Critical Analysis of The Relationship Between Sexual Dysfunctions and Lower Urinary Tract Symptoms Due To Benign Prostatic Hyperplasia

EUROPEAN UROLOGY 60 (2011) 809–825
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Collaborative Review – Sexual Medicine – LUTS
Critical Analysis of the Relationship Between Sexual

Dysfunctions and Lower Urinary Tract Symptoms Due to
Benign Prostatic Hyperplasia
Mauro Gacci a,*, Ian Eardley b, Francois Giuliano c, Dimitris Hatzichristou d, Steven A. Kaplan e,
Mario Maggi f, Kevin T. McVary g, Vincenzo Mirone h, Hartmut Porst i, Claus G. Roehrborn j
a
Department of Urology, University of Florence, Italy; b Department of Urology, St James University Hospital, Leeds, England; c Raymond Poincaré Hospital,
d
Department of Physical Medicine and Rehabilitation, Garches, France; Centre for Sexual and Reproductive Health, Aristotle University of Thessaloniki,
e
Thessaloniki, Greece; Department of Urology, Weill Cornell Medical College, Cornell University, New York, USA; f Sexual Medicine & Andrology Unit,
g
Department of Clinical Physiopathology, University of Florence, Florence, Italy; Department of Urology, Northwestern University, Feinberg School of
h
Medicine, Chicago, IL, USA; Department of Urology, University Federico II of Naples, Naples, Italy; i Private Practice of Urology and Andrology, Hamburg,
Germany; j Department of Urology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, J8 142, Dallas, TX, USA
Article info Abstract
Article history: Context: This review focuses on the relationship among sexual dysfunction (SD), lower
Accepted June 20, 2011 urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related
therapies.
Published online ahead of Objective: We reviewed the current literature to provide an overview of current data
print on June 29, 2011 regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the
impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and
ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in
Keywords: patients with ED and LUTS.
LUTS Evidence acquisition: We conducted a Medline search to identify original articles, reviews,
ED editorials, and international scientific congress abstracts by combining the following
terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile
BPH
dysfunction, and ejaculatory dysfunction.
PDE5 Evidence synthesis: We conducted a comprehensive analysis of more relevant general
PDE5-i population–based and BPH/LUTS or SD clinic-based trials and evaluated the common patho-
Prostate physiologic mechanisms related to both conditions. In a further step, the overall impact of
current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical
Benign prostatic hyperplasia procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically
EjD analysed, including preclinical and clinical research data as well as possible mechanisms of
IPSS action that may contribute to the efficacy of PDE5-Is with LUTS/BPH.
Conclusions: Community-based and clinical data demonstrate a strong and consistent
IIEF
association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated
Age for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD
as discussed in the literature are (1) alteration of the nitric oxide (NO)–cyclic guanosine
monophosphate (cGMP) pathway, (2) enhancement of RhoA–Rho-kinase (ROCK) contractile
signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most
important sexual adverse effects of medical therapies are ejaculation disorders after the use
of some a-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use
of a-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treat-
ments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated
significant improvements in both LUTS and ED in men with BPH; combination therapy with
PDE5-Is and a1-adrenergic blockers seems superior to PDE5-I monotherapy.
# 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. University of Florence, Department of Urology, Viale A. Gramsci 7, FI 50121,

Italy. Tel. +39 0557949402; Fax: +39 0554377755.
E-mail address: [email protected] (M. Gacci).
0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.06.037
810 EUROPEAN UROLOGY 60 (2011) 809–825
1. Introduction The research was conducted by combining the following

terms: benign prostatic hyperplasia, lower urinary tract
The relationship between lower urinary tract symptoms symptoms, sexual dysfunction, erectile dysfunction, and
(LUTS) and erectile dysfunction (ED) has been strongly ejaculatory dysfunction. Abbreviations (LUTS, BPH, SD, ED,
investigated for the high prevalence of both conditions in EJD [ejaculatory dysfunction]) were used to recover
elderly men. Community-based and clinical studies with eventually missed data. A total of 10 616 records were
adequate population and follow-up allow us to better define retrieved from Medline (2939), Scopus (4349), and Web of
the epidemiologic aspects of this comorbidity and to Science (3328).
improve counselling, allowing more effective management A nonsystematic review of other relevant papers,
of both conditions [1]. However, a full review, including including the latest unpublished data presented during
current single-centre and cross-sectional studies, and international meetings, was also performed. These records
analysis of data from both general and uro/andrologic were added at the discretion of the authors, with the aim of
populations are currently missing. including the most recent trials with updated data.
Although the mechanisms underlying the relationship Of the above-mentioned records, 2453 records with the
between LUTS and ED in men with benign prostatic highest level of evidence (1a to 2b) for the various end
hyperplasia (BPH) are not fully elucidated, several patho- points were selected and reviewed with the consensus of all
physiologic theories are currently proposed in literature, of the authors of this collaborative review. Finally, 274 full-
and possible common links between these pathways are text studies were included in the first draft of the review,
still under investigation [2]. and only 136 were selected by the expert panel for citation
The efficacy profiles of all treatments for LUTS/BPH are well in the final version of the manuscript.
defined; however, the effects of these therapies on sexual
function are currently under evaluation, with the aim of 3. Evidence synthesis
identifying the treatment options that provide effective relief
of LUTS with minimal sexual or other adverse events [3]. Some 3.1. Epidemiology
evidence from preclinical and clinical studies shows that
phosphodiesterase type 5 inhibitors (PDE5-Is), commonly 3.1.1. Background
used for ED, can also improve male LUTS [4]. Although the sites Several trials have analysed the association between LUTS
of action are now partially known, inhibition of phosphodies- and male SD [5]. The main differences between the studies
terase type 5 (PDE5) seems to affect different pathways are population (general population–based, LUTS/ED clinic-
involved in LUTS. Several trials have investigated safety, based), sampling (single or multicentre national, cross-
efficacy, and cost-effectiveness of chronic use of PDE5-Is national), inclusion and exclusion criteria (age, comorbidity,
either as a primary treatment or in combination with LUTS/ED severity), and assessment methodology (validated
conventional therapies; however, a systematic review of all questionnaire, structured interview) [6].
randomised controlled studies on the use of PDE5-Is in BPH-
related LUTS is currently not available. 3.1.2. General population
The aims of the present review are to provide a full Before looking at the relationship between LUTS and ED, a
overview of the most recent epidemiologic studies on LUTS brief overview of the prevalence of LUTS and ED is
and ED in men with BPH to analyse the common links worthwhile. Age is one of the most important risk factors
between pathophysiologic mechanisms underlying this for ED. Compared to men in their 40 s, men in their 50 s have
comorbidity and to measure the overall impact of current a two-fold increase in their relative risk of ED, and this
therapies of LUTS/BPH on sexual activities and the role of relative risk increases five-fold for men in their 60 s.
PDE5-Is in the treatment of LUTS in men with BPH. Looking at various community-based surveys [7–19], it
appears that the age of the enrolled men accounts for the
2. Evidence acquisition variability in the prevalence of LUTS/ED. For example, the
National Health and Social Life Survey suggested that LUTS
The overall selection and acquisition of the literature is a significant risk factor for ED, with an odds ratio (OR) of
was performed in August 2010. A systematic review using 3.13 in 1410 men 18–59 yr of age [8]. In the Krimpen survey
the Medline, Scopus, and Web of Science databases of men 50–78 yr of age, the prevalence of severe ED and
was outlined, with the aim of identifying simple abstracts, severe ejaculatory dysfunction was 10-fold higher in men
original articles, review articles, and editorials on 70–78 yr of age than in those 50–54 yr of age; logistic
LUTS, sexual dysfunction (SD), and BPH. For all databases, regression demonstrated that severe LUTS was associated
searches were limited to materials published in the English with ED (OR: 7.5) and ejaculatory dysfunction (OR: 4.2) [9].
language with an abstract available. For PubMed only, Table 1 lists many of the other community-based studies
‘‘Languages’’ (English) and ‘‘Text options’’ (abstracts) limits relating to ED and LUTS, including samples from Asia,
were used. Search strategies for Scopus included words northern Europe, and North and South America that support
reported in ‘‘article, title, abstract or keywords’’ and a strong and consistent relationship between LUTS and ED,
published in ‘‘all years to present’’ and in all ‘‘subject as well as a consistent assortment of risk factors, including
areas.’’ For Web of Science, words were indicated in ‘‘topic’’ diabetes, androgen deficiency, depression, smoking, hyper-
with ‘‘all years’’ in time span. tension, and cardiovascular disease.
Table 1 – Evidence of association between male lower urinary tract symptoms and erectile dysfunction in population based studies: monocentric and cross-sectional
Author (country) Level of Name of study Sample Assessment Prevalence Associations

evidence
Feldman et al, 1994 2b Massachusetts Male 1709 men (40–70 yr of age) Structured interview ED: 52% (66% in men ED: age, hypertension, heart disease,
[7] (USA) Aging Study of ED and LUTS with severe LUTS) medications, depression, LUTS
Laumann et al, 1999 2b National Health and 1410 men (18–59 yr of age) Self-report of LUTS SD: 31% ED: poor physical and emotional health
[8] (USA) Social Life Survey 1 question on ED ED: 10% ED-LUTS OR: 3.13
2 questions on EJD Complete EJD: 8%
Blanker et al, 2001 [9] 2b Krimpen survey 1688 men (30–80 yr of age) IPSS Severe ED: 11% ED: age, smoking, LUTS,
(Netherlands) 4 questions ICS-sex Severe EJD: 13% cardiovascular pulmonary problems
ED-LUTS OR: 7.5
EJD-LUTS OR: 4.2
Braun et al, 2000 [10] 2b Cologne Male Survey 4477 men (30–80 yr of age) IPSS ED: 19% ED: hypertension, diabetes,
(Germany) 18 questions KEED LUTS: 44% pelvic surgery, and LUTS
Li et al, 2b Asian Survey of 1155 men (50–80 yr of age) IPSS, IPSS-B ED: 63% (of whom ED: age, LUTS, diabetes,

