The cardiovascular system is the main "bottleneck" of testosterone safety. The three parameters that respond most quickly to the drug—lipid profile, blood pressure, and hematocrit—are easy to measure, but are often overlooked until symptoms appear. The editors analyzed what happens with each of them, how therapeutic doses differ from supraphysiological doses, and what large studies say.
Why the heart is a zone of increased attention
Androgen receptors are present in cardiomyocytes, vascular endothelium, smooth muscles of the vascular wall, liver and bone marrow. Testosterone thus simultaneously affects lipid metabolism, vascular tone, volume of circulating blood, number of erythrocytes and the structure of the heart muscle itself.
Each of these effects may be mild individually, but they stack on top of each other. A decrease in "good" cholesterol, an increase in blood pressure, and thickening of the blood together create conditions for atherosclerosis, thrombosis, and cardiac overload. That is why cardiologists do not evaluate a separate indicator, but the cumulative risk.
The situation is complicated by the fact that most changes are asymptomatic. A person can feel good, train with high intensity and not suspect that the hematocrit has already exceeded the safe limit, and the pressure is stably elevated. The first symptoms — shortness of breath, headache, nosebleeds, chest pain — often appear late.
It is important to distinguish between two contexts. Replacement therapy brings the hormone back into the physiological range in people with confirmed deficiency and is monitored by a doctor. Non-medical use in sports often involves doses that many times exceed physiological, long periods of use and combinations with other substances. Conclusions from one context cannot be mechanically transferred to another.
Lipids: HDL, LDL and atherosclerosis
The most stable lipid effect of androgens is the reduction of HDL, that is, high-density lipoproteins, which ensure the return transport of cholesterol from the vascular wall to the liver. The mechanism is associated with the stimulation of hepatic lipase, which accelerates the catabolism of HDL.
In a dose-dependent study by Bhasin et al (2001), HDL levels decreased with increasing doses of testosterone enanthate, whereas there was almost no change at low doses. For injectable testosterone, this effect is generally more moderate than for oral 17-alpha-alkylated steroids, which can lower HDL very dramatically.
Effects on LDL ("bad" cholesterol) and triglycerides are less predictable and depend on dose, diet, genetics, and co-occurring substances. In meta-analyses and reviews, including Achar et al. (2010), anabolic steroid users showed, on average, a decrease in HDL and a trend towards an increase in LDL, with changes more pronounced for oral agents.
How dangerous is such a displacement? The ratio of atherogenic and antiatherogenic lipoproteins is one of the main factors of atherosclerosis. A study by Baggish et al (2017) using CT coronary angiography found that long-term users of anabolic steroids had a higher volume of coronary plaque than controls, and this correlated with the total duration of use.
Blood pressure and myocardium
Testosterone promotes retention of sodium and water in the kidneys, increasing the volume of circulating blood. In combination with an increase in hematocrit and an effect on vascular tone, this can lead to an increase in blood pressure. In therapeutic doses, the effect is usually small, in supraphysiological doses, it is more pronounced and not always quickly reversible.
Prolonged pressure overload and the direct effect of androgens on cardiomyocytes lead to left ventricular hypertrophy. Unlike the "athlete's heart"—an adaptation to exercise that preserves normal function—steroid-induced hypertrophy is often accompanied by impaired diastolic and systolic function.
Baggish and colleagues described precisely this pattern: anabolic steroid users exhibited lower left ventricular ejection fractions and poorer diastolic relaxation indices compared to athletes who did not use steroids. Some of these changes persisted even in individuals who had ceased use by the time of the examination.
Cardiac rhythm disturbances represent another concern. Androgens can influence cardiac electrophysiology; notably, the TRAVERSE study recorded a higher incidence of atrial fibrillation in the testosterone group, even at therapeutic doses. Cases of sudden cardiac death among young users have been reported with supraphysiological doses, although establishing a definitive causal link in individual cases remains challenging.
Hematocrit and blood viscosity
Erythrocytosis is the most common side effect of testosterone therapy. Testosterone stimulates erythropoietin production and suppresses hepcidin, a hormone that limits iron availability. Bachman et al. (2014) demonstrated that testosterone effectively "resets" the equilibrium point between erythropoietin and hemoglobin to a higher level.
