Erectile Dysfunction and Lower Urinary Tract Symptoms

EUF-412; No. of Pages 12 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X

available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus

Review – Benign Prostatic Hyperplasia

Erectile Dysfunction and Lower Urinary Tract Symptoms Cosimo De Nunzio a,*, Claus G. Roehrborn b, Karl-Erik Andersson c, Kevin T. McVary d a

Department of Urology, Sant’Andrea Hospital, “La Sapienza” University, Roma, Italy; b Department of Urology, University of Texas Southwestern Medical

Center, Dallas, TX, USA; c Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark; d Southern Illinois University School of Medicine, Springfield, IL, USA

Article info Associate Editor: Christian Gratzke

Keywords: Prostate Lower urinary tract symptoms Erectile dysfunction Diagnosis Outcome Treatment

Abstract Context: Lower urinary tract symptoms (LUTSs) and erectile dysfunction (ED) are substantial health concerns with a significant impact on the overall male quality of life. Objective: To evaluate the available evidence of the association between LUTSs and ED in patients with benign prostatic hyperplasia (BPH), and discuss possible clinical implications for the management of LUTS/BPH. Evidence acquisition: A systematic review of the existing literature published between 1997 and June 2017 and available in the Medline, Scopus, and Web of Science databases was conducted using both the Medical Subject Heading (MeSH) and free-text protocols. The MeSH search was conducted by combining the following terms: “lower urinary tract symptoms,” “LUTS,” “benign prostatic hyperplasia,” “BPH,” “erectile dysfunction,” “sexual dysfunction,” “BPE,” and “benign prostatic enlargement.” The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. Evidence synthesis: Several community-based studies in different geographical areas have provided strong evidence of an age-independent association between LUTSs and ED. Several biological mechanisms have been proposed to explain this association, but further research is required to better understand the molecular pathways involved. It is necessary to evaluate the possible impact of the metabolic syndrome treatment on LUTS/ED management. Considering the possible relationship between LUTSs and ED, their impact on the quality of life, and the possible adverse effects associated with LUTS medical treatment, clinicians should always evaluate ED in patients with LUTSs and take the opportunity to evaluate patients reporting ED for LUTSs. Conclusions: Data from the peer-reviewed literature suggest the existence of an association between LUTS/BPH and ED, although their casual relationship has not been established yet. Emerging data also suggest that pathophysiological mechanisms involved in the metabolic syndrome are key factors in both disorders. Considering the association, it is also recommended that men presenting with LUTSs or ED should be evaluated for both disorders. A better understanding of the molecular pathways behind this association may also help identify new possible targets and develop novel therapeutic approaches to manage LUTSs and ED. Patient summary: In this manuscript, we report on all the available evidence linking erectile dysfunction and lower urinary tract symptoms. Our findings suggest the existence of a strong relationship between these two conditions. On the basis of these findings, we recommend that clinicians always explore both conditions in male patients presenting with either of symptoms. © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Sant’Andrea Hospital, “La Sapienza” University, Via di Grottarossa 1035-00189, Rome, Italy. Tel.: +390633777716; Fax: +390633775059. E-mail address: [email protected] (C. De Nunzio).

https://doi.org/10.1016/j.euf.2017.11.004 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: De Nunzio C, et al. Erectile Dysfunction and Lower Urinary Tract Symptoms. Eur Urol Focus (2017), https://doi.org/10.1016/j.euf.2017.11.004

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1.

Introduction

Lower urinary tract symptoms (LUTSs) and erectile dysfunction (ED) are significant health concerns that will become even more serious in the next few years because of the increase in population aging. Moreover, both conditions have—a significant impact on male quality of life [1]. LUTSs, including voiding, storage, and postmicturition symptoms, are common in aging individuals and benign prostatic hyperplasia (BPH) is considered the primary cause in men over 50 yr [2]. Autopsy prevalence of histological BPH is approximately 8% in men in their 40s, 50% in those in their 50s, 70% in those in their 60s, and about 90% in the octogenarians [3]. ED, defined as persistent inability to achieve and maintain an erection sufficient for satisfactory sexual performance, is generally considered the result of para-aging factors [1,4]. In 1994, the Massachusetts Male Aging Study (MMAS) was the first population-based study to evaluate ED prevalence in aging men [5]. Its results showed an overall ED prevalence of 52%, with about 35% revealing moderate/severe ED [5]. Moreover, ED prevalence was age dependent, increasing from 5% for men in their 40s to 15% for those aged 70 yr. As well, several age-independent comorbidities such as diabetes, depression, hypertension, and heart disease were found to be significantly associated with ED prevalence. Based on these data, it was estimated that in 2025 ED will affect more than 200 million men worldwide [1,6]. Although the MMAS study did not evaluate LUTSs as a possible predictor variable for ED [5], since then several large-scale epidemiological studies in different populations have demonstrated a relationship between these two conditions in aging men, which is, however, independent of the effects of age or other comorbidities [1,6,7]. Although the molecular and pathological pathways potentially linking LUTSs and ED have not been clearly defined, the possible association has resulted in new possible approaches to the evaluation of both disorders and in the identification of new possible targets for their prevention and treatment [8,9]. Medical treatment of LUTS/BPH may also have a significant impact on erectile function [10–12]. In addition, specific drug interactions and the possibility that LUTS/BPH medical therapy may affect erectile function are also causes of concern in today’s clinical practice [10–12]. The aim of our review is to provide an update on the association between LUTS/BPH and ED, with an analysis of the possible pathophysiological mechanisms that may be involved in this association. We will also discuss the potential implications of this evidence for LUTS/ED diagnosis and treatment, and suggest directions for future research. 2.

