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Abstract

Testosterone is an anabolic steroid hormone, which is the major circulating androgen hormone in males. Testosterone levels decreasing below the normal physiological levels lead to a status known as androgen deficiency. Androgen deficiency has been shown to be a major risk factor in the development of several disorders, including obesity, metabolic syndrome, and ischemic heart disease. In the past decades, although several studies from animal models as well as clinical studies demonstrated that testosterone exerted cardioprotection, particularly during ischemia–reperfusion (I/R) injury, other preclinical and clinical studies have shown an inverse relationship between testosterone levels and cardioprotective effects. As a result, the effects of testosterone replacement on the heart remain controversial. In this review, reports regarding the roles of testosterone replacement in the heart following I/R injury are comprehensively summarized and discussed. At present, it may be concluded that chronic testosterone replacement at a physiological dose demonstrated cardioprotective effects, whereas acute testosterone replacement can cause adverse effects in the I/R heart.

Keywords

testosterone ischemia–reperfusion injury heart aging

Introduction

Testosterone (or androgen) deficiency is a condition in which the concentration of testosterone hormone is lower than the normal physiological level.^1,2 The primary cause of testosterone deficiency is due to a testicular disorder or an abnormal function of the hypothalamus–pituitary axis, while a secondary cause or transient testosterone deficiency is caused by the effect of drugs; aging; acute or chronic diseases; or chronic comorbidities such as obesity, metabolic syndrome, dyslipidemia, and insulin resistance.^1,3
–5

The prevalence of symptomatic testosterone deficiency is approximately 481 000 new cases per year in US men aged between 40 and 69 years² and 5.6% in men aged 30 to 79 years.⁶ Another study reported a higher prevalence of hypogonadism (38.7%) in men aged ≥45 years (mean age = 60 years) visiting primary care practices in the United States.⁷ The prevalence of hypogonadism also increases substantially with age^6,8 in which the prevalence increased to 20% of men older than 60 years, 30% older than 70 years, and 50% older than 80 years.⁹ Although this condition commonly occurs in middle- to older aged men, it can also be found in younger men.^1,2,6,8 In addition, lower levels of serum testosterone are associated with the development of several disorders including obesity, dyslipidemia, insulin resistance, metabolic syndrome, cardiovascular disease, and coronary artery disease (ischemic heart disease).^5,10

–13

Previous studies reported that men have a higher incidence, mortality, and risk of coronary artery disease than women^14
–16 and the risk of coronary artery disease increases markedly with age.¹⁶ In addition, patients with coronary artery disease^17

–20 and congestive heart failure²¹ have been shown to have lower levels of endogenous testosterone compared with healthy men, and the severity of both diseases shows a strong correlation with the degree of testosterone deficiency.^5,17,22 It has also been suggested that low serum testosterone levels could be used as a predictive marker for cardiovascular disease in men.²³

Although there are many reports indicating that testosterone provided cardioprotective effects^24
–26 such as antiarrhythmic properties,²⁷ reduced infarct size,²⁸ enhanced vasodilatation,²⁹ decreased atherosclerosis,³⁰ and improved metabolic parameters,³¹ these findings are controversial at this time.^32

–36 Moreover, when it comes to the role of testosterone in the ischemic heart or cardiac ischemia–reperfusion (I/R) injury, limited data are currently available. Despite limited data, inconsistent reports exist regarding the effects of testosterone in I/R hearts. In this review, the roles of testosterone in the heart following I/R injury are comprehensively summarized and discussed. The consistent findings, as well as controversial results, are also presented, focusing on the effects of testosterone on the heart during an I/R injury.

Physiological Roles of Testosterone in the Heart

The cardiac muscle is one target tissue of the testosterone hormone.^37,38 It is well known that the level of testosterone is associated with effects on the cardiomyocytes such as hypertrophy and cardiomyocyte apoptosis^39,40 and is also associated with the contractility of cardiac muscle.^38,41
–43 Previous studies reported the beneficial effect of testosterone at physiological levels on cardiovascular function by inducing vasorelaxation of vascular smooth muscle.^39,44,45 Testosterone controlled cardiac relaxation by acting mainly through sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA),⁴⁶ increasing or regulating cardiac contractility, and Ca²⁺ handling in the heart.^38,43,47 However, conflicting evidence was that chronic administration of a synthetic testosterone (nandrolone decanoate) decreased left ventricular myocardial function and thus overall cardiac performance without altering contractility in rats.⁴⁸

The physiological effects of testosterone on cardiac electrophysiology have been reported. It has been shown that the Q-T interval was shorter in men than in women.^49

–52 Moreover, both endogenous and exogenous testosterone could shorten or decrease the dispersion of the Q-T interval,^50,53,54 whereas a contrasting study found that the testosterone level and the Q-T interval on electrocardiogram did not have any relationship with each other.⁵⁵ Furthermore, beneficial effects of testosterone on the ST-segment and atrial fibrillation have been reported. Testosterone was shown to modulate the early phase of ventricular repolarization resulting in decreasing the ST-segment.^56,57 Other studies reported that aging men with decreased serum testosterone levels had a high incidence of atrial fibrillation.^58,59 These were consistent with the study using a rat model, which reported that deficiency of testosterone was arrhythmogenic in rat atria possibly through less binding of FK506-binding protein (FKBP12.6) to ryanodine receptor type 2 (RyR2), resulting in calcium leakage from the sarcoendoplasmic reticulum.⁶⁰ Testosterone also plays an essential role in the Ca²⁺ regulation in male hearts in both genomic and nongenomic pathways.^46,61
–63 It has been shown that testosterone maintained or increased the expression of dihydropyridine receptor (α1c-subunit of L-type calcium channel) messenger RNA (mRNA) level and also increased the Na⁺/Ca²⁺ exchanger mRNA level,^62,64,65 improved the cardiac L-type calcium current,^62,63 increased Ca²⁺ released via the ryanodine receptor,⁶¹ maintained FK506-binding protein 12.6 in ryanodine receptor type 2,⁶⁰ maintained or increased SERCA and Na⁺/Ca²⁺ exchanger activity,^46,61 and maintained phosphorylation of phospholamban Thr₁₇,⁴⁶ thus resulting in faster Ca²⁺ removal out of the cytoplasm.

