Open access peer-reviewed chapter

Role of Androgens in Cardiovascular Diseases in Men: A Comprehensive Review

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Dilip Mukherjee, Koushik Sen, Shreyasi Gupta, Piyali Chowdhury, Suravi Majumder and Payel Guha

Submitted: May 20th, 2018 Reviewed: March 14th, 2019 Published: February 13th, 2020

DOI: 10.5772/intechopen.85852

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The present knowledge on the androgens role in cardiovascular physiology is not fully completed. It remains unclear whether low serum testosterone concentrations in men are an independent risk factor for cardiovascular diseases (CVDs) or a marker of the presence of CVD. However, we demonstrated that endogenous testosterone levels may be implicated in CVDs. Androgens role in modulating cardiovascular function is one of the highest importances, given that its deficiency is strongly associated with hypertension, atherosclerosis, diabetes, obesity, and cardiac hypertrophy. Although significant and independent association between testosterone levels and cardiovascular events in elderly men have not been confirmed in large prospective studies, cross-sectional studies, however, suggested that low testosterone levels in elderly men are associated with CVDs. The results of androgen therapy are not also conclusive. Perhaps, the effects of testosterone treatment of cardiovascular mortality and morbidity have not been extensively examined in control studies. Data on male animal experimentation of the effect of testosterone replacement therapy are either neutral or beneficial on the development of atherosclerosis. Since circulatory androgen levels modulation is expected to cause many other side effects, it seems to be essential to develop a strategy to target androgen receptor for better treating the CVDs.


  • testosterone
  • miocardial infarction
  • men
  • lipid profile
  • ROS

1. Introduction

Cardiovascular diseases (CVDs) refers to a class of diseases that involve the heart and/or blood vessels and still the highest leading cause of death in developed and developing countries with earlier onset and possibly of greater mortality risk seen in males compared to females. Approximately 17.5 million people died from CVDs in 2012 representing 31% of all global deaths. It is anticipated that by 2030, the number of death due to CVDs will be reach to more than 23.6 million [1]. Since male gender is one of the risk factors for premature coronary artery disease, stroke, peripheral vascular disease, and heart failure, androgens have often been considered as a cause underlying this male disadvantage [2, 3]. Androgens, mainly testosterone, may also play in cardiovascular morbidity and mortality by modulating the risk factors of atherosclerosis and vascular functions, lesions to cerebral and peripheral arterial vessel and myocardial infarction leading to heart failure in male [4].

A recent perspective study reveals that testosterone levels in men decline gradually with increasing age and this caused a dramatic increase in the incidence of CVDs [5, 6], but the mechanism of age-related cardiovascular performance remains to be completely understood. However, a protective role of androgen for CVDs in men has been reported and its deficiency may increase the significant risk factor for CVDs. Moreover, controversy also exists whether this age-associated decline in testosterone level is a natural physiologic processes or combination of co-morbidities and life-style choices [7]. With the prospects of much wider therapeutic approaches of testosterone on CVDs, it has become increasingly important to address whether testosterone treatment might increase the risk of severity of CVDs. Considering the importance of therapeutic use of testosterone as have been reflected in several recent studies, it is important to address the issue in a more critical way.


2. Cardiovascular diseases: types and risk factors

CVDs refer to any dysfunctional condition of the heart or the blood vessels (arteries, veins, and capillaries). Coronary heart disease (CHD) and stroke are two fundamental components of CVDs [8]. CVDs can be classified in eight major groups. These are: stroke-disruption of the blood supply to the brain either from blockage or from rupture of blood vessels; CHD-disease of blood vessels, transporting blood to the heart muscle; rheumatic heart disease-caused due to rheumatic fever by streptococcal bacteria when heart muscles and valves are damaged; congenital heart disease-structural malformation of heart; aortic aneurysm-dilation and rupture of aorta; peripheral arterial disease-disease of the arteries that supply blood to arms and legs; deep venous thrombosis and pulmonary embolism-blood clot in leg veins, which can dislodge and move to heart and brain; and other CVDs- tumors of the heart, vascular tumor of the brain, disorder of the heart muscle lining etc.

Risk factors can be categorized as modifiable and non-modifiable risk factors. Modifiable risk factors include; high blood pressure, abnormal blood lipids, tobacco use, physical inactivity, obesity, unhealthy diets, and diabetes mellitus. Non-modifiable risk factors are advancing age, hereditary or family history, gender, and race.


3. Testosterone and its function

Testosterone, a C19 androgen, is the most vital circulating androgens both in male and female. In men, it is mainly synthesized in the testes and a small amount is also derived from adrenal cortex. Testosterone is essential for male sexual differentiation, development and normal function of male reproductive organs, and maintenance of secondary sexual characters. In addition, testosterone promotes many other physiological processes like bone formation, growth of muscle, hair growth, body composition, and erythropoiesis and decreased the risk of osteoporosis [9]. In normal adult men, testosterone concentration ranges between 241 and 827 ng/dl [10]. Secretion of testosterone varies with circadian rhythm. Circulating testosterone is mainly bound to sex hormone binding globulin (SHBG) and albumin and only 1–2% remains as unbound form.

In target cells, testosterone binds to the intracellular androgen receptors (ARs) or is converted to dihydrotestosterone (DHT) catalyzed by 5α-reductase, which then binds to AR. In some target tissues, testosterone is converted to estrogens by cytochrome P450 aromatase enzyme and estrogens then bind to estrogen receptors. Both androgen and estrogen receptors act as transcription factors and mediate genomic effects [11]. In addition, various in vitroand in vivostudies have shown that testosterone and its derivatives can affect cellular processes in a non-genomic fashion [12]. Testosterone has been shown to regulate cell to cell ion exchange via gap junction in Sertoli cells and cardiac cells in young rats [13]. Testosterone also promotes vasoconstriction [14, 15] and rapid rise of Ca2+ in cultured cardiomyocytes by PLC/IP3-dependent mechanism [16].


4. Circulatory levels of testosterone and CVDs

Association of blood testosterone levels and incidence of CVDs in men with increasing age is based mainly on observational studies and the main disadvantages of such type of studies are the extremely variable endpoints of CVDs, heterogeneous study groups, and diverse selection criteria. A continuous study for months to several years on a particular study group of CVD patient is very difficult for various reasons. Importantly, patients in these study groups are mostly in medications or modified their life style. Moreover, selection of poorly-matched controls and timing of blood sampling are not always standardized for diurnal variation of hormone levels. All these factors have a serious impact to draw a definite conclusion. However, taking all these into consideration, recently, we investigated the relationship between serum total testosterone levels and lipid profiles as well as fasting blood glucose (FBG) levels in elderly men with angiographically confirmed CVDs from two thickly populated and socio-economically backward districts; Nadia and Murshidabad of West Bengal, India. We observed that relationship between sex hormones, lipid profiles and FBG levels of CVD patients is strikingly different from men with no CVDs of similar age group [17]. Considering the previous observational studies along with our study, we presented a comprehensive idea on the relationship between serum testosterone levels and CVDs globally.

