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Irritable bowel syndrome is associated not only with organic but also psychogenic erectile dysfunction

Subjects

Abstract

This study investigated the correlation between irritable bowel syndrome (IBS) and organic erectile dysfunction (OED) and psychogenic erectile dysfunction (PED), and analyzed the influence of various comorbidities. Data were obtained from reimbursement claims of the National Health Insurance Program in Taiwan. We selected male patients aged >20 years, who were diagnosed with IBS during the 2000–2011 period as the IBS cohort. The index date for patients with IBS was the date of their first medical visit. We excluded patients with a diagnosis of OED and PED at baseline and those without information on age and sex. The IBS to non-IBS cohorts were estimated using univariable and multivariable Cox proportional hazards regression model. Adjusted hazard ratios were determined after adjusting for age and comorbidities. The Kaplan–Meier method was used to plot the cumulative incidence of OED and PED, and a log-rank test was used to compare the cohorts. A total of 15 533 IBS patients and 62 124 controls without IBS were enrolled in our study. Among the study participants, 48.2% were 49 years of age or younger. Patients with IBS were more likely to develop erectile dysfunction (ED) than those without IBS. Patients with IBS were 2.12 times more likely to develop OED and 2.38 times more likely to develop PED than the controls. There is an increased risk of both PED and OED in patients with IBS. Not only with organic but also PED should be considered when patients with IBS complain of ED.

Introduction

According to the Rome III diagnostic criterion, irritable bowel syndrome (IBS) is defined as recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with at least two syndromes of improvement with defecation, onset with change in frequency or form of stool.

Psychogenic erectile dysfunction (PED) is the inability to achieve sexual arousal or satisfaction in appropriate situations because of mental or emotional disorders. IBS is strongly associated with psychological diseases, such as depression or anxiety.1 At least one-third of IBS patients experience depression or anxiety.2 Both of PED and IBS were related to emotional or psychological diseases, it seems the correlation between IBS and PED may exist.

Organic erectile dysfunction (OED) is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.3 The prevalence of OED ranges widely by at least 40%.4, 5, 6 Chao et al.7 defined the association between IBS and OED, they described that patients with IBS had a 2.92-fold higher risk of developing OED.

Nowadays, the correlation between IBS and PED remains unknown. The objective of this study is to investigate the association between IBS and OED and PED, and analyze the influence of various comorbidities.

Materials and methods

Data source

Data used in this study were obtained from reimbursement claims of the National Health Insurance (NHI) Program in Taiwan, which was implemented in 1995 and covers >99% of 23.74 million Taiwan residents. The National Health Research Institutes (NHRI) established a National Health Insurance Research Database (NHIRD). All the identifiers of individual patients are deleted by the NHIR before data are transferred to the NHIRD. The NHRI has released a cohort data set comprised of one million randomly selected cases from the registry of NHI beneficiaries during 2000 (Longitudinal Health Insurance Database 2000; LHID2000). The NHRI followed all of the aforementioned randomly sampled patients to Year 2011. This study was approved by the Institutional Review Board (CMU-REC-101-012). The International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) was used to identify health status.

Sampled participants

We selected male patients aged >20 years, who were diagnosed with IBS (ICD-9-CM codes 564.1) during the 2000–2011 period as the IBS cohort. The index date for patients with IBS was the date of their first medical visit. We excluded patients with a diagnosis of OED and PED (ICD-9-CM codes 607.84 and 302.72) at baseline and those without information on age and sex. For the non-IBS cohort, we used a simple random sampling method and selected four control patients without a history of IBS, who were excluded according to the same criteria as those of the IBS cohort. The IBS patients and non-IBS controls were frequency matched for age (every 5-year span), sex, monthly income, urbanization level and index year.

Outcome

We identified the first diagnosis of OED and PED as the study end point. Person-years of follow-up were calculated for each patient until OED and PED was diagnosed, death occurred, the patients withdrew from the insurance system or until the end of 2011.

