Urological Science 27 (2016) 3e7

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Urological Science
journal homepage: www.urol-sci.com

Review article

Impacts of medical treatments for lower urinary

tract symptoms suggestive to benign prostatic
hyperplasia on male sexual functions*
Shih-Tsung Huang a, b, *
a
Division of Andrology and Female Urology, Department of Urology and Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, ROC
b
Department of Urology and Surgery, Chang Gung University, College of Medicine, Taoyuan, Taiwan, ROC

a r t i c l e i n f o a b s t r a c t

Article history: Although alpha blockers with or without 5-alpha reductase inhibitors (5-ARIs) have become the standard
Received 4 March 2015 of treatment for men with moderate to severe lower urinary tract symptoms suggestive to benign
Received in revised form prostatic hyperplasia (LUTS/BPH), their negative adverse effects on male sexual functions have become
7 December 2015
another major issue, which may have a direct impact on patients' quality of life and overall satisfaction.
Accepted 9 December 2015
Available online 6 February 2016
Erectile dysfunction, ejaculation disorders, reduced libido, or anorgasmia have been noted among pa-
tients receiving these standards of treatments and these adverse events may be irreversible even after
discontinuation of medications. Physicians should inform and discuss with their patients about these
Keywords:
benign prostatic hyperplasia potential side effects before prescribing these medications for their LUTS/BPH treatment. Tadalafil is the
ejaculation disorder first phosphodiesterase type 5 inhibitor which has the indications for LUTS/BPH and erectile dysfunction
erectile dysfunction and its efficacy is comparable to alpha-blockers with regards to the reduction of LUTS and improvement
lower urinary tract symptoms of quality of life. Moreover, early clinical studies have showed that the combination use tadalafil with
alpha blockers or 5-ARIs may have an additional benefit on symptom relief and maximum urinary flow
rate (Qmax) improvement. As expected, the improvement on erectile function is significant, especially
among patients taking 5-ARIs regularly. Although there are promising data from the combination use of
tadalafil with 5-ARIs or tadalafil with alpha-blockers, more large-scale clinical studies are still needed to
confirm their long term safety and efficacy profiles.
Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction correcting for age and comorbidity. Therefore LUTS/BPH is also an

Lower urinary tract symptoms suggestive to benign prostatic
hyperplasia (LUTS/BPH) is common among men aged over 60 years.
Uncontrolled LUTS/BPH may have a direct impact not only on
quality of life (QoL) but also on sexual functions. Erectile dysfunc-
tion (ED) and ejaculation disorder (EjD) are two common male
sexual disorders among men with LUTS/BPH in daily urology
practice. Although age has been noted as an independent factor for
the development of ED and BPH, more epidemiological evidence
shows that sexual dysfunction is significantly more prevalent in
patients with LUTS/BPH than in men without LUTS/BPH, even after
* Corresponding author. Department of Urology, Chang Gung Memorial Hospital,
Number 5, Fu-Hsing Street, Queishan, Linkou, Taoyuan, Taiwan, ROC.
E-mail address: huangst@cgmh.org.tw.
*
There are 3 CME questions based on this article.
independent factor for developing sexual dysfunction.1e5 Further-
more the uses of medical or surgical treatments for LUTS/BPH
management have initiated another impact on male sexual func-
tions. This review will focus on the impacts of medical treatments
for LUTS/BPH on male sexual functions. Newer therapeutic mo-
dalities with their impacts on sexual dysfunction side effects will be
discussed in this review article.
