The objective of this study is to evaluate the association between chronic periodontitis (CP) and the risk of erectile dysfunction (ED). Electronic search using PubMed, Embase and the Cochrane Library was carried out for observational studies, longitudinal, cohort, case–control and epidemiological studies on humans, published up to December 2015. Manual searches were also performed. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to estimate the association between CP and the risk of ED. Methodological quality assessment was carried out using the Newcastle-Ottawa Quality Assessment Scale. Four case–control studies and one cross-sectional studies involving 213, 006 participants were included. Based on the random-effects model, analyses of all studies showed that CP was associated with an increased risk of ED (OR=2.28, 95% CI: 1.50–3.48). There was heterogeneity among the studies (P<0.001, I2=97.8%). Estimates of total effects were generally consistent with the sensitivity and subgroup analyses. In conclusion, our meta-analysis suggested that there was a significant association between CP and the risk of ED. Further epidemiological studies are needed to better estimate the key risk factors for periodontitis and their interaction effects.
Erectile dysfunction (ED) is defined by the National Institutes of Health as the persistent or recurrent incapability to complete or maintain an sufficient erection for satisfactory sexual performance.1 The prevalence rate of ED is quite high. Epidemiological studies suggested that more than 30 million men alone in the United States were affected by some degree of ED.2 ED is highly associated with negative effect on the sexual relationship and the quality of life of the patients and their partners.3 It is a multifactorial condition that may be influenced by organic or psychological causes, or their combination.4
Chronic periodontitis (CP) is a common bacterial-induced inflammatory disease. It is characterized by chronic bacterial infection of gingival tissue leading to a progressive loss of dental connective tissue and alveolar bone support.5 CP is a major cause of tooth loss in adults.5, 6 It has been discovered that CP is associated with increased incidence of cardiovascular disease.7 In addition, it is associated with an increased level of systemic inflammation and endothelial dysfunction.8 These conditions are implicated in the etiologies of atherosclerosis and stroke.9 Cardiovascular disease has also been demonstrated to be associated with ED.10
It has been discovered that ED and CP share the same risk factors and associated systemic conditions including but not limited to systemic inflammation, endothelial dysfunction and atherosclerosis. Other factors such as smoking, diabetes mellitus and coronary artery disease may also contribute to this equation.7 Furthermore, intensive periodontal treatment has been prospectively demonstrated to result in the improvement of the endothelial function after 6 months therapy.11 A recent study confirmed that the severity of ED improved following periodontal treatment.12 Therefore, the similar pathogenic process between the CP and cardiovascular disease are among the reasons to hypothesize that a link may exist between CP and ED. Zuo et al.13 reported that CP significantly decreased the expression of endothelial nitric oxide synthase and nitric oxide synthase activity in the penile cavernous tissue of the rat through systemic inflammation. Thus, the erectile function was impaired.
Although the link between CP and ED had been studied, it had not yet been demonstrated that CP was a risk factor for the development of ED. Many of the available studies were relatively small. The effect estimates thus had wide confidence intervals (CIs). Therefore, the purpose of this study was to evaluate the association between CP and the incidence of ED through a meta-analysis of the available studies.
Materials and methods
This systematic review and meta-analysis were conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.14
On the basis of patient, intervention, comparison, outcome and study design (PICOS), the question that guided this review was: Does CP increases the risk of ED?
The electronic databases of the Pubmed, the Embase and the Cochrane Library up to December 2015 were systematically searched for studies that investigated the association between CP and ED. The MESH terms used were words relating to 'chronic periodontitis' ('periodontitis' OR 'periodontal diseases' OR 'gingivitis') and 'erectile dysfunction' ('sexual dysfunction' OR 'impotence'). The complete search procedure used a combination of MESH terms and free text words. The search strategy used for MEDLINE including the MeSH and text words was ((((((periodontitis) OR chronic periodontitis) OR periodontal infection) OR gingivitis) OR periodontal infection)) AND ((((erectile dysfunction) OR sexual dysfunction) OR Sexual Dysfunction, Physiological (Mesh)) OR impotence). Additionally, we reviewed the reference lists of retrieved articles to identify additional studies. No restrictions were placed on the language of the articles and the publication date.
