Letter to the Editor regarding 'Treatment of Men for "Low Testosterone": A Systematic Review' by Huo et al.; Testosterone Replacement Therapy: Toward to the Robust Evidence and Facts.

We read with interest the systematic review (SR) by Huo et al [1] on the role of testosterone replacement therapy (TRT) for treating men with low testosterone, which suggests that there is no beneficial effect in most men. While we cannot rule out that the author's conclusions will ultimately be proven to be true, we believe that it is premature to make this determination based on the current study.

SRs play a critical role in guiding evidence-based clinical practice but to do so, they need to include a comprehensive search of the published and unpublished literature as well as rating of the quality of evidence [2]. The search of this SR was outdated (November 2013) by the time of publication (September 2016) and lacks a dedicated effort to search the so-called grey literature to avoid publication bias. Furthermore, the Jadad system for assessing risk of bias, despite an appealing simplicity, falls short of current methodological expectations and is no longer recommended [3]. Instead, the Cochrane risk of bias tool has become the widely excepted “gold standard” for assessing the risk of bias of randomized controlled trials [2]. Even more importantly, the study lacks a formal quality of evidence rating. This should be conducted on a per outcome basis and consider additional domains aside from study limitation such as indirectness, imprecision, inconsistency and publication bias. Another important issue is that of clinical heterogeneity. Studies included in this SR demonstrated a wide range of ages and medical comorbidities and encompassed a variety of questionnaires to evaluate sexual function, preparations of testosterone, and durations of follow-up period. These differences are likely important and deserve more attention that the current SR provides.

We are well aware of TRT remains somewhat controversial, over the risks and benefits. In 2015, the US Food and Drug Administration released recommending that all prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions due to possible increased risk of adverse cardiovascular effect [4]. However, they also agree that the signal of cardiovascular risk is weak and that only a prospective, well-controlled clinical trial could determine whether testosterone causes cardiovascular adverse events due to methodological limitations [4].

As a result, we should seek to provide the explicit systematically developed answers for hypogonadal men with erectile dysfunction using methodologically rigorous and transparent standards like those adopted by Cochrane Collaboration, while at the same time assessing the balance between desirable and undesirable effects, the patient's presumed values and preferences, and the potential economic impact of testosterone supplementation.