madman
Super Moderator
AUA Live Panel Discusses Management of Testosterone Therapy Complications
Since the start of the century, there has been an exponential rise in testosterone replacement therapy prescribing. The diagnosis and management of hypogonadism continue to constitute a significant portion of many urologists’ practice. The virtual format for the 2020 AUA Live allowed the panel (fig. 1) to have an interactive discussion about the management of the potential complications of polycythemia, gynecomastia, prostate concerns, and fertility issues surrounding testosterone replacement therapy (TRT) with the goal that the prescribing clinician understands the pathophysiology, incidence, and management of each of these potential complications.
Figure 1. Panel discussion virtual format. Top row (left to right): Drs. Guise, Morgentaler, and Shindel. Bottom row (left to right): Drs. Terlecki and Ramasamy.
Dr. Abraham Morgentaler started the discussion with an explanation of the saturation model of testosterone on prostate cells (fig. 2). There are a limited number of androgen binding sites per cell such that at low concentrations of testosterone (about 250 ng/dl) all those binding sites are filled, and at that point, there is no longer an impact of testosterone on prostate-specific antigen rise or prostate growth. As this translates to benign prostate issues there is a mild increase in prostate volume with the initiation of TRT but no worsening of lower urinary tract symptoms.
Figure 2. Saturation model of testosterone on prostate cells.
The summary of data about TRT and prostate cancer is more enlightening. Citing an observational trial from Wallis et al in Lancet in 2016 including 38,000 men, there was a lower incidence of prostate cancer in men treated with TRT, and the greater the duration of TRT the lower the risk of prostate cancer.1 For patients with prostate cancer after radical prostatectomy there is a single study showing a lower rate of biochemical recurrence in patients on TRT. Dr. Morgentaler highlights the notion that the historical fears about testosterone on rates of prostate cancer growth do not seem to be justified as the growing body of literature on TRT in men with prostate cancer shows reassuring results.
To address the impacts of TRT on fertility Dr. Alan Shindel reminded us that exogenous testosterone suppresses spermatogenesis and that patients should be advised of the risk of TRT on their fertility before initiation of treatment. Men who are trying to conceive should not be prescribed exogenous testosterone. For men presenting with infertility, exogenous testosterone should be discontinued. Fortunately, looking at large population studies, after cessation of TRT the majority of men will recover spermatogenesis spontaneously within 6 months and almost all will recover within 2 years.
Potential therapeutic interventions we can attempt in order to expedite recovery include inhibiting feedback at the level of the pituitary by the administration of a selective estrogen receptor modulator such as clomiphene or reducing circulating estrogen by giving an aromatase inhibitor such as anastrozole. Alternatively, you could replace gonadotropins with the administration of human chorionic gonadotropin or follicle-stimulating hormone to stimulate the testicles directly to make testosterone and sperm. However, Dr. Shindel concludes that the literature does not conclusively show that either modality improves spermatogenesis any further than just cessation of testosterone supplementation.
Dr. Ryan Terlecki gave a detailed explanation of the pathophysiology of gynecomastia. It is a hormone-mediated proliferation of glandular subareolar breast tissue related to increased estrogenic activity due to an absolute increase in estrogen or unfavorable estrogen-to-testosterone ratio. Asymptomatic gynecomastia has been reported in up to 70% of men older than 50 years old. Rates of subsequent gynecomastia after TRT have been reported as 13% to 43% in intervariable studies. Obesity is the biggest risk factor for low testosterone, which makes detection of gynecomastia complex. Confounding factors can also increase the risk of gynecomastia. These include the use of 5 alpha-reductase inhibitors, nutraceuticals, statins, proton pump inhibitors, spironolactone, and antiretrovirals. Gynecomastia can be seen in up to half of former or current anabolic steroid users. Alcohol abuse and marijuana use are also common confounding factors. Stromal fibrosis can occur as soon as 6 months after the development of symptoms and typically by 2 years. If detected early before the onset of stromal fibrosis, stopping TRT should improve gynecomastia within 1 month. There are also reports of the use of tamoxifen to resolve gynecomastia in 90% of patients within 90 days.
To conclude the panel discussion Dr. Ranjith Ramasamay highlighted the avoidable risk factors for polycythemia associated with TRT. According to AUA guidelines, patients should have baseline hemoglobin or hematocrit prior to initiation of TRT, and therapy withheld for hematocrits greater than 50% until the etiology is explained. Erythropoiesis secondary to TRT is caused by decreased hepcidin production by the liver, exacerbation of obstructive sleep apnea, and/or increased erythropoietin production by the kidney. Data suggest that a longer duration of high testosterone levels may predict the risk of polycythemia. Intramuscular injections and subcutaneous pellets have the highest rate of polycythemia compared to transdermal and intranasal modalities. Lower doses and higher frequency injection therapy have a lower incidence of polycythemia. If the hematocrit is greater than 54%, consider phlebotomy and adjust down TRT dosing if high T levels are present. If therapeutic testosterone levels are normal or low but hematocrit is still greater than 54%, evaluation by a hematologist for further evaluation is recommended. Dr. Ramasamy highlighted the importance of screening for obstructive sleep apnea in men who develop polycythemia on TRT. ◆
Since the start of the century, there has been an exponential rise in testosterone replacement therapy prescribing. The diagnosis and management of hypogonadism continue to constitute a significant portion of many urologists’ practice. The virtual format for the 2020 AUA Live allowed the panel (fig. 1) to have an interactive discussion about the management of the potential complications of polycythemia, gynecomastia, prostate concerns, and fertility issues surrounding testosterone replacement therapy (TRT) with the goal that the prescribing clinician understands the pathophysiology, incidence, and management of each of these potential complications.
