Ageing and Erectile Dysfunction


addition to the endothelial injuries caused by VRFs, the decline in the sex hormone milieu in the ageing man was reported to contribute to loss of endothelial and erectile functionality.14


It is now considered


that EDys is an early marker of atherosclerosis, ED and systemic vascular disease, and should therefore be evaluated.15


Furthermore,


the magnitude of EDys and endothelial damage should be regarded as a balance between endothelium injury and the endogenous capability for endothelial regeneration.16


However, in the elderly, local


(angiogenic) and systemic (vasculogenic) vascular repair mechanisms are thought to be impaired, therefore contributing to the maintenance of an EDys state, further enhancing atherosclerotic disease, ED and generalised vasculopathy.17,18


Vascular Risk Factors, Endothelial Dysfunction and Erectile Dysfunction in the Aged Man It is considered that ageing per se represents a risk factor for the development of EDys and ED.19


relationship between OS and EDys in elderly ED patients was established after the observation that aged cavernosal endothelium produces high levels of the reactive oxygen species, superoxide anion (O2-).28


The uncoupling of eNOS in the aged vascular system, may be one of the mechanisms responsible for the increased formation of O2-.31


experimental CC reduces O2- formation, ameliorating erectile function.28


Furthermore, superoxide dismutase gene transfer to aged


Regarding eNOS/eNO, it was reported that the production/bioavailability of this vasodilator was downregulated in elderly erectile tissue. This eNO deregulation was directly associated with the decrease in vascular endothelial growth factor (VEGF) expression,32


alterations in eNOS activation30 Rho-kinase.33


an increase in the endothelial activity of arginase,29 and the increased release/activity of


Additionally, other co-morbidities


such as diabetes, hypertension, lipidic disorders, the more recently recognised metabolic syndrome (MetS) and smoking are highly prevalent and frequently co-exist in the elderly male, contributing to altered endothelial and erectile function. As these VRFs are general correlates of both ED and cardiovascular disease (CVD), EDys was identified as the common denominator between these conditions.20,21


EDys is characterised by endothelial


decreased responsiveness to vasodilator mediators and/or increased sensitivity to vasoconstrictor molecules affecting the normal regulatory role of peripheral vascular endothelium,22


including


In fact, EDys was considered to be responsible for the late structural vascular abnormalities, that lead ultimately to atherosclerosis, which is commonly present in ED and CVD patients.20,21,24


cavernosal arterial and venous systems. As consequence, the vasodilator potential is reduced and vascular structures are unable to fully dilate in response to appropriate stimuli. The decrease in endothelial vasodilation is mostly caused by the diminished synthesis and/or loss of eNO bioavailability/bioactivity in the vasculature.23 Besides vasodilation, eNO-associated alterations may also impair a series of relevant mechanisms, including anticoagulation and anti-inflammatory activities, vascular growth and remodelling capability, predisposing to the development of atherosclerotic lesions.15,22,23


Given the close connection between EDys, atherosclerosis, ED and CVD, it is most likely that the status of endothelial function may reflect the propensity of an individual to develop these pathological conditions. As atherosclerosis of the pudendal–cavernosal arteries is the common cause of vasculogenic ED in the geriatric patient,25


it should be perceived as the


‘silent tip of the iceberg’ of systemic vascular disease and a relevant parameter for the prevention of acute cardiovascular events.26


It is


then of extreme relevance to recognise and evaluate EDys as a biomarker of atherosclerosis and CVD, having ED as the initial clinical manifestation.


The Impact of Endothelial Dysfunction in Aged Corporeal Tissue


Oxidative Stress and Impaired Endothelial Nitric Oxide Bioactivity – Unifying Mechanisms in Endothelial Dysfunction and Erectile Dysfunction The pathogenesis of ageing cavernosal EDys is associated with interlinked mechanisms, including oxidative stress (OS) and impaired eNO synthase (eNOS)/eNO functional activities that in fact hamper SM relaxation and endothelium-dependent vasodilation.27–30


The EUROPEAN UROLOGICAL REVIEW


In addition to these mechanisms, it needs to be taken into consideration that ageing is accompanied by the accumulation of VRFs, with synergistic noxious effects on the endothelium, exacerbating penile EDys and ED. In certain cases endothelial injuries may be so extensive that ultimately cavernosal endothelium activates apoptotic mechanisms.34


Confirming the relevance of eNO in erection, penile eNOS molecular therapy showed improved erectile responses in older animals.27


Additionally, when atherosclerosis is


installed, penile oxygen tension decreases, causing several alterations in cavernosal functionality.35,36


corporeal delivery of the free oxygen necessary for NO production,37 which further aggravates cavernosal EDys. Moreover, hypoxic conditions are also responsible for changes in SMC content37–39


and


predispose to corporeal fibrosis through the increased activation of collagen synthesis.40


All of these alterations occurring in the geriatric


penis further impair vasorelaxation responses and modify penile elasticity and compliance, aggravating ED conditions.


Testosterone, Endothelial Health and Erectile Dysfunction


The effect of reduced testosterone levels varies among subjects and has become known as androgen decline in the ageing male (ADAM).41 Androgen deficiency with advancing age has been associated with a reduction in the number and quality of erections.42,43 Testosterone, which stimulates the release of endothelial vasorelaxation factors, was shown to play a role in endothelial health, and its decrease with ageing may affect both vascular reactivity and sexual function.14,44


Low oxygen tension prevents the


In fact, hypogonadism and ED are concomitant disorders present in elderly men that are closely linked with MetS, diabetes and CVD, conditions having EDys as common grounds.45 Furthermore, low testosterone levels correlate with the presence and severity of atherosclerosis, indicating a protective action on endothelium functionality. In fact, testosterone is thought to have beneficial effects on vascular reactivity by influencing inflammatory cytokine production, modulating adhesion molecules and serum lipids, thus ameliorating endothelial and erectile function.46


However,


the major effects of testosterone in the endothelium are related to its roles in vasodilation. Systemically, testosterone activates ECs to release eNO and EDHFs and inhibits underlying SMC contraction mechanisms.47–49


In addition to these


These vasorelaxation events are also relevant at penile levels where testosterone increases eNO production and modulates phosphodiesterase type 5 (PDE5) expression, exerting a dual action on cavernosal ECs and SMCs.50–52


biological roles, testosterone may have an influence on other corporeal structures. Effectively, androgen deprivation has deleterious effects on CC by inducing the accumulation of adipocytes,53


SMC degeneration, increase in ECM content and 45


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