Introduction

Erectile dysfunction (ED) is defined as the lack of ability to initiate or sustain a penile erection adequate for sexual intercourse [1]. It is a mishap for both patients and their partners with significant influence on the quality of life globally [2]. The mechanism underlying ED is thought to be a vascular abnormality since the risk factors of ED such as aging, metabolic syndrome, vascular disease, smoking, and obesity [3,4,5]. Vasculogenic ED can result from several pathological factors occurring in blood vessels, including atherosclerosis [6], endothelial dysfunction, and inflammation [7]. These pathological factors disrupt the endothelial cells and lead to disturbance of vascular homeostasis [4, 5]. Platelet activation contributes to the development of atherothrombosis and the inflammatory vascular response [4, 5, 8].

Recently, several studies reported that men with vasculogenic ED have an increased value of MPV [9,10,11,12,13,14]. MPV is considered an indicator of PLT dimension that is automatically measured by blood counter devices [15]. MPV measurement has a relatively low cost and reflects PLT activity indirectly [16]. The high number of large platelet could associate with the development of atherothrombosis since the metabolic rate and enzymatic activity of large PLTs are higher than small PLTs. The production of thromboxane as the most potent vasoconstrictor substance by large PLT tends to be higher [17]. Moreover, the MPV was elevated in subjects with higher blood pressure, diabetes mellitus, hypercholesterolemia, obesity, and smoking [12,13,14]. These findings support the statement that high MPV may associate with the risk for cardiovascular problems, specifically vasculogenic ED. The increase in PLT activity contributes to the development of atherosclerosis [4, 5]. The process of atherogenesis involves the aggregation of thrombocytes, production of thromboxane, and synthesis of adhesion molecules [4, 17,18,19]. Increased PLT activity could contribute to the development of vasculogenic ED through a similar process of atherogenesis [9, 10].

Several studies have studied the association between vasculogenic ED and PLT activity; [9,10,11,12,13,14] however, the results are conflicting. For instance, while Ciftci et al. [13] stated that both PLT count and MPV increased in vasculogenic ED, Aldemir et al. [14] reported that PLT count was normal. Previously, a meta-analysis investigated the relationship between MPV and ED; however, the studies that were included were only up to 2018 [20]. The present study aims to broaden the previous meta-analysis to confirm the association of MPV and ED.

Methods

The target population included in this study is patients with ED and the intervention is the MPV blood test with healthy subjects as the control for the main comparison. Another comparison for analysis in this review are between vasculogenic and non-vasculogenic ED; severe ED and mild ED patients. The expected outcome was higher MPV levels in ED patients as it might be considered as a predictive marker of ED diagnosis. The methods for conducting and writing this review based on the guidance from the Preferred Reporting Items for Systematic Reviews and Meta-analyses [21] informed the methods for conducting and reporting this review.

Literature searching

The databases included in the search were: MEDLINE (PubMed) and CINAHL (EBSCOhost). The combination of subject heading index terms and the free text was used to expand the literature searching. The keywords used are presented in Table 1. Non-English language articles were excluded from this review. Additional studies were further explored from the reference lists of all qualified studies, systematic reviews, and meta-analyses. Searches were finished in September 2021.

Table 1 Detailed strategy.
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Measurement of ED

The instruments involving ED measurement in the qualified studies including (1) the five-item International Index of Erectile Dysfunction (IIEF-5) questionnaire [22]; (2) the standard 15-item International Index of Erectile Function (IIEF-15) questionnaire [23]; (3) history taking and physical examination; and (4) penile Doppler ultrasound.

Study selection

Two reviewers (NR and MH) were independently involved in selecting titles and abstracts to select appropriate studies to be included or excluded. The studies were considered suitable using the eligibility criteria in Table 2.

Table 2 Eligibility criteria.
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Data extraction

Extraction of the relevant data was conducted independently by two authors (NR and MH) in compliance with the eligibility criteria. Extracted studies were noted in the collection form. Discussion and consensus finding was performed if a disagreement occurred. In the present meta-analysis, we gathered these variables for each literature: (1) the first author’s name, year of publication, region; (2) sample size of the study case and control groups; (3) data including the MPV.

Statistical analysis

Meta-analysis was conducted based on guidance from the Cochrane Collaboration [24]. The strength of the association between MPV and the ED risks was evaluated using weighted mean differences (MDs) and the 95% confidence interval (CI). Pooling eligible studies’ data was conducted using both fixed and random effect models. All numerical variables were reported as mean ± SD. The criteria for significant heterogeneity was p < 0.10. I2 values of 25, 50, and 75% were considered low, medium, and high levels of heterogeneity. The Z-test was conducted to evaluate the significance of the pooled results. A two-tailed xi value was statistically significant if it was <0.05. The statistical analysis was conducted with RevMan 5.2. Estimation of possible publication bias was performed by using Egger’s test and funnel plots. Sensitivity analysis was conducted to assess the stability of the results. Estimation of the pooled MDs was performed by excluding one study each time to assess the impact of individual studies.

Random effect model (method of Dersimonian and Laird) analysis was used when items had high levels of heterogeneity (with I2 > 75%); otherwise, the fixed-effects model was applied. In a random-effects model, there is an assumption of variation between studies, and thus the measured OR represents a more conservative value.

Results

Literature search

A total of 168 publications were initially retrieved (Fig. 1). Twenty studies were excluded for being duplicates. Of these, 136 were excluded during abstract screening, and 12 articles were considered for both qualitative and quantitative analysis. The risk of bias and applicability concern in each study was identified using the QUADAS-2 tool. The risk of bias and applicability concern graph and summary were showed in Figs. 2 and 3.

