Testosterone Replacement Therapy After Prostate Cancer: What Patients Need to Know

Table of Contents

• Key Points
• Background: Why Testosterone Was Historically Considered Risky
• The Saturation Model: A New Understanding
• TRT in Men With No History of Prostate Cancer
• Study: Coward et al (2009)
• Meta-Analysis of 19 Randomized Trials (2005)
• Systematic Review by Shabsigh et al
• Registry of Hypogonadism in Men (RHYME) Study
• Swedish Registry Study by Loeb et al
• The TRAVERSE Trial
• Current Guidelines from Major Organizations
• Clinical Implications for Patients
• Limitations of the Evidence
• Recommendations for Patients and Clinicians
• Frequently Asked Questions
• Source Information

Key Points

• Testosterone replacement therapy may be considered for men who are disease-free after treatment for low-risk prostate cancer, meeting criteria of PSA below 10 ng/mL, Gleason score below 7, and stage T1–T2a.
• Current evidence suggests that in appropriately selected men, testosterone replacement therapy does not increase the risk of prostate cancer recurrence or progression, though long-term data are limited.
• Monitoring during testosterone replacement therapy includes PSA levels at 3, 6, and 12 months in the first year, then annually, and hematocrit levels, especially with injectable formulations.
• If PSA levels rise during testosterone replacement therapy, treatment should be stopped and further evaluation performed.
• For men with a history of intermediate- or high-risk prostate cancer, the decision to use testosterone replacement therapy should be made with caution and on an individual basis.

Background: Why Testosterone Was Historically Considered Risky

The debate about testosterone replacement therapy (TRT) in men with a history of prostate cancer dates back more than 80 years. In 1941, a pivotal study by Huggins and Hodges demonstrated that prostate cancer depends on hormones. The researchers showed that reducing androgen levels through castration or estrogen administration significantly decreased serum acid phosphatase levels, which correlated with reduced prostate cancer activity.

Conversely, when testosterone was administered, serum acid phosphatase levels increased, indicating stimulation of tumor growth. Based on these findings, the study hypothesized that testosterone could promote prostate cancer progression, even at low levels of exposure.

This hypothesis shaped a long-standing assumption that TRT could worsen prostate cancer or increase its risk. It led to cautious clinical approaches regarding TRT in men with prostate cancer or at high risk for the disease. The study's findings also formed the basis for androgen deprivation therapy (ADT), which remains a cornerstone of treatment for advanced prostate cancer.

However, subsequent research has refined this understanding. Scientists now suggest a more complex relationship between testosterone and prostate cancer. Concepts such as the saturation model propose that prostate cancer's sensitivity to testosterone is limited to a threshold level. Beyond that threshold, additional testosterone has minimal or no effect on tumor progression.

The Saturation Model: A New Understanding

The saturation model, formalized by Morgentaler and Traish in 2009, offers a new perspective. It moves away from the traditional belief that prostate cancer growth is directly tied to testosterone levels.

This model suggests that testosterone and its metabolite 5α-dihydrotestosterone are essential for prostate tissue growth. However, these hormones are already abundant at normal physiological levels. According to the theory, prostate tissue, including cancerous cells, is sensitive to testosterone only up to a certain threshold. This threshold is known as the saturation point, which occurs at near-castrate androgen levels.

Below this point, androgen availability limits growth. Beyond it, additional testosterone has little or no effect. This concept is supported by clinical observations of hypogonadal men undergoing testosterone therapy. In these men, significant changes in prostate-specific antigen (PSA) or tumor progression were not observed. Preclinical data also show that androgen receptor (AR) activity plateaus at higher testosterone levels.

Similarly, studies on prostate cancer found no direct correlation between higher testosterone levels and increased cancer growth. Endogenous testosterone variation within the normal range did not influence PSA levels or prostate cancer risk. This challenges the traditional assumption that increased testosterone universally accelerates prostate cancer.

