International Journal of Urology (2010) 17, 38–47 doi: 10.1111/j.1442-2042.2009.02426.

Review Article iju_2426 38..47

Endothelial dysfunction and erectile dysfunction in the

aging man
Antonio Aversa,1 Roberto Bruzziches,1 Davide Francomano,1 Marco Natali,1 Pietro Gareri2 and
Giovanni Spera1
1
Department of Medical Pathophysiology, ‘Sapienza’ University of Rome, Rome and 2Operative Unit ‘Elderly Health Care’, ASP
Catanzaro, Italy

Abstract: Penile erection is a vascular event that requires an intact endothelium to occur. A dysfunctional endothelium
is an early marker for the development of atherosclerotic changes and can also contribute to the occurrence of acute
cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction (ED) is intimately linked through
decreased expression and activation of endothelial nitric oxide (NO) synthase, and the subsequent blunted physiological
actions of NO naturally occurring with aging. It is now well-understood that ED is a symptom of underlying disease rather
than a disease itself; for this reason in the near future both general practitioners, internal medicine practitioners and many
specialists will have to interplay with sexual medicine. Aging in the man is also associated with several changes in arterial
structure and function, part of them related to the decline of circulating levels of steroids, that is, testosterone and
estradiol. These changes may be responsible, in part, for the lack of efficacy of ED treatments. The recent discovery that
chronic administration of phosphodiesterase type 5 inhibitors may improve erectile and endothelial responsiveness of
men previously non-responsive to on-demand regimes, and the knowledge that testosterone is one of the main modula-
tors of the expression of penile phosphodiesterase type 5 isoenzyme, opens a new scenario in the treatment of men with
ED and co-morbidities. The aim of this review is to discuss the pathophysiology of endothelial dysfunction and its
relationship with ED in the aging male, and to suggest possible strategies to improve arterial function with regard to sexual
dysfunctions.
Key words: cardiovascular risk factors, endothelial dysfunction, erectile dysfunction, nitric oxide, phosphodiesterase
type 5 inhibitors.

Introduction treated with medications that can interfere with sexual func-
tion at a central and peripheral level. Obesity, cigarette
Erectile dysfunction (ED) is not a life-threatening disorder,
smoking and the presence of diabetic complications (periph-
but it influences the daily routine, social interactions, well-
eral neuropathy, vascular disease, retinopathy and nephropa-
being and quality of life of the patient. It may often consti-
thy) show a significant relationship with the occurrence of
tute the first manifestation of important systemic (in
ED in both type 1 and type 2 DM.4 The association between
advancing age) or relational (in younger age) pathologies
ED and clinical atherosclerosis has been documented.5
and it is considered a possible marker of clinically undiag-
There is a high incidence of cardiovascular disease (CVD) in
nosed disease, thus representing the ‘tip of the iceberg’ of a
men with ED, and data suggest that ED may be an early
systemic vascular disorder.1 It is more common in men with
manifestation of endothelial dysfunction (EDys) in the pres-
diabetes mellitus (DM) and is often associated with other
ence or absence of cardiovascular risk factors (CRF).6 ED
disseminated vascular diseases, such as coronary and
and CAD overlap in CRF, the pathological basis of disease
peripheral atherosclerosis, and an increased risk of future
and disease progression.7 The common underlying factor is
cardiovascular events similar to that of men with coronary
EDys; men with penile vascular damage may have EDys in
artery disease (CAD).2,3 Aging per se represents a risk factor
other vascular beds, as well.8 Therefore, men with ED may
for ED and pathological conditions that are commonly
be at increased risk for cardiovascular adverse events and
encountered in the aging male, as well as chronic diseases
ED may be considered as a sentinel symptom in patients
that represent other causes of organic ED, and are often
with occult CVD.9 In fact, EDys measured as impaired
Correspondence: Antonio Aversa MD PhD, Dipto Fisiopatologia vasodilation of the brachial artery is prognostic for cardio-
Medica, Room 37, Viale Policlinico 155, 00161 Rome, Italy. vascular events, such as myocardial ischemia and stroke.10,11
Email: antonio.aversa@uniroma1.it The aim of this article will be to give fundamentals
Received 1 October 2009; accepted 21 October 2009. regarding endothelial pathophysiology and its relevance to
Online publication 25 November 2009 ED in the aging male. Moreover, the role of age-related

