The relationship between complete blood cell count-derived inflammatory biomarkers and erectile dysfunction in the United States

Abstract

Erectile dysfunction(ED), a prevalent condition within the male genitourinary system, significantly impairs the quality of life for affected men. Although certain inflammatory indicators, such as the neutrophil-to-lymphocyte ratio(NLR), systemic inflammatory response index (SIRI), and systemic immune-inflammation index(SII), have been linked to ED, the correlation with other markers and their impact on survival outcomes in ED patients remain largely unexplored. This research aims to investigate the correlation between inflammatory biomarkers derived from a complete blood cell count(CBC) and the occurrence of ED. Data regarding ED were extracted from the 2001–2004 National Health and Nutrition Examination Survey(NHANES), and mortality events were ascertained through the National Death Index up to December 2019. The CBC-derived inflammatory indicators assessed in this study included the NLR, derived neutrophil-to-lymphocyte ratio(dNLR), monocyte-to-lymphocyte ratio(MLR), neutrophil-monocyte to lymphocyte ratio (NMLR), SIRI, and SII. The prognostic significance of these CBC-derived inflammatory indicators was evaluated using random survival forests(RSF) analysis. Our study encompassed a cohort of 3,639 individuals, among whom 1,031 were diagnosed with ED. Among individuals with ED, 610 experienced all-cause mortality. Following adjustment for all confounding variables, it was observed that elevated levels of NLR(OR = 1.09, 95%CI 1.00–1.19, p = 0.021), MLR (OR = 2.97, 95% CI 1.18–7.50, p = 0.01), NMLR(OR = 1.10, 95% CI 1.01–1.11, p = 0.006), and SIRI(OR = 1.11, 95% CI 1.01–1.22, p = 0.017) were associated with an increased prevalence of ED. Among participants with ED, those in the highest quartile of NLR(HR = 1.06, 95% CI 1.00–1.11, p = 0.032), MLR(HR = 2.00, 95% CI 1.33–3.01, p < 0.001), NMLR (HR = 1.06, 95% CI 1.01–1.11, p = 0.024), and SII(HR = 1.00, 95% CI 1.00–1.00, p = 0.015) exhibited an elevated risk of all-cause mortality compared to those in the lower levels of inflammation-derived indicators. Our research suggests that, compared with other inflammatory markers derived from complete blood cell count, MLR has the highest predictive power for the prevalence of ED and all-cause mortality in these populations.

Introduction

Erectile Dysfunction(ED) is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance¹. A recent study has shown that the overall prevalence of ED among adult men in the United States is 24.2%, and this rate increases significantly with age, with a prevalence of 48.0% in men aged 65 to 74 years and as high as 52.2% in men aged 75 years or older². As the most common type of male sexual dysfunction, ED not only seriously affects patients’ quality of life, but may also be an early sign and risk signal for cardiovascular disease³. The etiology and predisposing factors of ED are complex, including ageing, poor lifestyle choices (such as smoking, alcoholism, and obesity), psychosomatic factors (such as depression and anxiety) and chronic medical conditions (such as cardiovascular disease, diabetes, gastrointestinal diseases and obstructive sleep apnoea)^4–8. Particularly, systemic inflammatory response has been widely recognized as an important factor leading to vascular endothelial dysfunction, which in turn triggers ED⁹. Therefore, individualised assessment of biomarkers that can accurately reflect the state of systemic inflammation can not only serve as an indicator for assessing the severity of the condition, but may also be a potential target in future therapeutic strategies.

The complete blood count (CBC) is a routine and cost-effective laboratory test that provides information on a variety of blood components, including white blood cells, red blood cells, platelets, and so on. Notably, CBC-derived inflammation indicators provide a more comprehensive response to the systemic inflammatory state of the body than single indicators¹⁰. Among them, Neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio(dNLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-monocyte to lymphocyte ratio(NMLR), systemic inflammatory response index (SIRI), and systemic immune-inflammation index (SII), have been shown to be of significant value in the diagnosis, management and mortality risks assessment in a variety of diseases such as prostatic hyperplasia, bladder cancer, and sarcopenia^11–14. Furthermore, it has been observed that there is a positive correlation between NLR, SIRI, SII and the prevalence of ED^15–17. Nevertheless, the relationship between other CBC-derived inflammatory biomarkers and the incidence of ED, as well as the role of these markers in the survival prognosis of ED patients remains currently unknown.

