Association of oxidative stress with erectile dysfunction in community-dwelling men and men on dialysis

Abstract

Objectives

To investigate the association between oxidative stress and erectile dysfunction (ED) in community-dwelling men and men on dialysis.

Methods

This cross-sectional study included 398 community-dwelling men and 42 men on dialysis. Oxidative stress was assessed using 8-hydroxy-2'-deoxyguanosine (8-OHdG). Univariable and multivariable logistic regression analyses were performed to evaluate the association between oxidative stress and ED.

Results

Spearman’s rank correlation test showed no significant correlation between urine 8-OHdG levels and the 5-Item International Index of Erectile Function scores in community-dwelling men (ρ = −0.005, p = 0.917) and between plasma 8-OHdG levels and the Sexual Health Inventory for Men scores in men on dialysis (ρ = 0.166, p = 0.295). In community-dwelling men, univariable and multivariable analyses revealed that urine 8-OHdG level was not significantly associated with ED (odds ratio [OR]: 1.005, 95% confidence interval [CI]: 0.884–1.144, p = 0.934; OR: 0.930, 95% CI: 0.798–1.084, p = 0.353; respectively). In men on dialysis, univariable analyses revealed that plasma 8-OHdG level was not significantly associated with severe ED (OR: 0.967, 95% CI: 0.876–1.066, p = 0.498).

Conclusions

Oxidative stress was not significantly associated with ED prevalence and severity in community-dwelling men and men on dialysis.

Keywords:

• Erectile dysfunction
• oxidative stress
• 8-OHdG
• end-stage renal disease
• community-dwelling

Introduction

Erectile dysfunction (ED) is defined as the inability to achieve or maintain sufficient penile erection for satisfactory sexual intercourse and frequently perceived by the patient as a serious condition [1,2]. It has been reported that the global prevalence of ED was 3.0–77% [3].

Oxidative stress reflects an imbalance between the production of reactive oxygen species (ROS) and host antioxidant defense systems [4]. Oxidative stress decreases the bioavailability of nitric oxide (NO) and induces mitochondrial dysfunction, inflammation, and endothelial NO synthase uncoupling. These develop endothelial dysfunction by increasing the adhesion of monocytes to endothelial cells (ECs), impairing the angiogenic potential of ECs, and inducing apoptosis. In addition, ROS-induced mitochondrial dysfunction contributes to the additional ROS production by altered mitochondrial metabolism, leading to the exacerbation of endothelial dysfunction. Endothelial dysfunction enhances the phenotypic change of vascular smooth muscle cells and eventually contributes to the development of atherosclerotic disease and cardiovascular disease (CVD) [5].

The preceding evidences suggest that oxidative stress is closely associated with well-known risk factors of ED, including hypertension (HTN), dyslipidemia, diabetes mellitus (DM), metabolic syndrome, and hypogonadism [6–10]. Therefore, numerous studies have investigated the role of oxidative stress in the etiology of ED using animal models [11–14] and identified oxidative stress as a potential therapeutic target. However, the association between oxidative stress and ED in humans remains to be elucidated. Thus, we aimed to evaluate this association in community-dwelling men in the present study.

Moreover, although it has been reported that end-stage renal disease (ESRD) and dialysis were associated with elevated oxidative stress [15–18], no study has investigated the association between oxidative stress and ED in patients with these backgrounds. We hypothesized that oxidative stress might contribute greatly to the severity of ED in men on dialysis. Therefore, we also aimed to evaluate this association in men on dialysis.

Materials and methods

Ethics statement

This study was conducted in accordance with the ethical standards of the Declaration of Helsinki. This study was comprised of two cross-sectional studies that evaluated community-dwelling men and men on dialysis. The data of community-dwelling men were collected from the Iwaki Health Promotion Project, and the study was approved by the ethics review board of Hirosaki University Graduate School of Medicine (authorization number: 2014–377). The project was designed to prevent lifestyle-related diseases, promote health, and extend the lifespan of the residents of Hirosaki City (Iwaki District) in collaboration with Hirosaki City, Hirosaki University, and the Aomori Prefecture General Screening Centre. All the participants voluntarily participated in the project and provided written informed consent. The other cross-sectional study evaluating men on dialysis was approved by the ethics review board of Mutsu General Hospital (authorization number: H28-2). All the participants provided written informed consent.

