#Vasectomy and #Prostate Cancer Incidence and Mortality in a Large US Cohort
http://m.jco.ascopubs.org/content/early/2016/09/15/JCO.2015.66.2361
Conclusion Results from these large prospective cohorts do not support associations of vasectomy with either prostate cancer incidence or prostate cancer mortality.
http://m.jco.ascopubs.org/content/early/2016/09/15/JCO.2015.66.2361
Conclusion Results from these large prospective cohorts do not support associations of vasectomy with either prostate cancer incidence or prostate cancer mortality.
#Saturated fat intake and #prostate cancer aggressiveness: results from the population-based North Carolina-Louisiana Prostate Cancer Project
http://www.nature.com/pcan/journal/vaop/ncurrent/full/pcan201639a.html
Conclusions: High total fat-adjusted saturated fat intake was associated with increased PC aggressiveness, with a suggestion of a stronger effect in men not using statins. The association between total fat-adjusted cholesterol intake and PC aggressiveness was most pronounced in European Americans.
http://www.nature.com/pcan/journal/vaop/ncurrent/full/pcan201639a.html
Conclusions: High total fat-adjusted saturated fat intake was associated with increased PC aggressiveness, with a suggestion of a stronger effect in men not using statins. The association between total fat-adjusted cholesterol intake and PC aggressiveness was most pronounced in European Americans.
Nature
Prostate Cancer and Prostatic Diseases - Saturated fat intake and prostate cancer aggressiveness: results from the population-based…
Prostate Cancer and Prostatic Diseases, covering all aspects of prostatic diseases, in particular prostate cancer. The journal is of interest to surgeons, oncologists, clinicians, and researchers involved in disease of the prostate.
#Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk #prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30661-1/abstract
Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30661-1/abstract
Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy
Diagnostic accuracy of multi-parametric #MRI and TRUS biopsy in #prostate cancer (PROMIS): a paired validating confirmatory study
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32401-1/fulltext
Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32401-1/fulltext
Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer
#Vasectomy and #Prostate Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition (EPIC)
http://ascopubs.org/doi/abs/10.1200/JCO.2016.70.0062
These findings from a large European prospective study show no elevated risk for overall, high-grade or advanced-stage prostate cancer, or death due to prostate cancer in men who have undergone a vasectomy compared with men who have not.
http://ascopubs.org/doi/abs/10.1200/JCO.2016.70.0062
These findings from a large European prospective study show no elevated risk for overall, high-grade or advanced-stage prostate cancer, or death due to prostate cancer in men who have undergone a vasectomy compared with men who have not.
Reconciling the Effects of #Screening on #Prostate Cancer Mortality in the ERSPC and PLCO Trials
http://annals.org/aim/article/2652567/reconciling-effects-screening-prostate-cancer-mortality-erspc-plco-trials
The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction
Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening
After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality
http://annals.org/aim/article/2652567/reconciling-effects-screening-prostate-cancer-mortality-erspc-plco-trials
The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction
Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening
After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality
annals.org
Effects of Screening on Prostate Cancer Mortality in ERSPC and PLCO | Annals of Internal Medicine | American College of Physicians
Background: The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction. Objective: To…
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Assessment of the Diagnostic Accuracy of Biparametric Magnetic #Resonance Imaging for #Prostate Cancer in Biopsy-Naive Men
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2683950
A total of 1020 men were enrolled, with a median age of 67 years (interquartile range, 61-71 years) and a median prostate-specific antigen level of 8.0 ng/mL (interquartile range, 5.7-13.0 ng/mL). Combined biopsies detected any and significant prostate cancer in 655 of 1020 men (64%) and 404 of 1020 men (40%), respectively. Restricting combined biopsies to men with suspicious bpMRI findings meant 305 of 1020 men (30%) with low-suspicious bpMRIs could avoid prostate biopsies (biopsy in 715 men with suspicious bpMRIs vs all 1020 men who required standard biopsies 70%; P < .001). Significant prostate cancer diagnoses were improved by 11% (396 vs 351 men; P < .001), and insignificant prostate cancer diagnoses were reduced by 40% (173 vs 288 men; P < .001) compared with our current diagnostic standard, standard biopsies alone in all men. The NPV of bpMRI findings in ruling out significant prostate cancer was 97% (95% CI, 95%-99%).
