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Erectile Dysfunction in Inflammaging
C H A P T E R
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Erectile Dysfunction in Inflammaging Carla Costa1, Maarten Albersen2 1Department
of Biochemistry and Department of Experimental Biology, Center for Medical Research, Faculty of Medicine, University of Porto, Portugal, 2Laboratory for Experimental Urology, Department of Urology, University Hospitals Leuven, Belgium
INTRODUCTION Until relatively recently, it was generally assumed that a loss of sexuality was a natural development and inevitable with aging, which resulted in little attention being given to sexual behavior and the treatment of sexual dysfunctions in the geriatric population. However, nowadays it is known that with improvements in life expectancy, both men and women are seeking to preserve their sexuality into older age. However, while the interest in sexual activity persists with aging, a decline in sexual activity is typically seen with, and can be attributed to, both general health problems and specific sexual dysfunctions. In a large US-based study, the proportion of males who were sexually active declined from 83.7% in the 57–64-year age group to 38.5% in the 75–85-year age group [1]. In a smaller pilot study of a cohort of 50 patients with a mean age of 81 years, Smith et al. reported that the main reason for older men being sexually inactive was erectile dysfunction (ED) [2], a condition defined as the persistent inability to attain and maintain penile erection sufficient for sexual intercourse [3]. Although premature ejaculation is the most prevalent sexual dysfunction in men, ED is probably the most thoroughly studied and the most common sexual complaint with which men present to their healthcare providers [4]. The advent of safe oral therapy [cGMP-specific 3′,5′-cyclic phosphodiesterase, or phosphodiesterase 5 inhibitors (PDE5is)] for the treatment of ED has brought attention to the disease and probably results in increased treatment-seeking behavior in the aging male. Despite the overwhelming success of oral PDE5is, the demand for pharmacotherapeutic and surgical options for ED continues to rise as a result of the increased elderly population, as well as the increasing recognition that approximately one-third of ED patients
Inflammation, Advancing Age and Nutrition. http://dx.doi.org/10.1016/B978-0-12-397803-5.00024-1
do not respond to PDE5is [5]. This is especially applicable to the older patient with multiple pathophysiological alterations in erectile mechanisms, which are among the various end results of inflammatory disorders, such as neuropathy and vasculopathy. Therefore, ED remains a topic of interest to physicians treating the aging and older male. This chapter will address erectile biology and the age-related changes thereof, the prevalence of ED, its etiological factors in the older population, and contemporary treatment options for the treatment of ED in aging and aged males.
PREVALENCE AND ETIOLOGY A multitude of large-scale studies have substantiated the global prevalence of ED and its close relationship to aging. The Massachusetts Male Aging Study is a large-scale longitudinal project investigating the effects of aging on male sexual health, among other domains of general health. The authors reported a prevalence of ED of no less than 52% of subjects [6]. The prevalence of complete ED (no tumescence at all) tripled from 5% to 15% between subject aged 40 and 70 years [6]. In the European Male Aging Study (EMAS), a collaborative effort of eight European centers investigating ED in a male population aged 40–79 years with a mean age of 60 years, 30% of the EMAS sample reported ED [7]. The prevalence of ED was higher in the older age groups, peaking in men aged 70 years and older (64%). It was further shown that men in higher age groups, although more often affected, were less concerned with the presence of ED [7]. Finally, approximately 617,000 new cases occur annually in men aged 40–69 years in the United States alone [8].
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The above-mentioned studies indicate that ED is strongly associated with advancing age. It logically follows that ED is therefore highly prevalent in the geriatric population [9]. With the rapidly expanding aging population and the increase in life expectancy, an increase in the prevalence of ED is expected in the years to come. One estimation shows that by 2025, 9.5% of the population worldwide will be men older than 65 years of age [10]. By then, the number of men suffering from ED will have reached 322 million worldwide. Further evidence for a relationship between age and ED is provided by the fact that the prevalence of ED rises steadily with age, from 30.7% in men aged 57–64 years to 43.3% in men aged 75–85 years [11]. In other studies, prevalence rates up to 77.5% are reported for patients aged 75 years and older [12]. However, not only the prevalence but also the severity of ED increases with advancing age. The relationship between aging and ED is in part based on the increasing morbidities that aged men experience, such as polypharmacy, hypertension, vascular disease, chronic kidney disease, depression, and many others [13]. Beside these concurrent conditions, changes induced by the process of aging itself that contribute to ED are specified below.
PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION IN THE AGING MAN Erectile Function and the Aging Process Erectile tissue is composed of small resistance helicine arteries that empty into lacunar spaces lined by vascular endothelial cells (ECs) embedded in a meshwork of interconnected smooth muscle cells (SMCs), and an extracellular matrix composed of elastic fibers and collagen produced by dispersed fibroblasts [14,15]. Erectile function is a complex neurovascular phenomenon under psychological control that requires interplay between the central and peripheral nervous systems, hormonal factors, and the structural integrity of the cellular components of the penis [16]. These cellular and molecular interactions are crucial for the erectile process and any impairment may result in ED. During sexual arousal, an initial stimulus originating from supraspinal centers results in parasympathetic nonadrenergic noncholinergic cavernosal nerve activation, leading to the production of nitric oxide (NO) by neuronal NO synthase (nNOS) [17]. NO is diffused into adjacent SMCs and activates the enzyme guanylyl cyclase, which results in intracellular increase of the second messenger, cycling guanosine monophosphate (cGMP). The NO-cGMP pathway activates multiple signaling cascades, thus promoting SMC relaxation, cavernous sinusoidal dilation, and an inflow of arterial blood [18,19]. This initial blood inflow increases shear stress,
which mechanically stimulates endothelial NOS (eNOS) to produce NO, and the release of prostanoids and endothelium-derived hyperpolarizing factors (EDHFs) [20]. These events result in the engorgement of sinusoidal spaces, eventually leading to an increase in intracavernous pressure by compression of the subtunical venules, thus activating the venoocclusive mechanism, which allows the maintenance of erection. With the advancement of age, relevant alterations will occur to change this scenario. In fact, the aging process may affect erectile components, and penile molecular and hemodynamic events, resulting in ED. In the older male, loss of erectile function has been associated with impaired neurogenic function and failure of the arteriogenic and/or venous systems, thus altering crucial mechanisms involved in the initiation/maintenance of an erection [21]. Despite the essential role of all penile cellular and molecular interactions, aging ED has been considered a vascular-related pathology. In fact, vasculogenic ED was recognized as the most common etiology in the elderly, promoted by occlusive disease of the pudendal-cavernosal-helicine arterial tree, through the development of atherosclerosis [22,23]. The concomitant presence of vascular risk factors (VRFs) in the geriatric man contributes to the development of atherosclerotic foci, which occur as consequence of endothelial dysfunction (EDys). EDys is characterized by loss of the functional biology and structural integrity of the endothelium, which alters the ability of ECs to properly respond to vasodilation/vasoconstriction stimuli and affects blood flow regulation [24,25]. In addition to the endothelial damage caused by VRFs, the decline in androgens is also reported to contribute to the loss of endothelial and erectile function in the aging man [26,27]. It is currently recognized that EDys is an early sign of atherosclerosis, which manifests first as ED, later contributing to the development of systemic vascular disease. ED is therefore considered the initial clinical presentation of subclinical EDys, prior to the manifestation of cardiovascular disease (CVD) and preceding the occurrence of cardiovascular events [28,29]. Moreover, it is now reported that EDys and endothelial integrity depend not only on the extent of injury but also on the endogenous capacity for regeneration [30]. However, vascular repair mechanisms of angiogenesis (local) and vasculogenesis (systemic) are reported to be impaired as result of the aging process, further contributing to EDys, atherosclerosis, ED, and the increased severity of vascular disease [31,32].
The Vascular Etiology of Erectile Dysfunction in the Aged Man Aging per se is considered to be a risk factor for the development of EDys and ED [33]. In addition, other comorbidities that are highly prevalent and frequently
Pathophysiology of Erectile Dysfunction in the Aging Man
coexist in the elderly male significantly contribute to altered endothelial and erectile function. In fact, the Massachusetts Male Aging Study—a prospective 10-year study that followed over 1100 men age 40 to 70 years at study entry—found that ED was more prevalent in patients presenting VRFs, including, diabetes, hypertension, low high-density lipoprotein (HDL) levels (clusters of metabolic syndrome), smoking, and hypogonadism [6]. All of these factors are general correlates for both ED and CVD, with EDys being the common denominator [34,35]. The key features of EDys are decreased responsiveness of the endothelium to vasodilators and/or increased sensitivity to vasoconstrictor mediators. These alterations affect the regulatory role of systemic vascular endothelium, affecting the penile arterial and venous systems [36]. As consequence, the vasodilator potential is reduced and vascular structures are unable to fully dilate in response to appropriate stimuli, which results in blood flow changes and inadequate tissue perfusion. EDys and the decrease in endothelial vasodilation are mostly induced by the noxious actions of VRFs, which are responsible for causing a reduction in the bioactivity/bioavailability of eNOS/ eNO in the vasculature [37]. In addition to increased vasoconstriction, disruption of vascular homeostasis predisposes the vessel wall to leukocyte adherence, platelet adhesion, thrombosis, vascular inflammation, and atherosclerotic lesions, which are commonly presented in ED and CVD [28,34–37]. Since aging-related vascular EDys is closely linked to atherosclerosis, ED, and CVD, it is most likely that the status of endothelial function may reflect the predisposition of an individual to develop these pathologies [38]. As atherosclerosis of the pudendal-cavernosal arteries is the most common cause of vasculogenic ED in the geriatric male, it should be perceived as the “tip of the iceberg” of a generalized vascular disorder. Therefore, endothelial function should be evaluated in ED patients and regarded as a potential parameter for the prevention of acute cardiovascular events [29,39].