38 © 2009 The Japanese Urological Association


decline of testosterone (T) levels with respect to erectile and
endothelial function and the beneficial effects of T supple-
mentation along with phosphodiesterase type 5 inhibitor
(PDE5-i) administration will be discussed.
Endothelial dysfunction
EDys has gained increasing notoriety as a key player in the
pathogenesis of atherosclerosis.12 As atherosclerosis is the
most common cause of vasculogenic erectile dysfunction in
older men, it is frequently considered another manifestation
of vascular disease.13 The mutual risk factors shared by ED
and CAD each contribute to EDys. Just as the presence of
these risk factors overlap within patient populations, so do
their effects on the endothelium. Several traditional CRF,
such as aging, smoking, hypertension, dyslipidemia and
DM, and some less-traditional risk factors, including
inflammation, hypoxia, oxidative stress and hyperhomocys-
teinemia, are related to EDys.14 EDys is also a feature of
acute coronary syndromes, heart failure, reperfusion injury,
renal failure, systemic inflammatory disorders and ED.15 A
number of novel plasma markers have been associated with
atherosclerosis and EDys. Erectile function is dependent
upon nitric oxide (NO) production by penile endothelium
and thus ED is associated with reduced plasma NO levels.
EDys is characterized by significant modifications in the
physiological and biochemical parameters. These include:
vascular stiffness, increased vascular tone, production of
inflammatory cytokines, increased permeability, suscepti-
bility to invasion of immunocytes, decrease in endothelial
cell growth, and dysregulation of fibrinolytic factors. Clini-
cal and biochemical markers of EDys include: (i) reduced
expression and activity of endothelial nitric-oxide synthase
(eNOS), reduced synthesis of NO, and increased production
of the asymmetric dimethylarginine (ADMA), a competi-
tive, endogenous inhibitor of eNOS; (ii) increased produc-
tion of reactive oxygen species (ROS); (iii) increased
synthesis and release of the vasoconstrictor peptide
endothelin-1 (ET-1); (iv) increased production of inflamma-
tory cytokines such as interleukin-6 (IL-6), C-reactive
protein (CRP) and tumor necrosis factor-a (TNF-a); (v)
increased expression of markers of cell adhesion such as
E-selectin,16 intracellular adhesion molecules (ICAM),17 and
vascular cell adhesion molecules (VCAM); (vi) dysregula-
tion of fibrinolytic factors such as Von Willebrand Factor
(vWF), tissue plasminogen activator (tPA), and plasminogen
activator inhibitor (PAI-1); (vii) inability to regenerate from
endothelial progenitor cells (EPC); (viii) increased endothe-
lial apoptosis; (ix) increased cellular permeability; and (x)
increased vascular tone.18 Overall, a reduction in NO results
in EDys.19 These mechanisms, along with a reduction in
bone-marrow-derived EPC, could underpin a common
pathogenesis for both ED and EDys.20,21 In individuals with
established ED, elevated ADMA levels have been shown to
© 2009 The Japanese Urological Association
ED3 in the elderly man
correlate with the severity of various CRF as in patients with
renal disease,22 insulin resistance and DM23, and CAD,24,25
indicating the impact they could have on endothelial
function.26
In addition to the biochemical markers of EDys, diagnos-
tic tools of EDys are characterized by the evaluation of
flow-mediated dilation (FMD) of the brachial artery.27 This
clinical measurement of EDys is strongly linked to coronary
EDys and predicts cardiovascular events.28–30 EDys can be
tested in vivo using several techniques that rely principally
on measuring change in arterial diameter or flow in response
to stimuli.31 Longitudinal observations confirmed that dys-
function of the endothelium of the coronary and peripheral
circulation is predictive of cardiovascular events, the sensi-
tivity and specificity being greater for coronary artery EDys
than for peripheral dysfunction.32
Recently, a new operator-independent technique, that is,
digital pulse amplitude by fingertip peripheral arterial
tonometry (PAT) device, became very popular for diagnos-
ing endothelial dysfunction in CAD patients.33 A recent
study was carried out by investigating men with ED using
PAT and indicated that the average FMD was not different in
men with or without ED, independently from the presence or
absence of VRFs. By contrast, the augmentation index,
which is an indirect measurement of arterial stiffness, was
higher in men with ED compared with controls even when
controlled for age and VRF. In that study, it was concluded
that an increased arterial stiffness but not EDys, is present in
men with vascular ED and may represent an early detection
of vascular impairment that may precede endothelial dys-
function in populations at low risk for developing vascular
ED34 (Fig. 1).
Insulin-resistance and endothelial
dysfunction
The past decade has witnessed a dramatic increase in the
prevalence of obesity. Co-morbidities of obesity include
aging, type 2 DM, hypertension, and lipid abnormalities, all
contribute to CVD and are associated with EDys. These
abnormalities frequently cluster in individuals, and the term
metabolic syndrome (MeS) is now widely used to define this
cluster. The syndrome is frequently (although not invariably)
associated with insulin resistance and CVD.35 In recent
years, it has become clear that the correlation between
insulin resistance and EDys plays a central role in the patho-
genesis of atherosclerosis. EDys is an important component
of the metabolic or insulin resistance syndrome, as demon-
strated by inadequate vasodilation and/or paradoxical vaso-
constriction in coronary and peripheral arteries in response
to stimuli that release NO.36 Metabolic actions of insulin to
promote glucose disposal are augmented by vascular actions
of insulin in endothelium to stimulate production of the
vasodilator NO. Indeed , NO-dependent increases in blood
39
A AVERSA ET AL.

