Introduction

Hypogonadism is a common condition among ageing men, affecting up to 30% of those aged 40–79 years-old [1]. It is marked by a reduction in serum testosterone levels, which may lead patients to present with fatigue, reduced libido and/or erectile dysfunction, as well as changes in body composition such as loss of lean muscle mass and increased fat accumulation [2, 3]. Beyond these effects, hypogonadism is linked to adverse health outcomes such as insulin resistance, type 2 diabetes, cardiovascular disease, and depression, collectively reducing quality of life and increasing long-term morbidity and mortality risks [4,5,6,7].

Testosterone replacement therapy (TRT) is a well-established treatment for men with symptomatic hypogonadism [8]. It has been shown to improve muscle mass, reduce fat mass, and improve cardiovascular and mental health parameters [8,9,10]. While lifestyle interventions remain the first-line approach, adherence and effectiveness can be limited, making TRT an important therapeutic option for appropriately selected individuals [8, 11].

However, the use of TRT in men with a history of prostate cancer remains controversial. Historically, this concern stemmed from early work by Huggins and Hodges, who demonstrated that reducing testosterone levels led to regression of metastatic prostate cancer, implying a stimulatory role of androgens in tumour progression [12]. This interpretation, drawn from limited data, led to longstanding caution around TRT in this population. Similarly, Fowler and Whitmore’s 1981 series of 67 men with metastatic prostate cancer treated with exogenous testosterone observed rapid disease progression primarily in those previously treated with androgen deprivation therapy (ADT), further reinforcing this conservative stance [13].

Given the increasing prevalence of prostate cancer survivors [14], many of whom experience hypogonadism either due to age [2] or prior ADT [15] there is a growing need to understand the safety and efficacy of TRT in this context. While several individual studies have reported on this issue, the evidence remains heterogeneous and methodologically varied.

Objective

The objective of this scoping review is to systematically map the existing literature on the safety and efficacy of TRT in men following definitive treatment for prostate cancer (i.e., radical prostatectomy or radiotherapy). Specifically, this review aims to:

  1. 1.

    Identify the nature and extent of available evidence;

  2. 2.

    Summarise oncological safety outcomes (e.g., biochemical recurrence [BCR], PSA kinetics, progression); and

  3. 3.

    Describe therapeutic efficacy outcomes (e.g., symptom improvement, hormonal normalisation, quality of life).

This review is conducted in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines [16], to provide a comprehensive overview of the current state of research and inform future investigations and clinical practice.

Materials and methods

Eligibility criteria

Studies were eligible for inclusion if they met the following criteria:

  • Peer-reviewed, human studies examining TRT in men post-radical prostatectomy or radiotherapy for prostate cancer.

  • Reported at least one oncological outcome (e.g., PSA kinetics, BCR, metastasis, or cancer-specific mortality) or one efficacy outcome (e.g., hormonal response, symptom relief, or quality of life).

  • Study types included RCTs, prospective or retrospective cohort studies, or case series with ≥10 participants.

  • Studies were excluded if they were reviews, editorials, letters, conference abstracts, lacked a clearly defined TRT intervention, involved men with untreated or metastatic disease, or did not report relevant outcomes.

Information sources and search strategy

A systematic search was performed on June 23, 2025, in three databases: PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), and Embase. An initial pilot search was conducted, via PubMed, to refine search terms. The final search strategy, developed iteratively, was applied across all databases and included terms related to TRT and definitive prostate cancer treatments. The full PubMed strategy is included in Appendix A to allow for full replication.

  1. 4.

    PubMed: Initial search returned 491 results. A refined strategy resulted in 220 results, which were narrowed to 82 after filters for human studies, adult male populations, and English language.

  2. 5.

    CENTRAL: 69 results (17 duplicates).

  3. 6.

    Embase: 342 results (29 duplicates).

After removing 46 duplicates across all databases, 447 titles and abstracts were screened.

Selection of sources of evidence

Titles and abstracts were independently screened by two reviewers to determine eligibility based on the predefined inclusion and exclusion criteria. Any disagreements were resolved through discussion and consensus. Full texts of potentially relevant articles were then retrieved and assessed for inclusion. Of the 447 screened studies, 38 full-text articles were reviewed, and 12 studies met the eligibility criteria and were included in the final synthesis. The study selection process is illustrated in the PRISMA-ScR flow diagram (Fig. 1).

Fig. 1: PRISMA 2020 flow diagram for study selection.
Fig. 1: PRISMA 2020 flow diagram for study selection.
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Page MJ, et al. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

Synthesis of results

Data were synthesised narratively, with findings grouped by oncological and hormonal outcomes. Given heterogeneity in study design, outcome measures, and follow-up durations, no quantitative synthesis was performed. Key results were tabulated to facilitate cross-study comparison (Tables 1 and 2).

