Sleep disorders increase risk of subsequent erectile dysfunction in individuals without sleep apnea: a nationwide population-base cohort study.

Sleep disorders increase risk of subsequent erectile

dysfunction in

individuals without sleep apnea: a nationwide

population-base

cohort study

Kuan-Fei Chen

, Shinn-Jye Liang

, Cheng-Li Lin

,Wei-Chih Liao

,

Chia-Hung Kao

*

1. Introduction

Erectile dysfunction (ED) is the inability to achieve or maintain a sufficient penile erection during sexual activity. The prevalence of erectile dysfunction (ED) in the general population has increased [1]. This may be because: people with ED have the courage to seek medical help; people, in general, have a longer life span; of the advancement in diagnostic tools and treatments; or there is an increased prevalence of possible etiologies. Several risk factors are associated with ED, including: hypertension, diabetes

mellitus, obesity, dyslipidemia, cardiovascular disease, smoking, medication use, sleep disorders, and emotional problems [2–5]. According to the International Classification of Sleep Disorders (ICSD-3) (American Academy of Sleep Medicine [AASM], 2014), sleep disorders (SDs) are divided into seven broad categories, namely: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep disorders,

parasomnias, sleep-related movement disorders, and other sleep disorders; insomnia is the most common. Increasingly more diseases have been found to correlate with SD, including: cardiovascular disease, stroke, hypertension, cognitive impairment, headache, and ED [6–12].

Sleep disorders and ED both play crucial roles in quality of life and have received increasing attention in the general population and among physicians. Therefore, a longitudinal nationwide

population-based cohort studywas conducted to investigate whether SDs increase the subsequent risk of ED. 2. Methods

2.1. Data source

The data were accessed from the Taiwan National Health Insurance Research Database (NHIRD). The National Health Insurance

(NHI) program, which was initiated in 1995, covers approximately 99% of the 23.74 million residents in Taiwan, and 97% of Taiwan clinics are enrolled in the NHI system [13,14]. The Bureau of NHI

possesses registration and claims data on one million insurants systematically selected from all residents in Taiwan. The NHIRD

comprises many registration records, including details on inpatient, outpatient, ambulatory and inpatient care, and contains

registration files that have been published in previous studies [15,16]. Diagnoses were coded by physician specialists according to the International Classification of Diseases, Ninth Revision, Clinical

Modification (ICD-9-CM). The accuracy and high validity of diagnoses in the NHIRD have been demonstrated [17,18]. To protect the privacy of all persons registered in the program, the NHRI encrypts and converts the identification numbers of all NHIRD records

before releasing them for researchers. Thus, the institutional research ethics committee fully reviewed and approved the present

study (CMU-REC-101-012).

2.2. Participants

People who were diagnosed with SD between 1998 and 2001 and >20 years of age were distributed into two case cohorts: a sleep apnea cohort (ICD-9-CM codes 780.51, 780.53, and 780.57) and a non-apnea SD cohort (ICD-9-CM codes 307.4 and 780.5, excluding 780.51, 780.53, and 780.57). Non-apnea SD was divided into insomnia (ICD-9-CM code 780.52), sleep disturbance (ICD-9-CM codes

780.5, excluding 780.51, 780.53, and 780.57), and others (ICD-9-CM codes 307.4, 780.50, 780.54–780.56, and 780.58–780.59). The date of the first visit, during which a person was diagnosed with an SD, was defined as the index date. People with a history of SD

before the index date, or for whom age or sex information was incomplete, were excluded. A control cohort of people without SD was

randomly selected from the NHI beneficiaries and frequency matched with the SD cohort at a 2:1 ratio according to age (in 5-year increments), sex, and year of SD diagnosis. All three cohortswere followed

until: an initial diagnosis of ED (ICD-9-CM code 607.84); loss to follow-up; death; withdrawal from the NHI; or December 31, 2011. The following diagnoses were recorded to establish the baseline comorbidity history for each participant: hypertension (ICD-9-CM codes 401–405); diabetes 9-CM code 250); hyperlipidemia

(ICD-9-CM code 272); chronic kidney disease (CKD) (ICD-(ICD-9-CM codes 580– 589); coronary artery disease (CAD) (ICD-9-CM codes 410–414); stroke (ICD-9-CM codes 430–438); chronic obstructive pulmonary disease (COPD) CM codes 490–496); cancer

(ICD-9-CM codes 140–208); depression (ICD-9-(ICD-9-CM codes 296.2, 296.3, 300.4, and 311); and anxiety (ICD-9-CM code 300.00). A medical history of benzodiazepine and zolpidem use was included in the analysis.