Participant selection

In a community-based cross-sectional study, of the 1,113 participants in the Iwaki Health Promotion Project 2015, 431 men were selected, excluding 682 women. Of these, 33 were excluded based on the following criteria: (1) insufficient information on ED questionnaires, (2) depression and/or taking antidepressants and/or antipsychotics, and (3) history of prostate cancer treatments, such as radical prostatectomy, radiation therapy, and androgen-deprivation therapy, because these therapies affect erectile function [19,20]. In total, 398 community-dwelling men were included in the analysis (Figure 1).

Figure 1. Participant selection of community-dwelling men. The number of included and excluded participants is shown. ED: erectile dysfunction.

Flowchart of the participant selection of community-dwelling men. Of 431 men, 33 were excluded. Of the remaining 398 men, one-fourth of men reported severe erectile dysfunction.

The other cross-sectional study assessed 186 men undergoing peritoneal dialysis (PD) and/or hemodialysis (HD) between July 2016 and May 2018 at Mutsu General Hospital. Of the 186 men, 144 were excluded based on the following exclusion criteria: (1) age ≥75 years; (2) cognitive deficiency, blindness, and/or inability to communicate; (3) depression and/or taking antidepressants and/or antipsychotics; (4) insufficient baseline information, including plasma 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels; and (5) refusal to participate in this study. Finally, 42 men on PD and/or HD were included in the analysis (Figure 2).

Figure 2. Participant selection of men on dialysis. The number of included and excluded patients is shown. PD: peritoneal dialysis; HD: hemodialysis; ED: erectile dysfunction; 8-OHdG: 8-hydroxy-2'-deoxyguanosine.

Flowchart of the participant selection of men on dialysis. Of 186 men, 144 were excluded. Of the remaining 42 men, two-third of men reported severe erectile dysfunction.

In this study, the sample size was not calculated to include as many participants as possible considering the relatively smaller sample size. Although hypogonadism is one of the most important factors of ED, men with hypogonadism were not excluded considering the limited association between plasma testosterone levels and the prevalence and severity of ED in this study.

Evaluation of variables

The following variables were analyzed: age, body mass index, HTN, dyslipidemia, DM, CVD, mental health status, depression, laboratory values, education level, smoking status, current habitual drinking, and medications being taken (antidiabetic medications, β-blockers, calcium-blockers, thiazide diuretics, spironolactone, and antidepressants). Blood samples were collected in the morning and separated by centrifugation. The laboratory values included creatinine, albumin, calcium, inorganic phosphorus, intact parathyroid hormone, total cholesterol, low-density lipoprotein, and triglycerides and were assayed with standard laboratory techniques. Serum total testosterone was measured using chemiluminescent immunoassay. Payne’s formula was used to calculate the adjusted calcium levels [21]. Hypogonadism was defined as serum total testosterone level ≤300 ng/dL [22]. In community-dwelling men, mental health status was evaluated using the 36-Item Short Form Health Survey Mental Component Summary. Scores were added and transformed into 0–100 scales, with higher values indicating better health status [23]. In men on dialysis, self-reported depression was assessed using the Vitality Questionnaire of the Short Form-36 Health Survey. Patients with certain responses to the questionnaire (i.e. “all of the time” or “most of the time”) and/or who were taking antidepressants were considered to have depression [24]. Smoking status was quantified using the Brinkman index.

Evaluation of ED

In community-dwelling men, ED was assessed using the 5-Item International Index of Erectile Function (IIEF-5) [25]. The IIEF-5 scores were interpreted as follows: no ED (22–25), mild ED (17–21), mild-to-moderate ED (12–16), moderate ED (8–11), and severe ED (5–7). Based on this, participants were divided into the non-ED (IIEF-5 score ≥22), mild/moderate ED (IIEF-5 score 12–21), and moderate/severe ED (IIEF-5 score ≤11) groups (Figure 1).

In men on dialysis, ED was assessed using the Sexual Health Inventory for Men (SHIM), a validated abbreviated version of the IIEF [26]. The SHIM scores were interpreted as follows: no ED (22–25), mild ED (17–21), moderate ED (8–16), and severe ED (1–7). Based on this, patients were divided into the mild/moderate (SHIM score ≥8) and severe ED (SHIM score ≤7) groups (Figure 2).

