Abstract
This study aimed to measure the serum endocan level of patients with erectile dysfunction (ED) and to investigate the possible association between the Endothelial-specific molecule-1 (Endocan) level and ED. Twenty healthy and sixty-four male patients included in the study were divided into four groups: severe ED (19 patients), moderate ED (24 patients), mild ED (21 patients) and control group (20 healthy men). The erectile function of all the patients was evaluated using the International Index of Erectile Function-5 (IIEF-5) questionnaire. The body mass index (BMI) of each participant was determined, together with levels of fasting blood glucose, total testosterone, low- and high-density lipoprotein cholesterol, triglyceride and endocan in serum samples. No significant difference was found between the three ED groups and the control group in terms of the mean age, BMI and the levels of cholesterol and fasting blood glucose (P>0.05). The mean serum endocan level was found to 1.076±0.5, 0.674±0.40 and 0.671±0.3 ng ml−1 in the severe, moderate and mild ED groups, respectively. This indicated that the highest value was obtained from the severe ED group, and the difference between the severe ED group and the other groups was statistically significant. In the control group, the serum endocan level was 0.73±0.46 ng ml−1, which was significantly higher compared to the moderate and mild ED groups (P<0.05). The significant difference between the control and ED groups in terms of the serum endocan level can assist in the evaluation of endothelial pathologies in the etiology ED.
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Introduction
Erectile dysfunction (ED) is defined as penile erection that is insufficient and unsustainable for a satisfactory sexual performance.1 In various studies providing different definitions of ED, the incidence of ED has been reported to increase with age, ranging from 20 to 40% between 60 and 69 years, and 50 to 100% between 70 and 80 years of age.2 The etiology of ED is multifactorial including chronic diseases such as hypertension (HT), diabetes mellitus (DM) and coronary artery disease (CAD) and also the side effects of the medication used to treat these conditions.3 However, the main underlying cause is degenerative changes that result in endothelial dysfunction.4 In addition, metabolic conditions associated with ED lead to endothelial dysfunction and a pro-inflammatory state, which reduces the usability and activity of nitric oxide (NO). NO is a powerful force for sustaining penile blood flow; therefore, there are many cardiovascular risk factors associated with ED in men.5 Furthermore, in ED cases without apparent atherosclerosis, impaired endothelial dysfunction is one of the early signs of the development of atherosclerosis.6 As ED emerges as secondary to atherosclerosis, it is considered an early sign of atherosclerosis and severe systemic diseases.7
Endothelial-specific molecule-1 (Endocan) is a sulfate proteoglycan released from endothelial cells.8 Endocan has a role in endothelial-dependent pathological conditions such as tumor adhesion, progression, migration, angiogenesis and inflammatory diseases.8 It increases the production of pro-inflammatory cytokines by the endothelial cells and microvascular permeability, and regulates leukocyte migration.9 Endocan is also considered an endothelial mediator contributing to neointima formation in atherosclerosis by stimulating the proliferation and migration of vascular smooth muscle cells.8, 9 The serum endocan level has been reported to increase in patients with vascular involvement or vascular invasion.10, 11
Owing to its role in a wide range of endothelium-dependent pathologies from cardiovascular diseases to cancer, endocan has been suggested as a marker for endothelial dysfunction.12, 13, 14 In a recent study, the serum endocan level of patients with acute coronary syndrome (ACS) was found to be significantly higher than the healthy control group.15 However, to the best of our knowledge, there are no studies in the literature that investigated the relationship between ED and serum endocan level. Therefore, the present study is significant in terms of being the first report on this subject.
Materials and methods
Following approval from the local ethics committee, a total of 64 ED patients who had been referred to our urology clinic and 20 healthy hospital personnel (control) were included in the study. All the participants gave their written informed consent. All the patients reported having experienced ED problems in their sexual activity within the last 6 months. The participants were all asked to complete the International Index of Erectile Function-5 (IIEF-5) questionnaire, taking into consideration their sexual activities within the last 6 months. The answers were assessed on a 25-point scale: a score of ⩾22 indicated no ED, and scores of 17–21, 12–16, 8–11 and 1–7 indicated mild, mild–moderate, moderate and severe ED, respectively.16 According to their IIEF-5 scores, the ED patients were divided into three groups: severe ED (n:19, score: 1–7), moderate ED (n:24, score: 8–11) and mild ED (n:21, score: 11–21). The IIEF-5 score of the healthy control group (n:20) was >21. The patients with a history of major psychiatric disorders or with psychological cause of ED, any tumoral diseases, neurological disorders, pelvic trauma, anemia, thyroid disease, acute/chronic urinary tract inflammation and end-stage renal failure, those that had used any medication affecting the sex hormone and/or vitamin metabolism within the last 3 months or those who were currently undergoing ED treatment were excluded from the study. Demographic information such as age and the medical history of all the participants was recorded. The participants’ weight and height were measured and their body mass index (BMI) was calculated dividing weight in kg by the square of the body height in m2.
