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

Abstract

Hypogonadism in men with a history of prostate cancer presents a complex clinical challenge, with longstanding concerns that testosterone replacement therapy (TRT) could potentially stimulate cancer recurrence or progression. This paper provides an up-to-date review of the evidence on the safety and efficacy of TRT, focusing on its use in key clinical scenarios such as active surveillance, post-radical prostatectomy, and post-radiotherapy. We examine the latest data on oncological safety, including risks of disease progression and biochemical recurrence, alongside the benefits of TRT in addressing hypogonadal symptoms such as fatigue, mood disturbance, and sexual dysfunction. The discussion also considers how TRT safety aligns with advancements in prostate cancer biology, including the saturation model, and how these insights are reflected in guidelines from major organisations such as the British Society for Sexual Medicine (BSSM), American Urological Association (AUA), and European Association of Urology (EAU). Gaps in long-term data and areas for further research are identified, underscoring the need for careful application in clinical practice. This paper emphasises a multidisciplinary approach in patient selection, rigorous monitoring protocols, and fully informed decision-making. By presenting a comprehensive review of the evidence, we aim to clarify the role of TRT in improving quality of life for men in remission from prostate cancer, while ensuring that oncological safety remains the highest priority.

INTRODUCTION

Testosterone replacement therapy (TRT) has long been a subject of debate in men with a history of prostate cancer due to concerns that testosterone may stimulate tumor growth. However, a growing body of evidence suggests that TRT, when carefully administered to appropriately selected patients, may be both safe and offer significant benefits.

This document serves as a consensus guideline for the British Society for Sexual Medicine (BSSM) on the use of TRT in symptomatic hypogonadal men in remission from prostate cancer. It is informed by the latest research, clinical guidelines, and expert insights, providing healthcare professionals with a comprehensive understanding of the risks, benefits, and current gaps in knowledge surrounding TRT. The aim is to offer evidence-based guidance to support informed decision-making and enhance quality of life for patients through symptom relief, while maintaining rigorous monitoring to ensure oncological safety. Decisions regarding the use of TRT in this population should, wherever possible, be made in a multidisciplinary team (MDT) setting to ensure a thorough evaluation of individual patient risks and benefits.

CURRENT GUIDELINES

TRT is increasingly recognized as a safe option for appropriately selected men with a history of prostate cancer, aligning with guidelines from major professional organizations. The BSSM assert that there is no compelling evidence linking TRT to the initiation or promotion of prostate cancer [1,2,3]. Similarly, the American Urological Association (AUA) [4] and European Association of Urology (EAU) support the cautious use of TRT in hypogonadal men with a history of prostate cancer who are disease-free, provided certain criteria are met. Key points from these guidelines are included in Table 1 [1,2,3,4,5,6].

Table 1. Comparison of TRT Guidelines from BSSM, AUA, and EAU on risk, eligibility, monitoring, and safety.

TRT aspect	BSSM [1,2,3]	AUA [4]	EAU [5,6]
General statement on prostate cancer risk	No compelling evidence to suggest that TT increases the risk of developing prostate cancer or is associated with the progression of existing prostate cancer (Level of Evidence 2, Grade B)	No evidence of increased risk: Inform patients that there is no evidence linking TT to the development of prostate cancer, despite FDA warnings. (Strong Recommendation; Grade B)	TRT does not increase the risk of prostate cancer in hypogonadal men
		Inform patients of the lack of evidence for harm but also of insufficient data for quantifying risk-benefit in those with prior prostate cancer
Eligibility for TRT	Offer to symptomatic men with treated, localized, low-risk prostate cancer (Gleason score <8, stages 1–2, preoperative PSA <10 ng/mL) after 1-year post-treatment (Evidence 3B)	Inform patients with a history of prostate cancer that evidence is insufficient to quantify the risk-benefit ratio of TT. Decisions should be individualized, weighing potential benefits against risks	Limit TRT to disease-free, low-risk men after localized prostate cancer treatment (PSA <10 ng/mL, Gleason <7 [ISUP Grade 1–2], T1-T2a staging, PSA <0.01 ng/mL for at least 1-year post-surgery)
Monitoring before starting & during TRT	Ensure no active disease (stable/undetectable PSA, normal DREa, no metastases)	PSA levels should be monitored as frequently as in untreated men, with increased monitoring if needed. Discuss stopping TT if PSA rises, with awareness of potential PSA decline after stopping	Evaluate total PSA at 3, 6, and 12 months during the first year of TRT, then annually
	Perform cardiovascular, prostate, breast, and hematologic assessments pre- and during TRT
Safety and risks	Acknowledges that data from long-term studies and meta-analyses suggest that TRT is safe and does not increase all-cause or cardiovascular mortality when properly managed. They stress the importance of achieving therapeutic testosterone levels and avoiding under- or overtreatment	Strong recommendation: No evidence links TT to the development of prostate cancer.	Fully counsel symptomatic hypogonadal men about the potential benefits and risks of TRT
		Studies show no difference in PSA, urinary symptoms, or prostate cancer diagnosis between TT and placebo groups	Emphasize the lack of sufficient long-term safety data and the uncertainty regarding long-term effects
Contraindications	TRT contraindicated in men with active prostate cancer or metastases	Individualize decisions for men with a history of prostate cancer. No absolute contraindication stated for men with prior cancer but stresses evaluation of risks and benefits	TRT contraindicated in advanced or metastatic prostate cancer cases
	Male breast cancer
	Hematocrit >54%
	Severe chronic heart failure
	A wish for paternity
Specific treatment group scenarios	Therapy to begin no earlier than 1 year after prostate cancer treatment	Active surveillance: Limited data indicate no significant increases in PSA or cancer diagnosis in men on TT during active surveillance	Therapy to begin no earlier than 1 year after prostate cancer treatment
		Post-radical prostatectomy: TT may be considered for men with favorable pathology (negative margins, seminal vesicles, and lymph nodes) and undetectable PSA levels postoperatively	Stricter criteria than BSSM as above
		Radiation therapy: Studies suggest no recurrence or progression of prostate cancer in men treated with TT post-radiation therapy, with stable or declining PSA levels

TRT: testosterone replacement therapy, BSSM: British Society for Sexual Medicine, AUA: American Urological Association, EAU: European Association of Urology, TT: testosterone therapy, PSA: prostate-specific antigen, ISUP: International Society of Urological Pathology.

