Inflammatory biomarkers may predict response to phosphodiesterase type 5 inhibitor treatment in patients with erectile dysfunction

Erectile dysfunction (ED) is defined as the inability to achieve and/or maintain adequate penile erection for satisfactory sexual intercourse [1]. ED is a multifactorial disease in which neurogenic, vasculogenic, hormonal, iatrogenic, psychogenic, and anatomical factors play a role in pathophysiology [2]. Among the most important risk factors of ED are cardiovascular disease (CVD), diabetes mellitus (DM), hypertension, dyslipidemia, metabolic syndrome, chronic systemic diseases, smoking, and obesity [3].

Owing to the dense vascular network of the penis, vascular causes are more predominant than other etiological factors and are responsible for 60% to 80% of all ED cases [4]. It is widely accepted that there is a close relationship between ED and CVD, two clinical entities that share many risk factors [3, 4]. The common pathophysiological conditions underlying ED, CVD, and other vascular diseases are inflammation, atherosclerosis, and endothelial dysfunction associated with the above-mentioned risk factors [5, 6]. According to the hypothesis that smaller arteries are more vulnerable to the same vascular lesions, sexual symptoms develop first in patients with endothelial dysfunction, and ED always occurs earlier than CVD, because the arteries in the penis are less tolerant of the same quantity of atheromatous plaques owing to their smaller size [4, 7]. Thus, current evidence confirms that vascular ED may be a precursor for CVD, stroke, and peripheral arterial disease [8].

Studies have shown that the intensity of inflammation is closely related to endothelial dysfunction and the development of atherosclerosis. Hematological and biochemical parameters, such as the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and monocyte/high-density lipoprotein (HDL) cholesterol ratio (MHR) have been used as biomarkers to assess the intensity of inflammation [9, 10, 11, 12]. These parameters can be useful not only in the prediction of the occurrence of vascular diseases but also in the assessment of the severity and prognosis of these diseases [8].

Phosphodiesterase type 5 inhibitors (PDE5is), which are the first-line medical treatment of ED, block the PDE5 enzyme that causes cGMP degradation by entering the smooth muscle, thereby maintaining a high level of intracellular cGMP and continuation of vasodilation and ensuring the continuity of erection [13]. Therefore, a healthy vascular structure is required for PDE5i to be effective. Because ED is closely related to CVDs, many biochemical predictive factors have been investigated [8, 10, 11]. To the best of our knowledge, however, there are no studies in the literature investigating the effect of hemogram parameters on ED treatment. In this study, we aimed to evaluate the clinical utility of NLR, PLR, MHR, and LMR in predicting response to PDE5i when used in the first-line medical treatment of ED.

After receiving the approval of the Ethics Committee of Health Sciences University Bursa Yuksek Ihtisas Training and Research Hospital (approval number: 2011-KAEK-25 2021/08-04), we began to enroll patients in the study in accordance with the principles of the Declaration of Helsinki. A total of 185 patients who presented to the urology outpatient clinic of our hospital and started PDE5i treatment with a diagnosis of ED were prospectively included in the study. The erectile function of the patients was evaluated by using the five-item form of the International Index of Erectile Function (IIEF-5). Patients with an IIEF-5 score of 22 and above are considered to have normal erectile function, whereas an IIEF-5 score of 17–21 indicates mild ED, 12–16 mild to moderate ED, 8–11 moderate ED, and 5–7 severe ED.

The exclusion criteria were as follows: any endocrinological disease (e.g., hyperprolactinemia, hypogonadism, hypo/hyperthyroidism), neurological disease, hematological disease, accompanying malignancies, psychiatric disease, ED-related drug and addictive substance use, collagen tissue disease, history of penile or pelvic surgery/trauma/radiotherapy, history of spinal cord trauma, presence of penile curvature/Peyronie’s disease, chronic liver failure, chronic renal failure, heart disease causing a contraindication to PDE5i use, and previous medical or surgical treatment for ED.

