madman
Super Moderator
* Interestingly, when analyzing our data by individual patients, 16% exhibited an elevated PSA (≥1 ng/mL) throughout the one-year period. These patients had a median (IQR) baseline PSA of 3.5 (1.8–5.5) ng/mL, which was higher compared to the overall cohort. Notably, three of these patients (Patients A–C as elucidated in Results) progressed to intermediate-risk disease on subsequent biopsies. This finding suggests that an elevated baseline PSA may be a potential risk factor for disease progression in patients initiated on TRT. Future studies will focus on further investigating this subgroup as the sample size continues to grow.
* It is important to interpret our findings in the context of the overall study design as it involves several limitations. As this was a retrospective study, our findings cannot be used to draw definitive conclusions regarding the safety of TRT in men on AS. Currently, all studies on TRT for men on AS are retrospective. Definitive recommendations for TRT in this group necessitate large-scale, randomized controlled trials. For now, TRT initiation in men on AS for low-grade PCa should be based on shared decision-making and individualized clinical judgment.
------
* Overall, these data contribute to the mounting evidence suggesting that TRT may be a safe and viable option for men on AS for PCa. To date, there have been no randomized controlled trials on men receiving TRT on AS for PCa and the number of patients remains limited. Currently, there are no studies that definitively show that men undergoing TRT have a higher rate of PCa progression than men not undergoing TRT.
-----------
* It is estimated that one in six men will develop PCa in their lifetime, and the prevalence of occult PCa is as high as 60%–70% in men older than 80 years.32,33 Therefore, many men with undiagnosed PCa are receiving TRT. Gathering more data regarding the safety of TRT in men with low-grade PCa is imperative to understand the risks and benefits for all men, not just those on AS. We aim to build on this current study by increasing sample size, analyzing subgroups such as individuals with elevated baseline PSA initiating TRT, and adding control groups.
--------------4
Discussion
To date, this is the largest retrospective, single-center study of men on AS for low-grade PCa. The significant increase in mean TT level after initiating TRT demonstrates a robust response to androgen replacement treatment. According to the androgen hypothesis, the mean PSA values should significantly increase as the TT increases. Furthermore, we would expect an increase in the rate of PCa progression on biopsies. However, our data demonstrates no significant variation or increase in PSA levels over time (Figure 2) and shows a rate of progression-free biopsies like the general population of men on AS for PCa. Interestingly, sensitivity analysis demonstrated that age was not shown to significantly influence the PSA levels over time.
------------
Providing context to our findings, a retrospective study involving 2084 men from 1995 to 2016 suggested a 5-year rate of biopsy progression-free survival of 83% in men on AS for PCa over 60 years of age.19 The 5-year treatment-free survival was 71%.19 Therefore, in 5 years, ∼17% of men over 60 years of age on AS would be expected to demonstrate a progression on biopsy and 29% would require treatment for disease progression. Thus, the rate of biopsy progression in our patients on TRT (20%) is consistent with the overall rates of biopsy progression, irrespective of TRT use.
-------------------
While three of the 15 patients (20%) with subsequent biopsies available eventually progressed to intermediate risk PCa based on pathology (Grade Groups 2 and 3), this occurred after years of follow-up on TRT (4.17 years, 5.0 years, 8.4 years). None of the patients developed Grade Group 4 or 5 pathology on prostate biopsy. As none of the men in the short term demonstrated disease progression over the two-year time interval, these findings are consistent with recent literature showing that TRT in men on AS for PCa does not increase the risk of disease progression.
