Effects of androgens on cardiovascular remodeling

in Journal of Endocrinology

Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well-known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males.

Abstract

Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well-known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males.

Keywords:

Introduction

Cardiovascular disease remains a major cause of death in both women and men worldwide and appears to increase morbidity and mortality in industrial countries. The various risk factors for development of cardiovascular disease include aging, hypertension, dyslipidemia, diabetes, obesity, and smoking. In addition to these cardiovascular risk factors, there are several sex differences in cardiovascular disease. The incidence of cardiovascular disease is approximately twofold higher in males than in females (Kalin & Zumoff 1990). This sex discrepancy in cardiovascular disease rates has been thought to be associated with sex hormone-mediated actions. Estrogens, which are female sex hormones, are generally considered to exert favorable effects against cardiovascular diseases. Many studies have revealed preventive and favorable effects of estrogen on cardiac hypertrophy (Malhotra et al. 1990, Weinberg et al. 1999, van Eickels et al. 2001, Cavasin et al. 2003) and vascular remodeling (Zhang et al. 2000).

In contrast, male sex is generally believed to be one of the major cardiovascular risk factors, along with other traditional determinants such as hypertension, hyperlipidemia, diabetes, and smoking (Criqui 1986). Therefore, the male sex hormones, androgens, are thought to be detrimental to cardiovascular organs. In fact, androgen replacement is associated with cardiovascular-related adverse events in aged men who have limitations in mobility (Basaria et al. 2010). In addition, previous studies have shown that testosterone replacement tends to increase cardiovascular risk among men of all ages (Calof et al. 2005, Haddad et al. 2007, Fernandez-Balsells et al. 2010). On the other hand, recent epidemiological studies have revealed that lower testosterone levels in men are associated with higher mortality rates, due largely to cardiovascular disease (Khaw et al. 2007, Laughlin et al. 2008, Tivesten et al. 2009, Yeap et al. 2009, Akishita et al. 2010, Corona et al. 2010, Malkin et al. 2010, Araujo et al. 2011; Fig. 1). Moreover, patients undergoing androgen-deprivation therapy for prostate cancer are at increased risk of coronary heart disease and heart failure (Martin-Merino et al. 2011). It has been reported that low testosterone is associated with metabolic syndrome or diabetes in men (Stanworth & Jones 2009, Grossmann 2011). Prospective studies have also revealed that men with higher testosterone level have a low risk of type 2 diabetes (Ding et al. 2006).

Figure 1
Figure 1

Relationship between serum testosterone level and cardiovascular mortality in men. Reduced levels of endogenous testosterone worsen the mortality of cardiovascular disease in men, indicating that testosterone is a predictive factor of cardiovascular disease. (Modified from Khaw et al. (2007)).

Citation: Journal of Endocrinology 214, 1; 10.1530/JOE-12-0126

Although the mechanisms of the heart- and blood vessel-protective activities of androgens remain unclear, recent studies have shown preventive effects of androgens against cardiovascular disease. In addition, analysis of androgen receptor (AR)-knockout (KO) mice (Sato et al. 2003) has revealed new aspects of the functional activities of androgens in various tissues, including adipocytes (Sato et al. 2003, Fan et al. 2005), brain (Sato et al. 2004), bone (Kawano et al. 2003), and cardiovascular organs (Ikeda et al. 2005, 2009, 2010). Thus, the androgen–AR system plays an important role in homeostasis of various organs in males, although the favorable effects of androgens remain controversial.

In this review, we give an overview of the pathophysiological roles of androgen activity in the cardiovascular system and focus on the cardiovascular stress-induced phenotypes observed in male ARKO mice in order to elucidate the effect of AR against cardiovascular diseases.

Male sex hormones, androgens

Androgens in the human body comprise testosterone, dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA) and its sulfate DHEAS. Most of the testosterone is secreted by the testis. Approximately 5% of the serum testosterone produced in men undergoes 5α-reduction to form a more potent androgen, DHT. DHT has threefold greater affinity than testosterone and 15- to 30-fold greater affinity than adrenal androgens for ARs. DHEA and DHEAS, the most abundant adrenal steroids in humans, are precursors for intracellular production of androgens and estrogens in nonreproductive tissues. Most of the DHEA in blood exists as DHEAS, with ∼300-fold more DHEAS than free DHEA. Therefore, DHEAS is the most physiologically active of this class of adrenal steroids in humans. Most testosterone exists as forms bound to plasma proteins, including 40–50% bound to albumin and 50–60% strongly bound to sex hormone-binding globulin (SHBG), with 1–2% being free (Dunn et al. 1981). Both free testosterone and albumin-bound testosterone are fractions available for biological action, so-called bioavailable testosterone. On the other hand, SHBG-bound testosterone is not a readily bioactive form (Cefalu et al. 1986). DHT also strongly binds to SHBG, and only 0.8% is a free fraction. Other androgens including DHEA and DHEAS are bound to albumin (Plager 1965).

The levels of all androgens increase at puberty and peak during adolescence, then gradually decrease with age (Giusti et al. 1975).

Mechanisms of androgen activity via AR activation

The actions of androgens are initiated by the binding of androgens to the AR. AR, a 110-kDa ligand-inducible nuclear receptor, is a member of the nuclear receptor superfamily. The effects of androgens are generally mediated by AR activation (Chang et al. 1988a,b, Orlic et al. 2001). The biological actions of androgens via transcriptional regulation of target genes by the AR are referred to as ‘genomic action’ (Orlic et al. 2001). Initially, androgen enters the cells and binds to AR; the ligand-bound AR then dimerizes and translocates into the nucleus, and binds to specific androgen response element sites located within the promoter regions of the target genes to modulate their transcriptional activities. Androgens also exert effects through extranuclear–nontranscriptional action, known as nongenomic action (Losel et al. 2003, Simoncini & Genazzani 2003). Nongenomic androgen effects are distinct from genomic action in that they are exerted for a shorter time. Nongenomic androgen activity involves rapid induction of second messenger signal transduction cascades, including upregulation of cytosolic calcium concentration and activation of protein kinase A, protein kinase C (PKC), and MAP kinases (Kousteni et al. 2002). The nongenomic action of androgen might exert, in part, through stimulating protein kinase A and cAMP via binding to G-protein coupled membrane receptor for the SHBG–testosterone complex (Heinlein & Chang 2002; Fig. 2).

Figure 2
Figure 2

Biological actions of androgens via ARs. Androgen binds to the AR. The liganded AR forms homodimers and moves it into the nucleus to bind to specific DNA elements referred to androgen-responsive elements in target gene promoters and regulates the target gene expression at the transcriptional level. This action of the AR is called genomic action. Androgen–AR also exerts its function without transcription by interaction with other signaling pathways. This action is called nongenomic action.

Citation: Journal of Endocrinology 214, 1; 10.1530/JOE-12-0126

AR expression in cardiovascular tissues

Androgens exert biological effects on many target organs (Mooradian et al. 1987, Wilson 1999). While AR expression is highest in male sex organs (Wilson & French 1976), the AR is known to be widely if weakly expressed in other tissues, including skeletal muscle (Snochowski et al. 1980), bone (Riggs et al. 2002), and the brain (McGill et al. 1980). The AR is also found in cardiac myocytes (McGill et al. 1980, Marsh et al. 1998), endothelial cells, vascular smooth muscle cells, and fibroblasts (Horwitz & Horwitz 1982, Lin et al. 1982). Therefore, androgen–AR effects are also thought to be exerted on the heart and vasculature.

Androgen effects on cardiac remodeling

The AR gene is expressed in mammalian cardiomyocytes (McGill et al. 1980, Marsh et al. 1998), indicating that androgens might have a function in the heart. The estrogen receptor gene also exists in cardiomyocytes (Grohe et al. 1997, 1998), and many studies have shown preventive effects of estrogen on cardiac hypertrophy (Malhotra et al. 1990, Weinberg et al. 1999, Cavasin et al. 2003). However, the physiological actions of androgens in the heart have remained unclear compared with those of estrogen. Marsh et al. (1998) have shown that androgen exerts a hypertrophic effect on cardiac myocytes via a direct AR-mediated pathway, and other studies have also shown that androgens induce cardiac hypertrophy (Malhotra et al. 1990, Weinberg et al. 1999, Cavasin et al. 2003), while castration (Morano et al. 1990, Cavasin et al. 2003, Li et al. 2004) and flutamide (Baltatu et al. 2002), an AR antagonist, remarkably reduce cardiac hypertrophy. In addition, androgens modulate male cardiac performance by regulating the functional expression of L-type calcium channels in cardiac myocytes (Golden et al. 2003). Li et al. (2004) showed that castration mitigated not only cardiac hypertrophy but also cardiac fibrosis in male guanylyl cyclase-A-deficient mice.

In the clinical setting, male patients with chronic heart failure exhibit declines in serum androgen levels (Anker et al. 1997, Kiilavuori et al. 1999, Moriyama et al. 2000, Kontoleon et al. 2003), and deficiencies in circulating androgens, including testosterone, in men with chronic heart failure have been shown to be independent predictors of poor outcome (Jankowska et al. 2010). On the other hand, administration of testosterone with moderate heart failure has been shown to reduce left ventricular mass index, indicating the amelioration of cardiac hypertrophy without improving cardiac function. The effects of physiological androgen levels on cardiac remodeling and function thus remain controversial, and the molecular mechanisms of the underlying effects of androgens on the heart are still a matter of debate.