In normal men of developed countries, the overall incidence of testosterone deficiency increases with age and approximately one half a million new cases of testosterone deficiency are expected in men aged 40–90 years old (Figure 1) [18]. An independent effect of age on serum testosterone in a study of 890 men has also been demonstrated [19]. Prevalence of testosterone deficiency in men aged >45 years is approximately 38.7% based on total testosterone (T) levels and about 36.3% based on bio-available or free T [20]. They have documented that major risk factors such as obesity, diabetes, hypertension, hyperlipidaemia, prostate disease, and asthma or chronic obstructive pulmonary disease are responsible for low testosterone levels in men compared without such conditions. A schematic representation of the association of testosterone and cardiovascular risk factors is depicted in Figure 2. It has been reported that low testosterone levels are associated with increased death from CVDs [21]. Whereas, for a long time prospective studies failed to find significant association between testosterone levels and risk of cardiovascular events in middle aged men [22, 23]. However, a study of osteoporotic fractures in elderly men of Sweden reported that high serum testosterone level is associated with reduced risk of cardiovascular events [24]. This is consistent with the influence of testosterone levels on multiple risk factors such as obesity, diabetes, blood pressure, and carotid atherosclerosis [25, 26]. A recent meta-analysis showed that low testosterone levels predicted risk for CVDs in elderly men but not middle-aged men [27]. Interestingly, using data from the French Three-City prospective cohort study (3650 men aged >65 years) after adjustment for cardiovascular risk factors, a J-shaped association between plasma total testosterone and incidence of ischemic arterial disease (IAD) in elderly men has been reported [28]. They have suggested that both high and low plasma testosterone levels are associated with an increased risk of arterial ischemic events in elderly men and an optimal range of testosterone levels may confer protection against cardiovascular events. In a recent study, Kelly and Jones [29] observed that testosterone replacement in men diagnosed with hypogonadism shown to be a beneficial effect on several cardiovascular risk factors, cardiac ischemia, functional exercise capacity, and mortality.

Figure 1.

Testosterone levels in men at different ages of life.

Figure 2.

Association of testosterone deficiency and cardiovascular risk factors.


5. Association of various risk factors with CVD

5.1 Role of lipids in CVD

It has long been established that lipids play a central role in the initiation and progression of CVDs [30, 31, 32]. Dyslipidemia comprises the abnormalities of lipid profiles characterized by high levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) along with low levels of high density lipoprotein (HDL) that contributes to the development of atherosclerosis [33]. In older men, reduced testosterone levels are associated with adverse profiles of lipids. Low testosterone level is associated with high TC, high LDL [34, 35], and high TG [36, 37]. Hypo-gonadal men exhibit abdominal or central adiposity [38, 39]. This finding has led to conclude that all parameters of lipid profile except HDL might be more strongly associated with CVD risk, whereas some investigators reported a negative correlation between HDL and CVD [40, 41]. A strong inverse correlation between body fat and testosterone level is also observed [42]. Higher mass of visceral adipose tissue is inversely correlated with bio-available testosterone [43]. In an epidemiological study from our laboratory, we studied the relationship between serum total testosterone levels and lipid profiles in male patients ranging the age group between 40 and 70 years with angiographically proven CVDs from Nadia and Murshidabad district of West Bengal, India and compared the data with normal men with no CVD history. We observed a significantly low serum total testosterone levels in CVD patient group compared to normal group and further demonstrated a significant negative association between serum total testosterone and TC, TG, LDL, and VLDL among CVDs patients. However, a significant positive correlation between serum total testosterone and HDL was observed [17]. Thus, in these two districts of West Bengal, low levels of serum total testosterone in elderly men are associated with CVD that appear together with an atherogenic lipid milieu that may be involved in pathogenesis of CVD. The molecular mechanism of sex hormone-induced changes in the serum lipid profile is incompletely understood [33]. However, there are evidence from animals, cell, and clinical studies that testosterone controls the expression of important regulatory protein involved in lipid and cholesterol metabolism namely, apolipoprotein A-1 (apoA1) [44, 45], and scavenger receptor class B type 1 (SRB1) [46, 47, 48]. The major component of HDL is apoA1, which is secreted by the liver in lipid free or minimally lipidated form [44]. The interaction between apoA1 and lipid transfer ABCA1 present in the peripheral tissues results in the formation of minimally lipidated apoA1, which through a series of steps is converted to discoid shaped pre-HDL. This does not possess atheroprotective properties [45]. In addition to apoA1 and SRB1, lipoprotein modifying enzymes are also critical in maintenance of serum lipid homeostasis. One of the most important lipoprotein modifying enzymes is lipoprotein lipase (LPL), present on the endothelial cell surface [49]. Other enzymes are lecithin-cholesterol-acyl-transferase (LCAT) which esterifies the free cholesterol of HDL and cholesterol ester transferase protein (CETP), which mediates the exchange of cholesterol ester between HDL and LDL [44]. Testosterone might promote the expression of SRB1 receptor and facilitate the selective uptake of HDL, thereby exerting an antiatherogenic role [50]. A schematic association of testosterone deficiency and atherogenic lipid profile is depicted in Figure 3.

Figure 3.

Changes in lipid profile due to androgen deficiency, leading to atherosclerosis.


6. Relationship between low testosterone levels and cardiovascular risk factors

6.1 Role of androgens in hypertension

Hypertension is one of the major risk factors for developing CVDs leading to atherosclerosis and sudden cardiac death. Studies with human reveal that hypertension is more prevalent and occurs earlier in men than in women [51, 52]. Sexual dimorphism in blood pressure develops and is maintained until the age of 60 years [53, 54, 55]. Epidemiological data further indicate that women older than 60 years, show gradual increase in systolic blood pressure over a period of 5–20 years, until hypertension is highly prevalent in women as in men [55, 56, 57]. In hypertensive patients, treatment with antihypertensive drugs can reduce sexual activity and blood concentrations of testosterone [58, 59]. However, treatment of androgen to such patients found to exacerbate hypertension and increase the risk of CVDs [60, 61, 62]. There is also higher incidence of hypertension in individual with reduced free testosterone [63].

In animal studies, all major mouse and rat models (noncastrated, castrated, and anti-androgen treated) potential role for androgen in the pathogenesis of hypertension have been documented [55, 64]. In mice, castration and subsequent treatment with testosterone at high dose produce the onset of hypertension and further observed that this effect is mediated by androgen receptor [65]. Long back, it was found that tfmX chromosome (including a mutated non-functional AR) rats and castrated rats have lower blood pressure than intact control rats, suggesting that androgen/AR signaling pathway might be involved in hypertension [66]. Thus, androgen-AR signaling pathway appears to be involved in the regulation of hypertension in men and as androgen level reduce with increasing age this might have a deleterious effect on the development of hypertension. Antiandrogen treatment might be able to suppress hypertension. Moreover, some recent studies using AR knockout mice in selective cells suggest that AR in individual cell types may have independent role in the development of hypertension [67, 68].

6.2 Testosterone association in type 2 diabetes and insulin resistance, a risk factor of CVD

Low level of testosterone is associated with type 2 diabetes mellitus (T2DM) irrespective of age, race, and obesity [69, 70, 71, 72]. High plasma testosterone level is associated with reduced risk of developing T2DM [73]. Insulin resistance is the most common hyperglycemic condition and hallmark of T2DM [74]. It is a state where target cells are not responding to normal levels of circulating insulin leading to development of T2DM [75, 76]. An inverse relationship between total testosterone concentration and insulin resistance has also been reported in men [77, 78]. Clinical trials have demonstrated that testosterone administration improved insulin sensitivity, reduced glycaemia, and heart failure progression in men [79].