Age-related Tx Ad
diseases eq
uate
Tx Life
CVD - Diabetes sty
le +
Die
5-i ± e t+
PDE teron Ph
tos ysi
Erectile Dysfunction Tes c al a
3
ED dify cti
Mo ctors vit
fa y
Endothelial Dysfunction risk f
no
l u atio ffness
a
Ev ial st i
r
Early Detection of vascular disease arte Tx
d aily
c ific
Spe nts
Obesity
Metabolic
Dyslipidemia Hyperglycemia Hypertension ox ida
Syndrome nti
ic a
riod
Pe
Oxidative Stress

AGING MAN

Fig. 1 The aging male ‘pyramid’: ED3 represents the mainstay for the prevention of common diseases associated with increased
mortality in the aging male. CVD, cardiovascular disease; PDE5-i, phosphodiesterase type 5 inhibitors; Tx, pharmacological
treatment.

flow to skeletal muscle account for 25% to 40% of the
increase in glucose uptake in response to insulin stimulation.
Phosphatidylinositol 3-kinase-dependent (PI3K) insulin-
signaling pathways related to production of NO in endothe-
lium share striking similarities with metabolic pathways that
promote glucose uptake in skeletal muscle. Other distinct
non-metabolic branches of insulin-signaling pathways regu-
late secretion of the vasoconstrictor ET-1 in endothelium.
Metabolic insulin resistance is characterized by pathway-
specific impairment in PI3K-dependent signaling, which in
endothelium may cause imbalance between production of
NO and secretion of ET-1, leading to decreased blood
flow, which worsens insulin resistance.24 Deficiency of
endothelial-derived NO is believed to be the primary defect
that links insulin resistance and EDys. NO deficiency results
from decreased synthesis and/or release, in combination
with exaggerated consumption in tissues by high levels of
reactive oxygen (ROS) and nitrogen (RNS) species, which
are produced by cellular disturbances in glucose and lipid
metabolism. EDys contributes to impaired insulin action, by
altering the transcapillary passage of insulin to target
tissues. Reduced expansion of the capillary network, with
attenuation of microcirculatory blood flow to metabolically
active tissues, contributes to the impairment of insulin-
stimulated glucose and lipid metabolism. This establishes a
reverberating negative feedback cycle in which progressive
EDys and disturbances in glucose and lipid metabolism
develop secondarily to the insulin resistance.37 Hyperglyce-
mia may impair endothelial function by promoting release
of free radicals. Vascular damage, which results from lipid
deposition and oxidative stress to the vessel wall, triggers an
inflammatory reaction, and the release of chemoattractants
and cytokines that worsen the insulin resistance and EDys. A
recent study provided consistent evidence for a role of
insulin-resistance in determining endothelial dysfunction in
ED patients; it was found that chronic cannabis use deter-
mined early EDys, and that the hallmark of that condition in
young cannabis users was a lower insulin sensitivity (as
detected by the homeostatic model assessment index) com-
pared with the control group. It was hypothesized that pro-
longed activation of the endocannabinoid system is able,
somehow, to alter endothelial function and to determine an
early damage of the erectile process.38
Role for testosterone in erectile and
endothelial function/dysfunction
The observation that androgen decline in aging men is asso-
ciated with a reduction in the number and quality of erections
dates long ago.39 T has a central role on endothelial health
(Fig. 2); in fact its decline over the aging process may affect
either arterial reactivity or sexual function.40 Hypogonadism
and ED are common disorders found in aging men present-
ing to andrology clinics. Increasing evidence indicates that
both disorders have important associations with the MeS,
DM and CVD, all conditions with an increased morbidity