Therefore, the aim of our study was to investigate the relationship between CBC-derived inflammatory biomarkers and the incidence of ED, and the prognostic value of these biomarkers, in order to elucidate the potential link between inflammation levels and ED and to provide new guidelines for the prevention and treatment of ED patients.

Materials and methods

Study population

The National Health and Nutrition Examination Survey (NHANES) is a comprehensive, cross-sectional survey conducted in the United States. The ethical approval for NHANES was granted by the Research Ethics Review Board of the National Center for Health Statistics, and each participant provided a signed informed consent form. The dataset, as well as complete documentation and protocols, is publicly accessible through the designated website (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx).

Assessment of CBC-derived inflammatory indicators

Fasting venous blood samples were collected from all study participants to ascertain leukocyte, neutrophil, lymphocyte, monocyte, and platelet counts. The CBC-derived inflammatory indicators were calculated using the following formulas: Neutrophil-to-Lymphocyte Ratio (NLR) = neutrophil counts / lymphocyte counts, Derived Neutrophil-to-Lymphocyte Ratio (dNLR) = neutrophil counts / (white blood cell counts - lymphocyte counts), Monocyte-to-Lymphocyte Ratio (MLR) = monocyte counts / lymphocyte counts, Neutrophil-to-Monocyte-to-Lymphocyte Ratio (NMLR) = (monocyte counts + neutrophil counts) / lymphocyte counts, Systemic Immune-Inflammation Index (SIRI) = neutrophil counts × monocyte counts / lymphocyte counts, and Platelet-to-Lymphocyte Ratio (SII) = platelet counts × neutrophil counts / lymphocyte counts¹⁸.

Assessment of erectile dysfunction

Participants were queried regarding erectile dysfunction (ED) with the question: “How would you describe your ability to develop and maintain an erection sufficient for sexual intercourse?” Responses were categorized into “never,” “sometimes,” “usually,” or “almost always or nearly always.” Individuals who selected “never” or “sometimes” were classified as having ED.

Assessment of mortality

We ascertained the vital status of participants by referencing the National Death Index (NDI). Data on all-cause mortality were collected through the end of December 2019, utilizing the 2019 Linked Mortality File (LMF). This file represents the most recent amalgamation of specific National Center for Health Statistics (NCHS) surveys with the NDI.

Covariates

In line with previous studies, we identified several potential covariates that may influence the outcomes, including age, race, body mass index (BMI), marital status (categorized as living with a partner or single), poverty-to-income ratio (PIR), education level, exercise status, alcohol consumption (binary: yes or no), smoking status (categorized as current, former, or never), and the presence of hypertension, diabetes, hypercholesterolemia, and cardiovascular disease. The PIR was stratified into three groups: ≤1.5, 1.5 to 3.5, and > 3.5. Data on the prevalence of diabetes, hypertension, hypercholesterolemia, and cardiovascular disease were obtained through self-reported questionnaires.

Statistical analysis

The Mann-Whitney U test was utilized to evaluate differences in continuous variables, with results presented as medians and their corresponding interquartile ranges (IQR). For categorical variables, comparisons were made using the chi-square test, and results were expressed as frequencies and percentages. Multiple logistic regression analyses were conducted to calculate adjusted odds ratios (OR) and their respective 95% confidence intervals (CI), assessing the association between CBC-derived inflammatory markers and erectile dysfunction (ED) occurrence. Furthermore, multiple Cox regression analyses were employed to determine adjusted hazard ratios (HR) and 95% CI for all-cause mortality among individuals with ED. The association between CBC-derived inflammatory markers and the prevalence and mortality of ED was further investigated using dose-response curves with restricted cubic splines (RCS). Spearman’s rank correlation coefficient was applied to assess the correlation between CBC-derived inflammatory markers and CBC parameters. The predictive value of CBC-derived inflammatory markers for all-cause mortality in ED patients was compared using the random survival forest method. All statistical analyses were conducted using R software, version 4.3.2, with statistical significance defined as a P-value less than 0.05.

