Testosterone Therapy: What We Have Learned From Trials

Abstract

Introduction: The role of testosterone (T) replacement therapy (TRT) in men is still conflicting. In particular, safety concerns and cardiovascular (CV) risk related to TRT have not been completely clarified yet. Similarly, the clear beneficial effects of TRT are far to be established. Aim: To systematically and critically analyze the available literature providing evidence of the benefit-risk ratio derived from TRT in aging men. Methods: A comprehensive PubMed literature search was performed to collect all trials, either randomized controlled trials (RCTs) or observational studies, evaluating the effects of TRT on different outcomes. Main Outcome Measure: Whenever possible, data derived from RCTs were compared with those resulting from observational studies. In addition, a discussion of the available meta-analyses has been also provided. Results: Data derived from RCT and observational studies clearly documented that TRT can improve erectile function and libido as well as other sexual activities in men with hypogonadism (total T < 12 nM). Conversely, the effect of TRT on other outcomes, including metabolic, mood, cognition, mobility, and bone, is more conflicting. When hypogonadism is correctly diagnosed and managed, no CV venous thromboembolism or prostate risk is observed. Clinical Implications: Before prescribing TRT, hypogonadism (total T < 12 nM) must be confirmed through an adequate biochemical evaluation. Potential contraindications should be ruled out, and an adequate follow-up after the prescription is mandatory. Strength & Limitations: When correctly diagnosed and administered, TRT is safe, and it can improve several aspects of sexual function. However, its role in complicated vasculogenic erectile dysfunction is limited. Conversely, TRT is not recommended for weight reduction and metabolic improvement. Further well-powered studies are advisable to better clarify TRT for long-term CV risk and prostate safety in complicated patients as well as in those curatively treated for prostate cancer. Conclusion: TRT results in sexual function improvement when men with hypogonadism (total T < 12 nM) are considered. Positive data in other outcomes need to be confirmed.

Critical evaluation of different available guidelines for late‐onset hypogonadism

“…These results should also be interpreted in light of previous findings on the topic 5,53‐63 . Concerning sexual function, scanty improvements of ejaculatory dysfunction were found in other studies 61 .…”

“…Limited evidence is available in elderly men on the association between TT or FT when considered independently and with clinical variables, including muscle strength, bone mineral density (BMD), body mass index (BMI) and fat mass either in prospective studies or in randomized controlled trials 47 . Instead, only the combined measurement of TT and FT has been shown to be associated with BMI and sexual disturbances, including erectile dysfunction, decreased libido and decreased morning erection in prospective researches and, more recently, in randomized controlled trials 5,20 …”

“…Two cohort studies, one randomized controlled trial and one meta‐analysis of randomized controlled trials, found TRT to be associated with an increased risk of adverse outcomes 68‐71 . Several warnings followed the publication of these studies 5,72,73 . However, those studies suffered from several limitations.…”

Testosterone Deficiency and Risk of Cognitive Disorders in Aging Males

“…Aging is associated with an impairment of cognitive ability, including memory, attention, language and visuospatial ability [2][3][4][5]. Some authors have hypothesized that the age-related reduction in cognition and the T decline are temporally related, suggesting a possible role of low T in cognition impairment [27,28]. Accordingly, cognition impairment has been considered a possible component of LOH [10,[28][29][30][31].…”

Is Testosterone Replacement Safe in Men with Cardiovascular Disease?

“…However, its safety in patients with CV risks and previous CV events is still doubtful due to recent studies showing conflicting results for TRT in patients with adverse CV risk factors. Hence, the ACC guidelines now recommend avoiding TRT in patients with recent MI, revascularization, advanced or severe heart failure, and stroke within the last six months [15]. However, there still is a need for prospective randomized control trials where patients are followed for at least a year or more, including patients with a valid diagnosis of hypogonadism, using two standardized early-morning testosterone samples.…”