Mechanisms Involved in Aging-Induced Vascular Endothelial and Erectile Dysfunction Oxidative Stress, Impaired Endothelial Nitric Oxide Production, and Penile Endothelial Dysfunction EDys in aging cavernosal tissue results from alterations in several molecular mechanisms, including oxidative stress and impaired eNOS/NO biology [40]. These modifications were reported to hamper crucial events involved in smooth muscle relaxation and endothelium-dependent vasodilation mechanisms [40–45]. In elderly erectile tissue, it was observed that
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the endothelium produces high levels of the reactive oxygen species, the superoxide anion (O2•−), which affects endothelial and erectile function by altering the redox status [42]. One of the most important mechanisms of action of O2•− is to accelerate the degradation of NO. The diffusion-controlled reaction between NO and O2•− leads to formation of the peroxynitrite anion (ONOO−), which can easily penetrate cells, causing oxidative modifications of macromolecules [43]. On the other hand, it was recently proposed that the uncoupling of eNOS in the aged penis increases O2•− production, thus exacerbating EDys and ED [45]. In addition, eNOS/NO activity/bioavailability is reported to be downregulated in elderly erectile tissue as result of several molecular alterations [46]. In the aging penis, a decrease in the expression of vascular endothelial growth factor (VEGF), a known regulator of NO production, has been observed [47]. Another mechanism involves an increase in the endothelial activity of arginase, the enzyme that competes with eNOS for the substrate l-arginine, thereby reducing NO formation [40]. Alterations in eNOS activation have also been described as a result of multiple molecular mechanisms that act in concert to affect its function both positively and negatively. In fact, a decrease in phosphorylation of the eNOS positive regulatory site (serine-1177) and an increase in the phosphorylation at its negative regulatory site (threonine-495) have been reported in elderly cavernosal tissue [44]. Confirming the relevant role of NO in erectile physiology, it was shown that penile NOS3 gene (encoding eNOS) transfer improves erectile responses in older animals [41]. Given that aging is accompanied by the simultaneous presence of multiple VRFs, it is important to take into account all of the synergistic deleterious actions they have on the endothelium that exacerbate penile EDys and ED. In certain cases, damage to the endothelium is so extensive that the endothelial monolayer activates programmed cell death [48]. Furthermore, the presence of atherosclerosis has been reported to decrease penile oxygen tension, thus causing molecular and structural alterations that affect cavernosal functionality [49,50]. Low oxygen tension may dysregulate the production of vasoactive substances present in the penile vascular bed, including NO [50]. Additionally, hypoxic conditions are also responsible for altering the synthesis of cytokines and growth factors, which play major roles in regulating trabecular smooth muscle tone/content and in connective tissue metabolism. As result, changes in the SMC layer and a predisposition to corporeal fibrosis, through the increased activation of collagen synthesis, have been reported [51–53]. All of these age-related modifications contribute to the impairment of cavernosal vasorelaxation and altered penile compliance, thus aggravating ED conditions.
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Hypogonadism, Endothelial Dysfunction, and Erectile Dysfunction: How Testosterone Affects Penile Endothelial Function Reduced testosterone levels are a common feature of the aging male, designated as late-onset hypogonadism or androgen decline in the aging male [54]. There are multiple signs and symptoms of testosterone deficiency; at the level of sexual function, these include diminished libido, difficulty in achieving orgasm, diminished intensity of the experience of orgasm, reduced penile sensation, and a reduction in the number and quality of erections [55,56]. In addition, it has been reported that testosterone plays a role in endothelial health by stimulating the release of endothelial vasorelaxation factors. Therefore, its decrease with aging may directly affect vascular and sexual function [26,57]. Additionally, in aged men, hypogonadism and ED are closely linked with comorbidities including metabolic syndrome, diabetes, and hypertension, all of which are involved in CVD and have EDys as a common precursor [58]. These VFRs also predispose to the development of atherosclerosis. In fact, a hypogonadal state stimulates visceral fat formation and central obesity. Low testosterone has also been associated with metabolic syndrome, insulin resistance, type II diabetes, an unfavorable lipid profile, and hypertension. The relationship of each of these risk factors to hypogonadism is most likely to be bidirectional. On the other hand, reduced testosterone levels have been implicated in the pathogenesis of atherosclerosis through modulating vascular endothelial function [59]. Testosterone is thought to have beneficial effects on vascular reactivity by regulating inflammatory cytokines and modulating adhesion molecules and serum lipids; thus, it has a protective effect on both endothelial and erectile function [60]. As mentioned above, the major role of testosterone in the endothelium is reported to be associated with vasodilation events. In fact, testosterone is an important player in the regulation of vascular tone through nongenomic actions exerted via the blockade of extracellular calcium entry or activation of potassium channels; increasing NO and VEGF production; modulating PDE5 expression; and finally, by promoting the production of hydrogen sulfide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue [61–65]. These effects exert dual actions on cavernosal ECs and SMCs, thus improving erectile function. Furthermore, androgen decline may also affect the integrity of other penile structures, synergistically altering its anatomical and hemodynamic properties. Effectively, testosterone deprivation also induces the accumulation of adipocytes in corporeal tissue; promotes SMC degeneration; increases extracellular matrix deposition; and induces modifications to the arrangement of elastic fibers [66–68]. In conjunction with the effects on vascular