Approach for study of androgen activity: overview and aberrant cardiac remodeling in ARKO mice

The effects of androgens on the cardiovascular system are usually studied in animal models using castration or pharmacological interventions. While gonadectomy is indeed an easy way to eliminate androgen activity in vivo, the AR itself is still present in the castrated animal model. Flutamide, an AR antagonist, has been used for treatment of prostate cancer and also to clarify the influence of androgen activity blockade in numerous experimental studies. However, flutamide activates estrogen receptors, complicating the understanding of AR action. To elucidate the physiological function of the androgen–AR system in nonclassical target organs in vivo, we used the Cre–loxP system to generate ARKO mice (Sato et al. 2003). Male ARKO mice exhibit extremely low serum levels of testosterone and DHT, while estrogen levels are similar between male ARKO and wild-type (WT) mice. Therefore, ARKO mice are a unique animal model with a normal estrogen–ER system. Studies using ARKO mice have in recent years provided several new insights into the androgen–AR system. Male ARKO mice demonstrate late-onset obesity (Sato et al. 2003), with decreased energy expenditure and enhanced insulin sensitivity (Fan et al. 2005), disordered hypothalamic leptin signaling (Fan et al. 2008), high turnover osteopenia (Kawano et al. 2003), impaired brain masculinization (Sato et al. 2004), dysregulation of the pituitary glucocorticoid feedback system (Miyamoto et al. 2007), enhanced hair growth (Naito et al. 2008), and altered skeletal muscle strength (Chambon et al. 2010). ARKO mice are thus a useful tool for investigating androgen–AR activity in classical and nonclassical target organs and may have advantages over conventional models such as gonadectomized animals or administration of AR antagonists. Therefore, we used male ARKO mice to clarify the physiological role of the androgen–AR system in the heart. AR regulates physiological cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during angiotensin II (Ang II)-induced cardiac remodeling (Fig. 3; Ikeda et al. 2005). Ang II-treated ARKO mice showed the reduced activation of extracellular signal-regulated kinases (ERKs) 1/2 and 5, hypertrophy-related signaling pathways, acceleration of the transforming growth factor-β1 (TGF-β1)–Smad pathway, and increased expression of genes related to fibrotic change in the heart. The AR also counteracts doxorubicin (Dox)-induced cardiotoxicity, in part via activation of the Akt pathway, which upregulates TFAM and reduces oxidative stress and thus protects cardiac myocytes against mitochondrial damage and apoptosis (Fig. 4; Ikeda et al. 2010). These findings might account for the effect of testosterone replacement in male patients with severe heart failure (Malkin et al. 2006).

Figure 3
Figure 3

The AR system participates in physiological cardiac growth and inhibits angiotensin II-induced cardiovascular remodeling. (Modified from Ikeda et al. (2005, 2009)).

Citation: Journal of Endocrinology 214, 1; 10.1530/JOE-12-0126

Figure 4
Figure 4

ARKO mice are susceptible to Dox-induced cardiotoxicity. (Upper panels) Echocardiography shows greater reduction of cardiac systolic function in Dox-treated ARKO mice than in Dox-treated WT mice. (Middle panels) Electron microscopy shows larger numbers of cardiac vacuoles and abnormal mitochondrial formation in Dox-treated ARKO mice. (Lower panels) Dox-induced cardiac superoxide production is accelerated in Dox-treated ARKO mice relative to Dox-treated WT mice. (Modified from Ikeda et al. (2010)).

Citation: Journal of Endocrinology 214, 1; 10.1530/JOE-12-0126

Effects of androgens on vascular remodeling

The effects of androgens on blood vessels are also controversial. As male sex is one of the major risk factors for the development of cardiovascular disease, it is hypothesized that androgens promote atherosclerosis. In fact, several in vivo and in vitro studies have suggested that androgens increase expression of proatherogenic factors (Adams et al. 1995, McCrohon et al. 1999, Ng et al. 2003, Nheu et al. 2011). In contrast, recent clinical studies have shown that low endogenous testosterone levels are associated with advanced atherosclerosis of the carotid artery in middle-aged males and that this association is independent of the traditional cardiovascular risk factors (Muller et al. 2004, Makinen et al. 2005). Low testosterone level is also associated with poor vasodilation of the brachial artery and is an independent risk factor for endothelial dysfunction in men (Akishita et al. 2007). Androgen replacement has been shown to prevent aortic atherosclerotic changes in castrated male rabbits fed a high cholesterol diet (Alexandersen et al. 1999), and arterial AR mRNA upregulation by testosterone has been shown to reduce neointimal plaque formation in male rabbits (Hanke et al. 2001). Endogenous testosterone also inhibits coronary neointimal formation after balloon injury through enhanced expression of PKC δ and p27 (kip1; Tharp et al. 2009). Qiu et al. (2010) showed that physiological levels of DHT attenuated the development of atherosclerosis by AR-mediated suppression of the formation of intimal foam cells by macrophages. Furthermore, we have reported that DHEAS level is inversely associated with carotid atherosclerosis, as measured by increased max-intima–media thickness (IMT) and mean-IMT, in males but not in females (Yoshida et al. 2010). Therefore, in order to elucidate the pathophysiological roles of AR activity in the cardiovascular system, we studied male ARKO mice under vascular stress (Ikeda et al. 2009). Male ARKO mice exhibited exaggerated Ang II-induced medial thickening and perivascular fibrosis in the coronary artery and aorta. Ang II-induced oxidative stress was exacerbated and nitric oxide bioavailability decreased in male ARKO mice. Androgen activity thus influences Ang II-induced vascular remodeling by suppressing oxidative stress and preserving nitric oxide production (Ikeda et al. 2009). Androgen–AR system-promoted eNOS activation was mediated by both phosphatidylinositol 3-kinase (PI3K)/Akt signaling and the direct interaction of AR with p85 α (Ikeda et al. 2010, Koizumi et al. 2010). In addition, AR deletion in Apo-E-deficient mice accelerated the atherosclerotic changes; this effect was partially attenuated by androgen supplementation (Bourghardt et al. 2010). Interestingly, physiological testosterone supplementation inhibited cholesterol-enriched diet-induced fatty streak formation in Tfm mice, which have a deletion in the gene encoding the classical AR (Nettleship et al. 2007). These results suggested that androgen exerts an atheroprotective effect via AR-dependent and -independent signaling. The androgen–AR system thus protects vascular remodeling through multiple signaling pathways.

The effects of androgens on angiogenesis

While the effect of estrogens on angiogenesis has been studied extensively and characterized in detail (Losordo & Isner 2001), very little is known about the effect of androgens on angiogenesis. As proof that the androgen–AR system is involved in angiogenesis, Sieveking et al. (2010a) demonstrated both in vitro and in vivo that androgens elicit an AR-mediated angiogenic effect in males but not in females. They concluded that androgens promote angiogenesis via vascular endothelial growth factor (VEGF)-related mechanisms (Cai et al. 2011) and also by stimulation of erythropoietin production (Sieveking et al. 2010a,b). Further studies are necessary to clarify the significance of androgens in angiogenesis.

Androgens and peripheral arterial disease

Peripheral arterial disease (PAD) not only decreases quality of life due to intermittent claudication, but also, more importantly, is a powerful predictor of future cardiovascular and cerebrovascular events such as myocardial infarction, stroke, and death (Smith et al. 1990, Criqui et al. 1992, Murabito et al. 2003). Previous clinical studies have shown that PAD is two- to three-fold more prevalent in men than in women (Dormandy & Rutherford 2000) and that low testosterone levels are associated with lower extremity PAD in elderly men (Tivesten et al. 2007). Conversely, it has been reported that sex hormones are not associated with the development of PAD in men or postmenopausal women (Price et al. 1997). Therefore, the pathophysiological roles of androgen activity in the development of PAD remain a matter of debate.

Androgens and hypertension

It has been believed that blood pressure is higher in males than in females after puberty (Burt et al. 1995) and that there are sex differences in the prevalence and complications of hypertension. Indeed, patients undergoing androgen-deprivation therapy due to prostate cancer showed decreased central arterial compliance (Dockery et al. 2000), and several studies have shown that low serum testosterone level is associated with high blood pressure in elderly men (Fogari et al. 2005, Akishita et al. 2010) and that suppression of testosterone production increases arterial stiffness (Dockery et al. 2003). In addition, testosterone replacement therapy has been shown to improve arterial stiffness in elderly hypogonadal men (Yaron et al. 2009). These findings suggest that physiological androgen levels preserve appropriate blood pressure by modulating vascular stiffness.

In experimental animal models, castration reduced blood pressure in male rats with spontaneous (Martin et al. 2005, Ojeda et al. 2007) or fructose feeding-induced (Song et al. 2004) hypertension. Testosterone has also been shown to inhibit L-type calcium channels via an AR-independent pathway, indicating nongenomic action of androgen on vasodilatation (Scragg et al. 2004, 2007, Hall et al. 2006). However, we have found that there is no difference in blood pressure between male ARKO and age-matched WT mice at 6 months of age (Ikeda et al. 2005). As the results of these animal studies are inconsistent with the results of clinical human studies, further research on the mechanisms by which androgens affect blood pressure is required.