Evidence acquisition

A systematic review of the literature published between 1997 and June 2017 was performed using both the Medical Subject Heading (MeSH) and free-text protocols as entries in Medline, Scopus, and Web of Science databases. The

MeSH search was conducted by combining the following terms: “lower urinary tract symptoms,” “LUTS,” “benign prostatic hyperplasia,” “BPH,” “erectile dysfunction,” “sexual dysfunction,” “BPE,” and “benign prostatic enlargement.” The searches on Embase and Web of Science were conducted using only the free-text protocol, with the same key words. In addition; the references contained in the reference sections of the selected/retrieved publications were also added to the list. The use of the English language was not a specific parameter; however; only English-language publications were considered. Evidence was not limited to human data; data from animal studies were also included in this review. The title and abstract of each article were reviewed for their appropriateness and relevance with regard to the relationship between ED and LUTSs. In particular; we have selected articles focusing on the possible relationship between ED and LUTSs and addressing potential implications for treatment. In case of availability of more than one article sharing the same information; the most recently published one was used for this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines have been followed. A flow chart showing the selection process is shown in Figure 1. The initial list of the selected papers was further enriched with titles suggested by a pool of international experts in the topic, who also acted as coauthors of the present review. 3.

Evidence synthesis

3.1.

LUTSs and ED: epidemiological evidence

Although the casual relationship between LUTSs and ED has not been established yet, several community-based studies conducted in different geographical areas (including Europe, Asia, and America) and with different tools for assessing ED and LUTSs have provided strong evidence of an ageindependent association between these two disorders (Table 1). The landmark study of their association was the MultiNational Survey of the Ageing Male-7 (MSAM-7), which was conducted in the USA and six European countries (France, Germany, Italy, the Netherlands, Spain, and the UK) on 12 815 men, representative of the population aged 50–80 yr in each country [7]. Patients were evaluated using the International Prostatic Symptom Score (IPSS), International Index of Erectile Function (IIEF), and Danish Prostate Symptom Score. The survey reported that most men aged >50 yr were sexually active but with a decrease in the number of sexual intercourse with LUTS severity (ranging from with 7.5 per month in men in their 60s to 3.2 per month in men in their 80s). ED was reported by almost 49% of the overall sample, and the IIEF score was strongly related to LUTS severity: in the cohort aged 50–59 yr, the mean IIEF was 22.3 in patients with no LUTS and 14.9 in patients with severe LUTS; in the cohort aged 60–69 yr, it was 19.2 and 12.4, respectively; and in the cohort aged 70–79 yr, it was 15.3 and 7.5, respectively. LUTS severity resulted in the

Please cite this article in press as: De Nunzio C, et al. Erectile Dysfunction and Lower Urinary Tract Symptoms. Eur Urol Focus (2017), https://doi.org/10.1016/j.euf.2017.11.004

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Records idenfied through database searching (n = 1379 )

3

Addional records idenfied through other sources (n = 52)

Records aer duplicates removed (n = 1392)

Records screened (n = 1392 )

Full-text arcles assessed for eligibility (n = 80)

Records excluded because they did not meet our inclusion criteria (n = 1312 )

Full-text arcles excluded - Systemac reviews (n = 18) - Arcle not in english (n = 8) - Case reports (n = 2) - Others (n = 5)

Studies included in qualitave synthesis (n = 47 )

Studies included as addional references (n = 52 )

Fig. 1 – Flow diagram of the search results.

strongest predictor of ED with an odds ratio (OR) for severe versus mild of 8.9 (6.85–11.55), followed by diabetes (OR: 3.01; 2.60–3.49), cardiac disease (OR: 2.17; 1.92–2.46), hypertension (OR: 1.83; 1.66–2.01), and hyperlipidemia (OR: 1.57; 1.41–1.73) [7,13]. The UrEpik study, a population-based multinational study (the UK, the Netherlands, France, and Korea), investigated the association between LUTSs and ED in 4800 men. The overall prevalence of ED for men aged 40–79 yr, estimated as an ED score of 0–4, was 21.1% and it was significantly associated with age (p < 0.001) [14]. Once the ED score had been adjusted to age and country differences, it was apparent that men with diabetes (OR: 1.57; 1.09–2.25), high blood pressure (OR: 1.38, 1.09–1.75), and an IPSS of 8 (OR: 1.39, 1.10–1.74) were more likely to have ED [14]. In the Cologne Male Survey, Braun et al [6] evaluated the epidemiology of male sexuality in about 4500 German men aged 30–80 yr. Of the men, 96% (youngest age group) to 71.3% (oldest group) reported regular sexual activity. The overall prevalence of ED was 19.2%, with a steep age-related increase (from 2.3% to 53.4%) and a strong association with high blood pressure, diabetes, pelvic surgery, and LUTSs. In particular, the prevalence of LUTSs was 72% in men with ED versus 38% in those without ED [6]. More recently, the Boston Area Community Health survey evaluated about 5500 community-dwelling

