Endogenous and exogenous testosterone and prostate cancer: decreased-, increased- or null-risk?

For more than 70 years, the contention that high levels of testosterone or that the use of testosterone therapy (TTh) increases the development and progression of prostate cancer (PCa) has been widely accepted and practiced. Yet, the increasing and emerging evidence on testosterone research seems to challenge that contention. To review literature on the associations of endogenous and exogenous testosterone with decreased-, increased-, or null-risk of PCa, and to further evaluate only those studies that reported magnitude of associations from multivariable modeling as it minimizes confounding effects. We conducted a literature search to identify studies that investigated the association of endogenous total testosterone [continuous (per 1 unit increment and 5 nmol/L increment) and categorical (high vs. low)] and use of TTh with PCa events [1990–2016]. Emphasis was given to studies/analyses that reported magnitude of associations [odds ratio (OR), relative risk (RR) and hazard ratios (HRs)] from multivariable analyses to determine risk of PCa and their statistical significance. Most identified studies/analyses included observational and randomized placebo-controlled trials. This review was organized in three parts: (I) association of endogenous total testosterone (per 1 unit increment and 5 nmol/L increment) with PCa; (II) relationship of endogenous total testosterone (categorical high vs. low) with PCa; and (III) association of use of TTh with PCa in meta-analyses of randomized placebo-controlled trials. The first part included 31 observational studies [20 prospective (per 5 nmol/L increment) and 11 prospective and retrospective cohort studies (per 1 unit increment)]. None of the 20 prospective studies found a significant association between total testosterone (5 nmol/L increment) and increased- or decreased-risk of PCa. Two out of the 11 studies/analyses showed a significant decreased-risk of PCa for total testosterone per 1 unit increment, but also two other studies showed a significant increased-risk of PCa. Remaining studies reported null-risks values. Second part: eight of out of 25 studies reported an increased-risk of PCa for men with high levels of testosterone compared to low, but only four were statistically significant. However, 17 studies showed a decreased-risk of PCa after comparing high vs. low levels of testosterone, but 11 studies/analyses were statistically significant. Third part: two meta-analyses of randomized placebo-controlled trials (n=8 and n=11, each) that investigated use of TTh with PCa reported not significant decreased-risks of PCa. The contention that high levels of testosterone or that the use of TTh increases the risk of PCa doesn’t seem to be supported from the literature. Yet, we still need a study with the adequate power, follow-up data, epidemiological, pathological and clinical data that can support the safety and beneficial effects of high levels of endogenous testosterone or use of TTh in the natural history of PCa and in men’s health.