Conclusion

Although androgens, in contrast to estrogen, have been considered to have adverse effects on the cardiovascular system, recent studies have revealed favorable effects of androgens on cardiovascular remodeling. Based on these previous results, at least physiological levels of androgens are thought to be required for cardiovascular homeostasis in males. As a better understanding of the sex differences in cardiovascular diseases might lead to novel therapeutic strategies, the pathophysiology of the involvement of sex hormones in the cardiovascular system must be determined in detail. Figure 5 shows a conceptual summary of the currently known pathophysiological activities of ligand-bound AR described in this review.

Figure 5
Figure 5

Schematic diagram of cardiovascular-protective effects of ligand-bound AR.

Citation: Journal of Endocrinology 214, 1; 10.1530/JOE-12-0126

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported in part by Grants-in-Aid for Scientific Research and Young Scientist B from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and a Grant for a Study Group on Aseptic Femoral Neck Necrosis from the Ministry of Health, Labour and Welfare of Japan.

References

  • AdamsMRWilliamsJKKaplanJR1995Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arteriosclerosis Thrombosis and Vascular Biology15562570. doi:10.1161/01.ATV.15.5.562.

    • Search Google Scholar
    • Export Citation
  • AkishitaMHashimotoMOhikeYOgawaSIijimaKEtoMOuchiY2007Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertension Research3010291034. doi:10.1291/hypres.30.1029.

    • Search Google Scholar
    • Export Citation
  • AkishitaMHashimotoMOhikeYOgawaSIijimaKEtoMOuchiY2010Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis210232236. doi:10.1016/j.atherosclerosis.2009.10.037.

    • Search Google Scholar
    • Export Citation
  • AlexandersenPHaarboJByrjalsenILawaetzHChristiansenC1999Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circulation Research84813819. doi:10.1161/01.RES.84.7.813.

    • Search Google Scholar
    • Export Citation
  • AnkerSDChuaTPPonikowskiPHarringtonDSwanJWKoxWJPoole-WilsonPACoatsAJ1997Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation96526534. doi:10.1161/01.CIR.96.2.526.

    • Search Google Scholar
    • Export Citation
  • AraujoABDixonJMSuarezEAMuradMHGueyLTWittertGA2011Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism9630073019. doi:10.1210/jc.2011-1137.

    • Search Google Scholar
    • Export Citation
  • BaltatuOCaylaCIliescuRAndreevDJordanCBaderM2002Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. Journal of the American Society of Nephrology1326812687. doi:10.1097/01.ASN.0000033327.65390.CA.

    • Search Google Scholar
    • Export Citation
  • BasariaSCovielloADTravisonTGStorerTWFarwellWRJetteAMEderRTennstedtSUlloorJZhangA2010Adverse events associated with testosterone administration. New England Journal of Medicine363109122. doi:10.1056/NEJMoa1000485.

    • Search Google Scholar
    • Export Citation
  • BourghardtJWilhelmsonASAlexandersonCDe GendtKVerhoevenGKrettekAOhlssonCTivestenA2010Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology15154285437. doi:10.1210/en.2010-0663.

    • Search Google Scholar
    • Export Citation
  • BurtVLCutlerJAHigginsMHoranMJLabartheDWheltonPBrownCRoccellaEJ1995Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension266069. doi:10.1161/01.HYP.26.1.60.

    • Search Google Scholar
    • Export Citation
  • CaiJHongYWengCTanCImperato-McGinleyJZhuYS2011Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism. American Journal of Physiology. Heart and Circulatory Physiology300H1210H1221. doi:10.1152/ajpheart.01210.2010.

    • Search Google Scholar
    • Export Citation
  • CalofOMSinghABLeeMLKennyAMUrbanRJTenoverJLBhasinS2005Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. Journals of Gerontology. Series A Biological Sciences and Medical Sciences6014511457. doi:10.1093/gerona/60.11.1451.

    • Search Google Scholar
    • Export Citation
  • CavasinMASankeySSYuALMenonSYangXP2003Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. American Journal of Physiology. Heart and Circulatory Physiology284H1560H1569. doi:10.1152/ajpheart.01087.2002.

    • Search Google Scholar
    • Export Citation
  • CefaluWTPardridgeWMChaudhuriGJuddHL1986Serum bioavailability and tissue metabolism of testosterone and estradiol in rat salivary gland. Journal of Clinical Endocrinology and Metabolism632028. doi:10.1210/jcem-63-1-20.

    • Search Google Scholar
    • Export Citation
  • ChambonCDuteilDVignaudAFerryAMessaddeqNMalivindiRKatoSChambonPMetzgerD2010Myocytic androgen receptor controls the strength but not the mass of limb muscles. PNAS1071432714332. doi:10.1073/pnas.1009536107.

    • Search Google Scholar
    • Export Citation
  • ChangCSKokontisJLiaoST1988aMolecular cloning of human and rat complementary DNA encoding androgen receptors. Science240324326. doi:10.1126/science.3353726.

    • Search Google Scholar
    • Export Citation
  • ChangCSKokontisJLiaoST1988bStructural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. PNAS8572117215. doi:10.1073/pnas.85.19.7211.

    • Search Google Scholar
    • Export Citation
  • CoronaGMonamiMBoddiVCameron-SmithMFisherADde VitaGMelaniCBalziDSforzaAFortiG2010Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. Journal of Sexual Medicine715571564. doi:10.1111/j.1743-6109.2009.01690.x.

    • Search Google Scholar
    • Export Citation
  • CriquiMH1986Epidemiology of atherosclerosis: an updated overview. American Journal of Cardiology5718C23C. doi:10.1016/0002-9149(86)91022-2.

    • Search Google Scholar
    • Export Citation
  • CriquiMHLangerRDFronekAFeigelsonHSKlauberMRMcCannTJBrownerD1992Mortality over a period of 10 years in patients with peripheral arterial disease. New England Journal of Medicine326381386. doi:10.1056/NEJM199202063260605.

    • Search Google Scholar
    • Export Citation
  • DingELSongYMalikVSLiuS2006Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. Journal of the American Medical Association29512881299. doi:10.1001/jama.295.11.1288.

    • Search Google Scholar
    • Export Citation
  • DockeryFRajkumarCAgarwalSWaxmanJBulpittCJ2000Androgen deprivation in males is associated with decreased central arterial compliance and reduced central systolic blood pressure. Journal of Human Hypertension14395397. doi:10.1038/sj.jhh.1001028.

    • Search Google Scholar
    • Export Citation
  • DockeryFBulpittCJAgarwalSDonaldsonMRajkumarC2003Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clinical Science104195201. doi:10.1042/CS20020209.

    • Search Google Scholar
    • Export Citation
  • DormandyJARutherfordRB2000Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). Journal of Vascular Surgery31S1S296. doi:10.1016/S0741-5214(00)81002-2.

    • Search Google Scholar
    • Export Citation
  • DunnJFNisulaBCRodbardD1981Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. Journal of Clinical Endocrinology and Metabolism535868. doi:10.1210/jcem-53-1-58.

    • Search Google Scholar
    • Export Citation
  • van EickelsMGroheCCleutjensJPJanssenBJWellensHJDoevendansPA200117β-Estradiol attenuates the development of pressure-overload hypertrophy. Circulation10414191423. doi:10.1161/hc3601.095577.

    • Search Google Scholar
    • Export Citation
  • FanWYanaseTNomuraMOkabeTGotoKSatoTKawanoHKatoSNawataH2005Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes5410001008. doi:10.2337/diabetes.54.4.1000.

    • Search Google Scholar
    • Export Citation
  • FanWYanaseTNishiYChibaSOkabeTNomuraMYoshimatsuHKatoSTakayanagiRNawataH2008Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor. Endocrinology14960286036. doi:10.1210/en.2008-0431.

    • Search Google Scholar
    • Export Citation
  • Fernandez-BalsellsMMMuradMHLaneMLampropulosJFAlbuquerqueFMullanRJAgrwalNElaminMBGallegos-OrozcoJFWangAT2010Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism9525602575. doi:10.1210/jc.2009-2575.

    • Search Google Scholar
    • Export Citation
  • FogariRPretiPZoppiAFogariERinaldiACorradiLMugelliniA2005Serum testosterone levels and arterial blood pressure in the elderly. Hypertension Research28625630. doi:10.1291/hypres.28.625.

    • Search Google Scholar
    • Export Citation
  • GiustiGGonnelliPBorrelliDFiorelliGFortiGPazzagliMSerioM1975Age-related secretion of androstenedione, testosterone and dihydrotestosterone by the human testis. Experimental Gerontology10241245. doi:10.1016/0531-5565(75)90001-7.

    • Search Google Scholar
    • Export Citation
  • GoldenKLMarshJDJiangYBrownTMouldenJ2003Gonadectomy of adult male rats reduces contractility of isolated cardiac myocytes. American Journal of Physiology. Endocrinology and Metabolism285E449E453. doi:10.1152/ajpendo.00054.2003.

    • Search Google Scholar
    • Export Citation
  • GroheCKahlertSLobbertKStimpelMKarasRHVetterHNeysesL1997Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Letters416107112. doi:10.1016/S0014-5793(97)01179-4.

