Varicocele and Untreated Hypogonadism Synergistically Increase Prostate Cancer Risk via Testosterone Shunt Physiology and can be Ameliorated with Testosterone Therapy

OBJECTIVES: To evaluate whether varicocele modifies the relationship between hypogonadism and incident prostate cancer. Venous shunting of testosterone-enriched blood from the testicle to the dorsal venous complex occurs in ~20% of men and has been linked to prostate cancer progression. Although hypogonadism has been inconsistently linked to prostate cancer risk, the influence of varicocele remains unexplored. MATERIALS AND METHODS: Using the Merative MarketScan database, we identified men >40 years with varicocele and matched them by age and follow-up interval to two cohorts: (1) a general population cohort and (2) men with benign scrotal pathology associated with urological assessment. Time to prostate cancer was assessed using Cox proportional hazards models adjusted for age, obesity, rurality, family history, hypogonadism status, testosterone therapy, and varicocele status. An interaction term between varicocele and hypogonadism was included. RESULTS: Among 149,848 men (75,673 varicocele and 74,175 scrotal pathology controls), varicocele was associated with a higher incidence of prostate cancer (4.4 vs 3.8%, p<0.01) and hypogonadism (13.3 vs 11.2%, p<0.01). In adjusted models, varicocele alone was not associated with prostate cancer risk (HR: 1.04, p=0.18). Untreated hypogonadism was associated with a modestly increased risk of incident prostate cancer (HR: 1.27, p<0.01). Men with both varicocele and untreated hypogonadism experienced the highest hazard of incident prostate cancer (HR: 1.31, p<0.001). CONCLUSION: Varicocele amplifies the risk of prostate cancer associated with untreated hypogonadism. Testosterone therapy and possibly varicocelectomy mitigate this effect, supporting the notion that venous testosterone shunting to the prostate occurs in a subset of men.