Testosterone and the Pathological Heart

Previous studies demonstrated that a reduction in plasma testosterone levels can be either the direct cause or the consequence of several cardiovascular diseases such as hypertension, diabetes, atherosclerosis, and heart failure.^{23,66

–73} There is also a correlation between low levels of testosterone and the severity of each of these diseases.^71

–74 The incidence of chronic heart failure due to idiopathic dilated cardiomyopathy is associated with a significant decrease in testosterone concentrations,⁷⁴ in which androgen replacement therapy could improve heart failure symptoms.⁷⁵ Several lines of evidence indicate that testosterone may effectively provide protective effects in the cardiovascular system^76,77 and that decreased circulating testosterone may increase cardiovascular risk, atherosclerosis, and mortality in men.^76,77 Testosterone therapy has also been shown to improve the cardiac ischemic condition, comparable to the effects of existing antianginal drugs but has no beneficial effects in peripheral arterial and cerebrovascular diseases.⁷⁶ On the other hand, several conflicting studies have shown that testosterone replacement also increases the incidence of cardiovascular disease.^33,67,76,78 However, a recent review by Morgentaler et al clarified these controversial studies and concluded that low levels of total testosterone, bioavailable testosterone, and free testosterone are associated with an increased risk and severity of coronary artery disease, whereas high serum testosterone concentrations (endogenous or via testosterone therapy) markedly reduced cardiovascular disease and cardiovascular risk factors.⁷⁹ Furthermore, Morgentaler et al also revealed that testosterone therapy is associated with a reduction in obesity, fat mass, metabolic parameters, and inflammatory markers.⁷⁹

Testosterone and Cardiac I/R Injury

Testosterone deficiency plays a role in the development of ischemic heart disease.^19,76,77 Men with heart disease or ischemic heart disease had lower levels of testosterone than men with normal coronary angiograms¹⁸ and that testosterone improved ischemic tolerance and quality of life in hypogonadal men with angina.^80,81 However, inconsistent reports exist regarding the beneficial effects of testosterone in the heart,^32,33 and the questions remain whether it does truly provide cardioprotective benefits.^24,25 Currently, there are only a few studies investigating the roles of testosterone in the myocardial infarction model and in the I/R heart. In spite of limited data available, the effects of testosterone on several crucial parameters in the myocardial infarction as well as the I/R heart including infarct size, lactate dehydrogenase (LDH) release, myocyte viability, left ventricular contractile function, arrhythmias, and heart rate variability (HRV) have been reported with inconsistent findings. In this review, the effects of testosterone on each of these crucial parameters in the myocardial infarction and I/R heart are comprehensively summarized and discussed.

Effect of testosterone on the infarct size in I/R hearts

Testosterone has been shown to have an infarct limiting effect in ex vivo and in vivo models of orchiectomized (ORX) rats with I/R injury. These reports are summarized in Table 1. In the Langendorff isolated heart, a physiological dose of testosterone 2 mg/kg body weight has been shown to decrease the infarct size in I/R heart by either the reduction in myocardial apoptosis through α1-adrenoceptor stimulation²⁸ or the promotion of neovascularization of heart tissues in myocardial infarction model through increased synthesis of 70-kDa heat shock proteins (Hsp70s) ²⁵ and activated κ-opioid receptor agonist.⁸² Consistently, a recent in vivo model study in ORX rat’s heart demonstrated that acute injection of testosterone prior to the reperfusion period could reduce the infarct size.⁸³ However, the supraphysiological dose of testosterone replacement (500 and 50 mg/kg) in the myocardial infarction and I/R models exerted neither adverse effect nor infarct size reduction benefits.^84,85

Table 1.

Summary of the Effect of Testosterone on the Infarct Size in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
ORX rat	MI LAD ligation	Physiological dose testosterone propionate, 2 mg/kg, SC Pretreated for 1, 3, and 28 days	↓ Infarction size	Testosterone replacement decreasing the infarct size may be due to decrease in the number of apoptotic cells and testosterone-stimulating neovascularization by mobilization and homing of CD34+ cells into ischemic area. In addition, endogenous testosterone deprivations in rats impair angiogenesis following infarction.	²⁵
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia 120-Minute reperfusion	Physiological dose testosterone, 2 mg/kg, SC Pretreated for 8 weeks Noradrenaline 10⁻⁷ mol/L Pretreated during I/R	↓ Infarction size	The decreasing infarct size may be due to α1-adrenoceptor stimulation and reduction in myocardial apoptosis.	²⁸
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia 120-Minute reperfusion	Physiological dose testosterone, 2 mg/kg, SC Pretreated for 8 weeks Pretreated with U50-488H 10 mg/kg 24 hours before I/R	↓ Infarction size	Testosterone may decrease infarct size by enhanced stimulation of preconditioning by either metabolic inhibition or a κ-opioid receptor agonist resulting in increased heat shock protein 70 synthesis, which plays a role in cardioprotection.	⁸²
ORX rat	I/R LAD ligation 60-Min ischemia 4-Hour reperfusion	Testosterone 0.02, 0.2, and 2.02 µg/kg Acute IV injection 15 minutes prior to reperfusion.	↓ Infarction size	Acute exogenous testosterone can reduce infarct size in ORX rats, the mechanism may be mediated by a nongenomic testosterone pathway.	⁸³
ORX rat	MI LAD ligation	Testosterone undecanoate, 500 mg/kg Deep IM injection every 4 weeks for 8 weeks	No difference in myocardial infarct size analyzed by MRI	Chronic anabolic testosterone treatment had no detrimental effects following myocardial infarction.	⁸⁴
Rabbits	I/R LAD ligation 30-Minute ischemia 3-Hours reperfusion	Supraphysiological dose of testosterone, 50 mg/kg, IM Pretreated for 1 weeks and 50 mg/kg, acute treated 5-10 minutes before I/R	No difference was found in myocardial infarct size	Supraphysiological dose of testosterone treatment had no detrimental effects on the infarct size.	⁸⁵

Abbreviations: ORX rat, orchiectomized rat; MI, myocardial infarction; LAD, left anterior descending coronary artery; I/R, ischemic and reperfusion; IV, intravenous; MRI, magnetic resonance imaging; IM, intramuscular; SC, subcutaneous; IEI, infarct expansion index.

It is of interest to note from these findings that physiological levels or low doses of testosterone may provide a cardioprotective effect against I/R injury. Most of the positive effects of testosterone on the infarct size in I/R models also occurred in the combination of testosterone supplement and conditional treatments, including I/R preconditioning and adrenergic receptor stimulation. The underlying mechanisms responsible for these findings need to be investigated in future studies.