The model provides a framework for understanding why ADT is effective in advanced prostate cancer. It also explains why testosterone therapy in hypogonadal men does not appear to raise cancer risk. Furthermore, it explains why younger men, despite higher testosterone levels, do not exhibit excessive prostate growth or higher prostate cancer prevalence.

The model has gained significant traction for its ability to explain the limited impact of testosterone beyond the saturation point. However, several critiques remain. Prostate cancer's heterogeneity suggests that high-risk or advanced subtypes with AR overexpression or mutations may not conform to the model. The model primarily addresses low- to intermediate-risk disease, with limited applicability to advanced or metastatic prostate cancer. Variability in AR sensitivity among individuals raises questions about the generalizability of the model.

TRT in Men With No History of Prostate Cancer

The safety of TRT in men without a history of prostate cancer has been extensively studied. To date, there is strong evidence supporting the safety of TRT in this population.

Study: Coward et al (2009)

Coward et al retrospectively reviewed 81 hypogonadal men undergoing TRT over a mean follow-up of 33.8 months. The study assessed PSA changes and prostate cancer incidence. Participants had a mean baseline PSA of 1.32 ng/mL. Testosterone levels normalized from 241.1 ng/dL (8.36 nmol/L) to 379.8 ng/dL (13.17 nmol/L) at three years.

While PSA levels remained stable in 95% of participants, four men (4.9%) developed low-grade prostate cancer (stage T1c, Gleason 3+3 or 3+4) at a mean of 32.5 months. Men who developed cancer exhibited a significant PSA increase from baseline (3.2 ng/mL at three years, p<0.05), prompting diagnosis via biopsy.

The study found no statistically significant PSA changes in cancer-free men over five years. TRT also improved total cholesterol, reducing levels from 203.8 mg/dL (5.27 mmol/L) to 166.6 mg/dL (4.31 mmol/L) (p<0.05). Despite concerns about prostate health, the incidence of prostate cancer in the cohort was comparable to that in the general population. Diagnosed cancers were effectively treated without compromising outcomes.

Limitations include the retrospective design, lack of a control group, and a relatively small sample size. These factors reduce statistical power for long-term conclusions. However, these findings suggest that TRT effectively normalizes testosterone levels and improves quality of life without increasing prostate cancer risk.

Meta-Analysis of 19 Randomized Trials (2005)

A meta-analysis in 2005 examined adverse events associated with TRT in men aged 45 and older. The analysis pooled data from 19 randomized, placebo-controlled trials with 651 testosterone-treated and 433 placebo-treated participants.

The combined rate of prostate events was significantly higher in the TRT group (odds ratio [OR] 1.78, 95% confidence interval [CI] 1.07–2.95). However, individual outcomes were not statistically significant. These outcomes were prostate cancer incidence, PSA elevations above 4 ng/mL, PSA increases of 1.5 ng/mL, and prostate biopsies. These outcomes were numerically higher in the TRT group.

This analysis assumes that each prostate event occurred in a separate individual. However, some individuals may have experienced multiple events, which could overestimate the total rate of prostate events. Moreover, biases likely contributed to the higher frequency of prostate events in testosterone-treated men. Prostate biopsies in these trials were often triggered by PSA increases, making biopsies more common in the TRT group. However, the higher biopsy rate could not be fully explained by modestly increased frequencies of PSA elevations or increments in the TRT group. On average, testosterone-treated men experienced a slight PSA increase of 0.3 ng/mL from baseline.

Hematocrit levels exceeding 50% were notably more frequent in the TRT group (OR 3.69, 95% CI 1.82–7.51), making it the most common TRT-related adverse event. The method of testosterone delivery plays an important role in the likelihood of hematocrit elevation. Injectable testosterone formulations, such as enanthate or cypionate, have been associated with greater increases in hematocrit compared to transdermal formulations like gels or patches. This difference may be linked to the higher serum testosterone levels achieved by injectable formulations, which can exhibit higher peaks in testosterone levels. Transdermal options provide a steadier absorption profile, potentially mitigating the risk of hematocrit elevation.

