European European Urology 47 (2005) 824–837

Urology

Review
Sexual Dysfunction and Lower UrinaryTract Symptoms
(LUTS) Associated with Benign Prostatic Hyperplasia (BPH)
Raymond C. Rosena,*, Francois Giulianob, Culley C. Carsonc
a
Department of Psychiatry, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
b
Department of Urology, CHU de Bicêtre, Le Kremlin Bicêtre, France
c
Department of Urology, University of North Carolina, Chapel Hill, NC, USA
Accepted 17 December 2004
Available online 5 January 2005

Abstract
Sexuality is an essential aspect of a couple’s relationship and has a significant impact on life satisfaction. Benign
prostatic hyperplasia (BPH) is a condition that commonly affects older men and is often associated with lower
urinary tract symptoms (LUTS) and sexual dysfunction. Men with moderate-to-severe LUTS are at increased risk
for sexual dysfunction, including moderate-to-severe erectile dysfunction (ED), ejaculatory dysfunction (EjD), and
hypoactive desire (HD). The results of several recent large-scale studies have shown a consistent and strong
relationship between LUTS and both ED and EjD. It appears that the pathophysiological mechanisms of LUTS and
the related prostatic enlargement of BPH as well as certain treatments for this condition may have an impact on both
the erection and ejaculation components of the sexual response. Validated questionnaires that assess sexual function
provide clinicians with valuable information to help guide treatment selection decisions. Effective medical therapies
for LUTS associated with BPH include a1-adrenergic receptor antagonists (i.e., alfuzosin, doxazosin, tamsulosin,
and terazosin) and 5a-reductase inhibitors (i.e., finasteride and dutasteride). The side effects of these medications,
including sexual dysfunction, are important distinguishing features. The successful management of patients with
LUTS associated with BPH should include assessments of sexual function and monitoring of medication-related
sexual side effects. For men with LUTS and sexual dysfunction, an appropriate integrated management approach,
based on each patient’s symptoms and outcome objectives, is warranted.
# 2004 Elsevier B.V. All rights reserved.

Keywords: Benign prostatic hyperplasia; Lower urinary tract symptoms; Sexual dysfunction; Impotence; Erectile
dysfunction; Ejaculatory dysfunction; Medical therapy

1. Introduction tion [2]), and hypoactive desire (HD; loss of desire or

decreased desire) were a natural consequence of the aging
Until recently, it was widely assumed that symptoms process. As a result, many older men did not seek help for
of male sexual dysfunction, including erectile dysfunc- their sexual problems and healthcare providers frequently
tion (ED; persistent inability to achieve and maintain an failed to ask their patients about their sexual concerns.
erection sufficient for satisfactory sexual performance Recent studies have shown that a decrease in sexual
[1]), ejaculatory dysfunction (EjD; any disturbance in the function and sexual activity is not an inevitable conse-
male ejaculatory reflex, including loss of ejaculation, quence of aging. Furthermore, effective and well-toler-
ejaculation with a decreased amount of semen, premature ated treatments (e.g., phosphodiesterase type 5 inhibitors
ejaculation, delayed ejaculation, and retrograde ejacula- for the treatment of ED) are available for managing many
of these conditions.
* Corresponding author. Tel. +1 732 2354485; Fax: +1 732 235 5818. Various studies have assessed the prevalence of
E-mail address: rosen@umdnj.edu (R.C. Rosen). different types of male sexual dysfunction, often using
0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2004.12.013
 R.C. Rosen et al. / European Urology 47 (2005) 824–837 825

varying definitions for the condition being assessed. particular focus on LUTS associated with BPH, as well
The results of a large-scale, population-based study of as medical treatment options for symptomatic BPH and
men aged 40 to 70 years, the Massachusetts Male their effects on sexual function.
Aging Study (MMAS), demonstrated that ED had a
high prevalence (52%), with nearly 35% of the men
reporting moderate-to-severe ED [3]. The prevalence 2. Relationship between LUTS/BPH and
of complete ED was age-dependent, increasing from male sexual dysfunction
5% for men aged 40 years to 15% for those aged 70
years. However, ED was also significantly associated 2.1. Epidemiological evidence
with various age-independent predictor variables [3]. 2.1.1. General population studies
Based on MMAS data, it has been estimated that the Data from the National Health and Social Life
worldwide prevalence of ED will be 322 million men in Survey (NHSLS), a population-based representative
2025 [4]. Other study results indicated that older sample of US adults aged 18 to 59 years, demonstrated
individuals retain significant interest in sexuality and a high prevalence of sexual dysfunction in men (31%)
that a large proportion of older men and women remain and women (43%) [9]. Increasing age in men was
sexually active [5,6]. Furthermore, sexuality is a associated with significantly higher prevalence rates
factor that correlates with individuals’ perception of of ED and HD. The results of the NHSLS also indicated
their well-being and quality of life [7]. With the that LUTS was a significant predictor for ED [9]. A
development of new measures for assessing sexual study of 2476 Spanish men aged 25 to 70 years
function and new medications for the treatment of indicated that the prevalence of ED was 12% to
ED, regular discussions between healthcare providers 19%, with the rate dependent on the self-administered
and patients on sexual problems can lead to effective questionnaire used to assess sexual function [10]. Age-
management strategies and improvements in patient adjusted risk factors for ED included LUTS, rheumatic
quality of life. disease, circulatory disease, lung disease, diabetes, and
Lower urinary tract symptoms (LUTS; urinary fre- hypertension. A population-based multinational (4
quency, urgency, decreased urine flow rates, nocturia) countries) study, the UrEpik study, investigated the
are common problems in aging individuals. Benign relationship between LUTS and sexual dysfunction
prostatic hyperplasia (BPH) is the primary cause of in 4800 men aged 40 to 79 years [11]. The overall
LUTS in men aged 50 years and older. The presence of prevalence of ED was 21%, which was significantly
histological BPH at autopsy is approximately 8% in associated with increasing age (p < 0.001). After
men aged 31 to 40 years, 50% in those aged 51 to 60 adjusting for age and country, men with diabetes,
years, 70% in those aged 61 to 70 years, and 90% in hypertension, or LUTS had a greater risk of ED.
those aged 81 to 90 years [8]. Unfortunately, the Age- and country-adjusted risk of HD was also
MMAS did not evaluate LUTS as a possible predictor strongly associated with LUTS, even after adjusting
variable for ED. Thus, although both male sexual for ED [11].
dysfunction and LUTS were known to be age-depen- Some subsequent large-scale studies examining the
dent, the exact relationship between these 2 conditions relationship between LUTS and sexual dysfunction
remained unclear. However, more recent large-scale controlled not only for the effect of age but also for
epidemiological studies with different population sam- various medical comorbidities and lifestyle factors
ples and various measurement approaches have (Table 1). In the Cologne Male Survey of approxi-
demonstrated consistent and compelling evidence of mately 5000 German men aged 30 to 80 years, the
a relationship between LUTS and sexual dysfunction in overall prevalence of ED was 19%, with a significant
aging men that is independent of the effects of age or association between ED and LUTS, hypertension,
other comorbidities. These studies, including the Mul- diabetes, and pelvic surgery [5]. In fact, the prevalence
tinational Survey of the Aging Male (MSAM-7) [6], of LUTS was 72% in men with ED versus 38% in those
and new pathophysiological insights have provided without ED. An additional analysis of the Cologne
valuable information on the relationship between Male Survey data used multifactorial methods to show
LUTS and sexual dysfunction in aging men. Moreover, that, in addition to age, diabetes, hypertension, and
these advances have resulted in new approaches to the pelvic surgery, LUTS is an independent risk factor for
evaluation of these disorders and the selection of ED [12].
treatment options. The present review article provides The results of a community-based study of 1688
an overview of current knowledge on the relationship men in the Netherlands showed that the prevalence of
between male sexual dysfunction and LUTS, with a severe ED increased from 3% in men aged 50 to 54
826 R.C. Rosen et al. / European Urology 47 (2005) 824–837