Effect of testosterone on cardiac function in I/R hearts

Testosterone exerts a beneficial effect on cardiac function in ex vivo models of ORX rats with I/R injury and in vivo models of ORX rats with myocardial infarction (Table 2). The beneficial effects of testosterone in the ex vivo model using the Langendorff isolated heart preparation technique demonstrates that a physiological dose of testosterone (2 mg/kg) combined with I/R preconditioning,⁸² and adrenergic receptor stimulation²⁸ improves contractile recovery during the I/R period. The postulated mechanism of this effect was through α1-adrenoceptor stimulation²⁸ and increased synthesis of Hsp70 via a κ-pioid receptor agonist.⁸² Interestingly, supraphysiological doses of both testosterone and its metabolite (5α-dihydrotestosterone [DHT]) also exhibited a beneficial effect on cardiac function during I/R injury by attenuating intracellular Ca²⁺ overload during the reperfusion period,^24,86 whereas the supraphysiological dose of testosterone replacement (50 mg/kg) in another I/R model exerted neither adverse nor beneficial effect on cardiac function.⁸⁵ This suggests that testosterone plays a cardioprotective role by reducing intracellular acidification resulting in the maintenance of physiological cytosolic Ca²⁺ levels during ischemic stress.⁸⁶ In addition, echocardiographic study also demonstrated that testosterone replacement therapy (2 mg/kg) could improve myocardial performance in a myocardial infarction model.²⁵

Table 2.

Summary of the Beneficial Effect of Testosterone on Cardiac Function in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia 120-Minute reperfusion	Physiological dose testosterone, 2 mg/kg, SC Pretreated for 8 weeks Noradrenaline 10⁻⁷ mol/L Pretreated during I/R	Improve contractile recovery during both I/R and sympathetic stimulation period	Testosterone may improve contractile function by enhancing the expression of α1a- and β1-adrenoceptors.	²⁸
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia 120-Minute reperfusion	Physiological dose testosterone, 2 mg/kg, SC Pretreated for 8 weeks Pretreated with U50-488H 10 mg/kg 24 h before I/R	Improve contractile recovery in reperfusion period by: ↑ LVDP ↓ LVEDP Improve ±dp/dt max	Preconditioning requires testosterone to increase heat shock protein 70 synthesis, which plays a role in cardioprotection.	⁸²
Isolated rat heart (ORX rat)	I/R 30-Minute global no flow ischemia 30-Minute reperfusion	Supraphysiological dose of testosterone undecanoate, 500 mg/kg, IM Pretreated for 2 weeks 5α-dihydrotestosterone (DHT), 75 mg/pellet, SC implantation, pretreated for 3 weeks	In testosterone treated group: ↑ LVDP ↓ LVEDP ↓ Intracellular Ca²⁺ overload at end-ischemic and reperfusion period	Testosterone improves left ventricular contractile functions during I/R injury and attenuates reperfusion induced Ca²⁺ overload.	⁸⁶
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 45-Minute reperfusion	Supraphysiological dose of testosterone, 1 mg/d (as pellet), SC implantation, pretreated for 3 weeks	↑ Aortic flow, cardiac output, cardiac work, LVDP, contractility (+dp/dt) in testosterone-treated group	Administration of high-dose testosterone confers cardioprotection via ARs by improved postischemic functional recovery.	²⁴
ORX rat	MI LAD ligation	Physiological dose of testosterone propionate, 2 mg/kg, SC, pretreated for 1, 3, and 28 days	↑ % EF ↑ % FS ↓ LVEDP	Testosterone replacement therapy improved myocardial performance.	²⁵

Abbreviations: ORX rat, orchiectomized rat; LAD, left anterior descending coronary artery; SC, subcutaneous; I/R, ischemic and reperfusion; IV, intravenous; IM, intramuscular; LVDP, left ventricular develop pressure; LVEDP, left ventricular end diastolic pressure; MI, myocardial infarction; ARs, androgen receptors; EF, ejection fraction; FS, fractional shortening.

Inconsistent findings of the effect of testosterone on cardiac contractile function have been reported in ex vivo models of ORX rats with I/R injury. These reports are summarized in Table 3. The study using Langendorff isolated hearts reported that chronic exogenous testosterone (subcutaneous implantation of DHT 200 mg) neither improved nor worsened myocardial functional recovery after I/R injury.⁸⁷ Acute infusion of 17β-hydroxy-4-androsterone at a physiological level (10 ng/mL/min) in isolated hearts could depress the recovery of myocardial function during I/R injury³⁶ by inducing hypertrophic response in the heart via androgen receptors, resulting in an increase in ventricular stiffness.³⁶ There is a report that the androgen receptor blocker flutamide could improve cardiac contractile function during cardiac I/R injury.⁸⁸ However, this study was carried out in intact animals without testosterone deprivation. These findings suggest that endogenous testosterone may also act via other mechanisms instead of just the genomic effect on cardiac function during I/R injury.^38,89 This could be due to the nongenomic effects that are similar to other steroids,⁸⁹ which could bind to specific membrane binding sites and stimulate the secondary messenger signaling cascades, protein kinases (A and C), mitogen-activated protein kinase (MAPK), adenylyl cyclase, and intracellular Ca²⁺.^39,89
–91 These alterations in the nongenomic effect could induce various cellular outcomes including a rapid rises in the intracellular Ca²⁺ concentration,^44,45,92 neuromuscular or junctional signal transduction,^39,44 and vasorelaxation^39,45 and could be responsible for cardioprotection.

Table 3.

Summary of the Adverse or Neutral Effects of Testosterone on Cardiac Function in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
Rabbits	I/R LAD ligation 30-Minute ischemia 3-Hour reperfusion	Supraphysiological dose of testosterone, 50 mg/kg, IM Pretreated for 1 weeks, and 50 mg/kg, acutely treated 5-10 minutes before I/R	No difference in left ventricular ejection fraction and left ventricular fractional shortening	Supraphysiological dose of testosterone treatment had no detrimental effects on cardiac function.	⁸⁵
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia, followed by 40-minute reperfusion	5α-Dihydrotestosterone (DHT), 200 mg (as pellet), SC implantation, pretreated for 3 weeks	No difference in postischemic recovery of LVDP between castrated male-treated and -untreated groups	Chronic exogenous testosterone neither improved nor had a detrimental effect on myocardial functional recovery following I/R injury.	⁸⁷
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-minute reperfusion	Physiologic dose of 17β-hydroxy-4-androsterone, 10 ng/mL/min, acute infusion 5 minutes before ischemia	↓ LVDP ↑ LVEDP ↓ Contractility (+dp/dt) and ↓ relaxation (−dp/dt)	Acute exogenous testosterone depresses myocardial contractile functional recovery during I/R injury via nongenomic pathway.	³⁶
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-minute reperfusion	Flutamide (testosterone receptor blocker) pellet, 10 mg SC implantation, pretreated for 3 weeks	Blocking of testosterone receptor: ↑ LVDP ↓ LVEDP ↑ −dp/dt and +dp/dt	Lack of testosterone receptors depresses cardiac functional recovery during I/R injury.	⁸⁸

Abbreviations: ORX rat, orchiectomized rat; MI, myocardial infarction; LAD, left anterior descending coronary artery; LV, left ventricular; I/R, ischemic and reperfusion; SC, subcutaneous; EF, ejection fraction; LVDP, left ventricular develop pressure; LVEDP, left ventricular end diastolic pressure.