The patients included in the study were asked to complete the IIEF-5 themselves after granting their informed consent. The physicians did not mark any responses and only provided detailed explanations of questions that the patients were unable to understand. A detailed anamnesis, including information on surgery and medication, was obtained from all patients, and a comprehensive physical examination was performed. Before PDE5i treatment, blood samples were taken from all patients between 08:00 and 11:00 in the morning after they had fasted overnight. From the blood samples, complete blood count, fasting blood glucose, hemoglobin A1c, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, albumin, total cholesterol, HDL, low-density lipoprotein, triglyceride, thyroid-stimulating hormone, free T3, free T4, total testosterone, and prolactin were examined. In addition, prostate-specific antigen values were determined for patients aged over 50 years. Before PDE5i treatment, NLR was calculated and recorded by dividing the absolute neutrophil count by the absolute lymphocyte count, LMR by dividing the absolute lymphocyte count by the absolute monocyte count, PLR by dividing the absolute platelet count by the absolute lymphocyte count, and MHR by dividing the absolute monocyte count by the HDL value.

After the patients with ED had used at least four tablets of PDE5i as prescribed (randomly, sildenafil 100 mg or tadalafil 20 mg), they were instructed to undergo four to six attempts to achieve sexual intercourse, after which their IIEF-5 scores were calculated again and compared [14]. After PDE5i treatment, the patients were divided into two groups: patients in Group 1 had IIEF-5 scores below 22, indicating that their erectile function did not return to the normal level with treatment, and patients in Group 2 had IIEF-5 scores of 22–25.

The mean age of the patients included in the study was 51.7±10.3 years, and their mean IIEF-5 score was 8.9±3.8 (range, 5–19). The mean IIEF-5 change after PDE5i was 8.4±4.6 points, being 6.1±4.2 points for Group 1 and 11.5±3.2 points for Group 2. The change in IIEF-5 score was statistically significantly higher in Group 2 (p=0.001). Fig. 1 presents the distribution of the patients in both groups according to their ED categories before and after PDE5i treatment. The demographic and clinical characteristics of the groups are summarized in Table 1. When we evaluated the correlation of statistically significant variables between the two groups, we found that age was negatively correlated and absolute monocyte count was positively correlated (r=-0.247, p=0.001 and r=0.199, p=0.007, respectively). The correlation between blood glucose and neutrophil count and IIEF score was not statistically significant (p=0.55, 0.156, respectively). In Group 1, there was a statistically significantly higher number of patients with DM than in Group 2 (37 [34.5%] and 14 [17.9%], respectively, p=0.01). There was no statistically significant difference between the groups in terms of the presence of hypertension or coronary artery disease (p=0.56 and p=0.79, respectively).

Fig. 1
Distribution of patients in study groups by erectile dysfunction (ED) category before and after treatment.

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Table 1
Demographic and clinical characteristics of the study groups

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Table 2 presents the data on proinflammatory markers, namely NLR, LMR, PLR, and MHR. The only statistically significant difference between the groups was in the comparison of the LMR and MHR values in the prediction of PDE5i response (p=0.044 and p=0.002, respectively). A positive correlation between MHR and IIEF score was found to be statistically significant (r=0.213, p=0.004). A negative correlation between LMR and IIEF score was not statistically significant (r=-0.03, p=0.65). In addition, the univariate and multivariate logistic regression analyses of the patients who benefited from PDE5i treatment are summarized in Table 3. Univariate indicators of those who benefited from PDE5i treatment were younger age (OR=0.93, p<0.001), decreased fasting blood glucose (OR=0.99, p=0.036), increased neutrophil count (OR=1.32, p=0.018), increased absolute monocyte count (OR=8.8, p=0.001), decreased LMR (OR=0.84, p=0.036), and increased MHR (OR=1.07, p=0.003). When multivariate analysis was applied, younger age (OR=0.93, p<0.001) and increased MHR (OR=1.06, p=0.033) were found to be independent risk factors.

Table 2
Comparison of NLR, LMR, PLR, and MHR values between the study groups

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Table 3
Univariate and multivariate logistic regression analyses to determine the independent predictors of benefit from PDE5i treatment

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Fig. 2 shows the ROC curves of age, MHR, and the combination of age and MHR cutoff values that can be used as independent predictors of normalization of the IIEF-5 score after PDE5i treatment. ROC curve analysis was performed to calculate Youden’s index of age and MHR. Univariate ROC curve analysis of age showed a sensitivity of 67.9% and a specificity of 62.6% for benefit from PDE5i treatment in case of age ≤52 years with area under the curve (AUC) of 0.676 (Fig. 2A). Univariate ROC curve analysis of MHR showed a sensitivity of 67.9% with a specificity of 58.9% for benefit from PDE5i treatment in case of MHR >14 with AUC of 0.651 (Fig. 2B).

Fig. 2
ROC curve analysis of markers used to predict treatment success. (A) Age. (B) MHR. (C) Combination of age ≤52 years and MHR >14. AUC, area under the curve; CI, confidence interval; MHR, monocyte/high-density lipoprotein cholesterol ratio; ROC, receiver operating characteristic.

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Multivariate ROC curve analysis with age and MHR as multivariate statistically significant parameters showed in case of age ≤52 years and MHR >14 a sensitivity for benefit from PDE5i treatment of 44.8% with a specificity of 85.9% and AUC of 0.714.

ED is a hemodynamic phenomenon with many factors involved in its pathophysiology [2]. In the Massachusetts Male Aging Study (MMAS), the prevalence of ED was reported as 52% in men between the ages of 40 and 70 years, and the prevalence of mild, moderate, and complete ED was determined to be 17.2%, 25.2%, and 9.6%, respectively [15]. In another study showing that the incidence of ED increases with age, the prevalence of ED was 20%–40% in men aged 60–69 years, and this rate increased to 50%–100% in men in the eighth and ninth decades of life [16]. With aging, endogenous nitric oxide (NO) production decreases [17]. In addition, NO levels are reduced in comorbid conditions, such as hypogonadism, diabetes, and atherosclerosis; therefore, response to PDE5i is lower in older than in younger patients [17, 18]. However, PDE5i is recommended as a first-line medical treatment in both older and younger patients because of its ease of use and excellent safety profile [17]. In our study, the mean age of Group 2, who benefited from PDE5i treatment (47.8±10.3 y), was significantly lower than that of Group 1 (54.6±9.2 y), who did not benefit from this treatment (p<0.001). In addition, age was an independent risk factor in the multivariate analysis. It can be predicted with 67.9% sensitivity and 62.6% specificity that patients aged 52 years and younger will benefit from PDE5i treatment. On the other hand, treatment failure increases with increasing age (OR=1.06, p<0.001).

ED is acknowledged as the most important sexual dysfunction in men with DM. The prevalence of ED is approximately 3.5 times higher in men with DM than in those without DM [19]. According to a meta-analysis, the overall prevalence of ED was reported to be 52.5% (95% CI, 48.8–56.2), similar to the MMAS, in patients with DM, and the prevalence of ED in patients with type 1 and type 2 DM was 37.5% and 66.3%, respectively [20]. It has been shown that diabetic patients with ED may respond less to first-line medical treatment and require 1.5–2 times more aggressive treatment [21]. In the current study, consistent with the literature, there were statistically significantly more patients with DM in Group 1 than in Group 2 (37 [34.5%] and 14 [17.9%], respectively, p=0.01). Fasting blood glucose levels were also statistically significantly higher in Group 1 than in Group 2 (105 [36] mg/dL and 97 [23] mg/dL, respectively, [p=0.010]). Although the difference between the groups was statistically significant, fasting blood glucose was not found to be an independent risk factor in the multivariate analysis (OR=0.99, p=0.133).

Today, one of the most important causes of ED is organic disease due to vascular disorders, which is observed in 60%–80% of all ED cases [4, 10]. Endothelial dysfunction, atherosclerosis, and inflammation can be seen in the pathophysiology of both ED and CVD [5, 6]. Since atherosclerosis is a systemic vascular disorder, it invades all vascular beds. However, because of the different tolerance levels of arteries of different diameters, the symptoms of ED usually occur earlier than those of CVD [4, 7]. ED and CVDs have many common risk factors, and ED has even been suggested as an independent risk factor and early messenger symptom of CVD [22]. Inflammation triggers atherosclerosis by impairing endothelial function [4]. Therefore, various parameters can be used to evaluate the severity of inflammation. Due to the close relationship between ED and CVD, hematological and biochemical inflammation parameters that can be used to predict or evaluate CVD have also been hypothesized to be of great clinical importance for ED, with their validity having been demonstrated by many studies [9, 11, 12, 23, 24, 25].

In recent years, NLR and PLR have been proposed as biomarkers of subclinical inflammation, and many studies have investigated these ratios [9, 10, 23]. In one of these studies, it was concluded that NLR was significantly higher in patients with atherosclerosis, and NLR was a biomarker of atherosclerosis progression [23]. Similarly, in another study evaluating 3,227 patients, NLR was shown to be an independent predictor of cardiovascular risk [24]. In a study conducted with 101 patients with ED and 31 healthy controls, NLR and PLR were found to be significantly higher in the patient group [10]. Consistently, Liao et al. [8], who studied 113 patients diagnosed with ED and 212 healthy controls, reported that NLR and PLR significantly increased the risk for ED, contributing to the diagnosis and evaluation of ED. In the current study, unlike the literature, there was no significant difference in NLR or PLR between Group 1, who did not respond to PDE5i treatment, and Group 2, who had a treatment response.

A study investigating the relationship between LMR and CVD showed that LMR was independently and positively associated with the severity of coronary atherosclerosis [12]. MHR, another proinflammatory marker, has been reported to be a new predictor and prognostic factor in CVD [11, 25]. In a study including 60 patients with ED and 60 healthy controls, MHR was found to be significantly higher in the ED group than in the control group (1.31 vs. 1.77, p<0.001), and it was suggested that this parameter could be used in the follow-up of ED [26]. Similarly, in a prospective study comparing 89 patients with ED and 100 healthy controls, the MHR value was reported to be significantly higher in the ED group than in the healthy group (10 vs. 8.3, p=0.004), and MHR could be used to determine and monitor the severity of ED [27].

In the literature, there are limited studies examining the relationship between LMR and ED. In a study investigating the effect of daily tadalafil on the IIEF-5 score, LMR, and MHR, 31 patients with ED using 5 mg tadalafil daily for 8 weeks were compared with 31 healthy controls. In the ED group that used tadalafil for 8 weeks, there was an increase of approximately 8 points (p=0.001) in the IIEF-5 score, whereas there was no statistically significant difference in LMR and MHR before and after treatment or when compared to the control group [28]. In our study, LMR was statistically significantly lower in Group 2, which benefited from treatment, than in Group 1, who did not show a treatment response (p=0.044). LMR was also a statistically significant predictive factor in the univariate analysis (OR=0.84, p=0.036). However, it was not detected as an independent factor in the multivariate analysis (p=0.917). Contrary to the literature, we found the MHR value to be statistically significantly higher in Group 2 than in Group 1 (17 vs. 13.8, p=0.002). The results also showed that increased MHR was an independent variable that could predict response to PDE5i treatment (OR=1.06, p=0.033). A benefit of treatment could be predicted with 67.9% sensitivity and 58.9% specificity in patients with MHR above 14. The most clinically significant scale is formed when age is 52 or under and MHR is over 14. The probability of benefiting from treatment in patients meeting both cutoff values can be estimated with 44.8% sensitivity and 85.9% specificity (AUC=0.714).

The limitations of our study include the unequal duration of PDE5i use among patients and the lack of standardization in PDE5i agent and dose. In addition, the blood tests of all the patients were performed before starting PDE5i, and changes in parameters after treatment were not evaluated. The strengths of our study are that the parameters used to predict treatment benefit can be easily used in daily practice. The results of our study can be discussed with studies to be conducted with larger series. It may also contribute to the generation of nomograms that can be used to predict index patients who will benefit from PDE5i treatment.

If the vascular characteristics of patients with various clinical features and biomarkers can be predicted before treatment, exposure to unsuccessful treatment attempts and associated psychological destruction can be prevented in many patients. Our study showed that age and MHR values could be used for this purpose. Our findings can be used to identify candidates who would benefit from the use of PDE5i treatment.