Results

Characteristics of the study participants

For our analysis, we selected two cycles of the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2002 and 2003–2004, as these were the only cycles providing comprehensive data on erectile dysfunction (ED) and complete blood count (CBC). A total of 21,161 individuals participated in NHANES from 2001 to 2004. The following exclusions were applied: (1) females (n = 16,207) and males under 20 years of age (n = 16,207); (2) participants with missing data on ED (n = 838), CBC (n = 142), and survival status (n = 6); (3) those with incomplete information on covariates, including BMI (n = 112), PIR (n = 52), education level (n = 1), marital status (n = 4), hypertension (n = 4), hypercholesterolemia (n = 68), cardiovascular disease (n = 6), diabetes (n = 1), smoking (n = 4), alcohol consumption (n = 2), and exercise status (n = 1). Ultimately, 3,639 participants were included in our study; of these, 1,031 had a self-reported history of ED, and 610 experienced all-cause mortality (Fig. 1).

Fig. 1.

Flow chart of the study.

Individuals with ED were more likely to be older males (over 59 years), non-Hispanic whites, with lower levels of education and income, married or cohabiting, former smokers, non-drinkers, physically inactive, and without hypertension but with comorbidities such as diabetes, hypercholesterolemia, and cardiovascular disease (Table 1).

Table 1.

Baseline characteristics of adults with CBC-derived inflammatory biomarkers.

Characteristic	Overall n = 78,785,355 N = 36391	Erectile dysfunction		P Value2
		No n = 63,793,918 N = 26081	Yes n = 14,991,437 N = 10311
Age (years)	45.1 ± 15.8	41.3 ± 13.4	61.1 ± 15.3	< 0.001
Race				0.2
Mexican American	753(7.8%)	538(8.1%)	215(6.9%)
Other Hispanic	121(4.2%)	85(4.0%)	36(5.0%)
Non-Hispanic White	1,998(74.6%)	1,387(74.0%)	611(77.1%)
Non-Hispanic Black	658(9.3%)	508(9.6%)	150(8.1%)
Other Race	109(4.1%)	90(4.3%)	19(2.9%)
BMI(kg/m2Superscript>)	28.1 ± 5.5	27.9 ± 5.3	29.1 ± 6.2	< 0.001
Education level				< 0.001
< High school	1,018(16.8%)	602(13.8%)	416(29.3%)
High school	893(27.1%)	681(27.9%)	212(23.5%)
> High school	1,728(56.2%)	1,325(58.3%)	403(47.2%)
Marital status				< 0.001
Married or living with partner	2,538(70.7%)	1,768(69.1%)	770(77.6%)
Living alone	1,101(29.3%)	840(30.9%)	261(22.4%)
Poverty-income ratio				< 0.001
< 1.5	1,032(19.2%)	699(18.5%)	333(22.5%)
1.5–3.5	1,255(32.7%)	859(31.4%)	396(37.9%)
> 3.5	1,352(48.1%)	1,050(50.1%)	302(39.6%)
Smoking				< 0.001
Nonsmoker	1,466(42.6%)	1,157(45.5%)	309(30.3%)
Former smoker	1,190(29.2%)	676(25.0%)	514(46.8%)
Current smoker	983(28.3%)	775(29.5%)	208(22.9%)
Alcohol intake	3,017(83.6%)	2,187(84.4%)	830(80.1%)	0.004
Physical Activity				< 0.001
Inactive	1,371(31.1%)	871(28.3%)	500(42.8%)
Moderate	1,032(29.1%)	676(27.2%)	356(37.3%)
Vigorous	1,236(39.8%)	1,061(44.4%)	175(19.9%)
Hypertension	2,159(65.5%)	1,780(71.2%)	379(41.4%)	< 0.001
Diabetes				< 0.001
No	3,220(92.1%)	2,448(95.6%)	772(77.4%)
Borderline	49(1.0%)	30(1.0%)	19(1.3%)
Diabetes	370(6.8%)	130(3.4%)	240(21.2%)
History of CVD	403(8.0%)	154(4.6%)	249(22.6%)	< 0.001
High cholesterol	1,334(36.3%)	847(33.0%)	487(50.7%)	< 0.001
CBC count, 103/µL
White blood cell	7.2 ± 2.5	7.2 ± 2.3	7.3 ± 3.0	0.5
Neutrophils	4.3 ± 1.6	4.2 ± 1.6	4.3 ± 1.5	0.004
Monocyte	0.6 ± 0.2	0.6 ± 0.2	0.6 ± 0.2	0.008
Platelet	254.4 ± 61.2	257.2 ± 59.8	242.5 ± 65.8	< 0.001
Lymphocyte	2.1 ± 1.5	2.1 ± 1.2	2.0 ± 2.4	< 0.001
CBC-derived indicators
NLR	2.3 ± 1.2	2.2 ± 1.1	2.6 ± 1.4	< 0.001
dNLR	0.8 ± 0.1	0.8 ± 0.1	0.8 ± 0.1	0.8
MLR	0.3 ± 0.1	0.3 ± 0.1	0.3 ± 0.2	< 0.001
NMLR	2.6 ± 1.2	2.5 ± 1.2	2.9 ± 1.5	< 0.001
SIRI	1.3 ± 1.0	1.3 ± 0.9	1.6 ± 1.1	< 0.001
SII	575.7 ± 354.3	565.0 ± 324.4	621.4 ± 457.8	0.003

