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Approximately 1 in 8 men will be diagnosed with prostate cancer in their lifetime, making prostate cancer the most common cancer among U.S. men. There is an old adage that more men die with prostate cancer than because of it. There is some truth to this, and thankfully prostate cancer is often not fatal. However prostate cancer is the second-leading cause of cancer death in men (behind lung cancer), demonstrating that prostate cancer is often more dangerous than we realize.
The average age of diagnosis of prostate cancer is approximate 67 years old, and 95% of cases of prostate cancer occur in men 55 years and older. Because prostate cancer is primarily a disease of older men, the coexistence of testosterone deficiency and prostate cancer is very common. It is certainly common in my practice.
When I went to medical school it was taught that testosterone therapy was never recommended for men with a diagnosis of prostate cancer because the testosterone would potentially “throw fuel on the fire” of the cancer. This belief was longstanding, and in medicine (as in all of life) dogma does not quickly disappear.
Over the past several years, while completing hormone optimization training through various medical organizations, I repeatedly heard that “testosterone does not cause prostate cancer.” I wanted to trust this guidance, but “unlearning” a belief taught in medical school and held for years was not easy. Before changing my view, I needed to examine the medical literature and reach my own conclusions. What follows is a summary of what I found.
Competing Hypotheses
For many decades, clinicians believed that higher testosterone levels increased the risk of developing prostate cancer and accelerated the growth of existing disease, a concept known as the androgen hypothesis. This caution toward testosterone replacement therapy (TRT) in men with prostate cancer stemmed largely from a 1941 research paper which reported on the clinical cases of three men. The paper reported that surgical castration (and subsequent decline in testosterone levels to essentially zero) led to regression of their prostate cancer, and furthermore the prostate cancer worsened when the men were given TRT. That early work shaped clinical dogma for generations and led to broad avoidance of TRT in any man with current or prior prostate cancer.
Over the last 20 years, however, the relationship between testosterone and prostate cancer has undergone serious re-evaluation, resulting in a major paradigm shift. For many researchers and clinicians, the androgen hypothesis has been replaced by the androgen saturation model. Proposed by Dr. Abraham Morgentaler, this model challenges the traditional assumption of a linear relationship between androgens and tumor growth. It suggests that prostate tissue is highly sensitive to changes in testosterone only at near-castrate levels (i.e. extremely low), but that androgen receptors become saturated at roughly 120–250 ng/dL. Beyond this point, further increases in testosterone level exert negligible effect on prostate cancer. This framework provides a biologically coherent explanation for the observations that 1) androgen deprivation therapy (aka chemical castration) is a legitimate treatment option for advanced prostate cancer, and 2) physiological, and even mildly supraphysiological, testosterone levels do not appear to increase prostate cancer risk.
The Relationship Between Testosterone Levels and Risk of Prostate Cancer
A substantial body of clinical research supports the androgen saturation model. Numerous population-based longitudinal studies have shown no relationship between serum testosterone (or other androgens) and prostate cancer risk (Morgentaler). A pooled analysis of 18 such studies, including 3,886 men with prostate cancer and 6,438 age-matched controls, found no association between prostate cancer risk and serum concentrations of testosterone or related hormones (Roddam et al.). Another study of 3,255 men in the placebo arm of the REDUCE trial, all of whom underwent scheduled biopsies at 2 and 4 years, similarly found no link between baseline testosterone or dihydrotestosterone (DHT) and prostate cancer risk (Muller et al.).
Several studies have even reported an inverse relationship, i.e. that lower testosterone levels are associated with higher-grade disease and more advanced stage at presentation. At a minimum, the above studies demonstrate that prostate cancer risk is not positively associated with testosterone concentrations.
The Relationship Between Testosterone Therapy and Prostate Cancer
For men without a history of prostate cancer who receive TRT, the literature is consistently reassuring. Although no controlled trials of sufficient duration exist to definitively answer the question, the available evidence strongly suggests no increase in prostate cancer risk. Large uncontrolled trials and smaller placebo-controlled studies repeatedly show no elevation in prostate cancer incidence among men receiving TRT. Most notably, the TRAVERSE trial, published in 2023 and representing the largest randomized, controlled testosterone trial ever conducted, found no increase in prostate cancer incidence in men treated with TRT compared to placebo. The TRAVERSE study was designed to test whether TRT increased the risk of cardiovascular disease (it did not), but prostate cancer occurrence was an important secondary outcome that was studied.
In men with a history of prostate cancer, several small observational studies have been published that report on the effects of TRT on prostate cancer recurrence. These studies, reviewed in detail in the references below, are broadly encouraging. Two are worth discussing in more detail.
A 2020 retrospective study by Ahlering examined recurrence rates in men who underwent robot-assisted radical prostatectomy (RARP). The study compared 152 men placed on postoperative TRT with 419 matched controls. After adjusting for Gleason grade, pathological stage, and other variables, the TRT group was 54% less likely to experience recurrence (hazard ratio 0.54, 95% CI 0.292–0.997) over an average follow-up of 3.4 years. Among the men who did have recurrence in their prostate cancer, TRT delayed the recurrence by approximately 1.5 years.
A second study, published in abstract form in 2019, reported outcomes from Memorial Sloan Kettering Cancer Center in high-risk prostate cancer patients receiving TRT. These men had adverse pathological features such as positive margins, lymph node involvement, seminal vesicle invasion, or Gleason ≥8. Biochemical recurrence occurred in 46% of men with low testosterone who received TRT, compared with 75% of men with low testosterone who did not receive TRT (p = 0.001).
While these studies focus on prostate cancer recurrence as the primary outcome of interest, it is important to remember that testosterone influences many outcomes beyond prostate cancer. Clinical research consistently shows that TRT in hypogonadal men improves energy, quality of life, body composition (increased muscle mass and reduced visceral fat), bone density, metabolic health, libido, and sexual function, among other benefits.
Conclusion
Unfortunately, well-designed prospective controlled trials evaluating TRT specifically in men with existing prostate cancer are still lacking. Much remains to be learned. However, the available short- and medium-term observational evidence is reassuring that TRT does not increase risk of disease progression or recurrence. As a result, TRT is increasing being offered in academic and community settings to carefully selected hypogonadal men with treated prostate cancer, a trend that I believe is clearly supported by the medical literature.
References
Lincoff AM. Cardiovascular Safety of Testosterone-Replacement Therapy. NEJM 2023
