**2. Causes of erectile dysfunction**

ED arises as a result of a collision of many factors: physical, psychological, physiological and biochemical abnormalities. The exact cause of ED is usually difficult to establish because it normally results from an underlying condition such as diabetes and/or heart disease. ED can also be caused by psychological conditions such as stress, depression and anxiety [5]. The physiological mechanism of erection is a complex neurovascular phenomenon that depends on neural, vascular, hormonal, and psychological factors. Integrated function of these factors is essential for production of a normal erectile response [3]. Recent advances in the under‐ standing of functional anatomy and of neurovascular interactions have improved our under‐ standing of the pathophysiological mechanism of ED [3].

**Figure 1.** Possible causes, managements and treatment strategies of Erectile Dysfunction

### **2.1. Aging**

known vascular disease [4]. Nevertheless, the hypothesis that ED, as a manifestation of autonomic neuropathy, may be linked with the lack of symptoms in a proportion of diabetic

ED arises as a result of a collision of many factors: physical, psychological, physiological and biochemical abnormalities. The exact cause of ED is usually difficult to establish because it normally results from an underlying condition such as diabetes and/or heart disease. ED can also be caused by psychological conditions such as stress, depression and anxiety [5]. The physiological mechanism of erection is a complex neurovascular phenomenon that depends on neural, vascular, hormonal, and psychological factors. Integrated function of these factors is essential for production of a normal erectile response [3]. Recent advances in the under‐ standing of functional anatomy and of neurovascular interactions have improved our under‐

patients with silent CAD cannot be excluded [4].

standing of the pathophysiological mechanism of ED [3].

**Figure 1.** Possible causes, managements and treatment strategies of Erectile Dysfunction

**2. Causes of erectile dysfunction**

280 Antioxidant-Antidiabetic Agents and Human Health

Aging has been considered to be one of the major reasons for decreased sexual functions, which are also affected by a change in lifestyle, increased day-to-day stress, depression, diabetes and/ or other metabolic and endocrine disorders. Various medications such as antidepressants, tranquilizers, hypnotics, antiandrogens and antihypertensive agents can also lead to the downfall of the sexual functions [6, 7]. There is a close relationship between aging and ED [8]. Research shows that chances of developing ED increase with age and are due to several agerelated factors such as a reduction in nonadrenergic noncholinergic nerve endings in the penis and decreased endothelial nitric oxide (eNOS) activity. The decreased activity of eNOS and bioavailability of NO impairs corpus cavernosum relaxation which can be exacerbated by an increased release of vasoconstrictors. These confounding events are responsible for the increase in the contractile tone in the penile vasculature [9]. Testosterone is secreted in a circadian manner in younger men, but diurnal fluctuation is reduced and may disappear in aging men [10]. Whatever the initiating factor of ED, the ultimate common pathological process is damage to smooth-muscle cells and an increase in the accumulation of fibrosis, which decrease the vasodilator response. This increased accumulation of collagen with aging has been observed in both human and rat corporal smooth muscle [11]. The increase in collagen accumulation leads to a decrease in blood flow as measured by peak systolic velocity, and this decrease of blood flow contributes to ED.

As men age, dysfunction of this complex process occurs with an increased incidence and prevalence. The cause of this age-related erectile dysfunction is not well understood and likely involves multifactorial alterations in the cavernosal endothelial cell lining, smooth muscle cells, and synthesis or activity of NO [12].

