2 Erectile dysfunction
Erectile dysfunction (ED) is defined as the impossibility of achieving or inability of maintaining an erection, which should be sufficient enough to allow a satisfactory sexual activity, lasting over a period of at least 6 months. It is a common condition in the general male population, and many risk factors may influence its development: general cardiovascular factors, age, smoking habits, hypercholesterolemia, arterial hypertension, psychological stress, but also hormonal and neurological causes [4].
Physiological penile erection is characterized by the combination of vascular, hormonal and neuronal processes, which control the balance between arterial inflow and venous outflow. In response to different stimuli, smooth muscle cells surrounding penile arteries relax, determining increased arterial inflow in the spaces of the corpora cavernosa. Subsequently, there is an expansion and an elongation of the tunica albuginea and the trabecular wall, leading to venules compression and reduced outflow. All these events contribute to penile erection, which then ends with the reversal of the same processes [5].
2.1 Assessment and management
When facing a male SSc patient ED should be always suspected. Therefore, it is important to routinely ask the patient whether they have relevant symptoms and if so, to define as clearly as possible the problem, including duration, triggering factor, entity of sexual desire and orgasmic function, relationship status, as well as past and concurrent medical, psychological and surgical history. Risk factors for ED are common to other cardiovascular diseases (sedentary life, obesity, smoking, hypercholesterolemia and metabolic syndrome). ED itself can be considered as a cardiovascular risk, determining a 1, 46 times increased risk for cardiac events [6]. Pharmacological history is also very important, as a constantly increasing number of drug favor or trigger ED. The list includes thiazides, antihypertensives (as beta-blockers and clonidine), digoxin, fenofibrate, antidepressants (tricyclics, MAOIs, lithium, SSRIs), ranitidine, hormones (such as estrogens/progesterone, corticosteroids, 5-aplpha reductase inhibitors, LHRH antagonists), cytotoxic agents as cyclophosphamide and methotrexate, and anticholinergics [7].
Patient examination should also focus on genital examination, patient reported penis deviation during erection, signs of endocrine disorders (i.e. hypogonadism), and of course blood pressure, heart rate and BMI [7,8]. Further investigation should be patient tailored, as ED could be the presenting sign of underlying diseases such as diabetes or central/peripheral arterial disease. Fasting lipid and glucose measurement should be performed on all patients. Hypogonadism is a common treatable cause of ED that makes the response to phosphodiesterase-5 inhibitor treatment less or non effective; therefore, morning testosterone levels, as well as PSA, LH, FSH and prolactine should be measured.
Patients with known cardiovascular diseases should be counseled appropriately, as ED could be the first sign of an underlying coronary artery disease. According to the level of cardiovascular risk, ED management should be undertaken in primary care or supervised by a specialist cardiologic team [8].
In some cases non-invasive or invasive investigation may be needed: nocturnal and early awaking erections can be evaluated through two strains applied to penis base and tip, measuring rigidity and number of erection in a home private ambient (nocturnal penile tumescence and rigidity test) [9]; penile rigidity assessment 10 min after PGE1 intracavernosal injection is useful to determine penile deformities and guide toward surgical management. Penile arteries Duplex ultrasound can be useful to quantify vascular parameters such as peak systolic velocity (PSV) to evaluate arterial blood inflow, end diastolic velocity (EDV) and resistive index (RI, calculated as [PSV-EDV]/PSV) to assess venous-occlusive function. Consecutively, selective pudendal arteriography is pivotal to confirm the presence of arterial lesion [10], while cavernosometry and cavernosography can evaluate and clarify the presence of veno-occlusive dysfunction, identifying sites of venous weakness. These assessments are usually performed after referral to an ED service.
As a subjective monitoring tool, the “Sexual Health Inventory for Men (SHIM)-International Index of Erectile Function (IIEF) 5” is a validated score to assess erectile dysfunction and it is available in several languages. It investigates all the relevant domains of male sexual function, including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satisfaction. Each item is scored 1 to 5, with lower scores representing more severe impairment. A cumulative score higher than 21/30 is considered as normal, while scores below 21 are clustered as mild (17–21 points), mild-to-moderate (12–16 points), moderate (8–11 points) and severe (5–7 points) erectile dysfunction [11]. Previous studies showed that general middle-aged population reported moderate erectile dysfunction in 8.5% of the cases, with mean IIEF-5 score of 21.3 ± 4.9 [12].
2.2 Erectile dysfunction in systemic sclerosis: literature review
When considering rheumatologic patients, ED has been reported as a widespread problem, involving up to 81% of the sexually active male SSc population [13–17]. When compared to rheumatoid arthritis patients, ED is significantly more frequent in SSc patients (84% vs. 59%) and strongly associated with the presence of Raynaud's phenomenon [18], with more frequent onset after disease symptoms and diagnosis, usually within a time gap of 3 to 4 years [19].
In SSc the pathogenesis of ED in SSc has been thoroughly investigated but not yet completely clarified. For ED, the presence of a hormonal and neurological cause has been excluded [13,18,20], while combined vasculopathic and fibrotic changes have been hypothesized [21,22]. A case presentation reported firm corporeal fibrosis with veno-occlusive dysfunction and loss of penile length [23]; these changes were then histologically related to accumulation of extracellular matrix. In fact, it is known that under hypoxic conditions there is over-expression of platelet derived growth factor, transforming growth factor beta 1 and their receptors in the corpora cavernosa. This may support the hypothesis that penile fibrotic changes are caused in SSc by events similar to those involved in the general skin and organs [24,25].