residents aged 30–79 yr using the IPSS and IIEF questionnaires. The overall prevalence of sexual problems was about 20% in men. Men with an IPSS of 8 were more likely to be sexually inactive in the 4 wk preceding the survey (OR: 2.09; 1.46–2.99) and to have decreased sexual desire (OR: 1.79; 1.17–2.75) or ED (OR: 1.99; 1.36–2.91). In multivariate logistic regression models for sexual activity with a partner, LUTSs (OR: 0.68; 0.46–0.99) and prostatitis (OR: 0.28; 0.16–0.50) were significantly associated with sexual inactivity [15]. The possible association between voiding or storage LUTSs and ED has also been investigated, although with controversial results [2]. In a 2004 health screening study of 2084 Japanese men, the prevalence of moderate to severe ED increased from 13.4% among those younger than 40 yr to 63.1% among those aged 60 yr. The severity of ED was significantly associated with moderate to severe LUTSs (age-adjusted OR: 1.52), specifically in the urgency (OR = 1.75) and nocturia (OR = 1.36) domains, and for those with diabetes mellitus (OR = 2.54) and coronary artery disease (OR = 8.04) [16]. In a health-screening study of about 3000 Austrian men aged 20–80 yr, conducted in 2004, the prevalence of LUTSs was 84% and that of ED was 32%, with both disorders significantly related to age [2,17]. In multivariable analysis, controlled for age, diabetes, hypertension,

Please cite this article in press as: De Nunzio C, et al. Erectile Dysfunction and Lower Urinary Tract Symptoms. Eur Urol Focus (2017), https://doi.org/10.1016/j.euf.2017.11.004

Authors (year)

Study design

Country

Age (yr) Cohort Size Outcome/comments

Kunelius et al (1998) [57] Braun et al (2000) [6]

Prospective cohort Cologne male survey

Finland Germany

69 30–80

155 4000

Blanker et al (2001) [58]

Krimpen community cohort

Netherlands

50–78

1688

Leliefeld et al (2002) [59] Moreira et al (2002) [60] Boyle et al (2003) [14]

Longitudinal multicenter study Brazilian cohort study UrEpik study: cross sectional

Netherlands 66 Brazil 40–70 Netherlands, France, UK, Korea 40–79

670 654 4800

Vallancien et al (2003) [61]

Cross-sectional European survey

Europe

36–92

1274

Rosen et al (2003) [7]

50–80

12 815

Chung et al (2004) [62]

Multinational survey of the aging male USA, UK, France, Germany, Netherlands, Spain Cross-sectional community survey USA

40–79

2115

Ponholzer et al (2004) [17]

Austrian study

Austria

20–80

2858

Hansen (2004) [63]

Danish study (population based)

Denmark

40–65

3442

Elliott et al (2004) [51]

US Veterans Administration survey

USA

68

234

Terai et al (2004) [16]

Japanese cross-sectional study

Japan

68

2084

McVary (2004) [64]

MTOPS secondary analysis

USA

62

3000

Sak et al (2004) [65]

BPH clinic based

UK

19–91

696

Shiri et al (2005) [66]

Finish cohort study (population based) Finland

50–70

1716

El-Sakka (2005) [67]

Clinic based

Saudi Arabia

54

374

Li et al (2005) [68] Paick et al (2005) [69] Liu et al (2006) [70] Reggio et al (2007) [71]

Cross sectional PLESS study and questionnaires Voluntary screening Prospective screening program

Asia USA Taiwan Brazil

50–80 45–78 60 58

1155 2981 141 1267

Brookes et al (2008) [72]

BACH Study Subset Analysis

UK

30–79

2301

Rhoden et al (2008) [73] Ikuerowo et al (2008) [74] Mehraban et al (2008) [75]

Cross sectional Prospective cohort Prospective

Brazil Nigeria Iran

40–81 65 64

192 132 357

Ozayar et al (2008) [76]

Cross sectional

Turkey

66

453

Li et al (2008) [77] Khoo et al (2008) [78] Mondul et al (2008) [79]

Multinational Cross sectional Prospective cohort

Asia Malaysia USA

40–88 58 40–75

994 351 51 529

In LUTS men, 74% had ED LUTSs in 72.2% of patients with ED vs 37.7% without ED; prevalence risk highly significant; odds ratio was 2.11, even after controlling for age ED RR: 1.8–7.5 for increasing urinary complaints; risk of ED greater with LUTSs than with smoking or cardiac symptoms In LUTS men 40% had ED; LUTS medical treatment did not alter erectile function Patients with moderate/severe LUTSs are at increased risk of ED (OR: 1.83–3.60) IPSS > 7 showed an OR of 1.39 of having ED in a weighted multiple regression model, including age; similar ORs for heart attack, hypertension, and smoking 55% of patients with mild LUTSs had ED vs 70% with severe LUTSs; patients with severe LUTSs are at increased risk of ED (RR: 1.94 [1.09–3.46]) RR for ED: 1.9–7.6; IPSS correlated with IIEF and sexual activity E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X