2005 [11] (Asia) Aging Males DAN-PSS-sex 57% were bothered) hypertension
IIEF EJD: 68% (of whom ED-LUTS OR: 3.17
52% were bothered) EJD-LUTS OR: 3.29
Shiri et al, 2b Tampere Aging Male 1126 men (50–70 yr of age) DAN-PSS ED: 70% ED: age and LUTS
2007 [12] (Finland) Urological Study 2 ED questions
Brookes et al, 2b Boston Area Community 2301 men selected from AUA Symptom Index ED prevalence: 10% 30–39 yr ED: incontinence LUTS,
2008 [13] (USA) Health Survey a population of 5506 of age, 59% 70–79 yr of age symptoms of prostatitis
(30–80 yr of age) Incontinence-ED: 1.73
Prostatitis-ED: 1.86
Khoo et al, 2008 [14] 2b Cross sectional 351 men (>50 yr of age) IPSS, IIEF, Geriatric ED: 70.1% LUTS: ED, ADAM, depression
(Malaysia) in Malaysia* assessed for ADAM and Depression Scale-15, St (severe ED 14.5%)
depression Louis University
questionnaire
Holden et al, 2010 [15] 2b Men in Australia 5990 men (40 yr of age) IPSS ED 21%; LUTS: 16% ED: cardiovascular disease,
(Australia) Telephone Survey* 1 question on ED ED/LUTS plus prostate diabetes
disease plus androgen LUTS: hypertension
deficiency: 34%
Nicolosi et al, 2b ED Epidemiology 2412 men (40–70 yr of age) IPSS ED 16% in healthy men ED: age, LUTS and smoking;
2003 [16] (Italy) Cross National Study 1 question on ED (32% in other men) inversely with physical
(Brazil, Italy, Japan, Malaysia)* activity and education level
Boyle et al, 2b UrEpik Study Group 4800 men (40–79 yr of age) IPSS ED: 21% ED: LUTS, diabetes, hypertension
2003 [17] (Italy) (UK, Netherlands, France, Korea)* O’Leary’s Sexual HD: 28% HD: ED, LUTS
Function Inventory ED-LUTS OR: 1.39
Rosen et al, 2b Multinational Survey of 12815 men (50–80 yr of age) IPSS ED: 49% ED and EJD: age and severity of LUTS
2003 [18] (USA) the Aging Male (USA/Europe*) DAN-PSS-sex EJD: 45% ED-LUTS OR 7.67
IIEF LUTS 90% EJD-LUTS OR: 6.25
Wein et al, 2b Epidemiology of LUTS 11 834 men (mean: SF-12, IPSS, IIEF, Male Mild/severe ED: 26% Multiple LUTS: Severe ED,
2009 [19] (USA) study (USA, UK, Sweden*) 56.1 yr of age) Sexual Health EJD: 7% frequent EJD, and premature
Questionnaire Premature ejaculation: 16% ejaculation
ED = erectile dysfunction; EJD = ejaculatory dysfunction; LUTS = lower urinary tract symptoms; SD = sexual dysfunction; OR = odds ratio; IPSS = International Prostate Symptom Score; ICS = International Continence
Society; KEED = Cologne Erectile Inventory; DAN-PSS = Danish Prostate Symptom Score; IIEF = International Index of Erectile Function; AUA = American Urological Association; ADAM = Androgen Deficiency in Aging Males;
HD = hypoactive desire.
*
Cross-sectional.
811
812
Table 2 – Evidence of association between male lower urinary tract symptoms and erectile dysfunction in uro/andrologic (benign prostatic hyperplasia/erectile dysfunction) population-based
studies: monocentric and cross-sectional
Author (country) Level of Name of study Sample Assessment Prevalence Associations

evidence
Schou et al, 1996 [20] 2b Scandinavian Survey 401 men with BPH DAN-PSS questionnaire: 3 questions EJD: 44% EJD and age
(Denmark) (<50 to >69 yr of age) concerning sexuality Pain during
ejaculation: 15%
Namasivayam et al, 2b Prostate-Assessment 168 men with LUTS IPSS ED: 56% LUTS: age, sexual drive, ED, EJD
1998 [21] (UK) Clinic in UK BPHII (46% according
to NIH)
EJD: 38%
Baniel et al, 2000 [22] (Israel) 2b BPH before prostatectomy 131 men with severe IPSS, PBI, NPT ED: 67% ED: severe LUTS
LUTS (55–74 yr of age)
Tubaro et al, 2001 [23] (Italy) 2b QOL in Italian Patients 877 men with LUTS/BPH IPSS, ICS-BPH, ICS-Sex ED: 58% ED: LUTS, in particular,
with LUTS Suggestive of BPH EJD: 56% with urinary loss
Delayed
ejaculation: 20%

Sak et al, 2004 [24] (UK) 2b Men with LUTS to a 1420 men with LUTS IPSS, BPHII ED: 47% ED: age, LUTS, Qmax, and PVR
nurse-led assessment clinic (mean: 63 yr of age) O’Leary Sexual Questionnaire
Hoesl et al, 2005 [25] (Germany) 2a 500 office-based urologists 8768 men (40 yr of age) IPSS ED: 62% ED: LUTS with impact on QoL
in Germany with LUTS/BPH KEED
QoL mediated
Morant et al, 2009 [26] (UK) 2a Health Improvement Network 11 327 men with LUTS Questionnaire assessing ED range: 1.7% ED: Overall LUTS, both voiding
database in 333 general and ED >18 yr of age) voiding and storage LUTS in 2000 to 4.9% and storage LUTS
practices in the UK in 2007 Storage LUTS-ED OR: 3.0
Voiding LUTS-ED OR: 2.6
El-Sakka et al, 2006 [27] (Egypt) 2b Prospective study on ED patients 476 men with ED IPSS LUTS: 27.6% mild, LUTS: ED risk factors (age, obesity,
(mean: 55 yr of age) IIEF 30% moderate, diabetes, hypertension, and IHD)
42.4% severe
McVary et al, 2008 [28] (USA) 2b Retrospective US claims 81 659 men with ED IPSS LUTS at baseline: 1.5% ED: Screened, diagnosed,
data analysis (1999–2004) (mean: 57 yr of age) LUTS after 2 yr: 7.6% and treated for LUTS
Reggio et al, 2007 [29] (Brazil) 2a PCa screening programme 1267 men screened for IPSS, IIEF-5 LUTS: 40.6% LUTS is an age-independent
in Joinville (Brazil) PCa (mean: 58 yr of age) ED: 59.9% predictor of ED
Antunes et al, 2008 [30] (Brazil) 2a PCa screening programme 1008 men screened for IPSS, IIEF LUTS: Mild 52%, LUTS: 5.4% of men with no ED
in San Paulo (Brazil) PCa (mean: 61 yr of age) moderate 30%, and in 27.1% of men with severe ED
severe 17%
ED: 81.4%
Frankel et al, 1998 [31] (UK) 2a 12 countries: Community 423 (40 yr of age) ICS-male and In-clinic men: ED-LUTS: in 8% of community
population and urology clinic* community ICS-sex questionnaires ED 60% population and in 46% of
1271 (>55 yr of age) EJD: 62% urology clinic
LUTS/BPH
Vallancien et al, 2003 [32] 2b Alf-One Study Group* 927 men (36–92 yr of age) IPSS, DAN-PSS, ED 62% ED: Age, LUTS, BMI
(France) (France, Denmark, UK, with LUTS/BPH DAN-PSS-Sex EJD: 63% EJD: Age, LUTS, BPH surgery
The Netherlands, Switzerland)
Li et al, 2008 [33] (Singapore) 2b Asian multinational registry* 994 men (40–88 yr of age) IPSS, DAN-PSS, LUTS: 90% ED: Age, LUTS
(Hong Kong, Malaysia, with BPH IIEF-5 ED: 82%
Philippines, Singapore, Thailand)
DAN-PSS = Danish Prostate Symptom Score; IPSS = International Prostate Symptom Score; BPHII = BPH Impact Index; ED = erectile dysfunction; EJD = ejaculatory dysfunction; NIH = National Institutes of Health;
LUTS = lower urinary tract symptoms; BPH = benign prostatic hyperplasia; PBI = Penile Brachial Index; NPT = nocturnal penile tumescence; QoL = quality of life; ICS = International Continence Society; Qmax = maximum
flow rate; PVR = postvoid residual; KEED = Cologne Erectile Inventory; OR = odds ratio; IIEF = International Index of Erectile Function; IHD = ischaemic heart disease; BMI = body mass index.
*
Cross-sectional.
EUROPEAN UROLOGY 60 (2011) 809–825 813
3.1.3. Urologic and andrologic population (benign prostatic severity of LUTS. A recent systematic review representing
hyperplasia/erectile dysfunction) 71 322 men summarised this positive correlation between
When examining a patient cohort drawn from a clinic LUTS and ED drawn from 20 community-based and clinic-
population [20–33], a similar relationship between ED and based studies; the overall ORs varied from 1.4 to 9.74 [34].
LUTS emerges, although there are slight quantitative
differences, as one would expect. In addition, the observa- 3.1.4. Summary
tional and retrospective nature of these reports detracts Several general population– or BPH/ED clinic-based studies
from one’s ability to draw solid conclusions. However, the demonstrated a consistent correlation between LUTS and
relationships between ED and LUTS remain consistent ED and/or ejaculatory dysfunction in men with BPH. LUTS
(Table 2). For instance, in a population referred to the and SD are highly prevalent in men with BPH; the
hospital for symptomatic BPH, an age-related increase of associations between LUTS and SD are independent of
both ED and ejaculatory dysfunction was reported; age and comorbidities such as heart disease and diabetes.
however, although young patients with ED were severely Evidence linking disorders of the prostate and bladder with
bothered, men with ejaculatory dysfunction were minimal- LUTS and SD is irrefutable, but the contribution of
ly bothered [20]. Similarly, in a study of 168 men with metabolic, cardiovascular, and endocrine factors cannot
symptomatic BPH undergoing prostate assessment, Nama- be discounted. Studies supporting alterations in mecha-
sivayam et al. reported an incidence of 56% for ED and 38% nisms associated with metabolic syndrome and cardiovas-
for ejaculatory dysfunction, with a significant correlation cular disease are critical to our understanding of the
between age and sexual drive, erection, and ejaculation pathways underlying the links between LUTS and sexual
[21]. dysfunction.
In the Asian registry, Li et al. reported an overall
prevalence of SD of 82%: Among patients with SD, 71% 3.2. Pathophysiology
had reduced erection, 66% had reduced ejaculation, and 18%
had pain on ejaculation [33]. In the MSAM-7, a large-scale, 3.2.1. Pathogenetic mechanisms underlying the association between
multinational survey conducted in the United States and six lower urinary tract symptoms and erectile dysfunction
European countries to investigate the relationship between The pathogenetic mechanisms underlying the relationship
LUTS and SD in older men, the pain or discomfort during between LUTS and ED are still not yet completely
ejaculation was reported by 6.7% of men, with a high rate of understood [35]. Hypothesised mechanisms include (1)
bothersomeness (88.3%) [18]; the overall prevalence of pain alteration of the nitric oxide (NO)–cyclic guanosine
or discomfort during ejaculation was related to age and monophosphate (cGMP) pathway, (2) enhancement of
[(Figure_1)TD$IG]
COMMON PATHOGENETIC MECHANISMS
Reduced NO– Increased

