A Mendelian randomization study from the University of Cambridge analyzed genetic data from over 1.4 million people and found that men with naturally higher testosterone levels carry a 17 percent greater risk of developing coronary artery disease. The mechanism appears to run partly through blood pressure.
The study, published in the Journal of Clinical Endocrinology and Metabolism and led by researchers at Cambridge's MRC Epidemiology Unit, does not contradict the TRAVERSE trial's finding that TRT does not increase heart attacks and strokes. But it adds a genetic layer to the cardiovascular safety picture that matters for anyone on testosterone therapy -- or considering it.
Key Takeaways
Men with genetically higher lifetime testosterone had 17 percent greater coronary artery disease risk (OR 1.17)
Lifetime risk translates from roughly 7.3 percent to 8.5 percent -- a 1.2 percentage point absolute increase
Blood pressure partially mediates the association; adjusting for BP weakened the effect
No significant testosterone-CAD link was found in women
The study examined lifelong genetic exposure, not the effects of TRT prescriptions
The TRAVERSE trial (direct TRT study) found no increase in major adverse cardiovascular events
Practical implication: blood pressure monitoring on TRT is not optional
What the Researchers Did
The team, led by Emily Morbey at Cambridge's MRC Epidemiology Unit with senior author Ken Ong, used Mendelian randomization -- a method that leverages naturally occurring genetic variants to approximate a lifelong controlled experiment.
Study Design
Parameter
Detail
Method
Two-sample Mendelian randomization
Genetic data source
Over 400,000 adults from UK Biobank
Coronary artery disease data
Over 1 million individuals from CARDIoGRAMplusC4D consortium
Total participants analyzed
Over 1.4 million
Genetic instruments
Variants reliably associated with higher circulating testosterone
Primary outcome
Coronary artery disease risk
Mediator analysis
Blood pressure (systolic and diastolic)
Publication
Journal of Clinical Endocrinology and Metabolism, October 2025
The logic of Mendelian randomization is straightforward: because genetic variants are assigned randomly at conception, they function like a natural experiment. If gene variants that raise testosterone also raise coronary artery disease risk, that suggests a causal relationship rather than mere correlation.
Unlike observational studies where confounders like obesity, diabetes, and lifestyle factors cloud the picture, Mendelian randomization largely sidesteps those issues. Unlike clinical trials, it reflects decades of continuous exposure rather than months or years of treatment.
The headline number -- a 17 percent relative increase in coronary artery disease risk -- needs context.
Relative vs. Absolute Risk
The average man's lifetime risk of coronary artery disease is approximately 7.3 percent. A 17 percent relative increase lifts that to approximately 8.5 percent. That is an absolute increase of 1.2 percentage points.
For perspective:
Risk Factor
Relative CAD Risk Increase
Smoking
200 to 400%
Uncontrolled type 2 diabetes
100 to 200%
Untreated hypertension
60 to 100%
Obesity (BMI over 30)
30 to 50%
Genetically higher testosterone (this study)
17%
Sedentary lifestyle
20 to 30%
The testosterone-associated risk is real but modest compared to established cardiovascular risk factors. It sits in the range of risks that clinicians manage routinely rather than risks that contraindicate treatment.
Blood Pressure as the Mediator
The study's most actionable finding is the mechanism. Men with genetically elevated testosterone showed higher systolic and diastolic blood pressure. When researchers adjusted for blood pressure in their models, the testosterone-coronary artery disease association weakened.
This suggests blood pressure mediates part -- but not all -- of the link between testosterone and coronary artery disease. The FDA reached a similar conclusion through different evidence: post-market ambulatory blood pressure studies led the agency to add a blood pressure warning to all testosterone product labels in 2025.
For men on TRT, this finding reinforces what disciplined clinics already practice: regular blood pressure monitoring is not a formality. It is the primary mechanism through which testosterone could plausibly increase cardiovascular risk.
Sex-Specific Results
The Cambridge team found no significant link between genetically higher testosterone and coronary artery disease in women. The researchers noted that testosterone's biology and genetic regulation differ substantially between the sexes, making it inappropriate to extrapolate the male findings to women's testosterone therapy.