LUTSs correlated with ED; sexual satisfaction and libido inversely correlated with LUTSs; Spearman coefficient: 0.21 to 0.31 RR for ED in men with LUTSs (IPSS > 7) was 2.2; controlled for age, vascular risk factors, and predominance of obstructive or irritative symptoms LUTSs predicted ED after multiple regression; RR: 2.3–3.4; overall LUTS prevalence 39% and ED prevalence 29% ED correlated with obstructive LUTSs after controlling for age, depression, hypertension, and coronary artery disease on multivariate analysis (correlation coefficient: 0.1) RR: 1.5; ED correlated with LUTSs (IIEF vs IPSS); correlation remained after controlling for age (correlation = 0.105) AUASS correlated with ED and other domains; included correlation with maximum flow rate (multivariate analysis controlled for confounders) An inverse correlation exists between LUTSs and ED (coefficient = 0.15); IPSS could not reach the level of a risk factor on multivariate analysis Patients with moderate–severe LUTSs are at increased risk of ED in a multivariate model with OR 2.6–4.4 In ED men, 77% have LUTSs; patients with LUTSs are at increased risk of ED; patients with LUTSs have poorer penile vascular parameters In LUTS men, 76% had ED; OR for ED: 3.17–4 compared with no LUTSs 2% increase in ED risk for unit increase in AUASS In LUTS men, 67% had ED; OR for ED 3.27 compared with mild LUTSs Patients with LUTSs are at increased risk of ED; RR: 2.72 (2.08–3.57) age adjusted; there is a negative correlation between LUTSs and ED (coefficient: 0.33) Multivariable regression model of ED found strong association of AUASS and ED independent of age; nocturia, incontinence, and prostatitis strongest factors; no differences found across race or ethnicity Patients with LUTSs are at increased risk of ED; OR:3.45–3.72, risk for ED In LUTS men, 71% had ED; LUTSs and ED are correlated In LUTS men, 68% had ED; LUTSs are inversely correlated with ED (coefficient = 0.655); LUTS represents a risk factor for ED in multivariable analysis In LUTS men, 78% had ED; OR for ED 28.7; IPSS negatively correlated with IIEF (rho = 0.62) In LUTS men, 80% had ED In ED men, 66% had LUTSs Patients with moderate/severe LUTS are at increased risk of ED (RR: 1.22–2.34)

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Table 1 – Relevant clinical studies of the relationship between LUTSs and ED.

EUF-412; No. of Pages 12

Authors (year)

Study design

Country

Age (yr) Cohort Size Outcome/comments

Rosen et al (2009) [80]

BPH registry

US

64  10 6924

Demir et al (2009) [81] Jung et al (2009) [82] Wong et al (2009) [83]

Prospective, cross sectional Prospective cohort Prospective cohort

Turkey South Korea China

60 62.04 72

190 365 1281

Tsai et al (2010) [84]

Prospective cohort

Taiwan

60

339

Nasir et al (2011) [85] Lee et al (2013) [86]

Prospective cohort Prospective cohort

Pakistan South Korea

60 49

585 2853

Aktas et al (2011) [87] Nakamura et al (2012) [88] Dutkiewicz et al (2012) [89] Song et al (2013) [90]

Prospective cohort Prospective cohort Retrospective cohort Cross-sectional study

Turkey Japan Poland Korea

61 65 NA 64

106 220 4354 124

Brazil USA Japan China Mexico Russia

61 62 65 64 48.6 42

898 672 258 1644 1041 1083

Barbosa et al (2013) [91] Prospective cohort Fwu et al (2015) [92] MTOPS study prospective cohort Shigehara et al (2014) [93] Prospective cohort Song et al (2014) [94] Cross-sectional study Gonzalez-Sanchez et al (2016) [95] MexiLUTS: epidemiological study Korneyev et al (2016) [96] Cross sectional

LUTS severity and bother correlated significantly with ED (R = 0.108 and R = 0.072, respectively) OR for severe LUTSs 2.3 compared with no ED A negative correlation between LUTSs and ED (coefficient = 0.235; p = 0.001) Patients with LUTSs are at increased risk of ED (OR = 2.00–4.07); LUTSs were the only independent predictor of ED IPSS (p < 0.001 and p = 0.013) as significantly associated with ED after controlling other comorbidities; in a further age-adjusted multiple regression analysis, our results showed that irritative symptoms (p = 0.042) have a more significant association with ED than obstructive symptoms (p = 0.101) There is a negative correlation between LUTSs and ED (coefficient = 0.336, p = 0.001) A negative correlation exists between LUTSs and ED (correlation coefficient = 0.311, p = 0.001) IN LUTS men, 40% have ED; no significant correlation between LUTSs and ED There is a negative correlation between LUTSs and ED (coefficient = 0.302, p = 0.001) In LUTS men, 80.4% had ED (IIEF < 15) There is a negative correlation between LUTSs and ED (coefficient = 0.260, p = 0.001) in patients with DMII In LUTS men, 50% had ED (OR = 1.99 [1.47–2.69]) Progression of LUTSs does not affect sexual function There is a negative correlation between LUTSs and ED (coefficient = 0.331, p = 0.001) There is a negative correlation between LUTSs and ED (coefficient = 0.335, p = 0.001) Men with severe LUTSs are at increased risk of ED (HR: 1.630 [1.205–2.206], p = 0.002) In LUTS men, 76% had ED; OR for ED: 4.10 (3.16–5.33)

AUASS = American Urological Association Symptom Score; BACH = Boston Area Community Health; BPH = benign prostatic hyperplasia; ED = erectile dysfunction; DMII = diabetes mellitus type II; IIEF = International Index of Erectile Function; IPSS = International Prostatic Symptom Score; LUTS = lower urinary tract symptom; MTOPS = Medical Therapy of Prostatic Symptoms; NA = not available; PLESS = Proscar Long-term Efficacy and Safety Study; OR = odds ratio; RR = risk ratio.

