Sexual dysfunction has been reported in 20% to 50% of men with chronic renal failure ( Carson and Patel, 1999 ). A cross-sectional study demonstrated a 45% prevalence of self-reported severe ED among men receiving hemodialysis ( Rosas et al, 2001 ). The risk increased with age, diabetes, and nonuse of ACE inhibitors. Many of the effects of persistent uremia can potentially contribute to the development of ED, including disturbance of the hypothalamic-pituitary-testis sex hormone axis, hyperprolactinemia, accelerated atheromatous disease, and psychologic factors ( Ayub and Fletcher, 2000 ).
Studies of the L-arginine–NO pathway in erythrocytes suggest that uremia decreases NO bioavailability ( Mendes Ribeiro et al, 2001 ). These findings have stimulated experiments to determine the effect of chronic uremia on cavernous smooth muscle in animal models. In in vitro experiments with cavernous strips from rabbit, Bagcivan and coworkers (2003) found that a chronic uremic state resulted in impaired neural and endothelium-mediated relaxation of cavernous smooth muscle, while relaxation induced by NO donors was preserved. These findings suggest either decreased production or reduced bioavailability of endogenous NO ( Bagcivan et al, 2003 ). In a similar set of experiments from the same laboratory, the investigators found no change in the cavernous relaxant response to activation of the purinergic system ( Kilicarslan et al, 2002 ). In a rat model, an earlier paper related low serum levels of testosterone to low intratesticular levels of zinc in uremic animals and suggested this as a factor in sexual dysfunction ( Ribeiro et al, 1982 ). A more recent study with this model suggested that deficiency of functional NO may result from oxidative stress, leading to inactivation of NO by oxygen radicals. Interestingly this effect was reversed by treatment with vitamin E, an antioxidant ( Vaziri et al, 2002 ). Evidence from animal models of chronic uremia therefore suggests that a decrease in functional NO may be responsible for vascular side effects, including ED. Several putative mechanisms may lead to such a deficiency, such as reduced bioavailability of the NO substrate L-arginine, reduced expression of NOS isoforms in the relevant organs, rapid quenching of NO by reactive oxygen species known to be increased in chronic renal failure, and the accumulation of uremic inhibitors of NOS ( Vaziri, 2001 ).
Evidence of autonomic neuropathy as a factor contributing to ED in men with chronic renal failure comes from three studies that found a high rate of abnormality in vascular and bulbocavernous reflexes, suggesting nerve dysfunction ( Campese et al, 1982 ; Vita et al, 1999 ). The putative role of hyperprolactinemia and zinc deficiency as factors reducing sexual and reproductive function in men and women receiving dialysis prompted researchers to determine a mechanism. The results were conflicting, with one controlled trial finding no benefit of treatment with either a prolactin inhibitor or zinc ( Rodger et al, 1989 ), whereas others found that treatment with erythropoietin (to reduce prolactin) ( Schaffer, 1989 ) or with zinc supplements ( Mahajan et al, 1982 ) improved sexual and reproductive function in patients with uremia. The significance of nonspecific factors related to a chronic disease state, such as depression and fatigue, was suggested by a case-control study that found similar rates of ED in age-matched men receiving renal replacement therapy and in those with rheumatoid arthritis and normal renal function ( Toorians et al, 1997 ). Investigation of cavernous vascular function in 20 men undergoing renal replacement therapy showed that 80% had both arterial insufficiency and veno-occlusive dysfunction ( Kaufman et al, 1994 ). Current knowledge would suggest that this combination represents failure of sinusoidal relaxation owing to functional or structural alterations of cavernous smooth muscle. A link with possible impairment of the NO-cGMP pathway relating to failure of cavernous relaxation is provided by the finding of increased serum levels of endogenous inhibitors of NO synthesis in uremic patients ( Vallance et al, 1992 ).
Patients with severe pulmonary disease often fear worsening dyspnea during sexual intercourse. Patients with angina, heart failure, or myocardial infarction can become impotent because of anxiety, depression, or arterial insufficiency. Other systemic diseases such as cirrhosis of the liver, scleroderma, chronic debilitation, and cachexia are also known to cause ED.
Primary Erectile Dysfunction
Primary ED refers to a lifelong inability to initiate or maintain erections, or both, beginning with the first sexual encounter. Although most cases owe to psychologic factors, a small number of afflicted men have a physical cause resulting from maldevelopment of the penis or the blood and nerve supply. Primary psychologic dysfunction is usually related to anxiety about sexual performance stemming from adverse childhood events, traumatic early sexual experience, or misinformation. Endocrine abnormalities, particularly low testosterone levels, may also be implicated in primary ED, although lowered sex drive is likely to be the main symptom. Evidence to support these concepts is confined to observation studies with varying numbers of cases. The largest study described 67 patients, of whom 10 (15%) had a predominantly psychologic cause ( Stief et al, 1989 ). Those with physical abnormalities had a variety of neurologic, arterial, and veno-occlusive dysfunction.