madman
Super Moderator
ABSTRACT
Men with hypogonadism have reduced risk of prostate cancer mortality; whether testosterone treatment increases the risk of prostate safety events in men with hypogonadism remains controversial. Several studies including four larger randomized trials — the Testosterone Trials, TEstosterone and Atherosclerosis Progression in Aging Men (TEAAM) Trial, Testosterone for Diabetes Mellitus Trial, and Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Trial — treated men with testosterone or placebo for one year or longer and reported prospectively-ascertained prostate safety data. The TRAVERSE Trial, because of its large size, longer duration, and adjudication of prostate events, has provided comprehensive data on the risk of adverse prostate events during TRT. Among men with hypogonadism, carefully screened to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer, acute urinary retention, surgical procedure for benign prostatic hyperplasia, prostate biopsy, or new pharmacologic therapy for lower urinary tract symptoms were low and did not differ between the testosterone and placebo groups. Testosterone did not worsen lower urinary tract symptoms. TRT was associated with a greater increase in PSA than placebo in the first year of treatment.
Conclusions
Testosterone treatment of men with hypogonadism, screened to exclude those at high risk of prostate cancer, is associated with low risk of adverse prostate events. Baseline evaluation of prostate cancer risk and a standardized monitoring plan can minimize the risk of unnecessary prostate biopsy while enabling the detection of high-grade prostate cancers in men receiving TRT.
Testosterone products have been approved in the United States for the treatment of men with hypogonadism since 1942 (1-3). The decision by the clinician and the patient to initiate testosterone replacement therapy (TRT) is guided by their assessment of the potential benefits and risks; this assessment is influenced by the burden of symptoms, the certainty of diagnosis, other co-morbid conditions, and the patient's and clinician's values. The concerns about prostate and cardiovascular safety weigh heavily on the decisions of patients as well as their clinicians to initiate TRT. Today, a majority of prescriptions for testosterone replacement therapy are written for middle-aged and older men, who have high prevalence of clinical as well as subclinical prostate cancers and lower urinary tract symptoms (4). The guidelines of the Endocrine Society (1) and other professional societies (2,3) have offered recommendations on how to minimize prostate risk. However, nearly all of these professional society guidelines were crafted prior to the publication of the three large testosterone trials - The TTrials (5), the T4DM Trial (6)14 and the TRAVERSE Trial (7). The TRAVERSE Trial with its large sample size, long intervention duration, and structured ascertainment and adjudication of prostate safety events has enabled the most comprehensive assessment to-date of the prostate safety of TRT. This review synthesizes the prostate safety data from the TRAVERSE trial and other previously published randomized trials of TRT in men with hypogonadism and offer our perspective on baseline evaluation of men being considered for TRT and subsequent prostate monitoring of men receiving TRT to minimize the risk of adverse prostate events during TRT.
A. PATIENT AND CLINICIAN CONCERNS ABOUT PROSTATE SAFETY DURING TESTOSTERONE REPLACEMENT THERAPY
A1. Testosterone and the Risk of Prostate Cancer
A.1.a. Testosterone and PSA Levels and the Risk of Prostate Biopsy
A1.b The Risk of Prostate Cancer Events During Testosterone Replacement Therapy: Findings of Recent Large Trials
*Strategies to address potential ascertainment bias in the estimation of prostate event rates in the TRAVERSE Trial
*The main findings of the TRAVERSE prostate substudy. (Table 1)
*What the TRAVERSE Trial did and did not show
A.2 Testosterone Treatment and the Risk of Lower Urinary Tract Symptoms, Invasive Prostate Procedures for Benign Prostatic Hyperplasia, and Initiation of New Pharmacologic Therapy for Benign Prostatic Hyperplasia
B. GUIDING PRINCIPLES FOR A STANDARDIZED PROSTATE RISK2 EVALUATION AND MONITORING DURING TRT BASED ON THE FINDINGS OF TRAVERSE AND OTHER RANDOMIZED TRIALS
B.1 Baseline assessment of prostate health
*The Potential Benefits and Risks of PSA Testing
*Standardized prostate safety monitoring plan during TRT - Managing PSA Elevations during TRT
C. TESTOSTERONE REPLACEMENT THERAPY IN PROSTATE CANCER SURVIVORS WITH TESTOSTERONE DEFICIENCY
D. CONCLUSIONS
In middle-aged and older men with hypogonadism, who have been carefully screened to exclude those at high risk of prostate cancer or with severe lower urinary tract symptoms, the incidences of high grade or any prostate cancer, acute urinary retention, invasive surgical procedure on the benign prostatic hyperplasia, prostate biopsy, or initiation of new pharmacologic therapy for lower urinary tract symptoms are low. These findings should be viewed in the context of the small number of prostate cancer events in the testosterone studies, the relatively short treatment duration of the trials relative to the long time it may take for carcinogens to induce cancer, and the exclusion of men at high risk for prostate cancer in these trials. A baseline evaluation of prostate cancer risk and implementation of a standardized monitoring plan to minimize the risk of unnecessary prostate biopsies while enabling the detection of high -grade prostate cancers and other prostate safety events, can help optimize the benefit to risk ratio in men receiving TRT. Because PSA screening and monitoring has the potential for harm, the decision to implement PSA monitoring should be made jointly by the patient and the clinician
Men with hypogonadism have reduced risk of prostate cancer mortality; whether testosterone treatment increases the risk of prostate safety events in men with hypogonadism remains controversial. Several studies including four larger randomized trials — the Testosterone Trials, TEstosterone and Atherosclerosis Progression in Aging Men (TEAAM) Trial, Testosterone for Diabetes Mellitus Trial, and Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Trial — treated men with testosterone or placebo for one year or longer and reported prospectively-ascertained prostate safety data. The TRAVERSE Trial, because of its large size, longer duration, and adjudication of prostate events, has provided comprehensive data on the risk of adverse prostate events during TRT. Among men with hypogonadism, carefully screened to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer, acute urinary retention, surgical procedure for benign prostatic hyperplasia, prostate biopsy, or new pharmacologic therapy for lower urinary tract symptoms were low and did not differ between the testosterone and placebo groups. Testosterone did not worsen lower urinary tract symptoms. TRT was associated with a greater increase in PSA than placebo in the first year of treatment.
