Abstract
Background and Purpose
To determine the risk of Parkinson's disease (PD) in relation to erectile dysfunction (ED) based on the National Health Insurance Research Database in Taiwan.
Methods
We identified 3,153 patients who were newly diagnosed with ED between January 1, 2004 and December 31, 2010. A total of 12,612 randomly selected people without ED served as healthy controls. All of the study subjects were followed-up from the index date to the date of PD diagnosis, withdrawal from the National Health Insurance program, or the end of 2012 whichever occurred first.
Results
The incidence density rate of PD was 1.52-fold higher in the ED cohort than the non-ED cohort (3.44 vs. 1.64 per 1,000 person-years), with an adjusted hazard ratio (HR) of 1.52 [95% confidence interval (CI)=1.09–2.12]. The combined effects on patients with ED and diabetes as well as hypertension showed a significant combined association with the PD risk compared with patients without ED, counterpart comorbidities, or medication use. The adjusted HR of PD for ED was higher for diabetes (2.82, 95% CI=1.42–5.63) and hypertension (2.19, 95% CI = 1.35–3.55).
Conclusions
ED leads to an increased risk of PD. ED patients with diabetes or hypertension have an elevated risk of PD.
Keywords: comorbidity, diabetes, erectile dysfunction, Parkinson's disease, risk
INTRODUCTION
Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection sufficient to permit successful sexual intercourse, and it is a complex and heterogeneous disorder.1 The incidence of ED is increasing globally, and it mainly affects men who are older than 40 years. It has been reported that approximately 150 million men worldwide suffer from ED.2,3 ED has also been found to be a symptom of serious illnesses such as cardiovascular diseases, diabetes, metabolic syndromes, and all-cause mortality.4,5
Erectile function is controlled by the autonomic system, which is frequently compromised in patients with ED. Parkinson's disease (PD) is another disease commonly affected by the autonomic nervous system,6 and ED is a common nonmotor symptom in PD. In contrast to motor disorders, ED is often unresponsive to levodopa treatment.7 Previous studies have found that ED can be detected several years before a diagnosis of PD.6,8 A retrospective analysis of a large cohort (32,616 men) found ED to be associated with a higher future risk of developing PD, and the authors hypothesized that the autonomic nervous system can be impaired for years before PD is clinically identified.6 However, the findings of that study might be unreliable due to recall bias.
To identify the relationship between ED and the subsequent risk of PD, we conducted a nationwide population-based retrospective cohort study using a data set from the Taiwan National Health Insurance (NHI) program. The National Health Insurance Research Database (NHIRD) is a well-validated nationwide population-based data set that allows researchers to trace the medical service usage history of all citizens in Taiwan.9,10,11 Several studies have used the NHIRD to investigate associations between different diseases;12,13 the present study used NHIRD data to examine the possible association between ED and the risk of PD.
METHODS
Ethics statement
The Institutional Review Board of Taichung Tzu Chi General Hospital in Taiwan approved the study protocol (approval no. REC103-43). Because personal identifiers were not included in the secondary files, informed consent did not need to be obtained.
Data sources
This study sampled cohort data from the NHIRD. The NHI program has provided comprehensive health-care coverage in Taiwan since 1995. Enrollment in this government-run, universal, single-payer insurance system is mandatory, and currently around 99% of the 23 million residents of Taiwan receive medical care through the NHI program. In addition, more than 97% of the hospitals and clinics in Taiwan are contracted to provide health-care services14 that are reimbursed by the NHI Bureau, and all data related to these services are collected and input to the NHIRD by the National Health Research Institutes (NHRI; http://www.nhri.org.tw) so as to provide a comprehensive record of medical care. The data consist of outpatient care records, inpatient care records, and the registration files of the insured, and the database includes all claims data from the NHI program. The NHI Bureau randomly reviews the charts of 1 out of every 100 outpatient cases and 1 out of every 20 inpatient cases, as well as performing patient interviews to verify the accuracy of diagnoses.15 The NHRI follows strict confidentiality guidelines for the protection of personal electronic data and maintains the NHI reimbursement data as anonymized files suitable for research use.