    • Search Google Scholar
    • Export Citation
  • GroheCKahlertSLobbertKVetterH1998Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. Journal of Endocrinology156R1R7. doi:10.1677/joe.0.156R001.

    • Search Google Scholar
    • Export Citation
  • GrossmannM2011Low testosterone in men with type 2 diabetes: significance and treatment. Journal of Clinical Endocrinology and Metabolism9623412353. doi:10.1210/jc.2011-0118.

    • Search Google Scholar
    • Export Citation
  • HaddadRMKennedyCCCaplesSMTraczMJBolonaERSiderasKUragaMVErwinPJMontoriVM2007Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proceedings822939. doi:org/10.4065/82.1.29.

    • Search Google Scholar
    • Export Citation
  • HallJJonesRDJonesTHChannerKSPeersC2006Selective inhibition of L-type Ca2+ channels in A7r5 cells by physiological levels of testosterone. Endocrinology14726752680. doi:10.1210/en.2005-1243.

    • Search Google Scholar
    • Export Citation
  • HankeHLenzCHessBSpindlerKDWeidemannW2001Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation10313821385. doi:10.1161/01.CIR.103.10.1382.

    • Search Google Scholar
    • Export Citation
  • HeinleinCAChangC2002The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Molecular Endocrinology1621812187. doi:10.1210/me.2002-0070.

    • Search Google Scholar
    • Export Citation
  • HorwitzKBHorwitzLD1982Canine vascular tissues are targets for androgens, estrogens, progestins, and glucocorticoids. Journal of Clinical Investigation69750758. doi:10.1172/JCI110513.

    • Search Google Scholar
    • Export Citation
  • IkedaYAiharaKSatoTAkaikeMYoshizumiMSuzakiYIzawaYFujimuraMHashizumeSKatoM2005Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. Journal of Biological Chemistry2802966129666. doi:10.1074/jbc.M411694200.

    • Search Google Scholar
    • Export Citation
  • IkedaYAiharaKYoshidaSSatoTYagiSIwaseTSumitomoYIseTIshikawaKAzumaH2009Androgen-androgen receptor system protects against angiotensin II-induced vascular remodeling. Endocrinology15028572864. doi:10.1210/en.2008-1254.

    • Search Google Scholar
    • Export Citation
  • IkedaYAiharaKAkaikeMSatoTIshikawaKIseTYagiSIwaseTUedaYYoshidaS2010Androgen receptor counteracts doxorubicin-induced cardiotoxicity in male mice. Molecular Endocrinology2413381348. doi:10.1210/me.2009-0402.

    • Search Google Scholar
    • Export Citation
  • JankowskaEADrohomireckaAPonikowskaBWitkowskaALopuszanskaMSzklarskaABorodulin-NadziejaLBanasiakWPoole-WilsonPAPonikowskiP2010Deficiencies in circulating testosterone and dehydroepiandrosterone sulphate, and depression in men with systolic chronic heart failure. European Journal of Heart Failure12966973. doi:10.1093/eurjhf/hfq108.

    • Search Google Scholar
    • Export Citation
  • KalinMFZumoffB1990Sex hormones and coronary disease: a review of the clinical studies. Steroids55330352. doi:10.1016/0039-128X(90)90058-J.

    • Search Google Scholar
    • Export Citation
  • KawanoHSatoTYamadaTMatsumotoTSekineKWatanabeTNakamuraTFukudaTYoshimuraKYoshizawaT2003Suppressive function of androgen receptor in bone resorption. PNAS10094169421. doi:10.1073/pnas.1533500100.

    • Search Google Scholar
    • Export Citation
  • KhawKTDowsettMFolkerdEBinghamSWarehamNLubenRWelchADayN2007Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation11626942701. doi:10.1161/CIRCULATIONAHA.107.719005.

    • Search Google Scholar
    • Export Citation
  • KiilavuoriKNaveriHLeinonenHHarkonenM1999The effect of physical training on hormonal status and exertional hormonal response in patients with chronic congestive heart failure. European Heart Journal20456464. doi:10.1053/euhj.1998.1277.

    • Search Google Scholar
    • Export Citation
  • KoizumiHYuJHashimotoROuchiYOkabeT2010Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. FEBS Letters58424402444. doi:10.1016/j.febslet.2010.04.049.

    • Search Google Scholar
    • Export Citation
  • KontoleonPEAnastasiou-NanaMIPapapetrouPDAlexopoulosGKtenasVRaptiACTsagalouEPNanasJN2003Hormonal profile in patients with congestive heart failure. International Journal of Cardiology87179183. doi:10.1016/S0167-5273(02)00212-7.

    • Search Google Scholar
    • Export Citation
  • KousteniSChenJRBellidoTHanLAliAAO'BrienCAPlotkinLFuQMancinoATWenY2002Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science298843846. doi:10.1126/science.1074935.

    • Search Google Scholar
    • Export Citation
  • LaughlinGABarrett-ConnorEBergstromJ2008Low serum testosterone and mortality in older men. Journal of Clinical Endocrinology and Metabolism936875. doi:10.1210/jc.2007-1792.

    • Search Google Scholar
    • Export Citation
  • LiYKishimotoISaitoYHaradaMKuwaharaKIzumiTHamanakaITakahashiNKawakamiRTanimotoK2004Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology145951958. doi:10.1210/en.2003-0816.

    • Search Google Scholar
    • Export Citation
  • LinALMcGillHCJrShainSA1981Hormone receptors of the baboon cardiovascular system. Biochemical characterization of aortic and myocardial cytoplasmic androgen receptors. Circulation Research4910101016. doi:10.1161/01.RES.49.4.1010.

    • Search Google Scholar
    • Export Citation
  • LoselRMFalkensteinEFeuringMSchultzATillmannHCRossol-HaserothKWehlingM2003Nongenomic steroid action: controversies, questions, and answers. Physiological Reviews839651016. doi:10.1152/physrev.00003.2003.

    • Search Google Scholar
    • Export Citation
  • LosordoDWIsnerJM2001Estrogen and angiogenesis: a review. Arteriosclerosis Thrombosis and Vascular Biology21612. doi:10.1161/01.ATV.21.1.6.

    • Search Google Scholar
    • Export Citation
  • MakinenJJarvisaloMJPollanenPPerheentupaAIrjalaKKoskenvuoMMakinenJHuhtaniemiIRaitakariOT2005Increased carotid atherosclerosis in andropausal middle-aged men. Journal of the American College of Cardiology4516031608. doi:10.1016/j.jacc.2005.01.052.

    • Search Google Scholar
    • Export Citation
  • MalhotraAButtrickPScheuerJ1990Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. American Journal of Physiology259H866H871.

    • Search Google Scholar
    • Export Citation
  • MalkinCJPughPJWestJNvan BeekEJJonesTHChannerKS2006Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. European Heart Journal275764. doi:10.1093/eurheartj/ehi443.

    • Search Google Scholar
    • Export Citation
  • MalkinCJPughPJMorrisPDAsifSJonesTHChannerKS2010Low serum testosterone and increased mortality in men with coronary heart disease. Heart9618211825. doi:10.1136/hrt.2010.195412.

    • Search Google Scholar
    • Export Citation
  • MarshJDLehmannMHRitchieRHGwathmeyJKGreenGESchiebingerRJ1998Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation98256261. doi:10.1161/01.CIR.98.3.256.

    • Search Google Scholar
    • Export Citation
  • MartinDSBiltoftSRedetzkeRVogelE2005Castration reduces blood pressure and autonomic venous tone in male spontaneously hypertensive rats. Journal of Hypertension2322292236. doi:10.1097/01.hjh.0000191903.19230.79.

    • Search Google Scholar
    • Export Citation
  • Martin-MerinoEJohanssonSMorrisTGarcia RodriguezLA2011Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a Nested Case–Control Study in UK Primary Care. Drug Safety3410611077. doi:10.2165/11594540-000000000-00000.

    • Search Google Scholar
    • Export Citation
  • McCrohonJAJessupWHandelsmanDJCelermajerDS1999Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1. Circulation9923172322. doi:10.1161/01.CIR.99.17.2317.

    • Search Google Scholar
    • Export Citation
  • McGillHCJrAnselmoVCBuchananJMSheridanPJ1980The heart is a target organ for androgen. Science207775777. doi:10.1126/science.6766222.

  • MiyamotoJMatsumotoTShiinaHInoueKTakadaIItoSItohJMinematsuTSatoTYanaseT2007The pituitary function of androgen receptor constitutes a glucocorticoid production circuit. Molecular and Cellular Biology2748074814. doi:10.1128/MCB.02039-06.

    • Search Google Scholar
    • Export Citation
  • MooradianADMorleyJEKorenmanSG1987Biological actions of androgens. Endocrine Reviews8128. doi:10.1210/edrv-8-1-1.

  • MoranoIGerstnerJRueggJCGantenUGantenDVosbergHP1990Regulation of myosin heavy chain expression in the hearts of hypertensive rats by testosterone. Circulation Research6615851590. doi:10.1161/01.RES.66.6.1585.