Figure 1. Panel discussion virtual format. Top row (left to right): Drs. Guise, Morgentaler, and Shindel. Bottom row (left to right): Drs. Terlecki and Ramasamy.
Dr. Abraham Morgentaler started the discussion with an explanation of the saturation model of testosterone on prostate cells (fig. 2). There are a limited number of androgen binding sites per cell such that at low concentrations of testosterone (about 250 ng/dl) all those binding sites are filled, and at that point, there is no longer an impact of testosterone on prostate-specific antigen rise or prostate growth. As this translates to benign prostate issues there is a mild increase in prostate volume with the initiation of TRT but no worsening of lower urinary tract symptoms.
Figure 2. Saturation model of testosterone on prostate cells.
The summary of data about TRT and prostate cancer is more enlightening. Citing an observational trial from Wallis et al in Lancet in 2016 including 38,000 men, there was a lower incidence of prostate cancer in men treated with TRT, and the greater the duration of TRT the lower the risk of prostate cancer.1 For patients with prostate cancer after radical prostatectomy there is a single study showing a lower rate of biochemical recurrence in patients on TRT. Dr. Morgentaler highlights the notion that the historical fears about testosterone on rates of prostate cancer growth do not seem to be justified as the growing body of literature on TRT in men with prostate cancer shows reassuring results.
To address the impacts of TRT on fertility Dr. Alan Shindel reminded us that exogenous testosterone suppresses spermatogenesis and that patients should be advised of the risk of TRT on their fertility before initiation of treatment. Men who are trying to conceive should not be prescribed exogenous testosterone. For men presenting with infertility, exogenous testosterone should be discontinued. Fortunately, looking at large population studies, after cessation of TRT the majority of men will recover spermatogenesis spontaneously within 6 months and almost all will recover within 2 years.
Potential therapeutic interventions we can attempt in order to expedite recovery include inhibiting feedback at the level of the pituitary by the administration of a selective estrogen receptor modulator such as clomiphene or reducing circulating estrogen by giving an aromatase inhibitor such as anastrozole. Alternatively, you could replace gonadotropins with the administration of human chorionic gonadotropin or follicle-stimulating hormone to stimulate the testicles directly to make testosterone and sperm. However, Dr. Shindel concludes that the literature does not conclusively show that either modality improves spermatogenesis any further than just cessation of testosterone supplementation.
Dr. Ryan Terlecki gave a detailed explanation of the pathophysiology of gynecomastia. It is a hormone-mediated proliferation of glandular subareolar breast tissue related to increased estrogenic activity due to an absolute increase in estrogen or unfavorable estrogen-to-testosterone ratio. Asymptomatic gynecomastia has been reported in up to 70% of men older than 50 years old. Rates of subsequent gynecomastia after TRT have been reported as 13% to 43% in intervariable studies. Obesity is the biggest risk factor for low testosterone, which makes detection of gynecomastia complex. Confounding factors can also increase the risk of gynecomastia. These include the use of 5 alpha-reductase inhibitors, nutraceuticals, statins, proton pump inhibitors, spironolactone, and antiretrovirals. Gynecomastia can be seen in up to half of former or current anabolic steroid users. Alcohol abuse and marijuana use are also common confounding factors. Stromal fibrosis can occur as soon as 6 months after the development of symptoms and typically by 2 years. If detected early before the onset of stromal fibrosis, stopping TRT should improve gynecomastia within 1 month. There are also reports of the use of tamoxifen to resolve gynecomastia in 90% of patients within 90 days.
To conclude the panel discussion Dr. Ranjith Ramasamay highlighted the avoidable risk factors for polycythemia associated with TRT. According to AUA guidelines, patients should have baseline hemoglobin or hematocrit prior to initiation of TRT, and therapy withheld for hematocrits greater than 50% until the etiology is explained. Erythropoiesis secondary to TRT is caused by decreased hepcidin production by the liver, exacerbation of obstructive sleep apnea, and/or increased erythropoietin production by the kidney. Data suggest that a longer duration of high testosterone levels may predict the risk of polycythemia. Intramuscular injections and subcutaneous pellets have the highest rate of polycythemia compared to transdermal and intranasal modalities. Lower doses and higher frequency injection therapy have a lower incidence of polycythemia. If the hematocrit is greater than 54%, consider phlebotomy and adjust down TRT dosing if high T levels are present. If therapeutic testosterone levels are normal or low but hematocrit is still greater than 54%, evaluation by a hematologist for further evaluation is recommended. Dr. Ramasamy highlighted the importance of screening for obstructive sleep apnea in men who develop polycythemia on TRT. ◆