Study population
We conducted a population-based retrospective cohort study that included two groups. We initially identified patients who had been newly diagnosed with organic ED [International Classification of Diseases, ninth revision, clinical Modification (ICD-9-CM) code 607.84] or psychogenic ED (ICD-9-CM code 302.72) from inpatient and outpatient files in at least two consistent diagnoses in outpatient care and who were followed up between January 1, 2004 and December 31, 2010. Similar methods for identifying patients with ED have been used in other studies.16,17 We used the date of ED diagnosis as the index date of the patient.
The control cohort included four non-ED patients per ED patient, who were selected from the same data set with propensity-score matching in order to reduce selection bias by bundling many confounding covariates that may be present in an observational study with this number of variables.
Charlson Comorbidity Index Score
The Charlson Comorbidity Index Score (CCIS) is a widely accepted measure for risk adjustment in administrative-claims data sets.18,19 The CCIS was calculated for each patient by assigning 1 point for each of myocardial infarct, congestive heart failure, peripheral vascular disease, dementia, cerebrovascular disease, chronic lung disease, connective-tissue disease, ulcer, chronic liver disease, and diabetes; 2 points for each of hemiplegia, moderate or severe kidney disease, diabetes with end-organ damage, tumor, leukemia, and lymphoma; 3 points for moderate or severe liver disease; and 6 points for each of malignant tumor, metastasis, and acquired immune deficiency syndrome.
Variables
The independent variables were age, CCIS, comorbidities (e.g., diabetes, hypertension, hyperlipidemia, anxiety, depression, alcoholism, obesity, bipolar disorder, and schizophrenia), drugs causing parkinsonism (i.e., diazepam, alprazolam, and haloperidol),20 antipsychotic medications (i.e., zolpidem, metoclopramide, and flunarizine),13 other premotor symptoms [i.e., constipation, rapid-eye-movement-sleep behavior disorder (RBD), and hyposomnia],21 geographic area of residence, and insurance premiums.22
Research outcomes
The main outcome of the study was the occurrence of PD (ICD-9-CM code 332.0), which was determined by linking records with outpatient and inpatient care data in the NHIRD. This method has been used in other studies to identify PD patients.13,23,24 In Taiwan, secondary PD (including drug-induced or vascular) is recorded as ICD-9-CM code 332.1, and multiple-system atrophy with predominant parkinsonism is recorded as ICD-9-CM code 333. As described in detail previously, patients who diagnosed as PD and those receiving antiparkinsonism medication for more than 60 days are defined as the occurrence of PD.13,23,24 All patients were observed from the index date to the date of PD diagnosis, withdrawal from the NHI program, or the end of 2012 whichever occurred first.25,26
Statistical analysis
Pearson's chi-square test was applied to categorical variables such as age, insurance premiums, drugs causing parkinsonism, antipsychotic medications, geographic region of residence, and comorbidities. Continuous variables were analyzed using one-way ANOVA. The cumulative risk of PD was estimated using Kaplan-Meier survival curves. A Cox proportional-hazards regression model adjusted for patient characteristics was used to analyze the association of ED with subsequent PD during the 7-year follow-up period. We calculated hazard ratios (HRs) along with 95% confidence intervals (CIs), and used a two-sided p value of <0.05 as a significance cutoff. All of these analyses were conducted using SPSS software (version 15, SPSS Inc., Chicago, IL, USA).
RESULTS
In total, 15,765 patients were included in our study cohort, of whom 3,153 had ED and 12,612 did not have ED (Supplementary Fig. 1 in the online-only Data Supplement). The demographic characteristics and selected morbidities for the two cohorts are presented in Table 1. The mean ages of the ED and non-ED cohorts were 56.7 and 53.4 years, respectively. The patients with ED were more likely to reside in northern and central Taiwan, have more comorbidities, use more medications, and have higher insurance premiums than those without ED.
