Abstract
Background: This case-control study aimed to estimate the association between erectile dysfunction (ED) and migraines using a nationwide population-based database in Taiwan.
Methods: The data used for this matched case-control study were retrieved from the Taiwan Longitudinal Health Insurance Database 2000. We identified 5763 patients with ED as the cases and randomly selected 17,289 patients as the controls. Conditional logistic regression was used to calculate the odds ratios (OR) for prior migraine between cases and controls.
Results: After adjusting for hypertension, diabetes, hyperlipidaemia, renal disease, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome, conditional logistic regression revealed that among ED patients the odds of having been previously diagnosed with migraines was 1.63 (95% CI, 1.39–1.91) that of the control group. This risk was more pronounced in younger groups, with the highest risk being detected among those aged between 30 and 39 years. After adjusting for the above mentioned comorbidities, ED patients aged between 30 and 39 years were found to be at 1.98 (95% CI, 1.67–2.23) times the risk of controls for having been previously diagnosed with migraines.
Conclusion: We conclude that ED is associated with having been previously diagnosed with migraines, particularly in younger populations.
Introduction
Migraine is a common cause of headaches worldwide, affecting about 18% of the female and 6% of the male population (1). As with other disorders that cause chronic pain, migraine headaches have the potential to exert a significantly deleterious effect on social activities and business life (2). Chronic pain has also been noted to have an effect on sexual function, including adverse effects on sexual desire, stimulation and activity (3–5).
Chronic pain disorders including migraine, irritable bowel syndrome, and interstitial cystitis have recently come to be recognised as different manifestations of deregulations of a common set of CNS processes. As these processes are largely regulated by neurotransmitters, and the dysregulation of these neurotransmitter pathways has been suggested to contribute to sexual dysfunction, it is possible that erectile dysfunction (ED) and migraine share similar mechanistic underpinnings (6,7).
However, although some studies have demonstrated that migraines affect sexual life in a negative way in female patients (8,9), and that the neurotransmitter levels of female migraineurs are associated with migraine risk (10), the role of neurotransmitters in the pathology of sexual dysfunction exhibits sexual dimorphism (11,12), and no study to date has ever attempted to explore the association between migraine and ED. Therefore, using a nationwide population-based database, this study aimed to examine the association of ED with prior migraine by comparing the risk of prior migraine between patients with ED and matched controls in Taiwan.
Methods
Database
The data used for this matched case-control study were retrieved from the Taiwan Longitudinal Health Insurance Database (LHID2000). The LHID2000 was created by the National Health Research Institute and consists of the original claim data and registration files for 1,000,000 individuals randomly selected from the 2000 Registry for Beneficiaries of the Taiwan National Health Insurance (NHI) program. This program is utilised by 23.72 million residents of Taiwan, over 98% of the overall population, and provides a wide range of coverage and very low out-of-pocket expenses. The LHID2000 provides an excellent opportunity for researchers to trace all the medical utilisation of these 1,000,000 enrollees since the initiation of the NHI program in 1995. Many researchers have used the LHID2000 to perform and publish their studies in internationally peer reviewed journals.
As the LHID2000 consists of de-identified secondary data released to the public for research purposes, this study was exempted from full review by the Taipei Medical University Institutional Review Board.
Selection of cases and controls
The cases included all patients aged ≥30 years with a diagnosis of ED (only including impotence, organic (ICD-9-CM code 607.84)) in their visits to ambulatory care centres (including outpatient departments of hospitals and clinics) between January 2001 and December 2009 (n = 6460). In Taiwan, physicians diagnose ED based on a thorough evaluation of the results of an IIEF-5 questionnaire and a review of the relevant risk factors for ED in the patient’s medical history. Because coding validity is often disputed for administrative databases, all selected ED cases consisted of at least two ED diagnoses made by urologists in order to increase the validity of ED diagnosis. We assigned the first ED diagnosis occurring during the period between 2001 and 2009 as the index date for cases. We ensured that every selected case had at least one medical care utilisation during each calendar year in the 5 years preceding the index date in order to mitigate the possibility of including cases that were absent from Taiwan during that time period (n = 6229).
Finally, although we only included organic ED diagnoses in this study, in order to better ensure that psychiatric disturbances did not contribute to the development of ED among our selected cases, we further excluded all the patients who were diagnosed with mental illness (ICD-9-CM codes 290-319) prior to the index date. As a result, 5763 cases were included in this study.