2.3. Statistical analysis

The demographic characteristics and clinical characteristics of the SD (sleep apnea and non-apnea SD) and comparison cohorts, including age (20–39 years, 40–64 years, and ≥65 years), comorbidities, and medical treatments, were compared using the Chi-squared test. For continuous variables, the t test was used to compare the SD and comparison cohorts. The incidence rate (per 1000 person-years) of follow-up for each cohort was also computed. A Poisson regression model was applied to measure the

incidence rate ratios (IRRs) with 95% CIs for ED of the sleep apnea and non-apnea SD cohorts compared with that of the control cohort. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazard models. The multivariable modelswere simultaneously adjusted for demographic characteristics,

comorbidities, and amedical history of benzodiazepine and zolpidem use. The cumulative incidence of EDwas calculated using the Kaplan– Meier method. Statistical significance was evaluated using the logrank test. All analyses were conducted using SAS statistical software (Version 9.2 for Windows; SAS Institute, Inc., Cary, NC, USA), with statistical significance set at p < 0.05 for a two-tailed test.

3. Results

Between 1998 and 2001, a total of 17,785 people were newly diagnosed with SD (603 in the sleep apnea cohort, and 17,182 in the

non-apnea cohort) (Table 1). The mean age of the SD cohort was 53.9 years and the control cohort was 53.8 years; nearly 75% of the participants were aged <65 years. The participants with sleep apnea were six years younger than those with non-apnea SD (54.1 years vs 48.2 years). The participants in the SD cohort were more likely to have hypertension, diabetes, hyperlipidemia, CKD, CAD, stroke,

COPD, cancer, depression, anxiety, and a medical history of benzodiazepine and zolpidem use than those in the control cohort

(p < 0.001). The participants with non-apnea SD were more likely to have comorbidities (excluding hyperlipidemia and COPD) and use benzodiazepine and zolpidem than those with sleep apnea.

The overall incidence density of ED was significantly higher in the sleep apnea cohort than in the control cohort (73.6 vs 10.1 per 1000 person-years) (Table 2). The overall incidence rate of ED was 7.45-fold higher in the sleep apnea cohort than in the control cohort, with an adjusted HR of 9.44 (95% CI 6.49–13.7). The incidence of ED was 3.05-fold higher in the non-apnea SD cohort than in the control cohort (30.6 vs 10.1 per 1000 person-years), with an adjusted HR of 3.72 (95% CI 3.13–4.41). An age-specific analysis revealed a 4.2-fold significantly higher risk of developing ED in the participants in the non-apnea SD cohort aged <40 years compared with

those in the control cohort (95% CI 25.6-5.52). A higher risk of ED was observed in the participants in the sleep apnea cohort aged <40 years than in those in the control cohort (adjusted HR 10.4,

95% CI 5.93–18.4). Participants with SD and comorbidities demonstrated a higher risk of developing ED than those in the control cohort

without comorbidities (adjusted HR in the sleep apnea cohort 13.1, 95% CI 7.31–23.3; adjusted HR in the non-apnea SD cohort 3.61, 95% CI 2.78–4.67). The participants with SD who used benzodiazepine and zolpidem exhibited a significantly higher risk of developing ED than those in the control cohort (sleep apnea cohort: adjusted HR of those using benzodiazepine 9.69, 95% CI 6.56–14.3, adjusted HR of those using zolpidem 12.1, 95% CI 5.17–28.5; nonapnea SD cohort: adjusted HR of those using benzodiazepine 3.83, 95% CI 3.20–4.59, adjusted HR of those using zolpidem 5.08, 95% CI 2.74–9.39).

Compared with the control participants, those with sleep apnea exhibited a significantly higher risk of developing ED (adjusted HR 7.86, 95% CI 5.66–10.9) (Table 3). In the non-apnea SD cohort, participants with non-apnea SD exhibited the highest risk of developing ED (adjusted HR 3.69, 95% CI 2.83–4.82), followed by those

with sleep disturbance (adjusted HR 3.51, 95% CI 2.90–4.25). Fig. 1 shows that the cumulative incidence of ED was higher in the sleep apnea cohort than in the other two cohorts (log rank, p < 0.001) by the end of follow-up.