Table 1. Demographic characteristics of and comorbidities in patients with and without ED in Taiwan from 2004 to 2010 (n=15,765).
| Variable | ED (n=3,153) | Non–ED (n=12,612) | p |
|---|---|---|---|
| n (%) | n (%) | ||
| Age (years), mean±SD | 56.7±9.8 | 53.4±10.5 | <0.006 |
| Follow–up duration (years), mean±SD | 5.07±1.77 | 6.83±0.70 | <0.0001 |
| CCIS | <0.0001 | ||
| 0 or 1 | 2,607 (82.7) | 11,813 (93.7) | |
| 2 or 3 | 463 (14.7) | 675 (5.3) | |
| >3 | 83 (2.6) | 124 (1.0) | |
| Comorbidity | |||
| Diabetes | 634 (20.1) | 837 (6.6) | <0.0001 |
| Hypertension | 1,051 (33.3) | 1,924 (15.3) | <0.0001 |
| Hyperlipidemia | 578 (18.3) | 734 (5.8) | <0.0001 |
| Anxiety | 351 (11.1) | 437 (3.5) | <0.0001 |
| Depression | 140 (4.4) | 136 (1.1) | <0.0001 |
| Alcoholism | 8 (0.3) | 20 (0.2) | 0.256 |
| Obesity | 11 (0.3) | 7 (0.1) | <0.0001 |
| Bipolar disorder | 34 (1.1) | 33 (0.3) | <0.0001 |
| Schizophrenia | 22 (0.7) | 54 (0.4) | 0.051 |
| Constipation | 140 (4.4) | 183 (1.5) | <0.001 |
| RBD | 408 (12.9) | 498 (3.9) | <0.001 |
| Hyposomnia | 355 (11.3) | 464 (3.7) | <0.001 |
| Drugs causing parkinsonism | 2,256 (71.6) | 6,629 (52.6) | <0.0001 |
| Antipsychotic medications | 2,175 (69.0) | 5,857 (46.4) | <0.0001 |
| Insurance premium | <0.0001 | ||
| <17,500 NTD/month | 884 (28.0) | 2,856 (30.6) | |
| 17,500–25,000 NTD/month | 883 (28.0) | 4,334 (34.4) | |
| >25,000 NTD/month | 1,386 (44.0) | 4,422 (35.0) | |
| Residence area | <0.0001 | ||
| Urban | 1,085 (34.4) | 3,791 (30.1) | |
| Suburban | 1,461 (46.3) | 5,774 (45.8) | |
| Rural | 607 (19.3) | 3,047 (24.2) | |
| Geographic region | <0.0001 | ||
| Northern/central | 2,302 (73.0) | 8,505 (67.4) | |
| Southern/eastern | 851 (27.0) | 4,107 (32.6) |
CCIS: Charlson Comorbidity Index Score, ED: erectile dysfunction, NTD: New Taiwan Dollar, RBD: rapid eye movement sleep behavior disorder.
Kaplan-Meier analysis demonstrated that the cumulative incidence of PD was significantly higher in the ED cohort than in the non-ED cohort (log-rank test p<0.001) (Fig. 1). The follow-up periods for the ED and non-ED cohorts were 5.07±1.77 and 6.83±0.70 years (mean±SD), respectively, and the incidence rates of PD were 3.44 and 1.64 per 1,000 person-years. Multivariate Cox proportional-hazards regression analyses revealed that the risk of PD was 1.52-fold higher in ED patients than in non-ED patients after adjusting for age and comorbidities (95% CI = 1.07–2.10) (Table 2). Since ED is an important variable, we applied the Cox proportional-hazards model to stratify by age and CCIS. Compared with the non-ED cohort, the ED cohort still had a higher risk of PD, with an adjusted HR of 1.38 (95% CI=1.02–1.86) (Table 3).
Fig. 1. Cumulative incidence of Parkinson's disease estimated using the Kaplan-Meier method for patients with and without ED. ED: erectile dysfunction.