However, there was no significant difference in cardiovascular events, including myocardial infarction (MI) and stroke, or in overall mortality between the groups. No deaths were recorded in the TRT group, but two were reported in the placebo group (causes not specified).

The study highlights the need for careful monitoring of PSA and hematocrit levels in men receiving TRT. However, the findings are limited by the short study durations (median 6 months) and variations in testosterone formulations and baseline participant characteristics.

Systematic Review by Shabsigh et al

A systematic review by Shabsigh et al evaluated the relationship between TRT and prostate cancer risk, including its impact on PSA levels and cancer progression. Of the 197 articles reviewed, 44 met the inclusion criteria. These comprised 11 placebo-controlled randomized studies, 29 non-placebo-controlled studies, and four studies involving hypogonadal men with a history of prostate cancer.

Across these studies, there was no evidence that TRT increased the risk of developing prostate cancer, progression of existing prostate conditions, or higher Gleason grades in cancers detected. Placebo-controlled trials revealed a prostate cancer incidence of 1.3% in TRT-treated men compared to 1.5% in placebo recipients, aligning with typical population screening rates. Similarly, PSA levels showed no consistent increase attributable to TRT.

Notably, studies involving men with prior prostate cancer demonstrated no evidence of recurrence or progression during TRT over periods of up to 12 years. However, the review identified limitations, including the heterogeneity of study designs, small sample sizes, short durations, and the retrospective nature of many studies.

Of particular interest, there is evidence suggesting that low testosterone levels may predispose men to more aggressive prostate cancers. This may be due to the metabolic disturbances associated with testosterone deficiency.

Registry of Hypogonadism in Men (RHYME) Study

Debruyne et al evaluated data from the Registry of Hypogonadism in Men (RHYME), a multi-national study involving 999 hypogonadal men from six European countries. The study investigated the effects of TRT on prostate cancer incidence, PSA levels, and lower urinary tract symptoms (LUTS).

Of the participants, 750 received TRT, while 249 remained untreated. During a follow-up period totaling 23,900 person-months, the positive biopsy rate was nearly identical between groups, at 37.5% for TRT users and 37.0% for untreated men. Biopsies, most of which were conducted within the first 12 months of enrollment, were primarily triggered by PSA elevations or abnormal digital rectal exam (DRE).

Analysis of oncological grading in positive biopsies revealed Gleason scores <7 in 77.8% of cases in the TRT group (14/18) and 57.1% in the untreated group (4/7). This aligns with observations that low testosterone may contribute to an increased risk of more aggressive disease. Notably, no prostate cancer-related deaths occurred in either group. The overall prostate cancer incidence rate (1,221.4 per 100,000 person-years) was consistent with general population norms.

PSA levels in the TRT group exhibited a slight increase during the first 12 months of treatment before stabilizing. This may account for findings in shorter-duration studies reporting PSA elevations with TRT. Mean baseline testosterone levels rose from 8.3 nmol/L (240 ng/dL) to 15.4 nmol/L (444 ng/dL) in the TRT group, moving from the hypogonadal range (<8 nmol/L or <231 ng/dL) into the normal range (>12 nmol/L or >346 ng/dL) as defined by the BSSM. Untreated men increased from 9.4 nmol/L (271 ng/dL) to 11.3 nmol/L (326 ng/dL), remaining within the borderline range (8–12 nmol/L or 231–346 ng/dL).

No significant differences were observed in PSA levels, total International Prostate Symptom Score (IPSS), or the IPSS obstructive sub-scale between the TRT and untreated groups. However, TRT was associated with mild improvements in the irritative sub-scale of the IPSS compared to untreated men. These findings support the conclusion that TRT does not elevate prostate cancer risk or exacerbate LUTS in hypogonadal men.