^aA normal digital rectal examination (DRE), in the context of prostate cancer screening, can be defined as the absence of findings suspicious for malignancy, such as firm or hard nodules, areas of induration, significant asymmetry, or irregularities in size, shape, or consistency that cannot be attributed to benign prostatic hyperplasia (a diffuse enlargement with a smooth or soft texture).

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.

This document outlines the rationale for offering TRT to men in remission who had low-risk prostate cancer prior to treatment, in line with a consensus approach from the BSSM. The approach is rooted in a commitment to fully informed decision-making, careful patient selection, and rigorous monitoring. Our goal is to offer symptomatic relief through TRT while ensuring the highest standards of safety and care.

BACKGROUND

1. Why TRT was historically considered risky

The 1941 study by Huggins and Hodges [7], was a pivotal contribution to the understanding of prostate cancer’s hormonal dependency. The researchers demonstrated that reducing androgen levels through castration or estrogen administration significantly decreased serum acid phosphatase levels, which correlated with reduced prostate cancer activity. Conversely, testosterone administration resulted in increased serum acid phosphatase levels, 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 the long-standing assumption that TRT could exacerbate prostate cancer or increase its risk, leading 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, suggesting a more complex relationship between testosterone and prostate cancer. Concepts such as the saturation model [8] propose that prostate cancer’s sensitivity to testosterone is limited to a threshold level, beyond which additional testosterone has minimal or no effect on tumor progression. This evolving evidence has informed modern approaches to evaluating the safety of TRT, particularly in men with hypogonadism and no active malignancy.

2. The saturation model

The saturation model, formalized by Morgentaler and Traish in 2009 [8], offers a new perspective, moving 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 but 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, known as the saturation point, which occurs at near-castrate androgen levels. Below this point, androgen availability limits growth, but beyond it, additional testosterone has little or no effect. This concept is supported by clinical observations of hypogonadal men undergoing testosterone therapy, where significant changes in prostate-specific antigen (PSA) or tumor progression were not observed, and by preclinical data showing 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, and 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, while testosterone therapy in hypogonadal men does not appear to raise cancer risk. It also 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, but 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.

MODERN RESEARCH AND RISK ASSESSMENT OF TRT BY PATIENT GROUP

1. Men with no history of prostate cancer

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

Coward et al (2009) [9], retrospectively reviewed 81 hypogonadal men undergoing TRT over a mean follow-up of 33.8 months, assessing PSA changes and prostate cancer incidence. Participants had a mean baseline PSA of 1.32 ng/mL and normalized testosterone levels 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, see Supplement Table 1) 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, and diagnosed cancers were effectively treated without compromising outcomes.

Limitations include the retrospective design, lack of a control group, and a relatively small sample size, reducing 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.

A meta-analysis [10] in 2005 examined adverse events associated with TRT in men aged 45 and older, pooling 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 such as prostate cancer incidence, PSA elevations above 4 ng/mL, PSA increases of 1.5 ng/mL, and prostate biopsies, while numerically higher in the TRT group, were not statistically significant.

This analysis assumes that each prostate event occurred in a separate individual, but some individuals may have experienced multiple events, which could result in an overestimation of 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. These findings underscore the importance of addressing potential biases when interpreting testosterone trials.

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 [11]. However, despite this, 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) [10].

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.

A systematic review by Shabsigh et al [12] 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, comprising 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 (Gl) 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, potentially due to the metabolic disturbances associated with testosterone deficiency [13,14].

Debruyne et al [15] evaluated data from the Registry of Hypogonadism in Men (RHYME), a multi-national study involving 999 hypogonadal men from six European countries, to investigate 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), aligning with observations that low testosterone may contribute to an increased risk of more aggressive disease [13,14]. Notably, no prostate cancer-related deaths occurred in either group and the overall prostate cancer incidence rate (1,221.4 per 100,000 person-years) was consistent with general population norms. These results suggest that TRT does not increase prostate cancer risk in hypogonadal men [15].

PSA levels in the TRT group exhibited a slight increase during the first 12 months of treatment before stabilizing, which may account for findings in shorterduration 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 [1,16]. 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.

Loeb et al’s [17] 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, while 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, while 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 the metabolic disturbances associated with low testosterone, as previously discussed. However, further research is needed to confirm these results.

The TRAVERSE trial: The placebo-controlled double-blind TRAVERSE trial is the largest randomized controlled trial (RCT) to date [18] investigating the prostate safety of TRT, enrolling 5,204 hypogonadal men aged 45 to 80 years and accumulating 14,304 person-years of follow-up. To ensure the study focused on a low-risk hypogonadal population and minimize confounding from pre-existing prostate cancer risk, participants underwent rigorous screening. This included baseline PSA testing, DRE, and comprehensive medical history reviews to identify and exclude men with elevated PSA levels (>3.0 ng/mL), abnormal prostate findings, or a prior diagnosis of prostate cancer.

Participants were randomly assigned to receive either transdermal TRT or placebo, with a mean follow-up duration of 33 months. The primary endpoint was the incidence of high-grade prostate cancer (Gleason ≥4+3), with secondary endpoints including any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatments for LUTS.

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, which 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 results’ applicability to these populations.

1) TRT in men with potential precursors

Rhoden and Morgentaler [19] evaluated the safety of TRT in hypogonadal men, including those with high-grade prostatic intraepithelial neoplasia (PIN), a condition considered a precursor to prostate cancer. A total of 75 men were studied over one year, with 55 having benign biopsies (PIN-) and 20 diagnosed with high-grade PIN (PIN+). All participants underwent prostate biopsy prior to TRT initiation, and testosterone was administered via injection or transdermal gel. PSA levels and DREs were monitored, with re-biopsy conducted for significant PSA increases or abnormal DRE findings. The study found no significant differences in PSA changes, testosterone levels, or cancer incidence between the PIN+ and PIN-groups, regardless of the mode of testosterone delivery. Only one case of prostate cancer (Gleason 4+3) was identified in the PIN+ group, a rate consistent with baseline risk for untreated PIN. These findings suggest that TRT does not increase prostate cancer risk in men with high-grade PIN over one year of treatment, indicating that PIN is not a contraindication to TRT. The study supports the short-term safety of TRT in men with high-grade PIN but was limited by its one-year follow-up and small sample size, particularly in the PIN+ group.