2. LUTS/BPH
LUTS includes a broad range of symptoms and is highly prevalent
among both men and women. Originally, LUTS are defined by the
International Continence Society (ICS) as all urinary symptoms
occurring during the phases of storage (increased daytime frequency,
nocturia, urgency, and/or urinary incontinence), voiding (terminal
dribble, hesitancy, intermittency, straining, and/or splitting/spray-
ing/slow stream), and postmicturition (incomplete emptying or

http://dx.doi.org/10.1016/j.urols.2015.12.001
1879-5226/Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
4 S.-T. Huang / Urological Science 27 (2016) 3e7
postmicturition dribble).6 In a large cross-sectional, multi-national
study, which is the first epidemiologic study using standard termi-
nology defined by ICS, showed that the prevalence of storage LUTS
(men, 51.3%; women, 59.2%) was greater than that for voiding (men,
25.7%; women, 19.5%) and postmicturition (men, 16.9%; women,
14.2%) symptoms. The most common storage symptom in this
multinational study was nocturia (48.6% men; 54.5% women) fol-
lowed by urgency (10.8% men; 12.8% women). Terminal dribble
(14.2% men; 9.9% women) was the most common voiding symptom,
and incomplete emptying (13.5% men; 12.3% women) was the most
frequently reported postmicturition symptom.7
3. The impacts of LUTS/BPH on male sexual functions
Libido, erection, ejaculation, and orgasm are four major com-
ponents in male sexual functions. Although ED is one of the most
common male sexual disorders, EjD, loss of libido or hypoactive
sexual desire, and orgasm dysfunction are also common among
men with LUTS/BPH. Although age is an independent factor for ED,
the development of these male sexual dysfunctions may be
multifactorial. The prevalence and severity of sexual dysfunctions
had been found to be closely related to the severity of LUTS, even
after controlling for confounding variables such as age or comor-
bidities.5 Most population- or community-based epidemiological
studies have confirmed that LUTS alone might have a direct impact
on sexual dysfunction and sexual life satisfaction. Braun et al2
found that the prevalence of LUTS in men suffering from ED was
about 72.2% (n ¼ 621) versus 37.7% (n ¼ 1367) in men with normal
erections. The occurrence of LUTS can be considered as an age-
independent risk factor for the development of ED with an odds
ratio (OR) of 2.11 (p < 0.001).2 Rosen et al5 conducted the first
multinational survey involving 12,825 men aged 50e80 years to
confirm that sexual disorders and their impact on quality of life
were strongly related to both age and severity of LUTS/BPH. The
severity of ED is also correlated to the severity LUTS in the same age
group. This relationship between ED and LUTS/BPH is independent
of comorbidities including diabetes, hypertension, cardiac disease,
and hypercholesterolemia.5 One cross-sectional study for LUTS
prevalence using ICS terminology criteria also revealed that men
with multiple LUTS had more severe ED and more frequent EjD and
premature ejaculation. Moreover, the findings of multiple LUTS
were associated with worse sexual functions, which were inde-
pendent of age, race, education, and body mass index.8
In another cross-sectional, multi-national study enrolling 5999
sexually active men with LUTS, reduced force of ejaculation (77.9%)
and reduced semen amount (74.4%) were two common ejaculatory
dysfunctions.9 The severity of LUTS was the strongest predictor for
the development of EjD. Men receiving previous BPH-related sur-
gery and men treated with a 5a-reductase inhibitor plus an a1-
blocker or tamsulosin had the highest rates of dry ejaculation
(67.4%, 57.2%, and 52.3%, respectively) compared with controls
(31.6%, p < 0.001).10 Painful ejaculation is another one of the most
common sexual dysfunctions among men with LUTS/BPH. In a real-
life, prospective study, 688 out of 3700 (18.6%) sexually active men
with LUTS/BPH were bothered by prostatitis-like symptoms or
discomfort on ejaculation. Men with LUTS/BPH associated with
prostatitis-like symptoms or discomfort on ejaculation had higher
prevalence of ED (72% vs. 57%), and reduced ejaculation (75% vs.
