The endothelial dysfunction observed following ROS and RNS overproduction has been clearly identified as a possible cause of impaired erectile function. It is therefore unsurprising that many researchers have tried to understand whether administration of antioxidants might have an effect on ED via improvement of the NO/cGMP pathway. PDE-5 inhibitors act at the end of the pathway, by reducing the intracellular breakdown of cGMP and therefore providing longer and more valid erections; however, it has been hypothesized that administration of antioxidants might improve the scavenging systems of the penile vascular bed, thus reducing the formation of ROS and RNS.

Several different mechanisms have been investigated as possible targets for treatment [18]. As previously reported, L-arginine is a fundamental substrate for the chemical reaction leading to the formation of NO. Arginase, an enzyme competing with NOS for the substrate L-arginine, is a possible target for treatment: arginase inhibition might in fact increase the availability of serum L-arginine. In animal models, this has shown promising results both in vivo and in vitro [5, 49]; furthermore, since arginase is also involved in aberrant vessel growth and remodeling, it is possible that its inhibition might reverse or prevent vascular and endothelial dysfunction [19]. Oral administration of L-arginine does not significantly increase its serum levels because of intestinal and liver metabolism [18]; administration of L-citrulline, on the other hand, might be useful in increasing the plasmatic concentration of L-arginine. This treatment has been proven effective in rats with arterial ED [53]; in men, administration of L-carnitine has induced some improvements in men with mild forms of ED [13], with good safety and compliance profiles. Polyphenols may also act as antioxidants: resveratrol, a polyphenol commonly found in red wine, is known to improve endothelial function by activation of NOS [17] and by suppression of apoptosis [59]; similar effects have been discovered following administration of a different polyphenol, quercetin, in animal models [60].

As previously discussed, NO reacts with free radicals, ultimately resulting in production of cytotoxic compounds; antioxidants and free radical scavengers – including vitamin E, selenium, and glutathione [54] – reduce the quantity of ROS and, therefore, improve the availability of NO while at the same time reducing ROS-mediated endothelial damage [1, 10]. It has recently been hypothesized that testosterone is somehow involved in ROS production [35]: oxidative stress might be the missing link between testosterone deficiency and cardiovascular risk [56]. Literature in regard to the effects of specific antioxidant compounds in treatment of erectile function is severely lacking, despite the potential for treatment. Administration of ROS scavengers might improve the efficacy of PDE-5 inhibitors [39], as these drugs act at different levels in the NO/cGMP pathway. Oxidative stress is perhaps the common trait between some closely related conditions – cardiovascular diseases, metabolic syndrome, diabetes, lower urinary tract symptoms, and ED to name a few – which can be associated as risk factors for each other [2].

Priapism is defined as persistent and often painful penile erection in the absence of sexual stimulation, frequently lasting more than 4 h and possibly resulting in penile fibrosis and erectile dysfunction: despite being a rare condition in the general population, its prevalence is higher among subjects with sickle cell disease or affected by perineal trauma [52]. Ischemic priapism is a medical and surgical emergency, similar to penile compartment syndrome; penile tissue shows a hypoxic and acidotic condition which requires immediate attention and might result in permanent ED if left untreated. Nonischemic priapism, occurring in about 5 % of cases, is the result of excess unregulated arterial flow to the corpora cavernosa; differently from ischemic priapism, this form is not considered an emergency, as oxygenation of the penile tissue is not interrupted. However, in almost 30 % of those affected, ED might develop despite the supposed benignity of the condition [8]: this phenomenon might be explained by the penile tissue damage associated with the traumatic development of this form of priapism.

Patients with sickle cell disease might develop a recurrent form of priapism, described as stuttering priapism, frequently occurring in their 20s; medical treatment of stuttering priapism is an emergency, although hormonal therapy for prevention of recurrences has been considered and is a viable choice [33].