Men with sneaky testosterone physiology have worse prostate cancer outcomes, study finds

First-of-its-kind study on 266 men found 20% have higher levels of the hormone in the vessels surrounding the prostate.

Drawing blood from the arms of prostate cancer patients to assess for testosterone is not generally useful for determining risk of outcomes after radical prostatectomy and might underreport levels of testosterone surrounding the prostate, according to a study by Nima Sharifi, M.D., scientific director of the Desai Sethi Urology Institute and a researcher at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.

Findings from the newly published study in The Journal of Clinical Investigation suggest a large proportion of men have testosterone concentrations that are much higher in and around the prostate than traditional blood draws suggest. And this elevated exposure near the prostate increases the risk of poor outcomes after surgical removal of the prostate gland.

“I describe this as ‘sneaky testosterone.’ It’s sneaky because we don’t see it — we don’t appreciate it — just by looking at general blood,” said Dr. Sharifi, who conducted much of this research while at Cleveland Clinic, before joining Desai Sethi Urology Institute earlier this year.

The general assumption today is that clinicians can assess the prostate’s testosterone exposure by measuring the level with blood drawn from the arm. High testosterone levels could have implications on prostate cancer development and progression.

Significant differences in testosterone concentration

In this first-of-its-kind study, Miller School and Cleveland Clinic researchers assessed 266 men with prostate cancer undergoing radical prostatectomies between 2014 and 2021. They studied not only general blood and prostate tissue specimens but also vessels surrounding the prostate.

Dr. Sharifi and colleagues found that 20% of the men had testosterone concentrations in vessels around the prostate that were twice as high as in the blood from their arms, with 5% of the men having 10 times the concentration in vessels surrounding the prostate.

This suggests that some men have a short circuit going from gonadal circulation to the prostate. Most importantly, men who had this sneaky testosterone physiology had worse long-term outcomes after they had surgery for prostate cancer.”

Dr. Nima Sharifi, M.D., scientific director of the Desai Sethi Urology Institute and researcher at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine

Associations with varioceles

There are other potential implications of the research, including in the area of infertility, he said.

“This sneaky testosterone physiology is probably common to varicoceles, a condition where the forward flow of the blood from the testes is impeded and this effectively creates back flow. Varicoceles is known to be associated with infertility,” Dr. Sharifi said. “Our study tells us that there may be other associations of varicoceles, potentially directly linking varicoceles to an aggressive form of prostate cancer.”

The identification of men with sneaky testosterone physiology adds new information to consider in the prognoses of men with prostate cancer and has broad implications for assessing risk in other diseases of the prostate, according to study author Eric A. Klein, M.D., emeritus chair of Cleveland Clinic’s Glickman Urological and Kidney Institute.

“For years, testosterone, T, and its derivative, dihydrotestosterone, DHT, have been known to affect prostate development and drive prostate cancer. However, peripheral blood T levels don’t correlate with prostate cancer risk or severity,” Dr. Klein said. “This study suggests this might be because some men have veins that directly link the prostate to the testes, enabling higher T and DHT levels in the prostate, potentially leading to aggressive tumors. These venous shunts bypass peripheral circulation, meaning arm vein blood samples do not reflect T and DHT exposure to the prostate.

This and future studies could lead to alternative treatment strategies for urological diseases that are impacted by sneaky testosterone physiology.”

Mohammad Alyamani, Ph.D., research assistant professor at the Miller School, first author on the study

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