Variables of interest

The sociodemographic variables used in this study comprised age (20–34 years, 35–49 years, 50–64 years and 65 years), monthly income and urbanization level. The subjects’ monthly costs for insurance premiums were classified into 3 groups of <15 000; 15 000–19 999; and 20 000 New Taiwan Dollars (1.0 USD is ~30 NTD). The urbanization level was categorized by the population density of the residential area, population ratio of the elderly, agriculture workers, different educational levels and the number of physicians per 100 000 people into 4 levels, with level 1 as the most urbanized and level 4 as the least urbanized. We considered several well-known risk factors of OED and PED including coronary artery disease (CAD; ICD-9 code 410–414), chronic obstructive pulmonary disease (COPD; ICD-9 codes 490–496), chronic kidney disease (CKD; ICD-9 codes 580–589), hypertension (ICD-9 codes 401–405), diabetes (ICD-9 code 250), hyperlipidemia (ICD-9 code 272), depression (ICD-9 code 296.2, 296.3, 300.4, 311) and anxiety (ICD-9 code 300.00), to be the comorbidities. A medical history of antihypertensive drug, antidepressants drug and benzodiazepines use was included in the analysis.

Statistical analysis

We used the χ2-test to determine the differences in categorical sociodemographic variables, comorbidities and medications between the IBS cohort and the non-IBS cohort, and used the Student’s t-test to examine the mean ages and follow-up time (years) between both cohorts. The overall, age- and comorbidity-specific incidence rates (per 10 000 person-year) were calculated for each cohort. The IBS to non-IBS cohort hazard ratio (HR) and 95% confidence interval (CI) were estimated using the univariable and multivariable Cox proportional hazards regression model. The multivariable-adjusted models included all statistically significant covariates in the univariable Cox model. The Kaplan–Meier method was used to plot the cumulative incidence of OED and PED, and a log-rank test was used to compare the cohorts. All analyses were performed using the statistical package SAS for Windows (Version 9.3, SAS Institute Inc., Carey, NC, USA). A two-tailed P<0.05 was considered statistically significant.

Results

A total of 15 533 IBS patients and 62 124 controls without IBS were enrolled in our study. Among the study participants, 48.2% of the patients were 49 years of age or younger (Table 1). The mean age in the non-IBS and IBS cohorts was 51.7±17.1 years and 52.2±16.9 years, respectively. Both cohorts tended to have lower income levels (23.3% vs 23.3%) and reside in urbanized areas (56.4% vs 56.4%). The IBS cohort included more cases of CAD, COPD, CKD, hypertension, diabetes, hyperlipidemia, depression, anxiety, antihypertensive drug, antidepressants drug and benzodiazepines than did the non-IBS cohort (all P<0.001). The overall incidence of OED was 2.30-fold greater in the IBS cohort than in the non-IBS cohort (26.6 vs 10.1 per 10 000 person-years), with an adjusted hazards ratio (AHR) of 2.12 (95% CI: 1.80–2.50; Table 2). Figure 1a shows that the cumulative incidence of OED was higher in the IBS cohort than that in the non-IBS cohort by 1.50% (log-rank test P<0.001) at the end of follow-up. The OED incidence increased with age in both cohorts, but the age-specific IBS to non-IBS relative risk was the greatest for the youngest group (crude HR=3.12; 95% CI: 2.40–4.07). The corresponding AHR reduced to 1.84 (95% CI: 1.33–2.55) for the oldest group. The OED incidence increased with comorbidities in both cohorts.

Table 1 Demographic characteristics and comorbidities in cohorts with and without irritable bowel syndrome
Table 2 Incidence of organic and psychogenic erectile dysfunction by age and comorbidity and Cox model measured hazards ratio for patients with irritable bowel syndrome compared those without irritable bowel syndrome
Figure 1
figure1

Cummulative incidence comparison of organic erectile dysfunction (a) and psychogenic erectile dysfunction (b) for patients with (dashed line) or without (solid line) irritable bowel syndrome.

The Kaplan–Meier graph shows that the cumulative incidence of PED was higher for the IBS cohort than for the non-IBS cohort (Figure 1b, the log-rank test P <0.001). In total, 32 IBS patients were diagnosed with PED, yielding an incidence of 3.17 per 10 000 person-years, whereas 43 cases of PED occurred in the non-IBS cohort, yielding an incidence of 1.08 per 10 000 person-years. The crude HR of PED in the IBS cohort was 2.94 (95% CI: 1.86–4.65), and the AHR of PED was 2.38 (95% CI: 1.47–3.85), indicating that the IBS patients were at increased risk of PED. The age-specific IBS cohort to the non-IBS cohort AHR of PED was significant for aged 49 years. IBS patients with or without comorbidity were associated with significantly higher risk of PED than the non-IBS patients were.