We included all of the available epidemiologic evidences on the association between CP and sexual dysfunction in the adults. Participants in this study were limited to the broad-spectrum population diagnosed with CP and ED. A record was considered relevant to this review if it assessed the following: men with ED (P), a history of CP or periodontal disease (I); compared with the general population (C); and patient outcomes including ED and erectile disorders (O). We accepted all study designs (S). Furthermore, studies on the pertinent subjects that provided relative risk (RR) estimates (or odds ratios (ORs) in case–control studies) with 95% CIs or sufficient data to allow calculation of these effect measures. The exclusion criteria included the following: if the patients in the study received periodontal treatment; the control data were not reported (from a separate control group or the unaffected side); the review articles; meeting abstracts; editorials and commentaries. When two or more papers published results originating from the same study sample, only the most recently published results were included. Two investigators (LHL and EML) independently selected the publications for the inclusion into this study. Disagreements between the investigators were resolved by discussion or in consultation with a third author (ZGZ).
All articles were reviewed and data were extracted using a specially designed data extraction form. The extracted data included the following: the authors’ names, year of the publication, country of origin, the sample size, age, study design, methods of periodontal disease and ED ascertainment. Variables were adjusted for authors’ conclusions and risk of bias. Furthermore, in order to conduct meta-analysis, effect measures (relative risk or OR) with 95% CI were recorded.
Assessment of methodological quality
The Newcastle-Ottawa Scale for the assessment of non-randomized studies was used to assess the quality of the included studies.15 The scale evaluates three elements: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or the outcome of interest for the case–control or for the cohort studies. A point was awarded for each item that was satisfied by the study. Studies with 7–9 points were arbitrarily considered to be of high quality, while studies with 5–6 points were classified as moderate quality and studies with less than 5 points were of low-methodological quality.
The degree of agreement between the two authors for judging study eligibility was measured using a Kappa statistic. OR and its 95% CI were used as the common measurement for the association between the CP and the risk of ED in the included studies. The effect size was considered to be significant if the P<0.05. Studies were combined by the use of the random-effects model (DerSimonian and Laird method), which considers both the within- and the between-study heterogeneity.16 Heterogeneity of study-specific effects was assessed using I2 statistics and the Cochrane’s Q statistic.17 We carried out predefined subgroup analyses on age, study design, the sample size, the year of publication and adjustment factors. Sensitivity analysis was carried out to verify the effect of each individual study on the stability of the summary estimates. All analyses were performed using STATA 12.0 (STATA Corporation, College Station. TX, USA).
Literature search and study characteristics
Figure 1 showed the results of the study selection. The systematic literature search yielded 58 relevant references; of which 15 potentially relevant articles were retrieved and assessed in more detail. Among them, seven studies were excluded for not reporting a relationship between periodontitis and ED; two for having no control group and one for not reporting prevalence of ED in the periodontitis. At the conclusion of the search, five studies met the inclusion criteria for this review.18, 19, 20, 21, 22 Agreement between the reviewers was moderate for the title screening (k statistic=0.52), moderate for the abstract screening (k statistic=0.49) and moderate for the full-text review (k statistic=0.55).
The main characteristics of the included studies are summarized in Table 1. These five studies were published between 2009 and 2014. Two of them were case–control studies,19, 22 one was a single-blinded, randomized-controlled clinical trial,20 one was a cohort study18 and one was cross-sectional study.21 A total of 213,006 participants were included. The sample size in the studies ranged from 88 to 197,136 adult subjects. Their ages ranged from 20 to 80 years old. The studies were all coming from the Asian continent: Israel,18 Taiwan,19, 22 Turkey20 and Japan.21 As assessed by Newcastle-Ottawa Scale, two case–control studies19, 22 were awarded with a score of nine points; one study20 received a score of seven points (Table 2).