Table 2. Results from the Cox proportional-hazards model measuring HRs and 95% CIs of PD associated with patients with ED.
| Characteristics | Crude | Adjusted | ||||
|---|---|---|---|---|---|---|
| HR | (95% CI) | p | HR | (95% CI) | p | |
| ED | 2.34 | (1.71–3.21) | <0.0001 | 1.50 | (1.07–2.10) | 0.019 |
| Comorbidity | ||||||
| Hypertension | 3.04 | (2.28–4.04) | <0.0001 | 1.11 | (0.81–1.52) | 0.512 |
| Depression | 4.61 | (2.63–8.09) | <0.0001 | 1.58 | (0.77–3.23) | 0.214 |
| Schizophrenia | 14.94 | (8.33–26.79) | <0.0001 | 19.44 | (10.35–36.54) | <0.0001 |
| Constipation | 5.03 | (3.06–8.28) | <0.0001 | 1.42 | (0.84–2.39) | 0.193 |
| Hyposomnia | 2.73 | (1.78–4.19) | <0.0001 | 1.50 | (0.90–2.51) | 0.123 |
| Insurance premiums | ||||||
| <17,500 NTD/month | 1.00 | Reference | 1.00 | Reference | ||
| 17,500–25,000 NTD/month | 0.71 | (0.51–0.98) | 0.038 | 1.01 | (0.71–1.44) | 0.938 |
| >25,000 NTD/month | 0.50 | (0.35–0.71) | <0.0001 | 0.99 | (0.68–1.45) | 0.960 |
| Geographic region | ||||||
| Northern/central | 1.00 | reference | 1.00 | Reference | ||
| Southern/eastern | 1.10 | (0.82–1.47) | 0.546 | 0.99 | (0.73–1.36) | 0.982 |
Adjusted HR: adjusted for ED, age, CCIS, insurance premiums, comorbidity of diabetes, hypertension, hyperlipidemia, anxiety, depression, alcoholism, bipolar disorder, schizophrenia, drugs causing parkinsonism, antipsychotic medications, constipation, RBD, and hyposomnia in Cox proportional-hazards regression.
CCIS: Charlson Comorbidity Index Score, CI: confidence interval, ED: erectile dysfunction, HR: hazard ratio, NTD: New Taiwan Dollar, PD: Parkinson's disease, RBD: rapid-eye-movement-sleep behavior disorder.
Table 3. Results of the stratified Cox proportion-hazards model for PD associated with ED patients and non-ED patients.
| Characteristics | Crude | Adjusted | ||||
|---|---|---|---|---|---|---|
| HR | (95% CI) | p | HR | (95% CI) | p | |
| ED | 1.42 | 1.08–1.88 | 0.011 | 1.38 | 1.02–1.86 | 0.034 |
| Comorbidity | ||||||
| Hypertension | 1.50 | 1.36–1.66 | <0.001 | 1.46 | 1.15–1.86 | 0.002 |
| Depression | 1.69 | 1.33–2.16 | <0.001 | 1.79 | 1.12–2.87 | 0.015 |
| Schizophrenia | 9.20 | 7.08–11.96 | <0.001 | 5.91 | 2.51–13.92 | <0.001 |
| Constipation | 1.91 | 1.64–2.23 | <0.001 | 1.62 | 1.14–2.31 | 0.007 |
| Hyposomnia | 1.38 | 1.15–1.65 | <0.001 | 1.60 | 1.12–2.30 | 0.010 |
| Insurance premiums | ||||||
| <17,500 NTD/month | 1.00 | 1.00 | ||||
| 17,500–25,000 NTD/month | 0.74 | 0.66–0.82 | <0.001 | 0.68 | 0.51–0.91 | 0.009 |
| >25,000 NTD/month | 0.77 | 0.69–0.87 | <0.001 | 0.75 | 0.57–0.99 | 0.044 |
| Geographic region | ||||||
| Northern/central | 1.00 | 1.00 | ||||
| Southern/eastern | 1.18 | 1.08–1.30 | <0.001 | 1.29 | 1.02–1.65 | 0.037 |
Stratified by age and CCIS. Adjusted HR: adjusted for ED, age, CCIS, insurance premiums, comorbidity of diabetes, hypertension, hyperlipidemia, anxiety, depression, alcoholism, bipolar disorder, schizophrenia, drugs causing parkinsonism, antipsychotic medications, constipation, RBD, and hyposomnia in Cox proportional-hazards regression.
