Journal of Andrology & Gynaecology
Erectile Dysfunction and Cardiovascular Disease: A Review
Charles N Walker1*, Stephanie M Meller2, Erik Stilp3, and Carlos Mena-Hurtado3
- 1Yale University School of Medicine, Department of Surgery, Section of Urology, USA
- 2Yale University School of Medicine, New Haven, CT, USA
- 3Yale University School of Medicine, Department of Internal Medicine, Section of Cardiovascular Medicine, USA
*Address for Correspondence: Charles Walker, MD, Yale University School of Medicine, Departmentof Urology, 789 Howard Avenue, FMP 323, New Haven, CT 06519, USA, E-mail: email@example.com
Citation: Walker CN, Meller SM, Stilp E, Mena-Hurtado C. Erectile Dysfunction and Cardiovascular Disease: A Review. J Androl Gynaecol. 2013;1(2): 10.
Copyright © 2013 Walker CN, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Andrology & Gynaecology |ISSN: 2332-3442 | Volume: 1, Issue: 2
Submission: 26 August 2013 | Accepted: 07 October 2013 | Published: 10 October 2013
AbstractErectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection for satisfactory sexual performance and it is estimated that >300 million men will suffer from this condition in 2025. ED is recognized as a harbinger of cardiovascular disease. Endothelial dysfunction and macrovascular atherosclerotic disease together represent the probable pathophysiological link between vasculogenic ED, coronary artery disease (CAD) and peripheral vascular disease (PAD), and research in these common areas in recent years has led to the emergence of a compelling body of evidence to support erectile dysfunction as the sentinel clinical event. The bidirectional relationship between low testosterone and components of metabolic syndrome (MetS) supports the conclusion that normal sex hormone production is an integral component for both metabolic and sexual health for the development of subsequent cardiac events and an improvement in overall health.
Keywords: Erectile Dysfunction; Cardiovascular Disease; Endothelial Dysfunction, Risk
IntroductionDespite its early description and documentation in 1948, erectile dysfunction (ED) has only been recognized as an organic failure of the normal neurovascular function of the penis within the past 2 to 3 decades . Defined as the inability to achieve or maintain a penile erection for satisfactory sexual performance, ED affects >50% of men aged 40 to 70 years and 70% of men aged 70 years or older [2,3]. Moreover, the prevalence increases with age and is expected to further rise, potentially affecting over 300 million men worldwide by the year 2025 . Organic, vasculogenic ED can result from aberrations in arterial and venous flow, endothelial and cavernosal smooth muscle function, and tunica albuginea compliance. The most common form of vascular ED results from penile arterial insufficiency, which will serve as the main focus for this review. Atherosclerotic occlusion or narrowing of the common iliac arteries, internal iliac arteries, and the internal pudendal arteries and their downstream branches may cause ED. Chronic arteriolar insufficiency leads to diminished neuronal and endothelial nitrous oxide (NO), and therefore causes impaired cavernosal smooth muscle relaxation resulting in ED.
The Relationship between Erectile Dysfunction and Cardiovascular DiseaseThe Massachusetts Male Aging Study established the association between ED and CAD, demonstrating a 39% probability of complete ED in men with heart disease and subsequent studies have shown rates of ED in patients with CAD as high as 75% [2,8,9].
Early impairment of endothelial dependent vasodilation has been shown in both vasculogenic ED and CAD. Without bioavailable NO, the vascular smooth muscle fails to relax and impedes vasodilation, necessary for erectile function. Kaiser et al. evaluated flow mediated vasodilation of the brachial artery in men with vasculogenic ED, as confirmed by penile Doppler, compared to age matched controls without ED. Men with ED had significantly impaired brachial artery vasodilation comparable to that seen in men with hyperlipidemia and early atherosclerotic disease. Treatment with PDE-5 inhibitors led to improvement in ED suggesting that the impairment in vasodilation involves the NO-cGMP system. Responsiveness to sublingual nitroglycerin was also reduced suggesting that the defect directly involves smooth muscle. That the impairment of vasodilation was shown to be both endothelium dependent and independent in this study is consistent with both a defect in eNOS bioavailability and intrinsic dysfunction of the smooth muscle. The authors concluded that in addition to the artery size hypothesis, a very plausible explanation for the manifestation of ED before other forms of vascular disease is the dependence of the penile vasculature on NO for vasodilation to a degree much greater than is seen in other vascular beds .