Autonomic Pelvic
cGMP RhoA–ROCK
hyperactivity atherosclerosis
signalling signalling
Reduced function of
nerves and endothelium
FUNCTIONAL
CONSEQUENCES AT
Altered smooth muscle
TISSUE LEVEL
relaxation or contractility
(corpora cavernosa, BPH / LUTS
prostate, urethra, and Arterial insufficiency, ED
bladder functional reduced blood flow, and
alterations) hypoxia-related tissue
damage
Chronic Steroid hormone

inflammation unbalance
Comorbidities:
hypertension, metabolic
syndrome, diabetes, etc.
Figure 1 – Schematic representation of the common pathogenetic mechanisms linking lower urinary tract symptoms resulting from benign prostatic
hyperplasia and erectile dysfunction.
NO = nitric oxide; cGMP = cyclic guanosine monophosphate; ROCK = Rho-kinase; BPH = benign prostatic hyperplasia; LUTS = lower urinary tract
symptoms; ED = erectile dysfunction.
RhoA–Rho-kinase (ROCK) signalling, (3) autonomic hyper- dysfunction has been investigated in SHR, which showed
activity, and (4) pelvic atherosclerosis (Fig. 1). decreased intercontraction intervals and bladder capacity
[51]. Treating SHR with vardenafil for 2 wk reversed
3.2.2. Nitric oxide–cyclic guanosine monophosphate pathway deterioration of urodynamic measures, prevented RhoA
The NO–cGMP pathway in the regulation of penile smooth activation, and decreased ROCK activity through a cGMP-
muscle relaxation and erection has been well characterised mediated mechanism.
[36]. A body of evidence exists for the role of NO in the
regulation of smooth muscle tone of bladder, prostate, and 3.2.4. Autonomic nervous system hyperactivity
urethra [37]. Following NO release, cGMP formation elicits Autonomic hyperactivity is subject to dysregulation of
smooth muscle relaxation involving a decrease in intracel- parasympathetic and sympathetic tone. It has been
lular calcium levels and the activity of downstream established that the a-adrenoceptor system with increased
proteins, such as cGMP-specific protein kinase. sympathetic activity plays an important role in the
Calcium-dependent NO synthase (NOS), including neu- pathophysiology of ED and LUTS secondary to BPH [52].
ronal NOS (nNOS) and endothelial NOS (eNOS), has been The various subtypes of a1-adrenergic receptors have been
identified in the corpora cavernosa and in lower urinary identified in bladder, prostate, and penile tissue, where they
tract (LUT) tissues. The nNOS isoform was identified in the mediate smooth muscle and vascular tone [53].
LUT in nerve terminals distributed within the prostatic a1A and a1D receptors have been identified as the
peripheral and transitional zones, including the stroma and predominant a1-adrenoceptor subtypes in penile corpus
the glandular epithelium [38]. cavernosum; a1A receptors concentrated in prostate and
The urothelium expresses NOS and releases NO in bladder neck are involved in voiding problems, and a1D
response to various stimuli [39]. Because the eNOS isoform receptors, found in hypertrophied detrusor muscle, are
has been described in endothelial cells of the prostate, it has involved in storage problems [52].
been hypothesised that eNOS regulates local vascular Studies in animal models support the correlation
perfusion, whereas nNOS regulates smooth muscle tone between autonomic hyperactivity and LUTS/ED: Hyperlipi-
and glandular activity [37]. NOS activity has been identified demic rats simultaneously developed prostatic enlarge-
in the urothelium, smooth muscle, blood vessels, and nerves ment, bladder overactivity, and ED after eating a high-fat
of the bladder, with a higher concentration in the outlet diet [53]. In a more recent study, rats fed a high-fat diet
region [40,41]. The antiproliferative and pro-apoptotic developed hyperglycaemia and hyperinsulinaemia accom-
effects of NO donors on cultured bladder, prostate, and panied by significantly increased cellular proliferation,
urethra smooth muscle cells [42] suggests a role for the enhanced a-adrenoceptor-mediated contraction, and BPH
nitrergic pathway in BPH-related LUTS. These findings may [54]; these mechanisms, in addition to other pathways such
explain why pathologic conditions characterised by the as increased advanced end products of glycation or reactive
deterioration of nerves and endothelium with impairment oxygen species could affect both LUTS and ED. Interestingly,
of NO production, as has been reported in hypertension or pioglitazone dosing (an insulin sensitizer) reverses prostate
metabolic syndrome, respectively, are associated with ED overweight, suggesting that the altered metabolic state was
and LUTS [43]. Finally, phosphodiesterases—enzymes that responsible for BPH [54]. Studies using SHR, which were
metabolise cGMP and thus limit the intracellular signalling shown to develop increased autonomic activity, prostatic
that NO initiates—are considered crucial modulators of the hyperplasia, LUTS, and ED [55], further support a significant
nitrergic pathway not only in the penis but also in the LUT, role of the autonomic nervous system in promoting the
as has been recently reported [42,44,45]. common pathophysiology of these disorders. SHR had an
overabundance of sympathetic fibres innervating the
3.2.3. RhoA/Rho-kinase calcium sensitising pathway bladder, prostate, and penis and showed improvement in
Smooth muscle tone is regulated not only through a erectile function after antihypertensive therapy [56].
calcium-dependent mechanism but also through the
activity of the RhoA–ROCK calcium-sensitising pathway. 3.2.5. Pelvic atherosclerosis
An upregulated RhoA–ROCK pathway can impair smooth Atherosclerosis of prostate, penis, and bladder is regarded
muscle relaxation, finally resulting in ED and LUTS. as the mechanism that connects all of the previously
Accordingly, penile RhoA–ROCK signalling was increased described theories because pelvic atherosclerosis reduces
in pathologic conditions associated with ED, such as NO signalling, upregulates the RhoA/ROCK pathway, and is
diabetes, and involuntary bladder contractions were a component of the metabolic syndrome and autonomic
associated with increased signalling of the muscarinic hyperactivity. Established risks for ED and atherosclerosis,
receptor-activated RhoA–ROCK pathway [46,47]. Upregu- such as hypertension and diabetes, also affect BPH and LUTS
lated RhoA–ROCK signalling was demonstrated in corpora [57,58].
cavernosa [48] and bladder [49] of spontaneously hyper- Clinical and preclinical studies have demonstrated that
tensive rats (SHR), a rat strain genetically prone to develop bladder ischemia/hypoxia closely correlates with alteration
BPH and overactive bladder (OAB). ROCK inhibition limits of erectile and LUT tissues [59] through the induction of
bladder hyperactivity, reduces contractions in bladder fibrosis and reduced NOS [60]. Du et al. [61] identified
strips from SHR [50], and improves erectile function [48]. positive immunostaining for hypoxia-inducible factor
The role of PDE5-Is in modulating ROCK-induced bladder (HIF)-1a in prostate tissue from men with BPH, whereas
Table 3 – Impact of therapies for lower urinary tract symptoms due to benign prostatic hyperplasia on sexual activity
Study (country) Level of Sample Drug or Timing Assessment Effect on ED

evidence procedure
Leliefeld et al, 2002 [71] 2a 261 BPH patients Watchful waiting 9 mo Four questions on Similar improvement and
(Netherlands) (>50 yr of age) vs a-blocker sexual activity, deterioration of erection,
Finasteride erection capacity, rigidity, libido, sexual activity
Surgery rigidity, and libido
Zlotta et al, 2005 [74] 1a 2511 men from Serenoa vs finasteride, 3 and IPSS, MSF-4 questionnaire No negative effect on SF ($ MSF-4)
(Belgium) three studies serenoa vs tamsulosin 6 mo (with four items for sex)
160 mg vs 320 mg
Wilt et al, 1a 5151 men with BPH Terazosin vs placebo, 4–56 wk – ED incidence:
2002 [80] (USA) from 10 RCTs finasteride, 6.2% placebo control
a-blockers 5.9% a-blocker control
MacDonald et al, 1a 6033 men (mean: 64 yr of age) Doxazosin vs placebo, 1–54 mo – OR of ED:
2004 [81] (USA) from 13 studies finasteride, combined 1.71 vs placebo

with a-blockers 1.18 vs finasteride
3.14 combined vs placebo
Hofner et al, 1999 [82] 1a 830 patients with symptoms of BPO Tamsulosin 12 wk SF score determined by Significant " in SF score ( p = 0.042)
(Germany) (three European studies) (0.4 mg once daily) a life style questionnaire Significant ## ejaculation ( p = 0.045)
vs alfuzosin
Roehrborn et al, 1a 2656 patients from the ALTESS, Alfuzosin 12 mo Adverse event recording Incidence of ED <2%
2008 [83] (USA) ALFORTI, and ALF-ONE studies (10 mg once daily)
Chapple et al, 1b 1228 men (50 yr of age) with Silodosin 8 mg once 3 mo IPSS, Qmax, QoL, adverse EJD: 14% after silodosin
2011 [91] (UK) IPSS 13 from European day vs tamsulosin event recording vs 2% after tamsulosin
Silodosin Study Group 0.4 mg and placebo
Moinpour et al, 1b 18 882 BPH men (55 yr of age) from Finasteride 6.5 yr Sexual Activity Scale " of ED at 6 mo compared to placebo
2007 [97] (USA) Prostate Cancer Prevention Trial 5 mg vs placebo score, SF-36 No differences at 6.5 yr
Roehrborn et al, 1b 4844 men with BPH from Dutasteride 24 mo Sexual adverse event ED incidence:
2008 [98] (USA) the CombAT study (0.5 mg daily) recording 3.8% tamsulosin
or tamsulosin 6.0% dutasteride
or combination 7.4% combined
Hoffman et al, 1a 1493 men (mean: 68 yr of age) TUMT vs TURP 3–60 mo Recording erectile and EJD RR compared to TURP:
2002 [100] (USA) with BPH 0.39 for ED
0.41 for EJD
Bouza et al, 1a Meta-analysis from 35 studies TUNA vs TURP 3 mo to Questionnaire, adverse Low incidence of ED
2006 [101] (Spain) (comparative and non-comparative) 5 yr event registration Better results than TURP for ED, EJD, libido
Kursh et al, 1b 72 symptomatic BPH men ILC vs TURP 2 yr SF Summary Score Better sexual score after ILC compared
2003 [102] (USA) (mean: 69 yr of age), to TURP; sexual scores stable after 2 yr
from a multicentre study
Wasson et al, 1b 556 men (mean: 66 yr of age) with TURP vs watchful waiting 3 yr Specific scale with No improvement in ED after
1995 [108] (USA) moderate symptoms of BPH 0–100 points TURP compared to watchful waiting
Lourenco et al, 1a 795 BPH men from 10 RCTs TUIP vs TURP >1 yr Structured question; Significant difference in EJD
2010 [109] (UK) specific questionnaire No difference in ED
Soleimani et al, 2a 246 men with BPH OP (suprapubic) – Structured question No differences in postoperative ED:
2009 [111] (Iran) (mean: 64 yr of age) vs TURP 13.4% TURP
11.5% OP
Chen et al, 2010 1b Patients (mean: 70 yr of age) TURIS vs TURP 2 yr IIEF-5 TURP vs TURIS:
[112] (China) with mean preoperative IIEF-5: 19.6 vs 20.4
IIEF score of 19 Retrograde ejaculation: 50% vs 36%
815
no HIF-1a immunostaining was detected in tissue from
No differences between HoLEP TURP for ED
TURP = transurethral resection of the prostate; TUNA = transurethral needle ablation; ILC = interstitial laser coagulation; TUIP = transurethral incision of the prostate; OP = open prostatectomy; TURIS = TURP in saline;
ED = erectile dysfunction; EJD = ejaculatory dysfunction; IPSS = International Prostate Symptom Score; MSF = Measure Male Sexual Function; SF = sexual function; BPH = benign prostatic hyperplasia; RCT = randomised
controlled trial; OR = odds ratio; BPO = benign prostatic obstruction; Qmax = maximum flow rate; QoL = quality of life; CombAT = Combination of Avodart and Tamsulosin; TUMT = transurethral microwave thermotherapy;
healthy controls. Treatment with 5a-reductase inhibitors
No significant # of ejection fraction (5-ARIs) could reduce prostate size in part by decreasing HIF-
No difference between OP and PVP

1a levels and other hypoxia-related growth factors that may
otherwise contribute to the growth of prostatic tissue [62].
Effect on ED
In SHR, autonomic hyperactivity may limit bladder

blood perfusion. Accordingly, a1-adrenoceptor antagonists
improve micturition parameters in SHR [63]. Moreover,
bladder tissue from SHR exhibited a high density of hypoxic
cells in both urothelium and muscular wall when compared
to normotensive counterpart Wistar Kyoto rats [64].
Administration of vardenafil to SHR reduced bladder
hypoxia, suggesting that blockade of PDE5 in bladder
endothelial and smooth muscle cells increases bladder
general assessment questions
perfusion and, in turn, ameliorates hypoxia-related func-

IIEF, IPSS, 10 nonvalidated
tional alterations.
Assessment
3.2.6. Summary
In conclusion, the complexity of pathogenetic mechanisms
HoLEP = holmium laser enucleation of the prostate; IIEF = International Index of Erectile Function; PVP = photoselective vaporisation of the prostate.
linking BPH/LUTS and ED has been recognised by several

IIEF-5
investigations in both human and animal studies. All

theories proposed for the common causality are inter-
connected; therefore, treatment options may overlap,
12–24 mo
allowing prevention or treatment of both conditions

Timing
18 mo
simultaneously. More recent research suggests the involve-

ment of additional contributing factors such as chronic
inflammation [65,66] and sex steroid ratio imbalance [67],
and these factors deserve further study.
procedure
3.3. Impact of therapies for lower urinary tract symptoms due

Drug or
HoLEP vs TURP
to benign prostatic hyperplasia on sexual activity

PVP vs OP
3.3.1. Background
The primary purpose of treating BPH-related LUTS is to
improve symptoms and to reduce bother while causing as
few side-effects as possible; in the context of this review,
there should ideally be as little effect on sexual function as
possible [68]. In fact, most therapies for BPH-related LUTS
are associated with some sexual side-effects, although they
120 men with symptomatic
BPH (mean: 65 yr of age)
differ in type, frequency, and severity (Table 3) [69].

