European Urology

Review

European Urology 47 (2005) 838845

Erectile Dysfunction and Lower UrinaryT ract Symptoms Secondary to BPH

Kevin T. McVary*
Department of Urology, Feinberg School of Medicine, Northwestern University Medical School, Tarry 16-749, 303 E. Chicago Ave., Chicago, IL 60611, USA Accepted 8 February 2005 Available online 16 March 2005

Abstract Introduction: The relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) have received increased attention recently because both diseases are highly prevalent, frequently co-associate in the same aging male group, and contribute signicantly to the overall quality of life. The association between these two diseases has also garnered attention as investigators have hypothesized a common pathophysiology to explain the assertion that they are causally linked. Methods: A causal association between LUTS and ED cannot be established on the basis of the ever-increasing number of epidemiological studies. Attempting to explain a causal relationship between ED and LUTS needs to be examined using Hills criterion, which is used by many epidemiologists to separate causal from non-causal explanations. Results: Given the epidemiological components of the Hills Causality method, it is clear that there is a strong strength of association, internal consistency, and dose response effects between ED and LUTS. Because of the strong cross-sectional avor to the epidemiological studies, the temporal relationships between ED and LUTS remain unknown. The issue of an alternate explanation to describe the LUTS-ED association appears to be accounted for in that several large studies have provided convincing multiple regression analyses in which the ED-LUTS relationship remains signicant. The link between ED and LUTS has biologic plausibility given the four leading theories of how these diseases interrelate. These explanations fall into four theories each with a variable amount of supporting data. These include: (1) NOS/NO levels decreased or altered in the prostate and penile smooth muscle, (2) Autonomic hyperactivity effects on LUTS, prostate growth and ED., (3) increased Rho-kinase activation/endothelin activity, and (4) prostate and penile ischemia. Conclusions: LUTS and sexual dysfunction are highly prevalent in aging men. Both conditions are also signicant contributors to overall quality of life. New data has emerged to indicate potential links in epidemiological, physiologic, pathophysiologic and treatment aspects of these two entities. # 2005 Elsevier B.V. All rights reserved. Keywords: BPH; LUTS; Erectile dysfunction; ED; Prostate; Penis; Autonomic hyperactivity

1. Introduction The relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) have
* Tel. +1 312 908 1987; Fax: +1 312 908 7275. E-mail address: k-mcvary@northwestern.edu.

received increased attention recently because both diseases are highly prevalent, frequently co-associate in the same aging male group, and contribute signicantly to the overall quality of life. The association between these two diseases has also garnered attention as investigators have hypothesized a common pathophysiology to explain the assertion that they are cau-

0302-2838/$ see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.02.001

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sally linked. This common-theme hypothesis has taken a life of its own as pharmaceutical companies have contemplated expanding indications for their drugs for both diseases. The link between ED and LUTS is also important for physicians to understand because the treatment of one may adversely impact the other disease. Almost all accepted therapies for LUTS (surgical or medical) can impact some aspect of sexual health, thus it is imperative that health care professionals understand their patients concerns and motivations in these two linked diseases. Thus, even if BPH/ LUTS and ED were simply coincidental, there are relevant clinical management questions related to their common association. Additionally, there are important specic drug interaction issues (e.g., alpha-blockers and PDE-5 inhibitors) that need special attention when dealing with any man with ED or LUTS. A causal association between LUTS and ED cannot be established on the basis of the ever-increasing number of epidemiological studies. Attempting to explain a causal relationship between ED and LUTS needs to be examined using Hills criterion, which is used by many epidemiologists to separate causal from non-causal explanations [1,2]. The Hill causality method establishes a link using general epidemiological data, case-control reports, and cohort studies grounded by supportive plausible mechanism of action investigations. The epidemiological data is examined for the strength of association (relative risk [RR], between study consistency (replication of ndings), dose-response effect and a temporal relationship between index disease development and progression. Most importantly, the observed epidemiological data must take into consideration alternative explanations (i.e. chance, bias and confounding factors).