40 © 2009 The Japanese Urological Association


GENOMIC EFFECT
APOPTOSIS
microparticles
Sexual Stimulation
Cavernous
nerve
Terminal NO
Non-adrenergic
Non-colinergic
Guanylate
cyclasi
Fig. 2 Schematic representation of GTP
5’ GMP
the molecular mechanisms underly-
ing the control of endothelial function
by testosterone and phosphodi-
esterase type 5 (PDE5) inhibitors.
NOS, nitric-oxide synthase.
and mortality.41 A low T-level is positively associated with
the presence and severity of atherosclerosis and a reduction
in plasma T might contribute to increased arterial stiffness,
which in turn has been associated with increased cardiovas-
cular risk.42 Numerous epidemiological and interventional
studies reported a controversial relationship between T and
CVD. T inversely correlates with the severity of atheroscle-
rosis and has beneficial effects upon vascular reactivity,
inflammatory cytokine, adhesion molecules, insulin resis-
tance, serum lipids, and hemostatic factors.43 Interestingly,
men with established CAD often have reduced circulating T
levels44 that are often associated with a certain degree of
EDys independently of other VRF, suggesting a protective
role of endogenous T on the endothelium.37 The Rotterdam
study, a population-based cohort study, showed that low
levels of endogenous androgens are associated with
increased likelihood of atherosclerosis in elderly men.45
Svaartberg demonstrated an inverse relationship between
total T levels and carotid intima-media thickness (IMT).46
This finding was not independent of body mass index (BMI).
Accumulating evidence has shown an association of low T to
cardiovascular mortality, morbidity in men of varying age,
and CRF.47 Men have a higher rate of CVD than women. The
likely culprits appear to be T, dihydrotestosterone (DHT),
dehydroepiandrosterone (DHEAS) and their metabolites.
Capaldo et al.48 showed that men with sex steroid deficiency
had a greater IMT and that low plasma T has also been
associated with cardiovascular risk in healthy men.49
Akishita et al.50 also found that DHEAS levels correlate with
© 2009 The Japanese Urological Association
ED3 in the elderly man
TESTOSTERONE
NON GENOMIC EFFECT
REGENERA TION
Endothelial
progenitor cells
L-Arginine
O2 Endothelial Cell
NOS 1/2/3
Smooth muscle cell
Reduction
Ca2+
GMPc
Protein Kinases
GMPc Smooth Muscle
K+ Cell Relaxation
PDE 5
Ca2+
PDE5 inhibitors
flow-mediated dilation analysis and it was irrespective of
other confounding factors in women. A conclusive view on
the effects of androgen deficiency on vascular function can
be seen with the adverse effects of androgen deprivation
therapy (ADT) in prostate cancer patients. Whether via
orchiectomy or use of gonadotropin-releasing hormone ago-
nists or antagonists and AR agonists, the net result of ADT is
low circulating T/DHT with concomitant changes in body
composition, insulin resistance and vascular disease.51 There
is a decrease in lean muscle mass and an increase in fat mass.
A long-term study (1–8 months) comparing men undergoing
ADT to eugonadal men found an increase in fat mass com-
pared to controls of eugonadal men.52 ADT has been impli-
cated in inducing MeS.53 Overall, ADT in men with prostate
cancer has been shown to increase the risk of cardiovascular
events.54 Keating reported that men undergoing ADT had
a 25% increase in risk of CAD compared with non-ADT
patients.55 A large study consisting of 23 000 men undergo-
ing ADT for at least 12 months had an increase of cardio-
vascular morbidity by 20% compared with non-ADT men
after controlling for confounding factors.56 A recent report
found that men receiving ADT were approximately 2.6 times
at greater risk of cardiovascular mortality than non-ADT
controls after adjusting for confounding factors.57 Interest-
ingly, a new study by D’amico et al.58 suggested that elderly
men with T-1 to T-2 localized prostate cancer should not be
given primary ADT due to reduced cancer as well as overall
survival in these patients. Montalcini et al. showed that post-
menopausal women in the lowest T tertile had the least
41
A AVERSA ET AL.
flow-mediated dilation, which implies that not only does
estrogen deficiency play a role in CVD, but T deficiency does
as well.59
The role of androgens in determining vasodilatation has
been investigated recently. T may activate the endothelium
and stimulate the NO-cyclic guanosine monophosphate
and/or the hyperpolarization-mediated vascular relaxation
pathway and may thus add potential beneficial effects
against coronary artery atherosclerosis. Additional
endothelium-independent effects of T may involve inhibi-
tion of the signaling mechanism of vascular smooth muscle
contraction, such as intracellular concentration [Ca2+] and
protein kinase C, whereas a significant portion of the vasore-
laxing effect of T appears to be endothelium independent
because no significant difference is observed between the
relaxing effect of the hormone in isolated vessels with or
without endothelium.60 Also, inhibition of NO-synthase,
prostaglandin synthase, and guanylate cyclase do not appear