Sample
125 men with prostate

adenomas >80 cm3
3.3.2. Watchful waiting

Both medical and surgical treatments have a significant
impact on sexuality compared to watchful waiting [69],
which is one reason why men with minor LUTS (Interna-
tional Prostate Symptom Score [IPSS] 7) and minimal
bother are good candidates [70]. The effect of watchful
waiting is variable, with some men finding that their sexual
evidence
Level of
function improves and others finding that it deteriorates.

1b
1b
This finding was confirmed in a recent study of 234 men

with LUTS in whom, after 9 mo of watchful waiting, 10% and
6% reported an increase or a decrease, respectively, in the
frequency of sexual activity [71]. In the same study, an
Table 3 (Continued )
Alivizatos et al, 2008

2006 [114] (Italy)
improvement or a reduction of penile rigidity was reported,

Study (country)
[115] (Greece)
respectively, by 11% and 6% of men [71].

Briganti et al,
3.3.3. Phytotherapy
Saw palmetto, also known as serenoa repens, pygeum
africanum, cucurbita pepo, secale cerelae, urtica dioica, and
quercetin, have all been reported as possible treatments for impairment (1–3%) and ED (3–5%) similar to placebo (3% and
BPH-related LUTS, although the evidence to support their 4%, respectively), but tamsulosin was associated with a
efficacy is limited in many cases. These free fatty acids, higher incidence of ejaculatory dysfunction (10%) than other
phytoesterol, carotenoids, phenol, lignans, and bioflavo- a1-adrenoceptor blockers (0–1%) and placebo (1%). The
noids have a variety of biochemical effects, including anti- higher incidence of ejaculatory dysfunction, based on
inflammatory and antioxidant properties and inhibitory patients’ spontaneous reports in clinical trials, is dose related.
activities on inflammatory cytokines and 5-ARIs [72]. In a 3-mo placebo-controlled study conducted in the
Although evidence that they have any efficacy in the United States, the incidence of abnormal ejaculation with
treatment of BPH-related LUTS is limited, clearly the side- tamsulosin increased from 6% with the 0.4-mg dose to 18%
effect profile is relatively mild with respect to SD, although with the 0.8-mg dose, whereas no patient receiving placebo
the therapeutic effects and the levels of evidence vary from reported ejaculatory dysfunction [85]. It was originally
drug to drug [73]. In a report of three trials using Permixon thought that the mechanism of action was bladder neck
in 2511 men (saw palmetto vs finasteride, saw palmetto vs relaxation with retrograde ejaculation, but a direct effect of
tamsulosin, and saw palmetto 160 mg vs 320 mg), Zlotta these drugs on the vas and seminal vesicles leading to
et al. reported a slight increase in sexual disorders in anejaculation has been proposed [86].
patients treated with tamsulosin and finasteride, with no The ABEJAC study and a Japanese study confirmed that
change in the saw palmetto arm after 3 mo and slight functioning of the bladder neck had no role in the different
improvement after 6 mo [74]. The Measure Male Sexual effects of alfuzosin and tamsulosin on ejaculatory function
Function-4 (MSF-4) questionnaire used in this study [87,88], with tamsulosin dose-dependently reducing the
consisted of four items that explore the patient’s interest amount of ejaculate, even leading to anejaculation. A central
in sex, quality of erection, achievement of ejaculation, and effect is also plausible because tamsulosin has a high
orgasmic function: Zlotta demonstrated that phytotherapy affinity for D2-like and 5HT1A receptors, which play a key
(Permixon), alpha blocker (tamsulosin) or 5-ARIs (finaste- role in the central control of ejaculation [89]. a-Blockers are
ride) have no negative impact on sexual desire and orgasmic often categorised as uroselective (ie, drugs without any
function. significant effect on cardiovascular smooth muscle) or
nonuroselective (ie, there is a significant effect on vascular
3.3.4. a-blockers smooth muscle). These latter drugs (eg, terazosin and
Over the last decade, a-adrenoceptor blockers have become doxazosin) have a relatively minor effect on ejaculation.
the first-line treatment for LUTS secondary to BPH. Their Uroselective drugs have a high affinity for the a1A-
proposed mechanism of action is the inhibition of a1- adrenoreceptor, with tamsulosin and particularly silodosin
receptors in the prostatic stroma, leading to relaxation of being the most uroselective [90], and it is these drugs that
prostate smooth muscle and possibly also of the bladder have the most marked effect on ejaculation.
neck [75]. In a multicentre trial with 1228 men with LUTS
a-Blockers have mixed effects on sexual function in that secondary to BPH, after 3 mo of treatment, ejaculatory
evidence shows both improved erectile function and dysfunction was reported in 14% of those using silodosin
ejaculatory dysfunction, although different a-blockers compared with 2% of men using tamsulosin [91]. Only 1.3%
have different effects on ejaculation [76]. It has been of men in the silodosin arm discontinued treatment
suggested that the positive effect of a-blockers on sexual because of ejaculatory dysfunction, suggesting that al-
function might be the result of the improvement in quality though the side-effect might be relatively prevalent, the
of life (QoL) following relief of BPH-associated LUTS [77], degree of bother is relatively minor. This conclusion may
but the more likely mechanism by which a-blockers reflect the maintained sensation of orgasm [92]. Intrigu-
improve erectile function is via a direct effect on the ingly, some evidence shows that the presence of ejacula-
cavernosal smooth muscle. Normally, penile smooth tory dysfunction is associated with a relatively good
muscle would be expected to contract in response to symptomatic response of LUTS [93]. Nevertheless, it
a-adrenoceptor activation; therefore, a-adrenoceptor is noteworthy that alfuzosin, although categorised as
blockade might relax the smooth muscle and enhance uroselective, does not exert any deleterious effect on
erections. The a-adrenoceptor blocker phentolamine has ejaculation [94].
been used to treat ED [78], but there are no comparable data
for the commercially available a-blockers. However, a 3.3.5. 5a-reductase inhibitors
community-based study suggested that a-blockers were 5a-Reductase inhibitors have sexual effects, including ED,
associated with improved sexual function [79], and the in 3–16% of patients, sexual desire impairment, (decrease or
meta-analysis by Van Dijk et al. appears to confirm a loss of libido) in 2–10%, and ejaculatory dysfunction in 0–8%
beneficial effect on erectile function [76]. Moreover, a [95]. There does not appear to be any significant difference
retrospective analysis of the doxazosin database suggested in the frequency of the sexual side-effects between the two
a beneficial effect on erectile function [80]. commercially available drugs, finasteride and dutasteride.
The effect of a-blockers on ejaculation varies according The underlying mechanism of these adverse effects is not
to the a-blocker used [81–84]. In the American Urological fully understood but presumably is related to the decrease
Association (AUA) meta-analysis [70], the four a1- of dihydrotestosterone [96] as well as a reduction of NO or
adrenoceptor blockers showed incidences of sexual desire NOS in the corpus cavernosum [96].
The Prostate Cancer Prevention Trial found an increase in prostatectomy (OP) as the main treatment for men with
the Sexual Activity Scale score for placebo compared to BPH, whereas transurethral incision of the prostate (TUIP)
finasteride after 6 mo, and although the benefit was or bladder neck incision is reserved for men with small
maintained at 6.5 yr, the magnitude of the difference was prostates. All procedures cause SD, although the incidence
less [97]. In the Combination of Avodart and Tamsulosin varies depending on the type of surgery.
(CombAT) study, a multicentre trial on combination therapy The data presented support the view that OP and TURP
with tamsulosin and dutasteride in 4844 men with BPH, the have a greater effect on sexual function than TUIP. In a large
rate of ED after 24 mo was 3.8% with tamsulosin, 6.0% with retrospective study evaluating 3885 men treated with
dutasteride, and 7.4% with combination therapy [98]. At 24 TURP, the impotence rate after TURP was 13% [105].
mo, retrograde ejaculation, ejaculation failure, and sexual Neuropraxia from thermal injury or capsular perforation
desire impairment were reported, respectively, in 1.1%, in the neighbourhood of the neurovascular bundle is
0.8%, and 1.7% of patients after tamsulosin; in 0.6%, 0.5%, presumed to be the cause [106], and it is often temporary,
and 2.8% after dutasteride; and in 4.2%, 2.4%, and 3.4% after as reported in a study of 98 potent men evaluated 4 d and 3
combination therapy. mo after TURP [107]. In this trial, a high rate of ED was
reported in the immediate postoperative period (35%), with
3.3.6. Mini-invasive therapies a significant reduction (8%) at the second assessment after 3
Recently, several mini-invasive therapies for BPH have been mo. If the injury is the result of a neuropraxia, erectile
introduced, including transurethral microwave thermo- function might be expected to improve continuously as
therapy (TUMT), transurethral needle ablation (TUNA), and time goes by, although in a multicentre randomised trial
interstitial laser coagulation (ILC). Conventionally, these comparing TURP with watchful waiting in 556 men with
therapies are positioned between pharmacotherapy and moderate symptoms of BPH, no improvement of ED was
transurethral resection of the prostate (TURP) [99] in that seen 3 yr after TURP [108].
they are invasive but do not provide the symptomatic Transurethral surgery would be expected to result in
benefit of TURP. retrograde ejaculation, because there is inevitable damage
The published data confirm that the frequency of sexual to the bladder neck smooth muscle, which normally acts as
side-effects is lower with the minimally invasive therapies the ‘‘genital sphincter’’ that closes at the time of ejaculation;