In patients with CAD and PAD, common cardiovascular risk factors create a pro-inflammatory, highly oxidative stressful state that stimulates free radical formation and atherogenesis leading to impaired NO release in such vascular beds. Similarly, obesity, diabetes, and MetS represent chronic inflammatory states and have been shown to damage the vascular endothelium and impair NO release in men with ED [39-41]. Men with obesity have been found to have impairment in multiple indices of endothelial function and significantly elevated levels of C-reactive protein . In other studies recombinant C- reactive protein has been shown to downregulate endothelial NO and to promote endothelial apoptosis . In a study of overweight patients with ED and without clinical evidence of DM, peripheral vascular disease, or CAD, circulating levels of endothelial progenitor cells (EPC) were reduced as compared to matched controls without ED, the extent of which correlated with severity of ED. Reduced levels of EPC, shown to be an independent predictor of cardiovascular disease, were also shown to independently predict ED in multivariate analysis . Free radical formation, in addition to reducing bioavailability of NO, also potentiates atherosclerosis through direct damage to the endothelium. NO inhibits plateletaggregation and adhesion and smooth muscle proliferation. Thus reduced bioavailability of NO is associated with vasoconstriction, platelet adhesion, and smooth muscle cell proliferation, which further the atherosclerotic burden of the penile vasculature .
Further evidence for the role of endothelial dysfunction in ED comes from studies in diabetic men with ED and in animal models. A comparative study on corpus cavernosal and penile resistance arterial tissue from diabetic and non-diabetic men with ED demonstrated that the functional deficiency of NO found in men with ED is exacerbated in diabetes, which correlates with impaired endotheliumdependent relaxation in these patients . Platelet aggregation and blood pressure response to L-arginine administration, surrogates for endothelial function, are believed to be mediated by NO, and have been shown to be lower in diabetic men with ED compared to diabetic patients without ED . In addition, patients with ED have higher levels of asymmetric dimethylarginine, a known inhibitor of eNOS . Insulin-like growth factor binding protein, which regulates the availability of insulin-like growth factor (IGF-1), is increased in hyperglycemic rats. Treatment with IGF-1 results in improvement in rat intracavernosal pressure and expression of endothelial NOsynthase [49-51] . Further evidence for the role of insulin resistance on endothelial NO production comes from the observation in obese rats that metformin administration induces eNos expression in penile tissue, via activated protein kinase .
Independent of NO regulation, there is evidence for the role of endothelin-1 in endothelial dysfunction in diabetes. Insulin stimulates production of endothelin-1, a potent vasoconstrictor, and NO in vascular endothelium. In non-diabetic individuals the vasodilatory effects of NO predominate; however, in insulin resistant states this does not occur. Accordingly, preservation of endothelin in the face of impaired nitric oxide production has been demonstrated in insulin resistant states .
Testosterone Deficiency, Metabolic Syndrome, and EDThe relationship between testosterone deficiency and the MetS is significant and bidirectional . Testosterone deficiency has been shown to be independently associated with the MetS as well as individual components of the syndrome. The two processes are tied by a number of shared pathophysiologic pathways including insulin resistance, hyperglycemia, dyslipidemia, visceral fat accumulation, inflammation, and endothelial dysfunction (Figure 3). Evidence for this comes from studies demonstrating that low levels of total testosterone in patients with ED have been associated with higher BMI, waist circumference, MetS, and insulin resistance, and treatment with testosterone can reduce central adiposity and insulin resistance [6,54,55]. In a prospective study of 1709 men, Kupelian et al. showed that low levels of total testosterone sex hormone binding globulin and symptomatic androgen deficiency were predictive of developing MetS with a RR of 1.41, 1.65, and 2.51 respectively . The reciprocal nature of the relationship between the MetS and low testosterone is supported by a study of aging adults with low testosterone the results of which suggest a causative role for MetS in the development of hypogonadism . Components of the MetS may directly promote hypogonadism through a number of mechanisms including decreased production of testosterone by Leydig cells, which is mediated by increased leptin levels in obesity. Visceral obesity and diabetes are both pro-inflammatory states and the production of a number of inflammatory cytokines have been shown to directly inhibit testosterone production, specifically TNF-α . Central obesity leads to increased aromatase activity resulting in conversion of testosterone to increased levels of estradiol (E2), which suppresses LH release through hypothalamic negative feedback resulting in a functional state of hypogonadotropic hypogonadism .
The role that testosterone deficiency plays in the evolution of both ED and CAD remains complex and controversial and while a full investigation of this subject is beyond the scope of this review, the topic is worthy of further discussion. It is generally well accepted that libido, frequency of sexual activity, and spontaneous (morning, nocturnal) erections are all testosterone dependent. Support for this comes from studies on hypogonadal men treated with testosterone replacement therapy . Testosterone exerts its effects on erectile function in a number of ways. Centrally, testosterone acts directly on supraspinal centers of sexual function in the preoptic area and paraventricular nucleus of the hypothalamus, where it stimulates the production and release of erectogenic neurotransmitters, such a dopamine and oxytocin. Peripherally, testosterone is required for the normal function of sacral spinal neurons involved in reflexogenic erections and it regulates parasympathetic nerves in corpus cavernosum. Animal studies have shown that testosterone regulates the production of both endothelial and neuronal nitric oxide synthases and androgen suppression has been shown to cause significant reduction in both NOS activity and that of cGMP in the corpus cavernosum [60,61].
