Restless Legs Syndrome and Erectile Dysfunction

Abstract

Study Objectives:

Dopaminergic hypofunction in the central nervous system may contribute to restless legs syndrome (RLS) and erectile dysfunction (ED). We therefore examined whether men with RLS have higher prevalences of ED.

Design:

RLS was assessed using a set of standardized questions. Men were considered to have RLS if they met 4 RLS diagnostic criteria recommended by the International RLS Study Group, and had restless legs ≥ 5 times/month. Erectile function was assessed by a questionnaire.

Setting:

Community-based.

Participants:

23,119 men who participated in the Health Professional Follow-up Study free of diabetes and arthritis.

Results

Multivariate-adjusted odds ratios for ED were 1.16 and 1.78 (95% confidence interval: 1.4, 2.3; P trend < 0.0001) for men with RLS symptoms 5–14 times/mo, and 15+ times/mo, respectively, relative to those without RLS, after adjusting for age, smoking, BMI, antidepressant use, and other covariates. The associations between RLS and ED persisted in subgroup analysis according to age, obesity, and smoking status.

Conclusions:

Men with RLS had a higher likelihood of concurrent ED, and the magnitude of the observed association was increased with a higher frequency of RLS symptoms. These results suggest that ED and RLS share common determinants.

Citation:

Gao X; Schwarzschild MA; O'Reilly EJ; Wang H; Ascherio A. Restless legs syndrome and erectile dysfunction. SLEEP 2010;33(1):75-79.

RESTLESS LEGS SYNDROME (RLS) IS A GENERALLY UNDERDIAGNOSED AND UNDERTREATED NEUROLOGICAL DISORDER CHARACTERIZED BY A complaint of an almost irresistible urge to move the legs, affecting 5% to 15% of adults.^1,2 RLS has a substantial impact on sleep, daily activities, and quality of life.¹ Although the etiology of RLS is still unclear, dopaminergic hypofunction in the central nervous system (CNS) is believed to have a role in disease pathophysiology.³ This hypothesis has been supported by evidence that RLS symptoms were improved by administration of L-dopa⁴ or dopamine agonist^5–7; and that dopamine antagonists that cross the blood-brain-barrier (BBB) (e.g., metoclopramide and pimozide) and exacerbate RLS symptoms, whereas those that do not cross the BBB (e.g., domperidone) do not have an effect on RLS.^3,8,9

Dopamine in the CNS plays important role in regulation of erectile function.^10,11 In a previous study, we found that men with erectile dysfunction (ED) were ∼4 times more likely to develop Parkinson disease during 16 years follow-up, another disorders associated with dopamine hypofunction in the CNS, than those who reported normal erectile function.¹² It is thus of interest to investigate whether RLS patients have a higher risk of ED. This association, however, has not been previously investigated.

We, therefore, conducted a cross-sectional analysis to examine whether men with RLS have a higher likelihood of having ED in the Health Professional Follow-up Study (HPFS), a large ongoing US cohort of men.

MATERIALS AND METHODS

Study Populations

The HPFS was established in 1986, when 51,529 male US health professionals (dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians) aged 40-75 years completed a mailed questionnaire about their medical history and lifestyle. Follow-up questionnaires have been mailed to participants every 2 years to update information on potential risk factors and to ascertain newly diagnosed diseases in both cohorts. The institutional review board at Brigham and Women's Hospital reviewed and approved this study, and receipt of each questionnaire implies participant's consent.

Assessment of RLS

We asked questions about RLS diagnosis and severity based on the International RLS Study Group criteria in 2002 (n = 37,431, mean age 68.7 ± 9 y) among participants who were still alive and actively participating in the study.¹³ The following question was asked: “Do you have unpleasant leg sensations (like crawling, paraesthesia, or pain) combined with motor restlessness and an urge to move?” The possible responses were as follows: no; less than once/month; 2-4 times/month; 5-14 times/month; and 15 or more times per month. Those who answered that they had these feelings were asked the following 2 questions: (1) “Do these symptoms occur only at rest and does moving improve them?”; and (2) “Are these symptoms worse in the evening/night compared with the morning?” A probable RLS case was considered to be present if the participant answered “yes” for all 3 of the above questions with a frequency ≥ 5 times/month.

The questions on RLS were completed by 31,729 (85%) men. Men who did not complete the RLS questions had similar age (mean 69.0 vs. 68.6 years) and prevalence of ED (44.8% vs. 43.9%) as those with RLS information. To reduce possible misclassification of RLS, we excluded participants with diabetes and arthritis, leaving 23,119 men in primary analyses. In a secondary analysis, we further examined the association between RLS and ED with including all participants with RLS information.