Laboratory tests
Following 12 h of fasting, blood samples were collected from all the participants at 0800 hours and stored at −20 °C until testing. The fasting levels of blood glucose, total testosterone, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and serum endocan were measured.
Human Endocan measurements
The serum endocan level was measured using the enzyme-linked immunosorbent assay (ELISA) method (SunRedbio ELISA Kit, Shanghai Sunred Biological Technology, Shanghai, China) and the Epoch Microplate Spectrophotometer (BioTek Instruments, Winooski, VT, USA).
Statistical analysis
The data were analyzed using the SPSS package program (Chicago, IL, USA, version 17). Descriptive statistics were expressed as mean±s.d. and frequency (%). After checking the assumptions of normality and the homogeneity of the variances, the variables were evaluated using Shapiro–Wilk and Levene tests. For the comparison of three or more groups, one-way variance analysis with post hoc Tukey honestly significant difference was used. When the assumptions of the parametric test were not met, Kruskal–Wallis and Bonferroni–Dunn's post hoc test were utilized. The analysis of categorical data was performed with χ2 and Fisher’s exact tests. In cases where the expected frequency was found to be less than 20%, the Monte Carlo Simulation method was used to include these frequencies in the analysis. The level of significance was accepted as α=0.05. A P-value<0.05 was considered to indicate statistical significance. The P-value is defined as the probability of obtaining a result equal to or ‘more extreme’ than what was actually observed, when the null hypothesis is true. α= A type I error (or error of the first kind) is the incorrect rejection of a true null hypothesis. Usually a type I error leads one to conclude that a supposed effect or relationship exists when in fact it does not. Examples of type I errors include a test that shows a patient to have a disease when in fact the patient does not have the disease, a fire alarm going on indicating a fire when in fact there is no fire, or an experiment indicating that a medical treatment should cure a disease when in fact it does not.
Results
The mean age of the all patients was 54, 6±8 and 19. No statistically significant difference was found between the four groups in terms of the mean age, BMI and the levels of fasting levels of blood glucose, HT, CAD, high-density lipoprotein, low-density lipoprotein and total cholesterol. The mean IIEF-5 scores were 6.1±0.94, 9.7±0.9, 15.5±3.3 and 23.8 ±1.3 in the severe, moderate, mild ED and control groups, respectively. Table 1 presents the clinical data and the results of the levels of the fasting endocrine. The mean serum endocan level was found to be 1.07±0.5, 0.674±0.40 and 0.671±0.3 ng ml−1 in the severe, moderate and mild ED groups, respectively. This shows that the highest endocan level was observed in the severe ED group, and the difference between the severe ED group and the other groups was statistically significant. In addition, the moderate ED group had higher serum endocan level than the mild ED group, but was not statistically significant. In the control group, the serum endocan level was found to be 0.73±0.46 ng ml−1, which was significantly higher compared to the moderate and mild ED groups (P<0.05). All the patients in the ED groups had a lower IIEF-5 score than the control group. There was no statistically significant difference between the groups in terms of DM, HT, CAD and the use of smoking. This shows that the highest total testosterone level was observed in the mild ED group, and the difference between the other groups was statistically significant. The mean serum TG level in severe ED group was significantly highest in all groups, and TG level of control group was higher than mild and moderate ED groups (P<0.05).