Cohort studies from Farmingham, Heart Study, EMAS, and Osteoporotic Fractures in Men study [80] and Western Australian Health in Men Study [81] reported that men with T2DM have lower testosterone levels compared with men without T2DM. In fact, different earlier studies showed that men with T2DM have 30–40% lower circulatory testosterone levels than that of healthy men [82, 83, 84]. In a study of 3156 men from various ethnic backgrounds, aged 45–84 years and after adjusting for age, ethnicity, BMI, it has been shown that T2DM and FBG levels are inversely associated with total testosterone concentration [70]. In a recent study with elderly male patients (40–70 years of age) of two district of West Bengal, we observed a highly significant negative correlation between serum total testosterone and FBG levels in CVD patients compared with non-CVD patients of same locality [17]. Our results further indicate that low levels of serum total testosterone might have role in the development of hyperglycemia as evidenced from high FBG levels in elderly men. Moreover, a recent study demonstrated that insulin resistance, hyperinsulinemia, and associated hyperglycemia can promote the development of specific form of cardio-morphopathy, which is independent of coronary artery disease and hypertension and a major cause of morbidity and mortality in developed countries [85]. It is characterized by myocardial insulin signaling, mitochondrial dysfunction, activation of sympathetic nervous system, activation of renin-angiotensin-aldosterone system, and male adaptive immune responses [86]. These patho-physiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction, and eventually systemic heart failure [87].

Association of testosterone deficiency with hyperglycemia has also been observed in animal model [88]. It has been demonstrated that castration-induced testosterone deficiency not only enhanced the hepatic gluconeogenesis but also decreased extra-hepatic insulin sensitivity in aged male rats [89]. Unpublished data from our laboratory also demonstrate that castration in adult male mice is followed by an increase in FBG level compared to sham operated control group and this increase in serum FBG levels was reversed after treatment with testosterone.

The mechanism linking androgen with T2DM and insulin receptor is not fully understood. Testosterone administration up-regulate the expression of GLUT-4, insulin receptor substrate-1 (IRS-1) in cultured adipocytes, and skeletal muscle cells [90]. Another study showed that testosterone promotes AKT and PKC phosphorylation, the major mediator of insulin receptor signaling, which regulate GLUT-4 translocation (Figure 4) [91]. The beneficial effects of testosterone on diabetes through increasing the metabolic rate in muscle promoting gain of energy from adipose tissue resulting decreased fat mass concentration has also been reported [92]. In vitrostudy of murine model also demonstrated that testosterone administration reduces β cell apoptosis [93], whereas, testosterone deficiency promote elevation of the expression of RBP4, which increases insulin resistance [94]. On the contrary, several studies demonstrate a non-positive correlation between testosterone supplementation and heart failure. Several clinical trials led to propose that testosterone supplementation at physiological doses could be a treatment for men with metabolic syndrome and heart failure [95].

Figure 4.

Proposed mechanism of action of testosterone on cellular IRS activation leading to glucose homeostasis. Testosterone increases GLUT4 expression and membrane translocation which increases cellular uptake and utilization of glucose. Abbreviations: GLUT4, glucose transporter 4; G6P, glucose-6-phosphate; HK2, hexokinase 2; IRS, insulin receptor substrate; T +ve indicates targets or activity increased by testosterone PKC and AKT.

6.3 Testosterone and vascular inflammation

It is now well accepted that atherosclerosis is a chronic inflammatory disease. Individuals with hyperlipidaemia and signs of systemic inflammation develop atherosclerosis, with specific defects in lipid processing and immune activity consequentially occurring at the vessel wall. It is known that the activation of endothelial cells promotes the adhesion of leukocytes to the blood vessel wall as an early atherogenic event leading to increased vascular permeability for not only the inflammatory leukocytes, but also the circulating lipid components, such as LDL [96]. It has been suggested from observational studies that many pro-inflammatory cytokines like interleukin 1β (IL-1β), IL 6, TNF-α, C-reactive protein (CRP), and serum testosterone levels are inversely related in patients with CVDs and T2DM [97, 98, 99]. These inflammatory cytokines are known to modulate lipid metabolism, endothelial functions, and atherosclerosis [100]. Testosterone has been reported to reduce the levels of TNF-α and elevated circulating anti-inflammatory IL-10 [101, 102] and circulating CRP [102] in hypogonadal men with CVDs. In vitrostudies also support the protective effect of testosterone supplementation on atherosclerosis, but the mechanism is not fully known [103, 104].


7. Testosterone deficiency and vascular functions

A negative correlation between testosterone and hypertension has already been discussed. In a subpopulation study of 206 aged males, it was shown that serum testosterone level is an independent negative predictor for developing arterial stiffness and this association remained after adjusting for the other risk factors [105]. Carotid-intima media thickness (IMT) is a marker for CVDs [106]. The relationship among the progression of carotid-IMT, atherosclerotic plaque formation, and total testosterone was investigated and an inverse relationship between this hormone and atherosclerotic plaque formation was observed. This study also reported for a positive co-relation between carotid-IMT and atherosclerosis [107]. Men with low serum testosterone level exhibit higher IMT compared to normal control [108, 109, 110]. Long term testosterone administration reduced carotid-IMT in men with CVDs [111, 112]. Animal models also demonstrated that castration or hypogonadism in mice or rabbits fed a pro-artherogenic diet results in increased atherosclerosis and testosterone supplementation inhibits plaque formation [113]. The cellular and molecular mechanism by which testosterone induced IMT is little understood. Other studies, however, have shown that testosterone may reduce IMT by down regulating the inflammatory response or acting as a regulator of apoptosis or increasing vascular smooth muscle cell stability [7].

Endothelial cells play an important role in atherosclerosis, regulation of vascular tone and forming a barrier that regulates the uptake of cells and macromolecules into the vessel wall [114]. Clinical evidence suggests a link between testosterone deficiency and endothelial dysfunction [115, 116, 117]. Flow-mediated dilation (FMD), which represents endothelial dysfunction is decreased in men with testosterone deficiency and increased after exogenous administration of the steroid [118, 119]. Testosterone can exert direct effects on various cells of vascular wall by activation of androgen receptor or by non-genomic effects on plasma-membrane receptors and channels [114]. Testosterone can modulate calcium flux by mechanism that is independent of androgen and estrogen receptors in macrophages and endothelial cells [120]. Androgen receptors are expressed in endothelial cells, smooth muscle cells, and cardiomyocytes and all of these are relevant to atherosclerosis and heart failure [121]. It has also been demonstrated that testosterone may improve endothelial function through modulation of nitric oxide (NO) release. Endothelium-produced NO plays a variety of roles in vascular function maintenance like vasodilatation, inhibition of cell death, and platelet aggregation [96, 122].


