Review

Journal of Cardiovascular
Pharmacology and Therapeutics
Roles of Testosterone Replacement in 1-17
ª The Author(s) 2015
Reprints and permission:
Cardiac Ischemia–Reperfusion Injury sagepub.com/journalsPermissions.nav
DOI: 10.1177/1074248415587977
cpt.sagepub.com

Wanpitak Pongkan, DVM1,2,3, Siriporn C. Chattipakorn, DDS, PhD2,3,4,

and Nipon Chattipakorn, MD, PhD1,2,3

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 testos-
terone 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 replace-
ment can cause adverse effects in the I/R heart.

Keywords
testosterone, ischemia–reperfusion injury, heart, aging

Introduction Previous studies reported that men have a higher incidence,

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 testoster-
one 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, dyslipide-
mia, 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 ¼ 60 years) visiting primary care practices in the United
States.7 The prevalence of hypogonadism also increases sub-
stantially with age6,8 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 tes-
tosterone 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
mortality, and risk of coronary artery disease than women14-16
and the risk of coronary artery disease increases markedly with
age.16 In addition, patients with coronary artery disease17-20
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 corre-
lation 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
1
Faculty of Medicine, Cardiac Electrophysiology Research and Training Center,
Chiang Mai University, Chiang Mai, Thailand
2
Department of Physiology, Faculty of Medicine, Cardiac Electrophysiology
Unit, Chiang Mai University, Chiang Mai, Thailand
3
Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai
University, Chiang Mai, Thailand
4
Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry,
Chiang Mai University, Chiang Mai, Thailand
Manuscript submitted: March 3, 2015; accepted: April 20, 2015.
Corresponding Author:
Nipon Chattipakorn, Faculty of Medicine, Cardiac Electrophysiology Research
and Training Center, Chiang Mai University, Chiang Mai 50200, Thailand.
Email: nchattip@gmail.com

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2 Journal of Cardiovascular Pharmacology and Therapeutics
Although there are many reports indicating that testosterone
provided cardioprotective effects24-26 such as antiarrhythmic
properties,27 reduced infarct size,28 enhanced vasodilatation,29
decreased atherosclerosis,30 and improved metabolic para-
meters,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 dis-
cussed. 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 apoptosis39,40 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 Ca2þ-ATPase (SERCA),46
increasing or regulating cardiac contractility, and Ca2þ handling
in the heart.38,43,47 However, conflicting evidence was that
chronic administration of a synthetic testosterone (nandro-
lone decanoate) decreased left ventricular myocardial func-
tion and thus overall cardiac performance without altering
contractility in rats.48
The physiological effects of testosterone on cardiac electro-
physiology 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 relation-
ship 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 testoster-
one was arrhythmogenic in rat atria possibly through less bind-
ing 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 Ca2þ 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 (a1c-subunit of L-type calcium
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channel) messenger RNA (mRNA) level and also increased the
Naþ/Ca2þ exchanger mRNA level,62,64,65 improved the cardiac
L-type calcium current,62,63 increased Ca2þ released via the
ryanodine receptor,61 maintained FK506-binding protein 12.6
in ryanodine receptor type 2,60 maintained or increased
SERCA and Naþ/Ca2þ exchanger activity,46,61 and maintained
phosphorylation of phospholamban Thr17,46 thus resulting in
faster Ca2þ 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 conse-
quence 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 sever-
ity 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 system76,77 and that decreased circulating tes-
tosterone 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 car-
diovascular disease.33,67,76,78 However, a recent review by
Morgentaler et al clarified these controversial studies and con-
cluded that low levels of total testosterone, bioavailable testos-
terone, and free testosterone are associated with an increased
risk and severity of coronary artery disease, whereas high
serum testosterone concentrations (endogenous or via testoster-
one therapy) markedly reduced cardiovascular disease and car-
diovascular 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 testoster-
one improved ischemic tolerance and quality of life in hypo-
gonadal 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 pro-
vide cardioprotective benefits.24,25 Currently, there are only a
few studies investigating the roles of testosterone in the myo-
cardial infarction model and in the I/R heart. In spite of lim-
ited data available, the effects of testosterone on several
Pongkan et al 3