The results of multivariable Cox proportional hazard analyses for the OED association risk factor in patients with IBS are shown in Table 3. The risk of developing OED was 1.01-fold (95% CI: 1.01–1.02) increased with age (every year), higher income (AHR=1.66, 95% CI: 1.34–2.05), living in urbanized areas, and comorbidity of CKD (AHR=1.35, 95% CI: 1.07–1.72), diabetes (AHR=1.32, 95% CI: 1.04–1.67), hyperlipidemia (AHR=1.41, 95% CI: 1.16–1.70), antihypertensive drug (AHR=1.39, 95% CI: 1.12–1.72), antidepressants drug (AHR=1.45, 95% CI: 1.12–1.88), and benzodiazepines (AHR=1.29, 95% CI: 1.07–1.56) was associated with increased risk of OED. In the multivariable model, higher income (AHR=2.29, 95% CI=1.19–4.40), and living in urbanized areas were significantly associated with increased PED risk.

Table 3 Cox model with hazard ratios and 95% confidence intervals of organic and psychogenic erectile dysfunction associated with irritable bowel syndrome and covariates

Furthermore, relative to the non-IBS cohort without any comorbidity, the IBS patients with any comorbidity were at much higher risk of OED (AHR=3.81, 95% CI: 3.02–4.81; Table 4). Compared with patients without IBS and any comorbidity, patients with IBS and with any comorbidity were 3.05-fold more likely to develop PED (95% CI: 1.52–6.09), followed by patients with IBS and without any comorbidity (AHR=2.37, 95% CI: 1.31–4.28).

Table 4 Cox proportional hazard regression analysis for the risk of organic and psychogenic erectile dysfunction-associated irritable bowel syndrome with joint effect of comorbidity

In addition, NHIRD covers a highly representative sample of Taiwan’s general population because the reimbursement policy is universal and operated by a single-buyer, the government of Taiwan. All insurance claims should be scrutinized by medical reimbursement specialists and peer review. The diagnoses of ED were based on the ICD-9 codes, which were assessed and determined by related specialists and physicians according to the standard clinical criteria. If these specialists or physicians misdiagnosed diseases or miscoded diagnoses, they would be subject to punitive action. Therefore, the diagnoses and codes for ED used in this study should be correct and reliable.

Discussion

The correlation between IBS and PED has not yet been identified. To our knowledge, this is the first population-based study to identify IBS as a contributing factor for both PED and OED. We found that patients with IBS were more likely to develop erectile dysfunction (ED) than were those without IBS. After adjusting for age, year of index date and medical comorbidities (CAD, COPD, CKD, hypertension, diabetes, hyperlipidemia, depression and anxiety), patients with IBS were 2.12 times more likely to develop OED and 2.38 times more likely to develop PED than were the controls.

IBS is a common clinical gastrointestinal disorder. However, the pathogenesis of IBS is unclear. Several theories have been proposed. Serotonin imbalance caused visceral sensitivity or gastrointestinal motility leading to IBS.8, 9 Stasi et al.10 found that plasma cortisol was linearly related to plasma serotonin in patients with IBS. Because cortisol was an inhibitor in penile erection,11 it had a significant inverse correlation with penile rigidity.12 Therefore, serotonin regulation might play a leading role in IBS and ED.

A recent meta-analysis study showed that IBS was caused by cytokines imbalance.13 In 2004, Giugliano et al.14 described that ED could by caused by endothelial dysfunction through impaired nitric oxide availability from inflammatory cytokines. Bouloukaki et al.15 confirmed that inflammatory cytokines were involved in endothelial dysfunction as the pathogenesis of ED. They found that ED was associated with increasing levels of inflammatory cytokines. Cytokines were strongly related to the pathophysiologic mechanism of IBS and ED. SK-3, one of the small-conductance Ca2+-activated K+ (SK) channels members, was highly expressed in smooth-muscle-rich tissues such as the gastrointestinal tract and the corpus cavernosum. Chen et al.16 considered that a high presentation of SK-3 involved in the smooth muscle of the gastrointestinal tract and the corpus cavernosum led to IBS and ED. The association between IBS and ED were existed.