Discussion
Endothelial dysfunction is usually characterized by impaired NO bioavailability, reduced vasodilation and deteriorating inflammation prior to the development of atherosclerotic lesions.6, 7 There is a significant pathophysiological relationship between ED and cardiovascular risk factors.17 In the early stage of atherosclerosis, a loss of endothelial NO occurs. It has also been reported that reduced NO is associated with other atherogenic risk factors such as dyslipidemia, HT, DM, age, smoking, hyperhomocysteinemia, menopause and family history.18, 19
It is well known that underlying the formation and progression of atherosclerosis is a multifactorial process comprising conditions such as substantially increased oxidative stress and low-grade chronic inflammation.20, 21 ED is a stimulant biomarker for cardiovascular risk factors. Morley et al.22 reported that 57% of men who had undergone coronary bypass surgery and 64% of myocardial infarction patients had existing ED. In a 2-year, randomized, controlled trial investigating whether ED was an indication of cardiovascular events demonstrated that ED was a potent predictor of myocardial infarction, stroke and heart failure in patients with pre-existing cardiovascular disease.23
In their study, Menon et al.8 defined endocan as a new proteoglycan of endothelial origin that contributes to neointima formation in atherosclerosis by stimulating the proliferation and migration of vascular smooth muscle cells. Inflammatory cells, proteins and vascular cell responses have a central role in the different stages of the pathogenesis of atherosclerosis such as the initial stage, progression, plaque instability and rupture.24 Endocan is considered to have a specific mechanism in vascular diseases, organ-specific inflammation and endothelium-mediated diseases.25 Endocan is released from the vascular cells particularly in inflamed endothelia.26 The high levels of serum endocan reported by previous studies in tumor progression and inflammatory diseases indicate that endocan can be a potential biomarker for endothelial activation and dysfunction.8 Yilmaz et al.27 found a positive correlation between serum endocan concentrations and inflammatory markers. In addition, the authors demonstrated that the serum endocan level was also associated with morbidity in chronic kidney diseases and cardiovascular events.27
In a recent study, Kose et al.15 compared the serum endocan level of 53 patients with acute coronary syndrome (ACS) and 30 healthy individuals, and found it to be significantly higher in the ACS group compared to the control group. Balta et al.14 reported a significant increase in the endocan level of untreated HT patients. The authors considered that the association between HT and endothelial dysfunction was related to endothelial damage, activation and dysfunction caused by oxidative stress. Similarly, Wang et al.28 evaluated the serum endocan level in 164 patients with HT, and found it to be correlated with CAD regardless of the presence and severity of the disease.
Another condition that can cause endothelial damage is DM. A few studies have demonstrated the role of chronic and subclinical inflammation in the formation of insulin resistance leading to the development of apparent DM.29 In a recent study, Kose et al.15 explored the relationship between serum endocan level and DM, and reported that the serum endocan level was significantly higher in 11 patients with diabetes than in 42 non-diabetics with ACS. The authors concluded that diabetic patients with ACS can suffer from more severe vascular damage.15
İn this study, there was no statistically significant difference between the groups in terms of DM, HT, CAD and the use of smoking. However, in a previous study subclinical ED and low-grade inflammation underlie the pathogenesis of ED in young males; therefore, these patients complaining of ED should be screened for cardiovascular risk factors and possible subclinical atherosclerosis.30 A meta-analysis of 12 prospective studies involving 36 744 males confirmed a statistically increased overall risk for CVD, CAD and stroke, and an increase in all cause mortality in males with ED and no cardiac symptoms.31
Data from the Olmstead County Study showed that ED in males 40–49 years of age was far more predictive of CAD than ED in older patients.32
In the literature, there are also studies that evaluated the relationship between atherosclerosis and ED to investigate whether certain glycoproteins such as Fetuin-A can be used as a biomarker for these conditions.33 Similarly, in the present study, the serum levels of another protein, endocan, was found to be significantly higher in patients with severe ED compared to the control group. This indicates that determining the endocan level is useful for the diagnosis and follow-up of ED. The limitations of our study include the small number of participants and the absence of penile Doppler ultrasonography for the detection of ED.
Conclusion
This study is the first study evaluating the relationship between ED and serum endocan level. This study showed that the serum endocan level can be useful in the evaluation of the etiology of ED associated with atherosclerosis and endothelial events. Future studies with a larger series are needed to confirm the results of the present study.
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Karabakan, M., Bozkurt, A., Akdemir, S. et al. Significance of serum endothelial cell specific molecule-1 (Endocan) level in patients with erectile dysfunction: a pilot study. Int J Impot Res 29, 175–178 (2017). https://doi.org/10.1038/ijir.2017.19
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DOI: https://doi.org/10.1038/ijir.2017.19
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