    • Search Google Scholar
    • Export Citation
  • MoriyamaYYasueHYoshimuraMMizunoYNishiyamaKTsunodaRKawanoHKugiyamaKOgawaHSaitoY2000The plasma levels of dehydroepiandrosterone sulfate are decreased in patients with chronic heart failure in proportion to the severity. Journal of Clinical Endocrinology and Metabolism8518341840. doi:10.1210/jc.85.5.1834.

    • Search Google Scholar
    • Export Citation
  • MullerMvan den BeldAWBotsMLGrobbeeDELambertsSWvan der SchouwYT2004Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation10920742079. doi:10.1161/01.CIR.0000125854.51637.06.

    • Search Google Scholar
    • Export Citation
  • MurabitoJMEvansJCLarsonMGNietoKLevyDWilsonPW2003The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study. Archives of Internal Medicine16319391942. doi:10.1001/archinte.163.16.1939.

    • Search Google Scholar
    • Export Citation
  • NaitoASatoTMatsumotoTTakeyamaKYoshinoTKatoSOhderaM2008Dihydrotestosterone inhibits murine hair growth via the androgen receptor. British Journal of Dermatology159300305. doi:10.1111/j.1365-2133.2008.08671.x.

    • Search Google Scholar
    • Export Citation
  • NettleshipJEJonesTHChannerKSJonesRD2007Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor. Circulation11624272434. doi:10.1161/CIRCULATIONAHA.107.708768.

    • Search Google Scholar
    • Export Citation
  • NgMKQuinnCMMcCrohonJANakhlaSJessupWHandelsmanDJCelermajerDSDeathAK2003Androgens up-regulate atherosclerosis-related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis. Journal of the American College of Cardiology4213061313. doi:10.1016/j.jacc.2003.07.002.

    • Search Google Scholar
    • Export Citation
  • NheuLNazarethLXuGYXiaoFYLuoRZKomesaroffPLingS2011Physiological effects of androgens on human vascular endothelial and smooth muscle cells in culture. Steroids7615901596. doi:10.1016/j.steroids.2011.09.015.

    • Search Google Scholar
    • Export Citation
  • OjedaNBGrigoreDYanesLLIliescuRRobertsonEBZhangHAlexanderBT2007Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring. American Journal of Physiology. Regulatory Integrative and Comparative Physiology292R758R763. doi:10.1152/ajpregu.00311.2006.

    • Search Google Scholar
    • Export Citation
  • OrlicDKajsturaJChimentiSLimanaFJakoniukIQuainiFNadal-GinardBBodineDMLeriAAnversaP2001Mobilized bone marrow cells repair the infarcted heart, improving function and survival. PNAS981034410349. doi:10.1073/pnas.181177898.

    • Search Google Scholar
    • Export Citation
  • PlagerJE1965The binding of androsterone sulfate, ethiocholanolone sulfate, and dehydroisoandrosterone sulfate by human plasma protein. Journal of Clinical Investigation4412341239. doi:10.1172/JCI105229.

    • Search Google Scholar
    • Export Citation
  • PriceJFLeeAJFowkesFG1997Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study. Steroids62789794. doi:10.1016/S0039-128X(97)00103-7.

    • Search Google Scholar
    • Export Citation
  • QiuYYanaseTHuHTanakaTNishiYLiuMSueishiKSawamuraTNawataH2010Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology15133073316. doi:10.1210/en.2009-1268.

    • Search Google Scholar
    • Export Citation
  • RiggsBLKhoslaSMeltonLJIII2002Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews23279302. doi:10.1210/er.23.3.279.

    • Search Google Scholar
    • Export Citation
  • SatoTMatsumotoTYamadaTWatanabeTKawanoHKatoS2003Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochemical and Biophysical Research Communications300167171. doi:10.1016/S0006-291X(02)02774-2.

    • Search Google Scholar
    • Export Citation
  • SatoTMatsumotoTKawanoHWatanabeTUematsuYSekineKFukudaTAiharaKKrustAYamadaT2004Brain masculinization requires androgen receptor function. PNAS10116731678. doi:10.1073/pnas.0305303101.

    • Search Google Scholar
    • Export Citation
  • ScraggJLJonesRDChannerKSJonesTHPeersC2004Testosterone is a potent inhibitor of L-type Ca(2+) channels. Biochemical and Biophysical Research Communications318503506. doi:10.1016/j.bbrc.2004.04.054.

    • Search Google Scholar
    • Export Citation
  • ScraggJLDallasMLPeersC2007Molecular requirements for L-type Ca2+ channel blockade by testosterone. Cell Calcium421115. doi:10.1016/j.ceca.2006.11.003.

    • Search Google Scholar
    • Export Citation
  • SievekingDPChowRWNgMK2010aAndrogens, angiogenesis and cardiovascular regeneration. Current Opinion in Endocrinology Diabetes and Obesity17277283. doi:10.1097/MED.0b013e3283394e20.

    • Search Google Scholar
    • Export Citation
  • SievekingDPLimPChowRWDunnLLBaoSMcGrathKCHeatherAKHandelsmanDJCelermajerDSNgMK2010bA sex-specific role for androgens in angiogenesis. Journal of Experimental Medicine207345352. doi:10.1084/jem.20091924.

    • Search Google Scholar
    • Export Citation
  • SimonciniTGenazzaniAR2003Non-genomic actions of sex steroid hormones. European Journal of Endocrinology148281292. doi:10.1530/eje.0.1480281.

    • Search Google Scholar
    • Export Citation
  • SmithGDShipleyMJRoseG1990Intermittent claudication, heart disease risk factors, and mortality. The Whitehall Study. Circulation8219251931. doi:10.1161/01.CIR.82.6.1925.

    • Search Google Scholar
    • Export Citation
  • SnochowskiMDahlbergEGustafssonJA1980Characterization and quantification of the androgen and glucocorticoid receptors in cytosol from rat skeletal muscle. European Journal of Biochemistry111603616. doi:10.1111/j.1432-1033.1980.tb04977.x.

    • Search Google Scholar
    • Export Citation
  • SongDArikawaEGalipeauDBattellMMcNeillJH2004Androgens are necessary for the development of fructose-induced hypertension. Hypertension43667672. doi:10.1161/01.HYP.0000118018.77344.4e.

    • Search Google Scholar
    • Export Citation
  • StanworthRDJonesTH2009Testosterone in obesity, metabolic syndrome and type 2 diabetes. Frontiers of Hormone Research377490. doi:10.1159/000176046.

    • Search Google Scholar
    • Export Citation
  • TharpDLMasseauIIveyJGanjamVKBowlesDK2009Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine. Cardiovascular Research82152160. doi:10.1093/cvr/cvp038.

    • Search Google Scholar
    • Export Citation
  • TivestenAMellstromDJutbergerHFagerbergBLernfeltBOrwollEKarlssonMKLjunggrenOOhlssonC2007Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. Journal of the American College of Cardiology5010701076. doi:10.1016/j.jacc.2007.04.088.

    • Search Google Scholar
    • Export Citation
  • TivestenAVandenputLLabrieFKarlssonMKLjunggrenOMellstromDOhlssonC2009Low serum testosterone and estradiol predict mortality in elderly men. Journal of Clinical Endocrinology and Metabolism9424822488. doi:10.1210/jc.2008-2650.

    • Search Google Scholar
    • Export Citation
  • WeinbergEOThieneltCDKatzSEBartunekJTajimaMRohrbachSDouglasPSLorellBH1999Gender differences in molecular remodeling in pressure overload hypertrophy. Journal of the American College of Cardiology34264273. doi:10.1016/S0735-1097(99)00165-5.

    • Search Google Scholar
    • Export Citation
  • WilsonJD1999The role of androgens in male gender role behavior. Endocrine Reviews20726737. doi:10.1210/er.20.5.726.

  • WilsonEMFrenchFS1976Binding properties of androgen receptors. Evidence for identical receptors in rat testis, epididymis, and prostate. Journal of Biological Chemistry25156205629.

    • Search Google Scholar
    • Export Citation
  • YaronMGreenmanYRosenfeldJBIzkhakovELimorROsherEShenkermanGTordjmanKSternN2009Effect of testosterone replacement therapy on arterial stiffness in older hypogonadal men. European Journal of Endocrinology160839846. doi:10.1530/EJE-09-0052.

    • Search Google Scholar
    • Export Citation
  • YeapBBHydeZAlmeidaOPNormanPEChubbSAJamrozikKFlickerLHankeyGJ2009Lower testosterone levels predict incident stroke and transient ischemic attack in older men. Journal of Clinical Endocrinology and Metabolism9423532359. doi:10.1210/jc.2008-2416.

    • Search Google Scholar
    • Export Citation
  • YoshidaSAiharaKAzumaHUemotoRSumitomo-UedaYYagiSIkedaYIwaseTNishioSKawanoH2010Dehydroepiandrosterone sulfate is inversely associated with sex-dependent diverse carotid atherosclerosis regardless of endothelial function. Atherosclerosis212310315. doi:10.1016/j.atherosclerosis.2010.05.011.

    • Search Google Scholar
    • Export Citation
  • ZhangYStewartKGDavidgeST2000Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries. Hypertension36970974. doi:10.1161/01.HYP.36.6.970.

    • Search Google Scholar
    • Export Citation

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    Relationship between serum testosterone level and cardiovascular mortality in men. Reduced levels of endogenous testosterone worsen the mortality of cardiovascular disease in men, indicating that testosterone is a predictive factor of cardiovascular disease. (Modified from Khaw et al. (2007)).