compared to TURP. In a recent review of 14 studies however, the type of surgery affects the frequency with
including a total of 1493 men with BPH, TUMT was which retrograde ejaculation is seen. In a systematic review
associated with decreased risks of ED and ejaculatory comparing TUIP and TURP, including a total of 795 men
dysfunction compared to TURP, with a relative risk ratio from 10 randomised controlled trials, the risk of retrograde
(RR) of 0.41 for erection and 0.39 for ejaculation [100]. In ejaculation was lower after TUIP than after TURP (27.6% vs
addition, a meta-analysis considered 35 studies of TUNA in 51.8%; RR: 0.54), whereas there was no significant differ-
symptomatic BPH patients [101]. In the 26 noncomparative ence regarding ED (3.4% vs 5.8%; RR: 0.61) [109].
studies, the incidence of sexual adverse events was low, A retrospective meta-analysis of the results from 3304
with ED in 0.3% of cases, haematospermia in 0.3%, men after TUIP, TURP, or OP revealed a high incidence of
retrograde ejaculation in 0.2%, and loss of ejaculation in postoperative sexual problems: After OP, 65.0–80.8% of
0.08% of men [101]. In three of nine comparative studies, the patients reported retrograde ejaculation compared with
outcome of TUNA with regard to sexual side-effects 38.8% after TUIP and 70.4% after TURP [110]. In a more
(erection, ejaculation, and preservation of sexual desire) recent prospective trial comparing OP with TURP in men
was significantly better compared to TURP, whereas in the with large prostates, a total of 12.5% of men with either no
other studies, sexual side-effects were not assessed or were or mild preoperative ED developed moderate or severe ED
the same as following TURP. postoperatively—13.4% after TURP and 11.3% after OP [111].
In a multicentre study of 72 symptomatic BPH men that Recently, the use of bipolar electrosurgical technology,
compared ILC with TURP, sexual function scores favoured such as the Gyrus system (Gyrus ACMI, Southborough, MA,
the ILC arm at 6 mo and 2 yr and remained stable, whereas USA) for TURP in saline (TURIS), showed comparable
scores progressively declined after TURP [102]. In a symptomatic results with similar sexual side-effects
prospective study of 173 patients treated with TURP, TUMT, compared to TURP during short-term follow-up. In a
TUNA, and ILC, a mild to moderate decrease in erectile prospective study comparing TURP and TURIS in 100 men
function was noted in 26.5%, 18.2%, 18.4%, and 20.0%, with a mean preoperative International Index of Erectile
respectively, and there was a severe reduction in volume of Function (IIEF) score of 19, no significant difference was
the ejaculatein in 48.6%, 28.1%, 21.6%, and 24.3%, respec- seen regarding ED (IIEF-5 with TURP: 19.6; IIEF-5 with
tively [103]. TURIS: 20.4; p = 0.65), whereas the rate of retrograde
ejaculation was lower after TURIS than after TURP, although
3.3.7. Conventional surgical treatments this did not reach statistical significance (36% vs 50%;
TURP is considered the gold standard of surgical treatment p = 0.52) [112].
for LUTS related to BPH. Indications for TURP include LUTS
refractory to other treatments, renal function deterioration, 3.3.8. New surgical treatments
recurring urinary tract infections, gross haematuria, and Holmium laser enucleation of the prostate (HoLEP) and
chronic urinary retention [104]. It has largely replaced open photoselective vaporisation of the prostate (PVP) are the
newest surgical techniques being used to treat LUTS [51]. In a rat model of OAB associated with C-fibre afferent
secondary to BPH [113]. Both techniques damage the activation, PDE5-Is have been shown to inhibit the
bladder neck and, consequently, might be expected to micturition reflex via bladder sensory pathways [46]. An
produce retrograde ejaculation, and the (limited) published acute effect on the bladder storage phase has been
data appear to support this. In a prospective study of HoLEP confirmed by urodynamic studies in young men with
versus TURP in 120 men, it was demonstrated that both spinal cord injury who were treated with a single dose of
techniques significantly lowered the IIEF orgasmic function vardenafil [121]. To confirm that PDE5-Is can ameliorate
domain (presumably because of the occurrence of retro- storage LUTS with direct activity on the LUT by a pathway
grade ejaculation), although there was no difference in not including the prostate, Gacci et al. evaluated the effects
erectile function at 12 mo [114]. In a prospective random- of PDE5-Is on continence recovery after nerve-sparing
ised study of 125 men with large prostates >80 ml who prostatectomy for prostate cancer (PCa) [122]. In this
were treated with either PVP or OP, no significant study, ‘‘nightly’’ administration of vardenafil resulted in
differences in IIEF-5 scores were observed after 12 mo, significant improvement of urinary function compared to
although patients treated with PVP were older than those placebo administration. Finally, another possible mecha-
treated with OP (74 yr of age vs 67 yr of age; p = 0.03) [115]. nism for LUTS improvement following PDE5-I treatment is
It must be emphasised that with all minimally invasive via increased arterial blood flow, especially in the prostate
and conventional surgical treatments regarding iatrogenic or bladder neck [123].
ejaculatory disorders, there is likely a misclassification
when considering retrograde ejaculation. This disorder is 3.4.2. Studies on the use of phosphodiesterase type 5 inhibitors for
rarely documented. It is much more likely that there is lower urinary tract symptoms
anejaculation resulting from impaired emission. Clinical In a 12-wk randomised trial in 366 men with ED (IIEF 25)
research is warranted in this area. and LUTS (IPSS 12), more significant reduction of IPSS was
seen with sildenafil compared to placebo treatment (6.32
3.3.9. Summary vs 1.93 points, Table 4). Patients with severe LUTS
All treatments for BPH have the potential to affect sexual experienced greater improvement than those with moderate
function, although the type and the frequency of dysfunction LUTS (8.6 vs 3.6); however, flow rate remain unchanged
varies among treatments [116,117]. These risks should be [124]. In a study of 60 men with BPH-related LUTS, the
discussed with patients prior to treatment, and the younger combination of sildenafil and tamsulosin resulted in more
the man, the more important these risks will be. What is pronounced mean improvement of urinary symptoms
important to remember is that for many men, sexual function (40.1%) compared to tamsulosin (36.2%) or sildenafil mono-
actually improves with treatment of BPH, possibly via therapy (28.2%; p < 0.001). Erectile function was significant-
improved QoL [118]. Careful counselling is essential before ly improved in the sildenafil arm (65%) and the combination
commencing any of the treatments discussed. arm (67.4%) but not in the tamsulosin arm (12.4%; p < 0.001)
[125].
3.4. Impact of phosphodiesterase type 5 inhibitors on lower Similar effects were seen with the use of tadalafil and
urinary tract symptoms due to benign prostatic hyperplasia vardenafil. Tadalafil treatment produced a more pro-
nounced improvement in LUTS compared to placebo
3.4.1. Background and mechanisms of action treatment (2.8 vs 1.2 at 6 wk and 3.8 vs 1.7 at 12
Phosphodiesterase messenger RNA and protein have been wk). This effect was more obvious on storage symptoms
localised across the whole human urogenital tract with [126]. In a further dose-finding study in 1058 men, 5 mg
different patterns of expression and concentrations [119]. tadalafil appeared to provide the best risk–benefit profile,
The hypothesis that impaired NO–cGMP signalling contrib- although significant improvements of IPSS and IIEF scores
utes to the pathophysiology of BPH provided further were achieved with all daily doses from 2.5 mg to 20 mg
background for a potential role of NO donor drugs and [127]. Finally, combination therapy for BPH/LUTS and ED
PDE5-Is in the management of BPH-associated LUTS [37]. In with tadalafil 20 mg/d and tamsulosin 0.4 mg/d resulted in
this respect, PDE5-Is increased the levels of cyclic adenosine higher efficacy rates and was better tolerated compared to
monophosphate and cGMP in the human prostate and tamsulosin alone. Again, no differences were recorded
plasma, and the distribution of PDE5-Is was found to be between the treatment arms in urodynamic parameters
higher in the prostate than in the plasma of treated men [128].
[120]. In addition, PDE5-Is have shown antiproliferative In a multicentre trial with 222 men randomised to
effects in the prostatic stroma [44]. vardenafil (10 mg twice daily) or placebo for 8 wk, a
PDE5 regulates bladder smooth muscle tone via a strong reduction in the IPSS of 5.9 points was seen in the active arm
inhibition of NO–cGMP signalling, supporting a therapeu- versus 3.6 after placebo. Both the storage and voiding
tic role for PDE5-Is in bladder dysfunction [44]. In symptoms subscores improved significantly with active
particular, the effect of PDE5-Is on storage LUTS seems treatment but without a change in flow rate and postvoid
to be partially determined by a cGMP-dependent RhoA– residual (PVR) volume [129]. In another 12-wk randomised
ROCK signalling inhibition [46]. An animal study of trial, combination therapy with tamsulosin 0.4 mg and
vardenafil-treated rats suffering from genetically induced vardenafil 10 mg produced a more marked improvement in
bladder overactivity provided evidence for such an effect overall LUTS severity and bother as well as in OAB
820
Table 4 – Prospective studies on phosdiesterase type 5 inhibitors (alone or combined with alpha blockers) for lower urinary tract symptoms
Study (country) Level of Sample Drug Timing Assessment Effect on LUTS

evidence
Mc Vary et al, 2007 1b 369 men with LUTS (IPSS 12) Daily sildenafil 50 12 wk IPSS, IPSS QoL, BPHII Significant # IPSS
[124] (USA) and ED (IIEF-EF 25) or 100 mg vs placebo Significant " QoL
$ Qmax and Qave
Tuncel et al, 1b 60 men (mean age: 58 yr) Sildenafil only, (4 d/wk) 8 wk IPSS, IIEF-EF, SHIM " Urinary symptoms with tamsulosin/combin.