E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X

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Table 1 (Continued )

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hyperlipidemia, and several life factors, the OR values for the presence of ED were 2.2 (1.8–2.8) for LUTSs (defined as IPSS 7), 2.0 (1.7–2.4) for voiding symptoms, 1.4 (1.1–1.7) for nocturia (>2), and 2.5 (2.0–3.1) for the LUTS bother score. Several general population or BPH/ED clinic-based studies have demonstrated a significant association between LUTSs and ED. This association is independent of age and numerous comorbidities including metabolic syndrome (MetS), cardiovascular diseases (CVDs), and hormonal changes. However, a causal relationship between LUTSs and ED cannot be established considering that the underlying mechanisms behind this association remain to be determined and several questions are still unanswered [13]. 3.2.

LUTSs and ED: common biological mechanisms

Although there is a link between LUTSs and ED from an epidemiological standpoint, a biological mechanism needs to be found to explain this relationship with something more than a mere association. In the last few years, several possible pathophysiological mechanisms have been discussed, including NOS/NO (the nitric oxide synthase) and the Rho-kinase activation pathways, autonomic hyperactivity, pelvic ischemia and microvascular dysfunction, inflammatory pathways, sex hormones, and psychological factors [1,18–20]. These various putative biological mechanisms do not need to be independent or mutually exclusive to have validity. 3.2.1.

NOS/NO and RHO-kinase mechanisms

The role of NO in the prostate and the penis have deeply been investigated, particularly after following the development of phosphodiesterase-5 (PDE-5) inhibitors, which are now the first-line therapy for ED. NO is synthesized by NOS through the catalytic conversion of L-arginine to L-citrulline. There are three NOS isoforms in mammals: neuronal (nNOS), endothelial (eNOS), and inducible. Particularly in the penis, neurogenic NO is considered the main factor responsible for a rapid relaxation of corpus cavernosum smooth muscle and vasculature with a subsequent increase of the blood flow into the cavernosal tissue. Endothelial NO is thought to play a key role in the maintenance of the relaxed state [13,21]. NO activates soluble guanyl cyclase, which catalyzes the synthesis of cyclic guanosine monophosphate (cGMP). Increased level of intracellular cGMP induces the activation of protein kinase G (PKG), which inhibits calcium release with subsequent smooth muscle relaxation. Cyclic GMP phosphodiesterase terminates the cGMP signal by catalyzing the hydrolysis of cGMP [22]. Several conditions such as ageing, smoking, and MetS can cause circulatory changes in penile tissue with an imbalance in the NO/cGMP/PKG pathway, decreasing NO bioavailability resulting in ED. NO is also present in the human prostate, where it modulates smooth muscle tone. In particular, immunohistochemistry shows the presence of dense nitrinergic innervation of glandular epithelium, fibromuscular stroma, and blood vessel in the normal human prostate. NOS/NO levels as well as nitrinergic innervation are reduced in the transitional zone of human hyperplastic prostate, and

these changes may result in an increased smooth muscle cell contractile force at the bladder neck and prostatic urethra leading to urinary symptoms [23]. The urothelium also expresses and releases NO in response to various stimuli; it has also been hypothesized that eNOS regulates local vascular perfusion, while nNOS controls smooth muscle tone and glandular activity [24]. In mice lacking cGMP kinase type I, a cGMP analog and a NO donor relaxed wild-type urethra, but had only marginal effect in the cGMP-deficient urethra [25]. Bladder strips from cGKI2/2 mice responded normally to electrical field stimulation and carbachol, but not to a cGMP analog. In vivo, the cGKI-deficient mice showed bladder hyperactivity characterized by decreased intercontraction intervals and nonvoiding bladder contractions. The loss of cGKI abolishes NO–cGMP–dependent relaxations of urethral smooth muscle and results in hyperactive voiding [25]. The prevalence of PDE isozymes in the human prostate, urethra, and bladder wall also supports this theory and represents the background for the recent management of LUTSs in men using PDE-5 inhibitors [19,24]. Rho kinase inhibits myosin light chain phosphatase and phosphorylates the myosin light chain, promoting smooth muscle contraction through a major calcium-sensitizing mechanism [26]. It regulates the tonic contraction of the cavernosal smooth muscle and the normal flaccid state of the penis [27–29]. Inhibition of Rho kinase acts synergistically with the NO pathway to promote erection, decreases human and rat prostatic smooth muscle cell proliferation, and reduces adrenergic contractions in rat prostatic tissue. Conversely, an increase in Rho-kinase activity and a consequent increase in calcium sensitivity result in contraction of the smooth muscle of unstimulated prostates, of the detrusor, or of the corpus cavernosum smooth muscle in rabbits with bladder outlet obstruction, and in diabetes or hypertension [13,30,31]. In men with LUTSs, a-adrenoceptors are upregulated, and chronic exposure to a-adrenoceptor agonists stimulates the Rho-kinase pathway with resulting increased tonic smooth muscle contraction impacting detrusor muscle relaxation and possibly contributing to LUTS development [31]. Although the molecular mechanisms behind the NO and Rho-kinase pathways are not completely understood, intracellular smooth muscle calcium homeostasis seems to play a key role in the normal erectile and voiding functions. Significant changes in these pathways are involved in LUTS and ED pathogenesis. 3.2.2.