1.Sample sizes presented as n = weighted estimates/N = raw number; 2.Wilcoxon rank-sum test for complex survey samples; chi-squared test with Rao & Scott’s second-order correction. Continuous variables are presented as mean ± standard deviation. Categorical variables are presented as numbers (percentages). 3.Abbreviations: PIR, poverty income ratio; NLR, neutrophil-to-lymphocyte ratio; dNLR, derived neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; NMLR, neutrophil-monocyte to lymphocyte ratio; SIRI, systemic inflammatory response index; SII, systemic immune-inflammation index; CBC, complete blood cell.

Associations between CBC-derived indicators and ED prevalence

In patients with ED, neutrophil levels and CBC-derived markers were significantly elevated, whereas platelet and lymphocyte counts were significantly reduced (Table 1). The crude model indicated a positive association between CBC-derived inflammatory indicators and the prevalence of ED, with the exception of the dNLR (Table 2). After adjusting for confounding variables, this association remained significant for all markers except dNLR and the SII. In the crude model, individuals in the higher quartiles of CBC-derived inflammatory indicators, excluding dNLR, exhibited a higher prevalence of ED compared to those in the lower quartile. However, this association was not maintained in the fully adjusted Model 3. To further elucidate the relationship between CBC-derived indicators and ED prevalence, restricted cubic spline (RCS) curves were plotted (Fig. 2A), suggesting a nonlinear association between ED prevalence and the levels of NLR, NMLR and SIRI.

Table 2.

The relationship between the prevalence of ED and complete blood cell-derived inflammatory biomarkers.