### **2.2. Oxidative stress**

Oxidative stress (OS) is one of the major contributory factors towards ED. There is a growing interest among researchers regarding the role of oxidative stress in the pathophysiological mechanism of ED. Oxidative stress occurs when there is an imbalance between pro-oxidants and the ability of the antioxidants to scavenge excess reactive oxygen species (ROS) [3]. Penile erectile tissue is formed by 2 dorsal corporal bodies known as the corpora cavernosa. The cavernosal bodies are composed of sinusoidal spaces with a trabecular meshwork. These spaces are lined by endothelium. Neural transmitters, such as acetylcholine, are released from cavernosal nerve endings and stimulate the neuronal NOS (nNOS) enzyme, which leads to the release of NO from the endothelium. Erectile function is mediated by both nNOS and endo‐ thelial NOS (eNOS) [13]. NO is the principal mediator of penile erection [13]. Erectile function is dependent on relaxation of the cavernous smooth muscle, and its mechanism of action is dependent on penile smooth muscle relaxation, mediated by NO. Decreased production or absence of NO may play a major role in ED. Production decreases when the availability of substrate for NOS is reduced. NO is a highly reactive free radical that undergoes nonenzymatic reaction with the heme moiety of oxyhemoglobin or that reacts with free radicals, such as superoxide anion, to form peroxynitrite [14]. The relationship between OS in the penis and age related ED has only been recently investigated and it was shown that as one ages, free radicals are produced at a higher rate and their numbers increase in various vascular beds. These mechanisms ultimately produce an ineffective relaxation in cavernosal tissue, which leads to ED. NO interacts with superoxide to form peroxynitrite, which has been reported to play a central role in atherogenesis [14]. Peroxynitrite reacts with the tyrosyl residue of proteins, which inactivates superoxide dismutase (SOD) and Leads to decrease the removal of super‐ oxide [15]. Previous studies have shown that penises from old rats display an increase in nitrotyrosine immunostaining which is a marker for peroxynitrite formation. Due to aging, there is not enough SOD produced to balance superoxide anions produced in aged rat penises, which is why their endothelium and corpus cavernosal smooth muscle display high amounts of superoxide anions as opposed to those of younger animals. Therefore, as extracellular SOD is transferred to aged rats, erectile dysfunction is restored because the superoxide anion formation is reduced [5]. Oxidative and nitrosative stress is associated with infertility, and directly involved in reproductive disorders as diverse as oocyte implantation, endometriosis, and pre-eclampsia in women, and ED, sperm damage and motility in men [16]. NO is reported to decrease the adhesion of platelets and leukocytes to the vascular endothelial cells. A reduced NO concentration aggravates the adhesion of these cells to the endothelium and releases substances (thromboxane A2 and leukotriens) that cause vasoconstriction. These substances further aggravate ED [5].

cardiovascular disease, three pathological conditions increasingly recognized as having an

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Erectile dysfunction represents an early surrogate marker of forthcoming cardiovascular disease (CVD) [22]. It has been hypothesized that ED becomes evident earlier than CVD because the smaller penile arteries reach critical narrowing, with insufficient blood flow, earlier

The recognition of ED, focusing attention on risk profile, could be of help in the prevention of CVD. ED can be used to screen for the presence of hypogonadism, metabolic syndrome,

Abnormalities of the vasodilator system play an important role in the pathophysiology of ED as it is now recognized as a common cause of ED [25, 26]. Therefore, the earliest events in the development of atherosclerosis (endothelial dysfunction) are similar to the earliest events in the development of ED [27] have suggested that a diagnosis of ED is a sentinel event that should prompt investigation for CHD in asymptomatic men [27] Interestingly enough, Kaiser et al [28] recently reported that subjects with ED but without evidence of clinical cardiovascular disease and free of traditional cardiovascular risk factors present widespread abnormality of endothelial function as has been seen in patients with cardiovascular risk factors. Thus, many patients with ED seem to have a vascular mechanism similar to that seen in atherosclerosis [29].