How This Relates to the TRAVERSE Trial
The TRAVERSE trial -- the largest randomized controlled trial of TRT ever conducted -- enrolled 5,246 men with hypogonadism and either pre-existing cardiovascular disease or elevated cardiovascular risk. Over a median of 33 months, testosterone gel did not increase the rate of major adverse cardiovascular events compared with placebo (7.0 percent versus 7.3 percent).
The Cambridge study does not contradict TRAVERSE. The two studies ask different questions:
TRAVERSE Trial
Cambridge Mendelian Randomization
Question
Does TRT cause heart attacks and strokes?
Does lifelong higher testosterone raise coronary artery disease risk?
Over 1.4 million from UK Biobank and CARDIoGRAMplusC4D
MACE finding
No increase
Not measured (CAD incidence only)
Blood pressure finding
Small increase confirmed
Identified as partial mediator of CAD risk
Limitation
Median 33-month follow-up may miss long-term effects
Reflects lifetime exposure, not therapeutic doses
The European Expert Panel's 2026 position statement synthesized both TRAVERSE and broader evidence, concluding that TRT does not increase MACE risk but noting real signals for atrial fibrillation and pulmonary embolism. The Cambridge genetic data adds to the overall picture: testosterone's cardiovascular effects are nuanced, not binary.
What This Means for TRT Patients
The Study Does Not Apply to You the Way Headlines Suggest
Lead author Emily Morbey was explicit: genetic analyses "reflect lifelong exposure, not the effects of a prescription taken for years or decades." A man who starts TRT at 40 is not experiencing the same exposure as someone whose genes produced higher testosterone from birth.
Morbey also stated: "When there is a medical need to boost testosterone, the benefits are likely to outweigh the risks, but this might not necessarily be the case when taken to boost performance."
What You Should Actually Do
Monitor blood pressure -- The blood pressure mediation finding is the most directly actionable result. If you are on TRT, check blood pressure at every clinic visit and consider a home monitor. The TRT blood pressure guide covers thresholds and management.
Do not stop TRT based on this study alone -- TRAVERSE showed no increase in major adverse cardiovascular events from therapeutic TRT. This genetic study examines a different question and does not override direct clinical trial evidence.
Know your baseline cardiovascular risk -- If you already have hypertension, family history of coronary artery disease, or elevated hematocrit, these are compounding factors worth discussing with your prescriber. A disciplined TRT clinic will already be monitoring these parameters.
Distinguish medical TRT from supraphysiological use -- The Cambridge study's risk signal may be more relevant to men pushing testosterone levels well above the reference range. Therapeutic TRT targets the upper end of normal (600 to 900 ng/dL total testosterone), not the supraphysiological levels seen in performance enhancement.
The UK Policy Gap
Senior author Ken Ong highlighted that the United Kingdom has "no national guidance on potential cardiovascular risk of high testosterone levels," contrasting with the FDA's labeling requirements in the United States. The study's authors called for formal UK guidance on cardiovascular monitoring for men receiving testosterone therapy.
This mirrors a broader international trend. While the FDA has updated testosterone labels to include blood pressure warnings and remove the cardiovascular black box warning based on TRAVERSE data, many countries still rely on outdated safety frameworks that either overstate heart attack risk or ignore blood pressure entirely.
For US patients, the regulatory landscape has shifted toward more accurate labeling: the FDA removed the cardiovascular black box warning but added a specific blood pressure warning -- a change that aligns precisely with what the Cambridge genetic data now supports at a mechanistic level.
Limitations
The Cambridge study has important limitations that affect how its findings should be applied:
Lifetime exposure is not TRT -- Mendelian randomization instruments reflect testosterone levels from conception onward, not from the start of a prescription at age 35 or 50
Pleiotropy -- Genetic variants that raise testosterone may also affect other biological pathways, potentially confounding the association
Population-level data -- The 17 percent relative risk increase is a population average; individual risk depends on baseline cardiovascular profile, blood pressure control, and other factors
No dose-response analysis -- The study cannot determine whether the risk scales linearly with testosterone level or has a threshold effect
Observational by nature -- Even with Mendelian randomization's advantages over traditional observational studies, it cannot match the causal certainty of a randomized controlled trial
The Bottom Line
The Cambridge Mendelian randomization study is the largest genetic investigation into testosterone and coronary artery disease to date. Its finding that genetically higher testosterone raises coronary artery disease risk by 17 percent in men -- partially mediated by blood pressure -- adds important context to the TRT safety conversation.