Conclusions and Relevance Low-suspicion bpMRI has a high NPV in ruling out significant prostate cancer in biopsy-naive men. Using a simple and rapid bpMRI method as a triage test seems to improve risk stratification and may be used to exclude aggressive disease and avoid unnecessary biopsies with its inherent risks. Future studies are needed to fully explore its role in clinical prostate cancer management.
Assessment of the Diagnostic Accuracy of Biparametric Magnetic #Resonance Imaging for #Prostate Cancer in Biopsy-Naive Men
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2683950
A total of 1020 men were enrolled, with a median age of 67 years (interquartile range, 61-71 years) and a median prostate-specific antigen level of 8.0 ng/mL (interquartile range, 5.7-13.0 ng/mL). Combined biopsies detected any and significant prostate cancer in 655 of 1020 men (64%) and 404 of 1020 men (40%), respectively. Restricting combined biopsies to men with suspicious bpMRI findings meant 305 of 1020 men (30%) with low-suspicious bpMRIs could avoid prostate biopsies (biopsy in 715 men with suspicious bpMRIs vs all 1020 men who required standard biopsies 70%; P < .001). Significant prostate cancer diagnoses were improved by 11% (396 vs 351 men; P < .001), and insignificant prostate cancer diagnoses were reduced by 40% (173 vs 288 men; P < .001) compared with our current diagnostic standard, standard biopsies alone in all men. The NPV of bpMRI findings in ruling out significant prostate cancer was 97% (95% CI, 95%-99%).
Conclusions and Relevance Low-suspicion bpMRI has a high NPV in ruling out significant prostate cancer in biopsy-naive men. Using a simple and rapid bpMRI method as a triage test seems to improve risk stratification and may be used to exclude aggressive disease and avoid unnecessary biopsies with its inherent risks. Future studies are needed to fully explore its role in clinical prostate cancer management.
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Radical #Prostatectomy or Watchful Waiting in #Prostate Cancer — 29-Year Follow-up
https://www.nejm.org/doi/full/10.1056/NEJMoa1807801
The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).
CONCLUSIONS
Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer
Radical #Prostatectomy or Watchful Waiting in #Prostate Cancer — 29-Year Follow-up
https://www.nejm.org/doi/full/10.1056/NEJMoa1807801
The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).
CONCLUSIONS
Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer
The New England Journal of Medicine
Radical Prostatectomy or Watchful Waiting in Prostate Cancer — 29-Year Follow-up | NEJM
Radical prostatectomy reduces mortality among men with clinically detected localized
prostate cancer, but evidence from randomized trials with long-term follow-up is sparse.
We randomly assigned 69...
prostate cancer, but evidence from randomized trials with long-term follow-up is sparse.
We randomly assigned 69...
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#Ejaculation Frequency and Risk of #Prostate Cancer: Updated Results with an Additional Decade of Follow-up
https://www.europeanurology.com/article/S0302-2838(16)00377-8/abstract/abstract_52392463?mobileUi=0
Evidence suggests that ejaculation frequency may be inversely related to the risk of prostate cancer (PCa), a disease for which few modifiable risk factors have been identified.
Ejaculation frequency at age 40–49 yr was positively associated with age-standardized body mass index, physical activity, divorce, history of sexually transmitted infections, and consumption of total calories and alcohol. Prostate-specific antigen (PSA) test utilization by 2008, number of PSA tests, and frequency of prostate biopsy were similar across frequency categories. In multivariable analyses, the hazard ratio for PCa incidence for ≥21 compared to 4–7 ejaculations per month was 0.81 for frequency at age 20–29 yr and 0.78 for frequency at age 40–49 yr. Associations were driven by low-risk disease, were similar when restricted to a PSA-screened cohort, and were unlikely to be explained by competing causes of death.
