Post-Traumatic Stress Disorder and the Risk of Erectile Dysfunction: A Nationwide Cohort Study in Taiwan

BACKGROUND: This study aimed to investigate the association between posttraumatic stress disorder and the risk of developing erectile dysfunction. METHODS: In this population-based, retrospective cohort study, we used Taiwan’s National Health Insurance Research Database to analyze the patients who were newly diagnosed with posttraumatic stress disorder (PTSD) between 2000 and 2013, with a 1:3 ratio by age, and index year matched in the non-PTSD comparison group, for the risk of erectile dysfunction. RESULTS: In total, ve out of 1,079 patients with PTSD developed erectile dysfunction, and three out of 3,237 patients in the non-PTSD group (47.58 vs 9.03 per 100,000 per person-year) developed erectile dysfunction. The Kaplan-Meier analysis showed that the PTSD cohort had a signicantly higher risk of erectile dysfunction (log-rank, p<0.001). The Cox regression analysis revealed that the study subjects were more likely to develop an injury (HR: 12.898, 95% CI=2.453- 67.811, p=0.003) after adjusting for age, monthly income, urbanization level, geographic region, and comorbidities. Psychotropic medications in the patients with PTSD were not associated with the risk of erectile dysfunction. CONCLUSIONS: Patients who suffered PTSD had a higher risk of developing erectile dysfunction.


Introduction
As a devastating and debilitating mental illness that occurs after exposure to traumatic events, post-traumatic stress disorder (PTSD) involves a cluster of symptoms, such as intrusion, hyperarousal, avoiding stimuli associated with traumatic events, and negative alterations in cognition and mood (Stein et al., 2007;Yehuda, 2002). PTSD can also lead to negative impacts on quality of life and functional impairment in various domains, especially poorer relationship functioning, followed by sexual dysfunction (Cook Few studies have investigated the correlation or rates of ED across PTSD populations (Arbanas, 2010;Badour et al., 2015), in which almost no literature addressed the longitudinal effects of sexual dysfunction. It is worth noting that one cross-sectional study in Turkey reported no association between the lifetime PTSD and ED (Evren et al., 2006). The previous studies have demonstrated that the prevalence of PTSD varied across countries and inadequate treatment is common (Alonso et al., 2018;Kessler et al., 2009), not to mention PTSD with sexual dysfunction. Co-occurring physical illnesses may also have a bidirectional relationship, as sexual health is linked to nearly every organ system. Sexual dysfunction often manifests from physical illnesses, including cardiovascular illness (e.g., stroke, coronary artery disease, and hypertension), diabetes mellitus, asthma and alcohol-related disease (Clayton and Ramamurthy, 2008). Moreover, prescription medications could stand for the probable mechanism that explains the co-occurrence of ED and PTSD, such as serotonin reuptake inhibitors and benzodiazepines (Anticevic and Britvic, 2008;Fossey and Hamner, 1994).
There are only a few studies and systematic reviews examining the impact of PTSD on ED in the general population of Asian countries. Since the association between PSTD and ED has remained unclear, we conducted this study so as to investigate the association between PTSD and the risk of ED. We hypothesize that there is an increased risk of ED after PTSD, and we used the Taiwan National Health Insurance Research Database (NHIRD) to examine as to whether there is an association between PTSD and ED.

Data sources
The Taiwan National Health Insurance (NHI) program was launched in 1995 to provide a centralized health insurance for its citizens, and as of 2014 approximately 93% of the nation's medical care institutions were contracted, with an enrollment rate exceeding 99% of Taiwan's population (Ho Chan, 2010). The NHIRD is derived from the Taiwan NHI program, and all claims data are released by the Bureau of National Health Insurance for research purposes. The NHIRD uses the International Classi cation of In the present study, we used the data sets from the Registry for the one-million Longitudinal Health Insurance Database (LHID) which included comprehensive outpatient and inpatient information, such as demographic data, dates of clinical visits, diagnostic codes, and details of prescriptions, with regard to nearly 1 million bene ciaries over a 13-year period from the LHID in Taiwan (2000-2013).