-----------------
Morgentaler was the first to report utilization of TRT in a man on AS for low risk PCa in 2009, finding decreased PSA levels after two years of treatment.20 In 2011, Morgentaler et.al performed a retrospective study on thirteen testosterone deficient men with untreated PCa. TRT was not associated with disease progression, as measured by PSA and Gleason score.13 Similar results were obtained by Ory et. al, who found no evidence of Gleason upgrading in eight men undergoing TRT while on AS.21 Subsequently, Kacker et al. compared 28 men undergoing TRT on AS for PCa with a control group of men on AS not undergoing TRT.14 The authors demonstrated no difference in prostate biopsy progression rates in the menon AS on TRT. More recently, a population-based analysis of 167 men on AS for PCa receiving TRT found that TRT was not associated with conversion from AS to active treatment or worsening mortality.22 Finally, in 2023, Daza et. al matched 24 TRT patients on AS for PCa to 72 controls not on TRT and found the TRT group did not experience a significantly greater conversion to treatment or increase in PSA.15
----------------
These studies and our data align with the hypothesis proposed by the saturation model. This model suggests that the prostate androgen receptors become maximally saturated at a testosterone concentration of 240–250 ng/dL.23,24 The TRiUS registry supports this threshold, as men undergoing TRT with a baseline serum testosterone concentration of 250 ng/dL or greater did not demonstrate a statistically significant increase in PSA, while those with a baseline testosterone concentration under 250 ng/dL did.25 Perhaps the most robust support of the saturation model is a randomized controlled trial conducted by Muller et al. In this study, 8122 men were randomized to receive placebo or dutasteride, and the authors found that low baseline testosterone was associated with the lowest PCa risk but no association between higher baseline testosterone levels and PCa risk or progression was demonstrated.26 Notably, only seven men (16.3%) in our study had baseline testosterone levels below the saturation threshold of 250 ng/dL. With 83.7% of patients having baseline testosterone levels above this threshold, the overall lack of a significant increase in PSA levels observed in the cohort aligns with the androgen saturation model. However, to stratify and analyze PSA changes in men with baseline testosterone levels below versus above the saturation threshold, a larger study sample size is needed. As we continue to build our database, future studies will aim to address this by examining these subgroups in greater detail.
-------------
While there is mounting evidence suggesting the safety of TRT in men on AS for PCa, there is still data suggesting caution. Leibowitz et al. conducted a retrospective study on PCa survivors who underwent TRT. 41 of 96 men (42.7%) experienced a rise in PSA, and PSA values declined after stopping TRT.16 A meta-analysis conducted by Cui et al. reports a low risk of developing PCa on TRT in the short term but an elevated odds ratio (2.1 and 3.1 for men on injection or transdermal TRT, respectively) in the long term.27 However,the authors conclude that more long-term data is warranted as existing studies are limited. In practice, urologists remain divided on the provision of TRT to patients on AS for PCa with one survey of Canadian urologists finding 65% agreed with this practice.15
----------------
Interestingly, when analyzing our data by individual patients, 16% exhibited an elevated PSA (≥1 ng/mL) throughout the one-year period. These patients had a median (IQR) baseline PSA of 3.5 (1.8–5.5) ng/mL, which was higher compared to the overall cohort. Notably, three of these patients (Patients A–C as elucidated in Results) progressed to intermediate-risk disease on subsequent biopsies. This finding suggests that an elevated baseline PSA may be a potential risk factor for disease progression in patients initiated on TRT. Future studies will focus on further investigating this subgroup as the sample size continues to grow.
-----------------
It is important to interpret our findings in the context of the overall study design as it involves several limitations. As this was a retrospective study, our findings cannot be used to draw definitive conclusions regarding the safety of TRT in men on AS. Currently, all studies on TRT for men on AS are retrospective. Definitive recommendations for TRT in this group necessitate large-scale, randomized controlled trials. For now, TRT initiation in men on AS for low-grade PCa should be based on shared decision-making and individualized clinical judgment. Further limitations include missing data for certain individuals in the study, including some missing testosterone or PSA labs as well as unavailable surveillance biopsies. Acquiring surveillance biopsies from chart review was hindered by patient deferment in the context of a favorable clinical picture and patient amenability. Further, many patients did not have biopsies available in the chart review due to incomplete documentation at the time of transition from paper records to electronic health records at our institution.These factors unfortunately limited the number of men with available baseline and surveillance biopsies, resulting in a relatively small sample size. Additional, given the time period in which the data is collected (2009–2023), MRI data was not able to be collected for enough patients as many of the clinic visits occurred prior to the widespread implementation of prostate MRIs in our institution’s AS protocol.