Fig. 1: Preferred reporting items for systematic review and meta-analysis (PRISMA) flow chart.
figure 1

Preferred reporting items for systematic review and meta-analysis (PRISMA) flow chart describing the process for identifying included articles.

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Fig. 2
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Risk of bias and applicability concern graph.

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Fig. 3
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Risk of bias and applicability concern summary.

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Study characteristics

A total of 12 studies were included in this study, with 1643 subjects. Nine studies were case-control studies, two were retrospective studies, and one was cross-sectional study. All included publications were published from 2004 to 2020. We divided the included studies into three sections: (1) ED patients vs. healthy subjects (2), vasculogenic ED vs. non-vasculogenic ED patients, and (3) mild vs. severe ED patients. Two studies belonged to two groups. The characteristics of the studies are presented in Tables 3–5.

Table 3 Characteristics of the included studies that analyzed the MPV of ED patients and healthy subjects.
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Table 4 Characteristics of the included studies that analyzed the MPV of vasculogenic ED and non-vasculogenic ED patients.
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Table 5 Characteristics of the included studies that analyzed the MPV of severe ED and mild ED patients.
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Synthesis of results

We found that the MD of the MPV between ED patients and healthy subjects was 0.74 (95% CI 0.33–1.16). There was a statistically significant heterogeneity and overall effect among included studies ((I2 = 87%, p = 0.0004), and a random-effects model was used for the analysis (Fig. 4). The MD of MPV between vasculogenic ED and non-vasculogenic ED patients was 1.09 (95% CI: 0.69–1.50) (Fig. 5). There was also statistically significant heterogeneity and overall effect among included studies (I2 = 84%, p = < 0.00001), and a random-effects model was used for the analysis. The MD of the MPV between mild ED and severe ED patients was 0.57 (95% CI: 0.11–1.03) (Fig. 6). There was statistically significant heterogeneity, whereas the overall effect among included studies was statistically significant (I2 = 91%, p = 0.01).

Fig. 4
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Forest plot of the MPV between ED patients and healthy subjects.

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Fig. 5
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Forest plot of the MPV between vasculogenic ED and non-vasculogenic ED patients.

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Fig. 6
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Forest plot of the MPV between severe ED and mild ED patients.

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Discussion

ED is a common problem amongst sexually active male individuals [25]. Despite neuro or psycho-genic disorders, vascular disorders are the most common underlying cause [26, 27]. The risk factors for ED, such as diabetes mellitus, vascular disease, smoking habits, high-level lipid profile, desk-bound lifestyle, overweight, and metabolic disorders, parallel to risk factors for coronary artery disease (CAD) [28,29,30]. This indicates that ED is associated with CAD development. Several shreds of evidence stated that ED could independently predict cardiovascular disease in the future [8, 13]. Previous studies suggested that ED can be the initial feature of CAD symptoms [31]. A study stated that 19% of subjects with erectile problems had silent CADs revealed by angiography. This finding suggests comprehensive cardiovascular examinations for subjects with vasculogenic ED [32]. Other study reported that ED is a fundamental finding for future CADs [33]. These indicate that ED is closely related to CVD progression. PLTs have been considered to have a significant role in vascular disorders such as atherosclerosis and ED [4, 5, 8].

As MPV is an essential representation of PLT function, activity, production, and stimulation rate, the association between ED, PLT, and MPV becomes essential [11]. Large platelets have a higher metabolic rate and enzymatic activity than small platelets. The production rate of Thromboxane A2 (TXA2) as the most potent vasoconstrictor substance by large PLTs is higher. Increased platelet activity contributes to atherosclerosis development through mechanisms including aggregation of thrombocytes, production of thromboxane, and synthesis of adhesion molecules [7, 8, 11, 16, 17]. Some studies report that raised MPV induces and accelerates atherogenesis, resulting in thrombosis, CAD, and myocardium infarction [34, 35]. These are recognized as the basis of atherogenesis in penile arterial deficiency [9, 11, 13]. In vasculogenic ED, the adherence of PLTs to the cavernosal walls was proposed. PLTs produce TXA2, which increases oxidative stress during erection [14]. TXA2 secreted more abundantly in a larger PLT. Thus, its function mirrored the MPV raise [13]. Several studies stated that a rise of MPV parallel with CAD risk factors, such as smoking habit, metabolic disorder, overweight, hypertension, and abnormal lipid profile [19].

The present meta-analysis found that ED subjects’ mean MPV was significantly higher than healthy subjects (p < 0.0004). We also found that the mean MPV of vasculogenic ED subjects was also higher than those with non-vasculogenic ED. Furthermore, there was a significant difference in MPV level between mild ED and severe ED (p < 0.00001), suggesting that MPV levels also could be used to differentiate ED severity. This result showed vital evidence of the association between MPV and ED development. Commonly used blood counters automatically measure this marker of platelet size. It can be found easily and has a low cost. In addition, it indirectly represents the platelet activity.

Limitations

Several limitations in this review were low to moderate quality and a low number of included studies in each analysis group. From the study design, we also included retrospective studies that were less appropriate for this review and analysis. The results from the analysis also showed high heterogeneity among studies included and making it difficult to generalize the conclusions. In addition, most of the articles did not exclude subjects with psychological factors, associated comorbidities, and past illness history that could cause a potential bias.

Conclusion

There is a possible association between a high level of MPV and the development of ED. We found that the difference in MPV levels between ED subjects and healthy controls showed significant results. The level of MPV between mild and severe ED was also found to be significantly different. However, due to the limitations, these findings cannot justify the use of MPV as a predictive marker for ED and differentiate between ED severity.