madman
Super Moderator
Abstract
Since the 1940s, elevated serum testosterone (T) levels have been infamously suggested as a causal factor in the development of prostate cancer (PCa); this time was also the dawn of both surgically and pharmacologically induced castration. However, men suffering from primary or secondary hypogonadism and who are concomitantly paradoxically at risk for developing PCa cited the adverse effects of T deficiency. In the past 25 years, researchers have published on the genetic, biochemical, and clinical outcomes of testosterone replacement therapy (TRT) in hypogonadal men. The longstanding dogma of the deleterious effects of TRT has recently been challenged, and it now appears that TRT may have an important therapeutic role in the treatment of hypogonadism in those men with either low-risk, active, or previously treated PCa. This review summarizes the latest findings on the treatment of hypogonadal men with a history of PCa, emphasizing the results of clinical research studies.
Introduction
Prostate cancer (PCa) is the most common cancer in men in the United States, with *192,000 new cases in 2020.1 This number of annual cases is expected to rise as the population ages. For patients deemed to have low-risk PCa, active surveillance (AS) is an accepted treatment option.2–5 In cases that require treatment, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), and cryotherapy are available options. Even after successful treatment, biochemical recurrence (BCR) of PCa has been cited at a rate of 13– 53% in patients after radiation therapy6 and at 30.2% 3 years post–radical prostatectomy (RP).7 It is estimated that up to 30% of males between 40 and 79 years of age are hypogonadal and 39% of males between the ages of 45–85 have a testosterone (T) level <300 ng/dL.8,9 Hence, it is not uncommon for PCa patients to also be diagnosed with T deficiency at any stage in their disease, whether it is before treatment, after cure, in those who have BCR, or in those who are on AS. Low T levels have been studied regarding their potential to increase the risk of PCa complications in diagnosed men, including a higher incidence of extraprostatic metastasis,10 seminal vesicle invasion,11 and increased positive surgical margins.12
Irrespective of PCa, hypogonadal men treated with testosterone replacement therapy (TRT) experience clinical benefits through increased muscle mass, bone density, mood, and sexual health/performance.13 Normalization of T levels is also postulated to potentially lower cardiovascular disease risk by reducing cholesterol levels, ameliorating glucose metabolism, and lessening the risk of metabolic syndrome.14 Potential side effects of TRT include polycythemia, gynecomastia, BPH, and lowered HDL cholesterol.
The exact nature of the relationship between androgens and PCa is a particularly relevant topic given that PCa mortality has decreased by *50% in the past two decades, resulting in a significant increase in PCa survivors with potential for experiencing symptoms of hypogonadism.15 In this communication, the available evidence on the safety of TRT in men at risk for or with a previous or current diagnosis of PCa is reviewed.
*Androgen Receptors and the Prostate
*TRT and Risk of Developing PCa
*TRT in Patients with Untreated PCa
*TRT in Patients with Treated PCa
*TRT in Patients with Advanced PCa
Conclusion
The TRT for patients who have a history of untreated or treated PCa remains a debated practice, given the long-established dogma that T could act as ‘‘fuel on the fire’’ for PCa recurrence and growth. As previously described, this paradigm has shifted since the introduction of the saturation model hypothesis. Since then, a growing body of published case series appears to support TRT in this clinical setting. Researchers currently recommend that patients be prescribed the lowest necessary T dose to achieve serum androgen normalization and then be screened at regular intervals, depending on the administration method.
The American Urological Association (AUA) TRT guidelines recognize the lack of evidence linking TRT to the development of PCa, as well as insufficient evidence to quantify a risk-benefit ratio of TRT in patients with a history of PCa.64 As such, hypogonadal patients should make an informed consent before initiating TRT, after a thorough conversation with their provider of the risks and benefits. Until definitive evidence from long-term perspective or placebo-controlled RCTs becomes available, patients under AS, or with a history of PCa must understand the importance of strict compliance with increased T, PSA, and digital rectal exam monitoring frequency.
Currently, neither the AUA nor EAU provides guidelines on monitoring intervals for TRT patients on AS or after RP or radiation therapy. Data from available studies indicate that serum T, PSA, and digital rectal exam findings should be evaluated at least every 3–6 months, according to a physician’s best judgment given a patient’s goals, medical history, and perceived PCa risk.65 For patients on AS, it has been suggested that a patient’s relative risk be evaluated by a multidisciplinary medical team, including a urologist, endocrinologist, and oncologist.66 In all cases, serum T levels should be kept as low as possible to meet a patient’s replacement needs.
Future studies, in addition to focusing on specific PCa risk with TRT in populations stratified by factors such as GG group, treatment during AS, or history of the prior definitive treatment for localized PCa, should also, focus on providing results of quality-of-life metrics to help enumerate the risk-benefit ratio for patients when making health care decisions.