ECs, cellular and molecular impairment of these components will have an impact on erectile function [69]. Age-Induced Impairment of Vascular Repair Mechanisms Endothelial integrity and EDys depend on the balance between endothelium damage and the endogenous repair capacity [30]. When the endothelial monolayer suffers injuries, vascular repair mechanisms, consisting of angiogenesis and vasculogenesis, are activated in order to regenerate the affected area. Angiogenesis is a local repair process that involves the proliferation and migration of adjacent ECs to repair injured sites [70]. In addition, disrupted endothelium may also be regenerated through the activation of vasculogenesis. During postnatal vasculogenesis, endothelial progenitor cells (EPCs) are mobilized from the bone marrow to neovascular sites, where they differentiate into mature ECs, which integrate into and regenerate the vasculature [71]. Aging and the simultaneous presence of VRFs are reported to dysregulate angiogenesis and vasculogenesis mechanisms, thereby preventing effective re-endothelialization, and sustaining and exacerbating EDys, ED, and CVD. Angiogenesis and Vascular Aging With aging, the angiogenesis process is suggested to be delayed, therefore contributing to EDys. However, angiogenesis in aging is not merely hindered, but is altered due to multiple impairments in the local neovascular response, including dysregulation in growth factor expression, the extracellular matrix, and inflammatory modifications, as well as reduced NO bioavailability [72,73]. For these reasons, impaired angiogenic function has been linked to the increased risk of vascular disease in geriatric men [74]. Additionally, the concomitant presence of VRFs with advancing age and increased oxidative stress may act synergistically to hamper these mechanisms, further aggravating the EDys state. All of these mechanisms affect aging peripheral endothelium, including penile lining v ascular ECs. In fact, in age-prone experimental ED, cavernosal molecular therapies with VEGF and NO were reported to have beneficial effects on corporeal EC and erectile function [41,75]. These effects may be due to a transient induction of angiogenic mechanisms that improve local repair and vasodilation processes. Nonetheless, it is known that mature ECs have limited proliferative and regenerative potential, which becomes more restricted with the advancement of age. These factors significantly restrict the application of local proangiogenic treatments. For this reason, currently focus is on the vasculogenesis process and the role of immature EPCs, both as markers of EDys and as the basis of vascular regenerative therapies.
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Assessment
Vasculogenesis and Aging Aging EPCs are thought to play a critical role in determining the decline/impairment of vascular regenerative mechanisms, vascular function, and organ integrity in the elderly. It is reported that with age progression, the bioavailability, circulating numbers, and most of the relevant re-endothelialization properties of EPCs are altered, thus impairing endogenous vascular regeneration and enhancing both EDys and vascular disease risk [76–78]. In fact, aging is associated with a decrease in the number of circulating EPCs (cEPCs) in patients with ED and CVD [79,80]. In agreement, the progressive reduction of cEPCs was found to correlate with the severity of cavernous artery atherosclerosis [81]. In addition to the aging process, hypogonadism, exposure to VRFs, and increased oxidative stress can affect the biological roles of EPCs, including mobilization, homing, differentiation, and integration at injured vascular sites [82–86]. Reduced concentrations of testosterone are associated to impaired vasculogenesis. Hypogonadal men were reported to have low numbers of cEPCs, which significantly increased after testosterone replacement therapy [86,87]. Since EPCs express androgen receptors, testosterone may directly modulate EPC functions [88]. In addition, an age-related decline in the expression of proangiogenic factors, including growth factors and mobilizing cytokines, is likely to contribute to impaired EPC generation, mobilization, migration, and survival. Mobilization of EPCs from the bone marrow and homing to sites of injury/neovascularization are dependent upon a number of factors, including stromal-derived factor-1 (SDF-1), VEGF, and NO [89,90]. In addition, it was reported that altered constitutive telomerase activity can also affect the regenerative ability of human EPCs, thus preventing their response to adequate stimuli [91]. In the elderly, alterations in vasculogenesis may also result from the accelerated senescence and apoptosis of EPCs, and from an age-associated quantitative reduction of the available pool of EPCs in the bone marrow [31,92,93]. Highlighting the relevance of the vasculogenesis process to endothelial health and erectile function, it has been reported that EPC function may be improved by ED therapeutic strategies involving PDE5i administration [94,95]. In fact, besides transiently regulating the cavernosal NO-cGMP axis, PDE5i intake was shown to increase cEPC levels in ED patients. Furthermore, the mechanism by which PDE5is act on EPCs was recently identified: PDE5 inhibition was shown to increase the expression of C-X-C chemokine receptor type 4 (CXCR4), the receptor for SDF-1, in EPCs, thus potentiating their recruitment to the peripheral circulation. Further studies are required to confirm whether PDE5i modulates the CXCR4-SDF-1 pathways in EPCs under conditions of severe EDys. Nonetheless, cEPCs are currently considered to be a useful research tool. However, age-related impairments
in EPC biological functions may reveal the extent of EDys, thus indicating their use as a potential biomarker for endothelial health status. For this reason, it is crucial to assess and manage the status of penile and systemic EDys to prevent cardiovascular events.