-------------
While this is at the moment the largest single-center retrospective study of men on AS for PCa undergoing TRT, it still has a relatively small patient number, resulting in an inability to analyze subgroups. Moreover, the incidence of disease progression observed in a subset of patients warrants careful consideration and suggests the need for extended follow-up studies to elucidate the long-term implications of testosterone therapy in this population. We hope for longer follow-up as we continue to build our database to add more individuals. The lack of a control group further limits the generalizability and ability to draw a conclusion from this study. However, our aim is to present our data collected from our novel database at this time as there are few similar studies available. Future studies will involve adding control groups for comparisons a swe are able to increase overall patient sample size.
--------------
Overall, these data contribute to the mounting evidence suggesting that TRT may be a safe and viable option for men on AS for PCa. To date, there have been no randomized controlled trials on men receiving TRT on AS for PCa and the number of patients remains limited. Currently, there are no studies that definitively show that men undergoing TRT have a higher rate of PCa progression than men not undergoing TRT. Regardless, the number of people undergoing TRT continues to increase: around 3.75% of men over 60 are on TRT today, a number that has tripled in recent years.28 Recently, the results of the TRAVERSE study were published in 2023, showing no increased incidence of PCa or development of high-grade PCa in men receiving TRT vs. placebo, and TRT was non-inferior to placebo in the risk of major cardiac events.29 These results are expected to contribute to the rise in men initiating TRT in the coming years. The most recent AUA Testosterone Guidelines states that testosterone supplementation is not correlated with an increased risk for the development of PCa.30,31
---------------
It is estimated that one in six men will develop PCa in their lifetime, and the prevalence of occult PCa is as high as 60%–70% in men older than 80 years.32,33 Therefore, many men with undiagnosed PCa are receiving TRT. Gathering more data regarding the safety of TRT in men with low-grade PCa is imperative to understand the risks and benefits for all men, not just those on AS. We aim to build on this current study by increasing sample size, analyzing subgroups such as individuals with elevated baseline PSA initiating TRT, and adding control groups.
--------4
Conclusion
The results from our database of men with low testosterone demonstrated that after one year on TRT, no significant change in PSA levels was observed, despite a significant increase in testosterone levels. At the histological level, our findings demonstrate a low rate of disease progression, even after several years of TRT. However, conclusions regarding pathology cannot be made due to limited available biopsy data. These data contribute to the mounting evidence demonstrating that TRT may be a safe and effective option for symptomatic men with low testosterone levels on AS for PCa.
* It is important to interpret our findings in the context of the overall study design as it involves several limitations. As this was a retrospective study, our findings cannot be used to draw definitive conclusions regarding the safety of TRT in men on AS. Currently, all studies on TRT for men on AS are retrospective. Definitive recommendations for TRT in this group necessitate large-scale, randomized controlled trials. For now, TRT initiation in men on AS for low-grade PCa should be based on shared decision-making and individualized clinical judgment.
------
* Overall, these data contribute to the mounting evidence suggesting that TRT may be a safe and viable option for men on AS for PCa. To date, there have been no randomized controlled trials on men receiving TRT on AS for PCa and the number of patients remains limited. Currently, there are no studies that definitively show that men undergoing TRT have a higher rate of PCa progression than men not undergoing TRT.
-----------
* It is estimated that one in six men will develop PCa in their lifetime, and the prevalence of occult PCa is as high as 60%–70% in men older than 80 years.32,33 Therefore, many men with undiagnosed PCa are receiving TRT. Gathering more data regarding the safety of TRT in men with low-grade PCa is imperative to understand the risks and benefits for all men, not just those on AS. We aim to build on this current study by increasing sample size, analyzing subgroups such as individuals with elevated baseline PSA initiating TRT, and adding control groups.
--------------4
Discussion
To date, this is the largest retrospective, single-center study of men on AS for low-grade PCa. The significant increase in mean TT level after initiating TRT demonstrates a robust response to androgen replacement treatment. According to the androgen hypothesis, the mean PSA values should significantly increase as the TT increases. Furthermore, we would expect an increase in the rate of PCa progression on biopsies. However, our data demonstrates no significant variation or increase in PSA levels over time (Figure 2) and shows a rate of progression-free biopsies like the general population of men on AS for PCa. Interestingly, sensitivity analysis demonstrated that age was not shown to significantly influence the PSA levels over time.