Definition of ED
In the included studies, ED was diagnosed by International Classification of Disease, 9th edition, Clinical Modification (ICD-9-CM) coding (impotence, organic (based on ICD-9-CM code 607.84)), the International Index of Erectile Function or Sexual Health Inventory for Men questionnaire. In the study of Zadik et al.,18 the diagnosis of ED is based on the results of Sexual Health Inventory for Men questionnaire. In the study of Keller et al.,19 patients received two ED diagnoses (ICD-9-CM coding and International Index of Erectile Function questionnaire), with at least one diagnose made by a urologist. Two studies20, 21 used the International Index of Erectile Function questionnaire to detect ED and assess its severity. Furthermore, Tsao et al.22 made the clinical diagnosis based on the use of ICD-9-CM coding.
Definition of CP
CP was generally diagnosed during the clinical examination by the dentists at the annual checkups. This examination included a periodontal examination and radiographies. The periodontal examination consisted of the assessment of the plaque index, bleeding upon probing the sulci, probing depth and the clinical attachment level. In the study of Zadik et al.,18 bilateral pairs of standardized posterior bitewing dental radiographs were used to detect CP. The definition of CP was alveolar bone loss at least one site in the jaw with a distance of cement enamel junction to alveolar bone crest of 6 mm or more. In the study of Keller et al.,19 CP is diagnosed based on ICD-9-CM code 523.4 and a clinical examination included a periodontal examination, probing of the sulcus, and radiographs. In addition, in the study of Oguz et al.,20 a comprehensive periodontal examination, including documentation of the plaque index, bleeding on probing, probing depth and clinical attachment level, was conducted in all patients. Periodontal health was defined as the lack of probing depth 4 mm. In the study of Matsumoto et al.,21 the diagnosis was based on the chronic periodontal disease self-check sheet. Chronic periodontal disease severity was classified into four categories based on the total score of self-check questionnaire. Only Tsao et al.22 identified CP cases based on ICD-9-CM code 523.4.
Relationship between CP and ED
All the studies revealed a positive relationship between these two conditions. Each of the included studies found that the incidence of ED in the CP patients to be higher than those of non-periodontitis patients. The pooled summary OR was 2.28 (95% CI: 1.50–3.48) in a random-effect model for the patients with the periodontitis as compared with the non-periodontitis individuals (Figure 2). There was significant heterogeneity among these studies (P<0.001, I2= 97.8%).
To further elicit the association between CP and the risk of ED, subgroup analyses were performed. These were done according to the stratification in the age distribution, the sample size, the year of publication and adjustment for diabetes mellitus (Table 3). The results showed that CP was consistently associated with ED in the subjects aged less than 40 years old or over 59 years (P=0.003, P=0.02 and P=0.037, respectively). However, the association was not found in the men aged 40–59 years old (P=0.074 and P=0.06, respectively). The summary estimates were significantly higher for studies of small sample sizes than studies of large sample sizes, for studies published before 2012 than for studies published after 2012. When we restricted the meta-analysis to those studies controlled for diabetes mellitus, the positive association between CP and ED remained (OR=2.10, 95% CI: 1.49–2.95). Sensitivity analysis was performed to assess the influence of an individual study on the overall risk of ED. Each of the individual studies was excluded to recalculate the pooled OR. Similar OR and 95% CI were obtained after the exclusion. This indicated a high degree of stability of the results (Table 4).
The potential association between CP and the risk of ED has evoked great interest among the urologists, the dentists as well as the epidemiologists. Our results indicated a statistically significant association between CP and ED. Furthermore, the effect of CP at different age was further examined. The results showed that the relationship between CP and ED was more positively correlated in the younger population under 40 years of age and over 59 years than other age groups. It suggested that periodontal disease could play a role in the development of ED in adults. However, there was substantial evidence of heterogeneity. The different age, sample size, varied characteristics of participants and adjustment factors could all be partly responsible for this heterogeneity.