Psychological disorders such as depression and anxiety are risk factors of IBS.1 An Indian study showed that the prevalence of depression and anxiety was 37.1 and 31.4% in patients with IBS, and the odd ratios were 6.3 and 7.6 for depression and anxiety. The prevalence of depression and anxiety in IBS is relatively high. The authors suggested that screening for anxiety and depression might be necessary in patients with IBS.17 Zhang et al.18 reported that crucial psychogenic factors related to ED are anxiety and depression. Sugimori et al.19 found that patients with a combination of depression and anxiety had a significantly higher prevalence of ED than did the control. Depression and anxiety were associated with IBS and ED. We considered that anxiety and depression are risk factors for developing ED, because our population-based results show that patients with comorbidities of depression and anxiety had a higher risk of developing OED and PED compared to the control.

Stress exposure could increase the gastrin-releasing peptide level, which might stimulate the release of the adrenocorticotropic hormone and cortisol.20 Cortisol has an inhibitory role in penile erection,11 and a had significant inverse correlation with penile rigidity.12 Sakamoto et al.21 demonstrated that PED could be triggered by stress, which can involve the gastrin-releasing peptide system that is the primary mediator for male reproductive function. IBS as stress for affected people could induce ED.

Regarding comorbidities, the risk of developing OED was greater for patients with comorbidities of CKD, diabetes and hyperlipidemia; the risk of developing PED was greater for patients with the comorbidity of anxiety. The associations between ED and comorbidities are well defined. Several studies demonstrated that high prevalence of hyperlipidemia or diabetes was found in patients with ED.22, 23 We confirmed the results, atherosclerosis of blood vessels caused by hyperlipidemia or diabetes was strongly associated with OED in our study. Our finding also supported the correlation between anxiety and PED. However, regarding the powerful influence for PED, the IBS was stronger than the other comorbidities.

The strength of this study is identifying the correlation between IBS and OED and PED using a nationwide population-based data set, which can avoid the selection bias. However, this study has several limitations. First, because IBS diagnosis was made by individual physicians, we could not determine whether the diagnosis was confirmed by Manning, Rome II or Rome III criteria, or colonscopy. Second, disease severity was not included in the NHIRD; diarrhea-predominant, constipation-predominant or mixed-type of IBS could not be measured. Third, patient’s characteristics such as diet, lifestyle, marital status or smoking were unavailable from the NHIRD, which could involve gastrointestinal and sexual function. Fourth, because the confidential law in Taiwan to prevent us to check the personal chart for individual patient, we could not do manual chart extraction or informatics approaches to confirm the absence of codes (for example, diabetes mellitus, hypertension, prostate cancer and so on) that would suggest misclassification of an organic ED as psychogenic. Finally, because medication for ED is not covered by the NHI program, numerous ED patients seek alternative treatment. Self-payment for ED treatment might not be recorded in the NHIRD. However, our nationwide population-based data that avoids selection bias provides the sufficient statistical power for analysis.

Conclusion

There is an increased risk of both PED and OED in patients with IBS. Not only with organic but also PED should be considered when patients with IBS complain of ED.

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Acknowledgements

This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039-006); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. No additional external funding received for this study.

Author contributions

All authors have contributed substantially to, and are in agreement with the content of, the manuscript: C-YH and C-HK contributed to conception/design; C-HK contributed in provision of study materials; all authors contributed in collection and/or assembly of the data, manuscript preparation, data analysis and interpretation, and final approval of manuscript; C-HK, the guarantor of the paper, took responsibility for the integrity of the work as a whole, from inception to published article.

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Correspondence to C-H Kao.

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Hsu, CY., Lin, CL. & Kao, CH. Irritable bowel syndrome is associated not only with organic but also psychogenic erectile dysfunction. Int J Impot Res 27, 233–238 (2015). https://doi.org/10.1038/ijir.2015.25

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