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AUA 2024: Crossfire: Controversies in Urology: Testosterone Therapy May Be Reasonably Offered to Men on Active Surveillance – Pro/Con
AUA 2024, Testosterone Therapy, prostate cancer, prostate cancer progression, TRAVERSE trial, managing testosterone deficiency in men with prostate cancer under active surveillance.
(UroToday.com) Recent developments in urology have increasingly challenged the once prevalent notion that testosterone therapy exacerbates prostate cancer (PCa) progression. Dr. Abraham Morgentaler, in the latest session of the Crossfire: Controversies in Urology series, highlighted a significant shift over the past three decades, moving from a global reluctance to a cautious acceptance of testosterone therapy, even in the context of prostate cancer management.
Historically, the medical community held a universal belief that elevating testosterone levels could initiate or accelerate prostate cancer. This perspective changed dramatically following numerous studies challenging the link between testosterone therapy and adverse PCa outcomes. For instance, a 2016 survey revealed that 96% of Canadian urologists now believe testosterone therapy is safe post-radical prostatectomy, indicating a paradigm shift from "unthinkable to routine" in testosterone use among patients with a history of PCa1.
Dr. Morgentaler set the stage for the debate by outlining the American Urological Association's (AUA) 2018 guidelines, which cautiously endorse considering testosterone therapy in men post-radical prostatectomy with favorable pathology. However, the guidelines admit limited data on men on active surveillance—a group for whom the therapy's safety and efficacy remain under scrutiny2.
Dr. Larry Lipshultz argued in favor of testosterone therapy for men on active surveillance, citing studies by Morgentaler et al. (2011), which found no PCa progression in testosterone-deficient men treated with testosterone replacement therapy3. Furthermore, he highlighted the "Saturation Model," suggesting that prostate cells do not respond to testosterone levels above certain thresholds, which theoretically mitigates the risk of stimulating PCa growth4.
Figure 1. Saturation and maximal binding of androgen to androgen receptors occurs at low testosterone level (approximately 250 ng/dl).
Figure 2. Review of clinical studies evaluating testosterone use in men on active surveillance compiled and presented by Dr. Larry Lipshultz.
Supporting Dr. Lipshultz's view, Dr. Mike Hsieh pointed to the natural history of active surveillance, where the progression rate aligns with those observed in treated individuals. He referenced the Kaplan-Marans population-based study, which indicated that men on testosterone therapy were more likely to remain on active surveillance with no significant difference in overall mortality rates5.
Figure 3. Kaplan-Marans et al. reported no significant difference in overall mortality between men on active surveillance receiving testosterone therapy compared to placebo.
Conversely, Dr. Thomas Masterson provided a critical view of the Saturation Model and the evidence supporting testosterone therapy in this context, explaining that experiments were performed in animal models (mostly rats) of benign prostate tissue, rather than a prostate cancer model4. He pointed out methodological concerns in key studies, such as the TRAVERSE trial, which excluded men with a history of PCa or elevated PSA levels, thus not directly addressing the safety of testosterone therapy in men on active surveillance for PCa6.
Figure 4. TRAVERSE trial reported no difference in risk of high-grade PCa or any PCa between men in the testosterone group compared to placebo.
Dr. Helen Bernie further criticized the literature for its limitations, including small sample sizes and selection biases. She emphasized the need for comprehensive patient information regarding the inconclusive benefits of testosterone therapy on cognitive function, diabetes, energy, and fatigue, as per AUA guidelines. Meanwhile, she encouraged urologists foster open discussions with their patients about available evidence and alternative management strategies like lifestyle modifications.
The debate encapsulated a spectrum of perspectives reflecting the complexities involved in managing testosterone deficiency in men with PCa under active surveillance. While proponents underscored potential quality-of-life improvements, opponents urged caution, advocating for more robust data to ensure patient safety.