ASSESSMENT ED in the aging male is of multifactorial origin, and therefore a multimodal treatment approach is needed, which should always include counseling and relationship assessment. In addition, a thorough medical assessment is necessary for the evaluation of erectile complaints in the older male. The primary goal should be not only to understand the specific erectile problem but also to identify possible underlying and reversible or treatable disorders. Therefore, the initial evaluation of ED should include a complete medical, psychosocial, and sexual history. Since ED often is a sentinel symptom of generalized vascular/endothelial disease, it is important to screen for cardiovascular risk factors, especially in aging men, as specified in the previous section “Pathophysiology of Erectile Dysfunction in the Aging Man.” The use of questionnaires, such as the Sexual Health Inventory for Men, may be helpful for initiating a conversation about ED [9,96]. Sexual problems other than ED, such as lack of sexual interest and difficulty reaching orgasm, may point to underlying hypogonadism or concomitant relationship factors. The effect on the quality of life and satisfaction should be discussed, as well as partner issues and sexual satisfaction. Treatment goals and viable alternative means for intimacy and sexual expression should also be discussed [97]. Medical and psychosocial history should be taken for the evaluation of possible chronic diseases that contribute to ED or which can complicate treatment, such as depression, diabetes, CVD, and iatrogenic causes of ED. Furthermore, the use of medication by the patient should be thoroughly reviewed since certain medications (antidepressants, diuretics, β-blockers) can exacerbate ED, and others (e.g. nitrates) are contraindications for oral treatment with PDE5is [97,98]. Physical examination should include a general screening for risk factors and comorbidities that are associated with ED, such as CVD, neurological disease, and obesity. Special consideration should be given to a physical examination of the genitalia, a digital rectal examination, and evaluation of secondary sexual characteristics [9,97]. Recommended laboratory tests include urinalysis, a complete blood count, and measurements of serum glucose, creatinine, cholesterol, triglycerides, and testosterone, the latter particularly in patients with decreased libido or regression of secondary sexual characteristics.
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Prostate-specific antigen measurement is advised when ED is accompanied by voiding problems [97,99]. Radiological testing, nocturnal penile rigidity testing, or penile Doppler ultrasound are not routinely indicated in primary care settings but may be performed by a sexual medicine specialist in specific cases [99].
TREATMENT The treatment of ED in older patients should be holistic and is best started with patient and partner education and counseling. An effort should be made to translate the results of the assessment and further investigations into an understandable and clear management strategy with consideration for the preferences of the patient and his partner. Realistic outcome goals for therapy should be discussed; very few older men will be able to regain the potency of their youth but most should be able to experience restoration of satisfying sexuality of some sort [9,98]. Reversible causes of ED and its contributing factors such as hypogonadism should be identified and treated accordingly.
Oral Treatment Oral therapy should be considered as a first-line treatment for the majority of older patients, since these agents demonstrate a good risk-to-benefit ratio and are easy to administer. Phosphodiesterase 5 Inhibitors PDE5is are the oral pharmacotherapy of choice for ED. Over 400 substances are currently under investigation for their inhibitory effect on PDE5, but only three are available for clinical use in the United States: sildenafil, tadalafil, and vardenafil [100]. The three currently available drugs differ from each other in time to onset of action and duration of action (sildenafil and vardenafil, up to 5 h; tadalafil, up to 24–36 h) [98]. PDE5is possess the broadest efficacy and tolerability of all currently available oral ED treatment options, and all three PDE5is have been shown to be safe and effective in treating ED in older men [101]. Because of its prolonged half-life, tadalafil was approved for use as a daily medication for the treatment of ED, signifying a paradigm shift in the concept of ED as a chronic condition rather than a condition in need of only acute management [101,102]. While some men report that PDE5is are not efficacious with the first dose, results generally improve with repeated dosing. Patient education should cover this topic, address proper dosing intervals, and stress the fact that sexual stimulation is necessary for the drug to be effective. Current recommendations advise starting treatment with a dose of 50 mg for sildenafil and 10 mg
for both vardenafil and tadalafil [99]. This dose should be adapted according to effectiveness and adverse effects; furthermore, men with liver or kidney problems should start at lower doses (25 mg for sildenafil and 5 mg for the other drugs). A recent prospective, randomized, multicenter crossover study demonstrated an overall equivalence in the subjective perception of treatment benefits between all PDE5is, although patients and their partners may have had individual preferences [103]. Adverse events from PDE5is include headache, facial flushing, nasal congestion, myalgia, back pain, and blurred or disturbed vision; these effects are generally attributed to cross reactivity with other PDE isoforms. The nature and frequency of adverse events are similar in patients older than 65 years compared to their younger counterparts. Patients who are treated with nitrates or nitrate-donors should not take PDE5is, since PDE5is can potentiate the vasodilatory effects of nitrates resulting in precipitous declines in blood pressure [97,99]. PDE5is may also interact with α-blockers and result in postural hypertension. PDE5is are further relatively contraindicated or to be used with caution in patients with unstable angina pectoris, recent myocardial infarction, certain arrhythmias, and poorly controlled hypertension [9,97–99]. A synergistic effect between testosterone and PDE5i treatment has been demonstrated based on the finding that testosterone plays a major role in the homeostasis of erectile mechanisms by altering corporal smooth muscle content and thus expression of PDE5 [104]. Adjunctive testosterone therapy may be considered in hypogonadal men who fail a proper trial of PDE5i.