------------
Providing context to our findings, a retrospective study involving 2084 men from 1995 to 2016 suggested a 5-year rate of biopsy progression-free survival of 83% in men on AS for PCa over 60 years of age.19 The 5-year treatment-free survival was 71%.19 Therefore, in 5 years, ∼17% of men over 60 years of age on AS would be expected to demonstrate a progression on biopsy and 29% would require treatment for disease progression. Thus, the rate of biopsy progression in our patients on TRT (20%) is consistent with the overall rates of biopsy progression, irrespective of TRT use.
-------------------
While three of the 15 patients (20%) with subsequent biopsies available eventually progressed to intermediate risk PCa based on pathology (Grade Groups 2 and 3), this occurred after years of follow-up on TRT (4.17 years, 5.0 years, 8.4 years). None of the patients developed Grade Group 4 or 5 pathology on prostate biopsy. As none of the men in the short term demonstrated disease progression over the two-year time interval, these findings are consistent with recent literature showing that TRT in men on AS for PCa does not increase the risk of disease progression.
-----------------
Morgentaler was the first to report utilization of TRT in a man on AS for low risk PCa in 2009, finding decreased PSA levels after two years of treatment.20 In 2011, Morgentaler et.al performed a retrospective study on thirteen testosterone deficient men with untreated PCa. TRT was not associated with disease progression, as measured by PSA and Gleason score.13 Similar results were obtained by Ory et. al, who found no evidence of Gleason upgrading in eight men undergoing TRT while on AS.21 Subsequently, Kacker et al. compared 28 men undergoing TRT on AS for PCa with a control group of men on AS not undergoing TRT.14 The authors demonstrated no difference in prostate biopsy progression rates in the menon AS on TRT. More recently, a population-based analysis of 167 men on AS for PCa receiving TRT found that TRT was not associated with conversion from AS to active treatment or worsening mortality.22 Finally, in 2023, Daza et. al matched 24 TRT patients on AS for PCa to 72 controls not on TRT and found the TRT group did not experience a significantly greater conversion to treatment or increase in PSA.15
----------------
These studies and our data align with the hypothesis proposed by the saturation model. This model suggests that the prostate androgen receptors become maximally saturated at a testosterone concentration of 240–250 ng/dL.23,24 The TRiUS registry supports this threshold, as men undergoing TRT with a baseline serum testosterone concentration of 250 ng/dL or greater did not demonstrate a statistically significant increase in PSA, while those with a baseline testosterone concentration under 250 ng/dL did.25 Perhaps the most robust support of the saturation model is a randomized controlled trial conducted by Muller et al. In this study, 8122 men were randomized to receive placebo or dutasteride, and the authors found that low baseline testosterone was associated with the lowest PCa risk but no association between higher baseline testosterone levels and PCa risk or progression was demonstrated.26 Notably, only seven men (16.3%) in our study had baseline testosterone levels below the saturation threshold of 250 ng/dL. With 83.7% of patients having baseline testosterone levels above this threshold, the overall lack of a significant increase in PSA levels observed in the cohort aligns with the androgen saturation model. However, to stratify and analyze PSA changes in men with baseline testosterone levels below versus above the saturation threshold, a larger study sample size is needed. As we continue to build our database, future studies will aim to address this by examining these subgroups in greater detail.
-------------
While there is mounting evidence suggesting the safety of TRT in men on AS for PCa, there is still data suggesting caution. Leibowitz et al. conducted a retrospective study on PCa survivors who underwent TRT. 41 of 96 men (42.7%) experienced a rise in PSA, and PSA values declined after stopping TRT.16 A meta-analysis conducted by Cui et al. reports a low risk of developing PCa on TRT in the short term but an elevated odds ratio (2.1 and 3.1 for men on injection or transdermal TRT, respectively) in the long term.27 However,the authors conclude that more long-term data is warranted as existing studies are limited. In practice, urologists remain divided on the provision of TRT to patients on AS for PCa with one survey of Canadian urologists finding 65% agreed with this practice.15
----------------
Interestingly, when analyzing our data by individual patients, 16% exhibited an elevated PSA (≥1 ng/mL) throughout the one-year period. These patients had a median (IQR) baseline PSA of 3.5 (1.8–5.5) ng/mL, which was higher compared to the overall cohort. Notably, three of these patients (Patients A–C as elucidated in Results) progressed to intermediate-risk disease on subsequent biopsies. This finding suggests that an elevated baseline PSA may be a potential risk factor for disease progression in patients initiated on TRT. Future studies will focus on further investigating this subgroup as the sample size continues to grow.
