It is an important association of ED and hyperlipidemia which has been found in several clinical studies. Most of them suggest that hypercholesterolemia at baseline was also shown as a predictor of ED. High concentrations of low-density lipoprotein seem to be related to ED, although low levels of high-density lipoproteins have been shown to be predictive of ED [15].

The selective action of the endothelial NO/cGMP pathway in hypercholesterolemia could be due to increased superoxide production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase or to increased plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of NOS [16].

High blood pressure is an independent risk factor for development of ED [17, 18]. Cardiovascular complications following hypertension such as ischemic heart disease and renal failure are associated with an even higher prevalence of ED.

Hypertension affects blood vessels by shear stress, which can lead to endothelial abnormalities such as an altered production and activity of vasoactive substances. It has been proposed that in hypertension, the increased blood pressure per se does not induce an impairment of erectile function; therefore, it is thought that the resultant dysfunction could be caused by the associated arterial stenotic lesions [19].

In hypertensive population, ED was associated to older age, longer duration of hypertension, and a more severe hypertension. ED was also related to the antihypertensive therapy [20].

Together with high blood pressure, it should be emphasize that some endocrinological disorders and hormone irregularity can lead to ED.

Endocrinological erectile dysfunction thru androgens plays important parts in enhancing sexual desire and maintaining adequate sleep-related erections but have a limited effect on visually induced erections. It is spot that testosterone is important in the regulation of the expression of NO synthase (NOS) and PDE5 inside the penis [21]. Testosterone deficiency or hypogonadism has been recently associated with cardiovascular morbidity and mortality. Hyperprolactinemia leads to sexual dysfunction, due to low testosterone concentrations. Increased prolactin concentration leads to the inhibition of gonadotropin-releasing hormones, which, in turn, decreases the secretion of luteinizing hormone, which is responsible for testosterone secretion [22].

Cigarette smoking is an important independent modifiable risk factor and it appears to have a deleterious effect on penile hemodynamic integrity. Mannino showed an odds ratio (OR) of 1.4 for smokers vs. nonsmokers. Some researchers furthermore demonstrated an OR of 1.7 and also that the risk of ED increases with duration of this habit [23]. Cigarette smoking showed also to increase the age-adjusted risk of ED in addition to increasing the relative risk for antihypertensive medications, cardiac drugs, and systemic illness as diabetes mellitus (50 vs. 45.4 % of complete ED, smokers vs. nonsmokers, respectively). The authors reported that there are strong parallelisms and shared risks among smoking, CAD, atherosclerosis, and ED [7]. Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by the impairment of endothelium-dependent smooth muscle relaxation. They also confirmed that the association of ED with risk factors such as CAD and hypertension appears to be amplified by cigarette smoking [24].

From a pathophysiological point of view, nicotine may inhibit smooth muscle function or the neurovascular mediators, such as prostacyclin, causing many types of hemodynamic alterations. Hypercoagulability and increased platelet aggregation, the release of fatty acids and catecholamines, or direct toxic effects on the vascular endothelium have also been considered as possible mechanisms. Recently, literature data showed that smoking may act as a risk factor for ED by reducing high-density lipoprotein (HDL) and increasing fibrinogen concentrations [25].

Enhanced basal and myogenic tone has been observed in arteries from hypertensive rats [26]. It is unclear whether enhanced myogenic constriction reflects a primary pathological defect contributing to the hypertensive state or a secondary adaptive process protecting the exchange vessels from elevated pressures [27]. Although the role of myogenic tone in the penile vasculature for erection remains to be clarified, the increased vasoconstriction could contribute to decreased arterial inflow and erectile response [28].

Enhanced adrenergic activity keeping the penile smooth muscle contracted is expected to result in ED. Sympathetic nerve activity accompanies hypertension in man and hypertensive animals [29]. However, in corpus cavernosum from spontaneously hypertensive rats, the content of sympathetic neurotransmitters was found to be unchanged [30]. Neither the contractions evoked by the ά1-adrenoceptor agonist, phenylephrine, nor the contractions induced by electrical field stimulation were enhanced in arteries or erectile tissue from renal hypertensive compared to normotensive rats.