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

25
ORX rat MI Physiological dose testosterone # Infarction size Testosterone replacement decreasing
LAD ligation propionate, 2 mg/kg, SC the infarct size may be due to decrease
Pretreated for 1, 3, and 28 days in the number of apoptotic cells
and testosterone-stimulating
neovascularization by mobilization and
homing of CD34þ cells into ischemic
area. In addition, endogenous
testosterone deprivations in rats impair
angiogenesis following infarction.
28
Isolated rat heart I/R Physiological dose testosterone, # Infarction size The decreasing infarct size may be due to
(ORX rat) LAD ligation 2 mg/kg, SC a1-adrenoceptor stimulation and
30-Minute ischemia Pretreated for 8 weeks reduction in myocardial apoptosis.
120-Minute Noradrenaline 107 mol/L
reperfusion Pretreated during I/R
82
Isolated rat heart I/R Physiological dose testosterone, # Infarction size
Testosterone may decrease infarct
(ORX rat) LAD ligation 2 mg/kg, SC size by enhanced stimulation of
30-Minute ischemia Pretreated for 8 weeks preconditioning by either metabolic
120-Minute Pretreated with U50-488H inhibition or a k-opioid receptor agonist
reperfusion 10 mg/kg 24 hours before I/R resulting in increased heat shock protein
70 synthesis, which plays a role
in cardioprotection.
83
ORX rat I/R Testosterone # Infarction size Acute exogenous testosterone can reduce
LAD ligation 0.02, 0.2, and 2.02 mg/kg infarct size in ORX rats, the mechanism
60-Min ischemia Acute IV injection 15 minutes may be mediated by a nongenomic
4-Hour reperfusion prior to reperfusion. testosterone pathway.
84
ORX rat MI Testosterone undecanoate, No difference in Chronic anabolic testosterone treatment
LAD ligation 500 mg/kg myocardial had no detrimental effects following
Deep IM injection every 4 weeks infarct size myocardial infarction.
for 8 weeks analyzed by
MRI
85
Rabbits I/R Supraphysiological dose of No difference Supraphysiological dose of testosterone
LAD ligation testosterone, 50 mg/kg, IM was found in treatment had no detrimental effects
30-Minute ischemia Pretreated for 1 weeks and myocardial on the infarct size.
3-Hours 50 mg/kg, acute treated infarct size
reperfusion 5-10 minutes before I/R
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.

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 func-
tion, 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 Lan-
gendorff 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 apop-
tosis through a1-adrenoceptor stimulation28 or the promo-
tion of neovascularization of heart tissues in myocardial
infarction model through increased synthesis of 70-kDa heat
shock proteins (Hsp70s) 25 and activated k-opioid receptor
agonist.82 Consistently, a recent in vivo model study in
ORX rat’s heart demonstrated that acute injection of testos-
terone prior to the reperfusion period could reduce the
infarct size.83 However, the supraphysiological dose of tes-
tosterone 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
It is of interest to note from these findings that physiolo-
gical levels or low doses of testosterone may provide a cardi-
oprotective 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.

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4 Journal of Cardiovascular Pharmacology and Therapeutics

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

28
Isolated rat heart I/R Physiological dose Improve contractile Testosterone may improve
(ORX rat) LAD ligation testosterone, 2 mg/kg, SC recovery during both I/R contractile function by
30-Minute ischemia Pretreated for 8 weeks and sympathetic enhancing the expression of
120-Minute reperfusion Noradrenaline 107 mol/L stimulation period a1a- and b1-adrenoceptors.
Pretreated during I/R
82
Isolated rat heart I/R Physiological dose Improve contractile Preconditioning requires
(ORX rat) LAD ligation testosterone, 2 mg/kg, SC recovery in reperfusion testosterone to increase
30-Minute ischemia Pretreated for 8 weeks period by: heat shock protein 70
120-Minute reperfusion Pretreated with U50-488H – " LVDP synthesis, which plays a role
10 mg/kg 24 h before I/R – # LVEDP in cardioprotection.
– Improve +dp/dt max
86
Isolated rat heart I/R Supraphysiological dose of In testosterone treated Testosterone improves left
(ORX rat) 30-Minute global no testosterone undecanoate, group: ventricular contractile
flow ischemia 500 mg/kg, IM – " LVDP functions during I/R injury
30-Minute reperfusion Pretreated for 2 weeks – # LVEDP and attenuates reperfusion
5a-dihydrotestosterone – # Intracellular Ca2þ induced Ca2þ overload.
(DHT), 75 mg/pellet, SC overload at end-
implantation, pretreated ischemic and
for 3 weeks reperfusion period
24
Isolated rat heart I/R Supraphysiological dose of " Aortic flow, cardiac Administration of high-dose
(ORX rat) 25-Minute global no testosterone, 1 mg/d (as output, cardiac work, testosterone confers
flow ischemia pellet), SC implantation, LVDP, contractility cardioprotection via ARs
45-Minute reperfusion pretreated for 3 weeks (þdp/dt) in testosterone- by improved postischemic
treated group functional recovery.
25
ORX rat MI Physiological dose of " % EF Testosterone replacement
LAD ligation testosterone propionate, 2 " % FS therapy improved
mg/kg, SC, pretreated for # LVEDP myocardial performance.
1, 3, and 28 days