56%),compared with LUTS/BPH men without prostatitis-like
symptoms.11 Therefore LUTS/BPH should be considered as an in-
dependent risk factor for the development of sexual dysfunctions
based on an epidemiological survey. The exact linkage between
LUTS/BPH and sexual dysfunctions is unclear, but aging with
increased sympathetic tone, pelvis arteriosclerosis, increased
smooth muscle Rho-kinase activity, and reduced nitric oxideecyclic
guanosine monophosphate signal pathway had been suggested
as common pathogenesis to LUTS/BPH and ED.12 Recently aging,
diabetes mellitus, and endothelial nitric oxide synthase 894T
allele carrier gene polymorphism were the three independently
common risk factors for both ED and BPH/LUTS in the Taiwanese
population.13
4. The impact of LUTS/BPH medical treatments on male
sexual function
The goal of medical treatments for men with LUTS/BPH is to
relieve the bothersome symptoms and to prevent the development
of complications. Since sexual dysfunction has a direct negative
effect on the patient's QoL, any treatment of LUTS/BPH should aim
not only to alleviate urinary symptoms, but also to maintain or
improve sexual function. The mainstay choices of medical treat-
ments for LUTS/BPH consist of alpha-blockers, 5-alpha reductase
inhibitors (5-ARIs), or a combination of both for men with mod-
erate to severe symptoms or larger prostates. Alpha-blockers (alpha
adrenergic antagonists) are smooth muscle relaxants and can
relieve the dynamic component in prostate stroma. Although
alpha-blockers may also play an important role in relaxation of
smooth muscles within corpus cavernosum, its impact on erectile
function is still controversial. Intracavernosal injection of phentol-
amine, a nonselective alpha-blocker for smooth muscles relaxation,
has been used as one of the pro-erectile agents for ED treatment
before the era of phosphodiesterase type 5 inhibitors (PDE5Is). But
the pro-erectile potential of these alpha-blockers should be
balanced by their blood pressure lowering potential.14 Furthermore
5-ARIs inhibit the transformation of dihydrotestosterone from
testosterone, which is the active hormone for prostate growth and
enlargement. EjD and ED are two common side effects among pa-
tients receiving 5-ARIs with or without alpha-blockers.15e19
Reduced libido, orgasm disorder, or gynecomastia have also been
noted among patients receiving 5-ARIs, which may be irreversible
and lasted even after stopping medication. Therefore the Food and
Drug Administration requested a 5-ARIs label revision in 2012 to
state that libido disorders, ejaculation disorders, and orgasm dis-
orders may continue after discontinuation of these drugs.20,21
5. Alpha-blockers
Five alpha-blockers including three pharmacologically non-
uroselective a1 antagonists (alfuzosin, doxazosin, terazosin) and
two highly uroselective a1A antagonists (tamsulosin and silodosin)
are commonly used for the treatment of LUTS/BPH in Taiwan. The
structures among these five agents may be different but their
effectiveness on LUTS/BPH therapy is similar. However, their im-
pacts on sexual function may be different. The influences on libido
or sexual desire ranged from 0.6% to 2% and no documented orgasm
disorder had been described in their package inserts. Moreover, the
incidence of ED is also mild with <2% described in the package
inserts (Table 1). Only limited clinical studies showed that the use
of alpha-blockers may actually improve erectile function in men
with LUTS/BPH.22,23 However, all package inserts from the five
drugs mentioned case report of priapism (Table 1). Ejaculation
disorders might also become one of the major adverse events when
prescribing highly uroselective a1A antagonists including tamsu-
losin and silodosin.15e19 About 8.4e18.1% of patients receiving
0.4e0.8 mg tamsulosin and 28% of patients receiving 8 mg silodosin
developed abnormal ejaculations such as reduced semen amount
or dry ejaculation possibly due to highly uroselective a1A receptors
inhibition on vas and seminal vesicles.14,18,19 Physicians should
inform patients about these potential sexual side events when
prescribing these alpha-blockers for their LUTS/BPH treatment.
 S.-T. Huang / Urological Science 27 (2016) 3e7
Table 1
Impacts of approved benign prostatic hyperplasia medications on male sexual functions.
Mechanism of action Erectile
dysfunction (%)
Alfuzosi16 Alpha-1 antagonist 1e2
Doxazosin17 Alpha-1 antagonist 1.1
Silodosi19 Selective alpha-1A antagonist 0.86
Tamsulosin18 Selective alpha-1A antagonist 0.55
Terazosi15 Alpha-1 antagonist 1.6
Finasteride24 5-alpha reductase inhibitors 5.1e8.1
Dutasteride25 5-alpha reductase inhibitors 4.7
Dutasteride þ Combination of 5-ARI & selective 5.4
tamsulosin42 alpha 1A antagonist
Tadalafil43 Phosphodiesterase-5 inhibitors None
5-ARI ¼ 5-alpha reductase inhibitors.
a
Data from hypertension patients receiving hytrin.
6. 5-ARIs and its combination with alpha-blockers
The use of 5-ARIs alone or the combination use of 5-ARIs with
alpha-blockers can slow BPH progression and reduce the incidence
of urinary retention or the necessity of prostate-related surgery. But
the incidences of ED, EjD, and decreased libido are also higher than
those using alpha-blockers alone.20,21 5-ARIs such as finasteride
and dutasteride are associated with a negative effect on libido or
sexual desire, erectile function, and ejaculation function. Finaste-
ride provokes decreased libido or sexual desire in 2e10% of pa-
tients, ED in 3e16%, and ejaculatory disorders in 0e8%.24 Similarly
dutasteride, a more potent 5-ARI, may also cause decreased libido
in 3e4% of patients, ED in 5e6%, and EjD in 2e7.6%.25 In a longi-
tudinal study, treatment with finasteride or combined with dox-
azosin was associated with worsening sexual function while
treatment with doxazosin alone was associated with minimal
negative impact.26 Recently in a meta-analysis study, more the
alpha-blockers is effective over time, greater is the incidence of EjD.