2. Men with prostate cancer

Systematic and other reviews [20,21] evaluating the safety of TRT in men with prostate cancer have increasingly challenged its long-standing contraindications. Evidence from studies involving men on active surveillance (AS), as well as those treated with radical prostatectomy (RP) or radiation therapy, suggests that TRT does not significantly increase the risk of recurrence or progression when carefully monitored.

A population-based observational study by Kaplan et al [22] assessed the safety and utilization trends of TRT in prostate cancer survivors using data from the SEER-Medicare database. Among 149,354 men diagnosed with prostate cancer between 1992 and 2007, only 1,181 (0.79%) received TRT. TRT was more common in younger men, those with higher socioeconomic status, and patients with better tumor differentiation. Median follow-up was six years for non-TRT users and eight years for TRT users.

This study found no association between TRT and increased prostate cancer-specific or overall mortality. In fact, adjusted mortality rates were lower in the TRT group, with overall mortality at 5.4 events per 100 person-years compared to 6.9 in the non-TRT group, and cancer-specific mortality at 0.9 events per 100 person-years versus 1.6 in the non-TRT group (p<0.0001). Additionally, TRT did not increase the likelihood of requiring salvage ADT, a key marker of disease progression.

Building on these findings, Kaplan et al [23] conducted a complementary analysis to explore the temporal relationship between TRT duration and clinical outcomes within the same cohort. This study confirmed that TRT, regardless of duration, did not increase prostate cancer-specific or overall mortality (all HR<1.0, all p≤0.002). Moreover, longer TRT duration (over 60 days) was associated with a reduced need for salvage ADT, suggesting a potential protective effect of extended TRT use.

These findings indicate that TRT can be safely administered to carefully selected prostate cancer survivors, providing an effective option for managing symptomatic hypogonadism. They also align with the saturation model [8], which posits that prostate cancer growth is constrained by the saturation of ARs, rendering additional testosterone unlikely to have a significant impact.

1) Men on active surveillance

AS is a management approach for low-risk prostate cancer, involving regular monitoring with PSA tests, digital rectal exams, and biopsies, with the intention to intervene and treat curatively if the disease shows signs of progression. The safety of TRT in men on AS for prostate cancer has been investigated in several studies. Current evidence suggests that, with appropriate monitoring, TRT does not significantly elevate the risk of disease progression or necessitate conversion to definitive treatment. However, the available literature on men with untreated prostate cancer remains relatively limited, and further robust research is needed to confirm these findings, warranting cautious use in this patient population.

In 2011, Morgentaler et al [24] reported on 13 hypogonadal men with localized prostate cancer who underwent testosterone therapy while on AS. With a median follow-up of 2.5 years, 12 men had Gleason 6 disease at baseline, and one had Gleason 7 (3+4). All patients underwent follow-up biopsies, with no definitive progression or upgrading observed.

In a study evaluating TRT in hypogonadal men with prostate cancer [25], 8 patients on AS for low-risk Gleason 6 (3+3) disease were followed for a median of 27 months. None showed clinical or pathological progression, and none required definitive treatment. Among the six who underwent follow-up biopsies, five showed no evidence of disease, and one had persistent Gleason 6 cancer. PSA levels increased slightly during TRT but returned to baseline in two patients after therapy cessation. These findings suggest TRT does not promote disease progression in men on AS for low-risk prostate cancer.

Kacker et al [26] evaluated the safety of TRT in 28 hypogonadal men undergoing AS for prostate cancer. The cohort included men with Gleason 3+3 and low-volume Gleason 3+4 prostate cancer. Biopsy progression, defined as an increase in Gleason score or tumor volume, occurred in 32.1% of the TRT group over a mean follow-up of 38.9 months. Notably, only 10.7% experienced an increase in Gleason score. None of the men with Gleason 3+4 disease showed upgrading beyond this score. For a comparison cohort, 96 hypogonadal men on AS were examined, and those who did not receive TRT exhibited a higher rate of biopsy progression (44.7%), with 9.4% experiencing upgrading to Gleason 3+4. No significant differences were found in PSA changes or rates of progression between the TRT group and the comparison group. Importantly, no men in either cohort developed metastatic disease or died from prostate cancer.

These findings suggest that TRT does not accelerate prostate cancer progression in men on AS over the short to medium term. However, the comparison cohort (non-TRT) underwent a more comprehensive biopsy protocol, with 20-core systematic template biopsies compared to 12-core biopsies in the TRT group. This difference, along with the inclusion of low-volume Gleason 3+4 disease in the TRT group but not in the comparison cohort, underscores key methodological differences that limit the comparison cohort’s validity as a true control. The reliance on systematic random sampling and differing biopsy protocols likely influenced the detection of higher-grade disease. The 20-core protocol in the untreated group likely enhanced the detection of higher-risk cancers, while the less intensive 12-core protocol in the TRT group, combined with an inclusion criterion permitting a single core of Gleason 3+4 disease, may have contributed to an under-detection of more aggressive cancers in this group.

Kaplan-Marans et al [27] performed a population-based retrospective analysis in 2024 to evaluate the safety of TRT in men with prostate cancer managed on AS. The study included 167 men who received TRT and 6,658 controls who did not, with a median follow-up of 5.2 years and 4.7 years, respectively. No prostate cancer-specific deaths were observed in the TRT group, compared to 39 deaths (0.6%) in the control group. Conversion to active treatment occurred in 17% of the TRT group versus 22% of the controls, with TRT associated with a reduced hazard for conversion (HR 0.66; p=0.033). Additionally, TRT was not linked to increased overall mortality (HR 1.02; p>0.9).

