Diabetes mellitus is well known as a cause of ED and in turn the incidence of ED among diabetic men is significantly greater than in non-diabetic men. Data from the MMAS identified a 28% probability of complete ED among diabetics compared to a 9% probability among non-diabetics. This increased probability has been associated with the duration of the disease and the paucity of glycemic control. An Italian prevalence study conducted in 1010 men demonstrated that the incidence of ED was 1.64old higher in men with a history of diabetes of at least 11 years duration compared to men who had diabetes for 5 years or less. Patients also had a 1.74 fold increased incidence if the HbAlC was greater than 9% compared with an HbAlC of 7.5% or less. This prolonged hyperglycemic state appears to have a deleterious effect on both the endothelium and the nerve fibers supplying the smooth muscle cells, which in combination prevent vasodilation of the penile microvasculature and hence cause ED.
The endothelial effect of diabetes appears to be associated with anatomical changes in the endothelium as well as a reduction in endothelial function. Diabetic rats (DM) were compared with 10-week old controls (CT) and 18-month-old aged (AD) rats. 24 Penile shafts from these groups were excised and immunochemically stained to identify endothelial cells and smooth muscle cells. Mean cavernosal smooth muscle cell content was 15.28% in the CT group and 9.83% in the DM group (P=0.0001). Cavernosal endothelial cell content was also reduced in the DM group (4.01%) compared with the CT group (6.93%, P<0.0001). Human studies have shown deterioration in endothelial function in diabetic men with ED. Thirty type 2 diabetic impotent men were compared with 30 potent type 2 diabetic men matched for age and disease severity. Endothelial function was assessed by mean blood pressure response to an intravenous infusion of the NO precursor L-arginine. L-Arginine mimics some of the effects of NO, including vasodilation.
Since the vascular effects of L-arginine are derived from its metabolic conversion to NO, the L-arginine test is widely used for evaluating endothelial function. The changes in blood pressure recorded during the infusion of L-arginine were expressed as mean blood pressure variations from baseline. The changes in patients with erectile dysfunction were significantly lower (+0.3 mmHg) compared with potent men (-4.5 mmHg, P<0.05) suggesting a reduced vasodilation response by men with ED to L-arginine and hence endothelial dysfunction. This study also assessed the degree of peripheral and autonomic neurological impairment in both groups of men. Quantitative sensory testing (QST) using vibratory, thermal and pain sensory thresholds using a validated computerized system was performed to assess the peripheral nervous system. QST was pathological in 40% of diabetic men with ED and in only 15% of potent diabetic men (P>0.05). Autonomic nerve function tests included measuring the heart rate variation during deep breathing and squatting. Thirty percent of diabetic men with erectile dysfunctionhad abnormal deep breathing tests compared to 13.3% of potent diabetic men (P=0.05) and 70% of men with only 30% of potent men (P=0.02). Similar tests have been used in various studies comparing diabetic men with and without ED to assess the relative contribution of autonomic and peripheral neuropathy to the pathophysiology of ED .26,2' These studies have similarly shown a reduction in autonomic and peripheral nerve function in diabetic awn with ED, suggesting impairment of neurological function is important in the pathogenesis of erectile dysfunction in diabetic men. Although the relative contribution of endothelial and neurological dysfunction in the aetiology of diabetic-induced ED remains unclear, it appears that the final common pathway for both mechanisms terminates in reduced vascular flow. Recently, penile blood flow studies in 105 diabetic men with ED demonstrated that the most common cause of erectile dysfunction was arterial insufficiency, affecting 64% of men.
Thus, a long duration of the diabetic state and poor hyperglycemic control have a significant deleterious impact on erectile function through mechanisms involving neural and endothelial cells. The effect of this is a reduction in vascular flow in the penile tissues leading to ED, probably in a manner similar to the reduction in coronary blood flow that is commonly seen in these patients.
Hypertension is often cited as a risk factor for ED. Although the MMAS found that patients with hypertension only had an 8.5% risk of acquiring ED, two studies more recently suggest that the prevalence of ED in hypertensive men may in fact be higher and more severe than that predicted by the MMAS. A Spanish study showed the prevalence of ED among 512 hypertensive men to be relatively high at 46.5% and a similar study conducted among 104 hypertensive men in New York showed that the prevalence of erectile dysfunction was 68.3%, with 45.2% of all men complaining of being severely affected.
The question inevitably arises as to whether the ED is caused by penile atherosclerosis due to arterial hypertension or is it a result of antihypertensive therapy used to lower blood pressure. Bansal reviewed various studies comparing the onset of ED in hypertensive men after the initiation of anti hypertensive medication or placebo. In one study he found no difference in the incidence of erectile dysfunction in the active drug arm compared with the placebo arm. However, in a second study he found a 3.39 fold increase in the incidence of ED after active treatment was initiated. Jensen et at found that 44% of hypertensive men with ED attributed their erectile dysfunction to antihypertensive therapy. Although many studies report an increased incidence of ED after initiation of drug therapy, they often fail to establish a significant correlation between various classes of drug and onset of ED. Burchardt et al could not identify any relation between drug class and ED, inspire of the high prevalence of ED among hypertensive men in their study. Due to this lack of specific association between class of antihypertensive agents and ED, it has been suggested that hypertensive patients are more vulnerable to blood pressure reduction and are more likely to experience erectile dysfunction once antihypertensive medication has been initiated. The fact that a variety of pharmacologic agents has been incriminated and no specific mechanism for each of the agents has been identified also suggests that the mechanism may simply be related to a blood pressure- lowering effect.
Animal studies addressing the cellular effects of hypertension on penile tissue may provide some insight regarding the complex relation between ED and hypertension. Changes in cavernous tissue from spontaneously hypertensive rats (SHR) were compared with those in normotensive Wistar-Kyoto rats over an 8-month period.31 SHR had a higher proliferative score in cavernous smooth muscle (2.7 vs 1.1, P<0.001), in vascular smooth muscle (2.7 vs 1.0, P<0.001) and a higher cavernous tissue fibrosis score (2.8 vs 0.1, P<0.001) when compared to normotensive rats. An increase in surrounding connective tissue in the epineurium and endoneurium in the cavernous tissue was also found in the SHR. The degree of proliferation and fibrosis in the penile tissue was positively correlated to systolic blood pressure (SBP) in the SHR, indicating that a higher SBP was associated with a greater morphological change. These focal alterations were not found in age-matched normotensive controls and therefore