2010 [125] (Turkey) with BPH-related LUTS Tamsulosin 0.4 only " Erectile function with sildenafil/combin.
or combination
McVary et al, 1b 281 men 45 yr with LUTS Tadalafil 5 mg once daily followed 6 and IPSS (stratified in irritative Significant # IPSS at 6 and 12 wk
2007 [126] (USA) secondary to BPH of 6 mo by dose escalation to 20 mg 12 wk and obstructive voiding $ Qmax and Qave
symptoms)
Roehrborn et al, 1b 1058 men with LUTS (IPSS >13) Daily tadalafil (dosage: 2.5, 5, 10, 12 wk IPSS, IIEF-EF, IPSS QoL, Significant " urinary symptoms from
2008 [127] (USA) related to BPH (886 completed study) or 20 mg) BPHII, LUTS GAQ 5 mg. >dose $ > side effects
vs placebo
Bechara et al, 1b 30 men >50 yr with a history Tadalafil 20 mg/d plus tamsulosin 45 d IPSS, IPSS-QoL Combined therapy was more effective
2008 [128] (Argentina) of LUTS/BPH of at least 6 mo 0.4 mg/d vs and it was also well tolerated
tamsulosin 0.4 mg alone
Stief et al, 1b Men aged 45–64 yr with BPH/ 10 mg vardenafil or placebo 8 wk IPSS, IIEF-EF, Urolife Significant " of irritative/obstructive
2008 [129] (Germany) LUTS and IPSS 12 twice daily QoL-9 questionnaire and general QoL
Gacci et al, 1b 60 men (mean age: 67 yr) with Combination of vardenafil 10 mg 12 wk IPSS, IPSS-bother, OAB-q Significant reduction of irritative
2011 [130] (Italy) persistent irritative urinary symptoms and tamsulosin 0,4 mg or symptoms with combined therapy
tamsulosin alone
Chung et al, 2a 120 men with comorbid BPH/ Combination of a-blocker 8 wk IPSS, IIEF Significant reduction of IPSS score, after
2009 [131] (Korea) ED under stable a-blocker therapy and udenafil 100 mg once daily 4-8 wk compared to a-blockers alone
BPH = benign prostatic hyperplasia; ED = erectile dysfunction; LUTS = lower urinary tract symptoms; BPHII = BPH Impact Index; IIEF = International Index of Erectile Function; IPSS = International Prostate Symptom Score;
OAB = overactive bladder; Qmax = maximum flow rate; QoL = quality of life; SHIM = Sexual Health Inventory for Men.
symptoms specifically compared with tamsulosin alone Author contributions: Mauro Gacci had full access to all the data in the
(IPSS: 16.7 vs 12.8; p = 0.014; IPSS-B: 3.8 vs 3.1; p = 0.045; study and takes responsibility for the integrity of the data and the
OAB-q: 17.7 vs 13.6; p = 0.006) [130]. accuracy of the data analysis.
Finally, udenafil 100 mg (a potent PDE5-I with a similar Study concept and design: Gacci.
molecular structure to sildenafil and widely prescribed in Acquisition of data: Eardley, Giuliano.
Korea) administered in 120 men with BPH and ED who had Analysis and interpretation of data: Hatzichritou, Kaplan.
been undergoing steady-dose a-blocker therapy resulted in Drafting of the manuscript: Maggi, McVary.
more significant relief of both LUTS and ED when combined Critical revision of the manuscript for important intellectual content:
with the a-blocker therapy (IPSS 11.5 vs 14.3; IIEF-5 18.32 Mirone, Porst, Roehrborn.
vs 11.95; p = 0.05) [131]. Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
3.4.3. Summary
Supervision: Gacci.
Preclinical and clinical research (Table 4) suggests that
Other (specify): None.
impaired NO–cGMP pathway, RhoA–ROCK signalling
activation, hyperactivation of pelvic nervous fibres, and Financial disclosures: I certify that all conflicts of interest, including
improvement of blood perfusion of pelvic organs should be specific financial interests and relationships and affiliations relevant
the underlying pathophysiologic findings explaining the to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
efficacy of PDE5-Is on BPH-related LUTS. Several studies
stock ownership or options, expert testimony, royalties, or patents filed,
based on all currently available PDE5-Is were able to show
received, or pending), are the following: None.
significant improvements in both LUTS and ED in men
affected by both conditions without an increase in adverse Funding/Support and role of the sponsor: None.
events [132]. Combination therapy with PDE5-Is and a1-
adrenergic blockers seems to have an additive beneficial
effect on BPH/LUTS compared with monotherapy [133].
References
4. Conclusions [1] Rosen RC. Update on the relationship between sexual dysfunction
and lower urinary tract symptoms/benign prostatic hyperplasia.
LUTS and sexual dysfunction are highly prevalent in aging Curr Opin Urol 2006;16:11–9.
men with LUTS associated with BPH. Several studies in [2] McVary KT. Erectile dysfunction and lower urinary tract symp-
toms secondary to BPH. Eur Urol 2005;47:838–45.
general and urologic and andrologic populations suggest
[3] Lowe FC. Treatment of lower urinary tract symptoms suggestive of
that men with LUTS related to BPH should be evaluated for
benign prostatic hyperplasia: sexual function. BJU Int 2005;95
sexual dysfunction and that those presenting with sexual
(Suppl 4):12–8.
dysfunction should be evaluated for LUTS. The four [4] Mouli S, McVary KT. PDE5 inhibitors for LUTS. Prostate Cancer
theories underlie the association between LUTS and ED Prostatic Dis 2009;12:316–24.
in BPH men: (1) alteration of the NO–cGMP pathway in [5] MacFarlane GJ, Botto H, Sagnier P-PP, Teillac P, Richard F, Boyle P.
prostate, bladder, and penis; (2) enhancement of the The relationship between sexual life and urinary condition in the
RhoA–ROCK contractile signalling, particularly in OAB; French community. J Clin Epidemiol 1996;10:1771–6.
(3) autonomic adrenergic hyperactivity effecting LUTS, [6] Rosen RC, Giuliano F, Carson CC. Sexual dysfunction and lower
prostate growth, and ED; and (4) pelvic atherosclerosis, urinary tract symptoms (LUTS) associated with benign prostatic
inducing prostate and penile ischemia. These theories are hyperplasia (BPH). Eur Urol 2005;47:824–37.
[7] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB.
well defined, and the common pathways linking these
Impotence and its medical and psychosocial correlates: results of
mechanisms allow us to better understand the patho-
the Massachusetts Male Aging Study. J Urol 1994;151:54–61.
physiology of both conditions.
[8] Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United
Every treatment for LUTS/BPH may have an impact on States. Prevalence and predictors. JAMA 1999;281:537–44.
some aspects of sexual function. Men with LUTS related to [9] Blanker MH, Bohnen AM, Groeneveld FP, et al. Correlates for
BPH should be informed of all possible sexual adverse erectile and ejaculatory dysfunction in older Dutch men: a com-
events of each treatment, and physicians should monitor munity-based study. J Am Geriatr Soc 2001;49:436–42.
the evolution of sexual activity during treatments. [10] Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann
PDE5-Is have demonstrated significant improvement in U. Epidemiology of erectile dysfunction: results of the ‘‘Cologne
both LUTS and ED in men with BPH, although these Male Survey.’’. Int J Impot Res 2000;12:305–11.
therapies did not affect urinary flow, indicating that the [11] Li MK, Garcia LA, Rosen R. Lower urinary tract symptoms and male
sexual dysfunction in Asia: a survey of ageing men from five Asian
mechanisms of action of these drugs on LUTS are not
countries. BJU Int 2005;96:1339–54.
completely understood. PDE5-Is may have an additional
[12] Shiri R, Häkkinen J, Koskimäki J, Hakama M, Tammela TL, Auvinen A.
role in combination with other therapies for BPH, such as a- Erectile dysfunction influences the subsequent incidence of lower
blockers and a-reductase inhibitors, to avoid sexual side- urinary tract symptoms and bother. Int J Impot Res 2007;19:317–20.
effects related to these treatments. Large prospective [13] Brookes ST, Link CL, Donovan JL, McKinlay JB. Relationship between
studies with adequate levels of evidence and grades of lower urinary tract symptoms and erectile dysfunction: results
recommendation are needed before suggesting chronic use from the Boston Area Community Health Survey. J Urol 2008;
of PDE5-Is as monotherapy or combined therapy. 179:250–5.
[14] Khoo EM, Tan HM, Low WY. Erectile dysfunction and comorbid- [34] Bouwman II, Van Der Heide WK, Van Der Meer K, Nijman R.
ities in aging men: an urban cross-sectional study in Malaysia. Correlations between lower urinary tract symptoms, erectile dys-
J Sex Med 2008;5:2925–34. function, and cardiovascular diseases: are there differences be-
[15] Holden CA, McLachlan RI, Pitts M, et al. Determinants of male tween male populations from primary healthcare and urology
reproductive health disorders: the Men in Australia Telephone clinics?. A review of the current knowledge. Eur J Gen Pract
Survey (MATeS). BMC Public Health 2010;10:96. 2009;15:128–35.
[16] Nicolosi A, Glasser DB, Moreira ED, Villa M. Prevalence of erectile [35] Köhler TS, McVary KT. The relationship between erectile dysfunc-
dysfunction and associated factors among men without concomi- tion and lower urinary tract symptoms and the role of phospho-
tant diseases: a population study. Int J Impot Res 2003;5:253–7. diesterase type 5 inhibitors. Eur Urol 2009;55:38–48.
[17] Boyle P, Robertson C, Mazzetta C, et al. UrEpik Study Group. The [36] Moon A. Influence of nitric oxide signalling pathways on pre-
association between lower urinary tract symptoms and erectile contracted human detrusor smooth muscle in vitro. BJU Int
dysfunction in four centres: the UrEpik study. BJU Int 2003;92: 2002;89:942–9.
719–25. [37] Kedia GT, Uckert S, Jonas U, Kuczyk MA, Burchardt M. The nitric
[18] Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms oxide pathway in the human prostate: clinical implications in
and male sexual dysfunction: the multinational survey of the men with lower urinary tract symptoms. World J Urol 2008;26:
aging male (MSAM-7). Eur Urol 2003;44:637–49. 603–9.
[19] Wein AJ, Coyne KS, Tubaro A, Sexton CC, Kopp ZS, Aiyer LP. The [38] Dixon JS, Jen PY. Development of nerves containing nitric oxide
impact of lower urinary tract symptoms on male sexual health: synthase in the human male urogenital organs. Br J Urol 1995;76:
EpiLUTS. BJU Int 2009;103(Suppl 3):33–41. 719–25.
[20] Schou J, Holm NR, Meyhoff HH. Sexual function in patients with [39] Gillespie JI, Markerink-van Ittersum M, De Vente J. Endogenous
symptomatic benign prostatic hyperplasia. Scand J Urol Nephrol nitric oxide/cGMP signalling in the guinea pig bladder: evidence
Suppl 1996;179:119–22. for distinct populations of sub-urothelial interstitial cells. Cell
[21] Namasivayam S, Minhas S, Brooke J, Joyce AD, Prescott S, Eardley I. Tissue Res 2006;325:325–32.
The evaluation of sexual function in men presenting with symp- [40] Hedlund P. Nitric oxide/cGMP-mediated effects in the outflow
tomatic benign prostatic hyperplasia. Br J Urol 1998;82:842–6. region of the lower urinary tract—is there a basis for pharmaco-