	continuous		Quartiles of CBC-derived inflammatory biomarkers levels				P trend
	OR (95%CI)	P value	Q1	Q2	Q3	Q4
NLR
Crude	1.27(1.18,1.36)	< 0.001	-	0.92(0.67,1.25)	1.23(0.96,1.57)	2.16(1.70,2.73)	< 0.001
Model 1	1.09(1.01,1.19)	0.028	-	0.68(0.49,0.95)	0.97(0.71,1.24)	1.17(0.88,1.56)	0.091
Model 2	1.10(1.01,1.20)	0.018	-	0.74(0.52,1.06)	1.03(0.76,1.41)	1.25(0.91,1.71)	0.052
Model 3	1.09(1.00,1.19)	0.021	-	0.75(0.50,1.11)	1.01(0.73,1.39)	1.25(0.91,1.73)	0.061
dNLR
Crude	0.64(0.12,3.42)	0.6	-	0.87(0.69,1.10)	0.76(0.60,0.94)	1.05(0.81,1.38)	> 0.9
Model 1	1.11(0.12,10.1)	> 0.9	-	0.85(0.63,1.14)	0.70(0.53,0.94)	1.19(0.84,1.70)	0.5
Model 2	1.26(0.09,16.9)	0.9	-	0.89(0.63,1.24)	0.75(0.55,1.03)	1.23(0.82,1.83)	0.5
Model 3	0.92(0.07,12.6)	> 0.9	-	0.89(0.61,1.30)	0.74(0.54,1.02)	1.19(0.80,1.79)	0.6
MLR
Crude	13.8(6.88,27.6)	< 0.001	-	1.04(0.71,1.50)	1.46(1.09,1.94)	2.32(1.71,3.15)	< 0.001
Model 1	2.50(1.04,6.02)	0.032	-	0.80(0.53,1.22)	0.96(0.70,1.32)	1.11(0.75,1.64)	0.4
Model 2	2.94(1.15,7.51)	0.015	-	0.89(0.58,1.38)	1.10(0.77,1.57)	1.24(0.81,1.91)	0.2
Model 3	2.97(1.18,7.50)	0.01	-	0.88(0.54,1.41)	1.12(0.76,1.66)	1.25(0.79,1.97)	0.2
NMLR
Crude	1.26(1.18,1.35)	< 0.001	-	0.86(0.66,1.12)	1.17(0.92,1.49)	2.16(1.70,2.75)	< 0.001
Model 1	1.09(1.01,1.18)	0.014	-	0.65(0.49,0.86)	0.87(0.67,1.15)	1.15(0.86,1.54)	0.12
Model 2	1.10(1.02,1.19)	0.007	-	0.70(0.53,0.93)	0.96(0.70,1.31)	1.23(0.90,1.69)	0.064
Model 3	1.10(1.01,1.11)	0.006	-	0.71(0.52,0.98)	0.93(0.67,1.28)	1.25(0.90,1.73)	0.073
SIRI
Crude	1.27(1.17,1.39)	< 0.001	-	1.07(0.85,1.35)	1.43(1.08,1.88)	2.25(1.85,2.74)	< 0.001
Model 1	1.15(1.05,1.26)	0.002	-	0.89(0.69,1.14)	1.05(0.76,1.45)	1.45(1.09,1.93)	0.009
Model 2	1.11(1.01,1.22)	0.019	-	0.88(0.65,1.19)	1.04(0.71,1.51)	1.35(0.98,1.87)	0.055
Model 3	1.11(1.01,1.22)	0.017	-	0.82(0.60,1.13)	1.02(0.67,1.54)	1.28(0.91,1.81)	0.1
SII
Crude	1.00(1.00,1.00)	< 0.001	-	0.99(0.76,1.29)	1.06(0.81,1.39)	1.44(1.16,1.80)	0.003
Model 1	1.00(1.00,1.01)	0.2	-	0.92(0.66,1.29)	1.03(0.74,1.43)	1.23(0.89,1.70)	0.14
Model 2	1.00(1.00,1.02)	0.2	-	0.99(0.70,1.42)	1.14(0.81,1.61)	1.28(0.91,1.80)	0.1
Model 3	1.00(1.00,1.03)	0.2	-	0.98(0.68,1.42)	1.18(0.79,1.74)	1.25(0.86,1.82)	0.13

Crude Model: Unadjusted for covariates; Model 1: Adjusted for age and race; Model 2: Adjusted for age, race, marital status, BMI, PIR, education, smoking, alcohol consumption, and physical activity; Model 3: Fully adjusted model including all covariates.

Fig. 2A.

Utilization of Restricted Cubic Spline (RCS) Regression Analysis to Assess the Relationship between CBC-derived Indicators and ED prevalence in adult males; Fig. 2B: Application of RCS Regression Analysis to Investigate the Correlation between CBC-derived Indicators and All-Cause Mortality in Adults with ED.

Associations between CBC-derived indicators and all-cause mortality among adults with ED

During the subsequent observation period, of the 1,031 adults diagnosed with ED, 610 individuals, accounting for 59.17%, experienced all-cause mortality (Table 3). The decedent group demonstrated significantly higher levels of NLR(HR = 1.06[1.0–1.11], P < 0.05), MLR (HR = 2.0[1.33–3.01], P < 0.001), NMLR(HR = 1.06[1.01–1.11], P < 0.05), and SII(HR = 1.00 [1.0–1.0], P < 0.05) compared to survivors in the fully adjusted model. Except for SII and dNLR, individuals with ED in the higher quartiles of CBC-derived markers exhibited an increased risk of all-cause mortality in the crude model relative to those in the lower quartile. In the fully adjusted model, this association was significant only for MLR (P for trend < 0.001). Kaplan-Meier survival curves (Fig. 3) showed a positive association between CBC-derived markers (excluding dNLR) and all-cause mortality among participants with ED. Additionally, the restricted cubic spline analysis (Fig. 2B) indicated a nonlinear association between all-cause mortality and the levels of NLR, MLR, and SII among ED participants, with notable inflection points at 2.03, 0.26, and 471.21, respectively.

Table 3.

