Current evidence does not support the long-held fear that testosterone replacement therapy causes cancer. The worry centered almost entirely on prostate cancer, but the largest randomized trial to date found no significant difference in prostate cancer rates between men receiving TRT and those on placebo. The reality, though, is more textured than a simple all-clear. TRT raises PSA levels, which can trigger biopsies and uncover cancers that might never have been found otherwise, and the data on cancers outside the prostate is thinner and occasionally surprising.
Why Prostate Cancer Dominated the Conversation
The fear linking testosterone to prostate cancer traces back to a Nobel Prize-winning observation in the 1940s: castrating men with advanced prostate cancer caused their tumors to shrink. That finding cemented the idea that testosterone fuels prostate cancer growth, and for decades clinicians assumed that adding testosterone to a man’s system would accelerate any lurking malignancy. A history of prostate cancer became an absolute contraindication for TRT, a position many guidelines held well into the 2000s.
The problem with that logic is that it extrapolated from men with almost zero testosterone to men with normal or near-normal levels. The “saturation model,” described in detail by Abraham Morgentaler, proposes that prostate tissue is exquisitely sensitive to testosterone only at very low concentrations. Once androgen receptors in the prostate are saturated, which happens at relatively modest testosterone levels, additional hormone has little effect on growth. This explains why castrated men with metastatic disease see rapid tumor progression when testosterone is reintroduced, while men with intact hormone levels do not see the same response when their testosterone rises further.1PubMed. Testosterone therapy in men with prostate cancer: scientific and ethical considerations The saturation concept also fits the epidemiological observation that natural testosterone levels in the general population do not correlate with prostate cancer risk.2PubMed. Androgen regulation of prostate cancer: where are we now?
What the Largest Clinical Trials Found
The TRAVERSE trial, published in 2023, was the first large randomized, placebo-controlled trial designed with cardiovascular safety as its primary endpoint but also formally evaluated prostate outcomes. Its prostate substudy tracked over 5,000 men with low testosterone for a median follow-up exceeding three years. High-grade prostate cancer occurred in five men receiving TRT and three on placebo, a difference that was not statistically significant. Rates of any prostate cancer, acute urinary retention, and prostate surgery were also similar between the two groups.3JAMA Network Open. Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial Serum PSA did rise more in the testosterone group during the first year, but the rate of PSA change after that initial bump was no different from placebo.4The Journal of Clinical Endocrinology & Metabolism. Prostate Risk and Monitoring During Testosterone Replacement Therapy
A large cohort study from Sweden, following men with late-onset hypogonadism over roughly 58,000 person-years, came to a similar conclusion. TRT use was not associated with an increased risk of prostate cancer, with a hazard ratio of 0.97. That number held up across multiple sensitivity analyses and propensity-score matching, which helps control for the fact that men who receive TRT may differ from those who don’t in ways that affect cancer risk.5PubMed. Testosterone Replacement Therapy and the Risk of Prostate Cancer in Men With Late-Onset Hypogonadism
A systematic review and meta-analysis pooling 22 randomized trials found that no route of TRT administration (injection, transdermal, or oral) was associated with a statistically significant increase in prostate cancer, prostate biopsy, or prostate nodule detection. Some individual odds ratios were above 1.0 for certain routes, but none approached significance.6Prostate Cancer and Prostatic Diseases. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis
TRT After a Prostate Cancer Diagnosis
Perhaps the most provocative shift in thinking involves men who have already been treated for prostate cancer. For decades, these men were told testosterone was off limits permanently. Recent data challenges that blanket prohibition. A large retrospective study comparing testosterone users to non-users after radical prostatectomy or radiation found no differences in biochemical recurrence, prostate cancer-specific mortality, or overall mortality.7PubMed Central. Testosterone Therapy Does Not Increase the Risks of Prostate Cancer Recurrence or Death After Definitive Treatment for Localized Disease
One study went further, reporting that men on TRT after radical prostatectomy were actually about half as likely to experience biochemical recurrence compared to a matched control group. Among men who did recur, TRT delayed the time to recurrence by an average of a year and a half.8PubMed. Testosterone replacement therapy reduces biochemical recurrence after radical prostatectomy That finding sounds counterintuitive, but it aligns with the saturation model: if the cancer is localized and the receptors are already saturated at normal testosterone levels, restoring a hypogonadal man’s testosterone to the normal range should not provide additional growth stimulus to any remaining prostate tissue.