[22] Baniel J, Israilov S, Shmueli J, Segenreich E, Livne PM. Sexual logical targeting of cGMP? World J Urol 2005;23:362–7.
function in 131 patients with benign prostatic hyperplasia before [41] Persson K, Alm P, Johansson K, Larsson B, Andersson KE. Nitric
prostatectomy. Eur Urol 2000;38:53–8. oxide synthase in pig lower urinary tract: immunohistochemistry,
[23] Tubaro A, Polito M, Giambroni L, Famulari C, Gange E, Ostardo E. NADPH diaphorase histochemistry and functional effects. Br J
Sexual function in patients with LUTS suggestive of BPH. Eur Urol Pharmacol 1993;110:521–30.
2001;40(Suppl 1):19–22. [42] Fibbi B, Morelli A, Vignozzi L, et al. Characterization of phospho-
[24] Sak SC, Hussain Z, Johnston C, Eardley I. What is the relationship diesterase type 5 expression and functional activity in the human
between male sexual function and lower urinary tract symptoms male lower urinary tract. J Sex Med 2010;7:59–69.
(LUTS)? Eur Urol 2004;46:482–7. [43] Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED,
[25] Hoesl CE, Woll EM, Burkart M, Altwein JE. Erectile dysfunction metabolic syndrome and obesity: a pathological link supporting
(ED) is prevalent, bothersome and underdiagnosed in patients cardiovascular diseases. Int J Androl 2009;32:587–98.
consulting urologists for benign prostatic syndrome (BPS). Eur [44] Filippi S, Morelli A, Sandner P, et al. Characterization and func-
Urol 2005;47:511–7. tional role of androgen-dependent PDE5 activity in the bladder.
[26] Morant S, Bloomfield G, Vats V, Chapple C. Increased sexual Endocrinology 2007;148:1019–29.
dysfunction in men with storage and voiding lower urinary tract [45] Oger S, Behr-Roussel D, Gorny D, et al. Signalling pathways in-
symptoms. J Sex Med 2009;6:1103–10. volved in sildenafil-induced relaxation of human bladder dome
[27] El-Sakka AI. Lower urinary tract symptoms in patients with erec- smooth muscle. Br J Pharmacol 2010;160:1135–43.
tile dysfunction: analysis of risk factors. J Sex Med 2006;3:144–9. [46] Morelli A, Chavalmane AK, Filippi S, et al. Atorvastatin ameliorates
[28] McVary K, Foley KA, Long SR, Sander S, Curtice TG, Shah H. sildenafil-induced penile erections in experimental diabetes by
Identifying patients with benign prostatic hyperplasia through inhibiting diabetes-induced RhoA/Rho-kinase signalling hyper-
a diagnosis of, or treatment for, erectile dysfunction. Curr Med Res activation. J Sex Med 2009;6:91–106.
Opin 2008;24:775–84. [47] Morelli A, Vignozzi L, Filippi S, et al. BXL-628, a vitamin D receptor
[29] Reggio E, de Bessa Jr J, Junqueira RG, et al. Correlation between lower agonist effective in benign prostatic hyperplasia treatment, pre-
urinary tract symptoms and erectile dysfunction in men presenting vents RhoA activation and inhibits RhoA/Rho kinase signaling in
for prostate cancer screening. Int J Impot Res 2007;19:492–5. rat and human bladder. Prostate 2007;67:234–47.
[30] Antunes AA, Srougi M, Dall’oglio MF, Vicentini F, Paranhos M, [48] Fibbi B, Morelli A, Marini M, et al. Atorvastatin but not elocalcitol
Freire GC. The role of BPH, lower urinary tract symptoms, and PSA increases sildenafil responsiveness in spontaneously hypertensive
levels on erectile function of Brazilian men who undergo prostate rats by regulating the RhoA/ROCK pathway. J Androl 2008;29:
cancer screening. J Sex Med 2008;5:1702–7. 70–84.
[31] Frankel SJ, Donovan JL, Peters TI, et al. Sexual dysfunction in men [49] Wibberley A, Chen Z, Hu E, Hieble JP, Westfall TD. Expression and
with lower urinary tract symptoms. J Clin Epidemiol 1998;51: functional role of Rho-kinase in rat urinary bladder smooth mus-
677–85. cle. Br J Pharmacol 2003;138:757–66.
[32] Vallancien G, Emberton M, Harving N, van Moorselaar RJ. Sexual [50] Rajasekaran M, Wilkes N, Kuntz S, E Albo M. Rho-kinase inhibition
dysfunction in 1,274 European men suffering from lower urinary suppresses bladder hyperactivity in spontaneously hypertensive
tract symptoms. J Urol 2003;169:2257–61. rats. Neurourol Urodyn 2005;24:295–300.
[33] Li MK, Garcia L, Patron N, et al. An Asian multinational prospective [51] Morelli A, Filippi S, Sandner P, et al. Vardenafil modulates bladder
observational registry of patients with benign prostatic hyperpla- contractility through cGMP-mediated inhibition of RhoA/Rho ki-
sia, with a focus on comorbidities, lower urinary tract symptoms nase signaling pathway in spontaneously hypertensive rats. J Sex
and sexual function. BJU Int 2008;101:197–202. Med 2009;6:1594–608.
[52] Yassin A, Saad F, Hoesl CE, Traish AM, Hammadeh M, Shabsigh R. [71] Leliefeld HHF, Stoevelaar HJ, Mc Donnell J. Sexual function before
Alpha-adrenoceptors are a common denominator in the patho- and after various treatments for symptomatic benign hyperplasia.
physiology of erectile function and BPH/LUTS—implications for BJU Int 2002;89:208–13.
clinical practice. Andrologia 2006;38:1–12. [72] Nickel JC, Shosker D, Roehrborn CG, Moyad M. Nutriceuticals in
[53] Rahman NU, Phonsombat S, Bochinski D, Carrion RE, Nunes L, Lue TF. prostate disease: the urologist’s role. Rev Urol 2008;10:192–206.
An animal model to study lower urinary tract symptoms and [73] Wilt JT, Ishani A, Rutks I, MacDonald R. Phytotherapy for benign
erectile dysfunction: the hyperlipidaemic rat. BJU Int 2007;100: prostatic hyperplasia. Public Health Nutrition 2000;3:459–72.
658–63. [74] Zlotta AR, Teillac P, Raynaud JP, Schulman CC. Evaluation of male
[54] Vikram A, Jena GB, Ramarao P. Increased cell proliferation and sexual function in patients with lower urinary tract symptoms
contractility of prostate in insulin resistant rats: linking hyperinsu- (LUTS) associated with benign prostatic hyperplasia (BPH) treated
linemia with benign prostate hyperplasia. Prostate 2010;70: 79–89. with a phytotherapeutic agent (Permixon1), tamsulosin or finas-
[55] Golomb E, Rosen R, Zweig N, et al. Spontaneous hyperplasia of the teride. Eur Urol 2005;48:269–76.
ventral lobe of the prostate in aging genetically hypertensive rats. [75] Seo KK, Lee MY, Lim SW, Kim SC. Comparison of relaxation
J Androl 2000;21:58–64. responses of cavernous and trigonal smooth muscles from
[56] Persson K, Pandita RK, Spitsbergen JM, Steers WD, Tuttle JB, rabbits by alpha1-adrenoceptor antagonists: prazosin, terazosin,
Andersson KE. Spinal and peripheral mechanisms contributing doxazosin, and tamsulosin. J Korean Med Sci 1999;14:69–74.
to hyperactive voiding in spontaneously hypertensive rats. Am J [76] Van Dijk MM, De La Rosette JJ, Michel MC. Effects of alpha 1
Physiol 1998;275:R1366–73. adrenoceptor antagonists on male sexual function. Drugs 2006;
[57] Montorsi P, Ravagnani PM, Galli S, et al. Association between erectile 66:287–301.
dysfunction and coronary artery disease: matching the right target [77] Lepor H, Williford WO, Barry MJ, Haakenson C, Jones K. The impact
with the right test in the right patient. Eur Urol 2006;50:721–31. of medical therapy on bother due to symptoms, quality of life and
[58] Berger AP, Deibl M, Leonhartsberger N, et al. Vascular damage as a global outcome, and factors predicting response. J Urol 1998;160:
risk factor for benign prostatic hyperplasia and erectile dysfunc- 1358–67.
tion. BJU Int 2005;96:1073–8. [78] Goldstein I. Oral phentolamine: an alpha -1, alpha-2 adrenergic
[59] Ghafar MA, Anastasiadis AG, Olsson LE, et al. Hypoxia and an antagonist for the treatment of erectile dysfunction. Int J Imp Res
angiogenic response in the partially obstructed rat bladder. Lab 2000;12(Suppl 1):S75–80.
Invest 2002;82:903–9. [79] Kumar R, Nehra A, Jacobson DJ, et al. Alpha blocker use is associ-
[60] Tarcan T, Azadzoi KM, Siroky MB, Goldstein I, Krane RJ. Age-related ated with decreased risk of sexual dysfunction. Urology 2009;74:
erectile and voiding dysfunction: the role of arterial insufficiency. 82–7.
Br J Urol 1998;82(Suppl 1):26–33. [80] Wilt TJ, Howe W, MacDonald R. Terazosin for treating symptom-
[61] Du Z, Fujiyama C, Chen Y, Masaki Z. Expression of hypoxia- atic benign prostatic obstruction: a systematic review of efficacy
inducible factor 1alpha in human normal, benign, and malignant and adverse effects. BJU Int 2002;89:214–25.
prostate tissue. Chin Med J (Engl) 2003;116:1936–9. [81] MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower
[62] Lekas AG, Lazaris AC, Chrisofos M, et al. Finasteride effects on urinary tract symptoms compatible with benign prostatic ob-
hypoxia and angiogenetic markers in benign prostatic hyperpla- struction: a systematic review of efficacy and adverse effects.
sia. Urology 2006;68:436–41. BJU Int 2004;94:1263–70.
[63] Gu BJ, Ishizuka O, Igawa Y, Nishizawa O, Andersson KE. Role of [82] Höfner K, Claes H, De Reijke TM, Folkestad B, Speakman MJ.
supraspinal alpha1-adrenoceptors for voiding in conscious rats Tamsulosin 0.4 mg once daily: effect on sexual function in patients
with and without bladder outlet obstruction. J Urol 2002;167: with lower urinary tract symptoms suggestive of benign prostatic
1887–91. obstruction. Eur Urol 1999;36:335–41.
[64] Morelli A, Filippi S, Comeglio P, et al. Acute vardenafil adminis- [83] Roehrborn CG, Rosen RC. Medical therapy options for aging men
tration improves bladder oxygenation in spontaneously hyper- with benign prostatic hyperplasia: focus on alfuzosin 10 mg once
tensive rats. J Sex Med 2010;7:107–20. daily. Clin Interv Aging 2008;3:511–24.
[65] Penna G, Fibbi B, Amuchastegui S, et al. Human benign prostatic [84] Kirby RS, O’Leary MP, Carson C. Efficacy of extended release
hyperplasia stromal cells as inducers and targets of chronic doxazosin and doxazosin standard in patients with concomitant
immuno-mediated inflammation. J Immunol 2009;182:4056–64. benign prostatic hyperplasia and sexual dysfunction. BJU Int 2005;
[66] Penna G, Fibbi B, Amuchastegui S, et al. The vitamin D receptor 95:103–9.
agonist elocalcitol inhibits IL-8-dependent benign prostatic hy- [85] Lepor H. Phase III multicenter placebocontrolled study of tamsu-
perplasia stromal cell proliferation and inflammatory response by losin in benign prostatic hyperplasia. Urology 1998;51:892–900.
targeting the RhoA/Rho kinase and NF-kappaB pathways. Prostate [86] Kobayashi K, Masumori N, Hisasue S, et al. Inhibition of seminal
2009;69:480–93. emission is the main cause of anejaculation induced by a new
[67] Corona G, Maggi M. The role of testosterone in erectile dysfunc- highly selective alpha 1A-blocker in normal volunteers. J Sex Med
tion. Nat Rev Urol 2010;7:46–56. 2008;5:2185–90.
[68] Carbone Jr DJ, Hodges S. Medical therapy for benign prostatic [87] Hellstrom WJG, Sikka SC. Effects of acute treatment with tamsu-
hyperplasia: sexual dysfunction and impact on quality of life. Int J losin versus alfuzosin on ejaculatory function in healthy volun-
Impot Res 2003;15:299–306. teers. J Urol 2006;76:1529–33.