Table 1
Prevalence of sexual dysfunction and significant comorbidities in various large-scale, population-based, epidemiology studies

Study Country Sample Prevalence Significant comorbidities

Martin-Morales et al. [10] Spain 2476 men aged 25 to 70 y ED: 12%–19% ED: LUTS, diabetes,
(assessment dependent) lung disease, CVD,
allergy, rheumatic disease,
heart disease, hypertension
Boyle et al. [11] UK, Netherlands, 4800 men aged 40 to 79 y ED: 21% ED: LUTS, diabetes,
France, Korea hypertension
HD: 28% HD: ED, LUTS
Braun et al. [5]; Germany 8000 men aged 30 to 80 y ED: 19% ED: LUTS*,
Braun et al. [12] hypertension, diabetes
Blanker et al. [13,14] Netherlands 1688 men aged 50 to 78 y Severe ED: 3% (50–54 y); Severe ED: LUTS*,
26% (70–78 y) obesity*, CVD*, COPD*
Severe EjD: 3% (50–54 y); Severe EjD: ED*, LUTS*
35% (70–78 y)
Nicolosi et al. [15] Brazil, Italy, Japan, 2412 men aged 40 to 70 y ED (moderate-complete): ED: moderate-severe
Malaysia (n = 1335 healthy men 16% in healthy men LUTS* (healthy men)
with no CVD, prostate (32% in diseased men)
disease, diabetes, ulcer,
or depression diagnosis)
Rosen et al. [6] US, UK, France, 12,815 men aged 50 to 80 y ED: 49% ED: LUTS*
Germany, (US 55%, Europe 45%)
Netherlands, EjD: 45% EjD: LUTS*
Italy, Spain Pain during ejaculation: Pain during ejaculation: LUTS*
7% (LUTS: 90%)
Hansen [16] Denmark 3442 men aged 40 to 65 y ED: 29% (LUTS: 39%) ED: LUTS*
BPH: benign prostatic hyperplasia; COPD: chronic obstructive pulmonary disease; CVD: cardiovascular disease; ED: erectile dysfunction; EjD: ejaculatory
dysfunction; HD: hypoactive desire; LUTS: lower urinary tract symptoms.
*
Independent risk factor based on multiple logistic regression analysis.

years to 26% in those aged 70 to 78 years and severe June 1998, 1335 men answered a question on ED (How
EjD (defined as ejaculation with decreased amount of would you describe yourself: always, usually, some-
semen or loss of ejaculation) increased from 3% to times, or never able to get and keep an erection good
35% [13]. Age, LUTS, obesity, cardiovascular disease, enough for sexual intercourse?) and reported no pre-
chronic obstructive pulmonary disease, and smoking vious diagnosis of cardiovascular disease, prostate
were significant risk factors for ED. Significant risk disease or surgery, diabetes, ulcer, or depression and
factors for EjD included age, ED, LUTS, and previous that they were not taking hormones. The prevalence of
transurethral resection of the prostate (TURP) [13]. moderate or complete ED in these healthy men was
The results of multiple logistic regression analyses of 16%, which was markedly lower than the 32% pre-
data from this community-based study demonstrated valence rate in the 1077 men who reported 1 or more
that LUTS was an independent risk factor for severe concomitant conditions. In the healthy men, multi-
ED and severe EjD [14]. This study, which was the first variate logistic regression analysis indicated that mod-
large-scale, community-based survey of EjD in older erate (odds ratio 2.2, 95% CI: 1.2 to 3.9) and severe
men, also included transrectal ultrasonography of the (odds ratio 4.9, 95% CI: 1.4 to 16.7) LUTS were the
prostate and uroflowometry for most of the men. In most significant predictors for ED.
bivariate logistic regression analysis, prostate enlarge- In the most comprehensive study conducted to date
ment was a significant correlate for severe ED, but this on the association of age, LUTS, concomitant comor-
association was not significant in multiple logistic bidities, and male sexual dysfunction (both ED and
regression models [13]. EjD), the MSAM-7 analyzed survey results from
The Cross National Study on the Epidemiology of 12,815 men aged 50 to 80 years in the United States
ED and its Correlates assessed the prevalence of ED in and 6 European countries [6]. Overall, the results of
relatively healthy men in 4 countries (Brazil, Italy, this study strongly confirmed the relationship between
Japan, and Malaysia) [15]. Of 2513 men aged 40 to 70 LUTS and sexual dysfunction in men, independent of
years who were interviewed between October 1997 and the effects of age, other comorbidities, and lifestyle
 R.C. Rosen et al. / European Urology 47 (2005) 824–837 827