These findings support the oncologic safety of TRT in well-selected men on AS, aligning with the saturation model of androgen action. Despite its strengths, the retrospective design and lack of data on TRT dosing, serum testosterone levels, whether follow-up biopsies were targeted or systematic, and indications for therapy are noted limitations. Nevertheless, the study underscores the potential role of TRT in improving hypogonadal symptoms and quality of life, without compromising oncologic outcomes, provided standard AS protocols are rigorously followed.

A study by San Francisco et al [28] examined whether testosterone levels predict disease reclassification in men with low-risk prostate cancer undergoing AS. Among 154 men followed for a median of 38 months, 35% experienced reclassification based on biopsy findings. Free testosterone levels were significantly lower in men who experienced reclassification compared to those who did not (0.75 ng/dL [2.6 pmol/L] vs. 1.02 ng/dL [3.5 pmol/L]; p=0.034). A threshold of <0.45 ng/dL (<1.6 pmol/L) for free testosterone was associated with a fourfold higher risk of reclassification (OR 4.3, 95% CI 1.25–14.73, p=0.035), and Kaplan–Meier analysis demonstrated worse reclassification-free survival for men below this threshold (p=0.032).

Multivariate analysis identified free testosterone <0.45 ng/dL (<1.6 pmol/L) and a family history of prostate cancer as independent predictors of disease reclassification, with HRs of 2.4 (p=0.022) and 2.3 (p=0.007), respectively. These results indicate that moderately reduced free testosterone levels significantly increase the risk of reclassification, highlighting their potential as a biomarker for identifying men at higher risk of progression during AS. Further studies are needed to validate these findings.

Summary: Current evidence suggests that TRT may be safely administered to hypogonadal men on AS for prostate cancer, with consistently no indication of increased disease progression or the need for definitive treatment across existing studies. However, the data remains limited, with small sample sizes, short follow-up periods, and a lack of robust prospective trials. These findings, while encouraging, depend heavily on careful patient selection, frequent PSA monitoring, MRIs, and biopsies to detect early signs of progression. Observational and retrospective studies provide valuable insights but need further validation from well-designed prospective research. Theoretical models such as the saturation model offer a plausible biological basis for these findings, supporting the cautious use of TRT within structured AS protocols. Nonetheless, clinicians should approach TRT in this population with care, acknowledging the need for more comprehensive data to confirm long-term safety.

2) Men after radical prostatectomy

Evidence indicates that TRT can be safely administered to hypogonadal men following curative RP [21] without increasing the risk of biochemical recurrence (BCR). Moreover, TRT has been shown to improve quality of life and sexual function in these patients.

Pastuszak et al’s [29] retrospective study assessed the safety of TRT in 103 hypogonadal men with a history of prostate cancer treated with RP, including 26 with high-risk prostate cancer (Gleason ≥8, positive margins, or lymph node involvement). A reference group of 49 non-hypogonadal men with prostate cancer was also included. Median follow-up was 27.5 months for the TRT group and 16.5 months for the reference group. Outcomes evaluated included serum testosterone and PSA levels, PSA velocity (PSAV), and BCR.

TRT significantly increased serum testosterone levels, with a slight but clinically acceptable rise in PSA. Importantly, Pastuszak et al [29] observed that while PSA levels increased with TRT, the BCR rate was unaffected. BCR occurred 12 patients, all of whom were in the high-risk patients; but only in four patients (15%) in the high-risk TRT group compared to eight patients (53%) in the high-risk reference (non-testosterone) group (p=0.02). No BCR was reported in low/intermediate-risk TRT patients. PSAV did not differ significantly between groups, suggesting no PSA changes indicative of cancer progression. These findings suggest that TRT does not increase BCR risk, even in high-risk patients, when managed with careful monitoring. However, it is important to note that TRT in high-risk patients remains a contentious practice and is not endorsed by all the clinical guidelines as per Table 1.

Ahlering et al’s [30] retrospective study investigated the effect of TRT on BCR in 850 men who underwent robot-assisted radical prostatectomy (RARP) for localized prostate cancer, performed by a single surgeon. Preoperative testosterone and sex hormone binding globulin (SHBG) levels were measured for all patients, and free testosterone (cFT) was prospectively calculated. Of the cohort, 152 men (18%) with low preoperative cFT and delayed recovery of sexual function post-surgery received TRT, while 419 matched controls did not. Patients were matched by pathological Gleason Grade Group (GGG) and stage. BCR was defined as two consecutive PSA values ≥0.2 ng/mL.

Over a median follow-up of 3.5 years, BCR rates were lower in the TRT group (7.2%; 11/152) compared to controls (12.6%; 53/419). After adjusting for GGG, pathological stage, preoperative PSA, and cFT levels, TRT was associated with a 54% reduction in the risk of BCR (HR 0.54, 95% CI 0.292–0.997). Furthermore, for men who experienced BCR, those receiving TRT had a longer time to recurrence, averaging a 1.5-year delay compared to controls. There was no identifiable general health complications associated with TRT (including cardiovascular events), and the authors proposed that the risk of BCR might also be lowered with TRT due to improvements in patients’ metabolic syndrome, in terms of cardiovascular disease risk and glycaemic control.

Shahine et al [31] conducted a retrospective study evaluating the oncological safety and functional outcomes of TRT in 1,303 prostate cancer patients who underwent RARP for curative treatment. Among them, 47 patients received TRT for symptomatic hypogonadism, defined by low serum testosterone levels (<10.4 nmol/L [300 ng/dL]) and related symptoms such as low libido, energy, or erectile dysfunction (ED). The primary endpoint was BCR, defined as a PSA >0.1 ng/mL, and secondary outcomes included changes in serum testosterone levels and sexual health inventory for men (SHIM) scores.

With a median follow-up of 48 months, BCR occurred in 6.4% (3/47) of the TRT group and 12.56% (157/1256) in the non-TRT group. Multivariate analysis identified factors such as preoperative PSA, ISUP grade, seminal vesicle invasion, and positive surgical margins as predictors of BCR, but TRT was not associated with increased recurrence risk (p=0.389). TRT improved serum testosterone levels significantly (from 7.24 to 15.92 nmol/L [209 to 459 ng/dL], p<0.001) and enhanced erectile function as reflected in increased SHIM scores (p=0.022). This would complement other studies showing the regulatory and beneficial effect of testosterone on penile physiology and erectile tissue [32,33].