Swedish Registry Study by Loeb et al

Loeb et al's nested case-control study examined the association between TRT and prostate cancer risk using nationwide, population-based registry data from Sweden. The analysis included 38,570 men diagnosed with prostate cancer between 2009 and 2012, matched to 192,838 control subjects without prostate cancer.

Data from the Prescribed Drug Register were used to identify TRT exposure, treatment adherence, and type of administration. Prostate cancer cases were categorized as favorable-risk (low- and intermediate-risk) or aggressive (high-risk, locally advanced, or metastatic).

The results revealed no significant association between TRT and overall prostate cancer risk (OR 1.03; 95% CI 0.90–1.17). However, TRT was associated with an increased likelihood of favorable-risk prostate cancer (OR 1.35; 95% CI 1.16–1.56) and a significantly lower risk of aggressive prostate cancer (OR 0.50; 95% CI 0.37–0.67).

Subgroup analysis showed that favorable-risk cancers were more common during the first year of TRT. The reduced risk of aggressive cancers was apparent after more than one year of TRT exposure. These findings suggest that TRT may be oncologically safe and could reduce the risk of aggressive prostate cancer, likely by addressing testosterone deficiency.

The TRAVERSE Trial

The TRAVERSE trial was a large, prospective, randomized, placebo-controlled study. It examined the cardiovascular safety of TRT in hypogonadal men. Results demonstrated no significant difference in the incidence of high-grade prostate cancer (0.19% in the TRT group vs. 0.12% in the placebo group; hazard ratio [HR] 1.62, 95% CI 0.39–6.77, p=0.51) or any prostate cancer (0.46% vs. 0.42%; HR 1.07, 95% CI 0.47–2.42, p=0.87).

Rates of other prostate-related adverse events, including acute urinary retention and invasive procedures, were also comparable between groups. While PSA levels rose modestly during the first 12 months in the TRT group, they stabilized thereafter and did not result in increased rates of prostate biopsies. The study concludes that TRT in carefully screened hypogonadal men does not significantly increase the risk of prostate cancer or other adverse prostate events.

Strengths of this trial include its large sample size, extended follow-up period, and prospective design. These features effectively address limitations seen in earlier studies. Conducted during the COVID-19 pandemic, the trial faced retention challenges, but rates were similar between groups. The implementation of a pre-specified protocol to manage PSA elevations and minimize ascertainment bias further enhances the reliability of its findings. However, excluding men with elevated PSA, prostate cancer, or unconfirmed hypogonadism limits the applicability of the results to those specific groups.

Current Guidelines from Major Organizations

TRT is increasingly recognized as a safe option for appropriately selected men with a history of prostate cancer. This aligns with guidelines from major professional organizations.

The British Society for Sexual Medicine (BSSM) asserts that there is no compelling evidence linking TRT to the initiation or promotion of prostate cancer. Similarly, the American Urological Association (AUA) and European Association of Urology (EAU) support the cautious use of TRT. This support is for hypogonadal men with a history of prostate cancer who are disease-free. This support is provided certain criteria are met.

Key points from these guidelines include:

• BSSM: No evidence that TRT increases the risk of prostate cancer. TRT can be offered to symptomatic hypogonadal men who are disease-free after treatment for low-risk prostate cancer. Criteria include PSA <10 ng/mL, Gleason score <7, and stage T1–T2a.
• AUA: No evidence that TRT increases the risk of developing prostate cancer. Decisions should be individualized, weighing potential benefits and risks. For men with a history of prostate cancer, TRT may be considered after a thorough discussion of risks and benefits.
• EAU: No evidence that TRT increases the risk of prostate cancer. TRT should be monitored frequently in men with a history of prostate cancer. PSA levels should be evaluated at 3, 6, and 12 months during the first year of treatment, then annually.