factors. In the MSAM-7, the overall prevalence of from 41% to 71% and from 38% to 70%, respectively,
LUTS of any severity was 90%, with the prevalence whereas the prevalence of HD was 32% to 66% and of
of moderate-to-severe LUTS significantly related to pain with ejaculation was 17% to 23% [17–23]. Two of
age (p < 0.0001) [6]. Interestingly, only 19% of the these studies were multinational studies. In a urology
men with LUTS sought medical assistance and only clinic-based sample of 1271 men aged 45 years and
10% were treated. The overall prevalence of ED (dif- older from 12 countries, the prevalence rates of ED,
ficulty achieving an erection) in the MSAM-7 was EjD (defined as ejaculation with a decreased amount of
49%, with 10% reporting complete absence of erec- semen or loss of ejaculation), and pain/discomfort
tions [6]. The prevalence of self-reported ED was during ejaculation were 60%, 62%, and 17%, respec-
somewhat higher in US men (55%) than in European tively [18]. After adjusting for age, a significant posi-
men (45%). The prevalence of ED was age-dependent, tive association was found between ED and LUTS,
with rates of 31%, 55%, and 76% in men aged 50 to 59 between EjD and LUTS, and between pain/discomfort
years, 60 to 69 years, and 70 to 80 years, respectively. during ejaculation and LUTS in this clinic sample of
Importantly, the overall prevalence of EjD (defined men. Data on the prevalence of sexual dysfunction
as ejaculation with decreased amount of semen or loss according to country suggested international differ-
of ejaculation) in men able to achieve erections was ences in self-reported ED, EjD, and pain/discomfort
46%, with 5% of the men reporting complete absence during ejaculation [18]. In the second multinational
of ejaculation [6]. The rates of self-reported EjD were study of 927 men aged 36 to 92 years with LUTS
comparable in US men and European men. As was associated with BPH from 5 European countries, the
observed with ED, the prevalence of EjD was age- prevalence rates of ED (62%) and EjD (defined as
dependent, with rates of 29%, 55%, and 74% in men ejaculation with a decreased amount of semen or loss
aged 50 to 59 years, 60 to 69 years, and 70 to 80 years, of ejaculation; 63%) were comparable, whereas pain/
respectively. Sexual activity, which was reported as a discomfort during ejaculation was less prevalent (23%)
mean of 5.9 times each month for the total sample of [23]. ED was significantly associated with age, LUTS,
men, deceased significantly with increasing age and the body mass index >25 kg/m2, and hypertension treated
severity of LUTS. Both ED and EjD were also sig- with calcium channel blockers; age and LUTS were the
nificantly associated with the severity of LUTS main predictors of ED. EjD was significantly asso-
(p < 0.001). The bothersomeness of EjD, although ciated with age and LUTS, whereas LUTS was the only
not age related, increased significantly with increased significant predictor for pain/discomfort during ejacu-
LUTS severity. Pain and/or discomfort with ejaculation lation [23]. Analysis of baseline data from the rando-
were reported by 7% of the men, with the prevalence mized, placebo-controlled, Medical Therapy of
significantly associated with age (p < 0.001) and the Prostatic Symptoms (MTOPS) trial also indicate a
severity of LUTS (p < 0.04). Logistic regression ana- significant relationship between LUTS and erectile
lysis, which controlled for age, medical comorbidities, function, ejaculation, overall sexual satisfaction, and
tobacco use, and alcohol consumption, demonstrated sexual desire after controlling for age, hypertension,
that age and the severity of LUTS were independent lipid disorders, and diabetes [24].
risk factors for ED and EjD. Furthermore, age and
LUTS were stronger risk factors for ED and EjD than 2.1.3. Summary
was diabetes, hypertension, heart disease, or hyperli- Epidemiological evidence provides a clear and clini-
pidemia [6]. cally meaningful association between LUTS and var-
Another recent population-based study, which was ious types of sexual dysfunction in aging men
conducted in Denmark, investigated the relationship worldwide. The results of a recent longitudinal popu-
between LUTS and sexual dysfunction in men and lation-based study of 428 Brazilian men without ED at
women aged 40 to 65 years [16]. In men, the prevalence baseline indicate that the adjusted relative risk of
of LUTS was 39% and the prevalence of ED was 29%. developing ED is 3.67 (95% confidence interval,
In multivariate logistic regression analyses, LUTS was 1.17 to 11.48) for those with self-reported BPH after
an independent predictor of ED. a mean follow-up of 2 years [25]. Although this finding
might suggest that LUTS causes ED, the possible role
2.1.2. Clinic-based LUTS/BPH population studies of other unidentified factors needs to be considered.
In the last several years, many clinic-based studies Thus, the underlying mechanisms responsible for the
have investigated the prevalence of sexual dysfunction association between LUTS and male sexual dysfunc-
in men with LUTS associated with BPH (Table 2). The tion remain to be determined. It has been suggested that
prevalence rates of ED and EjD in these studies ranged this association may be psychosocial and/or pathophy-
828 R.C. Rosen et al. / European Urology 47 (2005) 824–837

Table 2
Prevalence of and risk factors for sexual dysfunction in men with LUTS/BPH