The importance of endogenous testosterone is emphasized by many reports of androgen deprivation therapy in patients with prostate cancer, which demonstrated that androgen deprivation therapy could increase cardiovascular events such as increased risk of ischemic heart disease,^93,94 induction of metabolic syndrome,^93

–96 increased fat mass and decreased lean mass,^97,98 and increased atherosclerosis in animal models.³⁰ However, there are a few clinical studies in patients with prostate cancer, demonstrating that androgen deprivation therapy did not have any correlation with cardiovascular disease and mortality.^99

–102 The discrepancies in these clinical findings could be due to differences in study design and populations, selection bias in men treated with Androgen suppression therapy (AST), and confounding factors such as comorbidity or lifestyle. However, on the basis of the current data, lacking of endogenous testosterone or androgen suppression may be associated with increased risks of cardiovascular diseases.

The discrepancies in these findings regarding the role of testosterone in cardiac function during I/R could be due to differences in the experimental model, an addition of conditional treatments, and dosages of testosterone treatment (physiological or supraphysiological dosage). Moreover, it is interesting that most reports showing the positive effects of testosterone used similar durations of treatment (chronic treatment for 2-8 weeks), whereas acute treatment of testosterone (infusion 5 minutes before ischemia) in myocardial infarction model resulted in decreased cardiac function. Further studies are needed to elucidate the mechanisms responsible for these effects on cardiac function.

Effect of testosterone on LDH release in I/R hearts

Testosterone has been shown to exert beneficial effects in ex vivo models of ORX rats with I/R injury (Table 4). These studies using the Langendorff isolated hearts demonstrated that both a physiological dose (2 mg/kg) or supraphysiological dose of testosterone could decrease LDH release in the I/R heart,^24,28,82 and the proposed mechanisms could be via either α1-adrenoceptor stimulation²⁸ or increased synthesis of Hsp70s.⁸²

Table 4.

Summary of the Effect of Testosterone on LDH Released in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
Isolated rat heart (ORX rat)	I/R 25-Minùte global no flow ischemia, followed by 45-minute reperfusion	Supraphysiological dose 1 mg/d (as pellet), SC implantation Pretreated for 3 weeks	Testosterone ↓ LDH release during pre- and post-I/R Prevented the reduction of LV catalase enzyme	Administration of high-dose testosterone confers cardioprotection via ARs by improving postischemic functional recovery.	²⁴
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia and 120-minute reperfusion	Physiological dose of testosterone 2 mg/kg, SC, pretreated for 8 weeks Noradrenaline 10⁻⁷ mol/L Pretreated during I/R	↓ LDH release during I/R	Testosterone decreases LDH release by enhancing the beneficial effect of α1-adrenoceptor resulting in reduced myocardial apoptosis.	²⁸
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia and 120-minute reperfusion	Physiological dose of testosterone 2 mg/kg, SC, pretreated for 8 weeks Pretreated with U50-488H, 10 mg/kg, 24 hours before I/R	↓ LDH release during I/R	Testosterone decreases LDH release by enhanced preconditioning or stimulation of a κ-opioid receptor agonist, resulting in increased synthesis of heat shock protein 70.	⁸²

Abbreviations: ORX rat, orchiectomized rat; I/R, ischemic and reperfusion; SC, subcutaneous; LDH, lactate dehydrogenase; LV, left ventricular; ARs, androgen receptors; LAD, left anterior descending coronary artery.

Effect of testosterone on myocyte viability in I/R hearts

Testosterone has been shown to have beneficial effects on cell viability in ORX rats with I/R injury and ORX rats with the myocardial infarction model (Table 5). Recent in vitro studies using the isolated ventricular myocytes demonstrated that a physiological concentration of testosterone combined with I/R preconditioning⁸² and adrenergic stimulation²⁸ could increase ventricular myocyte viability in the I/R model. Testosterone could work through the angiogenesis pathway⁸² and α1-adrenoceptor stimulation, which are mediated by both androgen receptors and nongenomic actions.²⁸ A physiological dose of testosterone (2 mg/kg) has also been shown to decrease the apoptotic cells in the myocardial infarction model, and these beneficial effects are thought to occur through the nongenomic pathway.²⁵

Table 5.

Summary of the Effect of Testosterone on Cardiomyocyte Viability in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
ORX rat	MI LAD ligation	Physiological dose of testosterone propionate, 2 mg/kg, SC Pretreated for 1, 3, and 28 days Flutamide (testosterone receptor blocker), 30 mg/kg/d, SC, pretreated for 1, 3, and 28 days	Testosterone replacement, with and without testosterone receptor blocker, decreases the percentage of TUNEL-positive cells compare with castrated group.	Testosterone replacement decreases the number of apoptotic cells through nongenomic pathway mechanism.	²⁵
Isolated rat ventricular myocytes (ORX rat)	I/R 10-Minute metabolic inhibition and anoxia 10-Minute reperfusion	Physiological dose of testosterone 2 mg/kg, SC, pretreated for 8 weeks Followed with 10⁻⁸ mol/L concentration of testosterone incubated for 24 hours before I/R Noradrenaline 10⁻⁷ mol/L Pretreated during I/R	↑ Expression of α1a- and β1-adrenoceptors. ↑ Cell viability compared with the castrated group.	Testosterone reduces I/R injury by enhancing the beneficial effect of α1-adrenoceptor stimulation, which was greater than the adverse effect of β1-adrenoceptor stimulation through both androgen and nonandrogen receptors.	²⁸
Isolated rat ventricular myocytes (ORX rat)	I/R 10-Minute metabolic inhibition and anoxia 10-Minute reperfusion	Physiological concentration Testosterone, 10⁻⁸ mol/L incubated for 24 hours before I/R pretreated with U50-488H 30 µmol/L 30 min before I/R	Testosterone combined with preconditioning restored the ventricular myocytes viability.	Testosterone is required for the cardioprotection of preconditioning. This effect is mediated by androgen receptors.	⁸²

Abbreviations: ORX rat, orchiectomized rat; MI, myocardial infarction; LAD, left anterior descending coronary artery; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; I/R, ischemic and reperfusion; SC, subcutaneous.