It does not mean testosterone therapy is dangerous. The TRAVERSE trial, the 41-RCT meta-analysis, and the European Expert Panel all support the cardiovascular safety of properly monitored TRT. What the Cambridge data does is provide a genetic explanation for why blood pressure monitoring matters on TRT: the pathway from testosterone to coronary artery disease appears to run through blood pressure.
For men on TRT or considering it, the practical message is reinforcing rather than alarming: work with a clinic that takes blood pressure monitoring seriously, keep levels in the therapeutic range, and manage cardiovascular risk factors aggressively. The genetic risk is real but modest -- and unlike your genes, your blood pressure is something you can control.
References
Morbey EJ, et al. Higher circulating testosterone linked to higher CAD risk in men: Mendelian randomisation and survival analyses. Journal of Clinical Endocrinology and Metabolism. 2025. DOI: 10.1210/clinem/dgaf582
Budoff MJ, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. TRAVERSE Trial. JAMA. 2023;329(17):1469-1480.
Zitzmann M, et al. Cardiovascular safety of testosterone therapy -- Insights from the TRAVERSE trial and beyond. Andrology. 2026. DOI: 10.1111/andr.70062
Patel AS, et al. Cardiovascular and prostate cancer risk associated to testosterone replacement therapy -- a systematic review and meta-analysis of 41 randomized controlled trials. International Journal of Impotence Research. 2026.
FDA. FDA Issues Class-Wide Labeling Changes for Testosterone Products. February 2025. FDA.gov
Frequently Asked Questions
Does testosterone cause heart disease?
A Cambridge Mendelian randomization study of over 1.4 million people found that men with genetically higher lifelong testosterone levels have a 17 percent greater risk of coronary artery disease. This does not mean testosterone therapy causes heart attacks. The study examined lifetime genetic exposure from birth, not the effects of a prescription taken for years or decades. For men with diagnosed hypogonadism, the TRAVERSE trial found no increase in major adverse cardiovascular events from testosterone therapy over 33 months. The genetic finding likely reflects blood pressure elevation as a partial mediator.
What does the 17 percent risk increase actually mean in practical terms?
The average lifetime risk of coronary artery disease for men is roughly 7.3 percent. The Cambridge study estimates that genetically elevated testosterone raises that to about 8.5 percent -- an absolute increase of 1.2 percentage points. That is meaningful at a population level but modest for any individual man. For comparison, smoking increases coronary artery disease risk by 200 to 400 percent. The 17 percent figure is a relative risk increase, not an absolute one.
Should I stop TRT because of this study?
No. This study examined genetically determined lifelong testosterone exposure, not the effects of testosterone replacement therapy. The TRAVERSE trial, which directly studied TRT in 5,246 men for a median of 33 months, found no increase in heart attacks or strokes. The Cambridge authors themselves stated that when there is a medical need to boost testosterone, the benefits are likely to outweigh the risks. What this study does reinforce is the importance of blood pressure monitoring while on TRT.
Why does testosterone raise blood pressure?
Testosterone increases sodium and water retention through renal mechanisms, stimulates the renin-angiotensin-aldosterone system, and increases vascular smooth muscle tone. The Cambridge study found that when researchers adjusted for blood pressure, the testosterone-coronary artery disease association weakened, suggesting blood pressure mediates part of the risk. The FDA now requires all testosterone product labels to carry a blood pressure warning based on post-market ambulatory blood pressure monitoring studies.
Does testosterone affect heart risk in women?
The Cambridge study found no significant link between genetically higher testosterone and coronary artery disease in women. The researchers noted that testosterone biology and its genetic regulation differ substantially between men and women, which may explain why the cardiovascular signal appears to be sex-specific.
How is a Mendelian randomization study different from a clinical trial?
A Mendelian randomization study uses naturally occurring genetic variants as proxies for an exposure like testosterone. Because gene variants are randomly assigned at conception, they function like a natural experiment that is less susceptible to confounding than observational studies. However, they reflect lifelong exposure rather than the controlled conditions of a clinical trial. The TRAVERSE trial directly tested testosterone gel versus placebo in 5,246 men. The Cambridge Mendelian randomization study analyzed genetic data from over 1.4 million people. Both approaches have strengths and limitations.