Study Country Sample Prevalence Significant risk factors

Namasivayam et al. [17] UK 140 men aged 43 to ED: 46% ED: age
89 y with LUTS/BPH EjD: 38% EjD: age
HD: 66% HD: age
Frankel et al. [18] 12 countries 1271 men aged >55 y ED: 60% ED: age, LUTS
with LUTS/BPH EjD: 62% EjD: age, LUTS
Pain during Pain during ejaculation: LUTS
ejaculation: 17%
Baniel et al. [19] Israel 131 men aged 55 to ED: 67% ED: severe LUTS
74 y with LUTS/BPH
Tubaro et al. [20] Italy 877 men with LUTS/BPH ED: 58% ED: LUTS
EjD: 56% EjD: LUTS
Pain during Pain during ejaculation: LUTS
ejaculation: 20%
Leliefeld et al. [21] Netherlands 670 men aged
50 y ED: 41% ED: LUTS*, urologic comorbidity*,
with untreated LUTS/BPH bladder stone*
HD: 32% HD: LUTS*
Brookes et al. [22] UK 340 men aged 48 to 90 y ED: 71% ED: age, LUTS
with LUTS/BPH EjD: 70% EjD: age
Pain during Pain during ejaculation: age
ejaculation: 18%
Vallancien et al. [23] France, Denmark, 927 men aged 36 to 92 y ED: 62% ED: age*, LUTS*, BMI >25 kg/m2*,
Netherlands, with LUTS/BPH hypertension treated with CCB*
Switzerland, UK EjD: 63% EjD: age*, LUTS*, BPH surgery*
Pain during Pain during ejaculation: LUTS*
ejaculation: 23%
BMI: body mass index; BPH: benign prostatic hyperplasia; CCB: calcium channel blocker; ED: erectile dysfunction; EjD: ejaculatory dysfunction; HD:
hypoactive desire; LUTS: lower urinary tract symptoms.
*
Independent risk factor based on multiple logistic regression analysis.

siological in nature [26]. A pathophysiological increase our understanding of the effects of LUTS/BPH
mechanism is suggested by an animal model of partial treatments on male sexual function.
bladder outlet obstruction that resulted in ultrastruc-
tural changes in the corpus cavernosum [27]. Until 2.2.1. LUTS/BPH
further research definitively elucidates the reasons for The prostate gland contains both epithelial and
the association between LUTS and male sexual dys- stromal components; excessive growth in either or both
function, our knowledge of the pathophysiology of components can contribute to the development of BPH.
LUTS and sexual dysfunction, particularly ED and Increased smooth muscle tone in the prostate capsule
EjD, has suggested some common components that and the bladder neck can also contribute to the LUTS
may be involved. associated with BPH. Although the pathophysiology of
LUTS associated with BPH was historically attributed
2.2. Pathophysiological mechanisms to prostate gland enlargement and bladder outlet
Why are LUTS in aging men, with or without pro- obstruction, the weak correlation between LUTS and
static enlargement, associated with ED, EjD, pain/dis- prostate size [28,29] has resulted in a greater focus on
comfort during ejaculation, and HD? Is there a single the role of increased smooth muscle tone in the prostate
underlying mechanism to account for these effects or are and bladder and highlighted the need to investigate
several mechanisms, some perhaps indirect, involved? other possible underlying mechanisms. Increased
If there is indeed an association between LUTS and smooth muscle tone in the prostate in BPH is related
male sexual dysfunction, an understanding of the to the stimulation of a1-adrenergic receptors [30].
specific underlying mechanisms might have an important Other receptors that have been identified in human
impact on the diagnosis and treatment of these disorders. prostate tissue and that may play a role in LUTS
Current research in this area is actively studying this associated with BPH include dopaminergic, muscari-
relationship in aging men. The results of these studies will nic, serotoninergic (5-HT2A), and histaminergic (H1)
 R.C. Rosen et al. / European Urology 47 (2005) 824–837 829

receptors [31]. Nitric oxide (NO), which is present in and colleagues suggested that hyposensitivity of 5-
the human prostate [32] and modulates prostatic HT2C receptors and/or hypersensitivity of 5-HT1A
smooth muscle tone [33], may also have a role in receptors may be responsible for premature ejaculation
the pathophysiology of LUTS associated with BPH. in humans [41].

2.2.2. ED 2.2.4. Possible common components

The physiology of penile erection and the patho- 2.2.4.1. a1-Adrenergic receptors. An imbalance in the
physiology of ED have been previously reviewed [34– autonomic control of smooth muscle contraction and
36]. In brief, the tone of the corpus cavernosal smooth relaxation may play an important role in both LUTS and
muscle and the penile vasculature, which regulates sexual dysfunction. a1-Adrenergic receptors are known
penile erection and detumescence, is under the control to play an important role in mediating the tone of smooth
of various central and peripheral mechanisms and muscle cells in various tissues. Various a1-adrenergic
involves multiple neurotransmitter systems [34]. Cen- receptor subtypes have been identified in the lower
tral neurotransmitters that appear to regulate penile urinary tract, including a1A- and a1D-receptors in pro-
erection/detumescence include acetylcholine, NO, static stromal cells [42,43], a1B-receptors in epithelial
dopamine, oxytocin, noradrenaline, and serotonin cells, a1A- and a1B-receptors in vascular smooth muscle
[37]. In the penis, noradrenaline and endothelins are [44], a1A- and a1D-receptors in the urethra and bladder,
putative promotors of penile detumescence (contrac- and a1D-receptors in the detrusor muscle [45]. It has
tion), whereas NO promotes penile erection (relaxa- been suggested that a1-adrenergic receptors are up-
tion). Penile erection involves acetylcholine-mediated regulated in patients with LUTS associated with
relaxation of the corpus cavernosal smooth muscle, BPH, resulting in increased smooth muscle tone in
with neurogenic NO considered the main factor the prostatic capsule and bladder neck [46]. This is
responsible for rapid relaxation and endothelial NO supported by the fact that a1-adrenergic receptor
thought to play a role in the maintenance of the relaxed antagonists, which relax the smooth muscle of the
state [35,38]. NO binds to soluble guanosine cyclase prostate and bladder, are effective first-line medications
and stimulates the formation of cyclic guanosine for the treatment of LUTS associated with BPH.
monophosphate (cGMP), which signals phosphodies- Penile detumescence and erection are dependent on
terases, protein kinases, and ion channels, resulting in the balance between contraction and relaxation of the
smooth muscle relaxation and penile erection [35]. ED corpus cavernosum smooth muscle [34]. In ED, the
can result from alterations or defects in one or more of balance favors contraction (detumescence) rather than
the steps involved in the normal erectile process. relaxation (erection). Noradrenaline is involved in the
Vascular disease, neurological disease, surgery, radia- contraction of penile tissues via activation of a1-adre-
tion therapy, injury, and treatment with certain medi- nergic receptors in the penile vasculature and corpus
cations are common causes of ED. cavernosum smooth muscle, with androgens possibly
regulating the responsiveness of these receptors [47].
2.2.3. EjD With a1D- and a1A-adrenergic receptors identified as
The physiological mechanisms of ejaculatory func- the receptor subtypes in the human vas deferens and
tion and the pathophysiological mechanisms of EjD are prostate gland, activation of a1-adrenergic receptors is
not fully elucidated. Emission (i.e., deposition of semi- a possible mechanism for both emission and ejacula-
nal fluid and sperm from the distal epididymis, vas tion. Any impairment in the activation of the a1-
deferens, seminal vesicles, and prostate gland into the adrenergic receptors of the seminal tract may theore-
prostatic urethra) and ejaculation (i.e., expulsion of tically result in EjD.
seminal contents through the urethral meatus) are The contraction and growth of vascular smooth
controlled by the sympathetic/parasympathetic and muscle cells is also mediated by a1-adrenergic recep-
somatic nervous systems. Both emission and ejacula- tors. In certain human arteries, a1-receptor expression
tion involve contractile processes [39]. Central sero- increases and the relative proportion of a1-adrenergic
toninergic neurotransmission also plays a role in receptor subtypes is modulated by aging [44]. In mam-
ejaculation [40]. Interestingly, the stimulation of dif- mary arteries from healthy individuals aged <55 years,
ferent serotonin (5-HT) receptor subtypes can result in a1A-adrenergic receptors were identified as the main
an increase or decrease in the ejaculatory latency time subtype, whereas the a1B-adrenergic receptor subtype
[41]. In the rat, postsynaptic 5-HT1A and 5-HT2C predominated in individuals aged
65 years. Tissue-
receptors appear to play a role in ejaculatory behavior specific regulation of a1-adrenergic receptor subtypes
[40]. Based on the results of animal studies, Waldinger may also occur in various disease states, especially
830 R.C. Rosen et al. / European Urology 47 (2005) 824–837