[69] Rosen RC, Wei JT, Althof SE, Seftel AD, Miner M, Perelman MA. BPH [88] Hisasue SI, Furuya R, Itoh N, et al. Ejaculatory disorder induced by
Registry and Patient Survey Steering Committee. Association of alpha–adrenergic receptor blockade is not retrograde ejaculation.
sexual dysfunction with lower urinary tract symptoms of BPH J Urol 2005;173(Suppl)(290):A1069.
and BPH medical therapies: results from the BPH Registry. Urology [89] Giuliano F, Clément P, Denys P, Alexandre L, Bernabé J. Comparison
2009;73:562–6. between tamsulosin and alfuzosin on expulsion phase of ejacula-
[70] AUA Practice Guidelines Committee. AUA guideline on manage- tion in rats. BJU Int 2006;98:876–9.
ment of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis [90] Yokoyama T, Hara R, Fukumoto K, et al. Effects of three types of
and treatment recommendations. J Urol 2003;170:530-47. alpha-1 adrenoceptor blocker on lower urinary tract symptoms
and sexual function in males with benign prostatic hyperplasia. [108] Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson
Int J Urol 2011;18:225–30. WG. A comparison of transurethral surgery with watchful waiting
[91] Chapple CR, Montorsi F, Tammela TLJ, Wirth M, Koldewijn E, for moderate symptoms of benign prostatic hyperplasia: the Veter-
Fernández Fernández E, on behalf of the European Silodosin Study ans Affairs Cooperative Study Group on Transurethral Resection of
Group. Silodosin therapy for lower urinary tract symptoms in men the Prostate. N Eng J Med 1995;332:75–9.
with suspected benign prostatic hyperplasia: results of an interna- [109] Lourenco T, Shaw M, Fraser C, MacLennan G, N’Dow J, Pickard R.
tional, randomized, double-blind, placebo- and active-controlled The clinical effectiveness of transurethral incision of the prostate:
clinical trial performed in Europe. Eur Urol 2011;59:342–52. a systematic review of randomized controlled trials. World J Urol
[92] Kobayashi K, Masumori N, Kato R, Hisasue S, Furuya R, Tsukamoto 2010;28:23–32.
T. Orgasm is preserved regardless of ejaculatory dysfunction with [110] Roehrborn CG. Standard surgical interventions: TURP/TUIP/OPSU.
selective alpha 1A-blocker administration. Int J Imp Res 2009;21: In: Kirby R, McConnell J, Fitzpatrick J, et al. editors. Textbook of
306–10. benign prostatic hyperplasia.. Oxford, UK: ISIS Medical Media;
[93] Homma Y, Kawabe K, Takeda M, Yoshida M. Ejaculation disorder is 1996. p. 341–78.
associated with increased efficacy of silodosin for benign prostatic [111] Soleimani M, Hosseini SY, Aliasgari M, Dadkhah F, Lashay A, Amini
hyperplasia. Urology 2010;76:1446–50. E. Erectile dysfunction after prostatectomy: an evaluation of the
[94] Giuliano F. Impact of medical treatments for benign prostatic risk factors. Scand J Urol Nephrol 2009;43:277–81.
hyperplasia on sexual function. BJU Int 2006;97(Suppl 2):34–8. [112] Chen Q, Zhang L, Fan QL, Zhou J, Peng YB, Wang Z. Bipolar
[95] Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride transurethral resection in saline vs traditional monopolar resec-
therapy for benign prostatic hyperplasia: results of a 2-year ran- tion of the prostate: results of a randomized trial with a 2-year
domised controlled trial (the PROSPECT study). CMAJ 1996;155: follow-up. BJU Int 2010;106:1339–43.
1251–9. [113] Naspro R, Bachmann A, Gilling P, et al. A review of the recent
[96] Erdemir F, Harbin A, Hellstrom WJ. 5-alpha reductase inhibitors evidence (2006–2008) for 532-nm photoselective laser vaporisa-
and erectile dysfunction: the connection. J Sex Med 2008;5: tion and holmium laser enucleation of the prostate. Eur Urol
2917–24. 2009;55:1345–57.
[97] Moinpour CM, Darke AK, Donaldson GW, et al. Longitudinal [114] Briganti A, Naspro R, Gallina A, et al. Impact on sexual function of
analysis of sexual function reported by men in the Prostate Cancer holmium laser enucleation versus transurethral resection of the
Prevention Trial. J Natl Cancer Inst 2007;99:1025–35. prostate: results of a prospective, 2-center, randomized trial.
[98] Roehrborn CG, Siami P, Barkin J, et al. CombAT Study Group. The J Urol 2006;175:1817–21.
effects of dutasteride, tamsulosin and combination therapy on [115] Alivizatos G, Skolarikos A, Chalikopoulos D, et al. Transurethral
lower urinary tract symptoms in men with benign prostatic photoselective vaporization versus transvesical open enucleation
hyperplasia and prostatic enlargement: 2-year results from the for prostatic adenomas >80 ml: 12-mo results of a randomized
CombAT study. J Urol 2008;179:616–21. prospective study. Eur Urol 2008;54:427–37.
[99] Tunuguntla HS, Evans CP. Minimally invasive therapies for benign [116] Miner MM. Primary care physician versus urologist: how does
prostatic hyperplasia. World J Urol 2002;20:197–206. their medical management of LUTS associated with BPH differ?
[100] Hoffman RM, Monga M, Elliot SP, Macdonald R, Wilt TJ. Microwave Curr Urol Rep 2009;10:254–60.
thermotherapy for benign prostatic hyperplasia. Cochrane Data- [117] Ahyai SA, Gilling P, Kaplan SA, et al. Meta-analysis of functional
base Syst Rev 2007:CD004135. outcomes and complications following transurethral procedures
[101] Bouza C, López T, Magro A, Navalpotro L, Amate JM. Systematic for lower urinary tract symptoms resulting from benign prostatic
review and meta-analysis of transurethral needle ablation in enlargement. Eur Urol 2010;58:384–97.
symptomatic benign prostatic hyperplasia. BMC Urol 2006;6:14. [118] Gacci M, Bartoletti R, Figlioli S, et al. Urinary symptoms, quality of
[102] Kursh ED, Concepcion R, Chan S, Hudson P, Ratner M, Eyre R. life and sexual function in patients with benign prostatic hyper-
Interstitial laser coagulation versus transurethral prostate resec- trophy before and after prostatectomy: a prospective study. BJU
tion for treating benign prostatic obstruction: a randomized trial Int 2003;91:196–200.
with 2-year follow-up. Urology 2003;61:573–8. [119] Montorsi F, Corbin J, Phillips S. Review of phosphodiesterases in
[103] Arai Y, Aoki Y, Okubo K, et al. Impact of interventional therapy for the urogenital system: new directions for therapeutic interven-
benign prostatic hyperplasia on quality of life and sexual function: tion. J Sex Med 2004;1:322–36.
a prospective study. J Urol 2000;164:1206–11. [120] Zhao C, Kim SH, Lee SW, et al. Activity of phosphodiesterase type 5
[104] Madersbacher S, Alivizatos G, Nordling J, Sanz CR, Emberton M, inhibitors in patients with lower urinary tract symptoms due to
de la Rosette JJMCH. EAU 2004 guidelines on assessment, therapy benign prostatic hyperplasia. BJU Int 2011;107:1943–7.
and follow-up of men with lower urinary tract symptoms sugges- [121] Gacci M, Del Popolo G, Macchiarella A, et al. Vardenafil improves
tive of benign prostatic obstruction (BPH guidelines). Eur Urol urodynamic parameters in men with spinal cord injury: results
2004;46:547-54. from a single dose, pilot study. J Urol 2007; 178:2040-3; discus-
[105] Mebust WK, Holtgrewe HL, Cockett AT, Peters PC. Transurethral sion 2044.
prostatectomy: immediate and postoperative complications. a [122] Gacci M, Ierardi A, Rose AD, et al. Vardenafil can improve conti-
cooperative study of 13 participating institutions evaluating nence recovery after bilateral nerve sparing prostatectomy:
3,885 patients. J Urol 2002;167:999–1003. results of a randomized, double blind, placebo-controlled pilot
[106] Bieri S, Iselin CE, Rohner S. Capsular perforation localization and study. J Sex Med 2010;7:234–43.
adenoma size as prognostic indicators of erectile dysfunctional [123] Bertolotto M, Trincia E, Zappetti R, Bernich R, Savoca G, Cova MA.
after transurethral prostatectomy. Scand J Urol Nephrol 1997;31: Effect of tadalafil on prostate haemodynamics: preliminary
545–8. evaluation with contrast-enhanced US. Radiol Med 2009;114:
[107] Tscholl R, Largo M, Poppinghaus E, Recker F, Subotic B. Incidence of 1106–14.
erectile impotence secondary to transurethral resection of benign [124] McVary KT, Monnig W, Camps Jr JL, Young JM, Tseng L-J, Van Den
prostatic hyperplasia, assessed by preoperative and postoperative Eeden G. Sildenafil citrate improves erectile function and urinary
Snap Gauge tests. J Urol 1995;153:1491–3. symptoms in men with erectile dysfunction and lower urinary
tract symptoms associated with benign prostatic hyperplasia: a [129] Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised,
randomized double-blind trial. J Urol 2007;177:1071–7. placebo-controlled study to assess the efficacy of twice-daily
[125] Tuncel A, Nalcacioglu V, Ener K, Aslan Y, Aydin O, Atan A. Sildenafil vardenafil in the treatment of lower urinary tract symptoms sec-
citrate and tamsulosin combination is not superior to monother- ondary to benign prostatic hyperplasia. Eur Urol 2008;53:1236–44.
apy in treating lower urinary tract symptoms and erectile dys- [130] Gacci M, Vittori G, Siena G, et al. Long term safety and efficacy of
function. World J Urol 2010;28:17–22. combination therapy with vardenafil 10 mg and tamsulosin
[126] McVary K, Roehborn C, Kaminetsky J, et al. Tadalafil relieves lower 0,4 mg for persistent irritative LUTS: a randomized double blind
urinary tract symptoms (LUTS) secondary to benign prostatic placebo controlled study. Eur Urol Suppl 2011;10:123.
hyperplasia (BPH). J Urol 2007;177:1401–7. [131] Chung BH, Lee JY, Lee SH, Yoo SJ, Lee SW, Oh CY. Safety and efficacy
[127] Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil of the simultaneous administration of udenafil and an alpha-
administered once daily for lower urinary tract symptoms sec- blocker in men with erectile dysfunction concomitant with
ondary to benign prostatic hyperplasia: a dose finding study. BPH/LUTS. Int J Impot Res 2009;21:122–8.
J Urol 2008;180:1228–34. [132] Speakman MJ. PDE5 inhibitors in the treatment of LUTS. Curr
[128] Bechara A, Romano S, Casabé A, et al. Comparative efficacy as- Pharm Des 2009;15:3502–5.
sessment of tamsulosin vs. tamsulosin plus tadalafil in the treat- [133] Wang C. Phosphodiesterase-5 inhibitors and benign prostatic
ment of LUTS/BPH. Pilot study. J Sex Med 2008;5:2170–8. hyperplasia. Curr Opin Urol 2010;20:49–54.

Critical Analysis of The Relationship Between Sexual Dysfunctions and Lower Urinary Tract Symptoms Due To Benign Prostatic Hyperplasia

Uploaded by

Copyright:

Available Formats

Critical Analysis of The Relationship Between Sexual Dysfunctions and Lower Urinary Tract Symptoms Due To Benign Prostatic Hyperplasia

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Critical Analysis of The Relationship Between Sexual Dysfunctions and Lower Urinary Tract Symptoms Due To Benign Prostatic Hyperplasia

Uploaded by

Copyright:

Available Formats

EUROPEAN UROLOGY 60 (2011) 809–825

Collaborative Review – Sexual Medicine – LUTS