Erectile Dysfunction

Epidemiology

Erectile dysfunction (ED), defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity (15), is one of the most common sexual dysfunctions in men. ED is more common with advancing age, and since the aged population will increase, its prevalence will continue to rise (16). Diabetes mellitus is the most frequent organic cause for ED, the onset of which starts about 15 years earlier in the diabetic than in the nondiabetic population. In the Massachusetts Male Aging Study (MMAS), the age-adjusted prevalence of minimal, moderate, or complete ED was 17, 25, and 10% among 1238 men without diabetes and 8, 30, and 25% among 52 treated men with diabetes, respectively (17). Thus, although the number of diabetic subjects in the MMAS was low, this population based study showed an increased prevalence particularly of complete ED among men with diabetes. In the Cologne Male Survey (18) the prevalence of ED was threefold increased, reaching 60% among men with diabetes compared with only 19% in the general population. The presence of diabetes was associated with an increased odds ratio for ED by 3.95 (2.98-5.23). The prevalence of ED in the younger age groups (40-60 years) with diabetes was as high as in the older groups without diabetes (60-80 years). Thus, in presence of diabetes the development of ED starts around 20 years earlier than in the nondiabetic population. The crude incidence rate of ED in the MMAS was 26 cases/1000 man-years in 847 men aged 40-69 without ED at baseline who were followed for an average of 8.8 years (19). Population projections for men in this age group suggest an estimate of 617.715 new cases of ED per year for the United States. The age adjusted risk of ED was higher for men with lower education, diabetes, heart disease, and hypertension. The incidence rate of ED in men with diabetes was twofold increased, with 50 cases/1000 man-years. In a population based study from southern Wisconsin the prevalence of ED among 365 patients with type 1 diabetes increased with increasing age from 1.1% in those aged 21-30 years to 47.1% in those 43 years of age or older and with increasing duration of diabetes (20). In a study from Italy including 9868 men with diabetes, 45.5% of those aged more than 59 years reported ED. Risk factors and clinical correlates included the following (OR [95% CI]): autonomic neuropathy (5.0 [3.9-6.4]), diabetic foot (4 [2.9-5.5]), peripheral neuropathy (3.3 [2.9-3.8]), peripheral arterial disease (2.8 [2.4-3.3]), nephropathy (2.3 [1.9-2.8]), poor glycemic control (2.3 [2-2.6]), retinopathy (2.2 [2.0-2.4]), hypertension (2.1 [1.6-2.9]), and diabetes duration (2 [1.8-2.2]) (21). In another survey from Italy the combination of diabetes and hypertension was the major risk factor for ED, giving an OR (95% CI) of 8.1 (1.2-55) as compared with diabetes without hypertension at 4.6 (1.6-13.7), hypertension without diabetes at 1.4 (0.7-3.2), current smoking at 1.7 (1.2-2.4), and exsmoking at 1.6 (1.1-2.3) (22). However, even when neuropathic complications are present, psychiatric illness such as generalized anxiety disorder or depression may be important contributors to ED in men with diabetes (23). Thus, a psychogenic component must not be overlooked in many patients.

Physiology and Pathophysiology

Penile erection is a neurovascular event modulated by psychological factors and hormonal status depending on appropriate trabecular smooth muscle and arterial relaxation in the corpus cavernosum. On sexual stimulation, nerve impulses cause the release of cholinergic and NANC neurotransmitters that mediate erectile function by relaxing the smooth muscle of the corpus cavernosum. A principal neural mediator of erection is nitric oxide (NO), which activates guanil cyclase to form intracellular cyclic guanosine monophosphate (GMP), a potent second messenger for smooth muscle relaxation (Fig. 1). Cyclic GMP in turn activates a specific protein kinase, which phosphorylates certain proteins and ion channels, resulting in a drop of cytosolic calcium concentrations and relaxation of the smooth muscle. During the return to the flaccid state, cyclic GMP is hydrolyzed GMP by phosphodiesterase (PDE) type 5 (2,9). In the corpus cavernosum four PDE isoforms have been identified (types 2-5), but PDE 5 is the predominant isoform, whereas the others do not appear to have an important role in erection (24).