those that are age-dependent. Interestingly, the mean cular endothelium function may be responsible for
efficacy of phenylephrine-induced contractions of various age-related conditions, including LUTS asso-
vascular smooth muscle strips, mediated by activation ciated with BPH and male sexual dysfunction.
of a1-adrenergic receptors, was significantly greater
for those isolated from the corpus cavernosum of older 2.2.4.3. Sex hormones. The development and growth
(
60 years) men with ED than for those isolated from of the normal prostate gland is known to be dependent
younger (<60 years) men with ED, without an alteration on an intact sex hormone-signaling axis. Dihydrotes-
in phenylephrine affinity [48]. Kinetic studies indicated tosterone (DHT), which is more potent than testoster-
that the maximal rate constant for the onset of these one and demonstrates a higher affinity for androgen
contractions was significantly greater in the older versus receptors, is predominantly produced peripherally
the younger men with ED [49]. from testosterone via the enzyme 5a-reductase. Andro-
Adrenergic-mediated contraction of smooth muscle gen receptors, which are present in both the stroma and
may also be regulated by Rho and Rho-associated epithelium of the prostate as well as in most blood
kinase [50], which has been found in human prostatic vessel endothelial cells, smooth muscle cells, and
smooth muscle cells [51] and the vas deferens of the fibrocytes [64], may play a role in the interaction
mouse [52]. The results of other studies have suggested between the stroma and the epithelium of the prostate.
a possible role for the Rho/Rho kinase pathway in the Age-related changes in circulating hormone levels
mechanism of penile smooth muscle contraction and an imbalance in the testosterone/estrogen ratio may
[53,54]. Thus, alterations in a1-adrenergic receptor- play a role in the pathophysiology of BPH and sexual
mediated smooth muscle tone and its regulators may be dysfunction. Longitudinal data from the MMAS indi-
a common component involved in LUTS associated cated that serum levels of total testosterone, dehydroe-
with BPH, ED, and EjD. piandrosterone (DHEA), DHEA-sulfate, cortisol, and
estrone declined, whereas levels of DHT, sex hormone
2.2.4.2. Endothelial dysfunction. Another mechanism binding globulin, luteinizing hormone, follicle-stimu-
that may link the pathophysiology of LUTS and male lating hormone, and prolactin increased in men who
sexual dysfunction is endothelial dysfunction, which were aged 40 to 70 years at baseline and followed for 7
refers to impaired endothelium-dependent vasodilation to 10 years [3]. It was suggested that higher levels
(i.e., relaxation) resulting from the decreased bioactiv- of DHT with aging may be an adaptation to compensate
ity of NO [55]. Endothelial dysfunction has been for decreased testosterone levels. With sex hormones
associated with aging, cardiovascular disease, diabetes, primarily produced from precursors in peripheral
hypertension, and hypercholesterolemia. Possible tissues in humans, each target tissue has the ability to
mechanisms responsible for endothelial dysfunction modulate hormone metabolism and signaling processes
include accelerated breakdown of NO by reactive through the regulation of tissue enzyme activities
oxygen species, alterations in antioxidant defense sys- [64,65] and hormone receptor subtypes [66]. Additional
tems, and alterations in the activity or expression of the studies are needed to assess whether alterations in sex
endothelial NO synthase (eNOS) enzyme [55,56]. In hormone levels and their receptors play a role in the
aging men, decreasing levels of testosterone and reduc- pathophysiology of BPH and sexual dysfunction.
tions in the conversion of testosterone to estradiol by
the aromatase enzyme may contribute to the deficits in 2.2.5. Summary
eNOS-derived NO [57]. In an animal model of age- Based on the possible common pathophysiological
related ED, endothelial dysfunction of the corpus mechanisms of LUTS/BPH and sexual dysfunction
carvernosum was associated with up-regulation of (Table 3) as well as other common comorbidities
eNOS and alterations in intracellular calcium flux observed in aging men with these conditions, further
[58]. Endothelial dysfunction has been suggested as multidisciplinary studies seem warranted [67]. The
the common component linking ED and cardiovascular
disease [59]. Furthermore, in prostatic tissue from men Table 3
with BPH, nitrergic innervation was demonstrated to Possible common components linking LUTS/BPH, ED, and EjD

