The steroid hormone testosterone is fundamental to male physical development and sexual behaviour. Deficiency of testosterone causes male hypogonadism, including diminished secondary sexual characteristics, sexual dysfunction, muscle wasting and weakness, osteoporosis, and reduced quality of life. Testosterone treatment is the standard of care for reversing the consequences of hypogonadism.
To address ongoing uncertainly about the safety of testosterone, the Testosterone Efficacy and Safety Consortium was established as a global collaboration of principal investigators of testosterone trials. Hudson et al reported results of the most extensive individual participant dataset (IPD) of testosterone trials available to analyse subtypes of all cardiovascular events observed during treatment. This was published in The Lancet in June 2022.
Inclusion criteria for studies included those ranging from three months to three years in duration, men >18 years with T <12nmol/L (346ng/dL) receiving any form of TTh with a comparator placebo arm. Thirty-five primary studies (5 601 participants, mean age 65 years) were deemed suitable for inclusion. Of these, 17 studies (49%) provided individual patient datasets (IPD) (3431 participants, mean duration 9·5 months). Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up.
The rate of cardiovascular events was not significantly higher for participants receiving testosterone treatment (120/1 601 [7·5%]) compared to placebo (110/1 519 [7·2%]). Fewer deaths were reported during testosterone (6/1 621 deaths, [0·4%]) than placebo (12/1 537 deaths, [0·8%]), but numbers were too small to establish whether testosterone reduced mortality risk.
Their IPD meta-analysis of more than 3 000 patients with hypogonadism from randomised placebo-controlled trials done by 17 research groups indicates that testosterone treatment was not associated with increased risk of various subtypes of cardiovascular events compared with placebo in the short to medium term.
The small total number of deaths within the IPD analysis precluded a meaningful evaluation of the impact of testosterone treatment on mortality.
Testosterone treatment did not have adverse effects on blood pressure or glycaemic markers compared with placebo. It did not increase thrombotic events despite increased haematocrit. Testosterone treatment was associated with a modest lowering of total and HDL cholesterol and triglyceride concentrations compared with placebo.
The researchers found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism. Neither patient age nor the previous diagnosis of cardiovascular events was associated with an increased risk of cardiovascular events.
The current results provide reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism, which has prompted the authors to state, “Men with hypogonadism should be counselled that there is no current evidence that testosterone treatment increases cardiovascular risk in the short to medium term.”
Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. Lancet Healthy Longev. 2022 Jun;3(6): e381-e393. doi: 10.1016/S2666-7568(22)00096-4. PMID: 35711614; PMCID: PMC9184259