2. Epidemiology of LUTS secondary to BPH and sexual dysfunction Before looking at the relationship between LUTS and ED, a brief overview of the prevalence of LUTS and ED is worthwhile. Age is one of the most important risk factors for ED. Compared to men in their 40s, men in their 50s have a 2-fold increase in their relative risk of ED. This increases to 5-fold increase in RR for men in their 60s [3]. The Massachusetts Male aging Study (MMAS) detailed that 52% of men from 4070 years old have some degree of ED, and 2/3 of these men have moderate to severe symptoms [4]. Similar to ED, the prevalence of histologic BPH increases progressively from the fourth (8%) through the eighth (82%) decade [5]. The prevalence of gross,

potentially clinically signicant BPH lesions shares this association with increasing age. The cumulative prevalence of a history/physical examination based diagnosis of LUTS or BPH voiding dysfunction similarly increased progressively from 26% to 79% from the 5th to 8th decade of life in the Baltimore Longitudinal Study of 1057 men [6]. An unequivocal role for BPH in the LUTS data should be viewed with some reservation as several studies have documented a comparable prevalence of similar symptoms in aging women [7,8]. Given the potential role of bladder and CNS roles in LUTS this seemingly surprising anomaly of women with LUTS does not impact the putative relationship between ED and LUTS. An early cross-sectional investigation of the role between sexual function and LUTS using a community-based survey noted sexual satisfaction negatively correlated with increasing age and LUTS [9]. The relative risk of ED stratied by International Prostate Symptom Score (IPSS) ranged from 0 at relative risk 1.0 to a 3.3 fold increase in relative risk for symptom scores greater than 19. Using a community based survey of over 4000 men the Cologne Male Survey noted the prevalence of ED was 19.2%, with a steep age-related increase (2.3 53.4%) and a high co-morbidity of ED with LUTS, as well as the more standard risks of hypertension, diabetes, and pelvic surgery [10]. Similarly, the Krimpen study of sexual dysfunction assessed the relative risk (RR) for ED in a community cohort [11]. In this important study LUTS had a strong relationship with increasing risk of ED (dose response curve). The authors noted an increased RR of ED from 1.8 to 7.5 depending upon the degree of urinary complaints. This increased RR of ED based on the severity of LUTS was greater than that found with the more traditional ED risk factors (cardiac symptoms, pulmonary problems and a history of smoking (Table 1). This suggests that ED is a worthwhile symptom to query in patients who present with LUTS. This association of ED with LUTS was also conrmed in several more recent cross sectional commuTable 1 Risk Factors for Erectile Dysfunction (Krimpen Study) Blanker 2001 Age (5578) BMI >30 LUTS Cardiac Sx COPD Smoking 2.314.3 3.0 1.87.5 2.5 1.9 1.6

The large variation in LUTS related Ed risk relates to the severity of the IPSS score (adapted from: [11]).

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nity-based populations. In a population-based household survey, Moreira et al. noted an age-adjusted prevalence of ED of 39.5% (minimal 25.1%, moderate 13.1%, severe 1.3%). Having never been married, diabetes, depression, or LUTS were signicantly (p < 0.05) associated with increased prevalence [12]. Evaluating the relationship between ED and LUTS was done in the context of the Olmstead County Study of LUTS. The authors noted that sexual drive, erectile function, ejaculatory function, problem assessment, and overall sexual satisfaction were signicantly and inversely correlated with LUTS [13]. The Multinational Survey of the Aging Male (MSAM-7) study revealed a strong association between the level of sexual activity and IIEF score with patients IPSS score [14] (Fig. 1). Importantly, this association between LUTS and ED persisted when controlled for age and other co-morbidities that are known to impact sexual function. Other measures of ejaculatory dysfunction, reduced ejaculate and ejaculation pain also strongly associated with LUTS. The results of the MSAM-7 suggest that older men still have an active sex life and that the severity of LUTS has an impact on sexual disorders independent of other risk factors. The NIH-sponsored MTOPS trial addressing the effect of nasteride and/or doxazosin on BPH progression was recently reported [15]. A secondary aim of this important study addressed the relationship between sexual function and LUTS severity in 3,000 men. Looking at the prevalence of SD and LUTS in a crosssectional analysis of baseline data, McVary reported a strong association between baseline AUA Symptom Index and the various domains of sexual function includ-