Local Therapy Intracavernous Injection Therapy For patients who fail to respond to oral therapy, intracavernous injections with vasoactive substances provide an alternative with broad efficacy, a good safety profile, and a rapid onset of action. The most commonly utilized substances include prostaglandin E1 (the only substance with formal US. US Food and Drug Administration approval), phentolamine, and papaverine. These substances can be injected alone or in combination (so-called bimix or trimix). Vasoactive intestinal peptide is also available for intracavernous injection therapy in some countries, although its efficacy is low and it is therefore typically used as part of a combination therapy. The major risks of injection therapy include priapism, painful erections, and (theoretically) penile fibrosis after long-term use [98]. A training program is required for the patient and his partner to learn the correct injection procedure [99]. The effectiveness of injection therapy declines with age and is less effective in older than in
Conclusions
younger patients, although the dose may be escalated to preserve efficacy [105]. Intraurethral Therapy Prostaglandin E1 is available for intraurethral administration in the form of a semisolid pellet called MUSE (Medicated Urethral Suppository for Erection). MUSE may have some side effects in common with intracavernous injection, and may also be associated with hypotension, syncope, urethral burning, or pain in the patient, as well as vaginal irritation in the partner [98,99]. Vacuum Constriction Device The vacuum constriction device (VCD) creates negative pressure around the penis, thereby initiating passive engorgement of the sinusoidal spaces and creating an erection. Maintenance of erection is facilitated by application of a rubber cuff around the base of the penis. VCD is a low-cost alternative for men who dislike pharmacological therapy, or who have cardiac or other contraindications for PDE5i use, although some men find it cumbersome to use. Its use is accompanied by relatively minor local side effects such as bruising, some discomfort, and ejaculatory obstruction.
CONCLUSIONS ED is one of the most prevalent sexual complaints in the aging population. The disease is multifactorial in origin and shares common pathophysiological alterations with vascular and cardiac diseases, which makes the penis the antenna of the heart, especially in the aging male. ED can be safely and effectively treated in aging men.
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[30] Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007;115(10):1285–95. [31] Beauséjour C. Bone marrow-derived cells: the influence of aging and cellular senescence. Handb Exp Pharmacol 2007(180):67– 88. [32] Ballard VL, Edelberg JM. Targets for regulating angiogenesis in the ageing endothelium. Expert Opin Ther Targets 2007; 11(11):1385–99. [33] Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000;30(4):328–38. [34] Kirby M, Jackson G, Simonsen U. Endothelial dysfunction links erectile dysfunction to heart disease. Int J Clin Pract 2005; 59(2):225–9. [35] Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. The ageing endothelium, cardiovascular risk and disease in man. Exp Physiol 2009;94(3):317–21. [36] Maxwell AJ. Mechanisms of dysfunction of the nitric oxide pathway in vascular diseases. Nitric Oxide 2002;6(2):101–24. [37] Sitia S, Tomasoni L, Atzeni F, Ambrosio G, Cordiano C, Catapano A, et al. From endothelial dysfunction to atherosclerosis. Autoimmun Rev 2010;9(12):830–4. [38] Tetè S, Tripodi D, Rosati M, Conti F, Maccauro G, Saggini A, et al. Endothelial cells, cholesterol, cytokines, and aging. Int J Immunopathol Pharmacol 2012;25(2):355–63. [39] Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai H, et al. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993;91(1):29–37. [40] Bivalacqua TJ, Burnett AL, Hellstrom WJ, Champion HC. Overexpression of arginase in the aged mouse penis impairs erectile function and decreases eNOS activity: influence of in vivo gene therapy of antiarginase. Am J Physiol Heart Circ Physiol 2007;292(3):H1340–51. [41] Champion HC, Bivalacqua TJ, Hyman AL, Ignarro LJ, Hellstrom WJ, Kadowitz PJ. Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat. Proc Natl Acad Sci USA 1999;96(20):11648–52. [42] Bivalacqua TJ, Armstrong JS, Biggerstaff J, Abdel-Mageed AB, Kadowitz PJ, Hellstrom WJ, et al. Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol 2003;284(4):H1408–21. [43] Yang YM, Huang A, Kaley G, Sun D. eNOS uncoupling and endothelial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol 2009;297(5):H1829–36. [44] Musicki B, Kramer MF, Becker RE, Burnett AL. Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis. J Sex Med 2005;2(3):347–55. [45] Johnson JM, Bivalacqua TJ, Lagoda GA, Burnett AL, Musicki B. eNOS-uncoupling in age-related erectile dysfunction. Int J Impot Res 2011;23(2):43–8. [46] El Assar M, Angulo J, Vallejo S, Peiró C, Sánchez-Ferrer CF, Rodríguez-Mañas L. Mechanisms Involved in the Aging- Induced Vascular Dysfunction. Front Physiol 2012;3:132. [47] Rajasekaran M, Kasyan A, Jain A, Kim SW, Monga M. Altered growth factor expression in the aging penis: the Brown-Norway rat model. J Androl 2002;23(3):393–9. [48] Costa C, Soares R, Castela A, Adães S, Hastert V, Vendeira P, et al. Increased endothelial apoptotic cell density in human diabetic erectile tissue—comparison with clinical data. J Sex Med 2009;6(3):826–35. [49] Brow SL, Seftel AD, Strohl KP, Herbener TE. Vasculogenic impotence and cavernosal oxygen tension. Int J Impot Res 2000;12(1):19–22.