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.

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 iso-
lated heart preparation technique demonstrates that a physiolo-
gical 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 postu-
lated mechanism of this effect was through a1-adrenoceptor
stimulation28 and increased synthesis of Hsp70 via a k-pioid
receptor agonist.82 Interestingly, supraphysiological doses of
both testosterone and its metabolite (5a-dihydrotestosterone
[DHT]) also exhibited a beneficial effect on cardiac function
during I/R injury by attenuating intracellular Ca2þ overload
during the reperfusion period,24,86 whereas the supraphysiolo-
gical dose of testosterone replacement (50 mg/kg) in another
I/R model exerted neither adverse nor beneficial effect on car-
diac function.85 This suggests that testosterone plays a cardio-
protective role by reducing intracellular acidification resulting
in the maintenance of physiological cytosolic Ca2þ levels dur-
ing ischemic stress.86 In addition, echocardiographic study also
demonstrated that testosterone replacement therapy (2 mg/kg)
could improve myocardial performance in a myocardial infarc-
tion model.25
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 implanta-
tion of DHT 200 mg) neither improved nor worsened myocar-
dial functional recovery after I/R injury.87 Acute infusion of
17b-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 hyper-
trophic 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 testoster-
one may also act via other mechanisms instead of just the geno-
mic effect on cardiac function during I/R injury.38,89 This could
be due to the nongenomic effects that are similar to other ster-
oids,89 which could bind to specific membrane binding sites
and stimulate the secondary messenger signaling cascades,

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Pongkan et al 5

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

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

protein kinases (A and C), mitogen-activated protein kinase
(MAPK), adenylyl cyclase, and intracellular Ca2þ.39,89-91
These alterations in the nongenomic effect could induce vari-
ous cellular outcomes including a rapid rises in the intracellular
Ca2þ concentration,44,45,92 neuromuscular or junctional signal
transduction,39,44 and vasorelaxation39,45 and could be respon-
sible for cardioprotection.
The importance of endogenous testosterone is emphasized
by many reports of androgen deprivation therapy in patients
with prostate cancer, which demonstrated that androgen depri-
vation therapy could increase cardiovascular events such as
increased risk of ischemic heart disease,93,94 induction of meta-
bolic 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 pros-
tate 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 ther-
apy (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 tes-
tosterone in cardiac function during I/R could be due to differ-
ences in the experimental model, an addition of conditional
treatments, and dosages of testosterone treatment (physiologi-
cal 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 physiolo-
gical dose (2 mg/kg) or supraphysiological dose of testosterone
could decrease LDH release in the I/R heart,24,28,82 and the pro-
posed mechanisms could be via either a1-adrenoceptor stimu-
lation28 or increased synthesis of Hsp70s.82
Effect of testosterone on myocyte viability in I/R hearts. Testoster-
one has been shown to have beneficial effects on cell viabi-
lity in ORX rats with I/R injury and ORX rats with the
myocardial infarction model (Table 5). Recent in vitro stud-
ies 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. Tes-
tosterone could work through the angiogenesis pathway82 and
a1-adrenoceptor stimulation, which are mediated by both
androgen receptors and nongenomic actions.28 A physiologi-
cal 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