Assessment of ED and Covariates

On the 2000 and 2004 questionnaire, we asked HPFS participants who were still alive and actively participating in the study to rate their ability to have and maintain an erection sufficient for intercourse. There were 5 possible responses: very poor, poor, fair, good, and very good. Reports of poor or very poor erectile function in or prior to 2004 were considered ED, as we did previously.^12,14

Information on potential confounders, including age, ethnicity, smoking status, weight, height, physical activity, use of medicines, phobic anxiety scale, and history of major chronic diseases, was collected via biennial questionnaires throughout the follow-up period. Body mass index (BMI) was calculated as weight (kg)/ height (m)². The phobic anxiety scale was assessed by the Crown-Crisp phobia index, a short, clinical self-rating scale for common phobias such as fear of enclosed spaces, illness, going out alone, heights, and crowds.^15,16 Anxiety has been shown to be associated with RLS and ED.^17–19

Statistical Analyses

Statistical analyses were completed with SAS version 9.1 (SAS Institute, Inc, Cary, NC). We categorized participants into 3 groups: no RLS, RLS with symptom 5-14 times/mo, and RLS with symptom 15+ times/mo. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) and to test differences in prevalence of ED across categories of RLS status. Analyses were adjusted for age (y), ethnicity (Caucasian, African American, and Asian and others), BMI ( < 23, 23-24.9, 25-26.9, 27-29.9, or ≥ 30 kg/m²), smoking (never smoked, former smoker, or current smoker: cigarettes/d, 1-14 or ≥ 15), physical activity (quintiles), use of antidepressants (yes/no), the Crown-Crisp phobic anxiety index (0-1, 2, 3, or ≥ 4), and presence of stroke, hypertension, or myocardial infarction (each of them, yes/no).

We examined potential interactions of presence of RLS (yes/no) with age ( < or ≥ 70 years, approximate median value), obesity (yes/no, based on BMI ≥ 30 kg/m²), and smoking status (never versus ever), by including multiplicative terms in the logistic regression models, with adjustment for other potential confounders.

RESULTS

Men with RLS were older; they were more likely to be white, to smoke, exercise less, and use antidepressants than participants without RLS. Men with RLS also had higher BMI, anxiety score, and prevalence of stroke and hypertension than participants without RLS (Table 1). As expected, the prevalence of ED increased with age (Figure 1). However, men with RLS had higher prevalence of ED than those without RLS in each age group. Up to 2004, 52.9% of RLS patients reported erectile dysfunction, relative to 40.3% of participants without RLS (age-adjusted OR = 1.47; 95% CI: 1.3, 1.7).

Table 1.

Basic characteristics according to restless legs syndrome status in 2002 in the Health Professionals Follow-up Study^*

	Restless legs syndrome status in 2002
	No RLS	RLS 5-14 times/mo	RLS 15+ times/mo
n	22175	549	395
Age, y	67.6	69.2	70.0
Current smokers, %	3.6	3.7	6.1
Past smokers, %	52.5	57.4	55.1
African Americans, %	0.6	0.5	0.9
Asian & other ethnicity, %	3.0	1.1	1.5
BMI, kg/ m2	25.9	26.4	26.2
Physical activity, Mets/wk	36.7	35.2	31.7
Phobic anxiety index	1.9	2.3	2.5
Use of antidepressant, %	4.4	8.0	11.3
Presence of stroke in or prior to 2002, %	1.3	2.4	2.9
Presence of hypertension in or prior to 2002, %	41.8	44.6	43.4
Presence of myocardial infarction in or prior to 2002, %	3.7	3.7	3.7

^*Values were standardized to the age distribution of the overall cohort.

Figure 1.

Prevalence of erectile dysfunction (ED) by restless legs syndrome status.

Higher frequency of RLS symptom, a marker for the disease severity, was associated with increased risk of having ED (Table 2). The ORs for ED were 1.16 and 1.78 (95% CI: 1.4, 2.3; P for trend < 0.0001) for men with RLS symptom of 5-14 times/mo, and 15+ times/mo, respectively, relative to those without RLS, after adjusting for age, BMI, use of antidepressants, and other covariates. The significant association with ED was not materially altered after excluding men with Parkinson disease, which is also associated with dopamine deficiency (Table 2).

Table 2.