Conclusions
These findings provide additional evidence of a beneficial role of more frequent ejaculation throughout adult life in the etiology of PCa, particularly for low-risk disease.
#Ejaculation Frequency and Risk of #Prostate Cancer: Updated Results with an Additional Decade of Follow-up
https://www.europeanurology.com/article/S0302-2838(16)00377-8/abstract/abstract_52392463?mobileUi=0
Evidence suggests that ejaculation frequency may be inversely related to the risk of prostate cancer (PCa), a disease for which few modifiable risk factors have been identified.
Ejaculation frequency at age 40–49 yr was positively associated with age-standardized body mass index, physical activity, divorce, history of sexually transmitted infections, and consumption of total calories and alcohol. Prostate-specific antigen (PSA) test utilization by 2008, number of PSA tests, and frequency of prostate biopsy were similar across frequency categories. In multivariable analyses, the hazard ratio for PCa incidence for ≥21 compared to 4–7 ejaculations per month was 0.81 for frequency at age 20–29 yr and 0.78 for frequency at age 40–49 yr. Associations were driven by low-risk disease, were similar when restricted to a PSA-screened cohort, and were unlikely to be explained by competing causes of death.
Conclusions
These findings provide additional evidence of a beneficial role of more frequent ejaculation throughout adult life in the etiology of PCa, particularly for low-risk disease.
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Computer simulations suggest that #prostate enlargement due to benign prostatic #hyperplasia mechanically impedes prostate cancer growth
https://www.pnas.org/content/116/4/1152
Prostate cancer and benign prostatic hyperplasia are common genitourinary diseases in aging men. Both pathologies may coexist and share numerous similarities, which have suggested several connections or some interplay between them.
The mechanical stress fields that originate as tumors enlarge have been shown to slow down their dynamics. Benign prostatic hyperplasia contributes to these mechanical stress fields, hence further restraining prostate cancer growth. We derived a tissue-scale, patient-specific mechanically coupled mathematical model to qualitatively investigate the mechanical interaction of prostate cancer and benign prostatic hyperplasia.
Our simulations show that a history of benign prostatic hyperplasia creates mechanical stress fields in the prostate that impede prostatic tumor growth and limit its invasiveness. The technology presented herein may assist physicians in the clinical management of benign prostate hyperplasia and prostate cancer by predicting pathological outcomes on a tissue-scale, patient-specific basis
Computer simulations suggest that #prostate enlargement due to benign prostatic #hyperplasia mechanically impedes prostate cancer growth
https://www.pnas.org/content/116/4/1152
Prostate cancer and benign prostatic hyperplasia are common genitourinary diseases in aging men. Both pathologies may coexist and share numerous similarities, which have suggested several connections or some interplay between them.
The mechanical stress fields that originate as tumors enlarge have been shown to slow down their dynamics. Benign prostatic hyperplasia contributes to these mechanical stress fields, hence further restraining prostate cancer growth. We derived a tissue-scale, patient-specific mechanically coupled mathematical model to qualitatively investigate the mechanical interaction of prostate cancer and benign prostatic hyperplasia.
Our simulations show that a history of benign prostatic hyperplasia creates mechanical stress fields in the prostate that impede prostatic tumor growth and limit its invasiveness. The technology presented herein may assist physicians in the clinical management of benign prostate hyperplasia and prostate cancer by predicting pathological outcomes on a tissue-scale, patient-specific basis
PNAS
Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer…
Benign prostatic hyperplasia (BPH) is a common disease in aging men that causes the prostate to enlarge progressively. Men with larger prostates tend to harbor prostatic tumors with more favorable features. The underlying mechanisms that explain this interaction…
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A four‐group #urine risk classifier for predicting outcomes in patients with #prostate cancer
https://onlinelibrary.wiley.com/doi/10.1111/bju.14811
To develop a risk classifier using urine‐derived extracellular vesicle (EV)‐RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS).
