Aversa.2_EU Urological Review 15/03/2010 13:01 Page 79
Endothelial Function and Erectile Dysfunction
plasminogen activator inhibitor-1 (PAI-1).
13
In a haemostatic response, A low T level is positively associated with the presence and severity
they produce key components of platelet activation and aggregation, of atherosclerosis and a reduction in plasma T might contribute
including von Willebrand factor (VWF), fibronectin and thrombospondin, to increased arterial stiffness, which in turn has been associated with
ultimately leading to initiation of the coagulation cascade.
14
These increased cardiovascular risk. Numerous epidemiological and
dynamic thrombotic functions are important, as thrombus formation is interventional studies have reported a controversial relationship
a key element in atherosclerosis progression. The endothelium between T and CVD. T inversely correlates with the severity of
regulates transmigration of circulating cells through a complex atherosclerosis and has beneficial effects on vascular reactivity,
interplay of trans-signalling molecules. Endothelial cells recruit inflammatory cytokines, adhesion molecules, insulin resistance,
inflammatory cells via expression of cell adhesion molecules such as serum lipids and haemostatic factors. Interestingly, men with
selectin and immunoglobulin superfamily adhesion molecules, and by established CAD often have reduced circulating T levels that are
responding to pro-adhesion signals from circulating cytokines.
15
often associated with a certain degree of EDys independently of
Platelets also have a range of endothelial signalling abilities, including other vascular risk factors (VRFs), suggesting a protective role of
the release of vasodilating agents (such as adenosine diphosphate endogenous T on the endothelium.
[ADP] and serotonin), as well as vasoconstricting and procoagulant
factors (such as endothelin- 1 and VWF). The effects of these circulating The Rotterdam study, a population-based cohort study, showed that
cell signals can further be attenuated by some endothelially derived low levels of endogenous androgens are associated with increased
substances such as nitric oxide (NO) and prostacyclin.
14
likelihood of atherosclerosis in elderly men.
19
Svaartberg
20
demonstrated an inverse relationship between total T levels and
The vascular endothelium also plays an obligatory role in carotid intima-media thickness (IMT). This finding was not
vasodilatation. The role of the arterial vasculature is to provide independent of body mass index (BMI). Accumulating evidence has
adequate tissue perfusion and to buffer the changes in blood pressure shown an association of low T with cardiovascular mortality and
and flow that occur with each cardiac cycle and during normal morbidity in men of varying age, as well as with CRFs. Men have a
activities. At the tissue capillary level, blood flow remains relatively higher rate of CVD than females. The likely culprits appear to be T,
constant despite rapid changes in the tone of arterioles and venules. dihydrotestosterone (DHT), dihydroepiandrosterone (DHEAS) and their
Regulation of flow depends on the ability to change the resistance of metabolites. Capaldo et al.
21
showed that men with sex steroid
the vascular bed. The endothelium produces and responds to several deficiency had a greater IMT, and low plasma T has also been
potent, locally active mediators. The most important of these is NO – a associated with cardiovascular risk in healthy men. Akishita et al.
22
simple, highly reactive gas. Endothelial NO possesses potent anti- also found that DHEAS levels correlate with flow-mediated dilation
atherogenic properties, in addition to inhibiting platelet aggregation analysis; this was irrespective of other confounding factors in women.
and regulating vascular tone.
16
Bioavailable NO can be increased by
enhancing its production or reducing its inactivation. As a freely A conclusive view of the effects of androgen deficiency on vascular
diffusible gas, NO acts not only within the lumen but also on the function can be seen with the adverse effects of androgen
surrounding smooth-muscle cells, where it increases cyclic guanosine deprivation therapy (ADT) in prostate cancer patients. ADT, whether
monophosphate (cGMP)-mediated vasodilation.
14
Endothelial cells also via orchiectomy or use of gonadotropin-releasing hormone (GnRH)
produce a number of prostaglandins, most notably prostacyclin agonists or antagonists and androgen receptor (AR) agonists, results
(PGI2) and thromboxane A
2
(TXA
2
). PGI2 initiates cyclic adenosine in low circulating T/DHT with concomitant changes in body
monophosphate (cAMP)-mediated smooth-muscle relaxation, while composition, insulin resistance and vascular disease. There is a
TXA
2
causes vasoconstriction. In normal physiological conditions, PGI2 decrease in lean muscle mass and an increase in fat mass. A long-
exerts predominantly vascular effects.
17
Another endothelially released term study (one to eight months) comparing men undergoing ADT
factor with variable vascular influences is angiotensin II. This peptide versus eugonadal men found an increase in fat mass in the former
has vasoconstricting, pro-thrombotic, oxidant and atherogenic effects, compared with the latter. ADT has been implicated in inducing MeS.
23
as well as the ability to counteract these effects depending on the Overall, ADT in men with prostate cancer has been shown to increase
receptor (subtype AT1 or AT2) activated. The endothelium also the risk of cardiovascular events. Keating reported that men
stimulates the production of bradykinin, which results in the release of undergoing ADT had a 25% increase in the risk of CAD compared with
the vasodilating agents NO and endothelium-derived hyperpolarising non-ADT. In a large study consisting of 23,000 men, those undergoing
factor (EDHF). By contrast, the endothelium also produces the ADT for at least 12 months had 20% increased cardiovascular
vasoconstricting hormones known as the endothelins.
18
As the exact morbidity compared with non-ADT men, after controlling for
roles of each of these agents in health and disease are delineated, it is confounding factors. A recent report found that men receiving ADT
clear that the endothelium has a diverse role in maintaining vascular were at approximately 2.6-fold greater risk of cardiovascular mortality
tone as well as arterial flow through a variety of mechanisms. than non-ADT controls, after adjusting for confounding factors.
24
Furthermore, a disruption in these regulatory functions at any level Interestingly, a new study by D’Amico et al. has suggested that elderly
could lead to impaired and insufficient tissue perfusion. men with T
1
to T
2
localised prostate cancer should not be given
primary ADT due to reduced cancer survival, as well as reduced
Testosterone (T) has a central role in endothelial health; in fact, its overall survival, in these patients.
25
Montalcini et al. showed that in
decline as part of the ageing process may affect either arterial reactivity post-menopausal women, those in the lowest T tertile had the least
or sexual function. Hypogonadism and ED are common disorders found flow-mediated dilation (FMD), which implies that not only oestrogen
in ageing men presenting to andrology clinics. Increasing evidence deficiency but also T deficiency plays a role in CVD.
26
indicates that both disorders have important associations with the
metabolic syndrome (MeS), diabetes and cardiovascular disease The role of androgens in determining vasodilatation has recently been
(CVD) – all conditions with increased morbidity and mortality. investigated. Several studies have shown that acute administration of
EUROPEAN UROLOGICAL REVIEW 79
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