Abnormalities in the vascular, neural, endocrine, muscular, or psychiatric systems can result in ED.2,3 EDDM is due to multisystemic disease. Atrophy or apoptosis of cavernosal smooth muscle can occur due to loss of Bcl-2 expression in cavernosal smooth muscle and lead to ED. Abnormal amounts of advanced glycation end products is a common occurrence. These chemicals may have an effect on potassium channels that facilitate intracellular calcium release and subsequent cavernosal smooth muscle relaxation. Connective tissue synthesis is increased due to transforming growth factor-beta. The decrease in smooth muscle and the increase in collagen decreases the compliance of the erectile tissue. Neuropathic damage to both the somatic and autonomic nerves has been clearly defined in DM. Partial occlusion of the pelvic or intracavernosal arteries, hypogonadotropic hypogonadism, and depression associated with a chronic illness (DM) can all play a primary or secondary role in the development of EDDM. On a molecular level, studies have demonstrated decreased levels of endothelial and neuronal nitric acid synthase (NS) and decreased cavernosal artery and sinusoidal response to nitric oxide. Abnormalities in nitric oxide rapidly render the functional syncytium of the corpora cavernosa unable to synchronously relax. As the patient with diabetes ages, the concentration of constrictors, including endothelin, prostanoids, and possibly angiotensin, increases as the production of the relaxants, including nitric oxide, vasointestinal peptide, and prostacyclin, decreases.
Obesity is a strong predictor of ED as it is associated with other risk factors, such as diabetes, hyperlipidaemia and hypertension.4 Obesity increases the risk of ED by 30–90 % and acts as an independent risk factor for CVD. Obese men with ED have greater impairment in endothelial function than non-obese men with ED.5 Moreover, high BMI causes low testosterone levels, which in turn leads to ED, as observed in a prospective trial involving 7,446 participants.50
It is recommended that testosterone be measured in patients with ED because low levels are a reliable measure of hypogonadism. Hypogonadism is not only a treatable cause of ED, but can also lead to reduced or lack of response to PDE5 inhibitors.73 Testosterone deficiency is also associated with increased cardiovascular and all-cause mortality.74 Levels >350 ng/dl do not usually require replacement, but in patients with testosterone <230 ng/dl, replacement can usually be beneficial.57 In patients with congestive heart failure, testosterone replacement can lead to fluid retention, so caution is advised. In these patients, the aim should be to keep testosterone levels in the middle range, i.e. 350–600 ng/dl.57