CCIS: Charlson Comorbidity Index Score, CI: confidence interval, ED: erectile dysfunction, HR: hazard ratio, NTD: New Taiwan Dollar, PD: Parkinson's disease, RBD: rapid-eye-movement-sleep behavior disorder.
We further explored the association between ED and PD by stratifying age, CCIS, insurance premiums, comorbidity of diabetes, hypertension, hyperlipidemia, anxiety, depression, alcoholism, bipolar disorder, schizophrenia, drugs causing parkinsonism, antipsychotic medications, residence area, and geographic region (Table 4). The adjusted HR of PD for ED was higher for the presence of diabetes (2.82, 95% CI=1.42–5.63) and hypertension (2.19, 95% CI=1.35–3.55), and the absence of anxiety (1.71, 95% CI=1.20–2.45), depression (1.65, 95% CI=1.17–2.33), bipolar disorder (1.56, 95% CI=1.11–2.20), schizophrenia (1.58, 95% CI=1.12–2.23), constipation (1.54, 95% CI=1.08–2.19), RBD (1.49, 95% CI=1.04–2.15), and hyposomnia (1.71, 95% CI=1.19–2.45).
Table 4. Risk for PD in patients with and without ED.
| Variables | ED (n=3,153) | Non–ED (n=12,612) | IRR (95% CI) | Adjusted HR (95% CI) | ||||
|---|---|---|---|---|---|---|---|---|
| Event | Person years | IR | Event | Person years | IR | |||
| Total | 55 | 15,989 | 3.44 | 0141 | 86,190 | 1.64 | 2.10 (1.54–2.87)‡ | 1.50 (1.07–2.10)* |
| CCIS | ||||||||
| 0 or 1 | 30 | 13,240 | 2.27 | 109 | 80,746 | 1.35 | 1.68 (1.12–2.51)* | 1.25 (0.81–1.93) |
| 2 or 3 | 22 | 2,372 | 9.27 | 28 | 4,591 | 6.10 | 1.52 (0.87–2.66) | 2.17 (1.18–4.02)* |
| >4 | 3 | 377 | 7.96 | 4 | 0852 | 4.69 | 1.70 (0.38–7.57) | 3.44 (0.42–27.92) |
| Comorbidity | ||||||||
| Diabetes | ||||||||
| No | 36 | 12,822 | 2.81 | 122 | 80,412 | 1.52 | 1.85 (1.28–2.68)‡ | 1.20 (0.81–1.79) |
| Yes | 19 | 3,166 | 6.00 | 19 | 5,779 | 3.29 | 1.83 (0.97–3.45) | 2.82 (1.42–5.63)† |
| Hypertension | ||||||||
| No | 23 | 10,815 | 2.13 | 95 | 72,905 | 1.30 | 1.63 (1.03–2.57)* | 1.03 (0.63–1.69) |
| Yes | 32 | 5,173 | 6.19 | 46 | 13,286 | 3.46 | 1.79 (1.14–2.81)* | 2.19 (1.35–3.55)† |
| Hyperlipidemia | ||||||||
| No | 40 | 13,204 | 3.03 | 126 | 81,101 | 1.55 | 1.95 (1.37–2.78)‡ | 1.39 (0.95–2.04) |
| Yes | 15 | 2,785 | 5.39 | 15 | 5,089 | 2.95 | 1.83 (0.89–3.74) | 1.79 (0.83–3.86) |
| Anxiety | ||||||||
| No | 48 | 14,181 | 3.38 | 123 | 83,172 | 1.48 | 2.29 (1.64–3.20)‡ | 1.71 (1.20–2.45)† |
| Yes | 7 | 1,808 | 3.87 | 18 | 3,018 | 5.96 | 0.65 (0.27–1.55) | 0.69 (0.26–1.81) |
| Depression | ||||||||
| No | 52 | 15,313 | 3.40 | 131 | 85,271 | 1.54 | 2.21 (1.60–3.05)‡ | 1.65 (1.17–2.33)† |
| Yes | 3 | 675 | 4.44 | 10 | 920 | 10.87 | 0.41 (0.11–1.49) | 0.16 (0.02–1.13) |
| Alcoholism | ||||||||
| No | 55 | 15,954 | 3.45 | 139 | 86,055 | 1.62 | 2.13 (1.56–2.92)‡ | 1.51 (1.08–2.12)* |
| Yes | 0 | 35 | 0 | 2 | 136 | 14.71 | 0 | |