Table 1 Summary of Study Characteristics and Oncological Outcomes.
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Table 2 Summary of TRT Efficacy Outcomes.
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Results

A total of 12 studies met the inclusion criteria and were included in this scoping review, published between 2005 and 2025. Most studies were retrospective cohort designs, with one study being a prospective case series, and sample sizes for TRT groups ranged from 10 to 152 men. Radical prostatectomy was the primary treatment in 6 studies, while 6 studies included patients primarily treated with radiotherapy. Patients receiving TRT post- definitive treatment for prostate cancer had reported mean ages ranging from 60.8 to 64.3 years, and median ages from 59 to 77 years across studies. The age range across all studies was 49 to 83 years.

The interval between definitive treatment for prostate cancer and TRT initiation varied widely across studies. Reported median times ranged from 12.3 to 45 months, with individual ranges extending from 2.6 to 170.9 months. Mean initiation times ranged from 14 to 36 months. One study stratified timing by treatment modality, with a median of 15 months post-prostatectomy and 45 months post-radiotherapy [17]. In 2 studies, timing of TRT post definitive treatment was not precisely specified [18, 19].

Across the 12 included studies, TRT was generally not associated with an increased risk of BCR or prostate cancer progression. Reported BCR rates in TRT groups were low, often lower than in non-TRT comparators [18, 20,21,22]. Ahlering et al. reported a BCR rate of 7.2% in the TRT treatment group compared to 12.6% in the matched control group [18], while Pastuszak et al. [20] observed BCR rates of 15.4% in the TRT treatment group versus 53.3% in the non-TRT treatment group, with all patients experiencing BCR in the high-risk prostate cancer groups [20]. Shahine et al. also reported favourable BCR outcomes in the TRT cohort with a rate of 6.4% compared to 12.6% in untreated controls [21]. PSA kinetics remained within expected post-treatment ranges [23]; Pastuszak et al. [20] reported PSA Velocity (PSAV) in the treatment group was 0.002 ng/mL/y [20] and Ory et al. [17] found the median PSAV in the treatment group was 0.0175 ng/mL/yr [17]. Several studies observed small PSA increases, especially in high-risk patients – e.g., a rise from 0.10 to 0.36 ng/mL in Gleason ≥8 patients [24], or from 0.004 to 0.007 ng/mL (p < 0.0001) [20], but these were not indicative of recurrence. Importantly, no study demonstrated a statistically significant increase in oncologic risk attributable to TRT use. Please see Table 1 for all oncological outcomes in each included study.

Of the 11 studies reporting hormonal outcomes, significant increases in total testosterone (TT) and/or free testosterone (FT) following TRT, with TT typically rising from hypogonadal to eugonadal levels were observed. Reported TT increases ranged from median 188 to 591 ng/dL. From the included studies, 7 noted improvements in sexual function, energy, and other hypogonadal symptoms including, where measured, validated instruments such as the Sexual Health Inventory for Men (SHIM) and Expanded Prostate Cancer Index Composite (EPIC) scores reflecting symptomatic benefit. Overall, TRT was effective in restoring testosterone levels and improving quality-of-life indicators in this post-treatment population. Please see Table 2 for full TRT efficacy outcomes in each included study.

Definitions of BCR varied across studies and follow-up duration ranged from 6 to 189 months. Studies differed in TRT modality, dosage, and monitoring protocols, introducing significant heterogeneity. Most included studies were retrospective and no studies focused on ethnically diverse populations or long-term recurrence outcomes. Only a minority of included studies stratified outcomes by Gleason score or cancer risk group.

Discussion

The findings from this scoping review systematically map the available evidence on the safety and efficacy of TRT in men following definitive treatment for prostate cancer. Historically, TRT has been contraindicated in this population due to concerns about oncological safety [12, 13]. However, the findings from the 12 included studies suggest that, in appropriately selected individuals, TRT may be both effective and oncologically safe.