Several studies were carried out in order to confirm that smoking is an independent risk factor for ED [30]. An example being a study that excluded diabetic patients that was controlled for other factors such as age, trauma history and hypertension concluded that smoking is independently associated with atherosclerosis in the pudendal artery. Tengs and Osgood carried out study in 2001 and reported that 40% of impotent men were current smokers as opposed 28% men in the general population [30]. Cross-sectional studies have reported that

Over the years, diabetes mellitus has been known as one of the major direct causes of ED. Research has proved that the probability of ED occurrence is higher in diabetic men than nondiabetic men of the same age and that this difference increases with age. In previous studies, it has been estimated that 50%-75% of men with diabetes have ED [32]. Most of the vascular complications that are linked to both Type l and Type ll diabetes are a result of hyperglycaemia, but the majority of studies apply to Type l diabetes. The impairment of NOS activity and the numerical reduction of nerves containing NOS are the reasons behind diabetes-associated ED. Neurogenic and endothelium controlled relaxation of the smooth muscle as well as the downregulation of mediators downstream from NO such as cGMP and cGMP-dependent protein kinase in the corpus cavernosum are also involved in ED caused by diabetes [33].

inflammatory genesis, and increasing the risk of ED [ 21].

than larger vessels [23].

**2.4. Smoking**

**2.5. Diabetes mellitus**

hypertension and silent CVD [24].

smoking is an independent risk factor for ED.

Hypercholesterolemia is associated with increased ultrastructural predisposition to athero‐ sclerosis and decreased cavernosal smooth-muscle relaxation [17]. Increased cavernosal superoxide levels in hypercholesterolemia may decrease the availability of NO, which may lead to the development of ED. Decreased NO bioavailability in obesity-prone animals has been shown to be due, in part, to increased OS [18]. Oxidative modification of LDL (oxLDL), the major carrier of plasma cholesterol, plays a crucial role in hypercholesterolemia and atherosclerosis development. LDL can undergo oxidative modification by superoxide and peroxynitrite, and it accumulates in atherosclerotic plaques. OxLDL also increases the production of caveolin-1 and its association with eNOS affecting the balance of NO and superoxide generation by eNOS and uncoupling eNOS activity [18]. In human vascular endothelial cells, oxLDL stimulates OS via induction of NAD(P)H oxidase [19].

### **2.3. The effects of cardiovascular disease, obesity, metabolic syndrome on erectile dysfunction**

Obesity is normally associated with generally accepted ED risk factors such as hypertension, hyperlipidaemia, and diabetes but has recently been categorised as an independent cause of ED. An age adjusted BMI has been found to be significantly high in men who have reported severe ED as well as those that are sexually inactive, and this indicates that obesity is a strong predictor of ED. In several analyses from previous studies, obesity remained a major inde‐ pendent predictor of increasingly severe ED [20]. Furthermore, Gazzaruso et al. (2004) suggested that ED could be considered to be the most efficient predictor of silent coronary heart disease (CHD) in a diabetic population, independently of glycometabolic control and ED severity [4]. The interest that is currently being addressed to inflammatory markers is not fortuitous, considered the link between obesity, type II diabetes mellitus and atherosclerotic cardiovascular disease, three pathological conditions increasingly recognized as having an inflammatory genesis, and increasing the risk of ED [ 21].

Erectile dysfunction represents an early surrogate marker of forthcoming cardiovascular disease (CVD) [22]. It has been hypothesized that ED becomes evident earlier than CVD because the smaller penile arteries reach critical narrowing, with insufficient blood flow, earlier than larger vessels [23].

The recognition of ED, focusing attention on risk profile, could be of help in the prevention of CVD. ED can be used to screen for the presence of hypogonadism, metabolic syndrome, hypertension and silent CVD [24].

Abnormalities of the vasodilator system play an important role in the pathophysiology of ED as it is now recognized as a common cause of ED [25, 26]. Therefore, the earliest events in the development of atherosclerosis (endothelial dysfunction) are similar to the earliest events in the development of ED [27] have suggested that a diagnosis of ED is a sentinel event that should prompt investigation for CHD in asymptomatic men [27] Interestingly enough, Kaiser et al [28] recently reported that subjects with ED but without evidence of clinical cardiovascular disease and free of traditional cardiovascular risk factors present widespread abnormality of endothelial function as has been seen in patients with cardiovascular risk factors. Thus, many patients with ED seem to have a vascular mechanism similar to that seen in atherosclerosis [29].