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6 Journal of Cardiovascular Pharmacology and Therapeutics

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 I/R
(ORX rat) 25-Minùte global no flow
ischemia, followed by
45-minute reperfusion
Isolated rat heart I/R
(ORX rat) LAD ligation
30-Minute ischemia and
120-minute reperfusion
Isolated rat heart I/R
(ORX rat) LAD ligation
30-Minute ischemia and
120-minute reperfusion
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.
24
Supraphysiological dose Testosterone Administration of high-dose
1 mg/d (as pellet), SC – # LDH release testosterone confers
implantation during pre- and cardioprotection via ARs
Pretreated for 3 weeks post-I/R by improving postischemic
– Prevented the functional recovery.
reduction of LV
catalase
enzyme
28
Physiological dose of # LDH release during Testosterone decreases LDH
testosterone 2 mg/kg, SC, I/R release by enhancing the
pretreated for 8 weeks beneficial effect of
Noradrenaline 107 mol/L a1-adrenoceptor resulting
Pretreated during I/R in reduced myocardial
apoptosis.
82
Physiological dose of # LDH release during Testosterone decreases LDH
testosterone 2 mg/kg, SC, I/R release by enhanced
pretreated for 8 weeks preconditioning
Pretreated with U50-488H, or stimulation of a k-opioid
10 mg/kg, 24 hours before receptor agonist, resulting in
I/R increased synthesis of heat
shock protein 70.

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

25
ORX rat MI Physiological dose of Testosterone replacement, with Testosterone replacement
LAD ligation testosterone propionate, and without testosterone decreases the number of
2 mg/kg, SC receptor blocker, decreases apoptotic cells through
Pretreated for 1, 3, and the percentage of TUNEL- nongenomic pathway
28 days positive cells compare with mechanism.
Flutamide (testosterone castrated group.
receptor blocker),
30 mg/kg/d, SC,
pretreated for 1, 3,
and 28 days
28
Isolated rat I/R Physiological dose of – " Expression of a1a- and Testosterone reduces I/R injury
ventricular 10-Minute metabolic testosterone 2 mg/kg, b1-adrenoceptors. by enhancing the beneficial
myocytes inhibition and SC, pretreated for – " Cell viability compared effect of a1-adrenoceptor
(ORX rat) anoxia 8 weeks with the castrated group. stimulation, which was greater
10-Minute Followed with 108 mol/L than the adverse effect of
reperfusion concentration of b1-adrenoceptor stimulation
testosterone incubated through both androgen and
for 24 hours before I/R nonandrogen receptors.
Noradrenaline 107 mol/L
Pretreated during I/R
82
Isolated rat I/R Physiological concentration Testosterone combined with Testosterone is required for the
ventricular 10-Minute metabolic Testosterone, 108 mol/L preconditioning restored the cardioprotection of
myocytes inhibition and incubated for 24 hours ventricular myocytes viability. preconditioning. This effect is
(ORX rat) anoxia before I/R pretreated mediated by androgen
10-Minute with U50-488H 30 receptors.
reperfusion mmol/L 30 min before I/R
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.