A scoping review of 12 studies examining TRT after definitive prostate cancer treatment reached a consistent verdict. Biochemical recurrence rates in TRT groups were consistently low, often lower than in control groups. PSA changes remained within expected post-treatment ranges, and no study found a statistically significant increase in cancer risk from TRT.9International Journal of Impotence Research. Testosterone replacement therapy following definitive treatment for prostate cancer: a scoping review of safety and efficacy
Men on Active Surveillance
Active surveillance is the strategy of monitoring low-risk prostate cancer closely rather than treating it immediately. Giving testosterone to these men might sound reckless, but two recent studies suggest it does not accelerate disease progression. In one matched cohort study, conversion to active treatment occurred at similar rates in men receiving TRT and those who were not (about one in four over nearly six years of follow-up), with no meaningful difference in treatment-free survival.10PubMed. Does testosterone replacement therapy increase the risk of conversion to treatment in patients with prostate cancer on active surveillance? A larger multicenter analysis confirmed this, reporting a hazard ratio of 0.99 for disease progression in men receiving testosterone therapy, which is as close to “no effect” as a study can find.11PubMed. Testosterone Therapy in Men on Active Surveillance for Prostate Cancer Is Not Associated With Increased Risk of Disease Progression
These studies are still relatively small, and most urologists would want a thorough conversation with any active-surveillance patient considering TRT. But the data so far does not suggest the feared acceleration of disease.
The PSA Detection Trap
If TRT does not cause prostate cancer, it does something that muddies the picture: it raises PSA levels, especially in the first year. In the Testosterone Trials (TTrials), an older-men trial embedded within the broader testosterone research program, men on testosterone were more likely to trigger PSA thresholds that required urological referral. Of those referred, some underwent biopsies, and a few cancers were found.12The Journal of Clinical Endocrinology & Metabolism. Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial
This creates what researchers call detection bias. Men on TRT are monitored more closely than the general population. Their PSA is checked regularly. When PSA rises, they get biopsied. When they get biopsied, low-grade cancers that might have been clinically insignificant are sometimes discovered. A meta-analysis of randomized testosterone trials confirmed that men randomly assigned to testosterone had more prostate biopsies than men on placebo.4The Journal of Clinical Endocrinology & Metabolism. Prostate Risk and Monitoring During Testosterone Replacement Therapy The cancers TRT appears to “cause” in some observational data may really be cancers that TRT helped detect. That distinction matters enormously for interpreting study results and for managing your own expectations if you start TRT and see your PSA tick up.
Cancers Outside the Prostate
Most research has focused on the prostate, but testosterone interacts with tissues throughout the body, and a handful of other cancer types have attracted attention.
Colorectal Cancer
The relationship between testosterone and colorectal cancer is actually the inverse of what you might expect. A prospective study found that men in the highest quarter of natural testosterone levels had roughly 40% lower colorectal cancer risk compared to men in the lowest quarter.13PubMed Central. Association between sex hormones and colorectal cancer risk in men and women That said, laboratory research has identified several pathways through which testosterone could theoretically promote colorectal tumor development, and some investigators have noted that the sex disparity in colorectal cancer rates (men get it more often) could reflect androgen effects.14PubMed Central. The role of testosterone in colorectal carcinoma: pathomechanisms and open questions The contradiction between observational data showing lower risk with higher testosterone and mechanistic data suggesting testosterone can promote colorectal tumors has not been fully resolved. For now, there is no clinical evidence that TRT increases colorectal cancer risk.
Melanoma
A large analysis of men in the SEER-Medicare database found that testosterone therapy was positively associated with distant-stage melanoma, particularly with injectable or implantable formulations. The odds ratio was about 1.7, meaning roughly a 70% higher chance of being diagnosed with advanced melanoma.15PubMed Central. Testosterone therapy and cancer risks among men in the SEER-Medicare linked database This is a single observational study, and it cannot prove that TRT caused the melanomas. Detection bias could play a role here too: men on TRT visit their doctors more often, which could lead to incidental discovery of skin lesions. But the association with distant-stage disease specifically, rather than early-stage, is harder to explain by detection alone and warrants further investigation.
Liver Tumors
Anabolic androgenic steroids taken at high doses have been linked to hepatic adenomas, benign liver tumors that can occasionally bleed or, very rarely, become malignant. This concern has sometimes been extended to therapeutic TRT, but the evidence for a meaningful link at prescribed doses is weak. A systematic review of transgender men receiving gender-affirming testosterone therapy found insufficient evidence to conclude that hormonal therapy caused liver tumors, and noted that the risk profile of high-dose anabolic steroids should not be directly translated to therapeutic doses.16PubMed. Transgender Males on Gender-Affirming Hormone Therapy and Hepatobiliary Neoplasms: A Systematic Review A case report described hepatic adenomas in a transgender man on testosterone that regressed after the hormone was temporarily discontinued, suggesting a hormonal driver in that individual case.17PubMed Central. Hepatic Adenomatosis in a Transgender Man on Gender-Affirming Testosterone Therapy The takeaway is that liver tumors are exceedingly rare at therapeutic doses, but physicians should be aware of the possibility.
Bladder Cancer
Men develop bladder cancer at roughly three to four times the rate women do, and emerging research suggests androgen receptor signaling in bladder tissue may contribute to that gap. Laboratory evidence indicates the androgen receptor can promote bladder cancer development, progression, and recurrence.18Nature Reviews Urology. The androgen receptor in bladder cancer Whether TRT specifically increases bladder cancer risk has not been tested in clinical trials, so this remains a mechanistic concern rather than a demonstrated clinical risk.