Analyzing the EUSTAR database, ED assessed with IIEF-5 was more frequent in SSc patients with higher alcohol consumption and older age, showing an association with disease activity (in terms of impaired pulmonary function tests, as indicator of restrictive lung disease and/or pulmonary vasculopathy) but not with disease duration [15]. In the same study population, no significant association between qualitative nailfold videocapillaroscopy (NVC) and ED, with no difference in prevalence of advanced late pattern in ED vs. non ED group. This could suggest a possible lack of sensitivity of the qualitative classification in detecting and distinguishing smaller degrees of vascular involvement [26].
From the vascular point of view, dynamic color power Doppler sonography may thoroughly evaluate and characterize blood flow in the cavernosal arteries [27]. A marked reduction of PSV in 15 SSc male patients, associated with concomitant veno-occlusive dysfunction was found in 66% of SSc population [21], excluding the presence of atherosclerotic macrovascular involvement. A few years later the same data were confirmed, showing a correlation of Medsger disease severity scale with either reduced IIEF5 and indices of veno-occlusive dysfunction. The same parameters were also statistically different when comparing patients with low (i.e. early and active NVC patterns) and high vascular damage (i.e. late NVC pattern), showing a greater impairment in the latter group [28]. Recently, a positive correlation was also found between IIEF-5 and PSV, while negative correlation was shown between IIEF-5 and EDV and RI. This suggests that both aterogenic ED and veno-occlusive dysfunction are associated with progression of endothelial dysfunction and microvascular NVC damage [29]. In SSc, other data on penile and kidney arteries indexes of veno-occlusive dysfunction, as well as penile and digital arteries Doppler indices of both arterial inflow and venous function, showed a correlation with vascular impairment in the different districts [30]. The penile temperature assessed by non-contact thermal imaging is reduced in SSc patients with ED, with significantly impaired recover from cold test when compared to healthy controls, both in terms of amplitude and time [31].
All these data are currently supporting the hypothesis that ED and SSc vascular damage are strongly correlated. In early SSc this can mainly be as reduced penile inflow, similar to Raynaud's phenomenon, configuring the so called “scleroderma penis”. The fibrotic and veno-occlusive components occurring with disease progression then determine a more severe and challenging ED [24].
2.3 Treatments
ED shares modifiable risk factors with other cardiovascular diseases (CVD): as modification of life-style, psychological or drug-related factor might be helpful with CVD, in turn it might help with ED as well. A recent review [32] concluded that life-style intervention and reduction of CV risk factor had a sexual effect on ED and sexual function in the general population. Such treatments alone can often be of partial efficacy and the necessity of pharmacological treatment should then be considered.
Oral pharmacological treatment with phosphodiesterase-5 inhibitors (PDE-5i) is considered as a first line option. This may increase the penile concentration of cGMP by inhibition of PDE-5, determining relaxation of penile smooth muscle cells and temporarily increasing penile arterial blood supply. The effect of this class of drug requires a previous sexual stimulation to initiate the erection and it is useful in maintaining it through the sexual intercourse. Three different PDE-5i have been commonly available for the treatment of ED: sildenafil, tadalafil and vardenafil. More recently new molecules of the same family have been commercialized: udenafil, avanafil and mirodenafil. Despite the similarity in pharmacological and clinical characteristics, they strongly differ for half-life, which is usually 3 times longer for tadalafil when compared to sildenafil [33]. A recent review [34] confirmed the equivalence of these different PDE5-I, with minor differences in the safety profile.
Few data are available on the efficacy of PDE-5i in SSc: a small case series from Ostojic and Damjanov [22] showed low efficacy of sildenafil 20–50 mg on demand. Tadalafil has proven to be more effective in the general population when administered on a fixed alternate dose of 20 mg, in comparison to the same dose on an on-demand regimen. An increase of flow-mediated dilatation and PSV, as well as an improvement in morning erections, have been reported after a treatment period of 4 weeks [35]. A following study evaluated a smaller daily dose of tadalafil (10 mg): after 12 weeks of treatment an increase in the IIEF-5 score was obtained together with an improvement of PSV and morning erection, even in asymptomatic patients [36].
Patients not responding to or not tolerating PDE-5i oral treatment may benefit from vacuum constriction devices, which determine increased blood flow by using vacuum, followed by an elastic bondage of penis base, in order to prevent blood outflow. This technique was reported to significantly improve sexual performance and partner sexual satisfaction [37]. As an alternative, prostaglandin analogues can be administered via intracavernous injection, intra-urethral suppositories or topical application [38]. Alprostadil is an analogue of prostaglandin E1 which has vasodilatant effect through reduction of intracellular calcium concentration, therefore determining smooth muscle cell relaxation; several randomized clinical trials supported its effectiveness, which was higher in case of intracavernosal administration [39]. Interestingly, a recent phase I study showed also the efficacy of iloprost, a prostacyclin analogue, in improving the fibrotic changes in Peyronie's disease when used as intra-lesional administration [40].
Penile prosthesis is considered as a third line option in case of pharmacological treatment failure and the choice of the device nature (malleable or inflatable) is mainly related to patient's ability to manage it. The overall satisfaction for this treatment is high, with excellent mechanical reliability and improved overall patient's and partner's sexual satisfaction. As a surgical intervention, evaluation of risk factors has to be taken into consideration, such as device failure and infection, even though it is considered a safe and permanent solution for ED [41]. Recent studies are also evaluating the possible approach of mesenchymal stem cell or adipose tissue stem cell transplantation as a possible treatment for ED, as well as gene therapy to act on endothelial nitric oxide synthase or vascular endothelial growth factor pathways [42].