to affect the vasorelaxing effect of T, suggesting that the
T-induced vascular relaxation may involve inhibition of the
mechanism of vascular smooth muscle contraction.61,62
Several studies have shown that acute administration of T
induces a rapid relaxation in vascular tissues of different
species including humans,63,64 suggesting a non-genomic
effect of this hormone on vasomotion.65 Different mecha-
nisms have been proposed to explain T-induced vasodilata-
tion,66 but as to which are the effective mechanisms and
which are the mediators involved with the T-induced vasore-
laxation remain a matter of debate. T might induce relax-
ation in human isolated corpora cavernosa strips by
activation of smooth muscle adenosine triphosphate-
sensitive K(+) channels (Fig. 2). This finding suggests that T,
in addition to its known endothelial action, might regulate
erectile function locally by its action on the smooth muscle
of the human corpus cavernosum.67 It is now accepted that
different thresholds for sexual desire and erectile function
are present in humans, the former being quite higher than
the latter.68 In humans, T deficiency determines a sequence
of molecular penile events leading to reduced capacity of
smooth muscle and endothelial cells to relaxation as well as
to increased sensitivity to contractile factors, that is,
a-adrenergic agonists and deficiency of NO-induced relax-
ation during sexual stimulus. Recent evidences in humans
suggest that T may directly control the expression and activ-
ity of PDE5 in human corpus cavernosum so that in some
selected patients, that is, total-T < 10 nmol/L and/or free-T
below 200 nmol/L, androgen supplementation may improve
therapeutic efficacy to PDE5-i.
Erectile dysfunction and endothelial
dysfunction in the aging male
ED is predominately a disease of vascular origin. It is widely
known that it dramatically increases in men with diabetes
42
mellitus, hypercholesterolemia and cardiovascular disease.
It has a high prevalence and mainly affects men between 40
and 70 years of age.69,70 Loss of the functional integrity of
the endothelium and subsequent endothelial dysfunction
plays a pivotal role in the occurrence of ED. There is a close
relationship between ED, aging and EDys. ED problems due
to organic causes comprise up to 80% of cases, while vas-
cular disease is the most common pathophysiology of ED.71
ED is the first clinical presentation of subclinical endothelial
dysfunction disease prior to the appearance of cardiovascu-
lar disease or CRF.72 In particular, it was shown that 64% of
men who presented with myocardial infarction had ED prior
to their heart problems, and 57% of men undergoing coro-
nary artery bypass graft surgery had ED before the opera-
tion.73 The more coronary vessels are involved , the more
severe ED is. EDys is an early abnormality of the artery;
it may occur many years before vascular disease, such as
atherosclerosis. As it is widely known, advanced age is a
risk factor for atherosclerosis and ischemic heart disease.74
EDys occurring in the healthy elderly might have a
pathogenic role in the increased risk of atherosclerosis
and its complications in the elderly.75 EDys and atheroscle-
rosis may affect all major vascular beds with different
sizes (i.e. 1–2 mm of the penile artery, 3–4 mm of the
proximal left anterior descending artery, 5–7 mm of the
internal carotid artery and 6–8 mm of the femoral
artery).70,72 Symptoms of vascular disease are more frequent
in elderly people and the threshold for the development of
symptoms is reached when the lumen of the artery is
occluded by 50%.72 As there is a close relationship among
EDys, ED and aging and as EDys appears to precede not
only ED but cardiovascular complications too, the assess-
ment of endothelial function in the elderly is a crucial point.
In recent years venous occlusion plethysmography, arteriog-
raphy and intracoronary Doppler catheter techniques during
an intra-arterial infusion were performed for this purpose.74
Recently, brachial artery flow-mediated dilation (FMD) was
used as a measure of endothelial function in humans.76 The
aim of FMD is to increase brachial artery blood flow in
response to transient hyperemia, which is provoked by
inducing post-ischemic dilation of distal vascular beds.72,77
Reactive hyperemia is reproduced by inflating a pediatric
blood pressure cuff up to 200 mm Hg above systolic blood
pressure for five minutes to occlude arterial flow. Sixty
seconds after cuff deflation arterial diameter and flow
velocity measurements are performed.76 Patients with
impaired endothelial function present a lower increase in
arterial diameter. FMD is a commonly used , accurate,
non-invasive and reproducible method for evaluating endot-
helial function. Limb vessels are suitable for assessing
endothelial function in the elderly, as EDys is a diffuse
process and peripheral vessel examination is non-invasive
compared to coronary artery assessment.75 Furthermore,
FMD was shown to be nearly as sensitive as exercise
© 2009 The Japanese Urological Association