8. Role of androgens in cardiac hypertrophy

Cardiac growth can be divided into two categories: normal growth in the developmental process and cardiac hypertrophy induced by hemodynamic overload. Since cardiomyocytes are terminally differentiated and lost their ability to multiply soon after birth, they respond to increased workload by an increase in cell size (hypertrophy), not by an increase in cell number (hyperplasia). Cardiac hypertrophy is prevalent in men with hypertension and recognized as an independent risk factor for congestive heart failure and sudden cardiac death [123]. The most impressive evidence of the effect of androgens on heart is the case of highly conditioned athletes, who died by sudden cardiac death. Examination of such death indicated anatomical abnormalities in heart, known as hypertrophy-cardiac myopathy [124]. Since, the net weight of heart is increased as a result of individual cardio-myocyte, the cardiac hypertrophy is assessed as heart weight to body weight ratio and left ventricular hypertrophy (LVH). LVH is the most potent predictor of adverse cardiovascular outcomes in hypertensive populations and is independent risk factors for coronary heart disease, sudden death, heart failure, and stroke. Clinically LVH is diagnosed by evaluating ventricular functions, such as left ventricular ejection fraction, left ventricular shortening fraction, end-systolic, and end-diastolic volume by electro physiological studies. Although directly related to systolic blood pressure, other factors including age, sex, race, body mass index, and stimulation of renin-angiotensin-aldosterone system and sympathetic nervous system play an important role of pathogenesis of LVH. LVH is associated both with hypertension and increased cardiovascular morbidity and mortality [125], and it has been suggested that testosterone could be influential in modulating left ventricular mass [126]. Low level of testosterone in male is associated with high blood pressure and left ventricular mass [127]. Interestingly, this association is mediated through obesity. Very recently, it has also been suggested that testosterone can induce hypertrophy in rat heart, which is independent of exposure duration [128].

A central link for the development of skeletal muscle hypertrophy is the activation of mammalian target of rapamycin (mTOR) [129, 130], which also have been reported in testosterone-induced cardiomyocyte hypertrophy [131]. Both type I and type II skeletal muscle fibers have shown to respond in testosterone treatment increasing muscle mass, cross-sectional areas (CSA), and satellite cell number after hormone administration [132]. Testosterone and its synthetic cognates have been used both clinically and illicitly to increase muscle mass [133]. However, the cellular mechanism explaining these effects is not completely understood. Different cellular and molecular mechanisms are shown to be involved in skeletal muscle hypertrophy induced by testosterone, including promotion of nuclear accretion, entry of satellite cells into cell cycle [132, 133, 134], and activation of intracellular androgen receptor [135]. Besides regulating gene expression via AR, testosterone also produces fast, non-transcriptional responses involving membrane-linked signal transduction pathways [12]. A rapid non-genomic action exerted via G-protein coupled receptor, intracellular calcium increases, and extracellular signal regulated kinase ½ (ERK 1/2) activation has been described for the action of testosterone in skeletal myotubes [136]. Recently, a cellular lineage of myoblast, which lack the classical AR (L6 myoblast), testosterone has shown to promote the proliferation and differentiation of L6 cell via G-protein coupled receptor [137]. Altogether, these data suggest that in men testosterone, increased cardiac hypertrophy and aside from classical mechanism of action of testosterone, non-classical actions are also implicated in development of cardiac hypertrophy.


9. Testosterone replacement therapy in CVD patients

Testosterone replacement therapy (TRT) is increasingly promoted and suggested to be a possible curative way for the adverse effect of low testosterone on CVDs in elderly men. Whereas, the effectiveness of TRT in hypogonadal men has been shown to be effective in alleviating the symptoms of fatigue, sexual dysfunction, depression, decreased bone density, decreased muscle mass, among others [138, 139, 140, 141], uncertainties remain with respect to cardiovascular safety for its use. In 2004, a committee on assessing the need for clinical trial of testosterone replacement therapy by Institute of Medicine (IOM) in a review concluded largely based on placebo control trials and show that there is no clear evidence on benefit of the heath outcome examined. In fact, no positive effect of TRT on cardiovascular events was observed [142, 143, 144]. Observational studies evaluating the cardiovascular safety of TRT in men have also generated inconsistent results [145, 146]. An independent review conducted by European Medicines Agency (EMA) also found a lack of consistent evidence for TRT increasing cardiovascular risks (European Medicines Agency (EMA)), 2015 [147]. Very recently, in systematically review and meta-analysis by various authors did not find any significant association between exogeneous testosterone treatment and myocardial infarction, stroke or morbidity of randomized control trials [148, 149]. But, a recent study demonstrated that testosterone treatment in men with low endogenous testosterone shows improved survival rate in CVD patients [150]. Physiological replacement of testosterone has been shown to decrease cholesterol level and LDL concentration in men [101, 151]. Studies on the effect of TRT on HDL concentration yielded conflicting result with either a decrease [152] or no changes [102, 153]. Other investigators observed an increase in concentration of HDL level after testosterone administration [154]. In a recent study on the effects of TRT on lipid metabolism in hypogonadal men with T2DM, it has been hypothesized that because the relationship between lipid metabolism and artherosclerosis are unequivocal, TRT, which ameliorates lipid metabolism, may decrease the morbidity and mortality of CVD in hypogonadal men with T2DM by preventing atherogenesis [155]. Data from randomized placebo-controlled trials (RCTs) suggest that treatment with testosterone is not effective in reducing CV risk; however, when TRT is correctly applied, it is not associated with an increase in CV risk and it may have beneficial effects in sub-population [156]. On the contrary, available reports indicated that TRT is positively correlated with increased cardiovascular risk [157]. It has been reported that those who are under TRT showed increased risk of CVDs [158, 159]. A systemic review and meta-analysis of the effect of testosterone therapy on cardiovascular events showed that testosterone increases cardiovascular related events among men. The risk of TRT was particularly marked in trials [160].


10. Effects of testosterone on myocardial infarction

The myocardial cells undergo a dynamic repair process after myocardial infarction (MI), which is also regulated by hormonal factors and characterized by removal of necrotic tissue and chamber dilatation for so-called “cardiac remodeling” [161]. Recent cohort studies and meta-analyses of randomized clinical trials reported that testosterone therapy is associated with an increased risk of MI, ischemic stroke, and overall mortality [157, 159]. Supplemental testosterone treatment dramatically increased cardiac rupture and mortality in female mice with or without ovariectomy, whereas castration significantly decreased both the events in males [160]. This indicates role of testosterone is sex specific and even hypotesteronemic condition is good for MI associated cardiac remodeling. Findings suggest that testosterone may adversely affect myocardial healing and early remodeling during the acute phase of MI, causing the observed “gender difference.” However, this is highly controversial and association between testosterone therapies and cardiovascular disease is complex and need more dose-specific and time-specific statistical analyses and molecular studies to conclude that whether TRT is beneficial or not.

11. Conclusion

For last two decades, androgens have attracted significant interest in explaining the gender difference in CVDs. Although, strong evidences show that testosterone is associated with prevalence of CVDs and affects several key cardiovascular risk factors and increase the risk of cardiovascular mortality, significant independent association between androgen levels and cardiovascular events in men have not been confirmed in large prospective studies. Effects of testosterone therapy on cardiovascular mortality have not also been definitely confirmed in prospective controlled studies. Testosterone administration in men and animal induces both beneficial and deleterious effects on cardiovascular risk factors. Further research in this field is necessary to know the real cardiovascular effects of androgen and to understand the role of androgen in therapeutic applications in CVDs.