Evaluation of oxidative stress

We used 8-OHdG as a marker of oxidative stress. Among all the bases in nucleic acids, guanine is the most susceptible to oxidative damage and is oxidized to 8-OHdG. Because it is stable and excreted in bodily fluids with DNA repair, 8-OHdG is one of the most widely used and reliable oxidative stress markers [27].

In community-dwelling men, urine samples were used to measure 8-OHdG because urine has been regarded as a preferred diagnostic biofluid considering its sterility, simplicity to obtain large volumes, and noninvasive. Urine creatinine-adjusted urine 8-OHdG levels (ng/mgCr) were measured using the New 8-OHdG Check ELISA kit (Japan Institute for the Control of Aging, Shizuoka, Japan) according to the manufacturer’s instructions. Urine samples were collected in the morning and stored at −80 °C until analysis.

In men on dialysis, plasma samples were used to measure 8-OHdG because they could not provide urine samples. Plasma 8-OHdG levels (ng/ml) were measured using the OxiSelect Oxidative DNA Damage ELISA Kit (Cell Biolabs Inc., San Diego, USA) according to the manufacturer’s instructions. Plasma samples were collected in the morning and stored at −80 °C until analysis.

Statistical analysis

SPSS version 24.0 (SPSS Inc., Chicago, USA) and GraphPad Prism 5.03 (GraphPad Software, San Diego, USA) were used to perform statistical analyses. The Kolmogorov–Smirnov test was used to determine the distribution of the data. Quantitative variables are expressed as medians with interquartile ranges. Categorical variables were compared using the Fisher’s exact test or chi-squared test. Differences in quantitative variables between the two groups and among the three groups were analyzed using the Mann–Whitney U and Kruskal–Wallis tests, respectively. Correlations between variables were analyzed using Spearman’s rank correlation coefficient. Univariable and multivariable logistic regression analyses were performed to evaluate the association between oxidative stress and ED. Statistical significance was set at p < 0.05.

Results

Characteristics of the community-dwelling men

The median age of the community-dwelling men was 53 years. The median IIEF-5 score was 17. Of the 398 men, 66 (17%), 233 (59%), and 99 (25%) were classified into the non-ED, mild/moderate ED, and moderate/severe ED groups, respectively (Figure 1).

Variables such as age, prevalence of comorbidity, mental health status, renal function, plasma albumin levels, smoking status, and education levels were significantly different among the three groups (Table 1).

Table 1. Characteristics of community-dwelling men.

	All n = 398	Non-ED group n = 66	Mild/ moderate ED group n = 233	Moderate/ severe ED group n = 99	p Value
Age, years	54 (39–65)	37 (32–44)	51 (39–63)	66 (61–73)	<0.001
Body mass index, kg/m^2	23 (22–26)	23 (21–25)	23 (22–26)	24 (22–26)	0.969
Hypertension	167 (42%)	13 (20%)	96 (41%)	58 (59%)	<0.001
Dyslipidemia	128 (32%)	15 (23%)	68 (29%)	45 (46%)	0.003
Diabetes mellitus	42 (11%)	2 (3.0%)	21 (9.0%)	19 (19%)	0.002
Antidiabetic medications
Insulin	2 (0.5%)	0 (0.0%)	0 (0.0%)	2 (2.0%)	0.089
α-glucosidase inhibitors	3 (0.8%)	0 (0.0%)	2 (0.9%)	1 (1.0%)	1.000
Biguanides	7 (1.8%)	0 (0.0%)	5 (2.1%)	2 (2.0%)	0.751
DPP-4 inhibitors	11 (2.8%)	0 (0.0%)	5 (2.1%)	6 (6.1%)	0.060
Sulfonylureas	3 (0.8%)	0 (0.0%)	0 (0.0%)	3 (3.0%)	0.019
Others	3 (0.8%)	1 (1.5%)	9 (3.9%)	4 (4.0%)	0.802
Cardiovascular disease	34 (8.5%)	0 (0.0%)	16 (6.9%)	18 (18%)	<0.001
SF-36 MCS	51 (45–56)	49 (44–56)	51 (44–55)	52 (47–58)	0.048
Medications
β-blockers	10 (2.5%)	1 (1.5%)	4 (1.7%)	5 (5.1%)	0.220
Calcium-blockers	45 (11%)	2 (3.0%)	29 (12%)	14 (14%)	0.061
Thiazide diuretics	10 (2.5%)	0 (0.0%)	5 (2.1%)	5 (5.1%)	0.144
Laboratory blood test
eGFR, mL/min/1.73m^2	81 (72–89)	84 (76–94)	82 (74–92)	74 (66–85)	<0.001
Albumin, g/dL	4.6 (4.4–4.8)	4.7 (4.5–5.0)	4.6 (4.4–4.8)	4.4 (4.2–4.6)	<0.001
Total cholesterol, mg/dL	203 (179–224)	202 (174–219)	204 (179–225)	205 (180–228)	0.446
LDL-cholesterol, mg/dL	116 (95–132)	112 (90–125)	114 (96–132)	121 (99–137)	0.064
Triglyceride, mg/dL	97 (68–147)	99 (54–162)	100 (71–161)	90 (69–127)	0.172
Testosterone, ng/dL	605 (467–755)	584 (461–757)	610 (467–748)	622 (467–794)	0.738
Hypogonadism	14 (3.5%)	5 (7.6%)	5 (2.1%)	4 (4.0%)	0.085
Brinkman index	152 (0–440)	60 (0–240)	200 (0–455)	150 (0–600)	0.027
Current habitual drinking	268 (67%)	44 (67%)	158 (68%)	66 (67%)	0.972
Post-high school education	109 (27%)	27 (41%)	63 (27%)	19 (19%)	0.009
IIEF-5 score	17 (12–20)	23 (22–24)	17 (15–20)	8.0 (6.0–10)	<0.001