HRs (95% CIs) of all-cause mortality according CBC-derived inflammatory biomarkers among adults with ED.

	continuous		Quartiles of CBC-derived inflammatory biomarkers levels				P trend
	HR (95%CI)	P value	Q1	Q2	Q3	Q4
NLR
Crude	1.15(1.08,1.22)	< 0.001	-	1.08(0.80,1.46)	1.17(0.83,1.64)	1.85(1.34,2.55)	< 0.001
Model 1	1.06(1.00,1.11)	0.041	-	0.76(0.59,0.98)	0.86(0.65,1.14)	1.15(0.88,1.52)	0.2
Model 2	1.06(1.00,1.12)	0.036	-	0.74(0.57,0.95)	0.92(0.70,1.20)	1.18(0.90,1.54)	0.08
Model 3	1.06(1.00,1.11)	0.032	-	0.68(0.51,0.92)	0.83(0.63,1.09)	1.09(0.84,1.44)	0.2
dNLR
Crude	0.14(0.01,1.22)	0.087	-	0.83(0.59,1.16)	0.84(0.62,1.13)	0.79(0.55,1.14)	0.2
Model 1	0.29(0.04,2.12)	0.2	-	0.81(0.61,1.06)	0.75(0.59,0.97)	0.93(0.67,1.28)	0.6
Model 2	0.44(0.06,3.30)	0.4	-	0.83(0.61,1.13)	0.76(0.59,0.98)	0.95(0.69,1.31)	0.6
Model 3	0.22(0.03,1.58)	0.13	-	0.80(0.59,1.07)	0.72(0.57,0.91)	0.86(0.61,1.21)	0.3
MLR
Crude	4.46(2.85,6.98)	< 0.001	-	1.23(0.82,1.85)	1.82(1.25,2.66)	2.64(1.92,3.62)	< 0.001
Model 1	1.67(1.14,2.45)	0.009	-	0.93(0.62,1.38)	1.18(0.83,1.69)	1.31(0.96,1.78)	0.033
Model 2	1.90(1.23,2.92)	0.004	-	1.01(0.69,1.50)	1.28(0.91,1.81)	1.45(1.07,1.95)	0.005
Model 3	2.00(1.33,3.01)	< 0.001	-	1.01(0.70,1.45)	1.29(0.92,1.82)	1.44(1.09,1.90)	0.002
NMLR
Crude	1.14(1.08,1.21)	< 0.001	-	1.12(0.85,1.47)	1.17(0.80,1.70)	2.01(1.48,2.71)	< 0.001
Model 1	1.05(1.00,1.00)	0.033	-	0.84(0.65,1.09)	0.87(0.63,1.19)	1.23(0.94,1.62)	0.2
Model 2	1.06(1.01,1.12)	0.029	-	0.84(0.64,1.09)	0.95(0.70,1.29)	1.29(0.99,1.68)	0.04
Model 3	1.06(1.01,1.11)	0.024	-	0.78(0.58,1.06)	0.86(0.63,1.16)	1.21(0.92,1.59)	0.14
SIRI
Crude	1.17(1.08,1.26)	< 0.001	-	1.13(0.84,1.51)	1.22(0.88,1.69)	1.83(1.36,2.47)	< 0.001
Model 1	1.07(1.00,1.14)	0.04	-	0.93(0.72,1.21)	0.99(0.73,1.33)	1.23(0.97,1.57)	0.1
Model 2	1.06(0.99,1.13)	0.1	-	0.99(0.77,1.28)	0.98(0.72,1.34)	1.21(0.92,1.59)	0.2
Model 3	1.06(0.99,1.14)	0.078	-	0.97(0.74,1.27)	0.93(0.69,1.25)	1.19(0.91,1.55)	0.3
SII
Crude	1.00(1.00,1.00)	< 0.001	-	0.72(0.52,0.99)	0.67(0.47,0.97)	1.10(0.81,1.51)	0.7
Model 1	1.00(1.00,1.00)	0.006	-	0.68(0.50,0.93)	0.70(0.50,0.99)	1.04(0.82,1.31)	0.7
Model 2	1.00(1.00,1.02)	0.007	-	0.70(0.51,0.96)	0.76(0.54,1.07)	1.05(0.83,1.31)	0.6
Model 3	1.00(1.00,1.00)	0.015	-	0.69(0.50,0.95)	0.75(0.54,1.04)	1.03(0.84,1.27)	0.6

Crude Model: Unadjusted for covariates; Model 1: Adjusted for age and race; Model 2: Adjusted for age, race, marital status, BMI, PIR, education, smoking, alcohol consumption, and physical activity; Model 3: Fully adjusted model including all covariates.