Current guidelines reflect significant progress in recognizing the safety of TRT for men with a history of prostate cancer. These guidelines affirm that TRT can be offered to symptomatic hypogonadal men who are disease-free following treatment for low-risk prostate cancer, provided they meet certain criteria.

Emerging evidence suggests that, with appropriate caution and robust monitoring, TRT could potentially be extended to a broader group of patients without compromising oncological safety. Studies consistently underline the benefits of TRT in improving survivorship by alleviating hypogonadal symptoms such as fatigue, low mood, and diminished sexual function, thereby enhancing overall quality of life.

Clinical Implications for Patients

For men with hypogonadism who have been treated for prostate cancer, TRT may offer significant benefits. These benefits include relief from symptoms such as fatigue, mood disturbance, and sexual dysfunction. The evidence suggests that TRT does not increase the risk of cancer recurrence or progression in appropriately selected patients.

However, patient selection is critical. TRT is generally considered for men who are disease-free following treatment for low-risk prostate cancer. This includes men with a PSA level below 10 ng/mL, a Gleason score below 7, and stage T1–T2a disease. For men with a history of intermediate- or high-risk prostate cancer, the decision to use TRT should be made with caution and on an individual basis.

Monitoring is essential during TRT. Patients should have their PSA levels checked at 3, 6, and 12 months during the first year of treatment, and then annually. Hematocrit levels should also be monitored, as TRT can increase hematocrit, especially with injectable formulations. If PSA levels rise during treatment, TRT should be stopped and further evaluation performed.

The decision to start TRT should be made in a multidisciplinary team (MDT) setting. This ensures a thorough evaluation of individual patient risks and benefits. Patients should be fully informed about the potential risks and benefits of TRT, including the lack of long-term data on safety in this population.

Limitations of the Evidence

Despite the growing body of evidence supporting the safety of TRT in men with a history of prostate cancer, several limitations remain.

• Many studies are retrospective, which introduces potential biases.
• Sample sizes are often small, reducing statistical power.
• Follow-up durations are frequently short, limiting conclusions about long-term safety.
• Study designs are heterogeneous, making comparisons difficult.
• There is a lack of randomized controlled trials specifically in men with a history of prostate cancer.
• Long-term data on the risk of recurrence or progression in men with prior high-risk prostate cancer are limited.

The TRAVERSE trial, while large and prospective, excluded men with elevated PSA, prostate cancer, or unconfirmed hypogonadism. This limits the applicability of its findings to men with a history of prostate cancer.

Additionally, the saturation model primarily addresses low- to intermediate-risk disease. Its applicability to advanced or metastatic prostate cancer is limited. Variability in androgen receptor sensitivity among individuals raises questions about the generalizability of the model.

Recommendations for Patients and Clinicians

Based on the current evidence, the following recommendations can be made for men with hypogonadism and a history of prostate cancer who are considering TRT:

1. Multidisciplinary decision-making: Decisions regarding TRT should be made in a multidisciplinary team setting. This ensures a thorough evaluation of individual risks and benefits.
2. Patient selection: TRT is most appropriate for men who are disease-free following treatment for low-risk prostate cancer. This includes men with a PSA level below 10 ng/mL, a Gleason score below 7, and stage T1–T2a disease.
3. Informed consent: Patients should be fully informed about the potential risks and benefits of TRT. This includes the lack of long-term data on safety in this population.
4. Monitoring: PSA levels should be checked at 3, 6, and 12 months during the first year of TRT, and then annually. Hematocrit levels should also be monitored.
5. Stopping TRT: If PSA levels rise during treatment, TRT should be stopped and further evaluation performed.
6. Shared decision-making: The decision to start TRT should be made jointly by the patient and their healthcare provider, taking into account the patient's symptoms, quality of life, and oncological history.

For men with a history of intermediate- or high-risk prostate cancer, the decision to use TRT should be made with caution. These men may be at higher risk of recurrence or progression, and the evidence for safety in this group is more limited.

