Low Testosterone May Signal Higher Risk of Prostate Cancer Progression in Active Surveillance Patients

For men diagnosed with low-risk prostate cancer, active surveillance has become an increasingly popular management approach. But one lingering challenge for health care providers is identifying which patients are most likely to see their cancer advance.

Data from a retrospective study published in the Journal of Urology suggest that serum testosterone levels at enrollment may offer meaningful insights. Specifically, low testosterone levels may increase the risk of higher-grade progression in prostate cancer, challenging existing views focused on the impact of high testosterone.¹

“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,” Justin R. Gregg, MD, of The University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. “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.”²

Notable Differences Between Low and High Testosterone Levels

Researchers analyzed data from 924 men enrolled in an active surveillance program between 2001 and 2024. The participants had a mean age of 63.6 years and were followed for a median of 46.1 months if they did not experience disease progression. At baseline, the average testosterone level was 394 ng/dL, and 29.4% (n = 272) of patients had low testosterone, defined as 300 ng/dL or below, in line with standard clinical guidelines.¹

The study’s primary aim was to determine whether low baseline testosterone was associated with progression to a higher cancer grade during surveillance. Researchers tracked 2 key outcomes: advancement to grade group 2 (GG2), representing moderate progression, and advancement to grade group 3 or higher (GG3+), classified as “extreme” progression.¹

The findings revealed a clear distinction between these 2 thresholds. Regarding moderate progression to GG2, low testosterone was not significantly associated with increased risk. However, men with low testosterone faced a 61% greater risk of advancing to GG3+ disease than those with normal testosterone levels, a finding that reached statistical significance with an HR of 1.61 (95% CI, 1.03-2.51; P = .04).¹

These associations held up after accounting for key confounding variables, including age, prostate-specific antigen density, and biopsy tumor volume. The research team also examined the potential influence of body mass index, smoking status, and ethnicity, and tested the findings using alternative testosterone cut-off values, all of which produced consistent results.¹

Questions Remain

The biological reasoning behind this link is not entirely understood, but it may relate to the complex interplay between androgens and prostate cancer biology. Testosterone, often thought to drive prostate cancer growth, paradoxically appears here to be associated with protection against higher-grade disease advancement in the surveillance setting.¹

If validated in results from prospective studies, low testosterone could serve as an accessible and inexpensive biomarker to help stratify risk among active surveillance patients, potentially guiding decisions about monitoring frequency or timing of intervention. Pharmacists managing men with borderline testosterone levels who are on active surveillance may want to factor this into their overall risk assessment.¹

The study authors acknowledge the retrospective design as a limitation and emphasize the need for prospective studies to confirm these findings and clarify the underlying mechanisms. Still, the results add to a growing body of evidence suggesting that hormonal status at the time of diagnosis may carry prognostic weight for determining long-term disease trajectory.¹

REFERENCES

1. Lawen T, Garcia RS, Smith MT, et al. Low testosterone levels and grade group progression among localized prostate cancer patients on active surveillance: a retrospective cohort study. J Urol. Published online February 24, 2026. doi:10.1097/JU.0000000000004986

2. Bassett M. Low testosterone may raise risk of ‘extreme‘ prostate cancer progression. MedPage Today. March 13, 2026. Accessed March 23, 2026. https://www.medpagetoday.com/hematologyoncology/prostatecancer/120302