In a study using graded doses of testosterone enanthate, Coviello et al. (2008) demonstrated that the increase in hemoglobin and hematocrit is dose-dependent and more pronounced in older men than in younger ones. Thus, both age and dosage increase the risk of erythrocytosis.
Endocrine Society clinical guidelines (2018) define a hematocrit level exceeding 54% as the threshold at which therapy should be suspended or modified pending investigation of the cause; a baseline hematocrit above 50% is considered a relative contraindication to initiating treatment. Blood thickening increases viscosity, the workload on the heart, and the risk of thrombotic complications.
Hematocrit levels are also influenced by dehydration, smoking, high altitude, and obstructive sleep apnea. Consequently, in athletes who combine intense training with fluid restriction, the actual value of this indicator may be even higher than at rest.
| Parameter | Typical direction of change | Guidance for the physician | Possible consequence |
|---|---|---|---|
| HDL | Decrease, dose-dependent | Serial lipid profile monitoring | Acceleration of atherosclerosis |
| LDL | Variable, most often an increase | Assessment of total risk | Atherosclerosis |
| Blood pressure | Increase | Regular measurement, ambulatory BP monitoring | LV hypertrophy, stroke |
| Hematocrit | Increase | Above 54% — review therapy | Thrombosis, cardiac overload |
| Myocardial structure | Hypertrophy, reduced function | Echocardiography | Heart failure, arrhythmias |
What major studies say
Throughout the 2010s, there was controversy regarding the safety of testosterone: some observational studies suggested an increase in heart attacks and strokes, while others indicated the opposite. In 2015, the FDA added a warning about potential cardiovascular risk to the prescribing information and required a randomized trial to be conducted.
The response was the TRAVERSE trial, the results of which were published in the *NEJM* in 2023. It involved over 5,000 men aged 45–80 with hypogonadism and either existing cardiovascular disease or high cardiovascular risk. Testosterone gel therapy did not increase the incidence of major adverse cardiovascular events compared to placebo.
At the same time, the editors draw attention to important nuances. Atrial fibrillation, acute kidney injury, and pulmonary embolism occurred more frequently in the testosterone group. Furthermore, the study utilized a transdermal gel to maintain physiological levels, rather than injections at supraphysiological doses.
Data from randomized trials regarding the long-term safety of supraphysiological doses do not exist—and cannot exist—for ethical reasons. Therefore, assessing the risks of non-medical use requires relying on observational studies of users, which consistently indicate poorer cardiovascular outcomes compared to control groups.
- Therapeutic doses under supervision: the TRAVERSE trial showed no increase in heart attacks or strokes.
- Supraphysiological doses: observational studies show left ventricular hypertrophy, reduced function, and coronary plaques.
- In both cases, there is a need for regular monitoring of hematocrit, blood pressure, and lipid levels.
Editorial conclusion
Testosterone enanthate affects the cardiovascular system through several simultaneous mechanisms: it lowers HDL, raises blood pressure via fluid retention, stimulates erythropoiesis, and acts directly on the myocardium.
At therapeutic doses, these effects are generally moderate, and the large TRAVERSE study found no increase in the incidence of heart attacks or strokes. However, even at these levels, the risk of atrial fibrillation and thromboembolism was elevated.
The picture differs with supraphysiological doses: observational studies show left ventricular hypertrophy and dysfunction, as well as accelerated coronary atherosclerosis. Some of these changes may persist after discontinuation.
The editorial team provides further details on health monitoring in articles covering the tests required during testosterone enanthate use, the full list of its side effects, and the history of its medical application.
References
- Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107â117.
- Baggish AL, Weiner RB, Kanayama G, et al. Cardiovascular toxicity of illicit anabolic-androgenic steroid use. Circulation. 2017;135(21):1991â2002.
- Achar S, Rostamian A, Narayan SM. Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm. Am J Cardiol. 2010;106(6):893â901.
- Coviello AD, Kaplan B, Lakshman KM, et al. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. 2008;93(3):914â919.
- Bachman E, Travison TG, Basaria S, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci. 2014;69(6):725â735.
- Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172âE1181.
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715â1744.