be decreased compared with that in normal prostate Possible links LUTS/BPH ED EjD
tissue [60], which suggests a possible role for NO in the " a1-adrenergic activity U U U
pathophysiology of BPH. Studies in animals also Alteration in a1-adrenergic receptor subtypes U U U
suggest that NO plays a role in preventing bladder # NO bioactivity (endothelial dysfunction) U U ?
contractions that result in bladder hyperactivity, as Testosterone/estrogen imbalance U U U
5-HT ? U U
observed in LUTS [61–63]. Thus, alterations in vas-
 R.C. Rosen et al. / European Urology 47 (2005) 824–837 831

results of future studies may also provide valuable

information on the most effective treatment options
for the concurrent management of these common age-
related conditions. If LUTS/BPH and male sexual dys-
function share a common pathophysiological mechan-
ism, the optimal therapeutic strategy would be to treat
with a single agent that improves both LUTS and sexual
dysfunction. For example, preliminary data have sug-
gested that treatment with sildenafil improves LUTS in
men with ED, possibly as the result of smooth muscle
relaxation in the lower urinary tract [68]. An alternative
management strategy for LUTS and sexual dysfunction Fig. 1. Erectile dysfunction (ED), ejaculatory dysfunction (EjD), and pain
would be combination therapy with agents that improve during ejaculation (Ej Pain) before and after treatment with transurethral
LUTS or sexual dysfunction without adversely affecting resection of the prostate (TURP), non-contact laser therapy (LT), or watch-
ful waiting (WW) in men with LUTS/BPH (Data from [22]).
the other condition. The following section focuses on
various current treatment options for LUTS associated
with BPH and their related effects on sexual function. (particularly retrograde ejaculation). The estimated
incidence of ED was 10% in 15 trials (versus 2%
for sham control) and the estimated incidence of
3. Therapy for LUTS associated with BPH EjD was 65% in 19 trials (versus 2% for sham control)
that had TURP as the control arm [70]. However, the
The main goals of therapy in men with LUTS asso- Veterans Affairs Cooperative Group Study on TURP
ciated with BPH are to alleviate the bothersomeness of demonstrated that the incidence of ED in men with
LUTS and to improve patient quality of life. Because of moderate LUTS/BPH who underwent TURP was
the significant association between LUTS/BPH and lower than that for those in the watchful waiting group
domains of sexual dysfunction in men, an assessment [71]. A recent randomized, controlled trial evaluated
of sexual function is recommended in the evaluation of all ED (stiffness of erection) and EjD (decreased amount
men with LUTS associated with BPH, and the effects of of semen with ejaculation, loss of ejaculation, and pain/
BPH treatments on sexual function should be carefully discomfort during ejaculation) at baseline and 6 to 12
considered by both the patient and the clinician. months after TURP, non-contact laser therapy, or
watchful waiting in 340 men aged 48 to 90 years with
3.1. Efficacy data LUTS/BPH [22]. A significant decrease from baseline
Although TURP remains the benchmark therapy for in the percentage of men with ED and a significant
LUTS associated with BPH [69], oral agents are now reduction in the percentage of men with pain during
the standard first-line therapy for men with bothersome ejaculation were demonstrated after TURP (Fig. 1).
and moderate-to-severe LUTS. The a1-adrenergic Men who underwent TURP were significantly more
receptor blockers alfuzosin, doxazosin, tamsulosin, likely to have an improvement in erectile function than
and terazosin are the most commonly prescribed oral those who had watchful waiting. Furthermore, men
therapies for LUTS associated with BPH. At therapeu- who had TURP were significantly less likely to have
tic doses, these 4 a1-adrenergic receptor blockers have pain during ejaculation than those who had laser
demonstrated similar effectiveness in relieving LUTS therapy or watchful waiting. The percentage of men
in men with BPH [70]. 5a-Reductase inhibitors (i.e., with EjD was significantly increased from baseline
finasteride and dutasteride) are an appropriate treat- after TURP, laser therapy, and watchful waiting
ment option for patients with LUTS and evidence of (Fig. 1). The results of this study indicate that TURP
marked prostatic enlargement. Based on evidence- has a more beneficial effect on certain aspects of sexual
based outcomes data, 5a-reductase inhibitors were function (i.e., erectile function and pain during ejacu-
not as effective as a1-adrenergic receptor blockers in lation) than does laser therapy [22].
alleviating the symptoms of BPH [70].
3.2.2. Alfuzosin
3.2. Effects on sexual function Alfuzosin is a clinically uroselective a1-adrenergic
3.2.1. TURP receptor antagonist that is distributed preferentially in
Surgical interventions for LUTS/BPH, such as the prostate versus vascular tissue [72]. Immediate-
TURP, have been reported to cause ED and EjD release (2.5 mg 3 times daily) and sustained-release
832 R.C. Rosen et al. / European Urology 47 (2005) 824–837

Table 4
Incidence of sexual side effects in various phase III studies of medical therapies for LUTS/BPH

Drug No. of studies (treatment duration) ED EjD HD

Alfuzosin 10 mg 3 (12 weeks) [74] 1.5% <1% <1%

Placebo 0.6% <1% <1%
Tamsulosin 2 (13 weeks) [88]
0.4 mg <2% 8.4% 1.0%
0.8 mg <2% 18.1% 2.0%
Placebo <2% 0.2% 1.2%
Finasteride 5 mg 1 (1 year) [93] 8.1% 0.8% 6.4%
# volume: 3.7%
Placebo 3.7% 0.1% 3.4%
# volume: 0.8%
Dutasteride 0.5 mg 3 (2 years) [95] 7.3% 2.2% 4.2%
Placebo 4.0% 0.8% 2.1%
Doxazosin 4–8 mg 1 (1 year) [93] 14.4% 4.5% 7.0%
Finasteride 5 mg 18.5% 7.2% 10.0%
Combination 22.6% 14.1% 11.6%
Placebo 12.2% 2.3% 5.7%