Fig. 3A.

Kaplan-Meier Survival Analysis of the relationship between CBC-derived Indicators and All-cause mortality in adult men with ED(adjusted by Model 3); Fig. 3B: Assessment of prognostic Significance of CBC-derived Indicators: Spearman Correlation Analysis of CBC parameters and inflammatory markers; Fig. 3C: Comparative Evaluation of CBC Parameters and CBC-derived Indicators in predicting All-cause mortality using Random Survival Forests (RSF) method.

Prognostic value of CBC-Derived indicators

The correlation among CBC-derived inflammatory markers is depicted in Fig. 3B. A remarkably strong positive correlation is observed between the NLR and NMLR, with a correlation coefficient of 1.00. In contrast, a significant negative correlation is present between the monocyte count and dNLR, with a coefficient of −0.35. Furthermore, among these markers, MLR exhibits the strongest predictive power for all-cause mortality in adults with ED, as shown in Fig. 3C.

Discussion

In this study, we investigated the relationship between six CBC-derived inflammatory markers—NLR, dNLR, MLR, NMLR, SIRI, and SII—and erectile dysfunction (ED) among adult US men using data from the 2001–2004 NHANES. Our findings revealed that elevated neutrophil counts and reduced lymphocyte counts were significantly associated with a higher prevalence of ED, aligning with the outcomes of prior research¹⁹. Furthermore, four markers (NLR, MLR, NMLR, and SIRI) exhibited a positive correlation with the prevalence of ED, which corroborates earlier findings that NLR, SIRI, and SII were significantly linked to ED^17,20,21. After stratifying the markers into quartiles and setting the lowest quartile (Q1) as the reference, our analysis indicated that, contrary to studies proposing NLR as a rapid, straightforward, and cost-effective measure for assessing ED severity with high sensitivity and specificity²², the fully adjusted model demonstrated no significant correlation between higher quartile fractions of CBC-based inflammatory biomarkers and ED incidence compared to the lower fractions. Discrepancies in the results of previous studies may be attributed to variations in study populations or methodologies.

We also investigated the relationship between CBC-derived metrics and all-cause mortality in patients with ED. Again, these metrics were stratified into quartiles, with the lowest quartile (Q1) as the reference category. We were particularly interested in the fact that among the four metrics associated with all-cause mortality (NLR, MLR, NMLR, and SII), MLR had the highest predictive value for all-cause mortality in ED patients. In summary, our results suggest that CBC-based inflammatory biomarkers have potential prognostic value in predicting all-cause mortality in ED patients. These findings provide new perspectives for future studies and may contribute to the development of new diagnostic tools and therapeutic strategies.

The role of inflammation in ED is currently a focus of research. Some researchers have suggested that ED is an immune-mediated inflammatory state, with significantly elevated levels of inflammatory factors in ED patients compared to controls²³, and that some inflammation-associated disorders appear to contribute to the increased prevalence of ED^24,25. However, the molecular mechanisms by which chronic inflammatory signalling is involved in the pathogenesis of ED are still poorly understood. Theoretically, stimuli from exogenous or endogenous antigens may induce an inflammatory response in the vascular endothelium, leading inflammatory cells to produce inflammatory and growth factors, activate the immune response of T cells and macrophages, and release additional inflammatory factors. At the same time, increased oxygen consumption due to cell proliferation creates a relatively hypoxic environment. The infiltration of inflammatory cells and the relatively hypoxic environment exacerbate tissue damage and promote vascular endothelial damage and thus ED²⁶. In contrast, biological therapies targeting inflammatory cytokines are effective in reducing the risk of CVD and ED²⁷.