This study supports the oncological safety of TRT in well-selected, closely monitored men following RARP, showing no significant effect on BCR rates and demonstrating functional benefits. Additionally, it highlights the important role of adequate preoperative testosterone levels in prehabilitation strategies.

Summary: Current evidence suggests that TRT is oncologically safe for hypogonadal men following RP, with no significant increases in BCR rates and PSA levels remaining within acceptable ranges across studies. In low- to intermediate-risk patients, the data is reassuring, supporting TRT as a viable option to improve quality of life, including energy, libido, and erectile function. For high-risk patients, some small studies have even shown reduced BCR rates, suggesting potential benefits; however, these findings are limited by very small patient numbers, a lack of robust data, and currently fall outside clinical guidelines. This highlights a critical need for further research to address these gaps in understanding. Increased monitoring remains essential for all patient groups to ensure safety.

3) Men after radiotherapy

TRT has been investigated in hypogonadal men following radiotherapy for prostate cancer, with evidence suggesting it can be safely administered when accompanied by appropriate monitoring. Beyond addressing oncologic safety concerns, once again TRT has demonstrated significant benefits in managing hypogonadal symptoms and improving quality of life for this population.

Pastuszak et al [29,34] evaluated the safety of TRT in 13 hypogonadal men treated for prostate cancer with brachytherapy or external beam radiotherapy (EBRT) between 2006 and 2011. Patients had Gleason scores ranging from 6 to 8, with a median age of 68 years at TRT initiation. Baseline testosterone, free testosterone, and PSA levels were measured, and follow-up assessments, conducted approximately every 3 months for up to 67 months, included serum testosterone, free testosterone, PSA, estrogen, SHBG, hemoglobin, and hematocrit.

Over a median follow-up of 29.7 months, significant increases in serum testosterone (from 178.0 ng/dL [6.2 nmol/L] to 368.0 ng/dL [12.8 nmol/L], p=0.012) and SHBG levels were observed, while free testosterone, PSA (from 0.30 ng/mL to 0.66 ng/mL, p=0.345), and other biomarkers showed no significant changes. Importantly, no prostate cancer recurrences or disease progression were reported during follow-up. These findings suggest that TRT after radiation therapy for prostate cancer can safely improve hypogonadal symptoms by restoring testosterone levels without increasing PSA or the risk of cancer recurrence. However, the study’s small sample size and retrospective design highlight the need for larger, long-term trials to confirm these results.

Sarosdy [35] evaluated the safety of TRT in 31 hypogonadal men treated for early, localized prostate cancer with brachytherapy, with or without EBRT. The study aimed to address the lack of clinical data and controversy surrounding TRT in this context. Patients received TRT for symptomatic hypogonadism, with follow-up ranging from 1.5 to 9 years (median 5.0 years). TRT was initiated 0.5 to 4.5 years post-treatment (median 2.0 years).

Before TRT, median serum testosterone levels were 188 ng/dL (6.5 nmol/L), increasing to 498 ng/dL (17.3 nmol/L) during therapy. PSA levels showed no significant rises except for transient increases in one patient, and no BCR or cancer progression was observed. At the most recent follow-up, PSA levels were <0.1 ng/mL in 74.2% of patients, <0.5 ng/mL in 96.7%, and <1 ng/mL in all patients. No patients discontinued TRT due to cancer concerns. The findings suggest that TRT can safely alleviate hypogonadal symptoms in men treated with brachytherapy for early prostate cancer when used with careful patient selection and close monitoring.

Morales et al [36] prospective case series evaluated TRT in five men with testosterone deficiency syndrome following EBRT for localized prostate cancer. Patients were aged 52 to 75 years with a mean baseline testosterone of 5.2 nmol/L (150 ng/dL, range 1.1–9.2 nmol/L [32–265 ng/dL]) and Gleason scores of 6–8. TRT was initiated after PSA levels reached a nadir and continued for a mean follow-up of 14.6 months (range 6–27 months).

Serum testosterone levels increased significantly to a mean of 17.6 nmol/L (508 ng/dL, range 8.5–32.4 nmol/L [245–935 ng/dL]) with TRT. One patient experienced a transient PSA rise, but no levels exceeded 1.5 ng/mL, and no prostate cancer recurrences were observed. All patients reported improvement in hypogonadal symptoms, including reduced fatigue, improved libido, and, in some cases, better erectile function when combined with phosphodiesterase-5 inhibitors. One patient discontinued TRT due to headaches. The study concluded that TRT may be safe and beneficial for carefully selected men with symptomatic hypogonadism after EBRT, provided PSA levels have stabilized, and close follow-up is maintained.

In a larger retrospective study by Pastuszak et al [37], the safety of TRT was evaluated in 98 hypogonadal men who had undergone radiation therapy for prostate cancer. The median age at TRT initiation was 70 years, with a median baseline testosterone level of 209 ng/dL (7.2 nmol/L) and a PSA level of 0.08 ng/mL. The cohort included men with Gleason scores ranging from 5 to 9, with 44.9% having Gleason 6 disease and 28.6% having Gleason 7 disease. Among the Gleason 7 subgroup, both 3+4 and 4+3 patterns were represented, though the exact proportions were not specified. TRT was administered via gels (65%), injections (24%), or subcutaneous pellets (11%), and the median time from radiation therapy to TRT initiation was 28.6 months.

The study employed a rigorous monitoring protocol to ensure patient safety during TRT. Serum testosterone, PSA, and free testosterone levels were measured at baseline and then reassessed every 3 to 6 months during follow-up. Additional biomarkers such as estradiol and SHBG were also evaluated at baseline. PSAV was calculated using at least three PSA measurements over 12 months or more to track trends and detect potential disease recurrence. Follow-up lasted a median of 40.8 months, with monitoring ensuring close observation of any changes in PSA or testosterone levels.