Finasteride has the same risk of dutasteride to cause EjD. Combi-
nation therapy with alpha-blockers and 5-ARIs resulted in a three-
fold increased risk of EjD compared with alpha-blockers (9.2% vs.
2.7%; OR 3.75; p < 0.0001) or 5ARIs (9.2% vs. 3.5%; OR 2.76; p ¼ 0.02)
alone.27
7. PDE5-Is
PDE5-Is remain the first-line treatment of choice in men with ED
since the launch of sildenafil in 1998 due to their high rate of effi-
cacy and generally benign safety profile. Furthermore, there are
many epidemiologic evidences to support the link between ED and
LUTS/BPH. Many studies have also been focused and supported on
the utilization of PDE5-Is for the treatment of LUTS/BPH. In a pooled
data analysis of 1500 men with LUTS/BPH, the use of 12-weeks
tadalafil 5 mg daily alone was associated with a significant
improvement in the International Prostate Symptom Score (IPSS)
score, BPH Impact Index, and QoL, compared with a placebo arm.
Interestingly the improvement on IPSS is consistent across different
subgroups analyses including baseline LUTS severity, age, testos-
terone and level, prostate size. and previous use of alpha-blockers
or PDE5-Is. Moreover the pooled analyses of safety data also
showed that the specific treatment-emergent adverse events were
not clinically meaningful differences according to categories of
baseline age, recent previous use of PDE5-Is, or cardiovascular
disease, hypertension, or diabetes mellitus.28 In another three-arm
monotherapy study comparing with a placebo (n ¼ 172), significant
improvements in IPSS and BPH Impact Index treatment in both
tamsulosin (0.4 mg, n ¼ 168) and tadalafil (5 mg, n ¼ 171) groups
were noted after 4-weeks treatment and through to the end of 12-
weeks treatment. The maximum urinary flow rate (Qmax) also
5
Ejaculation Reduced libido Priapism Gynecomastia39
dysfunction (%) or loss (%)
None None Case report40 Case report
0.01e0.03 0.8 Case report41 Case report
28 None Case report14 None
8.4e18.1 1.0e2.0 Case report14 0.2e0.4%
0.08 0.6a Case report14 Case report
0.2e0.8 2.6e6.4 None 0.4e0.7%
1.4 0.48e2.4 None 0.5e1.2%
7.8 0.2e4.5 None 0.6e1.1%
None None Case report None
increased significantly versus placebo with both tadalafil (2.4 mL/s;
p ¼ 0.009) and tamsulosin (2.2 mL/s; p ¼ 0.014). As expected, the
International Index of Erectile Function (IIEF) score improvement
was only noted in men receiving tadalafil.29 The use of 5-mg daily
dosing tadalafil in men with LUT/BPH with or without ED treatment
was approved in October 2012 by the Food and Drug Administra-
tion and in 2013 by the Taiwan Heath Authority. Although the use of
PDE5-Is for LUTS/BPH treatment should have no major negative
impacts on sexual function, there are also treatment-emerged
adverse events that should be made known to patients when
receiving this class of drugs. These adverse events are similar to
safety data profiles noted from ED treatment. The most commonly
reported side effects include flushing, headache, gastrointestinal
upset, congestion, visual disturbance, and myalgia. Most of these
adverse events are transient and mild in their severity and have no
long term consequence. However, the development of rare serious
adverse events such as nonarteritic ischemic optic neuritis,
ototoxicity with irreversible sensorineural hearing loss, and pria-
pism have also been reported in association with PDE5-Is use.30
Recently, the association of PDE5-Is with the development of skin
melanoma was found in two national cohort studies from the
United States and Sweden. In the Swedish study, men taking PDE5-
Is had an increased risk of skin melanoma [OR, 1.21 (95% confidence
interval, 1.08e1.36)] and basal cell carcinoma [OR, 1.19 (95% confi-
dence interval, 1.14e1.25)], compared with men not taking PDE5-Is.