electrocardiography in the detection of coronary artery
disease and more specific for diagnosis than exercise elec-
trocardiography. In a recent paper, endothelial function was
evaluated by FMD of the brachial artery by ultrasound in 30
elderly vs 30 younger subjects.75 FMD of the elderly group
was significantly lower than the younger group (7.9 ⫾ 3.1 vs
10.8 ⫾ 1.9, respectively, P < 0.001).75 FMD and age were
found to be inversely correlated. This result is remarkable,
as it was found in healthy elderly subjects. Celermajer
et al.78 examined patients aged 15–72 years and found
that aging is associated with impaired flow-mediated
endothelium-dependent vasodilation in the brachial artery;
in this study elderly healthy men were reported to be
affected earlier than women.
Therefore, the final message is that advanced age is a
strong predictor of EDys in the elderly; EDys may not only
precede ED onset, but also cardiovascular events. As it is
widely shown, it usually occurs in several age-related dis-
eases, such as chronic renal failure, heart failure, hyperten-
sion, diabetes mellitus, hypercholesterolemia, rheumatic
diseases and Alzheimer’s disease.79,80 For such diseases, the
continuous use of a PDE5-i for treating ED is indicated , but
to avoid the high dropout rate we recommend an adequate
initial instruction and long-term follow up, even for patients
with successful treatment.81
PDE5-i in the aging male: daily vs
on-demand therapy?
There are numerous conditions in the aging male that are
associated with ED, including DM, obesity, MS and CVD,
that require specific treatments that may in turn determine
sexual disturbances.82 The debate as to whether in such cases
a daily or on-demand therapy for ED with PDE5-i should be
instituted is still open and many concerns have been raised
regarding rehabilitative effects of PDE5-i given daily in men
with ED. There have been several publications in the past
two years regarding daily dosing of PDE5-i for two major
indications, penile rehabilitation after prostate cancer and
management of lower urinary tract symptoms (LUTS). Evi-
dence from basic science investigations has indicated that a
daily dose of PDE5-i may improve erectile function and
exert a number of beneficial tissue effects on the penis as
well as in other districts.83 Encouraging animal studies indi-
cate that EDys and oxidative stress associated with insulin
resistance can be reversed by daily sildenafil84 and insulin
sensitivity is significantly improved in an animal model
of diet-induced obesity;85 chronic PDE5 inhibition also
resulted in increased energy expenditure, suggesting that
improved energy balance and weight reduction might be
partially responsible for the enhanced insulin action without
any adverse effects on cardiac morphology or blood pres-
sure measured in vivo, supporting human studies that
showed no association between long-term use of sildenafil
© 2009 The Japanese Urological Association
ED3 in the elderly man
and risk of ischemic events. Unfortunately, data from human
series of routine dose PDE5-i for penile rehabilitation after
radical prostatectomy are conflicting, with the two largest
studies showing no benefit to daily dose therapy in the
post-radical prostatectomy and the general ED populations.
Clinical studies revealed good safety and efficacy of sildena-
fil given at bedtime in recovering spontaneous erections both
in aging men with mild-to-moderate arteriogenic etiology86
or in prostate cancer patients.87 A recent large controlled
trial comparing on-demand and nightly dosing of vardenafil