Over the course of follow-up, serum testosterone levels increased significantly to a median of 420 ng/dL (14.6 nmol/L, p<0.001). PSA levels showed a minor, statistically non-significant increase overall (from 0.08 ng/mL to 0.09 ng/mL, p=0.05). However, in high-risk patients (Gleason score ≥8), PSA increased significantly from 0.10 to 0.36 ng/mL (p=0.018). Six patients (6.1%) met criteria for BCR, predominantly in the intermediate- and high-risk groups. Their observed BCR rate is comparable to or lower than historical recurrence rates for similar patients treated with RT without TRT, which range from 13% to 65%, with higher recurrence rates correlating with increasing BCR risk [38,39,40,41].

These findings suggest that TRT after RT for prostate cancer is associated with a modest rise in PSA and a low rate of BCR, supporting its potential safety when administered with appropriate monitoring. However, key limitations of the study include its retrospective design, the absence of a eugonadal control group, and the relatively small sample size, which limits the generalizability of the results. Additionally, follow-up beyond three years remains limited, and the heterogeneity in radiotherapy modalities (external beam and brachytherapy) adds complexity to interpreting the findings. Prospective studies are needed to confirm these results and establish more definitive guidance for the use of TRT in this patient population.

A systematic review [42] and meta-analysis of 21 studies evaluated the impact of TRT on BCR in prostate cancer patients who underwent definitive local therapy with curative intent. The overall pooled BCR rate was 1% (95% CI 0.00–0.02), indicating no association between TRT and increased recurrence risk. There was no significant heterogeneity (I²=24.34%, p=0.15). Subgroup analyses showed a 0% pooled BCR rate (95% CI 0.00–0.02) in patients treated with RP (consistent with findings in the previous section) and 2% (95% CI 0.00–0.04) in those receiving external beam radiation therapy, brachytherapy, cryotherapy, or high-intensity focused ultrasound, again with no heterogeneity (I²=19.88%, p=0.18). These findings suggest TRT is safe for well-selected prostate cancer survivors with secondary hypogonadism, providing symptom relief without increasing oncological risks. The authors propose further prospective phase I/II trials to validate the safety and benefits of TRT in this population.

Summary: Evidence increasingly supports TRT as a safe and effective option for hypogonadal men postradiotherapy for prostate cancer, with studies showing stable PSA levels and no significant rise in recurrence rates. TRT also improves energy, mood, and sexual function, enhancing quality of life for symptomatic men. However, some studies indicate a slightly higher risk of BCR in men treated with radiotherapy on TRT compared to those who undergo surgery, likely due to the presence of residual prostatic tissue. This underscores the importance of careful, individualized patient selection, limiting TRT to men who are symptomatic and initiating treatment only after achieving a stable PSA nadir. Pre-treatment testosterone levels could also play a vital role in prehabilitation, optimizing overall health and readiness for therapy. Robust monitoring, including regular PSA assessments, remains essential to ensure oncological safety and to promptly identify any early signs of disease progression. MDT input from oncologists, endocrinologists, and urologists is particularly valuable in complex cases, supporting safe, individualized treatment plans. Larger, long-term studies are needed to confirm these findings and further refine the safety profile of TRT in this population.

CARDIOVASCULAR CONCERNS vs BENEFITS

TRT has faced significant scrutiny due to concerns regarding its cardiovascular safety. Morgentaler et al [43] conducted a comprehensive review of the literature on TRT and cardiovascular outcomes, focusing on studies published between 1940 and 2014. The review included over 200 articles aimed at evaluating the relationship between TRT and cardiovascular risk. Of these, only four studies suggested an increased cardiovascular risk associated with TRT.

One prominent study by Vigen et al [44], which had multiple flaws, retrospectively analyzed men undergoing coronary angiography within the Veterans Administration healthcare system and reported a 29% increase in adverse cardiovascular events (MI, stroke, or death) in TRT users. However, significant flaws undermine these findings. The raw data showed fewer cardiovascular events in TRT users (10.1% vs. 21.2% in non-users), but this was reversed using unvalidated statistical methods, including stabilized inverse propensity weighting. Major errors included the misclassification of over 1,000 participants, the inclusion of nearly 10% women in an all-male cohort, and the initial exclusion of over 1,132 adverse events from the non-TRT group, later corrected to 128. These issues prompted calls for retraction from 29 international medical societies. The FDA concluded the findings were unreliable, highlighting the study’s flawed methodology and significant data errors. Ultimately, the study’s conclusions contradict its raw data, which indicated, as expected, a lower incidence of cardiovascular events in TRT users.

A likewise flawed study by Finkle et al [45] used an insurance database to compare MI rates within 90 days post-TRT prescription to the preceding 12 months, reporting an increased rate ratio for MIs, particularly in men over 65 years. However, the study lacked a control group and failed to adjust for critical confounders such as diabetes, smoking, or obesity. Moreover, MI diagnoses were based solely on insurance codes without clinical validation. The pre- and post-treatment periods reflected different clinical scenarios, making the comparison methodologically unsound. Crucially, the study used phosphodiesterase type 5 inhibitor (PDE5I) prescriptions as a comparator group, failing to acknowledge that PDE5Is have been shown to reduce cardiovascular events by at least 20% and overall mortality by approximately 30% [46]. This oversight, combined with the absence of proper adjustment for baseline risk differences, likely exaggerated the perceived cardiovascular risk associated with TRT. Finally, despite these limitations, reported MI rates post-TRT remained lower than expected for this population, contradicting the study’s overall conclusion of harm.

Another flawed study by Basaria et al [47] conducted a prospective randomized trial evaluating the effects of TRT on functional and muscular outcomes in frail elderly men (it was not designed to investigate cardiovascular events). Although the trial reported an increased incidence of cardiovascular events in the TRT group, these events included subjective and minor outcomes, such as pedal edema and palpitations, rather than clinically significant cardiovascular events. The study was terminated early due to safety concerns, but the small number of major adverse cardiac events (MACE) precludes definitive conclusions. Importantly, supraphysiological dosing of testosterone in the treatment arm may have confounded the findings.