-----------------
It is important to interpret our findings in the context of the overall study design as it involves several limitations. As this was a retrospective study, our findings cannot be used to draw definitive conclusions regarding the safety of TRT in men on AS. Currently, all studies on TRT for men on AS are retrospective. Definitive recommendations for TRT in this group necessitate large-scale, randomized controlled trials. For now, TRT initiation in men on AS for low-grade PCa should be based on shared decision-making and individualized clinical judgment. Further limitations include missing data for certain individuals in the study, including some missing testosterone or PSA labs as well as unavailable surveillance biopsies. Acquiring surveillance biopsies from chart review was hindered by patient deferment in the context of a favorable clinical picture and patient amenability. Further, many patients did not have biopsies available in the chart review due to incomplete documentation at the time of transition from paper records to electronic health records at our institution.These factors unfortunately limited the number of men with available baseline and surveillance biopsies, resulting in a relatively small sample size. Additional, given the time period in which the data is collected (2009–2023), MRI data was not able to be collected for enough patients as many of the clinic visits occurred prior to the widespread implementation of prostate MRIs in our institution’s AS protocol.
-------------
While this is at the moment the largest single-center retrospective study of men on AS for PCa undergoing TRT, it still has a relatively small patient number, resulting in an inability to analyze subgroups. Moreover, the incidence of disease progression observed in a subset of patients warrants careful consideration and suggests the need for extended follow-up studies to elucidate the long-term implications of testosterone therapy in this population. We hope for longer follow-up as we continue to build our database to add more individuals. The lack of a control group further limits the generalizability and ability to draw a conclusion from this study. However, our aim is to present our data collected from our novel database at this time as there are few similar studies available. Future studies will involve adding control groups for comparisons a swe are able to increase overall patient sample size.
--------------
Overall, these data contribute to the mounting evidence suggesting that TRT may be a safe and viable option for men on AS for PCa. To date, there have been no randomized controlled trials on men receiving TRT on AS for PCa and the number of patients remains limited. Currently, there are no studies that definitively show that men undergoing TRT have a higher rate of PCa progression than men not undergoing TRT. Regardless, the number of people undergoing TRT continues to increase: around 3.75% of men over 60 are on TRT today, a number that has tripled in recent years.28 Recently, the results of the TRAVERSE study were published in 2023, showing no increased incidence of PCa or development of high-grade PCa in men receiving TRT vs. placebo, and TRT was non-inferior to placebo in the risk of major cardiac events.29 These results are expected to contribute to the rise in men initiating TRT in the coming years. The most recent AUA Testosterone Guidelines states that testosterone supplementation is not correlated with an increased risk for the development of PCa.30,31
---------------
It is estimated that one in six men will develop PCa in their lifetime, and the prevalence of occult PCa is as high as 60%–70% in men older than 80 years.32,33 Therefore, many men with undiagnosed PCa are receiving TRT. Gathering more data regarding the safety of TRT in men with low-grade PCa is imperative to understand the risks and benefits for all men, not just those on AS. We aim to build on this current study by increasing sample size, analyzing subgroups such as individuals with elevated baseline PSA initiating TRT, and adding control groups.
--------4
Conclusion
The results from our database of men with low testosterone demonstrated that after one year on TRT, no significant change in PSA levels was observed, despite a significant increase in testosterone levels. At the histological level, our findings demonstrate a low rate of disease progression, even after several years of TRT. However, conclusions regarding pathology cannot be made due to limited available biopsy data. These data contribute to the mounting evidence demonstrating that TRT may be a safe and effective option for symptomatic men with low testosterone levels on AS for PCa.