We selected three controls for each case from the remaining beneficiaries in the LHID2000. A total of 18,237 controls were selected, who were frequency-matched with cases in 10-year age groups (<40, 40–49, 50–59, 60–69, and >69), monthly income (<NT$15,841, NT$15,841–25,000, and ≥NT$25,001), urbanisation level of the patient’s residence (five levels, with 1 referring to the ‘most urbanized’, and 5 the ‘least urbanized’), geographic region (Northern, Central, Eastern, and Southern Taiwan), and index year. We matched monthly income, urbanisation level, and geographic region between cases and controls in order to help ensure that cases and controls were reasonably similar with regard to unmeasured neighbourhood socioeconomic characteristics. We also made sure that none of the selected controls had ever been diagnosed with ED or any type of mental illness since initiation of the NHI in 1995. For controls, we assigned their first use of ambulatory care occurring in the index year as their index date. We also ensured that all of the controls used in this study had at least one medical care utilisation every calendar year in the 5 years preceding the index date in order to mitigate the possibility of including controls that were absent from Taiwan during that time period.
Exposure assessment
Migraine cases were identified according to ICD-9-CM code 346. In Taiwan, the diagnosis of migraine in clinical settings is based on the International Headache Society (IHS) criteria (13). However, in order to increase migraine diagnostic validity, we only included patients who received at least three consensus migraine diagnoses from certified neurologists. Furthermore, as psychiatric comorbidities have long been known to have a renowned association with migraine, patients suffering from both migraine and mental illnesses were not included as migraine cases. In this study, we only included migraine cases if the migraine diagnosis was made within 5 years prior to the index date.
Statistical analysis
We used the SAS System for Windows, Version 8.2 (SAS Institute Inc., Cary, NC) for the statistical analyses. We first compared the distributions of comorbidities (including hypertension, diabetes, hyperlipidaemia, renal disease, and coronary heart disease) between cases and controls by using χ2 tests. We selected these comorbidities because they are all well-documented risk factors for ED. In addition, these comorbidities were only included if they occurred before the index date. We also used conditional logistic regression (conditioned on age group, income, urbanisation level, geographic region, and index year) to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for prior migraine between cases and controls. In the regression models, we also adjusted for obesity and alcohol abuse/alcohol dependence syndrome as well as medical comorbidities. In addition, we further analysed the OR of prior migraine between the cases and controls by stratifying by age groups. The p ≤ 0.05 level was used to assess statistical significance in this study.
Results
Demographic characteristics of patients with erectile dysfunction and controls in Taiwan in the years 2001–2009 (n = 23,052)
Crude and adjusted odds ratios for migraine stratified by the presence/absence of erectile dysfunction among the sampled patients
Conditional logistic regression (conditioned on age group, monthly income, urbanisation level, geographic region, and index year) was performed to adjust for hypertension, diabetes, hyperlipidaemia, renal disease, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome.
p < 0.001.
Odds ratios for migraine among patients with erectile dysfunction and comparison group, by age group
Conditional logistic regression (conditioned on age group, monthly income, urbanisation level, geographic region, and index year) was performed to adjust for hypertension, diabetes, hyperlipidaemia, renal disease, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome.
p < 0.01; ***p < 0.001.
Sensitivity analysis
Conditional logistic regression (conditioned on age group, monthly income, urbanisation level, geographic region, and index year) was performed to adjust for hypertension, diabetes, hyperlipidaemia, renal disease, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome.
p < 0.001.
Discussion
Research on sexuality in people suffering from headaches is very limited. To the best of our knowledge, this is the first study to use a nationwide population-based dataset to document the association between ED and prior migraine. We found that ED patients had a 1.69-fold higher risk of prior migraine than controls after adjusting for sociodemographic characteristics and medical comorbidities, including hypertension, diabetes, hyperlipidaemia, renal disease, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome. We also found that when compared with matched controls, the ORs for prior migraine among ED patients demonstrated a decreasing effect with age (p < 0.001). The prevalence of ED increases with age for many reasons (14), and a greater share of the older men in this study probably suffered from ED on account of factors unrelated to migraine. Two examples of such factors include decreased testosterone levels and the increased peripheral vascular resistance resulting from narrowing of the lumen due to accumulations on vessel walls (15). Decreased testosterone levels have been shown to contribute to ED (16), and increased vascular resistance has been demonstrated to result in structural changes to the penile vasculature (17).
Furthermore, if the younger group were more sexually active than their more mature counterparts, the inverse trend between age and magnitude of effect detected in this study could be explained through a surveillance basis. One investigation surveying 412 men and 204 women over 65 in Taiwan found that only 35.7% were sexually active, and only had a frequency of 21.4 (SD 16.9) times per annum (18). In another study conducted on 1002 Taiwanese men, it was found that more than 60% of those aged over 60 had sex with a frequency under once per month, while only about 20% of those aged between 40 and 60 years had sex as infrequently. By engaging in sexual activities more often, younger subjects are more likely to realise that they are suffering from ED, and are therefore more likely to seek medical care and be diagnosed (19).
