Low Testosterone May Raise Risk of ‘Extreme’ Prostate Cancer Progression

Low testosterone levels may increase the risk of higher-grade progression in prostate cancer patients under active surveillance, a retrospective cohort study suggested.

Among over 900 patients, low testosterone levels (≤300 ng/dL) were associated with a statistically significant increased risk of “extreme” progression to grade group 3 or higher disease (HR 1.61, 95% CI 1.02-2.54, P=0.04), after adjusting for age, prostate-specific antigen (PSA) density, body mass index, and biopsy tumor volume, reported Justin R. Gregg, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

However, there was no statistically significant association between low testosterone levels and moderate progression to grade group 2 disease (HR 1.25, 95% CI 0.93-1.67, P=0.13), they noted in the Journal of Urology.

“Given the increasing reliance on AS [active surveillance], incorporating testosterone levels into prognostic models may improve patient selection and monitoring strategies,” Gregg and team concluded.

Despite the study’s retrospective nature, “it does raise the prospect that a low testosterone level may be associated with an increased risk of future progression,” Gregg told MedPage Today. “It’s not to the point where you would recommend some kind of clinical change — for example, giving testosterone, or automatically checking testosterone levels, in someone who starts on surveillance. But, I think that it does call for the need for further study to really validate this and see if this is a consistent finding.”

In an editorial comment accompanying the study, Jeffrey J. Tosoian, MD, MPH, of Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues noted that the findings “further challenge the historical paradigm, now suggesting that low serum testosterone may in fact increase the risk of meaningful progression during AS.”

“Acknowledging that the decision to pursue testosterone replacement therapy must be based on several considerations, these data propose low serum testosterone as a potentially modifiable risk factor for patients undergoing AS,” they wrote. “With further validation in prospective, appropriately controlled settings, the current findings have potential to both advance our understanding of [prostate cancer] biology and improve clinical outcomes for our patients.”

A ‘Paradoxical Relationship’

Traditionally, the view has been that testosterone “kind of fuels prostate cancer,” Gregg noted — a longstanding belief that goes back to the mid-20th century when Charles Huggins, MD, demonstrated that androgen deprivation therapy (ADT) could shrink prostate tumors. ADT has since become fundamental in treating advanced prostate cancer, as has the use of medical and surgical castration to suppress testosterone and slow disease progression.

However, Gregg and colleagues noted that emerging evidence has suggested a potential “paradoxical relationship” between testosterone levels and localized prostate cancer aggressiveness, in which low serum testosterone may be associated with adverse prostate cancer outcomes.

“Part of the idea that low testosterone may lead to increased risk is the work other groups have done based on the idea of a testosterone saturation hypothesis,” Gregg said.

He and his colleagues explained that this hypothesis suggests prostate cancer may be sensitive to changes in serum testosterone only below certain thresholds, beyond which further changes in testosterone levels may have minimal effects on prostate tumor biology. Accordingly, early-stage prostate cancer behavior may differ at testosterone concentrations below a saturation point.

“So that was the big-picture reason to look at men’s testosterone levels at baseline, and evaluate if they were at increased risk of tumors getting worse over time,” Gregg noted.

The study included 924 men diagnosed with grade group 1 or 2 localized prostate cancer who were enrolled on an active surveillance protocol between February 2005 and September 2024.

Median age was 63 years, mean PSA was 4.7 ng/dL, and 88% had grade group 1 disease at enrollment. Mean baseline testosterone level was 394 ng/dL, and 29.4% had a baseline testosterone level ≤300 ng/dL.

At a median follow-up of 34 months, 23.2% of patients experienced grade group 2 progression, and 9% experienced grade group 3 progression, 37.3% of whom were upgraded to at least grade group 4.

The authors acknowledged the study had limitations — mainly the fact that it was completed in a single cohort of patients during an era in which MRI-based prostate cancer risk stratification was not used, “which may have led to imprecise initial grading.”