The subgroup analysis found that the men under 40 years of age or over the age of 50 who were diagnosed CP have a higher rate of ED. ED in men is common and increases with age. Many preclinical studies and clinical trials have indicated ED is a common medical condition in men at least 50 years old.1, 2 The stronger association detected among the older age group (>59 years) may be on account of long-term damage to endothelium function. Younger participants were investigated more often in the included. Thus, the stronger association in the younger groups (aged <30 years and 30–40 years) may stem from a surveillance bias. Oguz et al.20 selected the men aged between 30 and 40 years to assess the impact of CP on ED. CP at a younger age is a marker of higher disease susceptibility due to common pro-inflammatory factors.23 Furthermore, younger participants may be under higher social pressure. Thus, there is a larger percentage of ED in young men with CP.
Our findings were based on recent epidemiological studies. Zadik et al.18 were the first to report that CP was significantly more prevalent among men with mild to moderately severe ED than men without ED. On the other hand, the study by Sharma et al.24 failed to detect any association between these two conditions. Keller et al.19 analyzed the data of 32,856 ED patients and 162,480 controls by using a nationwide, population-based data set in Taiwan to explore the association between CP and ED in 2012. They found that ED patients were 3.35 times more likely than the controls for having been previously diagnosed with CP. The strengths of the study were the large sample size and the selection of participants from a population-based database. Oguz et al.20 also examined this issue. The findings of their study supported the hypothesis that CP had a high association with ED in young adults at 30–40 years. In the other study, Matsumoto et al.21 found that ED was related to the damages caused by the endothelial dysfunction and the systematic inflammatory changes associated with the CP. More recently, the population-based study by Tsao et al.22 showed a significant association between CP and ED. They suggested that the chronic inflammation resulting in the endothelium impairment was the link between CP and ED. Finally, a recent meta-analysis of four observational studies reported that a significant association between CP and ED (OR=3.07, 95% CI: 1.87–5.05).25
Several mechanisms might explain the increased risk of ED in patients with CP. CP is the most common form of periodontal disease. Several studies suggested that CP was associated with systemic markers of inflammation. These included serum C-reactive protein and plasma fibrinogen.26 It has been discovered that CP was associated with increased incidence of coronary heart disease among younger men and was independent of the established cardiovascular risk factors.7 ED and cardiovascular disease are considered to be a common end point of the same vascular pathology. The ED is deemed to be an early sign of coronary heart disease.10 Oxidative stress and systemic inflammation in endothelial dysfunction caused by CP are the primary foundation of the association between CP and ED.27 Excess production of the reactive oxygen species leads to a decrease of nitric oxide. The impaired activity of nitric oxide in the vascular beds and the damage to the antioxidant system may then contribute to the endothelial dysfunction in patients with periodontitis.23
It has been previously reported that high levels of inflammatory mediators such as tumor necrosis factor-α and other cytokines were found in the saliva and serum of the patients with periodontal disease.28 Tumor necrosis factor-α and other cytokines produced by the inflammatory stress could inhibit the nitric oxide synthase activity by impeding the degradation of the endogenous inhibitor of nitric oxide synthase.29 It was suggested that the impairment of the erectile function in the CP could be stemmed from the damage of the endothelium-dependent smooth muscle relaxation and the subsequent vascular insufficiency.
There was mounting evidence that vitamin D deficiency could also be a risk factor for ED associated with vascular dysfunction.30 Vitamin D had recently been shown to modulate endothelial function and promote vascular health by inhibiting inflammations. Low levels of vitamin D might increase the ED risk by promoting endothelial dysfunction. The study also showed that deficient vitamin D levels were likely to disrupt the NO pathway, which was responsible for maintaining healthy vascular function. Vitamin D supplementation had a modest positive effect on periodontal health and endothelial function.31 However, the role of vitamin D in reducing risk of ED had not been confirmed. The vitamin D deficiency hypothesis could be investigated if the 25-hydroxyvitamin D concentrations were monitored in patients with ED that was related to the periodontal disease.