#### **2.4. Smoking**

are produced at a higher rate and their numbers increase in various vascular beds. These mechanisms ultimately produce an ineffective relaxation in cavernosal tissue, which leads to ED. NO interacts with superoxide to form peroxynitrite, which has been reported to play a central role in atherogenesis [14]. Peroxynitrite reacts with the tyrosyl residue of proteins, which inactivates superoxide dismutase (SOD) and Leads to decrease the removal of super‐ oxide [15]. Previous studies have shown that penises from old rats display an increase in nitrotyrosine immunostaining which is a marker for peroxynitrite formation. Due to aging, there is not enough SOD produced to balance superoxide anions produced in aged rat penises, which is why their endothelium and corpus cavernosal smooth muscle display high amounts of superoxide anions as opposed to those of younger animals. Therefore, as extracellular SOD is transferred to aged rats, erectile dysfunction is restored because the superoxide anion formation is reduced [5]. Oxidative and nitrosative stress is associated with infertility, and directly involved in reproductive disorders as diverse as oocyte implantation, endometriosis, and pre-eclampsia in women, and ED, sperm damage and motility in men [16]. NO is reported to decrease the adhesion of platelets and leukocytes to the vascular endothelial cells. A reduced NO concentration aggravates the adhesion of these cells to the endothelium and releases substances (thromboxane A2 and leukotriens) that cause vasoconstriction. These substances

Hypercholesterolemia is associated with increased ultrastructural predisposition to athero‐ sclerosis and decreased cavernosal smooth-muscle relaxation [17]. Increased cavernosal superoxide levels in hypercholesterolemia may decrease the availability of NO, which may lead to the development of ED. Decreased NO bioavailability in obesity-prone animals has been shown to be due, in part, to increased OS [18]. Oxidative modification of LDL (oxLDL), the major carrier of plasma cholesterol, plays a crucial role in hypercholesterolemia and atherosclerosis development. LDL can undergo oxidative modification by superoxide and peroxynitrite, and it accumulates in atherosclerotic plaques. OxLDL also increases the production of caveolin-1 and its association with eNOS affecting the balance of NO and superoxide generation by eNOS and uncoupling eNOS activity [18]. In human vascular

endothelial cells, oxLDL stimulates OS via induction of NAD(P)H oxidase [19].

**2.3. The effects of cardiovascular disease, obesity, metabolic syndrome on erectile**

Obesity is normally associated with generally accepted ED risk factors such as hypertension, hyperlipidaemia, and diabetes but has recently been categorised as an independent cause of ED. An age adjusted BMI has been found to be significantly high in men who have reported severe ED as well as those that are sexually inactive, and this indicates that obesity is a strong predictor of ED. In several analyses from previous studies, obesity remained a major inde‐ pendent predictor of increasingly severe ED [20]. Furthermore, Gazzaruso et al. (2004) suggested that ED could be considered to be the most efficient predictor of silent coronary heart disease (CHD) in a diabetic population, independently of glycometabolic control and ED severity [4]. The interest that is currently being addressed to inflammatory markers is not fortuitous, considered the link between obesity, type II diabetes mellitus and atherosclerotic

further aggravate ED [5].

282 Antioxidant-Antidiabetic Agents and Human Health

**dysfunction**

Several studies were carried out in order to confirm that smoking is an independent risk factor for ED [30]. An example being a study that excluded diabetic patients that was controlled for other factors such as age, trauma history and hypertension concluded that smoking is independently associated with atherosclerosis in the pudendal artery. Tengs and Osgood carried out study in 2001 and reported that 40% of impotent men were current smokers as opposed 28% men in the general population [30]. Cross-sectional studies have reported that smoking is an independent risk factor for ED.

#### **2.5. Diabetes mellitus**

Over the years, diabetes mellitus has been known as one of the major direct causes of ED. Research has proved that the probability of ED occurrence is higher in diabetic men than nondiabetic men of the same age and that this difference increases with age. In previous studies, it has been estimated that 50%-75% of men with diabetes have ED [32]. Most of the vascular complications that are linked to both Type l and Type ll diabetes are a result of hyperglycaemia, but the majority of studies apply to Type l diabetes. The impairment of NOS activity and the numerical reduction of nerves containing NOS are the reasons behind diabetes-associated ED. Neurogenic and endothelium controlled relaxation of the smooth muscle as well as the downregulation of mediators downstream from NO such as cGMP and cGMP-dependent protein kinase in the corpus cavernosum are also involved in ED caused by diabetes [33].

ED is an important component of the metabolic or insulin resistance syndrome, as demon‐ strated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release NO [34]. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator NO [8]. Metabolic insulin resistance is characterized by pathway specific impairment in PI3K-dependent signalling, which may cause imbalance between production of NO and secretion of ET-1 in the endothelium, leading to decreased blood flow, which exacerbates insulin resistance [17]. Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and ED. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and reactive nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism. ED contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progres‐ sive ED and disturbances in glucose and lipid metabolism develop secondarily to the insulin resistance [35]. Studies were done on rats to show that transfer of the adenovirus mediated gene of eNOS to the diabetic rat penis can improve the decreased erectile response by causing an increase in cGMP formation [36]. An additional reason for the decreased eNOS activity in the diabetic rat penis is that there is a reduced L-arginene content. A study was carried out in which diabetic rats were orally administered L-arginine, and results indicated increased endothelium dependent relaxation of cavernosal tissue by improvment of the biosynthesis of NO which ultimately led to an increased erectile response [37].

Several studies have shown that acute administration of T induces rapid relaxation in vascular tissues of different species including humans [45, 46] suggesting a non-genomic effect of this hormone on vasomotion [47]. Different mechanisms have been proposed to explain T-induced vasodilatation, [48] but as to which are the effective mechanisms and which are the mediators involved with the T-induced vasorelaxation remain a matter of debate. Testosterone might induce relaxation in human isolated corpora cavernosa strips by activation of smooth muscle adenosine triphosphatesensitive K(+) channels. This finding suggests that T, in addition to its known endothelial action, might regulate erectile function locally by its action on the smooth muscle of the human corpus cavernosum [49 It has been established that different thresholds exist for sexual desire and erectile function in humans, the former being quite higher than the latter [50]. In humans, T deficiency determines a sequence of molecular penile events leading to reduced capacity of smooth muscle and endothelial cells to relax in addition to causing increased sensitivity to contractile factors, that is, alpha-adrenergic agonists and deficiency of NO-induced relaxation during sexual stimulus. Recent evidence in humans suggest that T may directly control the expression and activity of phosphodiesterase type 5 (PDE5) in human corpus cavernosum so that in some selected patients, that is, total-T < 10 nmol/L and/or free-T below 200 nmol/L, androgen supplementation may improve therapeutic efficacy to PDE5-i [8]. Reduced production of testosterone may increase the risk of osteoporosis, sexual dysfunc‐ tion, fatigue, cardiovascular disease and mood disturbances, and may decrease muscle mass [51]. Hypogonadism may be classified as hypergonadotrophic in cases of testicular failure or hypogonadotrophic in cases of hypothalamic/pituitary failure [51]. Finally, penile NO, the major smooth muscle relaxer responsible for penile erections, is in part regulated by testos‐ terone. To date, it is not known if the peripheral androgenic effects observed in animals also