CBC-derived indicators are commonly used as markers of the body’s immune and inflammatory status and have gained interest in clinical practice due to their simplicity and cost-effectiveness. These indicators reflect more than two immune pathways, are less affected by confounding conditions than assessing monocytes, lymphocytes, or neutrophils alone, and may be more predictive in assessing inflammation²⁸. Studies have shown that NLR, NMLR, PLR, SIRI, and SII are significantly associated with prognosis in cancer patients, and each parameter has a good predictive value^29,30, while MLR, PLR, and NLR are valid indicators for assessing cardiovascular disease (CVD) risk and predicting mortality³¹. Furthermore, the predictive performance of several CBC-derived indicators has been demonstrated for the incidence and all-cause mortality of a number of diseases, such as adult sarcopenia, psoriasis, cardiovascular disease, and prostate hyperplasia^11,14,32,33. CBCs have been found to be important components of the immune system and are involved in the regulation of inflammatory responses. Moreover, monocytes play a more critical role in the chronic inflammatory process, whereas neutrophils are primarily involved in the acute inflammatory response^34,35. Therefore, MLR demonstrates a closer correlation with ED associated with chronic inflammation than other biomarkers. Their immunoreactivity may lead to ED by increasing oxidative stress, enhancing cytokine release, and causing tissue damage through the production of free radicals and reactive oxygen species³⁶. Subsequently, it increases the risk of developing ED and mortality, especially from cardiovascular causes³⁷.

Among these indicators, we found that MLR had the greatest predictive power for the incidence of ED and all-cause mortality in the ED population compared to others. Monocytes are recognized as important effector cells in inflammatory processes and play a crucial role in microbial clearance and in the pathogenesis of inflammatory and degenerative diseases³⁸. The heterogeneous subpopulation composition of monocytes in different environments determines the progression of systemic inflammation by linking innate and acquired immunity through phagocytosis, cytokine and chemokine release, antigen presentation, and lymphocyte activation³⁹. During initial inflammation, monocytes are recruited from the bone marrow into the circulation, leading to an increase in the absolute and relative number of monocytes in the blood. Conversely, the inflammatory response can suppress the immune system by inhibiting the cytolytic activity of immune cells such as lymphocytes. One possible explanation is that lymphocytopenia is due to the direct effects of elevated serum cortisol and catecholamines, which contribute to increased apoptosis and downregulation of lymphocyte proliferation and differentiation^40,41. In contrast, combining monocytes and lymphocytes into a single measure (MLR) is theorized to be a more reliable indicator of systemic inflammatory status than a single parameter, especially when monocyte and lymphocyte counts are close to the upper or lower limits of normal⁴².

Our study provides insights into the relationship between blood-derived inflammatory markers and ED. These markers are clinically accessible and cost-effective, allowing for convenient assessment by clinicians. They may also offer valuable perspective into the immuno-inflammatory mechanisms underlying ED. Our study has several advantages over previous studies. Firstly, it is based on NHANES data, which provides a more representative and larger sample, enabling the discovery of significant associations between the independent and dependent variables. Secondly, we adjusted for confounding covariates to ensure the validity of the current findings. Lastly, CBC-derived indicators, consisting of multiple CBC parameters, may provide more comprehensive information than a single indicator.

It should be noted that the present study is not without limitations. The cross-sectional nature of the study precludes the establishment of definitive causal relationships. Furthermore, the diagnosis of ED was based on participants’ self-reports, which may have introduced recall bias. However, previous studies have confirmed the reliability of self-reports⁴³. Additionally, although exclusion criteria were employed to minimize the potential for confounding effects and a variety of confounders were adjusted for, it is possible that unknown or unmeasured confounders not included in the NHANES database may have influenced the analysis. Furthermore, hematological parameters may be influenced by numerous other factors, such as active infection or inflammation.

Conclusions

In conclusion, our study demonstrates that there is a significant association between CBC-derived inflammatory biomarkers and the prevalence of ED, as well as survival prognosis in participants with ED, and MLR exhibited the most pronounced predictive capacity. Therefore, CBC-derived markers, especially MLR, have promising applications in the initial assessment of ED patients and in the prognostic assessment of their survival. In the future, we plan to conduct prospective studies in a wider population and include more potential confounders to deeply explore the role of these biomarkers in the ED population.

Ethics statement

The studies involving humans were approved by the NCHS Research Ethics Review Board (ERB) Protocol #98 − 12. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. The article does not contain any identifying images or data.

Author contributions

ZY: Data curation, Supervision, Validation; LT: Validation, Resources; CQ: Investigation, Methodology, Formal analysis; SM: Visualization, Project administration; FX: Funding acquisition, Writing—review & editing; LC: Conceptualization, Software, Writing-original draft. All authors reviewed the manuscript.

Funding

The research did not receive specific funding.

Data availability

The data covered in this study are freely available in the NHANES database (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx).

Declarations

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.