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    Biological actions of androgens via ARs. Androgen binds to the AR. The liganded AR forms homodimers and moves it into the nucleus to bind to specific DNA elements referred to androgen-responsive elements in target gene promoters and regulates the target gene expression at the transcriptional level. This action of the AR is called genomic action. Androgen–AR also exerts its function without transcription by interaction with other signaling pathways. This action is called nongenomic action.

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    The AR system participates in physiological cardiac growth and inhibits angiotensin II-induced cardiovascular remodeling. (Modified from Ikeda et al. (2005, 2009)).

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    ARKO mice are susceptible to Dox-induced cardiotoxicity. (Upper panels) Echocardiography shows greater reduction of cardiac systolic function in Dox-treated ARKO mice than in Dox-treated WT mice. (Middle panels) Electron microscopy shows larger numbers of cardiac vacuoles and abnormal mitochondrial formation in Dox-treated ARKO mice. (Lower panels) Dox-induced cardiac superoxide production is accelerated in Dox-treated ARKO mice relative to Dox-treated WT mice. (Modified from Ikeda et al. (2010)).

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    Schematic diagram of cardiovascular-protective effects of ligand-bound AR.

  • AdamsMRWilliamsJKKaplanJR1995Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arteriosclerosis Thrombosis and Vascular Biology15562570. doi:10.1161/01.ATV.15.5.562.

    • Search Google Scholar
    • Export Citation
  • AkishitaMHashimotoMOhikeYOgawaSIijimaKEtoMOuchiY2007Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertension Research3010291034. doi:10.1291/hypres.30.1029.

    • Search Google Scholar
    • Export Citation
  • AkishitaMHashimotoMOhikeYOgawaSIijimaKEtoMOuchiY2010Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis210232236. doi:10.1016/j.atherosclerosis.2009.10.037.

    • Search Google Scholar
    • Export Citation
  • AlexandersenPHaarboJByrjalsenILawaetzHChristiansenC1999Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circulation Research84813819. doi:10.1161/01.RES.84.7.813.

    • Search Google Scholar
    • Export Citation
  • AnkerSDChuaTPPonikowskiPHarringtonDSwanJWKoxWJPoole-WilsonPACoatsAJ1997Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation96526534. doi:10.1161/01.CIR.96.2.526.

    • Search Google Scholar
    • Export Citation
  • AraujoABDixonJMSuarezEAMuradMHGueyLTWittertGA2011Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism9630073019. doi:10.1210/jc.2011-1137.

    • Search Google Scholar
    • Export Citation
  • BaltatuOCaylaCIliescuRAndreevDJordanCBaderM2002Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. Journal of the American Society of Nephrology1326812687. doi:10.1097/01.ASN.0000033327.65390.CA.

    • Search Google Scholar
    • Export Citation
  • BasariaSCovielloADTravisonTGStorerTWFarwellWRJetteAMEderRTennstedtSUlloorJZhangA2010Adverse events associated with testosterone administration. New England Journal of Medicine363109122. doi:10.1056/NEJMoa1000485.

    • Search Google Scholar
    • Export Citation
  • BourghardtJWilhelmsonASAlexandersonCDe GendtKVerhoevenGKrettekAOhlssonCTivestenA2010Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology15154285437. doi:10.1210/en.2010-0663.

    • Search Google Scholar
    • Export Citation
  • BurtVLCutlerJAHigginsMHoranMJLabartheDWheltonPBrownCRoccellaEJ1995Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension266069. doi:10.1161/01.HYP.26.1.60.

    • Search Google Scholar
    • Export Citation
  • CaiJHongYWengCTanCImperato-McGinleyJZhuYS2011Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism. American Journal of Physiology. Heart and Circulatory Physiology300H1210H1221. doi:10.1152/ajpheart.01210.2010.

    • Search Google Scholar
    • Export Citation
  • CalofOMSinghABLeeMLKennyAMUrbanRJTenoverJLBhasinS2005Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. Journals of Gerontology. Series A Biological Sciences and Medical Sciences6014511457. doi:10.1093/gerona/60.11.1451.

    • Search Google Scholar
    • Export Citation
  • CavasinMASankeySSYuALMenonSYangXP2003Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. American Journal of Physiology. Heart and Circulatory Physiology284H1560H1569. doi:10.1152/ajpheart.01087.2002.

    • Search Google Scholar
    • Export Citation
  • CefaluWTPardridgeWMChaudhuriGJuddHL1986Serum bioavailability and tissue metabolism of testosterone and estradiol in rat salivary gland. Journal of Clinical Endocrinology and Metabolism632028. doi:10.1210/jcem-63-1-20.

    • Search Google Scholar
    • Export Citation
  • ChambonCDuteilDVignaudAFerryAMessaddeqNMalivindiRKatoSChambonPMetzgerD2010Myocytic androgen receptor controls the strength but not the mass of limb muscles. PNAS1071432714332. doi:10.1073/pnas.1009536107.

    • Search Google Scholar
    • Export Citation
  • ChangCSKokontisJLiaoST1988aMolecular cloning of human and rat complementary DNA encoding androgen receptors. Science240324326. doi:10.1126/science.3353726.

    • Search Google Scholar
    • Export Citation
  • ChangCSKokontisJLiaoST1988bStructural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. PNAS8572117215. doi:10.1073/pnas.85.19.7211.

    • Search Google Scholar
    • Export Citation
  • CoronaGMonamiMBoddiVCameron-SmithMFisherADde VitaGMelaniCBalziDSforzaAFortiG2010Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. Journal of Sexual Medicine715571564. doi:10.1111/j.1743-6109.2009.01690.x.

    • Search Google Scholar
    • Export Citation
  • CriquiMH1986Epidemiology of atherosclerosis: an updated overview. American Journal of Cardiology5718C23C. doi:10.1016/0002-9149(86)91022-2.

    • Search Google Scholar
    • Export Citation
  • CriquiMHLangerRDFronekAFeigelsonHSKlauberMRMcCannTJBrownerD1992Mortality over a period of 10 years in patients with peripheral arterial disease. New England Journal of Medicine326381386. doi:10.1056/NEJM199202063260605.

    • Search Google Scholar
    • Export Citation
  • DingELSongYMalikVSLiuS2006Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. Journal of the American Medical Association29512881299. doi:10.1001/jama.295.11.1288.

    • Search Google Scholar
    • Export Citation
  • DockeryFRajkumarCAgarwalSWaxmanJBulpittCJ2000Androgen deprivation in males is associated with decreased central arterial compliance and reduced central systolic blood pressure. Journal of Human Hypertension14395397. doi:10.1038/sj.jhh.1001028.

    • Search Google Scholar
    • Export Citation
  • DockeryFBulpittCJAgarwalSDonaldsonMRajkumarC2003Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clinical Science104195201. doi:10.1042/CS20020209.

    • Search Google Scholar
    • Export Citation
  • DormandyJARutherfordRB2000Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). Journal of Vascular Surgery31S1S296. doi:10.1016/S0741-5214(00)81002-2.

    • Search Google Scholar
    • Export Citation
  • DunnJFNisulaBCRodbardD1981Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. Journal of Clinical Endocrinology and Metabolism535868. doi:10.1210/jcem-53-1-58.

    • Search Google Scholar
    • Export Citation
  • van EickelsMGroheCCleutjensJPJanssenBJWellensHJDoevendansPA200117β-Estradiol attenuates the development of pressure-overload hypertrophy. Circulation10414191423. doi:10.1161/hc3601.095577.

    • Search Google Scholar
    • Export Citation
  • FanWYanaseTNomuraMOkabeTGotoKSatoTKawanoHKatoSNawataH2005Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes5410001008. doi:10.2337/diabetes.54.4.1000.

    • Search Google Scholar
    • Export Citation
  • FanWYanaseTNishiYChibaSOkabeTNomuraMYoshimatsuHKatoSTakayanagiRNawataH2008Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor. Endocrinology14960286036. doi:10.1210/en.2008-0431.

    • Search Google Scholar
    • Export Citation
  • Fernandez-BalsellsMMMuradMHLaneMLampropulosJFAlbuquerqueFMullanRJAgrwalNElaminMBGallegos-OrozcoJFWangAT2010Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism9525602575. doi:10.1210/jc.2009-2575.

    • Search Google Scholar
    • Export Citation
  • FogariRPretiPZoppiAFogariERinaldiACorradiLMugelliniA2005Serum testosterone levels and arterial blood pressure in the elderly. Hypertension Research28625630. doi:10.1291/hypres.28.625.

    • Search Google Scholar
    • Export Citation
  • GiustiGGonnelliPBorrelliDFiorelliGFortiGPazzagliMSerioM1975Age-related secretion of androstenedione, testosterone and dihydrotestosterone by the human testis. Experimental Gerontology10241245. doi:10.1016/0531-5565(75)90001-7.

    • Search Google Scholar
    • Export Citation
  • GoldenKLMarshJDJiangYBrownTMouldenJ2003Gonadectomy of adult male rats reduces contractility of isolated cardiac myocytes. American Journal of Physiology. Endocrinology and Metabolism285E449E453. doi:10.1152/ajpendo.00054.2003.