Effect of testosterone on molecular signaling in I/R hearts

Most of the molecular studies on testosterone replacement demonstrated adverse effects in an ex vivo model of ORX rats with I/R injury (Table 6). In Langendorff isolated hearts of ORX rats, acute exogenous testosterone replacement at a physiological level had damaging effects on the myocardium after I/R injury by the inhibition of signal transducers and activators of transcription 3 (STAT-3) and the suppression of the cytokine signaling 3 (SOCS-3) antiapoptotic pathway.³² In addition, acute testosterone infusion to physiological level in an isolated heart also increased the activation of the p38 MAPK and c-Jun N-terminal kinase pathways. These molecular signalings were involved with myocardial inflammation,³⁶ increased apoptotic protein caspase 3,³⁶ decreased antiapoptotic protein BcI-2,^36,103 and Forkhead box O3a phosphorylation (p-FOXO3a),¹⁰³ and downregulation of PI3K/Akt antiapoptotic pathways, resulting in reduced phosphorylation of Bcl-2-associated death promoter protein (Bad) and unable to inhibit Bax-triggered apoptosis.¹⁰³ Consistent with these results, blocking of androgen receptor in an I/R injury model using the Langendorff isolated heart resulted in decreased proinflammatory cytokine production, decreased p38-MAPK and caspase 1, decreasing the expression of apoptotic protein caspases 3 and 11, and increasing the antiapoptotic protein Bcl-2.⁸⁸

Table 6.

Summary of the effect of Testosterone on Molecular Parameters in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
ORX rat	MI LAD ligation	Physiological dose of testosterone propionate, 2 mg/kg, SC Pretreated for 1, 3, and 28 days Flutamide (testosterone receptor blocker), 30 mg/kg/d, SC, pretreated for 1, 3, and 28 days	Testosterone ↓ Levels of HIF-1α, SDF-1α, and VEGF mRNA expression. ↑ The number of CD34+ cells Endogenous testosterone deprivation worsened cardiac function.	Exogenous testosterone replacement promotes neovascularization by the homing of CD34+ stem cells and increases the expression of cytokines HIF-1α, SDF-1α, and VEGF in the early stage of MI, resulting in an increased neovascularization in the MI heart.	²⁵
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-Minute reperfusion	5α-Dihydrotestosterone (DHT) 100 mg (as pellet), SC implantation, pretreated for 3 weeks Physiologic dose of 17β-hydroxy-4-androsterone 10 ng/mL/min, acute infusion (AI) 5 minutes before ischemia	Depletion of endogenous testosterone ↑ STAT-3 and SOCS-3 in male hearts Blockade of testosterone receptor ↑ SOCS-3 levels in males Administration of exogenous testosterone to ORX male and female hearts ↓ STAT-3 activity and SOCS-3 level	Testosterone downregulated antiapoptotic protein, STAT-3, and SOCS-3 expression in the myocardium after I/R injury.	³²
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-Minute reperfusion	Physiologic dose of 17β-hydroxy-4-androsterone 10 ng/mL/min, acute infusion 5 minutes before ischemia	Testosterone ↑ The activation of signaling enzymes of myocardial inflammation (p38 MAPK and JNK) ↑ An expression of apoptotic protein (caspase-3) ↓ Expression of antiapoptotic protein Bcl-2	Exogenous testosterone has detrimental effects on the myocardium after I/R injury.	³⁶
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-Minute reperfusion	Flutamide (testosterone receptor blocker) pellet 10 mg, SC implantation, pretreated for 3 weeks	Blocking of testosterone receptor and castration ↓ Proinflammatory cytokine production (TNF-α, IL-1β, and IL-6) ↓ Expression of p38 MAPK ↓ Expression of apoptotic protein (caspases 1, 3, and 11) ↑ Expression of antiapoptotic protein (Bcl-2)	Decrease in androgen receptors causes an adverse effect on the I/R heart	⁸⁸
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-Minute reperfusion	5α-Dihydrotestosterone (DHT) 100 mg (as pellet), SC implantation, pretreated for 3 weeks	Castration or flutamide treatment ↑ The activation of the myocardial Akt pathway, p-Bad, Bcl-2, and p-FOXO3a ↓ Fas-L in male hearts ↑ Bax	Acute exogenous testosterone has damaging effects on myocardium after I/R injury through downregulation of the Akt pathway in male hearts following I/R.	¹⁰³
Isolated rat heart (ORX rat)	I/R 25-Minute global no flow ischemia 40-Minute reperfusion	Physiologic dose of 17β-hydroxy-4-androsterone 10 ng/mL/min, acute infusion 5 minutes before ischemia	Acute testosterone replacement reversed the effects of Akt signaling in castrated male hearts ↓ p-Bad ↓ Bcl-2/Bax ratio ↓ Antiapoptotic protein p-FOXO3a Chronic testosterone replacement ↓ Bax ↑ Bcl-2/Bax ratio	The chronic treatment of testosterone can provide cardioprotective effects.	¹⁰³

Abbreviation: ORX rat, orchiectomized rat; MI, myocardial infarction; LAD, left anterior descending coronary artery; SC, subcutaneous; I/R. ischemic and reperfusion; HIF-1α, hypoxia-inducible factor 1-α; SDF-1α, stromal cell-derived factor 1α; VEGF, vascular endothelial growth factor; STAT-3, signal transducer and activator of transcription 3; SOCS-3, suppressor of cytokine signaling 3; mRNA, messenger RNA; p38 MAPK, p38 mitogen-activated protein kinase; JNK, c-Jun N-terminal kinases; Bcl-2, B-cell lymphoma 2; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1β; IL-6, interleukin 6; Akt, protein kinase B; p-Bad, The Bcl-2-associated death promoter; FOXO3a, Forkhead box O3; Bax, bcl-2-like protein 4; Fas-L, Fas ligand.

In contrast to findings following acute testosterone administration, a study using chronic exogenous testosterone replacement demonstrated improved cardiac function and restored the activation of the myocardial PI3K/Akt pathway including decreased proapoptotic (Bax and Fas-L protein) and increased antiapoptotic proteins (Bcl-2, p-Bad, and p-FOXO3a) in this isolated heart investigation.¹⁰³ The beneficial effect of testosterone on molecular parameters has also been demonstrated in ORX rats with an myocardial infarction model. Testosterone administration at a physiological dose level (2 mg/kg) could promote angiogenesis after myocardial infarction by increasing hypoxia-inducible factor 1α (HIF-1α) and stromal cell-derived factor 1α (SDF-1α) signaling cytokines, which are generated at low oxygen concentration to promote neovascularization.²⁵ Moreover, testosterone could also increase the number of CD-34 progenitor stem cells that can differentiate into hematopoietic and endothelial progenitor cells in the ischemic myocardium.²⁵

Regarding the effects of testosterone in an I/R model, it may be proposed that either acute exogenous testosterone replacement or endogenous testosterone could provide deleterious effects on the heart by accelerating the apoptotic signaling process after I/R injury. However, chronic exogenous testosterone replacement may exert a beneficial effect in both I/R and myocardial infarction models.