The mechanisms by which migraines may be associated with ED are complex and heterogeneous. As it has been demonstrated that chronic pain can cause sexual dysfunction (3–5), one possible explanation for the association seen in this study may be the chronic pain associated with migraine headaches (2). Current research suggests that the pain attributed to chronic pain disorders differs mechanistically from acute pain, with the most predominantly contributing factors stemming from the CNS. What were once understood to be a diverse range of disorders, including migraine, irritable bowel syndrome, and interstitial cystitis, are more recently being recognised as different manifestations arising from a common set of CNS processes, with neurotransmitters analogically acting as the ‘volume control’ of the pain processes involved (20).
Dopamine has been considered to play an important role in the pathogenesis of migraine for the past 30 years, with current research now associating certain dopamine-related gene variants with migraines (21–23). Neurotransmitter regulation is one critical juncture in the translation of long-term steroid effects into rapid behavioural events (6), with dopamine long being known to enhance sexual motivation and copulatory behaviour (24). It is released before and during copulation in several key integrative sites, and has also long been known to facilitate masculine sexual function clinically (6). Therefore, as neurotransmitter pathways, such as those of dopamine, have been suggested to be associated with both ED and migraine, it is possible that the dysregulation of neurotransmitter pathways is one mechanism underlying the associations detected in this study (6,7).
Although some studies have demonstrated that migraines affect sexual life in a negative way in female patients (8,9), and that the neurotransmitter levels of female migraineurs are associated with migraine risk (10), the role of neurotransmitters in the pathology of sexual dysfunction exhibits sexual dimorphism (11,12). Therefore, while it is possible that the associations detected in this study between migraine and ED, and the results reported by previous studies linking migraine to sexual dysfunction in women (8,9), may share neurotransmitter dysregulation as an underlying mechanism, it will be the work of future studies to verify and elucidate these putative underpinnings.
This study used a large national dataset to demonstrate that ED is associated with having been previously diagnosed with migraines. Even after adjusting for medical comorbidities related to ED, migraines were still independently associated with ED. We believe that the results of this investigation support the conclusions of previous clinical studies, and suggest the need for further investigation to better understand the underlying mechanisms and differentiate the effects of migraine from other significant factors influencing ED.
This study suffered from a few limitations that should be addressed. The first is the use of ICD-9-CM coding to diagnose ED. In many clinical studies, information on ED was collected using the IIEF or IIEF-5 questionnaire, which includes more objective items than using an ICD-9-CM code.
Second, Taiwanese cultural taboos may have contributed to the relatively low frequency of ED when compared with studies from Western countries (25,26). Moreover, as prescriptions for the treatment of ED are not covered by the NHI program, there is also no incentive for a Taiwanese to be diagnosed. But, this should work to increase the validity of the ED diagnoses used in this study, as many Taiwanese would only seek help for a shameful condition if they were truly suffering.
Third, the validity of the migraine diagnoses used in this study might be a concern. However, the coding of the migraine is generally based upon the IHS criteria in clinical settings (27). Further, the NHI Bureau implements routine sample cross-checks of each hospital’s and clinic’s claims with its medical charts. It is generally believed that the NHI’s checks and balances foster accurate coding (27).
Fourth, individual information such as smoking, alcohol consumption, and marital/partner status, all of which may contribute to ED, was not available through the administrative dataset.
Fifth, although we excluded patients suffering from both migraine and mental illnesses from this study, patients with mild mental illness might not look for medical assistance and therefore might not have been documented in the dataset.
Finally, even though the healthcare system in Taiwan provides universal coverage, this does not account for the fact that some people may be more or less likely to consult physicians. Therefore, it is possible that this study was vulnerable to Berkson’s bias, and that the associations detected in this study might in part reflect the greater propensity of the cases to be healthcare seeking. However, in order to respond to that concern, we analysed the number of urological healthcare utilisations of both the cases and controls during the 5 years preceding the index date. During that time, the cases enrolled in this study had an average of 8.22 visits to the urological department, while the controls had an average of 8.16 (p = 0.907). As there was no significant difference between the average number of visits between cases and controls, we feel that the cases in this study were probably not more likely than controls to consult a physician purely based on the merit of having previously demonstrated healthcare-seeking behaviour.
Conclusion
This study used data from the Taiwan LHID2000 to succeed in identifying a novel association between ED and prior migraine. We detected the largest magnitude of this association among adults aged 30 to 39. These findings work toward guiding future epidemiological research and highlight a need for doctors dealing with migraine patients to assess their erectile function.
Footnotes
Acknowledgements
This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, Taiwan and managed by the National Health Research Institutes. The interpretations and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or the National Health Research Institutes.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.