Over the past 20 years, we have seen a paradigm shift in our understanding and belief of how testosterone therapy (TTh) affects prostate cancer. While 20 years ago many urologists and clinicians believed that testosterone may increase the risk of prostate cancer recurrence and progression, today we are seeing studies demonstrating the potential preventive and therapeutic effects of TTh against prostate cancer.

Several studies have suggested that TTh may decrease the risk of developing aggressive prostate cancer or developing a biochemical recurrence after radical prostatectomy. A recent study by Ahlering et al evaluated 850 men following robotic assisted laparoscopic prostatectomy.¹ In this study, 152 hypogonadal men with low-risk prostate cancer were started on TTh. Prostate cancer recurred in approximately 7.2% of patients treated with TTh vs 12.6% of the patients who did not receive TTh. Patients on TTh were almost 54% less likely to have a prostate cancer recurrence. In men expected to have a prostate specific antigen (PSA) recurrence, TTh delayed time to recurrence by an average of 1.5 years. Another study by Loeb et al assessed 284 prostate cancer patients and 1,378 case controls who all filled testosterone prescriptions in the National Prostate Cancer Register of Sweden.² They found no association between TTh and overall prostate cancer risk (OR 1.03, 95% CI 0.90–1.17). In fact, patients who received TTh had a lower risk of developing aggressive prostate cancer (OR 0.50, 95% CI 0.37–0.67). The authors concluded that the decreased risk of aggressive prostate cancer with TTh was a novel finding that warrants further investigation.

Some of the most fascinating studies in this field over the past 5 years involve the use of bipolar androgen therapy (BAT) to treat castrate-resistant prostate cancer (CRPC). BAT involves rapid cycling between supraphysiologic serum testosterone levels and near-castrate serum testosterone levels. Patients are generally given 400 mg of intramuscular testosterone every month in addition to anti-androgen therapy. Supraphysiologic testosterone has been shown to promote CRPC cell death. In a study by Schweizer et al, 14 patients with CRPC were given 400 mg of testosterone cypionate every month for 3 months in conjunction with androgen deprivation therapy.³ BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic (5 of 10 evaluable patients) responses. In fact, 10 out of 10 patients demonstrated PSA reduction after receiving androgen ablative therapies after BAT. In a more recent study, Denmeade et al conducted a randomized trial comparing BAT (94) vs enzalutamide (101) in asymptomatic men with castration-resistant metastatic prostate cancer.⁴ The primary end point was clinical or radiographic progression-free survival (PFS). Crossover was permitted upon progression of disease. PFS was 5.7 months for both arms (HR 1.14, 95% CI 0.83–1.55; p=0.42). A 50% decline in PSA was present in 28.2% of BAT patients vs 25.3% of enzalutamide patients. BAT demonstrated similar time to progression and PSA response to enzalutamide following treatment with abiraterone. Finally, patients receiving BAT reported significantly greater improvements in fatigue and sexual function.

Over the past 10 years, there have been very few studies assessing the use of TTh in men on active surveillance (AS). Currently, there are 5 case reports or series and 1 case-controlled study assessing AS and the use of TTh.⁵ In the case-controlled study by Kacker et al, biopsy progression rates were similar for men receiving TTh and for controls.⁶ In addition, biopsy progression in men on AS appeared unaffected by TTh over 3 years. While there are still limited safety and efficacy data on TTh in men on AS, many urologists are still prescribing TTh to these men. A 2016 survey given to urologists found that 63% of the respondents believed that it was safe to give TTh to men on AS.⁷

The 2018 AUA Testosterone Guidelines are still cautious in using TTh in men with a history of prostate cancer.⁸ While the guidelines state that clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer (Strong Recommendation; Grade B), the guidelines go on to state that patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy (Expert Opinion). It is important to recognize that there are currently no large published randomized placebo controlled trials assessing the use of TTh in men with a history of prostate cancer. However, the results of the TRAVERSE Trial, which are expected to be released this year, may offer further insight into the true relationship between TTh and prostate cancer.⁹ This is a 5-year randomized placebo controlled trial of roughly 6,000 hypogonadal men receiving testosterone gel or placebo. While the primary end point is cardiovascular safety, a secondary end point is prostate safety defined as the incidence of adjudicated high-grade prostate cancer.

In conclusion, there is currently no evidence that TTh promotes the initiation of prostate cancer in hypogonadal men. Early data have not demonstrated any increased risk of prostate cancer progression in men on active surveillance, although these data are very limited. Finally, there may be a therapeutic and/or protective role of TTh against prostate cancer.