| Obesity | ||||||||
| No | 55 | 15,941 | 3.45 | 141 | 86,141 | 1.64 | 2.11 (1.54–2.88)‡ | 1.50 (1.18–1.90)‡ |
| Yes | 0 | 48 | 0 | 0 | 49 | 0 | 0 | |
| Bipolar disorder | ||||||||
| No | 54 | 15,834 | 3.41 | 137 | 85,973 | 1.59 | 2.14 (1.56–2.93)‡ | 1.56 (1.11–2.20)† |
| Yes | 1 | 155 | 6.45 | 4 | 217 | 18.43 | 0.35 (0.04–3.13) | |
| Schizophrenia | ||||||||
| No | 53 | 15,886 | 3.34 | 131 | 85,839 | 1.53 | 2.19 (1.59–3.01)‡ | 1.58 (1.12–2.23)† |
| Yes | 2 | 103 | 19.42 | 10 | 352 | 28.41 | 0.68 (0.15–3.12) | 0.82 (0.11–6.31) |
| Constipation | ||||||||
| No | 50 | 15,302 | 3.27 | 129 | 84,945 | 1.52 | 2.15 (1.55–2.98)‡ | 1.54 (1.08–2.19)* |
| Yes | 5 | 686 | 7.29 | 12 | 1,245 | 9.64 | 0.76 (1.27–2.15) | 1.05 (0.32–3.37) |
| RBD | ||||||||
| No | 44 | 13,939 | 3.16 | 128 | 82,744 | 1.55 | 2.04 (1.45–2.87)‡ | 1.49 (1.04–2.15)* |
| Yes | 11 | 2,049 | 5.37 | 13 | 3,445 | 3.77 | 1.42 (0.64–3.18) | 1.68 (0.69–4.11) |
| Hyposomnia | ||||||||
| No | 48 | 14,133 | 3.40 | 124 | 83,014 | 1.49 | 2.27 (1.63–3.17)‡ | 1.71 (1.19–2.45)† |
| Yes | 7 | 1,854 | 3.78 | 17 | 3,176 | 5.35 | 0.71 (0.29–1.70) | 0.69 (0.27–1.75) |
| Drugs causing parkinsonism | ||||||||
| No | 10 | 4,411 | 2.27 | 35 | 40,562 | 0.86 | 2.63 (1.30–5.31)† | 1.49 (0.70–3.18) |
| Yes | 45 | 11,578 | 3.89 | 106 | 45,629 | 2.32 | 1.67 (1.18–2.37)† | 1.53 (1.05–2.23)* |
| Antipsychotic medications | ||||||||
| No | 10 | 4,894 | 2.04 | 41 | 45,829 | 0.89 | 2.28 (1.14–4.56)* | 1.44 (0.69–3.01) |
| Yes | 45 | 11,094 | 4.06 | 100 | 40,361 | 2.48 | 1.64 (1.15–2.33)† | 1.54 (1.05–2.24)* |
| Insurance premium | ||||||||
| <17,500 NTD/month | 26 | 4,498 | 5.78 | 55 | 25,929 | 2.12 | 2.73 (1.71–4.34)‡ | 2.00 (1.21–3.29)† |
| 17,500–25,000 NTD/month | 11 | 4,517 | 2.44 | 54 | 29,746 | 1.82 | 1.34 (0.70–2.57) | 0.96 (0.47–1.98) |
| >25,000 NTD/month | 18 | 6,974 | 2.58 | 32 | 30,515 | 1.05 | 2.46 (1.38–4.38)† | 1.44 (0.76–2.73) |
| Residence area | ||||||||
| Urban | 19 | 5,507 | 3.45 | 39 | 25,928 | 1.50 | 2.29 (1.33–3.97)† | 1.47 (0.80–2.70) |
| Suburban | 28 | 7,438 | 3.76 | 55 | 39,484 | 1.39 | 2.70 (1.71–4.26)‡ | 1.99 (1.22–3.27)† |
| Rural | 8 | 3,044 | 2.63 | 47 | 20,778 | 2.26 | 1.16 (0.55–2.46) | 0.89 (0.40–2.00) |
| Geographic region | ||||||||
| Northern/central | 38 | 11,735 | 3.24 | 92 | 58,134 | 1.58 | 2.05 (1.40–2.99) | 1.42 (0.94–2.14) |
| Southern/eastern | 17 | 4,254 | 4.00 | 49 | 28,056 | 1.75 | 2.29 (1.32–3.97) | 1.91 (1.05–3.46)* |
Adjusted HR: adjusted for ED, age, CCIS, insurance premiums, comorbidity of diabetes, hypertension, hyperlipidemia, anxiety, depression, alcoholism, bipolar disorder, schizophrenia, drugs causing parkinsonism, antipsychotic medications, constipation, RBD and hyposomnia in Cox proportional-hazards regression.