ing libido, erectile capability, ejaculation, problem assessment, and overall satisfaction with sexual life (p < 0.001 for each domain) [16]. There was also signicant association of the sexual function domains and maximum ow rate (Qmax) (p < 0.001). The relationship between Qmax, total prostate volume, transition zone volume and ED noted in the MTOPS is important as it links the symptoms of ED with more fundamental biologic and physiologic measures of prostate and bladder dysfunction. This latest report is also important because the co-morbidities that are frequently associated with ED (including age, partner status, marital status, hypertension, lipid disorders, and diabetes) were controlled in a multivariate analysis and the patients were characterized clinically exceedingly well. Additionally, the duration of LUTS associated very strongly with erectile function, problem assessment and the overall satisfaction of sexual life (p < 0.01). These results support the association of LUTS and SD that is independent of the usual co-morbidities. It is well known that LUTS diminishes the quality of patients life. Of note, sexual satisfaction also signicantly associates with LUTS in that the more severe the LUTS, the more likely a poor sexual satisfaction was reported. In a follow-up report, Girman and colleagues demonstrated a similar relationship between prostate volume and sexual dissatisfaction [17]. This study is most interesting because of the association of prostate volume (as a proxy for basic biologic growth principles) and sexual dysfunction. The bothersomeness of SD in the aging male was conrmed by Vallancien et al., who noted that ED and reduced ejaculation were highly prevalent in men with LUTS and was strongly related to increasing age and LUTS severity [18]. Given the epidemiological components of the Hills causality method mentioned earlier, it is clear that there is a strong strength of association, internal consistency, and dose response effects (worse LUTS-worse ED) between ED and LUTS. Because of the strong crosssectional avor to the epidemiological studies, the temporal relationships between ED and LUTS remain unknown. The issue of an alternate explanation to describe the LUTS-ED association appears to be accounted for in that several large studies have provided convincing multiple regression analyses in which the ED-LUTS relationship remains signicant.

Fig. 1. Age and LUTS severity stratication of erectile dysfunction in the MSAM-7 Study. Note the increasingly common incidence of ED per each age group (5059, 6069, 7079 years). Within in age group there is an impressive variation in ED as stratied by LUTS severity (IPSS score). (Adapted from: [14]).

3. Mechanism of interaction between ED and LUTS As mentioned above, if there is link between ED and LUTS from the epidemiological standpoint then this

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relationship must have biologic plausibility. What are the possible biologic interrelationships between these two entities? These explanations fall into 4 categories or theories, each with a variable amount of supporting data. 3.1. NOS/NO levels decreased or altered in the prostate and penile smooth muscle This hypothesis attempts to explain the link between ED and LUTS by the reduced production of nitric oxide synthase (NOS)/nitric oxide (NO) in the pelvis, which includes both the penis and prostate [19] (Fig. 2). This theory closely adheres to the nitrinergic innervation-smooth muscle cell relaxation molecular mechanism of ED. It links these two diseases into a single unifying concept as it is reported that NOS/NO production of the prostate is reduced in BPH (transition zone) when compared to normal prostate tissue. It logically follows that prostate tissue levels of NO/ NOS are reduced in BPH progression, which then reduces prostatic tone relaxation. This proposed reduction in NOS isoforms results in an altered neurogenic inuence on voiding function that is recognized as progressive BPH or LUTS. This theory is supported by limited evidence in which BPH tissue NADPH-d staining and nNOS immunohistochemistry shows a qualitative decrease in the otherwise dense nitrinergic innervation of glandular epithelium, bromuscular stroma, and blood vessels. There are several methodological aws with this data but the concept does have a consistent appeal [20,21]. The steady reduction of

nNOS gene expression with increased age in adult rat prostates supports the biologic plausibility of this theory [22]. The physiologic role of NOS/NO is not well characterized in the prostate, the bladder, and the act of urination. For a reduction of NOS/NO to explain a role in LUTS, a NOS-mediated prostatic smooth muscle relaxation must occur at a critical point in the voiding reex, or as part of normal compliance. Given that this hypothesis is based on a limited number of studies that depend largely on descriptive immunohistochemistry and Rt-PCR measures of gene expression, evidence for a NOS role in voiding is currently lacking. Circumstantial evidence in human and canine organ chamber studies demonstrating prostatic smooth muscle relaxation with exposure to NO donors only goes part way in explaining the role of NOS in LUTS with normal or dysfunctional voiding [23] (Fig. 3). This data, combined with in vitro models that demonstrate an anti-proliferative effect on human prostatic smooth muscle cells by NO donors (nitroprussideSNP), increased cell proliferation with NO antagonists, and a negative effect on the proliferation signal transduction pathway (protein kinase C) with SNP, give credence to this theory [24]. The LUTS-ED:NOS/NO theory is further supported by the characterization and functional relevance of cyclic nucleotide phosphodiesterase (PDE) isoenzymes of the human prostate. [25]. The most common PDEs noted in prostate tissue were PDE-type 4 and PDE-type 5. The functional relevance of these PDE isoenzymes is noted in the relaxing effect of nonspe-

Fig. 2. Proposed theory of pelvic loss of nitric oxide synthase (NOS) and nitric oxide (NO). Reduction of NOS/NO from various systemic disease results in increased smooth muscle cell (SMC) contractile forces at the bladder neck and prostatic urethra. Additionally, the reduced NOS/NO results in prostatic smooth muscle cell proliferation and increased outlet resistance. Both forces result in the worsening of LUTS (adapted from: [19]).

Fig. 3. Increase in prostatic smooth muscle relaxation when exposed to NO donors. Human (n = 12) and canine (n = 8) prostatic tissue strips were exposed to sodium nitroprusside, an exogenous source of nitric oxide. Sodium nitroprusside elicited a relaxation response relative to baseline tension. Results expressed as mean grams per square centimeter crosssectional area SE. (Adapted from: [23]).

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cic PDE inhibitors (papaverine) as well the effect of specic PDE inhibitors (sildenal). Of more interest to this study is the recognition by Fawcett et al. in which Northern and RNA dot blots for PDE11A gene expression noted its presence in testes, skeletal muscle, and the prostate [26]. Type 11A protein abundance was greatest in the prostate compared to the other these organs. The role of prostatic PDE11A is unknown, but its relatively low abundance in the smooth muscle makes its pivotal role in the LUTS-ED relationship less likely. The concept that PDE-5 inhibitors could be utilized to improve LUTS is provocative. Several studies have attempted to assess the relationship between ED and LUTS by treating one symptom (i.e. ED) and measuring the impact on the other disease (i.e. LUTS). Investigators treating patients with both ED and LUTS using sildenal noted a lower IPSS. Those with a lower IPSS at baseline had a better response to ED therapy [27]. Most interesting, they also noted that treatment with sildenal appeared to improve urinary symptom scores. The authors reported no relationship between ED and LUTS. Whether this lack of relationship relates to the modest sample size, lack of blinding or other unrecognized factors is not known. In a similar vein, Hopps et al. reported mild improvements in LUTS when treated with on-demand PDE-5 therapy (sildenal) for ED in men with concomitant LUTS [28]. Although this pilot study was not blinded or placebo controlled, it does suggest a common mechanism and/or therapy for this LUTS-ED symptom complex. Clearly, a well-designed and controlled study is mandatory to further elucidate the relationship between these two important diseases. Limited pilot studies demonstrating an impact of sildenal on both ED and LUTS supports the NOS/NO theory, but enthusiasm must be tempered by the open-label noncontrolled nature of these single centered studies. 3.2. Autonomic hyperactivity and metabolic syndrome effects on LUTS, prostate growth and ED Our lab rst identied the autonomic nervous systems (ANS) control of prostate growth and differentiation. The ANS provides an environment that induces rat prostatic growth while its absence results in regression of the gland [29]. These ndings were supported by additional animal studies using a strain of rats (spontaneously hypertensive rats-SHR) that develop increased autonomic activity, prostate hyperplasia and erectile dysfunction [3032]. The improvement in erectile function noted in this model, after brief aggressive treatment of the hypertension, may be related to improvement in structurally based vascular

Fig. 4. Proposed theory of autonomic hyperactivity of LUTS and ED. Increased autonomic hyperactivity resulting from increased BMI, hyperinsulinemia, increased age, and decreased physical activity. This increased sympathetic tone effects BPH growth, LUTS and vasocontrictive forces that results in ED. (Adapted from: [34,19]).