  1. 1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2016 update: A report from the American Heart Association. Circulation. 2015;1:CIR350
  2. 2. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocrine Reviews. 2005;26(6):833-876
  3. 3. Banos G, Guarner V, Perez-Torres I. Sex steroid hormones, cardiovascular diseases and the metabolic syndrome. Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Cardiovascular & Hematological Agents). 2011;9(3):137-146
  4. 4. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of testosterone treatment in older men. New England Journal of Medicine. 2016;374(7):611-624
  5. 5. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease. Circulation. 2003;107(1):139-146
  6. 6. Ayaz O, Howlett SE. Testosterone modulates cardiac contraction and calcium homeostasis: Cellular and molecular mechanisms. Biology of Sex Differences. 2015;6(1):9. DOI: 10.1186/s13293-015-0027-9
  7. 7. Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: A comprehensive review of the clinical literature. Journal of the American Heart Association. 2013;2(6):e000272
  8. 8. Mackay J. The atlas of heart disease and stroke. World Health Organization. 2004:18-25
  9. 9. Matsumoto AM, Bremner WJ. Testicular disorders. In: Melmed S, Polonsky K, Larsen P, Kronenberg, editors. Williams Textbook of Endocrinology. 12th ed. Philadelphia: Elsevier; 2011. pp. 689-777
  10. 10. Seth M, Sachdeva A, Sahary P, Seth S, Madaan H. Relationship of testosterone levels in males with coronary heart disease. International Journal of Pharmacology and Biosciences. 2011;2(2):B-566-B-570
  11. 11. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions of steroid hormones—A focus on rapid, nongenomic effects. Pharmacological Reviews. 2000;52(4):513-556
  12. 12. Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Frontiers in Neuroendocrinology. 2008;29(2):169-181
  13. 13. Pluciennik F, Verrecchia F, Bastide B, Herve JC, Joffre M, Deleze J. Reversible interruption of gap junctional communication by testosterone propionate in cultured Sertoli cells and cardiac myocytes. The Journal of Membrane Biology. 1996;149(3):169-177
  14. 14. Masuda A, Mathur R, Halushka PV. Testosterone increases thromboxane A2 receptors in cultured rat aortic smooth muscle cells. Circulation Research. 1991;69(3):638-643
  15. 15. Schrör K, Morinelli TA, Masuda A, Matsuda K, Mathur RS, Halushka PV. Testosterone treatment enhances thromboxane A2 mimetic induced coronary artery vasoconstriction in guinea pigs. European Journal of Clinical Investigation. 1994;24(S1):50-52
  16. 16. Vicencio JM, Ibarra C, Estrada M, Chiong M, Soto D, Parra V, et al. Testosterone induces an intracellular calcium increase by a nongenomic mechanism in cultured rat cardiac myocytes. Endocrinology. 2006;147(3):1386-1395
  17. 17. Chowdhury P, Sen K, Gupta S, Majumder S, Guha P, Chakraborty A, et al. Association of endogenous testosterone with lipid and blood glucose profiles in elderly men with angiographically proven cardiovascular disease of Nadia and Murshidabad District, West Bengal. Proceedings of the Zoological Society. Springer Nature. 2018;71:48-55
  18. 18. Araujo AB, O’donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: Estimates from the Massachusetts Male Aging Study. The Journal of Clinical Endocrinology & Metabolism. 2004;89(12):5920-5926
  19. 19. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. The Journal of Clinical Endocrinology & Metabolism. 2001;86(2):724-731
  20. 20. Mulligan K, Zackin R, Von Roenn JH, Chesney MA, Egorin MJ, Sattler FR, et al. Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with human immunodeficiency virus-associated weight loss: A randomized, double-blind, placebo-controlled, multicenter trial. The Journal of Clinical Endocrinology & Metabolism. 2006;92(2):563-570
  21. 21. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: The Health in Men Study. The Journal of Clinical Endocrinology & Metabolism. 2012;97(1):179-189
  22. 22. Yarnell JW, Beswick AD, Sweetnam PM, Riad-Fahmy D. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arteriosclerosis, Thrombosis, and Vascular Biology. 1993;13(4):517-520
  23. 23. Ärnlöv J, Pencina MJ, Amin S, Nam BH, Benjamin EJ, Murabito JM, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Annals of Internal Medicine. 2006;145(3):176-184
  24. 24. Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men: The MrOS (Osteoporotic Fractures in Men) study in Sweden. Journal of the American College of Cardiology. 2011;58(16):1674-1681
  25. 25. Yeap BB. Are declining testosterone levels a major risk factor for ill-health in aging men? International Journal of Impotence Research. 2009;21(1):24-36
  26. 26. Soisson V, Brailly-Tabard S, Empana JP, Féart C, Ryan J, Bertrand M, et al. Low plasma testosterone and elevated carotid intima-media thickness: Importance of low-grade inflammation in elderly men. Atherosclerosis. 2012;223(1):244-249
  27. 27. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: A meta-analysis. Heart. 2011;97(11):870-875
  28. 28. Soisson V, Brailly-Tabard S, Helmer C, Rouaud O, Ancelin ML, Zerhouni C, et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: The French 3C cohort study. Maturitas. 2013;75(3):282-288
  29. 29. Kelly DM, Jones TH. Testosterone and cardiovascular risk in men. In: Cardiovascular Issues in Endocrinology. Vol. 43. Basel, Switzerland: Karger Publishers; 2014. pp. 1-20
  30. 30. Ginsberg HN. Lipoprotein metabolism and its relationship to atherosclerosis. The Medical Clinics of North America. 1994;78(1):1-20
  31. 31. Glew RH, Kassam HA, Bhanji RA, Okorodudu A, VanderJagt DJ. Serum lipid profiles and risk of cardiovascular disease in three different male populations in northern Nigeria. Journal of Health, Population and Nutrition. 2002;1:166-174
  32. 32. Chrysohoou C, Panagiotakos DB, Pitsavos C, Kosma K, Barbetseas J, Karagiorga M, et al. Distribution of serum lipids and lipoproteins in patients with beta thalassaemia major; an epidemiological study in young adults from Greece. Lipids in Health and Disease. 2004;3(1):3
  33. 33. Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis: The lipid link. Vascular Pharmacology. 2009;51(5-6):303-313
  34. 34. Simon D, Charles MA, Nahoul K, Orssaud G, Kremski J, Hully V, et al. Association between plasma total testosterone and cardiovascular risk factors in healthy adult men: The Telecom Study. The Journal of Clinical Endocrinology & Metabolism. 1997;82(2):682-685
  35. 35. Barud W, Palusiński R, Bełtowski J, Wójcicka G. Inverse relationship between total testosterone and anti-oxidized low density lipoprotein antibody levels in ageing males. Atherosclerosis. 2002;164(2):283-288
  36. 36. Mäkinen JI, Perheentupa A, Irjala K, Pöllänen P, Mäkinen J, Huhtaniemi I, et al. Endogenous testosterone and serum lipids in middle-aged men. Atherosclerosis. 2008;197(2):688-693
  37. 37. Akishita M, Fukai S, Hashimoto M, Kameyama Y, Nomura K, Nakamura T, et al. Association of low testosterone with metabolic syndrome and its components in middle-aged Japanese men. Hypertension Research. 2010;33(6):587
  38. 38. Haffner SM, Mykkänen L, Valdez RA, Katz MS. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. The Journal of Clinical Endocrinology & Metabolism. 1993;77(6):1610-1615
