The role of testosterone in cardiovascular health: benefits and risks of replacement therapy

madman

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* This paper examines testosterone’s dual role in the cardiovascular system. Low levels are linked to increased risks of heart failure (HF) and coronary artery disease (CAD), while testosterone replacement therapy (TRT) can improve heart function, exercise tolerance, and metabolic health. However, supraphysiological doses or long-term therapy may cause pathological heart hypertrophy and vascular complications. Testosterone influences cardiomyocyte apoptosis, calcium regulation, and oxidative stress reduction, with anti-inflammatory effects shown to lower pro-inflammatory cytokine levels.
* Low testosterone levels are typically linked to poor prognosis and an increased risk of fatal cardiovascular complications [76]. According to the American Urological Association, low testosterone is associated with a higher likelihood of severe cardiovascular complications, such as myocardial infarction and stroke, and is considered a risk factor for atherosclerosis-related diseases [77]. Other studies suggest that low testosterone may be linked to hypertension, although it is unclear whether it is the cause or consequence (28,29) Testosterone therapy in men suffering from testosterone deficiency may help reduce fatal incidents related to harmful cardiovascular complications, likely due to testosterone’s ability to improve metabolic processes in the body and reduce inflammation [78,79].


* Both testosterone deficiency and excess can lead to undesirable complications affecting both the heart and the vascular system [82].
Many of these complications are associated with structural damage to the heart muscle, an increased risk of heart attack, and elevated blood pressure [88].


* Studies also indicate that supraphysiological testosterone therapy may cause vascular problems [87] particularly affecting the vascular endothelium [90], further contributing to increased cardiovascular risk



* The outcome of TRT studies vary significantly depending on the mode of administration, dosage, and characteristics of the study population, all of which influence both treatment efficacy and the adverse event profile. This highlights the need for individualized therapy that takes into account pharmacokinetics, patient tolerance, and the potential risks of cardiovascular and hematological complications [117]. Nevertheless, due to considerable methodological limitations in most existing studies on TRT ― including their retrospective design, short follow-up duration, and population heterogeneity ― it is currently not possible to definitively determine the long-term safety of testosterone therapy. This underscores the urgent need for well-designed, multicenter, long-term randomized controlled trials that address patient diversity, as well as different routes of administration, dosages, and duration of treatment [1].





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Abstract

Testosterone, the primary male sex hormone, significantly impacts cardiovascular health. Produced mainly in the testes, its levels decline with age, leading to increased risks of cardiovascular diseases, sexual dysfunction, and metabolic disorders. This paper examines testosterone’s dual role in the cardiovascular system. Low levels are linked to increased risks of heart failure (HF) and coronary artery disease (CAD), while testosterone replacement therapy (TRT) can improve heart function, exercise tolerance, and metabolic health. However, supraphysiological doses or long-term therapy may cause pathological heart hypertrophy and vascular complications. Testosterone influences cardiomyocyte apoptosis, calcium regulation, and oxidative stress reduction, with anti-inflammatory effects shown to lower pro-inflammatory cytokine levels. Studies demonstrate TRT’s benefits in reducing cholesterol, blood pressure, and ischemic episodes in CAD patients, but conflicting data exist regarding its association with myocardial infarction risk. Additionally, testosterone’s effects vary in different cardiomyopathies, showing both protective and harmful outcomes. This review underscores the need for carefully tailored TRT.
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* The protective effects of testosterone on cardiac structure, function, and the cardiovascular system

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* Characteristics of major heart diseases


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* Cardiovascular consequences of testosterone deficiency

Testosterone deficiencies occur when the body is unable to produce adequate amounts of the hormone, leading to a decline in overall functionality. Despite aging being associated with decreasing testosterone levels, more than 80% of men maintain normal levels into old age [75]. Low testosterone levels are typically linked to poor prognosis and an increased risk of fatal cardiovascular complications [76]. According to the American Urological Association, low testosterone is associated with a higher likelihood of severe cardiovascular complications, such as myocardial infarction and stroke, and is considered a risk factor for atherosclerosis-related diseases [77]. Other studies suggest that low testosterone may be linked to hypertension, although it is unclear whether it is the cause or consequence (28,29) Testosterone therapy in men suffering from testosterone deficiency may help reduce fatal incidents related to harmful cardiovascular complications, likely due to testosterone’s ability to improve metabolic processes in the body and reduce inflammation [78,79]. Furthermore, in women with fraction HFrEF, testosterone deficiency significantly impacts mortality and complication risks [80]. Cohort studies on androgen deprivation therapy, commonly used in prostate cancer patients, have shown an increased risk of cardiovascular disease [81–85]. Some of these studies, along with the meta-analysis by Liang et al., indicate that the most common complications include myocardial infraction, HF, and stroke [82, 83,86].