PUR‐4 status predicted the presence of clinically significant intermediate‐ or high‐risk disease (area under the curve = 0.77, 95% confidence interval CI 0.70–0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub‐cohort (n = 87), groups defined by PUR status and proportion of PUR‐4 had a significant association with time to progression (interquartile range hazard ratio HR 2.86, 95% CI 1.83–4.47; P < 0.001). PUR‐4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26–20.81; P < 0.001).
Conclusion
Urine‐derived EV‐RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.
A four‐group #urine risk classifier for predicting outcomes in patients with #prostate cancer
https://onlinelibrary.wiley.com/doi/10.1111/bju.14811
To develop a risk classifier using urine‐derived extracellular vesicle (EV)‐RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS).
PUR‐4 status predicted the presence of clinically significant intermediate‐ or high‐risk disease (area under the curve = 0.77, 95% confidence interval CI 0.70–0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub‐cohort (n = 87), groups defined by PUR status and proportion of PUR‐4 had a significant association with time to progression (interquartile range hazard ratio HR 2.86, 95% CI 1.83–4.47; P < 0.001). PUR‐4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26–20.81; P < 0.001).
Conclusion
Urine‐derived EV‐RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.
Wiley Online Library
A four‐group urine risk classifier for predicting outcomes in patients with prostate cancer
Objectives
To develop a risk classifier using urine‐derived extracellular vesicle (EV)‐RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information f...
To develop a risk classifier using urine‐derived extracellular vesicle (EV)‐RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information f...
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Non-invasive Detection of Clinically Significant #Prostate Cancer Using Circulating #Tumor Cells
https://www.auajournals.org/doi/10.1097/JU.0000000000000475
PSA testing results in unnecessary biopsy and over-diagnosis with consequent over-treatment. Tissue biopsy is an invasive procedure, associated with significant morbidity
Combining PSA level, circulating tumor cell-score and the 12-gene panel, AUC for clinically significant prostate cancer prediction was 0.927 and in cases with multi-parametric MRI data, adding these to multi-parametric MRI significantly increased the prediction accuracy (AUC 0.936 vs 0.629).
Conclusions:
Circulating tumor cell analysis has the potential to significantly improve patient stratification by PSA and/or multi-parametric MRI for biopsy and treatment
Non-invasive Detection of Clinically Significant #Prostate Cancer Using Circulating #Tumor Cells
https://www.auajournals.org/doi/10.1097/JU.0000000000000475
PSA testing results in unnecessary biopsy and over-diagnosis with consequent over-treatment. Tissue biopsy is an invasive procedure, associated with significant morbidity
Combining PSA level, circulating tumor cell-score and the 12-gene panel, AUC for clinically significant prostate cancer prediction was 0.927 and in cases with multi-parametric MRI data, adding these to multi-parametric MRI significantly increased the prediction accuracy (AUC 0.936 vs 0.629).
Conclusions:
Circulating tumor cell analysis has the potential to significantly improve patient stratification by PSA and/or multi-parametric MRI for biopsy and treatment
Journal of Urology
Noninvasive Detection of Clinically Significant Prostate Cancer Using Circulating Tumor Cells | Journal of Urology
Purpose:Prostate specific antigen testing results in unnecessary biopsy and over diagnosis
with consequent overtreatment. Tissue biopsy is an invasive procedure associated with
significant morbidity. More accurate noninvasive or minimally invasive ...
with consequent overtreatment. Tissue biopsy is an invasive procedure associated with
significant morbidity. More accurate noninvasive or minimally invasive ...