Abstract | Full Text | Full Text PDF | PubMed | Scopus (272) | Google ScholarSee all References No data suggested adverse interactions between sildenafil and other drugs commonly used in the treatment of coronary artery disease, such as aspirin, heparin, or narcotics.10x10Kloner, RA and Zusman, RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol. 1999; 84: 11N–17N
The safety of PDE5 inhibitors in patients with IHD has been shown in multiple trials. Arruda-Olson et al. investigated the safety of sildenafil during exercise stress tests in patients with IHD to ascertain whether the drug induces or exacerbates myocardial ischaemia. This was a prospective, randomised crossover study that demonstrated safety of sildenafil when given 1 hour before an exercise stress test.69 Another study that investigated 120 trials of sildenafil revealed that the rates of MI and cardiovascular death with sildenafil are as low as with placebo.70
Penile arterial supply (top) and venous drainage (middle), longitudinal views. Bottom, Transverse and longitudinal views of venous return. From Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction and priapism. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ, eds. Campbell's Urology. Vol 2. 7th ed. Philadelphia, Pa: WB Saunders Co; 1998:1157-1179. With permission from Elsevier.
The incidence of ED is 42.0–57.0 % in men with CAD and 33.8 % in those who have diabetes with silent ischaemia, compared with 4.7 % in men without silent ischaemia.6 The prevalence of ED is likely to be higher than the reported figures, because men generally do not seek medical advice for ED.6 Erection is thought to be a process that is regulated by hormones and neurovascular mechanisms in cerebral and peripheral levels.7
Although a considerable number of patients report penile pain with IC injection therapy, it appears that diabetic men still have high compliance rates with therapy. In one study, 16 of 18 diabetic men continued IC injection therapy for 7 years, compared to 7 of 22 nondiabetic control subjects with ED.57 One possible explanation for this is that diabetic patients with ED have fewer options than do nondiabetic men with ED, who are more likely to have a successful response to oral PDE-5 agents, as documented in one study.58 Another explanation is the greater familiarity with needles and injections among men with diabetes than among their nondiabetic counterparts.
No matter what erectile dysfunction treatment or treatments (whether herbal remedies or not) a man ultimately decides upon, experts say it's important to eat healthily and to avoid smoking and heavy drinking. Moreover, adequate exercise, stress reduction, and sleep can improve erectile dysfunction in many. In addition, says Lamm, "A loving, receptive, and responsive partner is a home run. After all, this is still a couple's issue."
A considerable number of patients with ED can have psychogenic factors as the only cause, or in combination with organic causes of ED. Depression, low self-esteem and social stresses are among the psychogenic factors that can lead to ED. Depression is an independent risk factor for both ED and IHD; these three disease conditions are interlinked.51 Psychogenic ED can be managed by multiple psychological interventions such as cognitive behavioural therapy, couples counselling and guided sexual stimulation techniques.52
The number of men reporting improvement was at 88% during the study. The number of men involved in the study who reported impotence dropped from 75.3 % to 11.8%. The results of this study raise hope for men who have quit taking other blood pressure medications because they interfered with sexual function. Sexual dysfunction was defined for the study as decreased libido, impotence and poor sexual satisfaction.
Joel Fuhrman, M.D. is a board-certified family physician, six-time New York Times bestselling author and internationally recognized expert on nutrition and natural healing, who specializes in preventing and reversing disease through nutritional methods. Dr. Fuhrman coined the term “Nutritarian” to describe his longevity-promoting, nutrient dense, plant-rich eating style.
The links between hypertension and ED are increasingly recognized and the 2009 re-appraisal of European guidelines includes relevant statements.35,47 Erectile dysfunction is almost twice as frequent in hypertensive as in normotensive individuals and appears to be of higher severity. The relative risk of developing ED in hypertensive patients compared with normotensive individuals ranges from 1.3 to 6.9. Regarding pathophysiology, hypertension appears to cause ED per se, through a multitude of mechanisms that include prolonged exposure to elevated levels of systemic blood pressure, endothelial dysfunction, and circulation of vasoactive substance (with a pivotal role of angiotensin II) that lead to structural and functional alterations in the penile arteries. The largely unfounded (see earlier paragraph) notoriety of antihypertensive treatment for causing ED is one of the most predominant causes for non-adherence and discontinuation of antihypertensive therapy, and therefore, patients should be properly informed by physicians. Phosphodiesterase type 5 inhibitors are effective in hypertensive patients with ED and they can safely be co-administered with antihypertensive medication.39 Specifically for alpha-blockers, low starting doses of PDE5 inhibitors are preferred in patients already on alpha-blocker treatment, and likewise, low starting doses of alpha-blockers are encouraged in patients taking PDE5 inhibitors. Of clinical significance is that hypertensive men with ED are more likely to comply with their antihypertensive medication when under PDE5 inhibitors.

Phosphodiesterase Inhibitors. The cornerstone of first-line therapy is the PDE-5 inhibitor. No other class of oral agents approaches the efficacy of PDE-5 inhibitors. Yohimbine, trazodone, phentolamine, L-arginine, and OTC herbal remedies have been used with very limited success. The superiority of yohimbine over placebo in the treatment of organic ED is a matter of dispute.9 A recent trazodone study failed to detect any difference between trazodone and placebo on sexual function.10 Oral phentolamine, although available in Mexico, has not been approved by the US FDA for the treatment of ED. Apomorphine, a central dopaminergic receptor drug, has recently been voluntarily withdrawn from FDA consideration for the treatment of ED. The efficacy of ginkgo biloba and Korean red ginseng has yet to be demonstrated by randomized, placebo-controlled trials.

Crucial to the understanding of the relationship between ED and CVD and the management of ED patients within the context of the (potential) CVD were the consecutive Princeton Consensus Recommendations (I: 2000, II: 2005, and III: 2012). The reader is strongly encouraged to refer to the most recent, third (2012) Princeton Consensus.30 Key notions in the assessment and management of the patient with organic ED are that (i) he should be considered at increased CVD risk until recommended checks suggest otherwise, and (ii) ED identifies increased CVD risk in the presence or absence of CVD symptoms or history.

Abstract | Full Text PDF | PubMed | Scopus (16) | Google ScholarSee all References These medications cause intracavernosal pressure changes in animal models, and human studies have noted deleterious effects on erectile function, decreased libido, and ejaculatory problems.42x42Weiss, RJ. Effects of antihypertensive agents on sexual function. Am Fam Physician. 1991; 44: 2075–2082

Olsson et al. conducted a randomised, double-blind, placebo-controlled, parallel group, and flexible dose study in 224 men with ED and one CVD, including IHD (20 %) and hypertension (80 %). This study reported that the sildenafil-treated group showed 71 % improvement in ED compared with the placebo-controlled group (24 %).64 Furthermore, no treatment-related cardiovascular adverse events were reported.65 Conti et al. showed in an early study that sildenafil is an effective treatment for ED in patients with IHD; the majority of patients reported improvement in penile erection with it.66 Another double-blind, placebo-controlled study of patients with ED and stable CAD showed statistically significant improvement with sildenafil versus placebo in both the frequency of penetration and frequency of maintained erections after penetration.67