Overall, the evidence suggests that TRT can be a safe and effective option for appropriately selected men with hypogonadism and a history of low-risk prostate cancer. It can improve quality of life by alleviating symptoms such as fatigue, low mood, and sexual dysfunction. However, careful patient selection, rigorous monitoring, and fully informed decision-making are essential to ensure oncological safety.

Frequently Asked Questions

I had low-risk prostate cancer treated and I'm now disease-free. Can I be considered for testosterone replacement therapy?

Yes, you may be considered if you are disease-free after treatment for low-risk prostate cancer and meet specific criteria: a PSA below 10 ng/mL, a Gleason score below 7, and stage T1–T2a disease. Guidelines from major organizations support cautious use in this group, but the decision should be made individually with your healthcare team.

What monitoring will I need if I start testosterone replacement therapy after prostate cancer?

You will need regular monitoring. PSA levels should be checked at 3, 6, and 12 months during the first year of treatment, then annually. Hematocrit levels should also be monitored because testosterone can increase hematocrit, especially with injectable formulations. If your PSA rises during treatment, testosterone should be stopped and further evaluation performed.

Does testosterone replacement therapy increase the risk of my prostate cancer coming back?

Current evidence suggests that in appropriately selected men who are disease-free after low-risk prostate cancer, testosterone replacement therapy does not increase the risk of cancer recurrence or progression. However, long-term data are limited, especially for men with prior high-risk or advanced disease, so careful monitoring and informed discussion with your healthcare team are essential.

What does the saturation model mean for me?

The saturation model proposes that prostate tissue, including cancer cells, is sensitive to testosterone only up to a certain threshold, called the saturation point. Beyond that point, additional testosterone has little or no effect on tumor growth. This model helps explain why testosterone therapy in hypogonadal men does not appear to raise prostate cancer risk, though it mainly applies to low- to intermediate-risk disease.

I have a history of high-risk prostate cancer. Can I still have testosterone replacement therapy?

For men with a history of intermediate- or high-risk prostate cancer, the decision to use testosterone replacement therapy should be made with caution and on an individual basis. The evidence for safety in this group is more limited, and these men may be at higher risk of recurrence or progression. A multidisciplinary team should evaluate your specific situation.

What are the potential benefits of testosterone replacement therapy after prostate cancer treatment?

Testosterone replacement therapy may relieve symptoms of low testosterone such as fatigue, low mood, and sexual dysfunction, thereby improving overall quality of life. Studies consistently underline these benefits in men with hypogonadism. However, patient selection is critical, and the therapy is generally considered for men who are disease-free after treatment for low-risk prostate cancer.

I had low-risk prostate cancer treated and now my doctor recommends testosterone replacement therapy — when should I get a second opinion?

A second opinion is reasonable before starting testosterone replacement therapy after prostate cancer treatment. Guidelines support it only for men who are disease-free after low-risk disease, meaning PSA below 10 ng/mL, Gleason score below 7, and stage T1–T2a. For intermediate- or high-risk histories, evidence is more limited and decisions should be individualized. Because the choice involves multidisciplinary review, informed consent, and monitoring of PSA and hematocrit, an independent review can confirm whether you meet these criteria. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Testosterone Replacement Therapy in Hypogonadal Men with a Prostate Cancer Diagnosis: A British Society for Sexual Medicine Consensus Statement.

Authors: Edison MA, Kirby M, Hackett GI.

Affiliations: BURST Research Collaborative, London, UK; British Society for Sexual Medicine, Staffordshire, UK; Aston University Medical School, Birmingham, UK

Publication: World Journal of Men's Health, 2026 January; 44(1): 5-22

DOI: https://doi.org/10.5534/wjmh.250086

Received: March 2, 2025; Revised: March 9, 2025; Accepted: March 18, 2025; Published online: July 31, 2025

Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare provider. Patients should discuss their individual risks and benefits with their healthcare team before making any treatment decisions.