*p<0.05, †p<0.01, ‡p<0.001.
CCIS: Charlson Comorbidity Index Score, CI: confidence interval, ED: erectile dysfunction, HR: hazard ratio, IR: incidence rates, per 1,000 person-years, IRR: incidence rate ratio, NTD: New Taiwan Dollar, PD: Parkinson's disease, RBD: rapid-eye-movement-sleep behavior disorder.
Considering that ED is related to neurodegeneration in the premotor stage, we included organic ED in the analysis. The non-ED group was matched with the propensity score. The patient's age, CCIS, diabetes, hypertension, hyperlipidemia, anxiety, depression, alcoholism, obesity, bipolar disorder, schizophrenia, constipation, RBD, hyposomnia, drugs causing parkinsonism, antipsychotic medications, insurance premiums, residence area, and geographic region were used for propensity-score matching. The patients with organic ED still had a 1.43-fold higher risk of PD than non-ED patients after the adjustment (95% CI=1.06–1.93). The full results are presented in Supplementary Tables 1 and 2 (in the online-only Data Supplement).
DISCUSSION
This study evaluated independent and combined associations between ED and comorbidities (as well as medications) on PD in a large prospective cohort during a 7-year follow-up period. The findings add to the existing literature by showing a 1.52-fold higher risk of PD in all ED patients after adjusting for age, sex, insurance premiums, residence area, CCIS, comorbidities, and medications.
We also found that the risk of PD was higher for patients with ED along with diabetes or hypertension than for patients without ED or counterpart comorbidities. ED has been reported as a risk factor for the development of PD,6,8 but this association has so far been described as an independent effect. Some previous studies accounted for diabetes and hypertension,27,28 but none considered their combined effect with ED on PD. It is unclear whether ED and other comorbidities play significant combined roles. Our research showed that diabetes and hypertension are jointly associated with ED in producing 2.53- and 2.17-fold higher risks of PD, respectively.
ED is a complex and heterogeneous disorder that possibly has arterial, neurogenic, hormonal, cavernous, iatrogenic, and psychogenic causes. ED could also be associated with not only cardiovascular disease but also neurological disorders including migraine, epilepsy, and dementia.1,17,29,30 Furthermore, many studies have indicated that ED can be detected several years prior to a PD diagnosis.6,8 These findings and the present results can be combined in ongoing efforts to identify individuals at the earliest phase of PD.
ED is diagnosed by self-reporting. It is not easy to reliably classify organic ED and psychogenic ED clinically because all sexual dysfunctions involve the mind as well as the relationship with a sexual partner.31 For these reasons, we performed the analysis using both organic and psychogenic ED, and found that ED leads to an increased risk of PD.
The incidence of ED was lower in our patients than among those included in other studies. This is because ED is a taboo subject in Taiwan, with patients being reluctant to discuss sex.17 Thus, the control group may have included some unidentified ED cases. The risk of PD was still clearly demonstrated despite this possible confounding effect, but the true risk may be even greater when every ED case can be clearly identified.