  39. 39. Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC, Skinner JS, et al. Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: The HERITAGE Family Study 1. The Journal of Clinical Endocrinology & Metabolism. 2000;85(3):1026-1031
  40. 40. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79(1):8-15
  41. 41. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. New England Journal of Medicine. 2007;357(13):1301-1310
  42. 42. Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clinical Endocrinology. 2005;63(3):239-250
  43. 43. Nielsen TL, Hagen C, Wraae K, Brixen K, Petersen PH, Haug E, et al. Visceral and subcutaneous adipose tissue assessed by magnetic resonance imaging in relation to circulating androgens, sex hormone-binding globulin, and luteinizing hormone in young men. The Journal of Clinical Endocrinology & Metabolism. 2007;92(7):2696-2705
  44. 44. Rader DJ. High-density lipoproteins and atherosclerosis. The American Journal of Cardiology. 2002;90(8):62-70
  45. 45. Zannis VI, Kypreos KE, Chroni A, Kardassis D, Zanni EE. Lipoproteins and atherogenesis. Molecular Mechanisms of Atherosclerosis. 2004;8:111-174
  46. 46. Liu B, Krieger M. Highly purified scavenger receptor class B, type I reconstituted into phosphatidylcholine/cholesterol liposomes mediates high affinity high density lipoprotein binding and selective lipid uptake. Journal of Biological Chemistry. 2002;277(37):34125-34135
  47. 47. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: A meta-analysis. Clinical Endocrinology. 2005;63(3):280-293
  48. 48. Haring R, Baumeister SE, Völzke H, Dörr M, Felix SB, Kroemer HK, et al. Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. European Journal of Cardiovascular Prevention & Rehabilitation. 2011;18(1):86-96
  49. 49. Beigneux AP, Franssen R, Bensadoun A, Gin P, Melford K, Peter J, et al. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29(6):956-962
  50. 50. Langer C, Gansz B, Goepfert C, Engel T, Uehara Y, von Dehn G, et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochemical and Biophysical Research Communications. 2002;296(5):1051-1057
  51. 51. Wiinberg N, Høegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, et al. 24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. American Journal of Hypertension. 1995;8(10):978-986
  52. 52. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050
  53. 53. Himmelmann A, Svensson A, Hansson L. Influence of sex on blood pressure and left ventricular mass in adolescents: The Hypertension in Pregnancy Offspring Study. Journal of Human Hypertension. 1994;8(7):485-490
  54. 54. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, et al. Prevalence of hypertension in the US adult population: Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25(3):305-313
  55. 55. Wilson C, Maass R, Estrada M. Cardiovascular effects of androgens. In: Akin F, editor. Basic and Clinical Endocrinology Up-to-Date 2011. Rijeka: IntechOpen. ISBN: 978-953-307-340-8. Available from:
  56. 56. Stamler J, Stamler R, Riedlinger WF, Algera G, Roberts RH. Hypertension screening of 1 million Americans: Community hypertension evaluation clinic (CHEC) program, 1973 through 1975. JAMA. 1976;235(21):2299-2306
  57. 57. Kienitz T, Quinkler M. Testosterone and blood pressure regulation. Kidney and Blood Pressure Research. 2008;31(2):71-79
  58. 58. Suzuki H, Tominaga T, Kumagai H, Saruta T. Effects of first-line antihypertensive agents on sexual function and sex hormones. Journal of Hypertension. Supplement: Official Journal of the International Society of Hypertension. 1988;6(4):S649-S651
  59. 59. Fogari R, Corradi L, Marasi G, Zoppi A, Mugellini A, Banderali A, et al. I007: Sexual activity and testosterone levels in hypertensive males. American Journal of Hypertension. 2000;13(S2):278A
  60. 60. Tangredi JF, Buxton IL. Hypertension as a complication of topical testosterone therapy. Annals of Pharmacotherapy. 2001;35(10):1205-1207
  61. 61. Reckelhoff JF, Yanes LL, Iliescu R, Fortepiani LA, Granger JP. Testosterone supplementation in aging men and women: Possible impact on cardiovascular-renal disease. American Journal of Physiology-Renal Physiology. 2005;289(5):F941-F948
  62. 62. Cheung KK, Luk AO, So WY, Ma RC, Kong AP, Chow FC, et al. Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence. Journal of Diabetes Investigation. 2015;6(2):112-123
  63. 63. Fogari R, Preti P, Zoppi A, Fogari E, Rinaldi A, Corradi L, et al. Serum testosterone levels and arterial blood pressure in the elderly. Hypertension Research. 2005;28(8):625-630
  64. 64. Reckelhoff JF, Granger JP. Role of androgens in mediating hypertension and renal injury. Clinical and Experimental Pharmacology and Physiology. 1999;26(2):127-131
  65. 65. Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovascular Research. 2002;53(3):688-708
  66. 66. Ely DL, Salisbury R, Hadi D, Turner M, Johnson ML. Androgen receptor and the testes influence hypertension in a hybrid rat model. Hypertension. 1991;17:1104-1110
  67. 67. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. European Journal of Endocrinology. 2008;159(5):507-514
  68. 68. Lin TH, Yeh S, Chang C. Tissue-specific knockout of androgen receptor in mice. In: Androgen Action. Totowa, New Jersey, USA: Humana Press; 2011. pp. 275-293
  69. 69. Rhoden EL, Ribeiro EP, Teloken C, Souto CA. Diabetes mellitus is associated with subnormal serum levels of free testosterone in men. BJU International. 2005;96(6):867-870
  70. 70. Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson WG, et al. Androgens and diabetes in men: Results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care. 2007;30(2):234-238
  71. 71. Colangelo LA, Ouyang P, Liu K, Kopp P, Golden SH, Dobs AS, et al. Association of endogenous sex hormones with diabetes and impaired fasting glucose in men: The Multi-Ethnic Study of Atherosclerosis. Diabetes Care. 2009;32(6):1049-1051
  72. 72. Corona G, Monami M, Rastrelli G, Aversa A, Sforza A, Lenzi A, et al. Type 2 diabetes mellitus and testosterone: A meta-analysis study. International Journal of Andrology. 2011;34:528-540
  73. 73. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis. JAMA. 2006;295(11):1288-1299
  74. 74. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: The missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287
  75. 75. Mlinar B, Marc J, Janež A, Pfeifer M. Molecular mechanisms of insulin resistance and associated diseases. Clinica Chimica Acta. 2007;375(1-2):20-35
  76. 76. Grossmann M, Gianatti EJ, Zajac JD. Testosterone and type 2 diabetes. Current Opinion in Endocrinology, Diabetes and Obesity. 2010;17(3):247-256
  77. 77. Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. The Journal of Clinical Endocrinology & Metabolism. 2005;90(5):2636-2641
  78. 78. Osuna CJA, Gomez-Perez R, Arata-Bellabarba G, Villaroel V. Relationship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men. Archives of Andrology. 2006;52(5):355-361
  79. 79. Cook NL, Romashkan S. Why do we need a trial on the effects of testosterone therapy in older men? Clinical Pharmacology & Therapeutics. 2011;89(1):29-31
  80. 80. Bhasin S, Jasjua GK, Pencina M, D’agostino R, Coviello AD, Vasan RS, et al. Sex hormone–binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: The Framingham Heart Study. Diabetes Care. 2011;34(11):2664-2670