resistance within the penis and the decrease in responsiveness of alpha1-adrenoceptor mediated erectolytic signaling. The autonomic hyperactivity, or metabolic syndrome, explanation is attractive because it links established clinical physiologic ndings of LUTS, BPH and ED with established basic science evidence [19] (Fig. 4). It remains unclear whether the increase in LUTS or ED is the result of a central increase in sensitivity to peripheral signals, or a consequence of an alteration in the function of the bladder/penis itself that generates increased central activation. The various animal models suggesting a role between autonomic nervous system (ANS) overactivity and increased prostate growth is further supported by epidemiological investigations linking the clinical diagnosis of BPH with increased autonomic tone [33]. Given that ANS translates mood into objective physiology (e.g. fear leads to dry mouth and tachycardia), it is very possible that hyperactivity of the ANS could adversely impact LUTS and erectile function. We recently reported the quantitative relation between ANS tone and the subjective experience of dysfunctional voiding [34]. Our recent evidence has shown that ANS hyperactivity is signicantly associated with the most commonly employed measures of LUTS (AUA symptom score and BPH Impact Index score). Autonomic hyperactivity, or increased ANS activity, is signicantly associated with the signs and symptoms of BPH. This has implications for understanding the pathophysiology of BPH, prostate growth, ED and BPH progression. The ANS is well known to be intimately involved in the mechanisms of voiding. Also, the magnitude of increase in serum NE after provocative neurologic stress (tilt test) signicantly correlates with prostate

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size (p < 0.001). The relationship between ANS hyperactivity and LUTS still persists after controlling for extrinsic inuences on ANS activity (BMI, insulin level, physical inactivity and age). These ndings may have important implications concerning the pathophysiological mechanisms underlying or inuencing LUTS and ED (Fig. 4). The autonomic hyperactivity theory of LUTS proposes that the ANS acts as a modulator of voiding symptoms and/or ED about their anatomically or physiologically designated baseline. This modulation of LUTS and ED works under the inuence of central, mood related factors. Similarly, autonomic hyperactivity or increased sympathetic tone is a known regulator of SM relaxation and penile reactivity. 3.3. Alternate Pathway mechanism: Rho-kinase activation/endothelin activity Several investigators have suggested that the socalled Alternate Pathways of SM relaxation and contraction may be responsible for the relationship between ED and bladder outlet obstruction (BOO) [19]. Chang et al. reported that corpus cavernosum SM from rabbits with partial bladder outlet obstruction showed a broad range of molecular and functional differences versus controls. These changes include increased penile SMC contractility, reduced relaxation, and modest alterations in total SM myosin, decreased innervation and increased smooth muscle bundle size [35]. The suggestion that BOO induces ED via an upregulation of Rho kinase in the penis has experimental merit. There is also a possibility that a multisystem dysfunction of Rho kinase exists and leads to both ED and LUTS. This is supported by evidence of Rho kinase dysfunction in the bladder following BOO [36]. Although not entirely clear whether this putative mechanism is causative or even exclusive of the abovementioned possibilities, its inclusion here is well justied. 3.4. Pelvic atherosclerosis as a mechanism for LUTS and ED An additional hypothesis causatively linking ED and LUTS is diffuse atherosclerosis of prostate, penis and bladder [37]. The proponent theorized that the risks for ED (hypertension, smoking, hypercholesterolemia and diabetes mellitus) also impacts LUTS and BPH. Animal models mimicking pelvic ischemia and hypercholesterolemia show a striking similarity in the smooth muscle alterations of the detrusor and corpora. There are several potential mechanisms for this, including hypoxia-induced over-expression of TGFb1 and altered prostanoid production. Understanding how this

Fig. 5. The risk factors for ED impact pelvic arterial blood ow resulting in loss of smooth muscle from bladder, detrusor and resultant in loss of bladder compliance. At the same time there is an effect on prostate brosis with resultant increase in urethral resistance. This results in LUTS. A similar process occurring in the penis results in smooth muscle loss in the penis with resultant ED. (Adapted from: [37]).

could adversely effect penile SM function is consistent with our current understanding of the penile pro-erectile response. The relevant mechanism explaining the bladder effects may be very similar to those associated with bladder ischemia (bladder outlet obstruction or pelvic vascular disease) inducing the same SM loss with replacement of collagen deposition and brosis as well as loss of compliance, hyperactivity and impaired contractility. (Fig. 5). This theory is compatible with other proposed theories (NOS/NO, metabolic syndrome, etc.) as pelvic ischemia may induce ANS hyperactivity, reduce NOS expression, and upregulate Rho kinase.

