Ask the Experts – Thomas Ahlering

Question 1. What was the underlying rationale for conducting your study?

Answer
In 1962, the Nobel Prize in medicine was awarded to Charles B. Huggins and Clarence V. Hodges for their discovery that castration (i.e., low testosterone levels) was an effective method of treatment for advanced PCa. This finding led to the (false) idea that high testosterone may lead to disease progression. In this regard, in the late 1990s to 2000s, multiple sources began to demonstrate that men on long-term anti-testosterone treatments were at increased risk of metabolic/cardiovascular complications, and low testosterone may inhibit recovery of patient’s sexual function following successful cancer treatment with radiation or surgery. With knowledge of these findings, in 2009, we initiated TRT to improve sexual function recovery in hypogonadal men after radical prostatectomy.

Question 2.  Were you surprised by the main finding of a lower recurrence rate among TRT users?

Answer
Absolutely—this was not what we set out to prove. Of concern in our investigation was testosterone therapy-related recurrence. To our surprise, during our investigation of the safety of TRT, we found therapy not only did not increase the risk of recurrence, but that TRT resulted in a significant reduction of recurrence. Although these findings are initially counterintuitive, they are indeed logically supported, and with recent findings. In general, PCa is well known for its sensitivity to obesity, diabetes, and metabolic syndrome, an effect also documented for men following radical prostatectomy. Following this logic, TRT should not only improve the metabolic status of men with low testosterone and its associated morbidity, but it should also benefit long-term prognosis in PCa patients. What started as a safety analysis to show non-inferiority of outcome ended up showing a significant benefit in patients with testosterone replacement. Another interesting and new finding of our study is that in men destined to recur, time to recurrence appears to be significantly delayed by 1.5 years in the TRT group. If time to recurrence was equal between those who recurred in both groups, one could assume that TRT had no effect on the recurrence cells. However, the 18-month delay further supports a protective testosterone effect even in those destined to recur.

Question 3. How might TRT protect against prostate cancer recurrence?

Answer
Previous data strongly suggest a metabolic component to prostate cancer – morbidity such as diabetes mellitus, cardiovascular disease, etc. exacerbates PCa via higher BMI, metabolic syndrome, and attendance hypogonadism. Therefore, treating hypogonadal men with testosterone replacement therapy should correct for these issues (or, more so, further benefit health status) in these men.

Question 4. In your view, is the cumulative evidence to date, including your study, sufficient to allay concerns about prescribing TRT to hypogonadal men with a history of low-risk PCa?

Answer
Our findings are congruent with current literature. We and others have illustrated the persisting relationship of low testosterone levels on increasing cancer aggressiveness. First, a study by Pastuszak et al in 2013 suggested safety of TRT in PCa patients in a retrospective cohort of 103 hypogonadal and 50 eugonadal patients.¹ Neither group had a PSA increase at a rate suggestive of BCR. Even further, in 2017, Loeb and colleagues showed, in 38,570 patients, a decrease in high-risk PCa among patients receiving TRT compared with those who did not.² However, given the controversy surrounding TRT in patients with a history of PCa, we stress both the importance of indication (ie, symptoms suggestive of hypogonadism) and strict follow-up.

Question 5. Do you ever prescribe TRT in this setting?

Answer
Yes. We prescribe TRT to patients with normal preoperative sexual function, whose symptoms of hypogonadism appear to be inhibiting recovery of erectile function. Of note, patients had to be symptomatic, have low-risk status, and undetectable PSAs.

Question 6. What should be the next research step?

Answer
The present study demonstrates TRT post-radical prostatectomy significantly reduced BCR and in men destined to recur delayed time-to BCR. These results suggest the need for a multi-center randomized control trial.