Although the risk is similar with sildenafil, vardenafil, and tadalafil,
the exact causality is still unclear. Social economic status including
higher educational level and annual income may be associated with
an increased melanoma risk. Patients should be informed about
these potential risks before prescribing PDE5-Is for treatments.31,32
8. Combination of alpha-blockers and tadalafil
It has been recommended30 that all three PDE5-Is are not to be
used concomitantly with alpha-blockers other than tamsulosin due
to the risk of vasodilatory adverse events in their original package
inserts. However, in a multicenter, randomized, placebo controlled
study, 318 men with LUTS/BPH receiving stable alpha-blocker
therapy were randomized into 5-mg tadalafil or placebo treat-
ment. The changes in hemodynamic signs and symptoms were
similar for both groups. There is a trend for increased hemody-
namic signs and symptoms in men taking nonuroselective alpha-
blockers.33 Moreover in a comparative, randomized prospective
study, the combination use of tadalafil with tamsulosin was supe-
rior to tamsulosin or tadalafil alone in improving IPSS and IIEF
scores. Common side effects were dyspepsia, heartburn, headache,
flushing, myalgia, and backache, which were transient and mild in
severity.34 In another systematic review and meta-analysis study,
comparing the effects of combination therapy of PDE5-Is plus
6 S.-T. Huang / Urological Science 27 (2016) 3e7
alpha-blockers versus alpha-blockers alone, the authors noted that
a combination of PDE5-Is and alpha-blockers can significantly
improve Qmax compared with alpha-blockers alone; whereas PDE5-
Is alone cannot increase Qmax as compared with placebo.
Comparing safety data from men receiving combination therapy of
PDE5-Is plus alpha-blockers versus alpha-blockers alone, seven of
103 adverse events (6.8%) were reported in men with combined
therapy and five of 99 adverse events (5.1%) in men treated with
alpha-blocker alone. This meta-analysis of adverse events has also
confirmed that flushing, gastroesophageal reflux, headache, and
dyspepsia have a higher risk of occurrence after PDE5-I adminis-
tration.35 Recently, in another meta-analysis study enrolling seven
studies with 515 men with ED and LUTS/BPH, the authors
concluded that the combined use of PDE5-Is and alpha-blockers
results in additive favorable therapeutic effects in men with ED
and LUTS/BPH compared with PDE5-Is monotherapy alone with
regards to improvement of IIEF, IPSS, and Qmax values.36
9. Combination of 5-ARIs and tadalafil
Although the use of 5-ARIs with or without alpha-blockers can
slow BPH progression and reduce the incidence of urinary retention
or prostate-related surgery, its usage for LUTS/BPH treatment has
been restricted by the major impact on sexual functions.26 Since
PDE5-Is are the first line of medication for ED treatment, the
addition of PDE5-Is to men receiving 5-ARIs for their LUTS/BPH
treatment should alleviate this major side effect. Recently in an
international, randomized, double-blind, parallel study, a total of
696 men with LUTS/BPH were randomized into placebo/5 mg fi-
nasteride or 5 mg tadalafil/5 mg finasteride for 26-weeks treat-
ment. The results showed that significant improvements in IPSS
total scores, IPSS voiding and storage subscores, and I-PSS-QoL
among men receiving tadalafil/finasteride and this significant LUTS
improvement could be observed even earlier at 4-weeks treatment.
As expected, this tadalafil/finasteride combination treatment also
improves erectile function in men who have comorbid ED.37
However, cost issues may limit the use of this combination for
LUTS/BPH treatment. Men with LUTS/BPH in Taiwan had higher
healthcare utilization compared with patients without BPH. The
cost benefit of this combination treatment needs further pharma-
economic evaluation because of the necessity of long-term treat-
ment with 5-ARIs and no national insurance reimbursement for
PDE5-Is.38
10. Conclusions
LUTS/BPH and its medical treatments including alpha-blockers
and 5-ARIs have direct impacts on erectile, ejaculation, and libido
functions. Sexual function preservation should be considered when
making the treatment decision for men with LUTS/BPH. Physicians
should inform their patients about these potential sexual side
events when prescribing these drugs for LUTS/BPH treatment.
Combination use of PDE5-Is with alpha-blockers or PDE5-Is
with 5-ARIs may alleviate ED but more randomized, clinical
studies are necessary to support its safety profile.
Conflicts of interest
The authors declare that they have no financial or non-financial
conflicts of interest related to the subject matter or materials dis-
cussed in the manuscript.
Sources of funding
No funding was received for the work described in this article.
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