Effect of testosterone on cardiac arrhythmias in I/R hearts

In Langendorff perfused hearts, a physiological dose of testosterone (2 mg/kg) combined with adrenergic stimulation has been shown to reduce reperfusion arrhythmia during I/R injury by reducing the incidence of premature ventricular beats,²⁸ whereas the supraphysiological dose of testosterone replacement (50 mg/kg) demonstrated antiarrhythmic effect in I/R model.⁸⁵ The mechanism responsible for the protective effect of testosterone on arrhythmia reduction was thought to be through α1a-adrenoceptor stimulation²⁸ and shortened the QT interval.⁸⁵ Since this positive effect of testosterone on the cardiac arrhythmia during I/R occurred together with the use of adrenergic receptor stimulation (Table 7), it is still unclear whether testosterone alone could provide a similar benefit. This needs to be investigated further.

Table 7.

Summary of the Effect of Testosterone on Arrhythmia Parameters and Heart Rate Variability (HRV) in I/R Heart.

Animal Species	Model	Drugs/Dose/Route	Major Findings	Interpretation	Ref
Isolated rat heart (ORX rat)	I/R LAD ligation 30-Minute ischemia and 120-minute reperfusion	Physiological dose of testosterone 2 mg/kg, SC, pretreated for 8 weeks Noradrenaline 10⁻⁷ mol/L Pretreated during I/R	Testosterone restored the incidence of PVB to the sham control	Testosterone replacement, mediated by androgen receptors, reduces arrhythmia during I/R injury.	²⁸
Rabbits	I/R LAD ligation 30-Minute ischemia 3-Hour reperfusion	Supraphysiological dose of testosterone, 50 mg/kg, IM Pretreated for 1 weeks and 50 mg/kg, acute treated 5-10 minute before I/R	Testosterone significantly shortened the QT interval by 9% compared with the control group	Supraphysiological dose of testosterone treatment may be anti-arrhythmic by shortening the QT interval.	⁸⁵
Human aged 36-73 yr (cross-sectional study)	MI	88 Postinfarction men 24-Hour Holter monitoring Measure the levels of testosterone hormone	High level of blood testosterone associated with improved HRV by ↑ SDNN ↑ rMSSD ↑ pNN50	Testosterone has a positive impact on cardiac autonomic regulation in men after MI by promoting parasympathetic dominance.	¹⁰⁴

Abbreviations: ORX rat, orchiectomized rat; I/R, ischemic and reperfusion; LAD, left anterior descending coronary artery; SC, subcutaneous; PVB, premature ventricular beat; MI, myocardial infarction; SDNN, the standard deviation of NN intervals; rMSSD, root mean square of the successive differences; pNN50, the proportion of NN50; IM, intramuscular.

Effect of testosterone on HRV in myocardial infarction model

Currently, there is no basic study on the effects of testosterone on the HRV, and there is only 1 clinical study investigating the effect of testosterone on HRV in patients with coronary artery disease. This cross-sectional study in men with stable coronary artery disease (age 36-73 years, mean age: 56 years) reported that a high level of blood testosterone was associated with increased HRV (Table 7).¹⁰⁴ These findings suggested that testosterone might have a positive effect on cardiac autonomic regulation in men after myocardial infarction by promoting parasympathetic dominance. Future basic and clinical studies are needed to investigate the roles of testosterone in the cardiac autonomic balance in both I/R injury and myocardial infarction models.

The Relationship Between Testosterone Levels and Coronary Artery Disease in Clinical Studies

Clinical studies show that low levels of testosterone were linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, and endothelial dysfunction, as well as to impaired left ventricular function.¹⁰⁵ Haring and colleagues demonstrated that serum testosterone levels were inversely related to mortality rate due to cardiovascular disease or cancer, whereas low serum testosterone was associated with an increased risk of all-cause mortality²³ and that plasma testosterone level could potentially be used as a predictive tool for mortality from cardiovascular disease.¹⁰⁶ Regarding the relationship between plasma testosterone levels and coronary artery disease, a previous clinical study has shown that the plasma level of total testosterone, free testosterone, and bioavailability testosterone was significantly lower in men with coronary artery disease than healthy men.¹⁸ However, several reports found that only free testosterone was significantly lower in men with coronary artery disease.^107

–110 It has also been shown that a low testosterone level was associated with atherosclerosis¹¹¹ and myocardial infarction¹¹² in men, supporting the previous findings that low levels of testosterone could increase the risk and contribute to a high prevalence of coronary artery disease in men.^{22,110,113

–116} In addition, the level of testosterone shows an inverse correlation with the severity of coronary artery stenosis.^{17,107,108,117,118} These findings suggested that endogenous testosterone may play a preventive role in the development of coronary arteriosclerosis.^117,119 Despite these beneficial reports on testosterone, inconsistent findings exist. A recent clinical report demonstrated that both low and high levels of total testosterone were associated with an increased ischemic arterial disease risk ratio, suggesting that only an optimal range of plasma testosterone could provide cardiovascular protection.¹²⁰ A summary of clinical reports regarding the association between the plasma testosterone levels and coronary artery disease is shown in Table 8.

Table 8.

Summary of Clinical Studies Reported on the Association Between Testosterone Levels and Coronary Artery Disease.