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Pongkan et al
Effect of testosterone on molecular signaling in I/R hearts. Most of
the molecular studies on testosterone replacement demon-
strated 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 physiolo-
gical 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 sig-
nalings were involved with myocardial inflammation,36
increased apoptotic protein caspase 3,36 decreased antiapop-
totic protein BcI-2,36,103 and Forkhead box O3a phosphoryla-
tion (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
In contrast to findings following acute testosterone adminis-
tration, a study using chronic exogenous testosterone replace-
ment 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 testos-
terone 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 1a (HIF-1a) and stromal cell-derived
factor 1a (SDF-1a) 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 hemato-
poietic 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 replace-
ment or endogenous testosterone could provide deleterious
effects on the heart by accelerating the apoptotic signaling pro-
cess after I/R injury. However, chronic exogenous testosterone
replacement may exert a beneficial effect in both I/R and myo-
cardial infarction models.
Effect of testosterone on cardiac arrhythmias in I/R hearts. In Lan-
gendorff 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
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7
whereas the supraphysiological dose of testosterone replace-
ment (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 a1a-adrenoceptor stimulation28 and shortened the QT
interval.85 Since this positive effect of testosterone on the car-
diac 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.
Effect of testosterone on HRV in myocardial infarction model. Cur-
rently, 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 coron-
ary 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 clin-
ical studies are needed to investigate the roles of testosterone
in the cardiac autonomic balance in both I/R injury and myo-
cardial 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, athero-
sclerosis, arrhythmia, thrombosis, and endothelial dysfunc-
tion, 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 cardio-
vascular 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 dis-
ease.106 Regarding the relationship between plasma testoster-
one levels and coronary artery disease, a previous clinical
study has shown that the plasma level of total testosterone,
free testosterone, and bioavailability testosterone was signif-
icantly 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 testos-
terone level was associated with atherosclerosis111 and myo-
cardial 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
 8
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
25
ORX rat MI Physiological dose of testosterone Testosterone Exogenous testosterone replacement
LAD ligation propionate, 2 mg/kg, SC – # Levels of HIF-1a, SDF-1a, and VEGF mRNA expression. promotes neovascularization by the
Pretreated for 1, 3, and 28 days – " The number of CD34þ cells homing of CD34þ stem cells and
Flutamide (testosterone receptor increases the expression of cytokines
blocker), 30 mg/kg/d, SC, pretreated for Endogenous testosterone deprivation worsened cardiac function. HIF-1a, SDF-1a, and VEGF in the early
1, 3, and 28 days stage of MI, resulting in an increased
neovascularization in the MI heart.
32
Isolated rat heart I/R 5a-Dihydrotestosterone (DHT) 100 mg (as Depletion of endogenous testosterone Testosterone downregulated antiapoptotic
(ORX rat) 25-Minute global pellet), SC implantation, pretreated for – " STAT-3 and SOCS-3 in male hearts protein, STAT-3, and SOCS-3 expression
no flow ischemia 3 weeks in the myocardium after I/R injury.
40-Minute reperfusion Physiologic dose of 17b-hydroxy-4- Blockade of testosterone receptor
androsterone 10 ng/mL/min, acute – " SOCS-3 levels in males
infusion (AI) 5 minutes before ischemia
Administration of exogenous testosterone to ORX male and female
hearts
– # STAT-3 activity and SOCS-3 level
36
Isolated rat heart I/R Physiologic dose of 17b-hydroxy-4- Testosterone Exogenous testosterone has detrimental
(ORX rat) 25-Minute global no flow androsterone 10 ng/mL/min, acute – " The activation of signaling enzymes of myocardial effects on the myocardium after I/R injury.
ischemia infusion 5 minutes before ischemia inflammation (p38 MAPK and JNK)
40-Minute reperfusion – " An expression of apoptotic protein (caspase-3)
– # Expression of antiapoptotic protein Bcl-2
88
Isolated rat heart I/R Flutamide (testosterone receptor blocker) Blocking of testosterone receptor and castration Decrease in androgen receptors causes an
(ORX rat) 25-Minute global no pellet 10 mg, SC implantation, pretreated – # Proinflammatory cytokine production (TNF-a, IL-1b, and adverse effect on the I/R heart
flow ischemia for 3 weeks IL-6)
40-Minute reperfusion – # Expression of p38 MAPK
– # Expression of apoptotic protein (caspases 1, 3, and 11)
– " Expression of antiapoptotic protein (Bcl-2)
103
Isolated rat heart I/R 5a-Dihydrotestosterone (DHT) 100 mg Castration or flutamide treatment
(ORX rat) 25-Minute global no (as pellet), SC implantation, pretreated – " The activation of the myocardial Akt pathway, p-Bad, Bcl-2, Acute exogenous testosterone has damaging
flow ischemia for 3 weeks and p-FOXO3a effects on myocardium after I/R injury
40-Minute reperfusion – # Fas-L in male hearts through downregulation of the Akt

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Physiologic dose of 17b-hydroxy-4-
androsterone 10 ng/mL/min, acute
infusion 5 minutes before ischemia
– " Bax pathway in male hearts following I/R.
Acute testosterone replacement reversed the effects of Akt signaling The chronic treatment of testosterone can
in castrated male hearts provide cardioprotective effects.
– # p-Bad
– # Bcl-2/Bax ratio
– # Antiapoptotic protein p-FOXO3a
Chronic testosterone replacement
– # Bax
– " Bcl-2/Bax ratio