The theme continues with a study by Xu et al [48], who conducted a meta-analysis of 27 placebo-controlled trials and reported an increased risk of cardiovascular events with TRT. However, it selectively included only studies that reported cardiovascular events, excluding those without such events, thereby inflating the apparent risk. Furthermore, two studies (Basaria et al [47] and a 1986 Copenhagen trial using high-dose oral testosterone [49] to men with liver cirrhosis) disproportionately influenced the analysis. Re-analysis excluding these outliers found no significant difference in cardiovascular event rates between TRT and placebo groups. The meta-analysis was also contradicted by larger, more comprehensive reviews, such as Corona et al (2014) [50], which found no increased cardiovascular risk and identified metabolic benefits of TRT.

In contrast, several dozen other properly conducted studies highlighted the beneficial effects of a normal testosterone on cardiovascular health. They note that low testosterone levels are associated with adverse cardiovascular markers such as insulin resistance, dyslipidemia, and endothelial dysfunction—all of which are risk factors for cardiovascular disease. Meta-analyses and smaller RCTs reviewed in Morgentaler et al’s article [43] indicated that testosterone therapy could improve these cardiovascular risk markers, potentially reducing the risk of heart disease and cardiovascular mortality.

Morgentaler et al [43] concluded, prior to the TRAVERSE study, that without large, long-term, placebocontrolled trials, definitive conclusions about the cardiovascular safety or risks of TRT remain elusive. However, existing evidence strongly supports a beneficial relationship between higher testosterone levels—whether endogenous or achieved through TRT—and a reduction in cardiovascular disease and associated risk factors. Notably, there is no robust scientific evidence to suggest that TRT increases cardiovascular risk. On the contrary, decades of research consistently demonstrate that higher testosterone levels are associated with improvements in cardiovascular health. The TRAVERSE trial has subsequently been published, answering their call for larger scale studies to validate these initial conclusions.

The TRAVERSE trial [51], a large-scale, multicenter, randomized, placebo-controlled, non-inferiority study, was primarily designed to investigate the cardiovascular safety of TRT in men aged 45 to 80 years with hypogonadism and pre-existing or elevated risk of cardiovascular disease. This landmark trial sought to resolve concerns arising from previous conflicting evidence regarding the cardiovascular risks associated with TRT.

The trial enrolled 5,246 men with confirmed hypogonadism, defined by serum testosterone levels <300 ng/dL (<10.4 nmol/L), and included those with cardiovascular disease or elevated cardiovascular risk factors. Participants were randomized to receive either transdermal testosterone gel (adjusted to maintain levels between 350 and 750 ng/dL [12.1–26.0 nmol/L]) or placebo. The primary outcome was the occurrence of MACE, a composite of cardiovascular death, nonfatal MI, or non-fatal stroke. Secondary endpoints included coronary revascularization and other cardiovascular and thromboembolic events.

The results demonstrated a non-inferior reduction in MACE with TRT compared with placebo concerning the incidence of MACE, with HRs for the primary and secondary endpoints of 0.96 (95% CI, 0.78–1.17) and 1.02 (95% CI, 0.86–1.21), respectively. These findings were consistent across sensitivity analyses and subgroups. The study also highlighted a small increased incidence of atrial fibrillation, pulmonary embolism, and acute kidney injury, defined as an increase in creatinine—which can be a normal physiological response to TRT in the treated group, that should be taken into consideration when counseling patients. Further, as the trial was conducted during the COVID-19 pandemic, which has been associated with an increased risk of cardiovascular and thromboembolic events, this context should be taken into account when interpreting the findings. As such, the reported cardiovascular events, including atrial fibrillation and pulmonary embolism, may have been influenced by this broader risk, and further studies are needed to clarify their significance.

Regarding prostate safety, as stated previously, the trial did not report an increased risk of prostate cancer or progression in the TRT group, providing further reassurance on the oncological safety of testosterone therapy [18]. There were 33 fewer cases of new onset diabetes in the 1,175 patients with pre-diabetes (p=0.027), whereas the paper only reported a p-value of 0.06 for changes in HbA1c although this is acknowledged as an unreliable marker for diabetes progression especially in anemia, which was seen in 16% of patients [52,53]. TRAVERSE reported improved sexual desire but not ED, but this would be expected as 70% had diabetes and 90% dyslipidemia with less than 8% were taking any treatment for ED [53,54].

Overall, the TRAVERSE trial provides compelling evidence that TRT does not increase the risk of MACE in hypogonadal men, including those with cardiovascular comorbidities. It also offers valuable insights into TRT’s cardiovascular safety, supporting its use in appropriately selected patients. However, as the trial was conducted during the COVID-19 pandemic, which has been associated with an increased risk of cardiovascular and thromboembolic events, this context should be considered when interpreting the findings (Table 2).

Table 2. Summary TRAVERSE results.

	Cardiovascular	Prostate	Sexual function	Depression	Bone fracture	Anemia	Diabetes
Risk	MACE: No	Cancer: No	-	-	-	-	-
	PE: uncertain	BPH/LUTS: No	-	-	-	-	-
	AF: uncertain	-	-	-	-	-	-
Benefits	-	-	ED: Uncertain	Yes	No	Yes	Uncertain
	-	-	Libido: Yes	-	-	-	-

MACE: major adverse coronary events, PE: pulmonary embolism, AF: atrial fibrillation, BPH: benign prostatic hyperplasia, LUTS: lower urinary tract symptoms, ED: erectile dysfunction.

Furthermore, a recent 25-year systematic review and meta-analysis provides additional evidence supporting the cardiovascular benefits of TRT [55]. This meta-analysis, encompassing over 3 million participants, found an 18% reduction in MACE among men treated with TRT. Improvements in key cardiovascular risk markers, such as lipid profiles, endothelial function, and reductions in inflammatory markers, were also noted. Subgroup analyses revealed these benefits were particularly pronounced in men with pre-existing cardiovascular disease or metabolic syndrome, reinforcing the role of TRT in mitigating cardiovascular risk in high-risk populations.

Thus, beyond its favorable safety profile, TRT also appears to address key conditions associated with hypogonadism, including increased cardiovascular mortality and metabolic syndrome. By improving metabolic and endothelial function, TRT offers both safety and therapeutic benefit, reinforcing the need for a personalized, patient-centered approach tailored to individual clinical risks and needs.