Testosterone is also directly required for maintenance of the integrity of both the endothelium and the smooth muscle. Low testosterone is associated with impaired flow mediated vasodilation, a surrogate for endothelial dysfunction . In animal models of castration, atrophy and fibrosis of corporal cavernosal tissue is found to be in part due to the reduction of trabecular smooth muscle content and an increase in components of extracellular matrix . Androgen withdrawal also leads to apoptosis of corporal cavernosal smooth muscle . Animal models and human studies have shown that PDE5 expression is also regulated by testosterone [64,65]. In hypogonadal men with ED that is refractory to PDE5 inhibitors, supplementation with testosterone have been shown to improve erectile function and increase penile arterial flow as indicated by increased cavernosal peak systolic velocities [66,67]. Further evidence for the role of testosterone in the maintenance of normal erectile physiology comes from animal studies showing relaxation of corporal smooth muscle after treatment with testosterone .
Clinically, low levels of total and bioavailable testosterone have been associated with erectile dysfunction . Low testosterone is associated with both hypoactive desire and erectile dysfunction in a dose dependent fashion such that impairment of sexual function is seen when testosterone levels drop below the lower limit of the normal adult range . Corona and colleagues found in their study of 1647 men that low testosterone levels were associated with the severity of ED and the magnitude of penile blood flow .
However, reports of the prevalence of hypogonadism in men with ED are variable in the literature and depend in part on the threshold of testosterone used, whether total testosterone (TT), free testosterone (FT) or bioavailable testosterone (BT) are used to determine prevalence as well as whether or not determinations of testosterone are repeated. Assessment of total testosterone in men with ED reveals a prevalence of hypogonadism between 5-15% with rates of 20-40% being found when determinations of free and bioavailable testosterone are used [71-73]. Threshold levels of testosterone for impairment of sexual function are highly variable between individuals. Consequently there is no standardized lower limit of testosterone, however several definitions have been proposed. The lower limit of normal for total testosterone accepted by the FDA is 300 ng/dL while the recommendation from a 2007 position paper by the Endocrine Society is a testosterone level of < 200 ng/ml (6.9 nM) . For practical purposes the determination of hypogonadism depends on both the determination of testosterone below a threshold level and the presence of symptoms, including reduced sexual drive, impotence, infertility, fatigue, depression or irritability, decreased bone density, loss of lean muscle mass, anemia, and increased body fat.
Both the production and bioavailability of testosterone are reduced with aging at a rate of 0.5%-2% per year [75-78].
ED, Low Testosterone, and Cardiovascular MortalityGiven the extent of the association between low testosterone, MetS, endothelial dysfunction, ED, and CVD, it is not surprising that both low testosterone and ED are independent predictors of increased cardiovascular mortality . The relationship between ED and mortality has been demonstrated in a number of studies. Vlachopoulos et al. in their meta-analysis of 14 cohort studies found a RR of 1.19 and 1.23 for cardiovascular and all cause mortality respectively in men with ED . In their meta-analysis of 7 cohort studies of Guo et al. also found that men with ED were at increased risk for all cause mortality with a RR of 1.23 though only two studies reported information on all cause mortality . In a case control study of 291 diabetic men with angiographically confirmed silent CAD, ED significantly predicted an increased risk for major cardiac event defined as CAD Death, sudden death, nonfatal myocardial infarction, death due to congestive heart failure, unstable angina, need for repeat revascularization, stroke or TIA, and symptomatic peripheral artery disease with a hazard ratio of 2.1 .
The Role of Risk ModificationA Selective phosphodiesterase type 5 (PDE-5) inhibitors (sildenafil, vardenafil, and tadalafil) enhance NO-mediated relaxation of the corpus cavernosum via increased intracavernosal cGMP levels, resulting in erection initiation and maintenance . Given their ease of use and excellent safety profile, PDE-5 inhibitors are recommended as first line drug therapy; however, these drugs demonstrate lower response rates in older men. The reasons for this age discrepancy include an age-associated decrease in endogenous NO production, which is further diminished by other comorbidities . Of the 30-40% of patients who do not initially respond, counseling and daily low-dose administration may be helpful, and in men with low testosterone, testosterone replacement therapy has been shown to improve response to PDE-5 inhibitor therapy by increasing the bioavailable NO in the cavernous smooth muscle tissue .
Guidelines for Management of the Patient with ED and No Evidence of Cardiovascular DiseaseThe accumulation of evidence supporting ED as a predictor of CAD indicates that ED and hypogonadism should serve as potential warning signs of future cardiovascular disease . As proposed by Miner et al., a “window of curability” may exist in which treatment may stop the progression of cardiovascular disease and potentially ED, especially in men < 60 years old, where the cardiovascular risk portended by ED appears to be especially high [53,112].
ConclusionThe link between vasculogenic ED and CVD is well supported by the literature and very likely indicates that the disease processes are distinct manifestations of the same atherosclerotic process. ED may be the first overt manifestation of potentially serious cardiovascular disease. Because vasculogenic ED typically presents earlier than CVD, clinicians should recognize the condition as an early warning sign of future cardiovascular pathology particularly in diabetic men.
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