Conclusions
Testosterone treatment of men with hypogonadism, screened to exclude those at high risk of prostate cancer, is associated with low risk of adverse prostate events. Baseline evaluation of prostate cancer risk and a standardized monitoring plan can minimize the risk of unnecessary prostate biopsy while enabling the detection of high-grade prostate cancers in men receiving TRT.
Testosterone products have been approved in the United States for the treatment of men with hypogonadism since 1942 (1-3). The decision by the clinician and the patient to initiate testosterone replacement therapy (TRT) is guided by their assessment of the potential benefits and risks; this assessment is influenced by the burden of symptoms, the certainty of diagnosis, other co-morbid conditions, and the patient's and clinician's values. The concerns about prostate and cardiovascular safety weigh heavily on the decisions of patients as well as their clinicians to initiate TRT. Today, a majority of prescriptions for testosterone replacement therapy are written for middle-aged and older men, who have high prevalence of clinical as well as subclinical prostate cancers and lower urinary tract symptoms (4). The guidelines of the Endocrine Society (1) and other professional societies (2,3) have offered recommendations on how to minimize prostate risk. However, nearly all of these professional society guidelines were crafted prior to the publication of the three large testosterone trials - The TTrials (5), the T4DM Trial (6)14 and the TRAVERSE Trial (7). The TRAVERSE Trial with its large sample size, long intervention duration, and structured ascertainment and adjudication of prostate safety events has enabled the most comprehensive assessment to-date of the prostate safety of TRT. This review synthesizes the prostate safety data from the TRAVERSE trial and other previously published randomized trials of TRT in men with hypogonadism and offer our perspective on baseline evaluation of men being considered for TRT and subsequent prostate monitoring of men receiving TRT to minimize the risk of adverse prostate events during TRT.
A. PATIENT AND CLINICIAN CONCERNS ABOUT PROSTATE SAFETY DURING TESTOSTERONE REPLACEMENT THERAPY
A1. Testosterone and the Risk of Prostate Cancer
A.1.a. Testosterone and PSA Levels and the Risk of Prostate Biopsy
A1.b The Risk of Prostate Cancer Events During Testosterone Replacement Therapy: Findings of Recent Large Trials
*Strategies to address potential ascertainment bias in the estimation of prostate event rates in the TRAVERSE Trial
*The main findings of the TRAVERSE prostate substudy. (Table 1)
*What the TRAVERSE Trial did and did not show
A.2 Testosterone Treatment and the Risk of Lower Urinary Tract Symptoms, Invasive Prostate Procedures for Benign Prostatic Hyperplasia, and Initiation of New Pharmacologic Therapy for Benign Prostatic Hyperplasia
B. GUIDING PRINCIPLES FOR A STANDARDIZED PROSTATE RISK2 EVALUATION AND MONITORING DURING TRT BASED ON THE FINDINGS OF TRAVERSE AND OTHER RANDOMIZED TRIALS
B.1 Baseline assessment of prostate health
*The Potential Benefits and Risks of PSA Testing
*Standardized prostate safety monitoring plan during TRT - Managing PSA Elevations during TRT
C. TESTOSTERONE REPLACEMENT THERAPY IN PROSTATE CANCER SURVIVORS WITH TESTOSTERONE DEFICIENCY
D. CONCLUSIONS
In middle-aged and older men with hypogonadism, who have been carefully screened to exclude those at high risk of prostate cancer or with severe lower urinary tract symptoms, the incidences of high grade or any prostate cancer, acute urinary retention, invasive surgical procedure on the benign prostatic hyperplasia, prostate biopsy, or initiation of new pharmacologic therapy for lower urinary tract symptoms are low. These findings should be viewed in the context of the small number of prostate cancer events in the testosterone studies, the relatively short treatment duration of the trials relative to the long time it may take for carcinogens to induce cancer, and the exclusion of men at high risk for prostate cancer in these trials. A baseline evaluation of prostate cancer risk and implementation of a standardized monitoring plan to minimize the risk of unnecessary prostate biopsies while enabling the detection of high -grade prostate cancers and other prostate safety events, can help optimize the benefit to risk ratio in men receiving TRT. Because PSA screening and monitoring has the potential for harm, the decision to implement PSA monitoring should be made jointly by the patient and the clinician