A previous study found ED to be associated with PD diagnosed more than 10 years later.6 However, significant recall bias might have been present in that study. The present nationwide population-based cross-sectional study was able to avoid recall bias since it involved a large and representative sample. The NHIRD data set covers more than 99% of the 23.74 million residents of Taiwan and the NHIRD has been validated as being highly accurate.11,32 The high coverage rate of the NHI program in our study could also have minimized the number of cohort subjects lost during follow-up. Given the considerable differences in age, medications, and comorbidities between the present ED and non-ED patients, the risk of PD increased in the Cox proportional-hazards model. Our results have provided further epidemiological evidence of the relationship between PD and ED.
Many antipsychotic drugs (e.g., flunarizine and zolpidem) and antiemetic drugs (e.g., metoclopramide) can cause PD, and previous studies have investigated the association between ED and the risk of developing PD.6,8,13 However, most of these studies did not include potentially parkinsonism-causing medicines in the adjusted variables. In the current research, the ED patients took these medicines more frequently than non-ED patients (71.6% vs. 52.6% for parkinsonism-related drugs and 69.0% vs. 46.4% for antipsychotic medications, both p<0.0001)–the results may be misleading if the adjusted variables do not include these drugs. The present study also found an association between ED and PD in subgroups with and without the use of these medications.
While the present study was not able to identify the real connection between ED and PD, there are at least two possible mechanisms for a relationship between ED and PD. First, ED is one of manifestations of parasympathetic cholinergic failure,33 and the findings of previous studies suggest that many nonmotor symptoms and autonomic dysfunction could be early signs of preclinical stages of PD development.34 Second, testosterone levels are important for erectile function,35 and lower testosterone levels are an important component of ED. Many authors have reported that testosterone deficiency is often observed in PD patients relative to age-matched controls.36,37 Furthermore, beneficial effects of testosterone administration on both motor and nonmotor symptoms in PD patients have also been reported.37,38,39
One limitation of the present analysis is that the diagnoses of ED, PD, and comorbid conditions were completely dependent on ICD-9-CM codes, and so the presence of coding errors should be considered. However, the NHI Bureau randomly reviews patient charts and conducts patient interviews to verify the accuracy of diagnoses. Moreover, hospitals with outlier charges or practices may be audited, with subsequent heavy penalties for malpractice or discrepancies. Second, the database does not contain information on daily activity, dietary habits, tobacco use, education, or body mass index, which may also be risk factors for PD. Laboratory data are also not available in the database. Although we attempted to overcome these problems, they can only be addressed using observable variables, and unobservable variables may still have confounded our results. Further studies linking administrative-claims data and primary hospitalization information such as the severity of ischemic stroke and detailed risk factors are warranted. However, given the magnitude and statistical significance of the effects observed in this study, these limitations are unlikely to compromise the results.
In conclusion, the results of this population-based retrospective cohort study suggest that ED leads to an increased risk of PD. ED patients with diabetes or hypertension had an elevated risk of PD. Further research into the mechanisms underlying the effect of ED on PD is needed, but clinicians should already recognize the potential implications of ED and stay vigilant for the onset of PD.
Acknowledgements
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113004).
This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes, Taiwan. The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health, or National Health Research Institutes.
Footnotes
Conflicts of Interest: The authors have no financial conflicts of interest.
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.3988/jcn.2017.13.3.250.
Demographic characteristics and comorbidities in patients with and without organic ED in Taiwan from 2004 to 2010 (n=15,765)
Cox model measured HRs and 95% CIs of PD associated with patients with organic ED (n=2,875)
Flowchart of the study design. ED: erectile dysfunction, ICD-9-CM: International Classification of Diseases, ninth revision, Clinical Modification, NHIRD: National Health Insurance Research Database, PD: Parkinson's disease.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Demographic characteristics and comorbidities in patients with and without organic ED in Taiwan from 2004 to 2010 (n=15,765)
Cox model measured HRs and 95% CIs of PD associated with patients with organic ED (n=2,875)
Flowchart of the study design. ED: erectile dysfunction, ICD-9-CM: International Classification of Diseases, ninth revision, Clinical Modification, NHIRD: National Health Insurance Research Database, PD: Parkinson's disease.