All data is presented as n (%) or median (interquartile range). ED: erectile dysfunction; DPP-4: dipeptidyl peptidase-4; SF-36 MCS: 36-Item Short Form Health Survey Mental Component Summary; eGFR: estimated glomerular filtration rate; LDL: low density lipoprotein; IIEF: International Index of Erectile Function.

Characteristics of the men on dialysis

The median age and dialysis duration of the men on dialysis were 64 years and 64 months, respectively. Of the 42 patients, 3 (7.1%), 33 (86%), and 3 (7.1%) were undergoing PD, HD, and a combination of once-weekly HD with PD, respectively (Table 2).

Table 2. Characteristics of men on dialysis.

	All n = 42	Mild/moderate ED group n = 15	Severe ED group n = 27	p Value
Age, years	64 (55–66)	59 (54–65)	65 (56–66)	0.344
Body mass index, kg/m^2	23 (20–29)	24 (19–29)	23 (20–28)	0.753
Hypertension	37 (88%)	14 (93%)	23 (85%)	0.639
Dyslipidemia	30 (71%)	11 (73%)	19 (70%)	1.000
Diabetes mellitus	24 (57%)	9 (60%)	15 (56%)	0.780
Antidiabetic medications
Insulin	13 (30%)	4 (25%)	8 (30%)	1.000
α-Glucosidase inhibitors	3 (6.8%)	1 (6.3%)	2 (7.1%)	1.000
DPP-4 inhibitors	13 (30%)	6 (38%)	7 (25%)	0.345
None	3 (6.8%)	1 (6.3%)	2 (7.1%)	1.000
Cardiovascular disease	11 (26%)	2 (13%)	9 (33%)	0.273
Type of dialysis				1.000
PD	3 (7.1%)	1 (6.7%)	2 (7.4%)
HD	36 (86%)	13 (87%)	23 (85%)
Combination of PD and HD	3 (7.1%)	1 (6.7%)	2 (7.4%)
Duration of dialysis, months	64 (28–112)	51 (22–76)	84 (49–148)	0.028
Medications
β-blockers	17 (41%)	7 (47%)	10 (37%)	0.542
Calcium-blockers	13 (31%)	6 (40%)	7 (26%)	0.344
Thiazide diuretics	1 (2.4%)	0 (0.0%)	1 (3.7%)	1.000
Laboratory blood test
Albumin, g/dL	3.6 (3.4–3.8)	3.8 (3.5–4.0)	3.5 (3.1–3.8)	0.053
Phosphorus, mg/dL	4.6 (3.7–5.7)	5.1 (4.5–6.9)	4.0 (3.0–5.6)	0.016
Adjusted calcium, mg/dL	8.8 (8.3–9.2)	8.8 (8.2–9.2)	8.8 (8.3–9.2)	0.655
iPTH, pg/mL	116 (67–158)	147 (106–242)	95 (35–136)	0.004
Total cholesterol, mg/dL	145 (114–171)	145 (137–197)	131 (106–175)	0.429
LDL-cholesterol, mg/dL	67 (50–87)	50 (46–95)	68 (56–85)	0.253
Triglyceride, mg/dL	161 (109–177)	174 (164–178)	118 (92–220)	0.191
Testosterone, ng/dL	358 (222–509)	292 (221–436)	420 (222–511)	0.270
Hypogonadism	17 (41%)	8 (53%)	9 (33%)	0.206
Brinkman index	350 (4.5–633)	400 (0.0–700)	300 (6.0–611)	0.853
Current habitual drinking	10 (24%)	4 (27%)	6 (22%)	1.000
Post-high school education	7 (17%)	2 (13%)	5 (19%)	1.000
Having current sexual partner	26 (62%)	9 (60%)	17 (63%)	0.850
SHIM score	4.5 (1.0–10)	13 (9.0–18)	2.0 (1.0–4.0)	<0.001