4. Impact on erectile dysfunction of alpha-blockers If LUTS and ED are causally linked, then treatment of LUTS with alpha-blockers may improve ED. What is the impact on erectile function when patients are treated with alpha-blockers? Alpha-blockers might contribute to the improvement of ED by altering the balance of penile vasoconstrictive and vasorelaxant forces in favor of the proerectile mechanisms. On the contrary, a1blockers with excessive hypotensive effects may be anti-erectile by reducing penile lling pressure. Oral a-receptor antagonists exert their effects by blocking the actions of norepinephrine at a1-adrenoceptors on cavernosal smooth muscle cells. Norepinephrine released from sympathetic nerve terminals ordinarily acts at postjunctional a1-receptors to produce smooth muscle

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contraction and detumescence, and is a likely candidate for a mechanism of action in the autonomic hyperactivity model. This neurotransmitter also acts at presynaptic a2-receptors on the ends of nerve terminals to reduce norepinephrine release. It is not likely that the alphablockers used for LUTS would affect the presynaptic a2receptors given the selectivity prole [38]. There are few reports detailing the impact of alpha-blocker use on ED improvement. Lukacs et al. reported patients self-perceived sense of sexual satisfaction as signicantly improved from baseline, with the degree of improvement correlating with age while being treated with alfuzosin [39]. The biggest improvement was noted in middle-aged men with moderate to severe LUTS at baseline. Similarly, the effect of a once a day, and following one year of treatment [40]. Comparison of mean weighted scores using the DAN-PSS sex score showed improvement of the EF domain by 36% over baseline (2.5(2.2) decreased 0.9(2.0), p < 0.001). Improvement was most marked in those with the most severe LUTS. The open labeled nature of these latter two studies are problematic. Because the addition of alpha-blockers may have a benecial effect in patients with ED, Kaplan et al. investigated the synergistic effects of doxazosin and intra-cavernosal therapy (ICI) in those for whom ICI alone failed to induce an erection. Overall, 22 (57.9%) of 38 patients with the combined regimen had a signicant (more than 60% improvement in IIEF) therapeutic response. The synergistic effects of vascular dilation and blockade of sympathetic inhibition is one explanation for this response [41]. In general, the improvement of ED in conjunction with alpha-blocker treatment is not as robustly effected as the improvement of LUTS.

5. Conclusions LUTS and sexual dysfunction are highly prevalent in aging men. Both conditions are also signicant

contributors to overall quality of life. New data has emerged to indicate potential links in epidemiological, physiologic, pathophysiologic and treatment aspects of these two entities. There are numerous publications within the past 10 years based on sophisticated community and clinical based data suggesting a strong and consistent association between LUTS and ED. The association is supported by the consistent linear relationship of more severe LUTS with more severe ED. A signicant association between LUTS, sexual satisfaction, ow rates and prostate volume further supports this relationship. The link between ED and LUTS has biologic plausibility given the four leading theories of how these diseases interrelate. These explanations fall into four theories each with a variable amount of supporting data. These include: (1) NOS/NO levels decreased or altered in the prostate and penile smooth muscle, (2) Autonomic hyperactivity effects on LUTS, prostate growth and ED., (3) increased Rho-kinase activation/endothelin activity, and (4) prostate and penile ischemia. Several studies have attempted to assess the relationship between ED and LUTS by treating one symptom (i.e. ED) and measuring the impact on the other disease (i.e. LUTS). This positive effect appears to effect outcomes regardless of which disease is treated primarily, thus suggesting a common etiology or mechanism. The patient bother attributable to this affect is less clear. With the exception of tamsulosin, a1-blockers are associated with a low rate of sexual dysfunction. If the association between ED and LUTS was causally related, why should urologists worry about SD in men with LUTS in the rst place? This relationship is important because (1) additional information on risk factors for either disease could be important for patient screening, (2) there is an increasing pool of affected men given the age demographics in many societies, (3) sexual problems related to LUTS are not necessarily limited to ED and (4) many currently available LUTS treatments (medical and surgical) affect sexual function.

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