In this longitudinal population-based cohort study, it was observed that participants with SD had an increased risk of developing ED during a 13-year follow-up period. Those with sleep apnea and

those with non-apnea SD had 9.44-fold and 3.72-fold increased risks of developing ED, respectively, compared with the general population

after adjustment for age, sex, and comorbidities. Some previous studies have explored the association between SD and ED, particularly apnea SD [4,5]. Younger adults (≤39 years) and people with

SD and COPD using benzodiazepine also appeared to be at higher risk. The highest incidence of ED was associated with sleep apnea, followed by non-apnea SD. Therefore, it is suggested that sleep apnea and non-apnea SD increase the risk of developing ED.

In 2002, Seftel et al. observed that the urology patients reported a variety of sleep problems, but neither persistent snoring

nor suspected obstructive sleep apnea syndrome was uniquely correlated to ED [4]. Four years later, Teloken et al. demonstrated that

men presenting with symptoms consistent with sleep apnea had a significant risk of ED, and that the correlation between the severity of sleep apnea and the severity of ED was strong [19].

Furthermore, Budweiser et al. confirmed by polysomnography that obstructive sleep apnea is an independent risk factor of ED [20].

Treatment with continuous positive airway pressure may improve or preserve sexual function [21]. The present results indicate that the incidence of ED was higher in the sleep apnea cohort than in the control cohort after age and comorbidities were controlled for; these results are consistent with those of previous studies.

It is believed that, to date, few studies have examined the correlation between non-apnea SD and ED. Most studies that have

discussed the correlation between SD and ED have not excluded sleep apnea and obstructive sleep apnea groups. The proposed mechanisms include: decreased levels of luteinizing hormone and

testosterone; increased sympathetic activity; peripheral nerve dysfunction, which is related to nocturnal hypoxia; decreased NO levels;

and increased production of endothelin [22]. In the present study, it was observed that the non-apnea SD cohort had a 3.05-fold increased risk of developing ED compared with the control cohort after

age and comorbidities were controlled for. The age-specific analysis revealed a 4.2-fold higher risk of developing ED in people <40

years of age in the non-apnea SD cohort compared with those in the control cohort. These results suggest that non-apnea SD is a considerable factor in diagnosing or treating ED, particularly in young people.

The possible mechanisms through which non-apnea SD increases the risk of ED are unclear. Involuntary sleep-related erections

occur naturally during REM sleep. This may be a clue. The hypothalamus is an import area for controlling sleep cycles and the

primary regulatory center for the autonomic nervous system. The parasympathetic nervous system is active during REM sleep and releases both Ach and NO, which are considered to play an essential role in cavernosal vasodilatation. Sleep deprivation may induce sympathetic overactivity, which possibly affects the antagonistic functions of the sympathetic and parasympathetic nervous systems [23]. Another finding is that benzodiazepine use, which reduces REM sleep, increases the risk of ED. Testosterone cannot be ignored as a possible mechanism. The normal diurnal rhythm of testosterone may be disturbed by fragmented sleep, and the testosterone level peaks near the transition from NREM to REM sleep [24–26]. The parvocellular neurons of the hypothalamus secrete

hypophysiotropic hormones, which control the release of corresponding pituitary hormones through the portal vascular network.

The hypothalamus is the common pathway of the neural and endocrine systems. These proposed mechanisms require evidence from

further study.

In conclusion, both sleep apnea and non-apnea SDs increase the risk of ED, independent of age and comorbidities, and may share certain aspects of common mechanisms such as the autonomic system and testosterone.

The strength of this study was its use of population-based data, which are highly representative of the general population. However, the study also had limitations. First, the NHIRD does not contain detailed information on smoking habits, body mass index, dietary preference, occupational exposure, reproductive history, and socioeconomic status, all of which are potential risk factors for ED. Second, evidence derived from a retrospective cohort study is generally of lower statistical quality than that from randomized trials

variables. Although this study design was meticulous and included control for confounding factors, bias resulting from unknown confounders could have affected the results. Third, all data in the NHIRD are anonymous; therefore, relevant clinical variables such as serum laboratory data, polysomnography, and imaging and pathology results were unavailable.

Taiwan launched the NHI program in 1995, and a single payer – the government – operates this program. Medical reimbursement specialists and peer reviewers scrutinize all insurance claims. The diagnoses of SD and EDwere based on ICD-9-CM codes andwere

determined by relevant specialists and physicians, according to standard clinical criteria. The data on the diagnoses of SD and ED