All data is presented as n (%) or median (interquartile range).

ED: erectile dysfunction; DPP-4: dipeptidyl peptidase-4; PD: peritoneal dialysis; HD: hemodialysis; iPTH: intact parathyroid hormone; LDL: low density lipoprotein; SHIM: sexual health inventory for men.

The median SHIM score was 4.5. All patients (100%) had any level of ED. Of these, 15 (36%) and 27 (64%) patients were classified into mild/moderate and severe ED groups, respectively (Figure 2). No patient was receiving any type of ED treatment during the investigation.

No significant differences in the patient background were observed between the two groups, except for the duration of dialysis and plasma phosphorus and intact parathyroid hormone levels (Table 2).

Correlations between 8-OHdG levels and ED questionnaire scores

In community-dwelling men, spearman’s rank correlation test showed no significant correlation between urine 8-OHdG levels and IIEF-5 scores (Figure 3(A); ρ= −0.005, p = 0.917).

Figure 3. Associations between urine and plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and the severity of erectile dysfunction (ED). Correlations between urine 8-OHdG level and 5-Item International Index of Erectile Function (IIEF-5) score in community-dwelling men (A) and between plasma 8-OHdG level and Sexual Health Inventory for Men (SHIM) score in men on dialysis (B) were analyzed using Spearman’s rank correlation coefficient. Urine 8-OHdG levels were compared between the three groups using the Kruskal–Wallis test (C). Plasma 8-OHdG levels were compared between the two groups using the Mann–Whitney U test (E). The distribution of the ED degree in community-dwelling men (D) and the prevalence of severe ED in men on dialysis (F) were compared between men with lower and higher 8-OHdG levels using the chi-squared test.

Two correlation analyses and comparative analyses with box plots show no significant correlations and associations between 8-hydroxy-2'-deoxyguanosine levels and erectile dysfunction.

Similarly, Spearman’s rank correlation test showed no significant correlation between plasma 8-OHdG levels and SHIM scores in men on dialysis (Figure 3(B); ρ = 0.166, p = 0.295).

Association between 8-OHdG levels and the severity of ED

In community-dwelling men, the median urine 8-OHdG level was 5.0 ng/mgCr. No significant difference in urine 8-OHdG levels was observed among the three groups (Figure 3(C); p = 0.939). When these men were divided according to their median urine 8-OHdG values, no significant difference in the distribution of ED degree was observed between men with higher and lower 8-OHdG levels (Figure 3(D); p = 0.632).

In men on dialysis, the median plasma 8-OHdG level was 16 ng/mL. No significant difference in plasma 8-OHdG levels was observed between the two groups (Figure 3(E); p = 0.282). When these men were divided according to their median plasma 8-OHdG values, no significant difference in the prevalence of severe ED was observed between men with higher and lower 8-OHdG levels (Figure 3(F); p = 0.197).

Univariable and multivariable analyses for ED

In community-dwelling men, univariable analyses revealed that urine 8-OHdG levels were not significantly associated with ED (Table 3; odds ratio [OR]: 1.005, 95% confidence interval [CI]: 0.884–1.144, p = 0.934). Similarly, in the multivariable analysis, urine 8-OHdG levels were not significantly associated with ED (Table 3; OR: 0.930, 95% CI: 0.798–1.084, p = 0.353). When we focused only on men with ED (n = 332), urine 8-OHdG levels were not significantly associated with moderate/severe ED in the univariable analysis (Table 4; OR: 1.030, 95% CI: 0.922–1.149, p = 0.604).