Model	n	Major Findings	Interpretation	Ref
Men with CAD	201	Plasma testosterone levels in patients with CAD were lower than in the healthy participants.	Low plasma testosterone level may be a risk factor for CAD.	¹¹³
Men with CAD	56	Men with coronary artery disease had lower TT levels, testosterone/estradiol ratio, and free androgen index than the control group.	Testosterone may be involved in the pathogenesis of coronary atherosclerosis.	¹¹⁵
Men with CAD	803	Testosterone level was inversely associated with severity of coronary stenosis (Gensini coronary score). The severity of CAD was lower in participants with high level of testosterone.	Lower testosterone levels are associated with greater coronary stenosis.	¹⁷
Men with CAD	191	The level of FT and TT was lower in patients with CAD than in the control group. Low TT was significantly correlated with CAD. The severity of coronary stenosis (Gensini coronary score) was correlated with low TT and FT.	Low levels of testosterone are associated with premature coronary artery disease and its severity in young adults.	¹¹⁸
Men with CAD	201	Testosterone level was inversely associated with the level of arteriosclerosis. Lower concentrations of DHEA and testosterone were found in those men with more severe arteriosclerotic lesions.	Testosterone may play a preventive role in the development of coronary arteriosclerosis. Low levels of testosterone lead to greater severity of arteriosclerotic lesions.	¹¹⁷
Men with CAD	128	TT levels were not different from control. FT level in 3-vessel lesion group was lower than that in double-vessel lesion group and single-vessel lesion group.	FT levels are inversely associated with the severity of coronary artery lesions.	¹⁰⁷
Men with CAD	69	TT and FT levels in patients with CAD were lower than the control group. Patients with FT levels below the cutoff value of 17.3 pg/mL had 3.3-fold risk of developing premature CAD compared to those with FT levels above the cutoff level.	Low levels of FT may be related to the development of premature CAD.	¹⁰⁸
Men with CAD	129	Patients with CAD had lower levels of TT and FT than controls. Degree of CAD had an inverse relationship with plasma testosterone levels.	Low levels of plasma testosterone are associated with the increased risk of CAD in men.	²²
Men with CAD	139	TT, FT, SHBG, and AR levels in the CAD group were reduced compared with the control group. TT and FT levels were negatively correlated with CAD.	Low levels of TT and SHBG could be risk factors for CAD in elderly men.	¹¹⁶
Men with CAD	105	Men with CAD had lower levels of FT than the control group.	Low levels of FT are associated with the development of CAD.	¹¹⁴
Men with CAD	237	No differences in TT, SHBG, AR, and DHEA levels among groups. Serum level of FT was lower in the CAD group than in the control group. FT level was inversely correlated with CAD. Age was negatively correlated with the levels of FT and AR	Low levels of FT contribute to a high prevalence of CAD in elderly men. The age-related reduction in FT and AR accelerates the progression of coronary atherosclerosis.	¹¹⁰
Men with CAD	100	Patients with CAD had lower values of FT	Low levels of FT may contribute to the development of premature coronary artery disease.	¹⁰⁹
Men with MI	100	Patients with STEMI and SA had low testosterone level Hypotestosteronemia prevalence was higher among patients with STEMI compared with patients with SA Hypotestosteronemia independently predicted both angio-MVO and ECG-MVO	Testosterone deficiency may contribute to the development of coronary instability and MVO pathogenesis.	¹¹²
Men with CAD	111	Plasma testosterone level was inversely correlated with the degree of coronary stenosis. Higher blood level of TT was associated with the lower number of stenosis in the coronary arteries.	Endogenous testosterone may provide protective effects on coronary arteries.	¹¹⁹
Men with CAD	3650	Lowest total testosterone had IAD risk ratio 2.23, whereas highest total testosterone had IAD risk ratio 3.61.	High and low plasma testosterone levels are associated with an increased risk of IAD in elderly men. An optimal range of plasma testosterone may confer cardiovascular protection.	¹²⁰

Abbreviations: CAD, coronary artery disease; TT, total testosterone; FT, free testosterone; DHEA, dehydroepiandrosterone; SHBG, sex hormone binding globulin; AR, androgen receptor; MI, myocardial infarction; DHEA, dehydroepiandrosterone; MVO, microvascular obstruction; STEMI, ST-elevation myocardial infarction; SA, stable angina; ECG-MVO, electrocardiographic microvascular obstruction; angio-MVO, angiographic microvascular obstruction; IAD, ischemic arterial disease.

Effects of Testosterone Replacement on Myocardial Infarction and Heart Failure in Clinical Studies

Previous studies demonstrated that testosterone replacement therapy exerts protective effect against myocardial ischemia such as delayed time to ischemia,^80,81,121 reduced exercise-induced myocardial ischemia,^80,121 and decreased severity of coronary stenosis by increased coronary artery diameter and coronary blood flow.^122,123 This could be partly due to its effects of reducing cholesterol and triglycerides^81,122 and decreasing serum tumor necrotic factor α.⁸¹ It has also been shown that testosterone therapy was associated with a reduced risk of myocardial infarction.¹²⁴ However, as discussed earlier, inconsistent findings from clinical reports exist. Several studies found that testosterone therapy could increase the risk of myocardial infarction, especially in older men.^33,67 Several complications have been reported with supraphysiologic doses of testosterone replacement in athletes including hypertension, cardiomyopathy, pulmonary embolism, cardiac arrhythmias, and myocardial infarction,¹²⁵ suggesting that unnecessary use of testosterone without medical supervision is likely to cause undesirable effects. A summary of clinical reports regarding the effects of testosterone replacement on myocardial infarction and heart failure is shown in Table 9.

Table 9.

Summary of Clinical Studies Reported on the Effect of Testosterone Replacement on Myocardial Infarction and Heart Failure.