#Coffee consumption and risk of #prostate cancer: a systematic review and meta-analysis
https://2medical.news/2021/01/17/coffee-consumption-and-risk-of-prostate-cancer-a-systematic-review-and-meta-analysis/
To conduct a systematic review with meta-analysis of cohort studies to evaluate the association of coffee consumption with the risk of prostate cancer.. ..Sixteen prospective cohort studies were finally included, with 57 732 cases of prostate cancer and 1 081 586 total cohort members. Higher coffee consumption was significantly associated with a lower risk of prostate cancer. Compared with the lowest category of coffee consumption, the pooled relative …
https://2medical.news/2021/01/17/coffee-consumption-and-risk-of-prostate-cancer-a-systematic-review-and-meta-analysis/
To conduct a systematic review with meta-analysis of cohort studies to evaluate the association of coffee consumption with the risk of prostate cancer.. ..Sixteen prospective cohort studies were finally included, with 57 732 cases of prostate cancer and 1 081 586 total cohort members. Higher coffee consumption was significantly associated with a lower risk of prostate cancer. Compared with the lowest category of coffee consumption, the pooled relative …
#Ejaculation Frequency and Risk of #Prostate Cancer: Updated Results with an Additional Decade of Follow-up
https://2medical.news/2021/07/30/ejaculation-frequency-and-risk-of-prostate-cancer-updated-results-with-an-additional-decade-of-follow-up/
https://2medical.news/2021/07/30/ejaculation-frequency-and-risk-of-prostate-cancer-updated-results-with-an-additional-decade-of-follow-up/
2Medical.News
#Ejaculation Frequency and Risk of #Prostate Cancer: Updated Results with an Additional Decade of Follow-up
Evidence suggests that ejaculation frequency may be inversely related to the risk of prostate cancer (PCa), a disease for which few modifiable risk factors have been identified. ObjectiveTo incorpo…
The association between occupational #asbestos exposure with the risk of incidence and mortality from #prostate #cancer: a systematic review and meta-analysis
https://2medical.news/2021/08/26/the-association-between-occupational-asbestos-exposure-with-the-risk-of-incidence-and-mortality-from-prostate-cancer-a-systematic-review-and-meta-analysis/
https://2medical.news/2021/08/26/the-association-between-occupational-asbestos-exposure-with-the-risk-of-incidence-and-mortality-from-prostate-cancer-a-systematic-review-and-meta-analysis/
2Medical.News
The association between occupational #asbestos exposure with the risk of incidence and mortality from #prostate #cancer: a systematic…
There is conflicting evidence on the association between asbestos exposure and prostate cancer (PCa). Two recent meta-analyses have claimed that exposure is associated with increased PCa incidence …
Impact of #diverticular disease on #prostate cancer risk among #hypertensive men
https://2medical.news/2021/10/13/impact-of-diverticular-disease-on-prostate-cancer-risk-among-hypertensive-men/
https://2medical.news/2021/10/13/impact-of-diverticular-disease-on-prostate-cancer-risk-among-hypertensive-men/
2Medical.News
Impact of #diverticular disease on #prostate cancer risk among #hypertensive men
Prostate cancer (PCa) is a heterogenous disease with multiple etiological factors playing a role in its development. Recently, chronic and systemic inflammatory conditions such as inflammatory bowe…
#Prostate Safety Events During #Testosterone Replacement Therapy in Men With HypogonadismA Randomized Clinical Trial
https://2medical.news/2024/01/26/prostate-safety-events-during-testosterone-replacement-therapy-in-men-with-hypogonadisma-randomized-clinical-trial/
https://2medical.news/2024/01/26/prostate-safety-events-during-testosterone-replacement-therapy-in-men-with-hypogonadisma-randomized-clinical-trial/
2Medical.News
#Prostate Safety Events During #Testosterone Replacement Therapy in Men With HypogonadismA Randomized Clinical Trial
Importance The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.Objective To compare the effect of TRT vs placebo on th…