TRT and Prostate Cancer Risk

Rhoden et al sought to determine whether TRT could precipitate PCa development in men with high-grade prostatic intraepithelial neoplasia (HGPIN) of the prostate. The authors identified 75 hypogonadal men who had prostate biopsies prior to initiating TRT for 12 months. Fifty-five men had negative prostate biopsies (HGPIN-), and 20 had HGPIN identified on biopsy (HGPIN+). There was no statistical difference in PSA values of HGPIN- or HGPIN+ men both before and after one year of TRT.

Six men underwent rebiopsy for a PSA increase of more than 1 ng/ml, and no biopsy identified PCa. One man (HGPIN+) developed an abnormal DRE during the course of the study and a rebiopsy led to a diagnosis of Gleason 7 cancer.10 Given that 15%-25% of men have been found to have prostate cancer within three years of identifying HGPIN on biopsy, the finding of one incidence of PCa in 20 HGPIN+ men over one year suggests TRT does not increase the development of PCa in this subgroup.11

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Coward et al provide additional valuable insight into the role of TRT and PCa risk. Eighty-one hypogonadal men were followed for a mean of 34 months while receiving TRT. Four men (4.9%) were diagnosed with PCa at a mean of 33 months after initiating TRT, an incidence no greater than found in the general population. Notably, PSA did not significantly increase in the 95.1% of men who did not develop PCa, while the PSA did increase in the men diagnosed with PCa. Although a small study, the results strongly suggest not only that TRT does not increase the risk of developing PCa, but also that TRT does not eliminate the utility of PSA values in identifying PCa when it does occur.12

Likewise, Shabsigh et al demonstrated in their meta-analysis of 44 publications that there is no correlation between TRT and increasing PCa risk or increasing the risk of higher Gleason grade disease.13 Marks et al provide some interesting insight to understanding why TRT might not affect PCa risk. In their double-blind, placebo-controlled trial evaluating treatment of hypogonadal men with TRT, they measured both serum and prostate tissue levels of testosterone and dihydrotestosterone (DHT). Despite increases in serum levels of both, there was no increase in intraprostatic testosterone or DHT levels.14

While these studies are reassuring, we cannot draw firm conclusions given the need for additional research in this area. Clearly, the restricted duration of follow-up for the development of PCa after initiating TRT is just one resounding limitation in all studies to date. These studies, however, do serve to underscore the lack of evidence-based medicine physicians face when attempting to appropriately council patients regarding the risks and benefits of TRT. 

Testosterone and Risk of More Aggressive Prostate Cancer

At present, the relationship between testosterone level and risk of PCa is unclear. Some papers suggest that low testosterone levels predict more aggressive disease and poorer prognosis in men with advanced PCa. Hoffman et al demonstrated in 117 PCa patients a trend between low testosterone and more extensive disease. There was a statistically significant increase in Gleason 8 disease among men with low testosterone.15

Interestingly, Chodak et al demonstrated that the higher the serum testosterone prior to treating men with metastatic PCa with a gonadotropin-releasing hormone analogue, the better the survival.16 Massengil et al investigated the relationship of pre-operative testosterone and PCa prognosis through a retrospective analysis of 879 men treated with radical prostatectomy (RP).

They demonstrated that men with pT3-T4 disease had lower pretreatment total testosterone levels than those with organ confined cancer (pT1-T2), but also noted that total testosterone was not a significant predictor of biochemical recurrence.17 Isom-Batz et al retrospectively reviewed the pre-treatment testosterone level of 326 men who underwent RP and did not receive adjuvant therapy. They identified a statistically significant association between lower testosterone levels and higher clinical stage and biopsy grade. This study, too, found no association between testosterone levels and the 41 men in their study who experienced biochemical recurrence.18 Schatzl et al also independently demonstrated a correlation between patients with lower testosterone and the diagnosis of higher Gleason grades in 156 PCa patients.

Interestingly, gonadotropins were also lower in men with low testosterone in this study, suggesting that PCa may suppress the hypothalamic-pituitary-gonadal axis or that this is not a primary leydig cell-related issue.19 These studies underscore the possibility that low pretreatment testosterone may portend a poor prognosis and low testosterone does not appear to be protective against the development of biochemical recurrence.

The pathophysiology explaining these findings remains to be elucidated. Some theorize that PCa cells can inhibit testosterone production, and this hypothesis would suggest that low testosterone levels could play a role as a marker for high grade prostate cancer.15 PSA expression is androgen dependent, and low testosterone may mask an otherwise elevated PSA in the context of PCa; this in turn may cause a delay in diagnosis that would allow the cancer to grow to a more advanced stage. 

Alternatively, perhaps testosterone exerts growth maturation effects on PCa cells and can promote differentiation into a less aggressive cancer, promote senescence, or even stimulate apoptosis. These ideas allow for the possibility that testosterone itself could actually be therapeutic if its administration could attenuate PCa growth. Some researchers have touted 5α-reductase inhibitors (5ARIs), which block the conversion of testosterone to the more potent androgen receptor binder dihydrotestosterone (DHT), for PCa chemoprevention.20,21 Interestingly, 5ARIs, because of their mechanism of action, have been shown to increase the intraprostatic level of testosterone up to 20 times the level found before instituting 5ARI therapy.22,23

Additional research addressing whether it is not only the decrease in DHT, but also the elevation in intraprostatic testosterone, which plays a potential tumor suppressive role is certainly needed. Notably, both PCa cell lines and a PCa mouse model have been shown to exhibit androgen suppression of cell and tumor growth, suggesting a cellular mechanism for growth inhibition that remains to be identified and exploited as a novel PCa treatment method.24,25

Whether testosterone can repress growth of metastatic PCa has already begun to be investigated in nascent clinical studies. In a pioneering Phase 1 clinical trial, Morris et al tested the safety of high-dose exogenous testosterone in 12 men with castration-resistant metastatic PCa. None of the patients in the study had pain flares or grade 3 or 4 toxicity associated with treatment. One man with known epidural disease did develop cord compression without neurologic impairment that was treated with radiation.26 While this study was not designed to ascertain efficacy, the safety profile it demonstrated has opened the door for studies which can examine clinical response. 

Conversely, several published studies suggest that higher serum testosterone level increases PCa risk, correlates with more aggressive PCa, or even has no relationship with PCa risk. Gann et al found, through a prospective case-controlled study nested within the Physicians’ Health Study, an increased risk of PCa in men with higher (albeit within normal range) serum testosterone levels.27

Pierorazio et al found a statistically significant increase in calculated free testosterone and calculated free testosterone index in 26 men aged 65 and older with high-risk PCa when compared with 355 age-matched men without PCa or with low-risk PCa.28 Koo et al identified 120 men with PSA levels above 10 ng/mL who underwent prostate biopsy; 35 men were diagnosed with PCa. This study found no correlation between testosterone level (whether hypogonadal or eugonadal) and PCa risk, PSA elevation, or PCa aggressiveness.29

The sheer variety of conflicting data that often exonerates, sometimes condemns, and occasionally discounts a role for testosterone with regard to PCa risk and growth only serves to clarify the need for more data before a definitive conclusion can be drawn.