Model	n	Treatment	Major Findings	Interpretation	Ref
Men with MI	46	5 mg testosterone daily by transdermal patch or matching placebo for 12 weeks.	Testosterone increased the time to 1-mm ST-segment depression.	Low-dose supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia.	⁸⁰
Men with MI	10	Testosterone injections (1 mL of 100 mg testosterone/mL) every 2 weeks for 1 month.	Testosterone therapy increased the time to 1-mm ST-segment depression and reduced total cholesterol and serum tumor necrosis factor α.	Testosterone replacement therapy in hypogonadal men delays time to ischemia and reduces the total cholesterol and inflammation.	⁸¹
Men with MI	15	Testosterone undecanoate, 250 mg/mL every 12 weeks for 12 months (intramuscular injection).	Testosterone increased the time to 1-mm ST-segment depression and increased hemoglobin and hematocrit. Testosterone decreased the CIMT, BMI, and serum triglycerides.	Testosterone exerts protective effects on myocardial ischemia.	¹²²
Men with MI	6355	Eight-year follow-up of patients who treated with at least 1 intramuscular injection of testosterone enanthate, up to 1 mL; testosterone cypionate, up to 1 mL; testosterone cypionate, 100-200 mg; testosterone enanthate, 100-200 mg; testosterone suspension, up to 50 mg; testosterone propionate, up to 100 mg; and testosterone pellet, 75 mg	Testosterone therapy was not associated with an increased risk of MI. Testosterone therapy was associated with a reduced risk of MI.	Older men treated with intramuscular testosteroneinjections have no increased risk of MI. For men with high MI risk, testosterone use is modestly protective against MI.	¹²⁴
Men with CAD	14	Testosterone (2.5 mg; intravenous in 5 minutes) before exercise tests.	Testosterone increased the time to 1-mm ST-segment depression and increased total exercise time.	Short-term administration of testosterone exerts a beneficial effect on exercise-induced myocardial ischemia in men with CAD. This benefit may be related to a direct coronary-relaxing effect.	¹²¹
Men with CAD	13	3-Minute intracoronary infusion of physiological concentrations testosterone (10⁻¹⁰ to 10⁻⁷ mol/L).	Testosterone increased coronary artery diameter and coronary blood flow.	Intracoronary infusion of testosterone induces coronary artery dilatation and increases coronary blood flow in men with CAD.	¹²³
Men with MI (case report)	1	A recreational weight lifter was taking high-dose intramuscular testosterone for the previous 6 weeks and intermittently for 2 years.	Hematologic studies showed polycythemia and right coronary angiography revealed a total occlusion at the mid-portion of the vessel with intracoronary thrombus.	Association with and potential interplay between traditional cardiovascular risk factors, high-dose testosterone use, and possibly elevated plasma viscosity is proposed as possible contributors to this cardiovascular event.	¹²⁵
Men with MI	46	Received two 2.5-mg self-adhesive active testosterone patches each night for 12 weeks.	There was no change in fibrinogen, tPA activity or PAI-1 activity, and hemoglobin concentration in the testosterone group.	Physiological testosterone replacement does not interfere with blood coagulation status.	¹²⁶
Men with CAD	1223	13 Patients used testosterone gel (1% 5 g packets) 436 Patients with testosterone injections (200 mg/mL) 774 Patients used patches (2.5 mg/24-h patch) (Average 531 days)	Testosterone therapy was associated with increased risk of adverse outcomes including all-cause mortality, MI, and ischemic stroke. No difference in the risk of adverse outcomes across the 3 testosterone formulations.	Testosterone therapy was associated with increased risk of adverse outcomes.	⁶⁷
Men with MI	55 593	Compared the incidence rate of MI (post/preprescription rate ratio [RR]) following initiation of testosterone therapy (TT) prescription.	Younger men with a history of heart disease had a 2-3-fold increased risk of MI within 90 days after TT. Men aged 65 years and older had a 2-fold increase in the risk of MI within 90 days after TT.	In older men and in younger men with preexisting diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.	³³
Men with CHF	50	Testosterone enanthate (250mg/mL) 1 mL once every 4 weeks for 12 weeks (intramuscular injection).	Improved diastolic function and increased trend in 6-minute walk distance (6MWD) parameter.	Testosterone replacement exerts a beneficial role in improving functional capacity and quality of life in patients with heart failure.	¹²⁷
Men with CHF	70	Testosterone undecanoate 1000 mg long-acting once every 6 weeks for 12 weeks (intramuscular injection)	Testosterone therapy improved oxygen consumption, quadriceps isometric strength, insulin sensitivity, and baroreflex.	Long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and baroreflex sensitivity in men with moderately severe CHF.	¹²⁸
Men with CHF	76	Testosterone replacement therapy (5 mg Androderm) at physiological doses for 12 months	Improved exercise capacity, no adverse events.	Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.	¹²⁹

Abbreviations: MI, myocardial infarction; CIMT, carotid intima–media thickness; BMI, body mass index; CAD, coronary artery disease; PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; CHF, congestive heart failure; TT, testosterone therapy; RR, post/preprescription rate ratio.

Conclusion

The cardioprotective effects of chronic testosterone replacement to the physiological dose have been demonstrated in an I/R heart. This technique is seen to be effective by reducing the infarct size, improving contractile functions, decreasing LDH release, increasing ventricular myocytes viability, reducing arrhythmias, and improving autonomic regulation of the heart after I/R. These beneficial effects of testosterone are thought to occur via the stimulation and expression of α1a-adrenoceptor, increased synthesis of Hsp70, increased neovascularization of CD34+ stem cell and cytokines HIF-1α, SDF-1α, and vascular endothelial growth factor in the early stages of myocardial infarction. In addition, testosterone may play a beneficial role by maintaining intracellular Ca²⁺ homeostasis during ischemic stress (Figure 1). However, acute testosterone replacement might cause adverse effects in the I/R heart by reducing cardioprotective signaling proteins such as STAT-3 and SOCS-3 after I/R and also decreasing myocardial Akt activation, leading to reduced Bad phosphorylation and decreased Bcl-2 levels, which consequently results in worsened I/R-depressed myocardial function.

Figure 1.

The potential roles of testosterone replacement in cardiac ischemia–reperfusion (I/R) and myocardial infarction models. During cardiac I/R, testosterone administration has been shown to reduce infarct size, decrease lactate dehydrogenase (LDH) release, and increase cell viability via increased neovascularization, increased heat shock protein 70 syntheses, α1a-adrenoceptor stimulation, and decreased myocardial apoptosis. The reduction in sympathovagal imbalance may occur due to decreased oxidative stress. The reduction in cardiac arrhythmia could occur due to decreased intracellular Ca²⁺ accumulation and α1a-adrenoceptor stimulation. Furthermore, testosterone could decrease intracellular Ca²⁺ accumulation, increase an expression of α1a- and β1-adrenoceptors, decrease LVEDP, increase LVDP, and ejection fraction, thus resulting in increased contractility and improved cardiac function. HIF-1α indicates hypoxia-inducible factor 1-α; SDF-1α, stromal cell-derived factor 1α; VEGF, vascular endothelial growth factor; CD34, hematopoietic progenitor cell antigen CD34; LVDP, left ventricular develop pressure; LVEDP, left ventricular end diastolic pressure.

Footnotes

Author Contribution

W. Pongkan and N. Chattipakorn contributed to conception and design; acquisition, analysis, and interpretation; drafted the article; critically revised the article; gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. S. Chattipakorn contributed to conception and design, analysis and interpretation, drafted the article, critically revised the article, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Thailand Research Fund Royal Golden Jubilee PhD program (WP and NC), the Thailand Research Fund BRG5780016 (SC), a NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand (NC), and the Chiang Mai University Center of Excellence Award (NC).

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Roles of Testosterone Replacement in Cardiac Ischemia–Reperfusion Injury

Abstract

Keywords

Introduction

Physiological Roles of Testosterone in the Heart

Testosterone and the Pathological Heart

Testosterone and Cardiac I/R Injury

Effect of testosterone on the infarct size in I/R hearts

Effect of testosterone on cardiac function in I/R hearts

Effect of testosterone on LDH release in I/R hearts

Effect of testosterone on myocyte viability in I/R hearts

Effect of testosterone on molecular signaling in I/R hearts

Effect of testosterone on cardiac arrhythmias in I/R hearts

Effect of testosterone on HRV in myocardial infarction model

The Relationship Between Testosterone Levels and Coronary Artery Disease in Clinical Studies

Effects of Testosterone Replacement on Myocardial Infarction and Heart Failure in Clinical Studies

Conclusion

Footnotes

Author Contribution

Declaration of Conflicting Interests

Funding

References