MetS, autonomic hyperactivity, and pelvic ischemia

The MetS, a worldwide epidemic complex disorder, describes the combination or clustering of several metabolic abnormalities, including central obesity, dyslipidemia, hypertension, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance [32], all risk factors for CVD [33]. Recently, increasing evidence from several clinical studies has revealed a possible positive relationship between MetS and its components, and the occurrence and progression of LUTSs and ED [9,13]. Although insulin resistance and obesity are considered the core of the pathophysiology of MetS, other factors such as atherogenic

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Fig. 2 – Possible relationship between LUTS/BPH and obesity. BPH = benign prostatic hyperplasia; LUTS = lower urinary tract symptom.

dyslipidemia, deregulations of the hypothalamic–pituitary– adrenal axis, proinflammatory state, and cellular oxidative stress can also be involved in its pathogenesis and potential interactions. Central obesity, considered an early step in the development and progression of MetS, has been associated with LUTS/ED. Visceral adipose tissue secretes various bioactive substances known as adipocytokines, which can induce directly an increased sympathetic tone and have proinflammatory and proatherogenic effects. Circulating levels of cytokines including resistin, leptin, tumor necrosis factor alpha (TNFa), and interleukin-6 (IL-6); C-reactive protein; fibrinogen; plasminogen activator inhibitor; and AP-1 transcription factors are normally increased in obese patients and in patients with diabetes mellitus type 2 [34] (Fig. 2). These proteins are known to regulate innate immune and inflammatory responses and induce proliferation upon upstream activation by growth factors and stress signals. They may represent a novel molecular etiology for LUTS/ BPH development. On the contrary, adiponectin, a circulating tissue-specific hormone, is lower in individuals with visceral fat accumulation. A decrease in adiponectin, which is involved in glucose metabolism and inhibits monocyte adhesion and macrophage transformation to foam cells within the vascular wall, is associated with insulin resistance and endothelial dysfunction, both of which are involved in the pathogenesis of LUTSs and ED. Several studies have suggested that insulin resistance with secondary hyperinsulinemia is associated with BPH/ LUTS as well as ED (Fig. 3). Hyperinsulinemia is associated Hyperinsulinemia Age

Obesity-HWR-BMI Calorie intake

Increased sympathetic tone

Physical inactivity BPH growth Erectile dysfunction

7

with an increased autonomous sympathetic nervous system (ANS) activity and may contribute to increased enlargement. McVary et al [35] clearly showed in 2005 that ANS hyperactivity, evaluated by measuring plasma norepinephrine, plasma epinephrine, heart rate, blood pressure, and 24-h urinary catecholamine, is significantly associated with LUTSs and that the magnitude of the serum norepinephrine increases after tilt predicts prostate size. Hyperglycemia may play a role by increasing cytosolicfree calcium in smooth muscle cells and neural tissue, leading to sympathetic nervous system activation [35]. Sympathetic tone also plays a role in the pathophysiology of ED. Alpha-1A and alpha 1D receptors have been identified as the predominant alpha-1 adrenoceptor subtypes in penile corpora cavernosa [35]. The insulin-like growth factor (IGF) pathway may also contribute to the association between insulin resistance and BPH. Insulin presents a structural similarity to IGF-1 and can bind to its receptor, which may activate a complex pathway influencing prostate cell growth and proliferation [35]. These mechanisms, in addition to other pathways such as increased advanced end products of glycation or reactive oxygen species, could affect both LUTSs and ED. Studies using spontaneously hypertensive rats (SHRs), which develop an increased autonomic activity, further support these hypotheses. SHRs have an excess of sympathetic fibers innervating the lower urinary tract and penis. They exhibit detrusor overactivity [36] and reduced erectile function [37], and show an improvement of the erectile function after antihypertensive therapy [38]. One of the possible vascular consequences of MetS is pelvic ischemia, which may be caused by atherosclerotic reduction of blood flow to the lower part of the body and microvascular dysfunction in the bladder, prostate, and penis [20,21,38– 40]. Pelvic ischemia reduces NO signaling and upregulates the Rho-kinase pathway. In rabbits, chronic pelvic ischemia increases transforming growth factor (TGF)-beta1 expression in the bladder leading to fibrosis, smooth muscle atrophy, and reduced bladder compliance [41]. Similarly, chronic ischemia, which is associated with an increased production of TGFbeta1 [13], also results in stromal fibrosis, glandular cystic atrophy, and increases in smooth muscle contractility of the prostate and penile fibrosis in the corpora cavernosa. However, despite all these studies, the possible impact of pelvic ischemia and atherosclerosis on LUTS/ED is still investigational and should be further determined. All the risk factors included in MetS seem to be deeply involved in the pathogenesis of both LUTSs and ED (Fig. 4) through different and mostly unknown mechanisms. A recent meta-analysis of different clinical trials has also confirmed that MetS increases the risk of both LUTSs and ED [42,43]. The possibility of prevention or reversing of MetS through diet, physical activity, and medications opens new insights in LUTS and ED management, and suggests the importance of new studies evaluating the pathways behind these associations.

BPH voiding dysfunction

Fig. 3 – Possible relationship between autonomic hyperactivity, obesity, and ED/LUTS. BMI = body mass index; ED = erectile dysfunction; HWR = hip/waist ratio; LUTS = lower urinary tract symptom.

3.2.3.

