**7. Sexual functioning in male with systemic sclerosis**

Systemic sclerosis is an autoimmune connective tissue disorder characterized by following typical findings: endothelial changes, microangiopathic damages, and progressive fibrosis. These pathological processes may affect various organs including penile arteries leading to erectile dysfunction (ED). Male erectile dysfunction is defined as the consistent inability to reach and maintain an erection sufficient to permit satisfactory sexual performance. It is a widespread issue in men with systemic sclerosis. Sexual dysfunction in men has been given more attention than female sexual dysfunction, and the etiology is more obvious compared to women. Erectile dysfunction is a result of microangiopathic changes, when the blood flow is reduced in the small penile arteries due to corporal fibrosis and myointimal proliferation [5]. It was proven that damage of the penile cavernous arteries occurs in almost all SSc patients regardless of clinical symptoms. They are characterized by the presence of hyperechoic spots, suggesting fibrotic changes and low peak systolic velocities that are signs for vascular alterations [58].

The prevalence of erectile dysfunction in SSc patients ranged from 12 to 81% in different studies [28]. However, most studies agree that about 80% of SSc men are affected [11–13]. It was also found that ED is more prevalent in systemic sclerosis than other inflammatory rheumatic diseases. In a majority of men with systemic sclerosis, ED started to manifest after the onset of the disease. The mean duration from the onset of the first SSc symptom to erectile dysfunction was around 3 years [12]. Risk factors of erectile dysfunction such as smoking, hypertension, diabetes, and steroid use have been investigated. It was found that only self-reported history of nerve damage and diabetes are significant for predicting the likelihood of ED in systemic sclerosis. There are also risk factors that are presented in non-SSc men as well, like older age or alcohol consumption. The ED association with more severe diseases in terms of worse skin involvement, elevated pulmonary arterial pressures, presence of restrictive lung disease, and muscular and renal involvement in SSc patients was also confirmed [5, 12, 13, 59].

The most likely hypothesis of ED in SSc is a combination of vascular and fibrotic abnormalities. In men with SSc, decreased penile blood pressure, impaired peak systolic and diastolic blood flow in the penile arteries, and the presence of venoocclusive dysfunction were found. Also, a decreased penile temperature and a slow recovery after cold exposure were reported. A duplex sonography was conducted to reveal the thickening of tunica albuginea and diffuse hyperechogenic spots within the corpora cavernosa. All these findings point to the microangiopathic cause of ED in male SSc patients. This is confirmed by the fact that no carotid artery thickening has been found in SSc, which would predict atherosclerotic macroangiopathy. From a histological point of view, the ED cause in SSc men is the presence of severe corporal fibrosis, increased collagen production by penile smooth muscle cells, and increased accumulation of extracellular matrix. Due to these changes, penile hypoxia arises, which can lead to overexpression of platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β1 and TGF-β1 receptors in the corpora cavernosa, which are important profibrotic regulators of collagen synthesis and production of extracellular matrix. In addition, endothelin (ET-1) is also released by penile smooth muscle cells. Thus, penile hypoxia stimulates penile fibrosis. Therefore, it can be assumed that once ED in patients with SSc is manifested (due to disease), its next mechanisms are similar to those of non-SSc

population. Other causes such as hormonal abnormalities or neurological causes have not been confirmed. No disturbances have been found in follicle-stimulating hormone, luteinizing hormone, serum testosterone, prolactin, estradiol, and thyroid hormones in SSc patients [5, 11, 59, 60].
