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In the 1970s, the orally effective testosterone undecanoate was added to the spectrum of preparations. In the 1950s and 1960s, research concentrated on the chemical modification of androgens in order to emphasize their anabolic effects. Testosterone circulates in the body in a biologically inactive form bound to sex hormone-binding globulin (SHBG) (68%), while its biologically active form exists as loosely bound to albumin (30%) and free testosterone (1-2%) . These characteristics include male hair pattern, voice deepening, lean muscle mass, muscle strength, libido, as well as beneficial cognitive effects on mood. They suggested that further investigation of testosterone replacement in older men, perhaps targeting those with the lowest serum testosterone concentrations, was justified . Other bias was judged to be high if the study was sponsored or done by a pharmaceutical company. A full list of secondary outcomes is available in the appendix (p 3). Primary outcomes and additional secondary outcomes were categorised independently by two clinical review authors (CJ, RQ). Physiological markers were reported as secondary outcomes (appendix p 3). If this was not possible, the research team discussed discrepancies and decided whether data should be included. The use of testosterone in healthy older men is not an authorised use in the EU. Testosterone-containing medicines are used to replace testosterone in men with hypogonadism. Risk of myocardial infarction in older men receiving testosterone therapy. Results from animal studies have shown varying mechanisms of action for testosterone, making things even more complex. In patients with reversible causes of low testosterone ‘T’, one should aim to modify the underlying cause. In addition, prostate-specific antigen (PSA) levels and hematocrit levels should be monitored along with the testosterone levels with goal levels set (depending upon the formulation used). Patients who have been started on TRT should ideally be followed up in 6-8 weeks to repeat serum testosterone levels and adjust the dose accordingly. As people age, the levels of SHBG increase and bind the free testosterone; additionally, rising aromatase enzymes increase the conversion of testosterone to estradiol, both of which decrease the level of the biologically active form of testosterone . A meta-analysis of several observational studies63 reported an association between low endogenous testosterone concentrations and increased risk of cardiovascular events, suggesting, notwithstanding the possibility of reverse causality, that testosterone therapy might result in some beneficial effects on the cardiovascular system. Several thresholds for serum total testosterone (ranging between 8 and 12 nmol/L) have been proposed for the diagnosis of hypogonadism.60 A post-hoc subgroup analysis showed a lower risk of cardiovascular events with testosterone treatment when calculated free testosterone was 180–220 pmol/L. This individual IPD meta-analysis allowed us to conduct a reliable assessment of the frequency of mortality and cardiovascular events (including subtypes) during testosterone treatment in men with hypogonadism. We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. Two meta-analyses have reported that testosterone improves glycaemic parameters in men.68, 69 Furthermore, Corona and colleagues reported an improvement in blood pressure during testosterone treatment.70 However, our study suggests that testosterone has no significant effects on either blood pressure or glycaemic indices. However, fasting glucose and HbA1c analyses were not limited to patients with diabetes. Similar findings were observed for free testosterone but with substantial heterogeneity. Most reported events were arrhythmia, coronary heart disease, heart failure, myocardial infarction, and valvular heart disease (table 2). Of the 14 studies, eight reported no deaths11, 16, 39, 40, 41, 42, 43, 44 and six reported deaths.15, 17, 38, 45, 46, 47 We were unable to confirm whether any deaths occurred for the remaining three studies;48, 49, 50 therefore, they were not included. The two-stage analysis (figure 2A) and Mantel-Haenszel sensitivity analysis showed similar results (appendix p 35). Causes of death included myocardial infarction, cancer, and ruptured aortic aneurysm; in three studies (seven deaths in total) cause was undetermined (table 2). The very small total number of deaths recorded during testosterone trials limits our ability to analyse why they occurred. According to the results of our analysis, the overall short to medium-term effect of testosterone seems neutral. Results for the one-stage analysis for the remaining physiological marker outcomes are presented in the appendix (p 41).