on recovery of erectile function in bilateral nerve-sparing
radical prostatectomy patients with ED demonstrated that
nightly dosing did not have any additive effect over that of
on-demand use.88 Similar results were reported in a con-
trolled trial by Zumbè et al.,89 who compared the efficacy of
vardenafil given on-demand vs daily in men with mild-to-
moderate ED. It was concluded that daily vardenafil did not
produce greater sustained effects on erectile function than
the on-demand regime with no sustained clinical benefits
beyond cessation of treatment above those observed with
on-demand administration. By contrast, numerous studies
have shown the beneficial acute and chronic effects of
sildenafil and tadalafil on arterial function in men with ED,
thus presenting them as potential candidates for therapies
aimed at reducing the burden of EDys in selected categories
of aging men.90
Vascular damage, insulin resistance and EDys have been
recently implicated in the pathogenesis of benign prostate
hyperplasia (BPH), thus suggesting the hypothesis of an
increased sympathetic nerve activity in men with BPH.91
Evidences show that diabetic men are at higher risk for both
ED and BPH,92 and vascular damage being considered as the
mainstay of both;92 hyperplasia of the stromal and glandular
prostate compartments might be induced by stromal growth
secondary to hypoxia, which in turn results from reduced
blood flow patterns at the Duplex ultrasound.93 It appears
clear that EDys and the consequent adrenergic overtone
can be considered as the common denominator linking
atherosclerosis, cardiovascular disease and ED-BPH. To this
purpose, daily PDE5-i use in clinical trials has been reported
to be effective and safe in improving LUTS with no change
in urinary flow rates in men with BPH/LUTS, suggesting a
newer utilization to improve the quality of life for aging men
with symptoms secondary to BPH.94
Conclusions
ED is associated with the same underlying risk factors as
vascular disease and includes hypertension, DM, hyperlipi-
demia, smoking, obesity, and aging. Some evidence shows
that ED can be greatly improved not only with PDE5-i but
also by treating the risk factors directly. These include ces-
sation of smoking, correction of hyperlipidemia, and ame-
lioration of obesity through weight loss, all of which result
43
A AVERSA ET AL.
in amelioration of endothelial health (Fig. 1). Generally, in
these patients the co-administration of T when a deficiency
syndrome is present, does not produce detrimental or
obstructive effects on the prostate, but must be used with
caution in the long term. ED and LUTS frequently coexist in
men of advancing age but further studies are required to
elicit the exact mechanism of action in LUTS. There appears
to be an emerging role for PDE5-i as a treatment for both
conditions. Finally, it is important to remember that prostate
cancer is the most common cause of death in men with
advancing age; radical prostatectomy is often associated
with ED and no rehabilitative oral treatment has demon-
strated proven efficacy. When androgen deprivation therapy
is instituted , it is important to remember that it is able to
induce rapid metabolic changes, such as increased insulin
resistance and visceral adipose tissue accumulation, which
are associated with increased cardiovascular mortality.
Acknowledgment
Dr Aversa and Dr Gareri wish to thank Professor Marianna
Morrone for her ongoing assistance with the English
language.
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