Odds ratios (ORs) and 95% confidence interval (CI) of erectile dysfunction according to restless legs syndrome status in the Health Professional Follow-up Study

	No RLS (n = 22175)	RLS 5-14 times/mo (n = 549)	RLS 15+ times/mo (n = 395)	P trend
Erectile dysfunction
# cases	8934	266	233
Age adjusted OR	1 (ref.)	1.22 (1.01, 1.48)	1.93 (1.53, 2.43)	<0.0001
Multivariate adjusted OR1	1 (ref.)	1.16 (0.95, 1.40)	1.78 (1.40,2.25)	<0.0001
Excluding men with Parkinson's disease	1 (ref.)	1.18 (0.97, 1.43)	1.76 (1.39,2.23)	<0.0001

Logistic regression models were used to calculate ORs, adjusted for age (in years); smoking status (never smoker, former smoker, or current smoker: cigarettes/d, 1-14 or ≥ 15); BMI (<23, 23–24.9, 25–26.9, 27–29.9, or ≥ 30 kg/m²); use of antidepressant drugs (yes/no); physical activity (quintiles); the Crown-Crisp phobic anxiety index (0-1, 2, 3, or ≥ 4); and presence of stroke, hypertension, or myocardial infarction (each of them, yes/no)

To test the robustness of our observations, we conducted several sensitivity analyses and obtained similar significant results. Multiple-adjusted ORs comparing the men with RLS symptom 15+ times/mo with those without RLS were 1.74 (95% CI: 1.3, 2.3) for ED after excluding participants with highest levels of phobic anxiety, 1.81 (95% CI: 1.4, 2.3) after excluding participants with MI or stroke, and 1.68 (95% CI: 1.2, 2.3) after excluding those with hypertension. Excluding participants who used antidepressant did not materially change the associations between RLS and ED; adjusted ORs comparing the men with RLS symptoms 15+ times/mo with those without RLS were 1.80 (95% CI:1.4, 1.8). After further inclusion of participants with diabetes or arthritis, association between RLS and ED did not change. The multiple-adjusted ORs comparing men with RLS symptoms 15+ times/mo with men without RLS were 1.75 (95% CI: 1.5, 2.1).

We did not find significant interaction between presence of RLS and age, obesity, and smoking status (P interaction > 0.2 for all), in relation to likelihood of having ED (Table 3). The associations between RLS and ED persisted in subgroup analysis according to age, obesity, and smoking status. Further, the interactions between presence of RLS and antidepressant use were also not significant (P interaction = 0.67).

Table 3.

Odds ratios (ORs) and 95% confidence interval of erectile dysfunction according to presence of restless legs syndrome (RLS), stratified by age, smoking status, and BMI

	OR1 for erectile dysfunction
	No RLS	RLS	P interaction
Age
<70 y	1 (ref)	1.31 (1.07,1.61)	0.25
≥ 70 y	1 (ref)	1.49 (1.19, 1.87)
Smoking
Never	1 (ref)	1.41 (1.11,1.81)	0.76
Ever	1 (ref)	1.35 (1.11,1.63)
BMI
<30 kg/m2	1 (ref)	1.34 (1.05,1.70)	0.66
≥ 30 kg/m2	1 (ref)	1.39 (1.15, 1.69)

¹Logistic regression models were used to calculate ORs, adjusted for age (in years); smoking status (never smoker, former smoker, or current smoker: cigarettes/d, 1-14 or ≥ 15); BMI (<23, 23-24.9, 25-26.9, 27-29.9, or ≥ 30 kg/m²); physical activity (quintiles); the Crown-Crisp phobic anxiety index (0-1, 2, 3, or ≥ 4); and presence of stroke, hypertension, or myocardial infarction (each of them, yes/no)

DISCUSSION

In this large cohort of men, we observed that men with RLS had higher prevalences of ED, relative to those without RLS, across all age groups. Magnitude of the association was positive associated with frequency (i.e., severity) of RLS; men who reported to have RLS symptoms 15+ times/month had an approximately two-fold higher risk of having ED as with men without RLS. The associations were independent of age, BMI, use of antidepressants, anxiety, and other possible risk factors for RLS. Sensitivity and subgroup analyses also generated similar significant results, suggesting robustness of our findings.