The actual biological mechanism of ED in periodontitis patients remains poorly understood. It might still be too early to suggest that men with ED should have their teeth checked; and that men with CP should worry about their sexual function. However, it might be beneficial to inform patients with CP about its association with ED. We believe chronic inflammation and endothelial dysfunction link CP and ED. Since CP had been linked with several chronic disorders, it is sensible to recommend daily inter-dental cleaning to reduce dental plaque and gingival inflammation.26, 28 The CP treatment can control or eliminate inflammation and may reduce the risk of ED. Furthermore, clinicians should be aware of the potential role played by the periodontitis disease in the development of ED.
Two systematic reviews had investigated the link between CP and the risk of ED.25, 32 Wang et al.25 identified four case–control studies reporting the prevalence of CP in patients with ED. The results revealed a positive association between CP and ED (OR=3.07, 95% CI: 1.87–5.05). More recently, Kellesarian et al.32 also examined this issue. In all the included studies, a positive relationship between CP and ED was reported. The ORs ranged between 1.53 and 3.35. However, there were several limitations in the previously published meta-analyses. For the study by Wang et al.,25 only four case–control studies were included to investigate the relationship between periodontal disease and ED. Furthermore, subgroup analysis was not performed to explore sources of heterogeneity in this study. In the study by Kellesarian et al.,32 nine studies were included in the systematic review. However, in the included studies, four studies had no control group. We noted that It is a descriptive meta-analysis. Thus, this study cannot provided more information about the summary relative risk across the studies.
We conducted a comprehensive review and meta-analysis of all the currently available literature on the topic, finally including five observational studies assessing the relationship between CP and ED. First, strengths of this analysis included independent search and data abstraction by two researchers experienced in conducting systematic reviews. Second, explicit inclusion and exclusion criteria were used to select the eligible studies in this review. Third, the Newcastle-Ottawa Scale for the assessment of non-randomized studies was used to assess the quality of the included studies. The overall methodological quality was high. Finally, we also conducted subgroup analysis and sensitivity analysis to explore the source of heterogeneity among the studies.
Our research had several limitations that were inherent to any meta-analysis of observational studies. First, ED and CP in humans are caused by the similar risk factors, such as aging, smoking, diabetes mellitus and coronary artery disease.33, 34 Most of the included studies18, 20, 21, 22 were not adjusted for smoking and/or alcohol consumption, and in the studies of Zadik et al., Oguz et al. and Matsumoto et al., the results were not adjusted for coronary heart disease and diabetes mellitus. Therefore, these risk factors may have significantly contributed in aggravating ED. It is possible that this lack of information had an effect in biasing the results of this study. Second, the other potential limitation of the present meta-analysis was the various methods of assessment for ED and CP used among studies. The prevalence of ED was different when ED was measured using International Index of Erectile Function system and other assessment instruments. Third, the results of the observational studies might be affected by the recall bias or selection bias. Fourth, there was the evidence of the unavoidable heterogeneity in the studied population as well as the likelihood of some unmeasured confounders imparted across the studies. Although we had detected the major source of heterogeneity by conducting subgroup analyses and sensitivity analysis, other potential causes within the studies should be also considered. Fifth, periodontitis is a ubiquitous disease affecting over 50% of the adult population worldwide. However, our findings were mainly based on the Asian populations. Additional studies based on other populations are necessary to verify our result.
In conclusion, our review and meta-analysis suggested that an association might exist between the CP and ED. However, this evidence was derived from limited studies even after an exhaustive search. Further prospective epidemiological studies will be needed to confirm this relationship.
About this article
Chronic periodontitis and the risk of erectile dysfunction: a systematic review and meta-analysis: methodological issues
International Journal of Impotence Research (2017)