(5 mg 2 times daily) formulations of alfuzosin have the treatment of LUTS associated with BPH. Both
been widely used for more than 15 years in Europe for medications do not demonstrate uroselectivity and
the treatment of LUTS associated with BPH. The once- have equal affinity for the 3 subtypes of a1-adrenergic
daily (OD) formulation of alfuzosin 10 mg, which is receptors. As a result, the incidence of vasodilatory
bioequivalent to the other alfuzosin formulations [73], side effects (i.e., dizziness, asthenia) with these med-
was launched in Europe in 2000 and in the United ications is significantly higher than that with placebo
States in 2003. [70]. During treatment with doxazosin, the rates of ED
Treatment with alfuzosin 10 mg OD in men with and EjD are generally comparable to those observed
LUTS associated with BPH is well tolerated, as demon- with placebo treatment (Table 4). Of note, in 2 rando-
strated in 3 double-blind, placebo-controlled, clinical mized, double-blind, placebo-controlled studies in men
trials [74]. The incidence of sexual side effects was low with BPH, treatment for 13 weeks with doxazosin,
and similar in the alfuzosin 10 mg OD group (ED, 1.5%; which was titrated to 8 mg OD, resulted in significant
loss of ejaculation, 0.6%) and the placebo group (ED, improvements from baseline in sexual function for
0.6%; loss of ejaculation, 0%; Table 4). The low inci- those patients with sexual dysfunction at baseline
dence of sexual side effects, which was maintained [80]. Furthermore, in an observational study of men
during long-term (up to 12 months) treatment with with BPH, treatment with doxazosin for 1 month
alfuzosin 10 mg OD [75], confirms the results demon- resulted in a significant improvement in sexual func-
strated with the 2 other alfuzosin formulations [76,77]. tion compared with that at baseline, especially for
In addition, there is no dose-related effect with alfuzosin those with moderate-to-severe ED at baseline [81].
with respect to the incidence of sexual side effects
[78]. Moreover, recent data from an open-label study 3.2.4. Tamsulosin
have suggested that treatment with alfuzosin 10 mg Tamsulosin is a uroselective a1-adrenergic receptor
OD for 1 year significantly improves ED, EjD antagonist that has been reported to demonstrate
(defined as ejaculation with decreased amount of semen greater in vitro selectivity for a1A- and a1D-receptor
or loss of ejaculation), and pain/discomfort during subtypes than for a1B-receptors [82,83]. The safety
ejaculation in men with LUTS associated with BPH profile of tamsulosin has been evaluated in several
[79]. Additional studies are needed to further evaluate randomized, double-blind, placebo-controlled trials
these improvements in sexual function during alfuzosin [84–87]. In 2 US phase III trials, a significantly higher
treatment in men with LUTS associated with BPH. incidence of EjD was demonstrated in men receiving
tamsulosin 0.4 mg OD (8%) or 0.8 mg OD (18%) than
3.2.3. Doxazosin and terazosin in those receiving placebo (0.2%; Table 4) [88]. The
Doxazosin and terazosin were indicated for the effects of tamsulosin on sexual function were dose
treatment of hypertension before being approved for related. In 2 European trials, the incidence of EjD was
 R.C. Rosen et al. / European Urology 47 (2005) 824–837 833

4.5% in men receiving tamsulosin 0.4mg OD com- with dutasteride 0.5 mg OD in 3 randomized, double-
pared with 1% for those receiving placebo (p = 0.45) blind, clinical trials experienced significantly higher
[85]. In a long-term (>1 year), open-label, phase III, incidence rates of ED (7% versus 4% for placebo
extension study of treatment with tamsulosin 0.4 mg group), EjD (2% versus 1% for placebo group), and
OD, 30% of patients experienced EjD and 6% reported HD (4% versus 2% for placebo group) than those
ED [89]. treated with placebo (Table 4) [95]. In patients treated
Pharmacologic selectivity for the a1A-adrenergic with a combination of finasteride 5 mg OD and dox-
receptor subtype in the bladder neck and seminal vesicles azosin 4 mg or 8 mg for 1 year, the incidence of sexual
may play a role in the EjD observed during tamsulosin side effects was approximately the sum of the rates for
treatment. A study in rats investigating the effects of each medication alone [93]. The effects of 5a-reduc-
tamsulosin and alfuzosin on bladder neck closure and tase inhibitors on sexual function may be related to
seminal vesicle contractions induced by electrical sti- inhibition of androgen-stimulated NOS expression
mulation indicated that tamsulosin had a significantly [96].
greater inhibitory effect than did alfuzosin at the same
dose [90]. Another possible explanation for tamsulosin- 3.2.6. Summary
induced EjD may be the medication’s ability to cross the Of the 2 uroselective a1-adrenergic receptor block-
blood-brain barrier and block a1-adrenergic receptor ers used in the treatment of LUTS associated with
subtypes within the central nervous system [91]. More BPH, alfuzosin 10 mg OD appears to demonstrate a
recently, it has also been suggested that tamsulosin more favorable safety profile with respect to sexual
binding to 5-HT1A-receptors and/or dopamine receptors side effects than does tamsulosin 0.4 mg OD or 0.8 mg
may play a role in the EjD observed during tamsulosin OD. Treatment with finasteride or dutasteride can also
treatment [92]. Additional studies are needed to evaluate negatively affect sexual function in men with BPH who
whether central non-adrenergic mechanisms are are already at increased risk for sexual dysfunction.
involved in tamsulosin-induced EjD. Thus, sexual function should be assessed and discussed
when selecting a therapy for men with LUTS asso-
3.2.5. 5a-Reductase inhibitors ciated with BPH and when evaluating the outcomes of
Because DHT is the androgen primarily responsible a selected therapy.
for prostate growth and enlargement, inhibition of the
enzyme 5a-reductase enzyme, which catalyzes the
formation of DHT from testosterone, represents 4. Instruments for assessing male sexual
another approach to treating LUTS associated with function
BPH. Of the 2 isozymes of 5a-reductase, type 1 is
expressed in most tissues, whereas type 2 is the domi- Patient self-assessment questionnaires are extre-
nant isozyme in reproductive tissues, including the mely useful in assessing sexual function in a clinical
prostate. Two 5a-reductase inhibitors are currently setting. Validated questionnaires used in the assess-
used in the treatment of symptomatic BPH in men ment of male sexual function include the International
with enlarged prostates, finasteride and dutasteride. Index of Erectile Function (IIEF; 15 items; 5 domains
Treatment with finasteride, a selective inhibitor of of male sexual function: erectile function, orgasmic
5a-reductase type 2, is generally well tolerated, but function, sexual desire, intercourse satisfaction, and
side effects related to sexual function occur signifi- overall satisfaction [97], the Brief Sexual Function
cantly more frequently in men treated for 1 year with Inventory (11 items that focus on sexual drive, erection,
finasteride 5 mg OD than in those receiving placebo ejaculation, perceptions of problems in each of these
(Table 4) [93]. In patients treated with finasteride 5 mg areas, and overall satisfaction [98], and the Interna-
OD or placebo in the PROSPECT Study, a 2-year tional Continence Society Sex Questionnaire (4 items
double-blind, placebo-controlled prospective rando- assessing erectile function, ejaculatory function, pain/
mized trial, 16% of patients who received finasteride discomfort during ejaculation, and the extent that
experienced ED compared with 6% of patients who urinary symptoms spoil the patient’s sex life) [99].
received placebo (p  0.01) [94]. Moreover, the inci- The Danish Prostate Symptom Score Sex questionnaire
dence of EjD was 8% for finasteride-treated patients has also been used to assess erection, ejaculation, and
versus 2% for placebo-treated patients. Dutasteride, a pain/discomfort during ejaculation and the bother-
newer 5a-reductase inhibitor that blocks both the type someness of each of these items [100].
1 and type 2 isozymes, provides a greater suppression Since its development and validation in conjunction
of DHT production than finasteride. Patients treated with the clinical trial program of sildenafil [97], the
834 R.C. Rosen et al. / European Urology 47 (2005) 824–837