  81. 81. Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male ageing? Critical Reviews in Clinical Laboratory Sciences. 2012;49(5-6):168-182
  82. 82. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. The Journal of Clinical Endocrinology & Metabolism. 2004;89(11):5462-5468
  83. 83. Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. European Journal of Endocrinology. 2007;156(5):595-602
  84. 84. Grossmann M, Thomas MC, Panagiotopoulos S, Sharpe K, MacIsaac RJ, Clarke S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. The Journal of Clinical Endocrinology & Metabolism. 2008;93(5):1834-1840
  85. 85. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nature Reviews Endocrinology. 2016;12(3):144-153
  86. 86. Isfort M, Stevens SC, Schaffer S, Jong CJ, Wold LE. Metabolic dysfunction in diabetic cardiomyopathy. Heart Failure Reviews. 2014;19(1):35-48
  87. 87. Dhalla NS, Takeda N, Rodriguez-Leyva D, Elimban V. Mechanisms of subcellular remodeling in heart failure due to diabetes. Heart Failure Reviews. 2014;19(1):87-99
  88. 88. Muthusamy T, Murugesan P, Balasubramanian K. Sex steroids deficiency impairs glucose transporter 4 expression and its translocation through defective Akt phosphorylation in target tissues of adult male rat. Metabolism. 2009;58(11):1581-1592
  89. 89. Xia F, Xu X, Zhai H, Meng Y, Zhang H, Du S, et al. Castration-induced testosterone deficiency increases fasting glucose associated with hepatic and extra-hepatic insulin resistance in adult male rats. Reproductive Biology and Endocrinology. 2013;11(1): Article No. 106
  90. 90. Chen X, Li X, Huang HY, Lin JF. Effects of testosterone on insulin receptor substrate-1 and glucose transporter 4 expression in cells sensitive to insulin. Zhonghua Yi Xue Za Zhi. 2006;86(21):1474-1477
  91. 91. Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. American Journal of Physiology-Endocrinology and Metabolism. 2008;294(5):E961-E968
  92. 92. Kelly DM, Jones TH. Testosterone: A metabolic hormone in health and disease. Journal of Endocrinology. 2013;217:R25-R45
  93. 93. Palomar-Morales M, Morimoto S, Mendoza-Rodríguez CA, Cerbón MA. The protective effect of testosterone on streptozotocin-induced apoptosis in β cells is sex specific. Pancreas. 2010;39(2):193-200
  94. 94. McInnes KJ, Smith LB, Hunger NI, Saunders PT, Andrew R, Walker BR. Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis. Diabetes. 2012;61(5):1072-1081
  95. 95. Pugh PJ, English KM, Jones TH, Channer KS. Testosterone: A natural tonic for the failing heart? QJM. 2000;93(10):689-694
  96. 96. Kelly DM, Jones TH. Testosterone: A vascular hormone in health and disease. Journal of Endocrinology. 2013;217:R47-R71
  97. 97. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436(7049):356-362
  98. 98. Maggio M, Basaria S, Ble A, Lauretani F, Bandinelli S, Ceda GP, et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. The Journal of Clinical Endocrinology & Metabolism. 2006;91(1):345-347
  99. 99. Nettleship JE, Pugh PJ, Channer KS, Jones T, Jones RD. Inverse relationship between serum levels of interleukin-1β and testosterone in men with stable coronary artery disease. Hormone and Metabolic Research. 2007;39(05):366-371
  100. 100. Watkins LR, Hutchinson MR, Johnston IN, Maier SF. Glia: Novel counter-regulators of opioid analgesia. Trends in Neurosciences. 2005;28(12):661-669
  101. 101. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. The Journal of Clinical Endocrinology & Metabolism. 2004;89(7):3313-3318
  102. 102. Malkin CJ, Pugh PJ, Morris PD, Kerry KE, Jones RD, Jones TH, et al. Testosterone replacement in hypogonadal men with angina improves ischemic threshold and quality of life. Heart. 2004;90(8):871-876
  103. 103. Haider A, Gooren LJ, Padungtod P, Saad F. Improvement of the metabolic syndrome and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate. Experimental and Clinical Endocrinology & Diabetes. 2010;118(03):167-171
  104. 104. Nathan L, Shi W, Dinh H, Mukherjee TK, Wang X, Lusis AJ, et al. Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase. Proceedings of the National Academy of Sciences. 2001;98(6):3589-3593
  105. 105. Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MR, et al. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. American Journal of Physiology-Endocrinology and Metabolism. 2006;290(2):E234-E242
  106. 106. Mäkinen J, Järvisalo MJ, Pöllänen P, Perheentupa A, Irjala K, Koskenvuo M, et al. Increased carotid atherosclerosis in andropausal middle-aged men. Journal of the American College of Cardiology. 2005;45(10):1603-1608
  107. 107. Vikan T, Johnsen SH, Schirmer H, Njølstad I, Svartberg J. Endogenous testosterone and the prospective association with carotid atherosclerosis in men: The Tromsø study. European Journal of Epidemiology. 2009;24(6):289-295
  108. 108. Van den Beld AW, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men. American Journal of Epidemiology. 2003;157(1):25-31
  109. 109. Fukui M, Kitagawa Y, Ose H, Hasegawa G, Yoshikawa T, Nakamura N. Role of endogenous androgen against insulin resistance and athero-sclerosis in men with type 2 diabetes. Current Diabetes Reviews. 2007;3(1):25-31
  110. 110. Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian Journal of Andrology. 2008;10(2):214-218
  111. 111. Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. European Journal of Endocrinology. 2009;161(3):443-449
  112. 112. Zitzmann M, Vorona E, Wenk M, Saad F, Nieschlag E. Testosterone administration decreases carotid artery intima media thickness as a marker of impaired vascular integrity in middle-aged overweight men: 61. Journal of Men's Health. 2009;6(3):243
  113. 113. von Eckardstein A, Wu FC. Testosterone and atherosclerosis. Growth Hormone & IGF Research. 2003;13:S72-S84
  114. 114. Lu YL, Kuang L, Zhu H, Wu H, Wang XF, Pang YP, et al. Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 5α-reductase inhibitor. Asian Journal of Andrology. 2007;9(6):843-847
  115. 115. Miller VM, Mulvagh SL. Sex steroids and endothelial function: Translating basic science to clinical practice. Trends in Pharmacological Sciences. 2007;28(6):263-270
  116. 116. Foresta C, Zuccarello D, De Toni L, Garolla A, Caretta N, Ferlin A. Androgens stimulate endothelial progenitor cells through an androgen receptor-mediated pathway. Clinical Endocrinology. 2008;68(2):284-289
  117. 117. Ong PJ, Patrizi G, Chong WC, Webb CM, Hayward CS, Collins P. Testosterone enhances flow-mediated brachial artery reactivity in men with coronary artery disease. American Journal of Cardiology. 2000;85(2):269-272
  118. 118. Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertension Research. 2007;30(11):1029-1034
  119. 119. Rubio-Gayosso I, Garcia-Ramirez O, Gutierrez-Serdan R, Guevara-Balcazar G, Muñoz-Garcı́a O, Morato-Cartajena T, et al. Testosterone inhibits bradykinin-induced intracellular calcium kinetics in rat aortic endothelial cells in culture. Steroids. 2002;67(5):393-397
  120. 120. Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocrine Reviews. 2003;24(2):183-217
  121. 121. Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. 2014;88:106-116