11 of the included studies were retrospective cohort designs with small to moderate sample sizes, and one was a prospective case series. Despite methodological limitations, a consistent signal of oncologic safety was observed. BCR rates in men receiving TRT were low and, in several studies, even lower than in non-TRT comparators [18, 20, 21]. Where PSA kinetics were reported, increases were minor and align with established non-recurrence benchmarks [20, 23,24,25]. Importantly, no study demonstrated a statistically significant increase in oncologic risk attributable to TRT use. These findings are particularly notable given the historical hesitancy to use TRT in this setting, which stemmed from early studies by Huggins and Hodges suggesting that androgens promote prostate cancer growth [12]. However, emerging literature now challenges this paradigm; evidence supports the saturation model, which theorises that prostate androgen receptors become fully activated at low testosterone levels, beyond which additional testosterone does not stimulate further prostate cancer growth [26]. A schematic representation of the saturation model was tailored, providing a visual framework that supports the mechanistic insights discussed (Fig. 2) [26]. Furthermore, studies in both post-prostatectomy and post-radiotherapy patients demonstrate no increased risk of BCR, and in some cases, TRT may even confer a protective effect [18, 20, 22, 25].

Fig. 2: Schematic illustrating the principles of the testosterone saturation model.
Fig. 2: Schematic illustrating the principles of the testosterone saturation model.
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T testosterone.

TRT was effective in addressing hypogonadism in this post-treatment population. All studies reporting hormonal outcomes observed significant increases in TT and/or FT levels, often from hypogonadal to eugonadal ranges [18, 20, 21, 24, 25, 27,28,29]. Symptomatic improvements were also noted, particularly in libido, energy levels, and sexual function [18, 24, 28,29,30]. While some studies used validated instruments such as the SHIM and EPIC questionnaires [21, 28, 29], others reported subjective improvements without standardised assessment tools [18, 20, 24, 27, 30], highlighting variability in outcome measurement.

Timing of TRT initiation varied substantially, ranging from as early as 2.6 months to over 14 years post-treatment. Some studies stratified outcomes by treatment modality, with slightly earlier initiation post-prostatectomy compared to radiotherapy [17]. However, in some cases, the rationale for TRT timing and criteria for initiation were not explicitly reported. This reflects a broader lack of consensus on optimal timing and patient selection for TRT in prostate cancer survivors. It is also important to note that two studies included patients treated not only with traditional TRT but also with other testosterone-targeted hormonal therapies such as clomiphene citrate [17, 19]. However, in this review, patients from these studies who were not treated with TRT were excluded from data extraction to preserve consistency with the review objectives.

While this review excluded studies with fewer than 10 participants, a small case series by Kadomoto et al. reported favourable outcomes among six men with high-risk prostate cancer treated with injectable TRT following brachytherapy [31]. No BCR occurred with TRT therapy and five out of six patients had only minor increases in PSA levels, with one experiencing a transient PSA rise to 0.843 ng/mL which later declined to 0.338 ng/mL without the need for TRT cessation [31]. Although not eligible for data extraction, this study adds anecdotal support to the emerging safety profile of TRT in patients post definitive treatment for prostate cancer and underscores the need for larger, prospective studies in this subgroup.

Despite the promising findings, the evidence base mapped in this scoping review is limited by several important factors. Most included studies were retrospective in design, which introduces potential for selection bias, incomplete data capture, and confounding. Sample sizes were generally small to moderate, limiting the statistical power to detect rare oncologic outcomes such as metastasis or prostate cancer-specific mortality. Additionally, definitions of BCR varied across studies, and follow-up durations ranged widely from 6 months to over 15 years, contributing to significant heterogeneity. Variability in TRT regimens (formulation, dosage, and monitoring protocols) further complicates interpretation. Quality-of-life outcomes were often reported using non-validated or subjective measures, and few studies stratified outcomes by risk group, Gleason score, or other prognostic factors. Furthermore, most study populations lacked ethnic diversity, limiting generalisability. Finally, this review included only English-language, peer-reviewed studies and excluded case reports with fewer than 10 participants, which may have led to the omission of relevant but limited evidence.

Nonetheless, across the reviewed studies, a consistent finding of oncologic safety and therapeutic benefit was observed. These preliminary findings suggest that, in carefully selected men with stable disease, TRT may be both effective and safe. However, prospective trials with rigorous methodology, standardised outcome measures, and long-term follow-up are essential to validate these observations and better inform clinical decision-making.

Conclusion

This scoping review systematically mapped the available evidence on TRT in men following definitive treatment for prostate cancer. Across 12 studies published between 2005 and 2025, TRT was not associated with increased risk of BCR or cancer progression. Instead, TRT demonstrated consistent efficacy in restoring serum testosterone levels and alleviating hypogonadal symptoms.

These findings challenge the historical belief that TRT poses an inherent oncologic risk to prostate cancer survivors. However, limitations in the existing evidence, such as small sample sizes, retrospective study designs, heterogeneous outcome reporting, and underrepresentation of high-risk and diverse patient groups, highlight the need for high-quality prospective research. Until such data become available, TRT may be cautiously considered in men with documented hypogonadism and stable post-treatment disease, provided that treatment decisions are individualised and closely monitored.