Sex hormones

Prostate gland development and growth are dependent on an integral sex hormone signaling pathway, particularly

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Metabolic syndrome

Insulin resistance

High insulin level High IGF-1 level Lower IGF-

High cytosolic-free calcium in smooth muscle and neural

Hormone changes

Pelvic atherosclerosis

Inflammation

Increased estradiol Lower testosterone

Bladder, prostatic, and penis chronic ischemia

Cytokines release (IL-1, IL-2, IL-6, IL-8, IL-13, IL-17, IL-23, IL-18, TGFβ, IFNγ, FGF-2, PCR

cells/tiss

Sympathetic nervous system activation

Reduction in NO signal Rho-kinase activation

Increase in prostate smooth muscle tone

Increased in cavernosal muscle tone

ED and LUTS/BPH

Fig. 4 – Possible biological mechanism for ED and LUTS/BPH in relation to metabolic syndrome. BPH = benign prostatic hyperplasia; ED = erectile dysfunction; FGF = fibroblast growth factor; IFN = interferon; IGF = insulin-like growth factor; IL = interleukin; LUTS = lower urinary tract symptom; PCR = C-reactive protein; TGFb = transforming growth factor.

through the dihydrotestosterone (DHT) activity. Men with LUTSs and BPH often present with relatively low androgen and high estrogen levels. In classical studies on the effects of steroid hormones on canine prostate growth by the Johns Hopkins group, it was observed that estrogen markedly synergizes androgen effects and this induces a >4-fold increase in total prostate weight. This enhancement of prostate growth requires the combination of estrogen with a 5-alpha reduced steroid-like DHT or one of its metabolites [34,44]. Age- and MetS-related changes in circulating hormone levels and an imbalance in the testosterone/estrogen ratio may play a role in the development of LUTS/BPH and ED. In patients with visceral adiposity and MetS, an increased aromatase activity is also observed. Its amplified activity increases estradiol levels, which results in feedback inhibition at the level of the hypothalamus/pituitary to lower the testosterone level, leading to hypogonadotropic hypogonadism. Elevated estrogen levels lead to a further increase in visceral adipose deposition creating a self-sustained loop [34]. These hypotheses were also confirmed by a recent study evaluating hormonal status in 176 prediabetes patients with LUTSs and ED. In elderly patients with prediabetes, more severe ED was associated with low total testosterone levels, low dehydroepiandrosterone (DHEAS), CVD, and obesity (all p < 0.05); more severe LUTS symptoms were associated with low calculated free testosterone, DHEAS, and MetS [45]. In untreated SHRs, testosterone supplementation has also been associated with prostate growth and better erectile responses to electrical stimulation of the cavernous nerve, showing the importance of testosterone in both BPH and ED pathophysiology [46]. Longitudinal data from the MMAS also indicated that serum levels of total testosterone, DHEAS, cortisol, and estrone declined, whereas levels of DHT, sex hormone binding globulin, luteinizing hormone, follicle-stimulating

hormone, and prolactine increased in men who are aged 40–70 yr at baseline and followed for 7–10 yr [1,5]. All these studies support the role of hormonal changes in LUTS and ED development. Nevertheless, what we known is only the tip of a very large iceberg, and further studies are needed to assess whether variation in these hormones and their receptors plays a key role in LUTS and ED pathophysiology. 3.2.4.

Inflammatory pathway

Recent evidence suggests how a low-grade inflammatory process is an important pathophysiological component for CVD as well as for ED. Patients with CVD and ED present with an increase in serum levels of several proinflammatory cytokines, including IL-6, IL-8, IL-18, TNFa, and C-reactive protein. Sexual performance has also been negatively correlated with circulating levels of endothelial prothrombotic and inflammatory parameters such as fibrinogen, IL-6, and IL-1beta. Animal studies have also shown how TNFa knockout mice present changes in cavernosal reactivity with an increased number of spontaneous erections, a facilitated erectile response, a decreased response to adrenergic stimulation, and increased corporal eNOS and nNOS protein levels [47]. Numerous studies have attempted to clarify the connections between chronic inflammation and BPH, and hypothesized that BPH could be an immune-mediated inflammatory disease. In 2005, Robert et al [48] discovered statistically significant and clinically relevant associations among the degree of prostatic inflammation, prostate volume, and IPSS in about 300 patients undergoing BPH surgery. They reported chronic prostatic inflammation in 79%, 48%, and 20% of patients with severe, intermediate, and no BPH, respectively [48,49]. Many in vitro and in vivo studies have also investigated the possible mechanisms behind this relationship [34,49]. Particularly, IL-17 is considered a key cytokine as its concentration is negligible in normal

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prostate but is amplified in BPH tissues, where it is mostly secreted by T lymphocytes and prostate cells [49]. IL-17, which activates the NF-kB pathway, also regulates the expression of IL-6, IL-8, and IL-1 in epithelial, endothelial, and stromal cells and the release of TNFa, IFNc, IL-5, and IL10 by BPH T lymphocytes. So far, several stimuli, including infections or chemical irritation, through different molecular pathways, have been described as triggers for the dysregulation of prostate immune system with the release of several cytokines and development of inflammatory infiltrates. In any event, irrespectively of the mechanism that triggers the uncontrolled inflammatory response, the final result of this process iscontinuous tissue damage and a chronic process of wound healing that could lead to persistent stimulation of stromal and epithelial prostatic cells, potentially resulting in BPH [34,49]. Better knowledge of the role of the immune system dysregulation in ED and LUTSs is needed to be able to develop new anti-inflammatory drugs to manage patients with LUTS/ED. 3.2.5.

