The cardiovascular safety of testosterone use in ageing men has been a subject of extensive debate and research. Two landmark studies offer valuable insights into the associations between sex hormones and cardiovascular (CV) outcomes. 

Yeap et al's study investigates how circulating sex hormones affect mortality and cardiovascular disease (CVD) risk in ageing men. This study aims to clarify the relationships between testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and oestradiol with all-cause mortality, CVD death, and incident CVD events. The study accounted for various covariates, such as age, BMI, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, cholesterol ratios, and lipid medication use. 

From nine studies with data encompassing 255 830 participant-years and 11 studies with summary estimates including 24 109 participants, key findings emerged. Men with testosterone levels below 7.4 nmol/L had higher all-cause mortality, and those with levels below 5.3 nmol/L had higher CVD mortality. Higher all-cause mortality was associated with LH levels above 10IU/L and was linked to oestradiol levels below 5.1pmol/L. Lower SHBG concentrations correlated with lower all-cause and CVD mortality. In terms of DHT, there was a nonlinear association with mortality, where both low and very high levels increased all-cause and CVD mortality risks. Very low DHT also increased the risk of incident CVD events. 

Findings 

• Testosterone: Low levels are consistently associated with higher all-cause and CVD mortality, suggesting a direct impact regardless of the underlying cause.
• SHBG: Higher SHBG concentrations correlate with increased all-cause mortality, likely due to its role in modulating the bioavailability of sex hormones.
• DHT: Exhibits a U-shaped relationship with mortality, indicating that both low and high levels are detrimental.
• LH and oestradiol: High LH and very low oestradiol levels are linked to higher all-cause mortality but not specifically to CVD mortality.

Sex hormones and CVD risk 

Lincoff et al's traverse study addresses uncertainties about the cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism. It specifically examines whether this therapy increases the risk of CV events in men with pre-existing CVD or multiple risk factors. The FDA initiated a review of testosterone products in 2010 after a small trial indicated increased cardiovascular events. Subsequent meta-analyses showed inconsistent results. This trial, larger than all previous ones combined, provided a more definitive assessment. The consistency of results across analyses confirmed the noninferiority of testosterone therapy. In a randomised, placebo-controlled trial involving 5198 men over a mean follow-up of 22 months, testosterone therapy was noninferior to placebo concerning major adverse cardiac events (MACE), with a hazard ratio of 0.96 (95% CI, 0.78 to 1.17). 

The findings support the cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism, even among those with cardiovascular disease or multiple risk factors. Previous trials have shown additional benefits such as improved sexual function, bone mineral density, correction of unexplained anaemia, and reduced depressive symptoms.  

Summary 

While low testosterone is associated with higher all-cause and CVD mortality, testosterone-replacement therapy is noninferior to placebo regarding major adverse cardiac events, offering reassurance to clinicians and patients considering this treatment.  

References available on request.