The pathophysiological basis for the predictive ability of ED has been discussed above. It should be emphasized, however, that ED should not only be viewed as a manifestation of obstructive CAD that could be identified by ischaemia revealing tests. Owing to the inflammatory and pro-thrombotic activation of the disease,13 it should also be regarded as an early warning sign of an imminent acute event (mainly acute myocardial infarction)22 due to the rupture of a subclinical plaque, and thus identification of the risk should ideally include plaque vulnerability tests. Finally, an issue that has important clinical implications is by how long the clinical manifestation of ED precedes the clinical manifestation of CAD. According to studies, men with ED and no cardiac symptoms have an increased incidence of experiencing a cardiac event, both acute and chronic, in the ensuing 2–5 years, thus providing a ‘window of opportunity’ for risk reduction management in these patients.2
Diabetic damage doesn’t stop with these small vessels, he said. “You really have two parallel situations: You need blood flow that feeds the muscle of the penis, and you need an artery dedicated to bringing blood rapidly when a man becomes aroused and wants to be sexually active,” he said. “That artery is also affected by diabetes. They’ll say ‘I can get a partial erection, but I can’t maintain it.’ ”

Yohimbine is an indole alkaloid derived from the bark of the African yohimbe tree (33). Yohimbine has been noted to treat fatigue, depression, diabetes, and sexual dysfunction. A meta-analysis of seven placebo-controlled trials (34) deemed yohimbine superior to placebo for the treatment of ED with rare adverse events. The proposed mechanism of action (35) is via the inhibition of central alpha-2-adrenergic receptors, decreasing central inhibition of arousal, and increasing penile nerve stimulation resulting in increased NO. Common side effects include headache, sweating, agitation, hypertension and insomnia. Contraindications include patients on tricyclic antidepressants, anti-hypertensives and central nervous system stimulants.
Some blood pressure medicines can also cause erectile dysfunction. Thiazide diuretics and beta-blockers are most likely to cause problems, but this is not a common effect of these medicines and will not happen to everyone. If you are taking either of these medicines and are worried about erectile dysfunction, your GP may be able to change your medicines.
Few simple laboratory tests can help identify obvious causes of organic ED. Initial labs should include HbA1c, free testosterone, thyroid function tests, and prolactin levels. However, patients who do not respond to pharmacological therapy or who may be candidates for surgical treatment may require more in-depth testing, including nocturnal penile tumescence testing, duplex Doppler imaging, somatosensory evoked potentials, or pudendal artery angiography.
PubMed | Google ScholarSee all References As with sildenafil, use of nitrate or NO-donor medications is contraindicated while taking tadalafil because of the potential for marked hypotensive interactions.74x74Gresser, U and Gleiter, CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature. Eur J Med Res. 2002; 7: 435–446
The aetiology of predominantly psychogenic ED is multifactorial, and components may include psychiatric disorders (especially depression), interpersonal problems with the sexual partner or misconceptions about normal sexual activity. Identifying and getting treatment for those patients with psychogenic causes of ED such as depression that may also increase CVD risk is also important.
Physical and sexual activity can trigger acute cardiac events. In a recent meta-analysis, a significant association between acute cardiac events and episodic physical (relative risk 3.45 for myocardial infarction and 4.98 for sudden cardiac death) and sexual activity (relative risk 2.7 for myocardial infarction) was demonstrated.32 This association was attenuated among individuals with high levels of habitual physical activity (for every additional time per week the relative risk for myocardial infarction decreased by ∼45%, and the relative risk for sudden cardiac death decreased by 30%). The physical demands of sexual activity have been identified as follows. Studies conducted primarily in young married men showed that sexual activity with a person's usual partner is comparable with mild-to-moderate physical activity in the range of 3–4 metabolic equivalents of the task (METS).30,33 The heart rate rarely exceeds 130 b.p.m. and systolic blood pressure rarely exceeds 170 mmHg in normotensive individuals. Accordingly, demands during sexual activity correspond to walking 1.5 km (or 1 mile) on the flat in 20 min or briskly climbing two flights of stairs in 10 s. Generalization, however, may not characterize all individuals (especially those who are older, are less physically fit, or have CVD) or sexual activity circumstances (e.g. extramarital, unfamiliar setting, excessive food and alcohol consumption). Therefore, completing 4 min of the standard Bruce treadmill protocol (5–6 METS) without symptoms, ST segment changes, arrhythmias, or a fall in systolic BP identifies the safety of sexual activity.30,33

In many of these cases, a discussion between the physician, the man with erectile dysfunction, and possibly his partner can help to resolve the issues leading to treatment failure. For men who experience severe side effects, can’t take the drugs for other reasons (such as taking medicines such as nitroglycerin), or don’t respond in spite of further education on the correct use of the drugs, there are other treatment options that can help most men remain sexually active.