    • Search Google Scholar
    • Export Citation
  • GroheCKahlertSLobbertKStimpelMKarasRHVetterHNeysesL1997Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Letters416107112. doi:10.1016/S0014-5793(97)01179-4.

    • Search Google Scholar
    • Export Citation
  • GroheCKahlertSLobbertKVetterH1998Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. Journal of Endocrinology156R1R7. doi:10.1677/joe.0.156R001.

    • Search Google Scholar
    • Export Citation
  • GrossmannM2011Low testosterone in men with type 2 diabetes: significance and treatment. Journal of Clinical Endocrinology and Metabolism9623412353. doi:10.1210/jc.2011-0118.

    • Search Google Scholar
    • Export Citation
  • HaddadRMKennedyCCCaplesSMTraczMJBolonaERSiderasKUragaMVErwinPJMontoriVM2007Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proceedings822939. doi:org/10.4065/82.1.29.

    • Search Google Scholar
    • Export Citation
  • HallJJonesRDJonesTHChannerKSPeersC2006Selective inhibition of L-type Ca2+ channels in A7r5 cells by physiological levels of testosterone. Endocrinology14726752680. doi:10.1210/en.2005-1243.

    • Search Google Scholar
    • Export Citation
  • HankeHLenzCHessBSpindlerKDWeidemannW2001Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation10313821385. doi:10.1161/01.CIR.103.10.1382.

    • Search Google Scholar
    • Export Citation
  • HeinleinCAChangC2002The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Molecular Endocrinology1621812187. doi:10.1210/me.2002-0070.

    • Search Google Scholar
    • Export Citation
  • HorwitzKBHorwitzLD1982Canine vascular tissues are targets for androgens, estrogens, progestins, and glucocorticoids. Journal of Clinical Investigation69750758. doi:10.1172/JCI110513.

    • Search Google Scholar
    • Export Citation
  • IkedaYAiharaKSatoTAkaikeMYoshizumiMSuzakiYIzawaYFujimuraMHashizumeSKatoM2005Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. Journal of Biological Chemistry2802966129666. doi:10.1074/jbc.M411694200.

    • Search Google Scholar
    • Export Citation
  • IkedaYAiharaKYoshidaSSatoTYagiSIwaseTSumitomoYIseTIshikawaKAzumaH2009Androgen-androgen receptor system protects against angiotensin II-induced vascular remodeling. Endocrinology15028572864. doi:10.1210/en.2008-1254.

    • Search Google Scholar
    • Export Citation
  • IkedaYAiharaKAkaikeMSatoTIshikawaKIseTYagiSIwaseTUedaYYoshidaS2010Androgen receptor counteracts doxorubicin-induced cardiotoxicity in male mice. Molecular Endocrinology2413381348. doi:10.1210/me.2009-0402.

    • Search Google Scholar
    • Export Citation
  • JankowskaEADrohomireckaAPonikowskaBWitkowskaALopuszanskaMSzklarskaABorodulin-NadziejaLBanasiakWPoole-WilsonPAPonikowskiP2010Deficiencies in circulating testosterone and dehydroepiandrosterone sulphate, and depression in men with systolic chronic heart failure. European Journal of Heart Failure12966973. doi:10.1093/eurjhf/hfq108.

    • Search Google Scholar
    • Export Citation
  • KalinMFZumoffB1990Sex hormones and coronary disease: a review of the clinical studies. Steroids55330352. doi:10.1016/0039-128X(90)90058-J.

    • Search Google Scholar
    • Export Citation
  • KawanoHSatoTYamadaTMatsumotoTSekineKWatanabeTNakamuraTFukudaTYoshimuraKYoshizawaT2003Suppressive function of androgen receptor in bone resorption. PNAS10094169421. doi:10.1073/pnas.1533500100.

    • Search Google Scholar
    • Export Citation
  • KhawKTDowsettMFolkerdEBinghamSWarehamNLubenRWelchADayN2007Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation11626942701. doi:10.1161/CIRCULATIONAHA.107.719005.

    • Search Google Scholar
    • Export Citation
  • KiilavuoriKNaveriHLeinonenHHarkonenM1999The effect of physical training on hormonal status and exertional hormonal response in patients with chronic congestive heart failure. European Heart Journal20456464. doi:10.1053/euhj.1998.1277.

    • Search Google Scholar
    • Export Citation
  • KoizumiHYuJHashimotoROuchiYOkabeT2010Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. FEBS Letters58424402444. doi:10.1016/j.febslet.2010.04.049.

    • Search Google Scholar
    • Export Citation
  • KontoleonPEAnastasiou-NanaMIPapapetrouPDAlexopoulosGKtenasVRaptiACTsagalouEPNanasJN2003Hormonal profile in patients with congestive heart failure. International Journal of Cardiology87179183. doi:10.1016/S0167-5273(02)00212-7.

    • Search Google Scholar
    • Export Citation
  • KousteniSChenJRBellidoTHanLAliAAO'BrienCAPlotkinLFuQMancinoATWenY2002Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science298843846. doi:10.1126/science.1074935.

    • Search Google Scholar
    • Export Citation
  • LaughlinGABarrett-ConnorEBergstromJ2008Low serum testosterone and mortality in older men. Journal of Clinical Endocrinology and Metabolism936875. doi:10.1210/jc.2007-1792.

    • Search Google Scholar
    • Export Citation
  • LiYKishimotoISaitoYHaradaMKuwaharaKIzumiTHamanakaITakahashiNKawakamiRTanimotoK2004Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology145951958. doi:10.1210/en.2003-0816.

    • Search Google Scholar
    • Export Citation
  • LinALMcGillHCJrShainSA1981Hormone receptors of the baboon cardiovascular system. Biochemical characterization of aortic and myocardial cytoplasmic androgen receptors. Circulation Research4910101016. doi:10.1161/01.RES.49.4.1010.

    • Search Google Scholar
    • Export Citation
  • LoselRMFalkensteinEFeuringMSchultzATillmannHCRossol-HaserothKWehlingM2003Nongenomic steroid action: controversies, questions, and answers. Physiological Reviews839651016. doi:10.1152/physrev.00003.2003.

    • Search Google Scholar
    • Export Citation
  • LosordoDWIsnerJM2001Estrogen and angiogenesis: a review. Arteriosclerosis Thrombosis and Vascular Biology21612. doi:10.1161/01.ATV.21.1.6.

    • Search Google Scholar
    • Export Citation
  • MakinenJJarvisaloMJPollanenPPerheentupaAIrjalaKKoskenvuoMMakinenJHuhtaniemiIRaitakariOT2005Increased carotid atherosclerosis in andropausal middle-aged men. Journal of the American College of Cardiology4516031608. doi:10.1016/j.jacc.2005.01.052.

    • Search Google Scholar
    • Export Citation
  • MalhotraAButtrickPScheuerJ1990Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. American Journal of Physiology259H866H871.

    • Search Google Scholar
    • Export Citation
  • MalkinCJPughPJWestJNvan BeekEJJonesTHChannerKS2006Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. European Heart Journal275764. doi:10.1093/eurheartj/ehi443.

    • Search Google Scholar
    • Export Citation
  • MalkinCJPughPJMorrisPDAsifSJonesTHChannerKS2010Low serum testosterone and increased mortality in men with coronary heart disease. Heart9618211825. doi:10.1136/hrt.2010.195412.

    • Search Google Scholar
    • Export Citation
  • MarshJDLehmannMHRitchieRHGwathmeyJKGreenGESchiebingerRJ1998Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation98256261. doi:10.1161/01.CIR.98.3.256.

    • Search Google Scholar
    • Export Citation
  • MartinDSBiltoftSRedetzkeRVogelE2005Castration reduces blood pressure and autonomic venous tone in male spontaneously hypertensive rats. Journal of Hypertension2322292236. doi:10.1097/01.hjh.0000191903.19230.79.

    • Search Google Scholar
    • Export Citation
  • Martin-MerinoEJohanssonSMorrisTGarcia RodriguezLA2011Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a Nested Case–Control Study in UK Primary Care. Drug Safety3410611077. doi:10.2165/11594540-000000000-00000.

    • Search Google Scholar
    • Export Citation
  • McCrohonJAJessupWHandelsmanDJCelermajerDS1999Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1. Circulation9923172322. doi:10.1161/01.CIR.99.17.2317.

    • Search Google Scholar
    • Export Citation
  • McGillHCJrAnselmoVCBuchananJMSheridanPJ1980The heart is a target organ for androgen. Science207775777. doi:10.1126/science.6766222.

  • MiyamotoJMatsumotoTShiinaHInoueKTakadaIItoSItohJMinematsuTSatoTYanaseT2007The pituitary function of androgen receptor constitutes a glucocorticoid production circuit. Molecular and Cellular Biology2748074814. doi:10.1128/MCB.02039-06.

    • Search Google Scholar
    • Export Citation
  • MooradianADMorleyJEKorenmanSG1987Biological actions of androgens. Endocrine Reviews8128. doi:10.1210/edrv-8-1-1.

  • MoranoIGerstnerJRueggJCGantenUGantenDVosbergHP1990Regulation of myosin heavy chain expression in the hearts of hypertensive rats by testosterone. Circulation Research6615851590. doi:10.1161/01.RES.66.6.1585.