IIEF has become the gold standard for the assessment EjD in the general population of men and in those with
of treatment outcomes in clinical trials of ED in LUTS/BPH.
heterosexual men and can also be used to provide a
quantitative index of ED severity [101]. A new instru-
ment for evaluating erection quality (Erection Quality 5. Conclusions and future directions
Scale; 15 items assessing the ability to achieve an
erection, duration of erection, hardness of erection, Research during the past decade has firmly estab-
sensitivity of erection, and general feelings), which lished that ED and EjD are highly prevalent conditions
was designed to be applicable to men of any sexual in aging men, particularly those with LUTS associated
orientation, may become a useful adjunct to the IIEF in with BPH. Furthermore, the results of recent large-
assessments of erectile function [102]. Although the scale studies have demonstrated that LUTS associated
IIEF includes domains for sexual desire, orgasmic with BPH is an independent risk factor for male sexual
function, and sexual satisfaction, the main focus of dysfunction. Interestingly, LUTS is also an indepen-
this instrument is erectile function. As a result, the IIEF dent predictor of sexual dysfunction in women [16].
should not be used for assessments of ejaculation or Although the underlying mechanisms responsible for
orgasm. the relationship between LUTS and male sexual dys-
To address the need for an instrument to assess function are not fully elucidated, possible common
specific aspects of ejaculation in older men, a new links include the activation of a1-adrenergic receptors,
self-administered questionnaire, the 25-item Male endothelial dysfunction, and alterations in sex hor-
Sexual Health Questionnaire (MSHQ), was recently mone concentrations and receptor subtypes.
developed and validated [103]. The MSHQ, which has With our knowledge of the relationship between
domains for erection (3 items), ejaculation (7 items), LUTS and sexual dysfunction has come new insights
and sexual satisfaction (6 items), provides a more in- into the evaluation and management of patients with
depth assessment of ejaculatory function and sexual these conditions. It is now recommended that men pre-
satisfaction than the IIEF and other instruments. The senting with LUTS should be evaluated for sexual
ejaculation domain of the MSHQ assesses loss of dysfunction and those presenting with sexual dysfunc-
ejaculation, delayed ejaculation, the force of the eja- tion should be evaluated for LUTS. Furthermore, as it is
culation, the amount of semen ejaculated, pleasure now recognized that certain oral therapies for LUTS/
associated with ejaculation, and pain/discomfort dur- BPH can adversely affect sexual function in patients who
ing ejaculation. In validation studies, the 3 domains of are already at increased risk for sexual dysfunction,
the MSHQ demonstrate a high degree of internal con- healthcare providers should discuss sexual function with
sistency, rest-retest reliability, and construct validity as their patients both before and during treatment. The
well as the ability to differentiate between men development and validation of sexual function question-
with LUTS and sexual dysfunction and healthy men naires that allow more detailed assessments of the dif-
[103]. Of the 3 domains of the MSHQ, the ejaculation ferent aspects of male sexual function, including
domain has the most significant correlation with erection, ejaculation, and sexual satisfaction, has facili-
LUTS severity. Linguistic validation studies of the tated this process. Additional basic research and clinical
MSHQ are currently ongoing. The MSHQ is also being studies are needed to gain a better understanding of the
used to assess sexual function in a national survey of mechanisms by which currently available oral therapies
US men, a US observational BPH Registry that is for LUTS/BPH exert their effects on LUTS and sexual
collecting data on patient outcomes and the relation- function. Furthermore, studies evaluating combined
ship between LUTS/BPH and sexual dysfunction, and treatments (e.g., medical, surgical, and psychological)
various placebo-controlled clinical trials of the effects for LUTS, sexual dysfunction, and other concomitant
of treatment with alfuzosin 10 mg OD on sexual func- age-associated conditions are needed to provide new
tion in men with LUTS/BPH. The results of these insights on optimal management strategies for these
studies will provide valuable new information on prevalent symptoms in aging men.

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