Abbreviation: ORX rat, orchiectomized rat; MI, myocardial infarction; LAD, left anterior descending coronary artery; SC, subcutaneous; I/R. ischemic and reperfusion; HIF-1a, hypoxia-inducible factor 1-a; SDF-1a, stromal
cell-derived factor 1a; 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-a, tumor necrosis factor a; IL-1b, interleukin 1b; 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.
Pongkan et al 9

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

28
Isolated rat heart I/R Physiological dose of Testosterone restored the Testosterone replacement, mediated
(ORX rat) LAD ligation testosterone 2 mg/kg, incidence of PVB to the by androgen receptors, reduces
30-Minute ischemia SC, pretreated for sham control arrhythmia during I/R injury.
and 120-minute 8 weeks
reperfusion Noradrenaline 107
mol/L
Pretreated during I/R
85
Rabbits I/R Supraphysiological Testosterone significantly Supraphysiological dose of testosterone
LAD ligation dose of shortened the QT interval treatment may be anti-arrhythmic by
30-Minute ischemia testosterone, by 9% compared with the shortening the QT interval.
3-Hour reperfusion 50 mg/kg, IM control group
Pretreated for 1 weeks
and 50 mg/kg, acute
treated 5-10 minute
before I/R
104
Human aged MI 88 Postinfarction men High level of blood Testosterone has a positive impact on
36-73 yr 24-Hour Holter testosterone associated cardiac autonomic regulation in men
(cross- monitoring with improved HRV by after MI by promoting
sectional study) Measure the levels of – " SDNN parasympathetic dominance.
testosterone – " rMSSD
hormone – " pNN50
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.

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 cardio-
vascular protection.120 A summary of clinical reports regard-
ing the association between the plasma testosterone levels
and coronary artery disease is shown in Table 8.
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 triglycerides81,122 and
decreasing serum tumor necrotic factor a.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 myo-
cardial infarction, especially in older men.33,67 Several compli-
cations 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 infarc-
tion and heart failure is shown in Table 9.
Conclusion
The cardioprotective effects of chronic testosterone replace-
ment 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 a1a-
adrenoceptor, increased synthesis of Hsp70, increased neo-
vascularization of CD34þ stem cell and cytokines HIF-1a,
SDF-1a, and vascular endothelial growth factor in the early
stages of myocardial infarction. In addition, testosterone may
play a beneficial role by maintaining intracellular Ca2þ home-
ostasis during ischemic stress (Figure 1). However, acute tes-
tosterone 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 myocar-
dial Akt activation, leading to reduced Bad phosphorylation
and decreased Bcl-2 levels, which consequently results in
worsened I/R-depressed myocardial function.

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10 Journal of Cardiovascular Pharmacology and Therapeutics

Table 8. Summary of Clinical Studies Reported on the Association Between Testosterone Levels and Coronary Artery Disease.

Model n Major Findings Interpretation Ref

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

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.

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Pongkan et al 11

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 Testosterone increased the time to
patch or matching placebo for
12 weeks.
Men with MI 10 Testosterone injections (1 mL of
100 mg testosterone/mL) every
2 weeks for 1 month.
Men with MI 15 Testosterone undecanoate, 250 mg/
mL every 12 weeks for 12 months
(intramuscular injection).
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
1-mm ST-segment depression.
Testosterone therapy increased the
time to 1-mm ST-segment
depression and reduced total
cholesterol and serum tumor
necrosis factor a.
– Testosterone increased the
time to 1-mm ST-segment
depression and increased
hemoglobin and hematocrit.
– Testosterone decreased the
CIMT, BMI, and serum
triglycerides.
– Testosterone therapy was not
associated with an increased
risk of MI.
– Testosterone therapy was
associated with a reduced risk
of MI.
80
Low-dose supplemental testosterone
treatment in men with chronic
stable angina reduces exercise-
induced myocardial ischemia.
81
Testosterone replacement therapy in
hypogonadal men delays time to
ischemia and reduces the total
cholesterol and inflammation.
122
Testosterone exerts protective effects
on myocardial ischemia.
124
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.