Table 3. Univariable and multivariable analyses for erectile dysfunction in community-dwelling men.

	Factor	p Value	Odds ratio	95% CI
Univariable analysis
Age	Continuous	<0.001	1.087	1.062–1.113
Body mass index	Continuous	0.748	0.986	0.907–1.073
Hypertension	Positive	<0.001	3.527	1.853–6.715
Dyslipidemia	Positive	0.075	1.754	0.945–3.257
Diabetes mellitus	Positive	0.045	4.384	1.033–18.61
Calcium-blockers	Taking	0.034	4.761	1.124–20.16
β-blockers	Taking	0.576	1.811	0.226–14.54
Brinkman index	Continuous	0.005	1.001	1.000–1.003
Hypogonadism	Positive	0.061	0.340	0.110–1.049
eGFR	Continuous	0.006	0.973	0.955–0.993
Urine 8-OHdG level	Continuous	0.934	1.005	0.884–1.144
Multivariable analysis
Age	Continuous	<0.001	1.088	1.056–1.121
Hypertension	Positive	0.303	1.506	0.691–3.283
Diabetes mellitus	Positive	0.691	1.378	0.284–6.682
Calcium-blockers	Taking	0.889	1.124	0.219–5.779
Brinkman index	Continuous	0.284	1.001	0.999–1.002
eGFR	Continuous	0.109	1.021	0.995–1.048
Urine 8-OHdG level	Continuous	0.353	0.930	0.798–1.084

CI: confidence interval; eGFR: estimated glomerular filtration rate; 8-OHdG: 8-hydroxy-2'-deoxyguanosine.

Table 4. Univariable analyses for moderate/severe erectile dysfunction in community-dwelling men with erectile dysfunction.

	Factor	p Value	Odds ratio	95% CI
Age	Continuous	<0.001	1.104	1.077–1.133
Body mass index	Continuous	0.964	0.998	0.925–1.078
Hypertension	Positive	0.004	2.019	1.252–3.254
Dyslipidemia	Positive	0.005	2.022	1.244–3.288
Diabetes mellitus	Positive	0.011	2.398	1.225–4.694
Calcium-blockers	Taking	0.674	1.159	0.583–2.301
β-blockers	Taking	0.102	3.045	0.800–11.59
Brinkman index	Continuous	0.966	1.000	0.999–1.000
Hypogonadism	Positive	0.399	1.920	0.505–7.306
eGFR	Continuous	<0.001	0.963	0.947–0.980
Urine 8-OHdG level	Continuous	0.604	1.030	0.922–1.149

CI: confidence interval; eGFR: estimated glomerular filtration rate; 8-OHdG: 8-hydroxy-2'-deoxyguanosine.

In men on dialysis, univariable analyses revealed that plasma 8-OHdG levels were not significantly associated with severe ED (Table 5; OR: 0.967, 95% CI: 0.876–1.066, p = 0.498).

Table 5. Univariable analyses for severe erectile dysfunction in men on dialysis.

	Factor	p Value	Odds ratio	95% CI
Age	Continuous	0.429	1.027	0.961–1.099
Body mass index	Continuous	0.816	0.987	0.886–1.100
Hypertension	Positive	0.446	0.411	0.042–4.055
Dyslipidemia	Positive	0.839	0.864	0.211–3.542
Diabetes mellitus	Positive	0.780	0.833	0.231–3.003
Calcium-blockers	Taking	0.348	0.525	0.137–2.014
β-blockers	Taking	0.543	0.672	0.187–2.419
Brinkman index	Continuous	0.958	1.000	0.999–1.001
Hypogonadism	Positive	0.210	0.438	0.120–1.592
Albumin level	Continuous	0.053	0.164	0.026–1.025
Plasma 8-OHdG level	Continuous	0.498	0.967	0.876–1.066

CI: confidence interval; 8-OHdG: 8-hydroxy-2'-deoxyguanosine.