Psychological factors

Several psychological factors have also been investigated. Data from the BACH survey showed how depression was significantly associated with LUTSs and ED in both sexes [50]. These data were also supported by a study on 187 male veterans evaluated for LUTSs and ED using the IPSS and the Sexual Health Inventory for Men (SHIM) score. LUTSs and depression were the only independent predictors of the SHIM score [51]. Other reports suggest that urinary incontinence, painful urination, and changes in lifestyle due to LUTSs and particularly due to nocturia could lead to ED [19]. However, a possible LUTS- or ED-related decreased mood influence on the development of the other disorder remains to be further investigated. 3.3.

Implication for diagnosis and treatment

LUTSs and ED have a significant impact on the quality of life, but so far no study has evaluated treatment-seeking behavior for coexisting diseases. Data from the Cologne male studies reported that 19% presented with ED, but only 7% required urological management for their condition [6]. In the MSAM-7 study, about 19% of patients received treatment for their moderate LUTSs and 45% in case of severe LUTSs. Age is also considered another factor influencing LUTS treatment, with 1.5 times likelihood in men aged 50– 54 yr to 5.3 times likelihood in men aged 75 yr and older [13,52,53]. 3.3.1.

9

before initiating BPH/LUTS treatment. If sexual dysfunction is identified, nonpharmacological interventions such as lifestyle changes, including weight loss and increased physical activity, should be considered. If drug or surgical therapy is considered necessary, the possible impact of these treatments on ED should be considered and discussed with the patients. 3.3.2.

Impact of LUTS/BPH treatment

Most of the available medical treatments for LUTSs, including alpha blockers and 5-alpha reductase inhibitors alone or in combination, are also associated with possible side effects on sexual function [54]. Particularly oral alphablockers have no negative effect on erectile function, as reported by a meta-analysis provided by the American Urological Association in 2003 [55]. ED in patients treated with alpha-blockers occurred as frequently as in patients treated with placebo (3–5% vs 4%), whereas the incidence of ED associated with 5-alpha reductase inhibitors (dutasteride and finasteride), alone or in combination with alphablockers, was somewhat higher (8–10%) [56]. A beneficial effect of doxazosin treatment in terms of erectile function in patients with LUTSs associated or not with ED has also been demonstrated, although its use in clinical practice is minimal [56]. Currently, three PDE-5 inhibitors are approved for the ED treatment, which have been investigated for the treatment of LUTSs with or without ED in randomized double-blind clinical trials. In a recent meta-analysis, the association of PDE-5 inhibitors and alpha-blockers has been evaluated in patients with LUTS/BPH versus alpha-blockers alone [24]. PDE-5 inhibitors are effective and well tolerated either alone or in combination with alpha-blockers, particularly in young patients with severe LUTS/BPH. ED or ejaculatory dysfunction after BPH surgery is also not uncommon. Indeed, a recent meta-analysis of 15 trials suggested that the incidence of ED after a transurethral prostatic resection is up to 10% versus 2% for controls with an incidence of about 65% of retrograde ejaculation [55]. The development of new minimally invasive treatments such as the holmium laser enucleation or GreenLight prostatic vaporization have reduced these risks, but they are still present and impacting the ejaculatory function. As suggested by Mirone et al [10], there are a number of elements to consider when managing sexual dysfunction in men affected by LUTSs and receiving treatment for BPH/ LUTS, regardless of whether the sexual problems are comorbid conditions or an adverse effect of the medication/surgery for BPH/LUTS [10,56].

LUTS and ED diagnosis

Considering the possible relationship between LUTSs and ED and that LUTSs are generally considered a risk factor for sexual dysfunction, clinicians should always evaluate ED in patients with LUTSs and take the opportunity to evaluate patients presenting with ED for LUTSs. Beyond IPSS and IIEF evaluation, it is important to assess related comorbidities, including the MetS and concomitant medications, as well as to give advice on lifestyle changes in patients having both disorders [52]. Sexual function should always be assessed

4.

Conclusions

LUTSs and ED are highly prevalent, age-dependent disorders. Although the casual relationship has not been established, several epidemiological studies and potential common biological mechanisms seem to confirm the existence of this relationship. On the basis of the current evidence, we can state that, in clinical practice, it is fundamental that urologists recognize and manage MetS (either directly or via

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referral to a primary care doctor) for the benefit of their patients. Considering that many older men do not seek help for their sexual problems and physicians frequently fail to ask their patients about their sexual life, it is also recommended that men presenting with LUTSs should be evaluated for sexual dysfunction and ED, and that those presenting with ED should be assessed for LUTSs. In clinical practice, LUTS management should also consider the presence of concomitant ED and the possible positive and negative effects on sexual function associated with some of the available medical treatments of LUTS/BPH. In clinical research, a better understanding of the molecular pathways behind this association may also help identify new possible targets and develop novel therapeutic approaches to manage both disorders; identification of new biomarkers of both disorders is also compulsory in this area. Author contributions: Cosimo De Nunzio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: De Nunzio, McVary. Acquisition of data: De Nunzio. Analysis and interpretation of data: De Nunzio, Roehrborn, Andersson, McVary. Drafting of the manuscript: De Nunzio. Critical revision of the manuscript for important intellectual content: Roehrborn, Andersson, McVary. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: McVary. Other: None. Financial disclosures: Cosimo De Nunzio certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. Acknowledgments: Dr. Anna Romagnuolo, PhD, DEIM, Dipartimento Economia e Impresa, Universita della Tuscia, revised and edited the English version of this paper.

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Please cite this article in press as: De Nunzio C, et al. Erectile Dysfunction and Lower Urinary Tract Symptoms. Eur Urol Focus (2017), https://doi.org/10.1016/j.euf.2017.11.004