detection of testosterone below 12.1 nmol/L. Testosterone levels and PSA were monitored semiannually or annually during the entire follow-up period of 2 to 11 years.
Changes in testosterone levels in individual men were measured with 3 indicators:
- Intra-individual variation in testosterone levels over time.
- Maximum testosterone decline relative to the individual average testosterone level prior to the decrease.
- The average largest drop of testosterone in a short time period in an individual.
By the end of the study, a total of 26 new prostate cancer cases had been diagnosed (by biopsy). Results showed that the later (i.e. older age) the testosterone dropped below 12.1 nmol/L in a man, the lower his lifetime risk of prostate cancer. Further declines or dynamic variations of testosterone were also associated with increased risk of prostate cancer.
Men with a high intra-individual variation in testosterone levels over time had a nearly 5-fold increased risk for prostate cancer compared to men with a low variation. Men with a testosterone drop of 20% or greater from their individual average testosterone level during follow-up had over 8-fold higher risk for prostate cancer than men with a testosterone drop of less than 20% of their average. Men with the largest drop of testosterone in a short time period had a 2.7-fold higher risk of prostate cancer.
It was concluded that unstable testosterone levels, significant drops of testosterone levels, or decline in testosterone levels at a younger age increase the risk of prostate cancer. By collecting data from (semi)annual testosterone measurements for up to 11 years, this study provides insights regarding the role of testosterone in prostate cancer development, and suggest strategies for individualized testosterone therapy and prostate cancer prevention.
This is the first study showing evidence for an association between changes in testosterone levels and prostate cancer development. This knowledge may have substantial clinical impact on prostate cancer prevention and provides a critical message for doctors 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 averaged 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 initiation (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 cancer initiation is a process where normal prostate cells first adjust themselves to progressively declining testosterone 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.
Given the large inter-individual variation in testosterone levels, androgen receptor sensitivity and thresholds, regular 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.5 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.6 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.7 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.7-9 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.10 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.10 Both studies suggest that preventing the age-related testosterone decline with testosterone therapy may be an effective strategy for prostate cancer prevention.2,10