Discussion

To the best of our knowledge, this is the first study to investigate the association between urine and plasma 8-OHdG levels and ED in both community-dwelling men and men on dialysis. The results of the present study revealed that urine 8-OHdG levels were not significantly associated with the prevalence of ED in community-dwelling men (Table 3). Moreover, urine and plasma 8-OHdG levels were not significantly associated with ED severity in both community-dwelling men and men on dialysis, respectively (Tables 4 and 5). Although the etiology of ED is well-known to be multifactorial [28], these results suggest that oxidative stress may not have an important contribution to the development and severity of ED in humans. Because the present study was a cross-sectional study and did not have an enough sample size, our future prospective study with an enough sample size will clarity the association between oxidative stress and ED in humans.

The present study showed no significant association between urine 8-OHdG levels and the prevalence and severity of ED in community-dwelling men. Although oxidative stress is believed to play an important role in the etiology of ED, this concept may be derived from several basic studies using animal models [11–14]. In humans, a few studies have investigated the association between oxidative stress and ED, but the results have been inconsistent. Aldemir et al. have compared the serum oxidative and antioxidative status between healthy volunteers and patients with ED and showed increased oxidative and decreased antioxidative parameters in patients with ED [29]. Similarly, Yasuda et al. have demonstrated a significant association between salivary 8-OHdG levels and ED severity in healthy volunteers [30]. In addition, Ciftci et al. have revealed that the activity of serum paraoxonase 1, an antioxidant enzyme, in patients with ED was significantly lower than that in healthy men [31]. Although these results suggest a possible contribution of oxidative stress to the etiology of ED in humans, definitive conclusions cannot be drawn because of the small sample size and lack of adjustment for potential confounding variables. In contrast, Yang et al. have conducted a prospective study with a sufficient sample size of men (n = 917) and demonstrated that plasma fluorescent oxidation products, a global biomarker for oxidative stress, were not associated with the development of ED in a multivariable adjusted model [32]. This result was consistent with our findings. Considering the sample size and statistical methods, the concept that oxidative stress does not contribute to the etiology of ED in humans may be predominant. Further studies are required to clarify the association between oxidative stress and ED.

Although we hypothesized that oxidative stress might contribute greatly to the severity of ED in men on dialysis, considering the significant associations of ESRD and dialysis with elevated oxidative stress [15–18], the present study revealed that plasma 8-OHdG levels were not correlated with ED severity at all. The reason for this remains unclear. Because the etiology of ED in men on dialysis is multifactorial [33], oxidative stress alone may be insufficient to develop severe ED. Alternatively, plasma 8-OHdG levels may not accurately reflect oxidative stress in the penile region. Yeni et al. have compared total peroxide levels, an oxidative stress marker, between peripheral venous blood and the penile corpus cavernosum in healthy men and demonstrated no significant correlation between them [34]. Moreover, because 8-OHdG estimates oxidative DNA damage, it cannot reflect oxidative stress generated from other sources, including lipids and proteins [27]. Thus, a single oxidative stress marker may be insufficient for evaluating oxidative stress generated from multiple sources. Contrary to our expectations, the present study was not able to determine possible associations between oxidative stress and ED severity. However, we still cannot make a definitive conclusion, as this cross-sectional study in men on dialysis should be regarded as a preliminary study considering its sample size. In addition, no previous study has investigated the association between oxidative stress and ED in men on dialysis or in an animal model of ESRD. Further studies are warranted to clarify the role of oxidative stress in ED severity in men on dialysis.

This study has several limitations. First, its cross-sectional nature prevents us from determining cause-and-effect associations, and it also may involve selection bias and other unmeasurable confounding factors that we could not control. Second, a relatively small number of men on dialysis was included in this study. Third, we did not have the information on the duration of DM. Lastly, the measurement of 8-OHdG at a single point in time may not accurately reflect the average levels over a prolonged period. Despite these limitations, the results of the present study challenge the traditional understanding on the role of oxidative stress in the etiology of ED in humans.

Conclusions

Oxidative stress was not significantly associated with the prevalence and severity of ED in community-dwelling men and men on dialysis. Considering several limitations in the present study, further studies are warranted to clarify the role of oxidative stress in ED.

Acknowledgments

The authors would like to thank all participants and the data collection team of the Iwaki Health Promotion Project 2015 and the staff of the Department of Social Medicine, Hirosaki University for their contribution to this study. The authors also thank Editage (www.editage.com) for English language editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by a Error! Hyperlink reference not valid. [No. 19H05556, 20K09517, and 21K09339] from the Japan Society for the Promotion of Science and the Japan Science and Technology Agency, Center of Innovation Program, Hirosaki [JPMJCE1302].