Testosterone Replacement Therapy (TRT) restores testosterone levels in men diagnosed with hypogonadism, a condition characterized by abnormally low production of the male sex hormone. Prostate cancer (PCa) is the second most common cancer in men globally, and its cells are known to be sensitive to male hormones. The question of whether supplementing testosterone can cause men to develop prostate cancer has been a persistent medical concern. This historical worry has influenced the practice of prescribing TRT, despite a modern understanding that largely refutes the initial hypothesis.
The Historical Hypothesis of Testosterone and Prostate Cancer Growth
The initial association between testosterone and prostate cancer was established by the groundbreaking work of Charles Huggins in the 1940s. His research showed that manipulating androgen levels had a dramatic effect on advanced prostate tumors in men. Huggins observed that removing the source of testosterone, through surgical castration or by administering the female hormone estrogen, caused metastatic prostate tumors to shrink or regress.
The inverse was also observed: administering high doses of testosterone to men with advanced disease caused rapid tumor growth. This led to the widely accepted concept that testosterone acted like “food for a hungry tumor”. This foundational work established the medical dogma that increasing testosterone levels in any man was inherently risky and could promote the initiation or growth of prostate cancer.
Modern Evidence on TRT and New Cancer Risk
Current scientific evidence does not support the long-standing fear that Testosterone Replacement Therapy causes new prostate cancer in men without pre-existing disease. Multiple large-scale studies and meta-analyses have investigated this link, finding no statistical increase in the incidence of new prostate cancer in men receiving TRT compared to those receiving a placebo or no treatment. This shift in understanding is explained by a concept called the “saturation model”.
The saturation model suggests that the androgen receptors within prostate cells become saturated at relatively low testosterone concentrations. Studies suggest this saturation point is reached at serum testosterone levels around 240 nanograms per deciliter (ng/dL) in human prostate tissue. Once the receptors are saturated, increasing the serum testosterone level further, as occurs with standard TRT, does not lead to a greater stimulation of prostate cell growth.
This explains why lowering testosterone to near-castrate levels causes tumor regression, but raising testosterone from low to normal levels does not appear to initiate new cancer. The risk is now understood to be primarily related to the potential for TRT to accelerate the growth of an already existing, undiagnosed cancer.
Screening Protocols for Men Receiving TRT
Because TRT may accelerate the growth of an undiagnosed cancer, rigorous screening protocols are necessary before and during treatment to ensure safety. Before starting TRT, men over 40 must undergo a baseline Prostate-Specific Antigen (PSA) blood test and a Digital Rectal Examination (DRE). The PSA test measures a protein produced by the prostate gland, and a high or rapidly rising level can suggest the presence of cancer.
Monitoring continues after therapy begins, with the first follow-up PSA and DRE typically scheduled between three and twelve months after the start of TRT. Thereafter, if the PSA levels are stable, men generally follow the same screening schedule recommended for the general population. However, providers must be vigilant for any concerning changes, such as a confirmed PSA level above 4.0 ng/mL or a rapid PSA increase of more than 1.4 ng/mL within the first year of treatment, which requires urological consultation.
Treatment Considerations for Prostate Cancer Survivors
The use of TRT in men who have already been treated for prostate cancer is a distinct and complex scenario. For survivors, the primary concern is the risk of cancer recurrence, marked by a rising PSA level. Historically, a prior diagnosis of prostate cancer was considered an absolute contraindication for TRT.
This perspective is now evolving, and TRT may be cautiously offered to a select group of survivors who have severe symptoms of low testosterone and are considered disease-free. These men generally have a history of localized, low-risk disease that was successfully treated with surgery or radiation, and they must have a long disease-free interval. The decision is highly individualized and involves a careful discussion between the patient and their urologist or oncologist.
When TRT is initiated in this high-risk population, monitoring is meticulous, with a recommended goal of keeping total testosterone in the middle range, approximately 450 to 700 ng/dL. PSA levels are checked more frequently, sometimes as often as every six weeks initially, before transitioning to a longer-term schedule. While data remains limited, studies in survivors have not shown an increased rate of cancer recurrence or progression when carefully managed.