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* Cardiovascular consequences of excessive testosterone levels
Both testosterone deficiency and excess can lead to undesirable complications affecting both the heart and the vascular system [82]. Many of these complications are associated with structural damage to the heart muscle, an increased risk of heart attack, and elevated blood pressure [88]. Doctors typically do not prescribe testosterone doses that raise levels to supraphysiological ranges in patients with deficiency due to the increased risk of cardiovascular complications [87,89,90]. The duration of testosterone therapy can result in different types of myocardial hypertrophy. Short-term therapy may lead to physiological and non-harmful hypertrophy, whereas long-term therapy can result in severe and life-threatening cardiac complications related to pathological hypertrophy [91]. Studies also indicate that supraphysiological testosterone therapy may cause vascular problems [87] particularly affecting the vascular endothelium [90], further contributing to increased cardiovascular risk.

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* The use of testosterone therapy in patients with preexisting cardiovascular disease


-Heart failure
-Coronary artery disease
-Cardiomyopathies
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* Risks associated with testosterone replacement therapy: a review of clinical studies
The outcome of TRT studies vary significantly depending on the mode of administration, dosage, and characteristics of the study population, all of which influence both treatment efficacy and the adverse event profile. This highlights the need for individualized therapy that takes into account pharmacokinetics, patient tolerance, and the potential risks of cardiovascular and hematological complications [117]. Nevertheless, due to considerable methodological limitations in most existing studies on TRT ― including their retrospective design, short follow-up duration, and population heterogeneity ― it is currently not possible to definitively determine the long-term safety of testosterone therapy. This underscores the urgent need for well-designed, multicenter, long-term randomized controlled trials that address patient diversity, as well as different routes of administration, dosages, and duration of treatment [1].
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Conclusions


Many studies highlight the beneficial effects of testosterone on the heart and blood vessels, such as reducing symptoms of angina, improving heart function after a heart attack, and increasing exercise tolerance in patients with HF. These effects are attributed to testosterone’s role in calcium homeostasis regulation, its anti-inflammatory properties, and its influence on metabolic processes. As a result, testosterone therapy may provide significant benefits in treating cardiovascular diseases in men with testosterone deficiency. However, excessive testosterone supplementation leading to supraphysiological hormone levels is associated with serious complications, including pathological myocardial hypertrophy and vascular damage. Despite these potential benefits and risks, research findings on testosterone therapy remain partially contradictory, particularly regarding its long-term effects on cardiovascular health, underscoring the need for further investigation. Future research should focus on several key aspects. First, a better understanding of the molecular mechanisms of testosterone’seffects on the heart and vascular system is needed, particularly its role in apoptosis, calcium homeostasis, and anti-inflammatory processes. Another critical area of study is the long-term effects of testosterone therapy to better assess its safety in relation to cardiovascular complications. Optimizing hormonal therapy for patients with testosterone deficiency, while considering individual patient needs, is essential to maximize health benefits while minimizing risks. Additionally, the role of testosterone in women, particularly those suffering from HF, remains poorly understood, as there is a lack of data on its impact on their cardiovascular system. These studies could contribute to improving the effectiveness of testosterone therapy and enhancing the understanding of its potential benefits and risks, which is crucial for advancing medicine in the context of cardiovascular disease.
 

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Understanding Your Hormones

Estradiol (E2)

A form of estrogen produced from testosterone. Important for bone health, mood, and libido. Too high can cause side effects; too low can affect well-being.

DHT

Dihydrotestosterone is a potent androgen derived from testosterone. Affects hair growth, prostate health, and masculinization effects.

Free Testosterone

The biologically active form of testosterone not bound to proteins. Directly available for cellular uptake and biological effects.

Scientific Reference

Lakshman KM, Kaplan B, Travison TG, Basaria S, Knapp PE, Singh AB, LaValley MP, Mazer NA, Bhasin S. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. J Clin Endocrinol Metab. 2010 Aug;95(8):3955-64.

DOI: 10.1210/jc.2010-0102 | PMID: 20534765 | PMCID: PMC2913038

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