We found that 4.1% of men met 4 RLS diagnostic criteria recommended by the International RLS Study Group, and had restless legs ≥ 5 times/mo. This prevalence is consistent with previous studies. In a large population-based survey including 16,202 adults aged ≥ 18 y living in the US and 5 European countries,²⁰ 5% of participants had RLS symptoms ≥ 1 times/wk and 4.1% ≥ 2 times/wk. In a recent community-based study including 1730 men and 2101 women (mean age 68 y), prevalence of RLS was 6.4% in women and 3.4% in men.²¹ In this study, RLS was defined as meeting all 4 RLS diagnostic criteria, with symptoms occurring ≥ 5 times/mo and associated with at least moderate distress. A French study also reported that 4.3% men and women (aged ≥ 18 y) with RLS symptoms ≥ 1 time/wk.²²

Although there are no studies examining the association between RLS and erectile function directly, a case-control study showed that RLS was associated with reduced libido; the multivariate adjusted OR for reduced libido was 2.2 (95% CI: 1.4, 3.3) for men with RLS vs. controls.²³ The mechanisms underlying the observed association between RLS and ED could involve multiple pathways. Hypofunction of dopamine in CNS, which is associated with both conditions, could, at least in part, explain the association. Dopamine and its agonists control penile erection via activation of oxytocinergic neurons in the hypothalamus. L-DOPA and apomorphine, a dopaminergic agonist used to improve RLS symptoms, can elicit erection,^10,11,24,25 and the pro-erectile effects of these drugs have been abolished by administration of dopamine antagonist.²⁶

In an animal model of RLS, 6-hydroxydopamine lesions in the A11 dopamine nuclei increased locomotor activities and altered the dopamine D2/D3 receptors expression and binding capacity in the lumbar spinal cord.²⁷ In genetic studies, people with LBXCOR1 mutation, a gene involved development of spinal cord, were found to have a higher risk of RLS.²⁸ The spinal cord also plays a key role in sexual function and subjects with spinal cord injuries have a higher prevalence of sexual dysfunction.²⁹ Further, periodic limb movement disorder, a key feature of RLS which is generated in the spinal cord, was found to be associated ED in a case-control study.³⁰ The association between RLS and ED could also partially due to other sleep disorders which co-occur with RLS. These disorders may affect the hormonal, neural and endothelial physiology,³¹ and may therefore contribute to increased risk of sexual dysfunction.^32–34 For example, obstructive sleep apnea and sleep deprivation may decrease circulating testosterone levels.³¹

Several other chronic conditions could also underlie the association between RLS and ED. For example, cardiovascular diseases and obesity are positively associated with an increased risk of both ED¹⁴ and RLS,^13,21,35 and it has been suggested that vascular pathology may contribute to RLS.³⁶ However, we controlled for these variables in our models. The sensitivity analyses excluding men with cardiovascular diseases or obesity generated similar significant results.

Strengths of the current study include a large sample size, which enable us to obtain a relatively stable estimate for the associations, and use of standardized questionnaire to assess RLS. Although we controlled a set of potential confounders in our models, a possibility of residual confounding cannot be excluded. The cross-sectional design of our study precludes conclusions regarding direction or causality of the observed associations. Further we assessed erectile function with a single question, which inevitably leads to some degree of misclassification for ED. However, in a validation study including 137 men aged 55-85 y who participated in Massachusetts Male Aging Study,³⁷ erectile dysfunction measured by a self-reported single question, which is very similar to our question, were strongly correlated to (Spearman r = 0.80) the results of an independent urologic examination, which composed of four major components: a physical examination; detailed sexual history; medical history; and psychosocial history. Receiver operating curve analysis showed that the self-reported ED accurately predicts the clinician-diagnosed ED (area under the curve = 0.89).³⁷ Although we identified RLS cases by use of the standard criteria of RLS diagnosis, there is still a possibility that some RLS-like symptoms which could be misclassified as RLS.^38,39 We therefore excluded men with diabetes and arthritis in our primary analysis. Although we cannot exclude other two most common RLS mimics, positional discomfort and leg cramps,³⁹ there has been no evidence that these two conditions are associated with ED. This misclassification may lead to an attenuation of the associations between RLS and ED. We also conducted several sensitivity analyses by excluding men heart disease, hypertension, use of antidepressants and found similar significant results, suggesting the robustness of our findings.

In conclusion, we found that men with RLS had a higher likelihood of concurrent ED and the magnitude of the observed association was increased with a higher frequency of the restless leg symptoms. This finding indirectly supports a role of dopamine in RLS. Further epidemiological studies are warranted to clarify the temporal relationship between RLS and ED and to explore the biological mechanisms underlying this association.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest