**3. Mechanisms**

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].

descending spinal erection pathway to the spinal erection generator [44].

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

**2.6. Hormonal control on erectile dysfunction**

284 Antioxidant-Antidiabetic Agents and Human Health

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 states [53].
