Low Testosterone Levels and Grade Group Progression Among Localized Prostate Cancer Patients on Active Surveillance: A Retrospective Cohort Study

Abstract

Background: – Active surveillance (AS) is an increasingly utilized strategy for managing localized prostate cancer, yet reliable biomarkers for predicting disease progression remain limited. Low testosterone has been associated with aggressive prostate cancer features at diagnosis, but its role in grade group progression during AS remains unclear.Objective: – To evaluate the association between baseline serum testosterone levels and grade group progression in men undergoing AS for localized prostate cancer.Methods: – We conducted a retrospective cohort study of 924 men enrolled in an AS program between 2001 and 2024, with a median follow-up of 46.1 months among those who did not progress. Serum testosterone levels were categorized as low if they met a threshold of ≤ 300 ng/dl based on guideline recommendations. Primary outcomes were biopsy progression to grade group 2 (GG2) or “extreme” progression to grade group 3 or higher (GG3) disease. Multivariable Cox proportional hazards models were used to assess associations between testosterone levels and progression, adjusting for age, PSA density and biopsy tumor volume. Potential clinically significant confounding by BMI, smoking status, and ethnicity was also considered.Results: – Among 924 men, the mean age was 63.6 years (SD 8.1), and the mean PSA density was 0.13 ng/mL2 (SD 0.14). The average baseline testosterone was 394 ng/dL (SD 160.4), with 29.4% (n=272) of men having a testosterone level ≤ 300 ng/dL. Low testosterone was associated with a statistically significant increased risk of GG3 progression (HR 1.61, 95% CI 1.03–2.51, p=0.04). Further, evidence suggested that low testosterone was not associated with risk of GG2 progression (HR 1.23, 95% CI 0.93-1.64, P=0.15). Findings were consistent when employing alternative cut-points for testosterone and when considering other potential confounders.Conclusion: – These findings suggest that while low testosterone is not clearly associated with moderate progression (GG2), it may increase the risk of higher-grade “extreme” progression to GG3 or higher. Future studies should focus on prospective validation of our findings to elucidate the biological relationship between androgens and prostate cancer progression.