Since the 1940s, elevated serum testosterone (T) levels have been infamously suggested as a causal factor in the development of prostate cancer (PCa); this time was also the dawn of both surgically and pharmacologically induced castration. However, men suffering from primary or secondary hypogonadism and who are concomitantly paradoxically at risk for developing PCa cited the adverse effects of T deficiency. In the past 25 years, researchers have published on the genetic, biochemical, and clinical outcomes of testosterone replacement therapy (TRT) in hypogonadal men. The longstanding dogma of the deleterious effects of TRT has recently been challenged, and it now appears that TRT may have an important therapeutic role in the treatment of hypogonadism in those men with either low-risk, active, or previously treated PCa. This review summarizes the latest findings on the treatment of hypogonadal men with a history of PCa, emphasizing the results of clinical research studies.
Introduction
Prostate cancer (PCa) is the most common cancer in men in the United States, with *192,000 new cases in 2020.1 This number of annual cases is expected to rise as the population ages. For patients deemed to have low-risk PCa, active surveillance (AS) is an accepted treatment option.2–5 In cases that require treatment, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), and cryotherapy are available options. Even after successful treatment, biochemical recurrence (BCR) of PCa has been cited at a rate of 13– 53% in patients after radiation therapy6 and at 30.2% 3 years post–radical prostatectomy (RP).7 It is estimated that up to 30% of males between 40 and 79 years of age are hypogonadal and 39% of males between the ages of 45–85 have a testosterone (T) level <300 ng/dL.8,9 Hence, it is not uncommon for PCa patients to also be diagnosed with T deficiency at any stage in their disease, whether it is before treatment, after cure, in those who have BCR, or in those who are on AS. Low T levels have been studied regarding their potential to increase the risk of PCa complications in diagnosed men, including a higher incidence of extraprostatic metastasis,10 seminal vesicle invasion,11 and increased positive surgical margins.12
Irrespective of PCa, hypogonadal men treated with testosterone replacement therapy (TRT) experience clinical benefits through increased muscle mass, bone density, mood, and sexual health/performance.13 Normalization of T levels is also postulated to potentially lower cardiovascular disease risk by reducing cholesterol levels, ameliorating glucose metabolism, and lessening the risk of metabolic syndrome.14 Potential side effects of TRT include polycythemia, gynecomastia, BPH, and lowered HDL cholesterol.
The exact nature of the relationship between androgens and PCa is a particularly relevant topic given that PCa mortality has decreased by *50% in the past two decades, resulting in a significant increase in PCa survivors with potential for experiencing symptoms of hypogonadism.15 In this communication, the available evidence on the safety of TRT in men at risk for or with a previous or current diagnosis of PCa is reviewed.
*Androgen Receptors and the Prostate
*TRT and Risk of Developing PCa
*TRT in Patients with Untreated PCa
*TRT in Patients with Treated PCa
*TRT in Patients with Advanced PCa
Conclusion
The TRT for patients who have a history of untreated or treated PCa remains a debated practice, given the long-established dogma that T could act as ‘‘fuel on the fire’’ for PCa recurrence and growth. As previously described, this paradigm has shifted since the introduction of the saturation model hypothesis. Since then, a growing body of published case series appears to support TRT in this clinical setting. Researchers currently recommend that patients be prescribed the lowest necessary T dose to achieve serum androgen normalization and then be screened at regular intervals, depending on the administration method.
The American Urological Association (AUA) TRT guidelines recognize the lack of evidence linking TRT to the development of PCa, as well as insufficient evidence to quantify a risk-benefit ratio of TRT in patients with a history of PCa.64 As such, hypogonadal patients should make an informed consent before initiating TRT, after a thorough conversation with their provider of the risks and benefits. Until definitive evidence from long-term perspective or placebo-controlled RCTs becomes available, patients under AS, or with a history of PCa must understand the importance of strict compliance with increased T, PSA, and digital rectal exam monitoring frequency.
Currently, neither the AUA nor EAU provides guidelines on monitoring intervals for TRT patients on AS or after RP or radiation therapy. Data from available studies indicate that serum T, PSA, and digital rectal exam findings should be evaluated at least every 3–6 months, according to a physician’s best judgment given a patient’s goals, medical history, and perceived PCa risk.65 For patients on AS, it has been suggested that a patient’s relative risk be evaluated by a multidisciplinary medical team, including a urologist, endocrinologist, and oncologist.66 In all cases, serum T levels should be kept as low as possible to meet a patient’s replacement needs.
Future studies, in addition to focusing on specific PCa risk with TRT in populations stratified by factors such as GG group, treatment during AS, or history of the prior definitive treatment for localized PCa, should also, focus on providing results of quality-of-life metrics to help enumerate the risk-benefit ratio for patients when making health care decisions.