Genetic Variation in Androgen Receptor Sensitivity
Not everyone’s androgen receptor responds to testosterone the same way. A stretch of repeated DNA within the androgen receptor gene, known as the CAG repeat, varies in length from person to person. Shorter CAG repeats make the receptor more transcriptionally active, meaning each molecule of testosterone has a stronger effect on the cell. A major study in the Physicians’ Health Study found that men with shorter CAG repeats had a higher risk of prostate cancer, particularly aggressive forms with higher grade and more advanced stage.19PubMed Central. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer
A meta-analysis of 51 studies confirmed the broader trend: shorter CAG repeats were associated with increased prostate cancer susceptibility, though the strength of the association varied by ethnicity, with a stronger signal in Asian populations.20PubMed Central. Association between polymorphic CAG repeat lengths in the androgen receptor gene and susceptibility to prostate cancer: A systematic review and meta-analysis This genetic variability matters because it means the biological response to a given testosterone level is not uniform. Two men with the same serum testosterone can have meaningfully different androgenic stimulation at the tissue level. No current guideline recommends CAG repeat testing before starting TRT, but this is the kind of individual variation that makes blanket statements about testosterone and cancer risk inherently imperfect.
Supraphysiological Doses Versus Therapeutic TRT
A persistent source of confusion is the conflation of TRT with anabolic steroid abuse. Therapeutic TRT aims to bring testosterone into the normal physiological range, typically somewhere around 450 to 700 ng/dL depending on the laboratory and the clinician’s target. Anabolic steroid users may push their levels to several times that, sometimes sustaining supraphysiological concentrations for years. A cohort study from Finland tracked androgen users (people who had purchased testosterone or other androgens from pharmacies, many for non-medical reasons) over an average of 11 years and found a cancer incidence rate ratio of 1.05 compared to controls, which was not statistically significant. None of the androgen users developed prostate or breast cancer during follow-up.21PubMed Central. Excessive androgen exposure and risk of malignancies: A cohort study The study was relatively small, so it cannot rule out modest risk increases, but it provides some reassurance that even supraphysiological androgen exposure does not produce a dramatic cancer signal over a decade of observation.
That said, high-dose androgen abuse carries well-documented risks beyond cancer, including liver toxicity, cardiovascular strain, and hormonal disruption. The liver tumor concern discussed earlier is most relevant to oral anabolic steroids at high doses rather than to prescribed injectable or transdermal TRT.
Practical Screening While on TRT
The American Urological Association recommends measuring PSA in men over 40 before starting TRT to rule out an existing prostate cancer diagnosis.22The Journal of Urology. Evaluation and management of testosterone deficiency: AUA guideline After that, most clinicians check PSA at regular intervals during the first year, when the TRT-related PSA bump is steepest. A rise of more than 1.0 ng/mL or an absolute PSA above 4.0 ng/mL generally triggers urological referral and possible biopsy. Digital rectal exams remain part of standard monitoring in many practices.
The practical challenge for men on TRT is calibrating their anxiety when PSA rises. Knowing that TRT commonly causes a modest PSA increase, particularly early on, can prevent unnecessary panic. At the same time, a rising PSA should never be dismissed without evaluation. The goal of monitoring is not to catch TRT-caused cancer (there is little evidence it causes one) but to catch any cancer that happens to develop in a man who is also on TRT, just as you would in any man being screened appropriately for his age and risk profile.
TRT for Cancer Survivors With Low Testosterone
Cancer treatments frequently damage the testes. Chemotherapy, radiation, and surgical removal of a testicle can all produce hypogonadism, leaving survivors with fatigue, low libido, reduced bone density, and diminished quality of life. These men have a clear medical need for testosterone, but their cancer history creates understandable hesitation. A randomized, double-blind trial in testicular cancer survivors with mild Leydig cell insufficiency found that TRT did not significantly improve anxiety, depression, sexual function, fatigue, or overall quality of life compared to placebo.23PubMed. Effect of Testosterone Replacement Therapy on Quality of Life and Sexual Function in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency: Results From a Randomized Double-blind Trial The emphasis on “mild” matters here: men with more severe deficiency may respond differently. But the trial is a useful reminder that TRT is not a guaranteed fix for symptoms in cancer survivors, and that the decision to start therapy should weigh measurable testosterone deficiency against realistic expectations of benefit.
Why the Estrogen Conversion Matters
Testosterone does not stay as testosterone forever. The enzyme aromatase converts some of it into estradiol, the primary form of estrogen. In women with estrogen-receptor-positive breast cancer, this conversion is the theoretical mechanism by which testosterone could promote recurrence. That is why clinical trials investigating topical testosterone for breast cancer patients have required concurrent use of aromatase inhibitors, which block the conversion and prevent estradiol levels from rising.24PubMed Central. Safety and efficacy of topical testosterone in breast cancer patients receiving ovarian suppression and aromatase inhibitor therapy In men, aromatase conversion is also relevant: some of testosterone’s effects on bone density and cardiovascular health are actually mediated through estradiol. But the cancer concern in men is less direct, because male breast cancer is rare and prostate cancer is driven by androgens rather than estrogens. Still, men on TRT who develop gynecomastia or other signs of elevated estrogen should have their estradiol levels checked, as chronically elevated estradiol is not desirable for other health reasons.