    • Search Google Scholar
    • Export Citation
  • MoriyamaYYasueHYoshimuraMMizunoYNishiyamaKTsunodaRKawanoHKugiyamaKOgawaHSaitoY2000The plasma levels of dehydroepiandrosterone sulfate are decreased in patients with chronic heart failure in proportion to the severity. Journal of Clinical Endocrinology and Metabolism8518341840. doi:10.1210/jc.85.5.1834.

    • Search Google Scholar
    • Export Citation
  • MullerMvan den BeldAWBotsMLGrobbeeDELambertsSWvan der SchouwYT2004Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation10920742079. doi:10.1161/01.CIR.0000125854.51637.06.

    • Search Google Scholar
    • Export Citation
  • MurabitoJMEvansJCLarsonMGNietoKLevyDWilsonPW2003The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study. Archives of Internal Medicine16319391942. doi:10.1001/archinte.163.16.1939.

    • Search Google Scholar
    • Export Citation
  • NaitoASatoTMatsumotoTTakeyamaKYoshinoTKatoSOhderaM2008Dihydrotestosterone inhibits murine hair growth via the androgen receptor. British Journal of Dermatology159300305. doi:10.1111/j.1365-2133.2008.08671.x.

    • Search Google Scholar
    • Export Citation
  • NettleshipJEJonesTHChannerKSJonesRD2007Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor. Circulation11624272434. doi:10.1161/CIRCULATIONAHA.107.708768.

    • Search Google Scholar
    • Export Citation
  • NgMKQuinnCMMcCrohonJANakhlaSJessupWHandelsmanDJCelermajerDSDeathAK2003Androgens up-regulate atherosclerosis-related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis. Journal of the American College of Cardiology4213061313. doi:10.1016/j.jacc.2003.07.002.

    • Search Google Scholar
    • Export Citation
  • NheuLNazarethLXuGYXiaoFYLuoRZKomesaroffPLingS2011Physiological effects of androgens on human vascular endothelial and smooth muscle cells in culture. Steroids7615901596. doi:10.1016/j.steroids.2011.09.015.

    • Search Google Scholar
    • Export Citation
  • OjedaNBGrigoreDYanesLLIliescuRRobertsonEBZhangHAlexanderBT2007Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring. American Journal of Physiology. Regulatory Integrative and Comparative Physiology292R758R763. doi:10.1152/ajpregu.00311.2006.

    • Search Google Scholar
    • Export Citation
  • OrlicDKajsturaJChimentiSLimanaFJakoniukIQuainiFNadal-GinardBBodineDMLeriAAnversaP2001Mobilized bone marrow cells repair the infarcted heart, improving function and survival. PNAS981034410349. doi:10.1073/pnas.181177898.

    • Search Google Scholar
    • Export Citation
  • PlagerJE1965The binding of androsterone sulfate, ethiocholanolone sulfate, and dehydroisoandrosterone sulfate by human plasma protein. Journal of Clinical Investigation4412341239. doi:10.1172/JCI105229.

    • Search Google Scholar
    • Export Citation
  • PriceJFLeeAJFowkesFG1997Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study. Steroids62789794. doi:10.1016/S0039-128X(97)00103-7.

    • Search Google Scholar
    • Export Citation
  • QiuYYanaseTHuHTanakaTNishiYLiuMSueishiKSawamuraTNawataH2010Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology15133073316. doi:10.1210/en.2009-1268.

    • Search Google Scholar
    • Export Citation
  • RiggsBLKhoslaSMeltonLJIII2002Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews23279302. doi:10.1210/er.23.3.279.

    • Search Google Scholar
    • Export Citation
  • SatoTMatsumotoTYamadaTWatanabeTKawanoHKatoS2003Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochemical and Biophysical Research Communications300167171. doi:10.1016/S0006-291X(02)02774-2.

    • Search Google Scholar
    • Export Citation
  • SatoTMatsumotoTKawanoHWatanabeTUematsuYSekineKFukudaTAiharaKKrustAYamadaT2004Brain masculinization requires androgen receptor function. PNAS10116731678. doi:10.1073/pnas.0305303101.

    • Search Google Scholar
    • Export Citation
  • ScraggJLJonesRDChannerKSJonesTHPeersC2004Testosterone is a potent inhibitor of L-type Ca(2+) channels. Biochemical and Biophysical Research Communications318503506. doi:10.1016/j.bbrc.2004.04.054.

    • Search Google Scholar
    • Export Citation
  • ScraggJLDallasMLPeersC2007Molecular requirements for L-type Ca2+ channel blockade by testosterone. Cell Calcium421115. doi:10.1016/j.ceca.2006.11.003.

    • Search Google Scholar
    • Export Citation
  • SievekingDPChowRWNgMK2010aAndrogens, angiogenesis and cardiovascular regeneration. Current Opinion in Endocrinology Diabetes and Obesity17277283. doi:10.1097/MED.0b013e3283394e20.

    • Search Google Scholar
    • Export Citation
  • SievekingDPLimPChowRWDunnLLBaoSMcGrathKCHeatherAKHandelsmanDJCelermajerDSNgMK2010bA sex-specific role for androgens in angiogenesis. Journal of Experimental Medicine207345352. doi:10.1084/jem.20091924.

    • Search Google Scholar
    • Export Citation
  • SimonciniTGenazzaniAR2003Non-genomic actions of sex steroid hormones. European Journal of Endocrinology148281292. doi:10.1530/eje.0.1480281.

    • Search Google Scholar
    • Export Citation
  • SmithGDShipleyMJRoseG1990Intermittent claudication, heart disease risk factors, and mortality. The Whitehall Study. Circulation8219251931. doi:10.1161/01.CIR.82.6.1925.

    • Search Google Scholar
    • Export Citation
  • SnochowskiMDahlbergEGustafssonJA1980Characterization and quantification of the androgen and glucocorticoid receptors in cytosol from rat skeletal muscle. European Journal of Biochemistry111603616. doi:10.1111/j.1432-1033.1980.tb04977.x.

    • Search Google Scholar
    • Export Citation
  • SongDArikawaEGalipeauDBattellMMcNeillJH2004Androgens are necessary for the development of fructose-induced hypertension. Hypertension43667672. doi:10.1161/01.HYP.0000118018.77344.4e.

    • Search Google Scholar
    • Export Citation
  • StanworthRDJonesTH2009Testosterone in obesity, metabolic syndrome and type 2 diabetes. Frontiers of Hormone Research377490. doi:10.1159/000176046.

    • Search Google Scholar
    • Export Citation
  • TharpDLMasseauIIveyJGanjamVKBowlesDK2009Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine. Cardiovascular Research82152160. doi:10.1093/cvr/cvp038.

    • Search Google Scholar
    • Export Citation
  • TivestenAMellstromDJutbergerHFagerbergBLernfeltBOrwollEKarlssonMKLjunggrenOOhlssonC2007Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. Journal of the American College of Cardiology5010701076. doi:10.1016/j.jacc.2007.04.088.

    • Search Google Scholar
    • Export Citation
  • TivestenAVandenputLLabrieFKarlssonMKLjunggrenOMellstromDOhlssonC2009Low serum testosterone and estradiol predict mortality in elderly men. Journal of Clinical Endocrinology and Metabolism9424822488. doi:10.1210/jc.2008-2650.

    • Search Google Scholar
    • Export Citation
  • WeinbergEOThieneltCDKatzSEBartunekJTajimaMRohrbachSDouglasPSLorellBH1999Gender differences in molecular remodeling in pressure overload hypertrophy. Journal of the American College of Cardiology34264273. doi:10.1016/S0735-1097(99)00165-5.

    • Search Google Scholar
    • Export Citation
  • WilsonJD1999The role of androgens in male gender role behavior. Endocrine Reviews20726737. doi:10.1210/er.20.5.726.

  • WilsonEMFrenchFS1976Binding properties of androgen receptors. Evidence for identical receptors in rat testis, epididymis, and prostate. Journal of Biological Chemistry25156205629.

    • Search Google Scholar
    • Export Citation
  • YaronMGreenmanYRosenfeldJBIzkhakovELimorROsherEShenkermanGTordjmanKSternN2009Effect of testosterone replacement therapy on arterial stiffness in older hypogonadal men. European Journal of Endocrinology160839846. doi:10.1530/EJE-09-0052.

    • Search Google Scholar
    • Export Citation
  • YeapBBHydeZAlmeidaOPNormanPEChubbSAJamrozikKFlickerLHankeyGJ2009Lower testosterone levels predict incident stroke and transient ischemic attack in older men. Journal of Clinical Endocrinology and Metabolism9423532359. doi:10.1210/jc.2008-2416.

    • Search Google Scholar
    • Export Citation
  • YoshidaSAiharaKAzumaHUemotoRSumitomo-UedaYYagiSIkedaYIwaseTNishioSKawanoH2010Dehydroepiandrosterone sulfate is inversely associated with sex-dependent diverse carotid atherosclerosis regardless of endothelial function. Atherosclerosis212310315. doi:10.1016/j.atherosclerosis.2010.05.011.

    • Search Google Scholar
    • Export Citation
  • ZhangYStewartKGDavidgeST2000Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries. Hypertension36970974. doi:10.1161/01.HYP.36.6.970.

    • Search Google Scholar
    • Export Citation