The pathogenesis of ED in diabetes is thought to be multifactorial as it may be linked to neuropathy, accelerated atherosclerosis, and alterations in the corporal erectile tissue. Such alterations may include smooth muscle degeneration, abnormal collagen deposition, and endothelial cell dysfunction (25). If irreversible, these corporal degenerative changes can limit the success of any pharmacotherapy. Advanced glycation end products

NOiin diabetes through:

• Oxidative stresst

• Glycationt

• Aldose reductase f

Aldose Reductase
Fig. 1. Mechanisms of erection mediated by cavernosal smooth muscle relaxation including the generation of nitric oxide by nitric oxide synthase, which is impaired in diabetes. ROS, reactive oxygen species; PKC, protein kinase C; AR, aldose reductase.

have been shown to quench NO and to be elevated in human diabetic penile tissue. It has been hypothesized that advanced glycation end products may mediate ED through upregulation of inducible nitric oxide synthase and downregulation of endothelial NOS (eNOS) (26). Furthermore, protein kinase C activation by diabetes may reduce NOS activity (27).

In vivo studies of isolated corpus cavernosum tissue from men with diabetes have shown functional impairment in neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle (28). In diabetic rats endothelium-dependent NO mediated relaxation to acetylcholine and NANC stimulation are reduced by 40% after 4-8 weeks (29). These alterations were prevented by administration of the antioxidant a-lipoic acid, suggesting an involvement of increased oxidative stress. In contrast, endothelium-independent relaxation to the NO donor sodium nitroprusside is not impaired by diabetes (29). Increased penile endothelial and total NOS activity was found after 2-3 months in diabetic rats (30). However, after 4-8 months reduced penile total (endothelial and neuronal) NOS activity and neuronal NOS levels were observed in type 1 and type 2 diabetic rats (31). Thus, diabetes-induced changes in NOS activity may be biphasic, with an initial increase followed by a decrease. Because RhoA/Rho-kinase may suppress eNOS, RhoA/Rho-kinase could contribute to diabetes-related erectile dysfunction and downregulation of eNOS. Colocalization of Rho-kinase and eNOS protein is present in the endothelium of the corpus cavernosum. Diabetic rats trans-fected with an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in control rats. AAVT19NRhoA gene transfer

Neuroendocrine Control Penile Erection

NOiin diabetes through:

• Oxidative stresst

• Glycationt

• Aldose reductase f

Table 1

Practical Three-Step Algorithm for Diagnosis of Erectile Dysfunction

Step 1: General sexual history

Clinical examination; relevant laboratory parameters Information about treatment options Step 2: Therapeutic trial with PDE5 inhibitor

Step 3: Intracavernous pharmacotesting: color Doppler or duplex ultrasound of penile arteries improved erectile responses in the diabetic rats to values similar to controls. Thus, activation of the RhoA/Rho-kinase pathway may represent one important mechanism for the down-regulation of penile eNOS in diabetes, implying that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity and thereby restores erectile function in diabetes (32).

Diagnosis

A good clinical history and physical examination are the basis of assessment. It is important to establish the nature of the erectile problem and to distinguish it from other forms of sexual difficulty, such as penile curvature or premature ejaculation. An interview with the partner is advisable and will confirm the problem, but might also reveal other causes of the difficulties, for example, vaginal dryness. The relative importance of psychological and organic factors may be determined from the history. Drugs which may be associated with ED include tranquillizers (phenothiazines, benzodiazepines), antidepressants (tricyclics, selective serotonin reuptake inhibitors), and antihypertensives (P-blockers, vasodilators, central sympathomimetics, ganglion blockers, diuretics, ACE inhibitors) (33). In most patients sophisticated investigation is not indicated. A three-step diagnostic approach is shown in Table 1. A detailed history is most important, and for many patients examination can be limited to the regular monitoring of diabetes and its risk factors and complications as well as examination of the genitalia. Patients should be informed about the advantages and disadvantages of each treatment and given advice on treatment outcome and ease of use (34).

Management

A stepwise therapeutic approach for ED is shown in Table 2. An algorithm for treatment of ED has recently been suggested by the second international consultation on erectile and sexual dysfunctions (15; Fig. 2). The initial management should be to advise the patient to reduce possible risk factors and to optimize glycemic control. However, no studies are available to show that improvement in glycemic control will exert a favorable effect on ED. In fact, a recent study could not demonstrate an effect of intensive diabetes therapy maintained for 2 years on ED in men with type 2 diabetes (35). Healthy lifestyle factors are associated with maintenance of erectile function in men. A controlled study recently evaluated the effect of weight loss and increased physical activity on erectile and endothelial functions in obese men. Men randomly assigned to the intervention group received detailed advice about how to achieve a loss of 10% or more in their total body weight by reducing caloric intake and increasing their level of physical activity. Men in the control group were given general information about healthy food

Table 2

Stepwise Algorithm for Treatment of Erectile Dysfunction

Stepwise Algorithm for Treatment of Erectile Dysfunction

Table 2

General management

Control of risk factors and diabetes; sexual counseling

Pharmacological treatment

First line therapy

Dose range

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