121
Men with CAD 14 Testosterone (2.5 mg; intravenous in Testosterone increased the time to 1- Short-term administration of
5 minutes) before exercise tests. mm ST-segment depression and testosterone exerts a beneficial
increased total exercise time. effect on exercise-induced
myocardial ischemia in men with
CAD. This benefit may be related to
a direct coronary-relaxing effect.
123
Men with CAD 13 3-Minute intracoronary infusion of Testosterone increased coronary Intracoronary infusion of testosterone
physiological concentrations artery diameter and coronary blood induces coronary artery dilatation
testosterone (1010 to 107 mol/L). flow. and increases coronary blood flow
in men with CAD.
125
Men with MI 1 A recreational weight lifter was taking Hematologic studies showed Association with and potential
(case high-dose intramuscular polycythemia and right coronary interplay between traditional
report) testosterone for the previous angiography revealed a total cardiovascular risk factors, high-
6 weeks and intermittently occlusion at the mid-portion of the dose testosterone use, and possibly
for 2 years. vessel with intracoronary thrombus. elevated plasma viscosity is
proposed as possible contributors
to this cardiovascular event.

Men with MI 46 Received two 2.5-mg self-adhesive
active testosterone patches each
night for 12 weeks.
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)
126
There was no change in fibrinogen, tPA Physiological testosterone
activity or PAI-1 activity, and replacement does not interfere with
hemoglobin concentration in the blood coagulation status.
testosterone group.
67
– Testosterone therapy was Testosterone therapy was associated
associated with increased risk with increased risk of adverse
of adverse outcomes including outcomes.
all-cause mortality, MI, and
ischemic stroke.
– No difference in the risk of
adverse outcomes across the
3 testosterone formulations.
(continued)

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12 Journal of Cardiovascular Pharmacology and Therapeutics

Table 9. (continued)

Model n Treatment Major Findings Interpretation Ref

Men with MI 55 593 Compared the incidence rate of MI
(post/preprescription rate ratio
[RR]) following initiation of
testosterone therapy (TT)
prescription.
Men with CHF 50 Testosterone enanthate (250mg/mL) Improved diastolic function and
1 mL once every 4 weeks for 12
weeks (intramuscular injection).
Men with CHF 70 Testosterone undecanoate 1000 mg
long-acting once every 6 weeks for
12 weeks (intramuscular injection)
Men with CHF 76 Testosterone replacement therapy (5 Improved exercise capacity, no
mg Androderm) at physiological
doses for 12 months
– Younger men with a history of In older men and in younger men with
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.
increased trend in 6-minute walk
distance (6MWD) parameter.
Testosterone therapy improved
oxygen consumption, quadriceps
isometric strength, insulin
sensitivity, and baroreflex.
adverse events.
33
preexisting diagnosed heart disease,
the risk of MI following initiation of
TT prescription is substantially
increased.
127
Testosterone replacement exerts a
beneficial role in improving
functional capacity and quality of life
in patients with heart failure.
128
Long-acting testosterone therapy
improves exercise capacity, muscle
strength, glucose metabolism, and
baroreflex sensitivity in men with
moderately severe CHF.
129
Testosterone replacement therapy
improves functional capacity and
symptoms in men with moderately
severe heart failure.

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.

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, a1a-adrenoceptor stimulation, and decreased myocar-
dial apoptosis. The reduction in sympathovagal imbalance may occur due to decreased oxidative stress. The reduction in cardiac arrhythmia
could occur due to decreased intracellular Ca2þ accumulation and a1a-adrenoceptor stimulation. Furthermore, testosterone could decrease
intracellular Ca2þ accumulation, increase an expression of a1a- and b1-adrenoceptors, decrease LVEDP, increase LVDP, and ejection fraction,
thus resulting in increased contractility and improved cardiac function. HIF-1a indicates hypoxia-inducible factor 1-a; SDF-1a, stromal
cell-derived factor 1a; VEGF, vascular endothelial growth factor; CD34, hematopoietic progenitor cell antigen CD34; LVDP, left ventricular
develop pressure; LVEDP, left ventricular end diastolic pressure.

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Pongkan et al
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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