Ethical approval
To protect patient privacy, patient identity data were scrambled cryptographically in the NHIRD. This study was approved by the Institutional Review Board of Tri-Service General Hospital (TSGHIRB-2-106-05-029), and the written informed consents were waived.

Study design and sampled participants
This study is of a retrospective, matched-cohort design. Patients with PTSD were selected from January 1, 2000 to December 31, 2013, according to the ICD-9-CM codes: 309.81. In addition, each enrolled patient was required to have made at least three outpatient visits within the one-year study period for adult males with PTSD according to these ICD-9-CM codes. The patients diagnosed with ED before 2000 or before the rst visit for PTSD were excluded. In addition, all patients aged <20 years were also excluded. A total of 4,310 enrolled patients with the 1,079 subjects with PTSD and 3,237 in the age and index-year matched control group without PTSD in this study, in the 13 years of follow-up to December 31, 2013 ( Figure S1).

Covariates
The covariates included age group (20-39 years, ≥40 years), geographic area of residence (north, center, south, west, and east of Taiwan), urbanization level of residence (levels 1-4), levels of hospitals as medical centers, regional hospitals,

Comorbidity
Baseline comorbidities (in ICD-9-CM codes) included dementia, schizophrenia, anxiety disorder, bipolar disorder, depressive disorders, stroke, coronary artery diseases, hypertension, diabetes mellitus, asthma, and alcohol-related illness, with the reference from one previous study (Yang et al., 2018). Data on the usage of psychotropic medications, including antidepressants, antipsychotics, and hypnosedatives, were collected. The data of de ned daily dose (DDD) were obtained from the WHO Collaborating Centre for Drug Statistics Methodology (https://www. whocc.no/), and the duration of the use of drugs was calculated by dividing the cumulative doses by the DDD of drugs.

Main outcomes
All of the study participants were followed from the index date until the onset of erectile dysfunction, withdrawal from the NHI program, or the end of 2013. ED was divided into two subgroups: psychogenic ED and organic ED.

Statistical analysis
All statistical analyses were performed using the SPSS software V.22 (SPSS Inc., Chicago, Illinois, USA). χ2 test and t-test were used to evaluate the distributions of the categorical and continuous variables, respectively. The Fisher's exact test for the categorical variables was used to statistically examine the differences between the two cohorts. The Cox regression model was used to determine the risk of psychiatric disorders, and the results were present as HR with a 95% CI. The difference in the cumulative incidence of psychiatric disorders between the study and control groups was estimated using the Kaplan-Meier method with the log-rank test. A two-tailed p value <0.05 was considered to indicate the statistical signi cance.

Results
Sample characteristics Table 1 shows that the PTSD group had more anxiety, bipolar disorder, and depression, and less CAD and DM than the non-PTSD group. The PTSD group also tended to have lower CCI score, live in the northern and outlying islands of Taiwan, reside more in the regions of urbanization levels 2, and receive medical help from medical centers. There were no differences in the distribution of age and insurance premiums between these two groups.

Kaplan-Meier model for the cumulative risk of erectile dysfunction
At the end of the follow-up, ve in the PTSD group (5 in 1079, 47.58 per 10 5 person-years) and three in the non-PTSD group (3 in 3,237, 9.03 per 10 5 person-years). The Kaplan-Meier analysis for the cumulative incidence of erectile dysfunction in the study and control groups is as shown in Figure 1 (log-rank test, p <0.001).

Hazard ratios analysis of ED in the patients with PTSD
In the Cox regression analysis model, the crude HR of the PTSD group was 14.766 (95% CI:3.426-63.635, p<0.001), and the adjusted HR of the PTSD in the development of ED was 12.898 (95% CI: 2.453-67.811, p=0.003), in comparison to the non-PTSD group, after adjustment for age, insurance premiums, comorbidities, antidepressants, sedatives/hypnotics, urban levels and regions in Taiwan, and the levels of hospitals the patients sough for medical care. Patients with comorbidities, as such anxiety (adjusted HR: 1.864, p=0.025), bipolar disorders (adjusted HR: 1.998, p=0.014), and depression (adjusted HR: 2.970, p=0.001), were associated with the risk of ED ( Table 2). The patients using antidepressants, antipsychotics, and sedatives/hypnotics were not associated with the development of ED.
Subgroup analysis of ED in the patients with PTSD Table 3 depicts that the PTSD cohort was associated with an increased risk of ED, in comparison to the non-PTSD cohort in the subgroup analysis. When compared with patients without anxiety, PTSD owned a signi cantly adjusted HR (7.804, p=0.014). Patients with anxiety, PTSD had more signi cant adjusted HR (18.191, p<0.001) as compared to the patients with anxiety but no PTSD; with a similar phenomenon in bipolar disorder (8.406 vs 13.978) and depression (7.975 vs 19.911).

Association between PTSD and the risk of ED
Our results support the study hypothesis that patients with PTSD would have an increased risk of developing erectile dysfunction.
The log-rank of the Cox regression model was signi cant (p=0.003). The adjusted HR was 12.898 (95% CI: 2.453-67.811, p=0.003). When comparied with previous research about the association between PTSD and the risk of ED ( One study has shown the lifetime prevalence of PTSD ranges from 1.3 to 12.2%, and the one-year prevalence is 0.2 to 3.8% (Karam et al., 2014). Another previous study, using the NHIRD, has found that the one-year incidence of PTSD was 1.1% (Lin et al., 2014). In our study, the total incidence within the period of the 13-year follow up was around 0.31% (3,050 in 989,753), and while we excluded the 1,971 cases of PTSD which did not met the enrollment criteria of this study, the incidence was 0.11 % (1,079/989,753). Both were lower than the nding in the study of Lin et al., 2014. The discrepancy between the incidences in these two studies might well be related to the strict criteria we employed in the enrollment of the cases of PTSD, that is, each enrolled patient was required to have made at least three outpatient visits within the one-year study period for adult males with PTSD according to these ICD-9-CM codes 309.81.

Psychotropic medications and the risk of ED in patients with PTSD
In clinical practice guidelines, the most common psychotropic medications used in the patients with PTSD included selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), other antidepressants, sedative- Possible mechanisms for the increased risk of ED in patients with PTSD There is an enormous amount of evidence indicating a multifactorial etiology of erectile dysfunction; either organic or non-organic, and a complex interaction exists in the psychological, interpersonal, social, cultural, physiological, and gender-in uenced processes (Perelman, 2009; Reed et al., 2016). Several possible reasons could explain the underlying mechanism. PTSD itself can lead to a higher prevalence of erectile dysfunction, and also a higher prevalence of comorbidity exists among patients with PTSD (Arbanas, 2010). Besides, patients with PTSD are treated with psychotropic drugs which can cause side effects that could in uence their sexual function (Harvey and Balon, 1995; Reisman, 2017).

Limitations
Despite recent researches that highlighted the relationship between ED and PTSD, nding an absolute causation and mechanism for a patient with ED suffering from PTSD is still challenging. The main limitation of this study is that the number of ED patient in this sample was rare, which might be related to underestimation of self-report, the stigmatization, and a lower percentage of doctor visits due to culture factors. The patients with ED may choose not to talk to the doctors due to embarrassment, discouragement, or disbelief of the treatment possibilities.

Conclusion
The patients with PTSD had a higher risk of developing erectile dysfunction than those without PTSD, as determined after adjustment for demographic data and medical and psychiatric comorbidities. Further study is therefore necessary to clarify the de nite pathophysiology between PTSD and erectile dysfunction and to investigate as to whether prompt interventions for PTSD may reduce this risk.

Declarations
Declarations of interest: none Author Contributions: SCW, NST, and YPL conceived, designed and conducted the study, performed the statistical analyses, analyzed and interpreted the data, and drafted the manuscript. WCC and CHC participated in its conception, design, assisted with the data collection and scoring of the behavioral measures, analyzed and interpreted the data, and were involved in drafting the manuscript and revised the manuscript critically for important intellectual content. SCW wrote the rst draft. NST and YPL conducted the critical revision of the manuscript. All authors read and approved this manuscript.    Organic ED (N=2) 0.000 --0.998 ED: erectile disorder; PTSD: posttraumatic stress disorder; HR= hazard ratio, CI = con dence interval, Adjusted HR: Adjusted variables listed in Table 1. Figure 1 The owchart of study sample selection