Summary: The cardiovascular effects of TRT have been a topic of considerable debate. Early studies which initially raised the concerns about increased cardiovascular risks, were so significantly flawed in their methodology they cannot be deemed reliable. In contrast, the TRAVERSE trial, a large and well-designed RCT, has provided strong evidence that TRT does not significantly increase the risk of MACE, even in men with pre-existing cardiovascular conditions. Nonetheless, potential risks, such as pulmonary embolism, require careful consideration. On the other hand, TRT may offer cardiovascular benefits by improving metabolic and endothelial dysfunction associated with low testosterone, potentially mitigating cardiovascular risk factors. Clinicians should adopt a personalized approach, carefully balancing the potential risks and benefits of TRT for each individual patient. When appropriate, TRT should be integrated with lifestyle modifications and PDE5Is to enhance overall outcomes and provide a comprehensive strategy for symptom management.

OTHER CONSIDERATIONS

1. Bipolar androgen therapy

Bipolar androgen therapy (BAT) is a treatment strategy for advanced prostate cancer that alternates between supraphysiologic and near-castrate testosterone levels to exploit the prostate cancer cells’ sensitivity to rapid hormonal fluctuations, potentially resensitizing them to ADT.

The TRANSFORMER trial [56], a phase II randomized study, evaluated the efficacy of BAT compared to enzalutamide in asymptomatic men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on abiraterone. As stated, BAT employs rapid cycling between supraphysiologic and near-castrate testosterone levels to disrupt AR overexpression, a key driver of treatment resistance in mCRPC. Patients were allowed to cross over to the alternative treatment at progression, providing insight into sequential therapy outcomes. The trial demonstrated comparable progression-free survival (PFS) between BAT and enzalutamide (5.7 months in both arms), with 50% PSA declines (PSA50) observed in 28.2% of BAT-treated patients compared to 25.3% with enzalutamide.

Notably, at crossover, PSA50 responses were achieved in 77.8% of patients switching from BAT-to-enzalutamide, compared to 21.3% for those transitioning from enzalutamide-to-BAT. The PSA-PFS for enzalutamide improved significantly to 10.9 months after BAT, compared to 3.8 months when enzalutamide was used directly after abiraterone, supporting the hypothesis that BAT resensitizes tumors to subsequent AR-targeted therapies, which the authors suggest is via adaptive downregulation of AR expression. The trial was not designed to establish superiority between treatments but provided valuable data on comparative efficacy and the potential of sequential strategies. These findings align with earlier results from a pilot study demonstrating the safety and clinical activity of BAT in mCRPC [57].

In TRANSFORMER [56], the safety profile of BAT was favorable, with predominantly mild to moderate adverse events and consistently better patient-reported quality of life metrics compared to enzalutamide, which was associated with more fatigue and gastrointestinal symptoms. Overall survival (OS) was similar between the initial treatment groups (32.9 months for BAT versus 29.0 months for enzalutamide). However, the sequence of BAT followed by enzalutamide showed a potential survival advantage, with a median OS of 37.1 months, compared to 30.2 months for the reverse sequence (enzalutamide followed by BAT). Additionally, the PFS2 (PFS after crossover) for BAT-to-enzalutamide was significantly longer at 28.2 months versus 19.6 months for enzalutamide-to-BAT (HR, 0.44; p=0.02). These results underscore the therapeutic promise of BAT in sequential strategies and its potential to improve outcomes by resensitizing tumors to subsequent AR-targeted therapies.

The trial’s findings challenge the long-standing notion that testosterone universally promotes prostate cancer progression, suggesting a need to reassess its role across the disease continuum. In the metastatic setting, BAT demonstrates that AR-overexpressing tumor cells can be therapeutically targeted with supraphysiologic testosterone, providing clinical benefit rather than harm. This contrasts with earlier-stage prostate cancer, where androgen exposure has traditionally been considered a risk factor. However, the “saturation model” aligns with evidence from BAT and raises questions about the appropriateness of broadly contraindicating TRT, particularly in men with hypogonadism after definitive treatment for localized prostate cancer, underscoring the conclusions drawn above.

Although this is not the target population for this BSSM consensus, the TRANSFORMER trial highlights that testosterone’s impact on prostate cancer is highly context dependent. The ability to use testosterone therapeutically in men with advanced prostate cancer challenges the notion that TRT is inherently unsafe in men without active disease. Previous blanket contraindications for TRT in men with a history of prostate cancer may therefore have been overly cautious, particularly for those with no residual disease who experience significant quality-of-life impairments due to hypogonadism.

While these findings are specific to the mCRPC setting and cannot be directly applied to earlier-stage disease, they provide valuable mechanistic insights into androgen dynamics. These insights support the need for a more nuanced approach to TRT in earlier-stage prostate cancer, guided by patient-specific factors and disease context. Vigilance and individualized risk assessment remain crucial to ensuring safety and efficacy for patients.

CONCLUSIONS

The use of TRT in men with a history of prostate cancer must be considered on a case-by-case basis. Modern evidence, in contrast to historical concerns, supports its use in appropriately selected patients. For men with low- to intermediate-risk prostate cancer, multiple studies indicate that TRT is a safe and effective option, providing significant benefits without increasing the risk of cancer recurrence. The positive effects on quality of life, such as improvements in sexual function, energy levels and mood, suggest that symptomatic hypogonadal patients could derive substantial benefit from TRT and should be offered this treatment choice, provided they are fully informed of the potential risks and benefits. In contrast, for high-risk patients, the long-term safety of TRT remains unclear, and more caution is warranted. Further research is needed to better understand its impact in this group.

Ultimately, TRT offers an important treatment option for hypogonadal men with a history of prostate cancer, but patient selection and regular monitoring are essential to ensure safety. Decisions regarding TRT should be made, wherever feasible, in an MDT setting to ensure comprehensive evaluation of all relevant factors, including oncological risks, cardiovascular health, and patient-specific priorities. The decision to initiate TRT should be guided by a personalized approach, considering the patient’s individual wishes, health history, cancer risk, and quality of life considerations.

Supplementary Materials

Supplementary materials can be found via https://doi.org/10.5534/wjmh.250086.

Supplement Table 1

Gleason grade groups and associated risk