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Various mechanisms may disturb the regulatory function of eNOS and endothelial NO bioavailability, resulting in vasculogenic ED. As molecular mechanisms of normal erectile function and the pathways leading to vasculogenic ED associated with eNOS are becoming clearer, it seems that eNOS roles in the vascular pathophysiology of the penis are complicated and not always uniform. For example, eNOS phosphorylation in the penis is ineffectively regulated with aging and diabetes, although by different mechanisms. However, increased oxidative stress in the penis seems to be a common component of vasculogenic ED, and activation of the RhoA/ Rho-kinase contractile pathway is seen in several vasculogenic ED

Erectile dysfunction is a defect of penis reaching and or sustaining erection because of physiological or psychological factors [2]. Different treatments have been proposed including:

**4. Management and treatments of erectile dysfunction**

are present in man 52].

**3. Mechanisms**

states [53].

#### **2.6. Hormonal control on erectile dysfunction**

There may be a link between insulin resistance, endothelial dysfunction, metabolism syn‐ drome, ED, and diabetes [35]. Hypogonadism has been shown to be an independent determi‐ nant of endothelial dysfunction, thus contributing to vascular pathology, including ED [35]. Testosterone (T) and its metabolites, dihydrotestosterone (DHT) and estradiol (E2), have a critical role in the development and maintenance of normal male genitalia, testes, accessory sex organs, skeletal muscle mass, bone growth mass, male hair patterns, libido and erectile function [38]. Testosterone is also thought to influence central nervous system gender identi‐ fication [39]. DHT as well as testosterone can maintain libido and erectile function, indicating that estrogen is not required for their maintenance in men [40]. Androgen receptors (ARs) are present in the amygdala, lateral septum, and premamillary bodies in male primates [41]. AR linked brain sites in the hypothalamus, pituitary gland and preoptic areas appear to influence male sexual behaviour. For instance, stimulation of forebrain, hippocampus, and hypothala‐ mic nuclei causes penile erection and/or mating behaviour in laboratory animals [42, 43]. Other studies indicate that the hypothalamic paraventricular nuclei could be the main source of a descending spinal erection pathway to the spinal erection generator [44].

Several studies have shown that acute administration of T induces rapid relaxation in vascular tissues of different species including humans [45, 46] suggesting a non-genomic effect of this hormone on vasomotion [47]. Different mechanisms have been proposed to explain T-induced vasodilatation, [48] but as to which are the effective mechanisms and which are the mediators involved with the T-induced vasorelaxation remain a matter of debate. Testosterone might induce relaxation in human isolated corpora cavernosa strips by activation of smooth muscle adenosine triphosphatesensitive K(+) channels. This finding suggests that T, in addition to its known endothelial action, might regulate erectile function locally by its action on the smooth muscle of the human corpus cavernosum [49 It has been established that different thresholds exist for sexual desire and erectile function in humans, the former being quite higher than the latter [50]. In humans, T deficiency determines a sequence of molecular penile events leading to reduced capacity of smooth muscle and endothelial cells to relax in addition to causing increased sensitivity to contractile factors, that is, alpha-adrenergic agonists and deficiency of NO-induced relaxation during sexual stimulus. Recent evidence in humans suggest that T may directly control the expression and activity of phosphodiesterase type 5 (PDE5) in human corpus cavernosum so that in some selected patients, that is, total-T < 10 nmol/L and/or free-T below 200 nmol/L, androgen supplementation may improve therapeutic efficacy to PDE5-i [8]. Reduced production of testosterone may increase the risk of osteoporosis, sexual dysfunc‐ tion, fatigue, cardiovascular disease and mood disturbances, and may decrease muscle mass [51]. Hypogonadism may be classified as hypergonadotrophic in cases of testicular failure or hypogonadotrophic in cases of hypothalamic/pituitary failure [51]. Finally, penile NO, the major smooth muscle relaxer responsible for penile erections, is in part regulated by testos‐ terone. To date, it is not known if the peripheral androgenic effects observed in animals also are present in man 52].
