3rd Annual Jefferson Urology Symposium: Men’s Health Forum

© The Canadian Journal of Urology TM : International Supplement, August 2020 21 Controversies with testosterone therapy have symptoms such as erectile dysfunction. In fact, Wu et al found that sexual symptoms, such as decreased morning erections, erectile dysfunction and decreased frequency of sexual thoughts, were the most sensitive and specific symptoms for identifying hypogonadal men. 2 However, the American Urological Association (AUA) Erectile Dysfunction (ED) Guidelines do not recommend the use of TTh solely for the treatment of erectile dysfunction. 3 These guidelines recommend that men with ED and testosterone deficiency who are considering ED treatment with a PDE5i should be informed that PDE5i may bemore effective if combined with testosterone therapy. The AUA ED Guidelines further state “Men should be advised that testosterone therapy is not an effective mono-therapy for ED. If the man’s goal is amelioration of ED symptoms, then he should be counseled regarding the need for ED therapies in addition to testosterone therapy.” Testosterone therapy and cardiovascular risk For many years it was believed that low serumT levels increased the risk for cardiovascular (CV) events. Numerous prospective studies demonstrated that men with lower serum T levels were more likely to die at an earlier age, mainly due to increased CV events. On the contrary, there have been many published studies demonstrating that TTh may improve the risk factors for cardiovascular disease (CVD), such as obesity and metabolic syndrome. Areview article by Morgentaler et al found that of the over 200 articles assessing CV risk with TTh, only four studies suggested that TTh may increase the risk of CV events. 4 Several dozen studies demonstrated beneficial effects of normal T on CV risk andmortality. Low levels of Twere associated with increased risk of mortality and CVD. Finally, many studies suggested that severity of CAD was inversely correlated with serum T levels. Based on the four studies suggesting that TTh may increase CV risk, the FDA issued a warning in the testosterone label in 2015 stating “Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiological studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increase risk of MACE in association with the use of testosterone replacement therapy in men.” It is important to note that the European Medicines Agency (EMA), which is the equivalent to the FDA in Europe, performed its own review of CV and TTh literature and declined to add any new CV warnings. In 2018, Miner et al conducted a review of all articles since the FDA label change assessing the CV risk associated with TTh. 5 These authors identified 23 studies of which none reported an increase in MACE with TTh. In fact, they found that men whose T normalized with TTh had a reduced risk of MI and death compared with men whose T levels failed to normalize. The2018AUATGuidelinesofferedrecommendations on counseling hypogonadal patients regarding potential CV risk. 6 These guidelines recommended that clinicians should informT deficient patients that lowT is a risk factor for CV disease. The AUA T Guidelines also recommend prior to initiating treatment, clinicians should counsel patients that at this time, it cannot be stated definitively whether TTh increases or decreases the risk of CV events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality). Finally, the AUA T Guideline recommend “Testosterone therapy should not be commenced for a period of 3 to 6 months in patients with a history of CV events. Other testosterone guidelines, such as the Endocrine Guidelines, suggest waiting a minimum of 6 months before initiating TTh after a CV event. The AUA T Guidelines also recommend that prior to initiating TTh, patients at high risk for CV events should be referred for further evaluation. Currently underway is the largest randomized placebo-controlled trial assessing the use of TTh on MACE, which includes nonfatal MI and nonfatal stroke or death due to CV causes. This study, also known as the TRAVERSE trial, is expected to enroll 6000 participants and is anticipated to be completed by June of 2022. Testosterone and the prostate The effects of the TTh on the prostate have been a concern to most clinicians and patients for decades. However, over the past 15 years, this paradigm has shifted. Whereas 15 years ago most clinicians believed that TTh was unsafe to give to men due to the risk of developing prostate cancer, 7 now there are clinical trials using TTh to treat men on active surveillance as well as those with metastatic prostate cancer. In 2003, Rhoden and Morgentaler evaluated the use of TTh in hypogonadal menwith a history of high grade prostatic intraepithelial neoplasia (HGPIN). 8 In this study, 20 men had HGPIN and were considered high risk for developing prostate cancer. These authors found that after 1 year of TTh, men with HGPIN did not have a