Cardiovascular mortality associated with testosterone therapy in cisgender women and transgender men: a systematic review.

Thirteen randomized controlled trials of transdermal testosterone in cisgender women reported no cardiovascular deaths.

• Trials involved 2,628 cisgender women receiving transdermal testosterone therapy.
• Follow-up periods ranged from 8 to 52 weeks.
• Certainty of evidence was rated as moderate for short-term outcomes in cisgender women using the GRADE framework.
• Risk of bias was assessed using the Cochrane RoB 2.0 tool.

Thirteen observational cohort studies of testosterone therapy in transgender men reported 34 cardiovascular deaths.

• Studies included 7,837 transgender men receiving long-term testosterone therapy.
• The incidence rate of cardiovascular death was 1.81 per 1,000 person-years.
• Certainty of evidence was rated as low to very low for long-term cardiovascular outcomes in transgender men using the GRADE framework.
• Risk of bias in observational studies was assessed using the Newcastle-Ottawa Scale.

Quantitative meta-analysis was not performed due to substantial clinical and methodological heterogeneity across included studies.

• The review followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251009443).
• Included study designs differed fundamentally: randomized controlled trials for cisgender women and observational cohort studies for transgender men.
• Differences in follow-up duration, study design, and certainty of evidence were identified as primary drivers of observed differences rather than true comparative cardiovascular risk.

The absence of cardiovascular deaths in short-term randomized trials does not allow inference regarding long-term cardiovascular safety of testosterone therapy.

• Short-term RCT follow-up periods ranged only from 8 to 52 weeks, which limits generalizability to long-term safety.
• The authors highlight the need for adequately powered studies with extended follow-up and standardized outcome definitions.
• The review explicitly states this limitation applies to cisgender women receiving transdermal testosterone for sexual and metabolic indications.

Testosterone therapy is prescribed in two distinct clinical contexts with different evidence bases: cisgender women for sexual and metabolic indications, and transgender men as the cornerstone of gender-affirming hormone therapy.

• The review was designed to synthesize evidence with specific attention to study design, duration of follow-up, and certainty of evidence.
• The review explicitly states it does not aim to directly compare cardiovascular risk between populations.
• The nature and certainty of cardiovascular safety evidence supporting testosterone use differ across these clinical contexts.