The 80-Year-Old Fear About Testosterone and Prostate Cancer May Finally Be Overblown

Decades of concern about testosterone replacement therapy (TRT) triggering prostate cancer may not be justified by modern evidence. A comprehensive review of recent studies found no causal link between testosterone supplementation and prostate cancer development, even in men at high risk or with a history of the disease. This challenges a belief rooted in a single-patient case from 1941 that has shaped medical practice for over 80 years.

Where Did the Prostate Cancer Worry Come From?

The concern traces back to 1941 when researchers Huggins and Hodges demonstrated that lowering testosterone to castrate levels caused prostate cancer to shrink. They also reported that giving testosterone to one patient stimulated cancer growth. That single case became the foundation for decades of caution about testosterone therapy. However, modern researchers have questioned whether that one-patient finding actually holds up under scrutiny.

The fear made intuitive sense: if low testosterone could slow cancer, then high testosterone might accelerate it. But biology doesn't always work that way. Recent studies suggest the relationship between testosterone and prostate tissue is far more nuanced than doctors once believed.

What Do Recent Studies Actually Show About Testosterone and Prostate Cancer Risk?

A systematic review examining the relationship between testosterone replacement and prostate cancer identified 11 randomized controlled trials and 29 additional studies of men without prostate cancer history, plus four studies of men with a prior prostate cancer diagnosis. The key finding: none of these studies demonstrated an increased risk of prostate cancer diagnosis or higher-grade cancer in men who developed the disease.

Several specific studies provide reassuring data. In one trial, 43 healthy men received either 600 milligrams of testosterone enanthate or placebo for 10 weeks. Despite testosterone levels exceeding 2,500 nanograms per deciliter (ng/dL)—far above normal—neither prostate-specific antigen (PSA, a marker for prostate health) nor prostate volume increased significantly. Another study of 31 men receiving 100 to 500 milligrams of testosterone weekly showed the same pattern: testosterone levels rose substantially, but PSA and prostate volume remained stable.

Why Doesn't Extra Testosterone Affect the Prostate the Way Doctors Expected?

The answer lies in what researchers call the "prostate saturation theory." Think of testosterone receptors in the prostate like parking spaces. When testosterone levels are low, many spaces sit empty and the prostate doesn't function optimally. Once those receptors fill up—which happens at relatively low physiologic testosterone levels—adding more testosterone doesn't matter. The spaces are already full.

This theory gained support from a study of 451 hypogonadal men (those with abnormally low testosterone). Researchers divided them into two groups based on pretreatment testosterone levels: those below 250 ng/dL and those above 250 ng/dL. Only the men starting below 250 ng/dL showed a correlation between testosterone levels and PSA after 12 months of replacement therapy. The group that started above 250 ng/dL showed no such relationship, suggesting their prostate receptors were already saturated.

Is Testosterone Therapy Safe for Men Who Already Had Prostate Cancer?

This is the most controversial use of testosterone replacement, yet emerging evidence suggests it may be safer than previously thought. Studies have examined men across different prostate cancer treatment scenarios:

• After Radiation Therapy: One study followed 31 men who received testosterone replacement after prostate brachytherapy (internal radiation). The median time between cancer treatment and starting testosterone was 2 years, with follow-up ranging from 1.5 to 9 years. None of the men stopped testosterone due to cancer recurrence, and none showed cancer progression.
• After External Beam Radiation: A case series of five patients treated with testosterone after external beam radiation therapy showed that PSA levels transiently rose in one patient but never exceeded 1.5 ng/mL, a threshold that would suggest cancer recurrence.
• After Surgical Removal: Limited retrospective data exists for men who underwent radical prostatectomy (surgical removal of the prostate). In one study, 10 hypogonadal men who had prostate removal surgery showed no PSA recurrence after 19 months on testosterone replacement, along with statistically significant improvements in testosterone levels and hypogonadal symptoms.

A more recent analysis of 13 hypogonadal men who underwent either external beam radiation or brachytherapy and subsequently started testosterone replacement showed that serum testosterone increased to statistically significant levels without a significant increase in PSA or prostate cancer recurrence.

What About Men at High Risk for Prostate Cancer?

Men with high-grade PIN (prostatic intraepithelial neoplasia) on biopsy face roughly a 20% chance of finding prostate cancer on a subsequent biopsy, making them a higher-risk group. One review examined 75 patients treated with testosterone replacement, including 20 who had PIN before starting therapy. After 12 months of treatment, there was no significant change in PSA in either group. Only one of the 20 men with pretreatment PIN developed prostate cancer, which was detected during a biopsy for an abnormal digital rectal exam—not because of testosterone therapy. The authors concluded that men with PIN do not face increased cancer risk from testosterone replacement compared to men without PIN.

The shift in thinking reflects a broader recognition that the 1941 finding, while influential, was based on a single patient and may not apply to modern testosterone replacement practices. As research continues, the paradigm around testosterone therapy and prostate cancer appears to be changing, offering hope to men with hypogonadism who also have prostate cancer concerns.