  122. 122. Neyses L, Pelzer T. The biological cascade leading to cardiac hypertrophy. European Heart Journal. 1995;16:8-11
  123. 123. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: Recent observations regarding the specificity of three hallmarks of the disease: Asymmetric septal hypertrophy, septal disorganization and systolic anterior motion of the anterior mitral leaflet. The American Journal of Cardiology. 1980;45(1):141-154
  124. 124. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. New England Journal of Medicine. 1990;322(22):1561-1566
  125. 125. Hayward CS, Webb CM, Collins P. Effect of sex hormones on cardiac mass. The Lancet. 2001;357(9265):1354-1356
  126. 126. Svartberg J, von Muhlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. European Journal of Endocrinology. 2004;150(1):65-71
  127. 127. Pirompol P, Teekabut V, Weerachatayanukul W, Bupha-Intr T. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy. Journal of Endocrinology. 2016;229:13-23
  128. 128. Miyazaki M, Esser KA. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals. Journal of Applied Physiology. 2009;106(4):1367-1373
  129. 129. Fry CS, Drummond MJ, Glynn EL, Dickinson JM, Gundermann DM, Timmerman KL, et al. Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. Skeletal Muscle. 2011;1(1):11
  130. 130. Altamirano F, Oyarce C, Silva P, Toyos M, Wilson C, Lavandero S, et al. Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway. Journal of Endocrinology. 2009;202(2):299-307
  131. 131. Sinha-Hikim I, Cornford M, Gaytan H, Lee ML, Bhasin S. Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. The Journal of Clinical Endocrinology & Metabolism. 2006;91(8):3024-3033
  132. 132. Favier FB, Benoit H, Freyssenet D. Cellular and molecular events controlling skeletal muscle mass in response to altered use. Pflügers Archiv-European Journal of Physiology. 2008;456(3):587-600
  133. 133. Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, Lee MI, et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. American Journal of Physiology-Endocrinology and Metabolism. 2002;283(1):E154-E164
  134. 134. Kadi F. Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement. British Journal of Pharmacology. 2008;154(3):522-528
  135. 135. Estrada M, Espinosa A, Müller M, Jaimovich E. Testosterone stimulates intracellular calcium release and mitogen-activated protein kinases via a G protein-coupled receptor in skeletal muscle cells. Endocrinology. 2003;144(8):3586-3597
  136. 136. Fu R, Liu J, Fan J, Li R, Li D, Yin J, et al. Novel evidence that testosterone promotes cell proliferation and differentiation via G protein-coupled receptors in the rat L6 skeletal muscle myoblast cell line. Journal of Cellular Physiology. 2012;227(1):98-107
  137. 137. Tsitouras PD, Martin CE, Harman SM. Relationship of serum testosterone to sexual activity in healthy elderly men. Journal of Gerontology. 1982;37(3):288-293
  138. 138. Schweiger U, Deuschle M, Weber B, Korner A, Lammers CH, Schmider J, et al. Testosterone, gonadotropin, and cortisol secretion in male patients with major depression. Psychosomatic Medicine. 1999;61:292-296
  139. 139. Stepan JJ, Lachman M, Zvěřina J, Pacovský V, Baylink DJ. Castrated men exhibit bone loss: Effect of calcitonin treatment on biochemical indices of bone remodeling. The Journal of Clinical Endocrinology & Metabolism. 1999;69(3):523-527
  140. 140. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mechanisms of Ageing and Development. 1999;107(2):123-136
  141. 141. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, et al. Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2005;60(11):1451-1457
  142. 142. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, et al. Testosterone and cardiovascular risk in men: A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proceedings. 2007;82(1):29-39
  143. 143. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, et al. Adverse effects of testosterone therapy in adult men: A systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2010;95(6):2560-2575
  144. 144. Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836
  145. 145. Sharma R, Oni OA, Chen G, Sharma M, Dawn B, Sharma R, et al. Association between testosterone replacement therapy and the incidence of DVT and Pulmonary embolism: A retrospective cohort study of the veterans administration database. Chest. 2016;150(3):563-571
  146. 146. European Medicines Agency. No consistent evidence of an increased risk of heart problems with testosterone medicines. 2014. Available from:
  147. 147. Alexander GC, Iyer G, Lucas E, Lin D, Singh S. Cardiovascular risks of exogenous testosterone use among men: A systematic review and meta-analysis. The American Journal of Medicine. 2017;130(3):293-305
  148. 148. Loo SY, Chen BY, Yu OHY, Azoulay L, Renoux C. Testosterone replacement therapy and the risk of stroke in men: A systematic review. Maturitas. 2017;106:31-37
  149. 149. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. The Journal of Clinical Endocrinology & Metabolism. 2012;97(6):2050-2058
  150. 150. Muraleedharan V, Ranjan N, Rolfe C, Jones TH. The effect of testosterone undecanoate on cardiovascular risk factors in men with hypogonadism in clinical practice. Endocrine Reviews. 2010;31(3). Issue 3 Supplement
  151. 151. Bagatell CJ, Heiman JR, Matsumoto AM, Rivier JE, Bremner WJ. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. The Journal of Clinical Endocrinology & Metabolism. 1994;79(2):561-567
  152. 152. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. European Journal of Endocrinology. 2006;154(6):899-906
  153. 153. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. The Journal of Clinical Endocrinology & Metabolism. 2007;92(10):3844-3853
  154. 154. Zhang KS, Zhao MJ, An Q, Jia YF, Fu LL, Xu JF, et al. Effects of testosterone supplementation therapy on lipid metabolism in hypogonadal men with T2 DM: A meta-analysis of randomized controlled trials. Andrology. 2018;6(1):37-46
  155. 155. Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Testosterone and cardiovascular risk: Meta-analysis of interventional studies. The Journal of Sexual Medicine. 2018;15(6):820-838
  156. 156. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS One. 2014;9(1):e85805
  157. 157. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with testosterone administration. New England Journal of Medicine. 2010;363(2):109-122
  158. 158. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: A systematic review and meta-analysis of placebo-controlled randomized trials. BMC Medicine. 2013;11(1):108
  159. 159. Bouchardy B, Majno G. Histopathology of early myocardial infarcts: A new approach. The American Journal of Pathology. 1974;74(2):301
  160. 160. Knowlton KU, Chien KR. Inflammatory pathways and cardiac repair: The affliction of infarction. Nature Medicine. 1999;5(10):1122
  161. 161. Cavasin MA, Sankey SS, Yu AL, Menon S, Yang XP. Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. American Journal of Physiology-Heart and Circulatory Physiology. 2003;284(5):H1560-H1569

Written By

Dilip Mukherjee, Koushik Sen, Shreyasi Gupta, Piyali Chowdhury, Suravi Majumder and Payel Guha

Submitted: May 20th, 2018 Reviewed: March 14th, 2019 Published: February 13th, 2020