In view of these findings, it is unlikely that changes in the peripheral sympathetic neuro-effectors junction or responsiveness to ά-adrenoceptor agonists play a role for the decreased erectile function observed in hypertensive rats [31].

Immunohistochemical and functional studies of isolated penile small arteries indicate that NO is the main neurotransmitter mediating nonadrenergic noncholinergic relaxations to electrical field stimulation [32].

In patients with essential hypertension, endothelium-dependent vasodilatation elicited by infusion of agonists such as acetylcholine, bradykinin, or flow is diminished [33, 34].

There is a lack for studies addressing whether endothelium-dependent vasodilatation in the penile circulation is altered in hypertensive men.

Diabetes mellitus type 2 is the second most common risk factor for erectile dysfunction, which in turn develops in 50–75 % of diabetics. The prevalence of ED is three times higher in diabetic men (28 % vs. 9.6 %), occurs at an earlier age, and increases with disease duration, being approximately 15 % at age 30 rising to 55 % at 60 years [35]. Diabetes mellitus may cause ED through a number of pathophysiological changes affecting psychological function, central nervous system (CNS) function, androgen secretion, peripheral nerve activity, endothelial cell function, and smooth muscle contractility [36].

In diabetic patients, insulin is thought to enhance nitric oxide synthase (NOS) activity by increasing transport of L-arginine into the cell and furnishing greater quantities of the essential cofactor NADPH. These effects are reversed in the insulin lack or insulin resistance of diabetes. Plasmatic concentration and vascular content of L-arginine are reduced in diabetic rats [37]. Arginase is an enzyme that competes with NOS for the 30 substrate, L-arginine. The inducible form of the enzyme, arginase II, is overexpressed in corpus cavernosum from diabetic patients, where inhibition of arginase restores NOS activity. Intracellular availability of L-arginine in diabetic cavernosal tissue could be reduced not only by transport impairment but also by excessive metabolization through arginase pathway.

The ratio of reductase cofactors NADH/NAD + is increased in diabetes. This reduces the levels of NADPH, an essential cofactor for NOS, and increases the levels of calcium-elevating second messengers such as diacylglycerol and protein kinase C (PKC) thus increasing smooth muscle contractility [38].

Men suffering chronic renal failure (CRF) requiring renal replacement therapy have a high prevalence of sexual dysfunction (20–50 %) [39]. Many of the pathophysiological effects of persistent uremia can potentially contribute to the development of ED including disturbance of the hypothalamic-pituitary-testis sex hormonal axis, hyperprolactinemia, accelerated atheromatous disease, and psychological factors [40].

Uremia results in a decrease in bioavailable NO in erythrocytes. Sarioglu and coworkers demonstrated that a chronic uremic state resulted in impaired nerve and endothelial-mediated relaxation of rabbit cavernosal smooth muscle while relaxation induced by NO donors or purinergic activation was preserved [41].

Cavernosal vascular function in men undergoing renal replacement therapy showed that 80 % had both arterial insufficiency and veno-occlusive dysfunction. A link with possible impairment of the NO/cGMP pathway relating to failure of cavernosal relaxation is provided by the finding of increased serum levels of endogenous inhibitors of NO synthesis in uremic patients [42].

Treatment using higher doses of a thiazide showed a significant increase in ED compared to placebo [43]. Addition of a thiazide to existing treatment with propanolol or methyldopa also increased the prevalence of ED, while this effect did not occur when the thiazide was combined with an ACE inhibitor [44]. Data from a large UK trial showed that twice as many men taking thiazides for treatment of mild hypertension reported ED compared to those treated with propanolol or placebo, this being the commonest reason for withdrawal from the bendrofluazide arm of the study [45]. In the Treatment of Mild Hypertension Study (TOMHS), the prevalence of ED at 2 years in men taking low-dose thiazide was twice that of both the placebo group and those on alternative agents [46].

Psychotropic drugs are among the most common drug classes involved in the development of erectile dysfunction. In a first place, antidepressants are the most common psychotropic drugs associated with significant rates of erectile dysfunction, including the selective serotonin reuptake inhibitors and venlafaxine. Antipsychotics such as risperidone and olanzapine have the highest likelihood of all psychotropic drugs of causing erectile dysfunction [47].