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Erectile Dysfunction in Inflammaging Carla Costa1, Maarten Albersen2 1Department
of Biochemistry and Department of Experimental Biology, Center for Medical Research, Faculty of Medicine, University of Porto, Portugal, 2Laboratory for Experimental Urology, Department of Urology, University Hospitals Leuven, Belgium
INTRODUCTION Until relatively recently, it was generally assumed that a loss of sexuality was a natural development and inevitable with aging, which resulted in little attention being given to sexual behavior and the treatment of sexual dysfunctions in the geriatric population. However, nowadays it is known that with improvements in life expectancy, both men and women are seeking to preserve their sexuality into older age. However, while the interest in sexual activity persists with aging, a decline in sexual activity is typically seen with, and can be attributed to, both general health problems and specific sexual dysfunctions. In a large US-based study, the proportion of males who were sexually active declined from 83.7% in the 57–64-year age group to 38.5% in the 75–85-year age group [1]. In a smaller pilot study of a cohort of 50 patients with a mean age of 81 years, Smith et al. reported that the main reason for older men being sexually inactive was erectile dysfunction (ED) [2], a condition defined as the persistent inability to attain and maintain penile erection sufficient for sexual intercourse [3]. Although premature ejaculation is the most prevalent sexual dysfunction in men, ED is probably the most thoroughly studied and the most common sexual complaint with which men present to their healthcare providers [4]. The advent of safe oral therapy [cGMP-specific 3′,5′-cyclic phosphodiesterase, or phosphodiesterase 5 inhibitors (PDE5is)] for the treatment of ED has brought attention to the disease and probably results in increased treatment-seeking behavior in the aging male. Despite the overwhelming success of oral PDE5is, the demand for pharmacotherapeutic and surgical options for ED continues to rise as a result of the increased elderly population, as well as the increasing recognition that approximately one-third of ED patients
Inflammation, Advancing Age and Nutrition. http://dx.doi.org/10.1016/B978-0-12-397803-5.00024-1
do not respond to PDE5is [5]. This is especially applicable to the older patient with multiple pathophysiological alterations in erectile mechanisms, which are among the various end results of inflammatory disorders, such as neuropathy and vasculopathy. Therefore, ED remains a topic of interest to physicians treating the aging and older male. This chapter will address erectile biology and the age-related changes thereof, the prevalence of ED, its etiological factors in the older population, and contemporary treatment options for the treatment of ED in aging and aged males.
PREVALENCE AND ETIOLOGY A multitude of large-scale studies have substantiated the global prevalence of ED and its close relationship to aging. The Massachusetts Male Aging Study is a large-scale longitudinal project investigating the effects of aging on male sexual health, among other domains of general health. The authors reported a prevalence of ED of no less than 52% of subjects [6]. The prevalence of complete ED (no tumescence at all) tripled from 5% to 15% between subject aged 40 and 70 years [6]. In the European Male Aging Study (EMAS), a collaborative effort of eight European centers investigating ED in a male population aged 40–79 years with a mean age of 60 years, 30% of the EMAS sample reported ED [7]. The prevalence of ED was higher in the older age groups, peaking in men aged 70 years and older (64%). It was further shown that men in higher age groups, although more often affected, were less concerned with the presence of ED [7]. Finally, approximately 617,000 new cases occur annually in men aged 40–69 years in the United States alone [8].
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The above-mentioned studies indicate that ED is strongly associated with advancing age. It logically follows that ED is therefore highly prevalent in the geriatric population [9]. With the rapidly expanding aging population and the increase in life expectancy, an increase in the prevalence of ED is expected in the years to come. One estimation shows that by 2025, 9.5% of the population worldwide will be men older than 65 years of age [10]. By then, the number of men suffering from ED will have reached 322 million worldwide. Further evidence for a relationship between age and ED is provided by the fact that the prevalence of ED rises steadily with age, from 30.7% in men aged 57–64 years to 43.3% in men aged 75–85 years [11]. In other studies, prevalence rates up to 77.5% are reported for patients aged 75 years and older [12]. However, not only the prevalence but also the severity of ED increases with advancing age. The relationship between aging and ED is in part based on the increasing morbidities that aged men experience, such as polypharmacy, hypertension, vascular disease, chronic kidney disease, depression, and many others [13]. Beside these concurrent conditions, changes induced by the process of aging itself that contribute to ED are specified below.
PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION IN THE AGING MAN Erectile Function and the Aging Process Erectile tissue is composed of small resistance helicine arteries that empty into lacunar spaces lined by vascular endothelial cells (ECs) embedded in a meshwork of interconnected smooth muscle cells (SMCs), and an extracellular matrix composed of elastic fibers and collagen produced by dispersed fibroblasts [14,15]. Erectile function is a complex neurovascular phenomenon under psychological control that requires interplay between the central and peripheral nervous systems, hormonal factors, and the structural integrity of the cellular components of the penis [16]. These cellular and molecular interactions are crucial for the erectile process and any impairment may result in ED. During sexual arousal, an initial stimulus originating from supraspinal centers results in parasympathetic nonadrenergic noncholinergic cavernosal nerve activation, leading to the production of nitric oxide (NO) by neuronal NO synthase (nNOS) [17]. NO is diffused into adjacent SMCs and activates the enzyme guanylyl cyclase, which results in intracellular increase of the second messenger, cycling guanosine monophosphate (cGMP). The NO-cGMP pathway activates multiple signaling cascades, thus promoting SMC relaxation, cavernous sinusoidal dilation, and an inflow of arterial blood [18,19]. This initial blood inflow increases shear stress,
which mechanically stimulates endothelial NOS (eNOS) to produce NO, and the release of prostanoids and endothelium-derived hyperpolarizing factors (EDHFs) [20]. These events result in the engorgement of sinusoidal spaces, eventually leading to an increase in intracavernous pressure by compression of the subtunical venules, thus activating the venoocclusive mechanism, which allows the maintenance of erection. With the advancement of age, relevant alterations will occur to change this scenario. In fact, the aging process may affect erectile components, and penile molecular and hemodynamic events, resulting in ED. In the older male, loss of erectile function has been associated with impaired neurogenic function and failure of the arteriogenic and/or venous systems, thus altering crucial mechanisms involved in the initiation/maintenance of an erection [21]. Despite the essential role of all penile cellular and molecular interactions, aging ED has been considered a vascular-related pathology. In fact, vasculogenic ED was recognized as the most common etiology in the elderly, promoted by occlusive disease of the pudendal-cavernosal-helicine arterial tree, through the development of atherosclerosis [22,23]. The concomitant presence of vascular risk factors (VRFs) in the geriatric man contributes to the development of atherosclerotic foci, which occur as consequence of endothelial dysfunction (EDys). EDys is characterized by loss of the functional biology and structural integrity of the endothelium, which alters the ability of ECs to properly respond to vasodilation/vasoconstriction stimuli and affects blood flow regulation [24,25]. In addition to the endothelial damage caused by VRFs, the decline in androgens is also reported to contribute to the loss of endothelial and erectile function in the aging man [26,27]. It is currently recognized that EDys is an early sign of atherosclerosis, which manifests first as ED, later contributing to the development of systemic vascular disease. ED is therefore considered the initial clinical presentation of subclinical EDys, prior to the manifestation of cardiovascular disease (CVD) and preceding the occurrence of cardiovascular events [28,29]. Moreover, it is now reported that EDys and endothelial integrity depend not only on the extent of injury but also on the endogenous capacity for regeneration [30]. However, vascular repair mechanisms of angiogenesis (local) and vasculogenesis (systemic) are reported to be impaired as result of the aging process, further contributing to EDys, atherosclerosis, ED, and the increased severity of vascular disease [31,32].
The Vascular Etiology of Erectile Dysfunction in the Aged Man Aging per se is considered to be a risk factor for the development of EDys and ED [33]. In addition, other comorbidities that are highly prevalent and frequently
Pathophysiology of Erectile Dysfunction in the Aging Man
coexist in the elderly male significantly contribute to altered endothelial and erectile function. In fact, the Massachusetts Male Aging Study—a prospective 10-year study that followed over 1100 men age 40 to 70 years at study entry—found that ED was more prevalent in patients presenting VRFs, including, diabetes, hypertension, low high-density lipoprotein (HDL) levels (clusters of metabolic syndrome), smoking, and hypogonadism [6]. All of these factors are general correlates for both ED and CVD, with EDys being the common denominator [34,35]. The key features of EDys are decreased responsiveness of the endothelium to vasodilators and/or increased sensitivity to vasoconstrictor mediators. These alterations affect the regulatory role of systemic vascular endothelium, affecting the penile arterial and venous systems [36]. As consequence, the vasodilator potential is reduced and vascular structures are unable to fully dilate in response to appropriate stimuli, which results in blood flow changes and inadequate tissue perfusion. EDys and the decrease in endothelial vasodilation are mostly induced by the noxious actions of VRFs, which are responsible for causing a reduction in the bioactivity/bioavailability of eNOS/ eNO in the vasculature [37]. In addition to increased vasoconstriction, disruption of vascular homeostasis predisposes the vessel wall to leukocyte adherence, platelet adhesion, thrombosis, vascular inflammation, and atherosclerotic lesions, which are commonly presented in ED and CVD [28,34–37]. Since aging-related vascular EDys is closely linked to atherosclerosis, ED, and CVD, it is most likely that the status of endothelial function may reflect the predisposition of an individual to develop these pathologies [38]. As atherosclerosis of the pudendal-cavernosal arteries is the most common cause of vasculogenic ED in the geriatric male, it should be perceived as the “tip of the iceberg” of a generalized vascular disorder. Therefore, endothelial function should be evaluated in ED patients and regarded as a potential parameter for the prevention of acute cardiovascular events [29,39].
Mechanisms Involved in Aging-Induced Vascular Endothelial and Erectile Dysfunction Oxidative Stress, Impaired Endothelial Nitric Oxide Production, and Penile Endothelial Dysfunction EDys in aging cavernosal tissue results from alterations in several molecular mechanisms, including oxidative stress and impaired eNOS/NO biology [40]. These modifications were reported to hamper crucial events involved in smooth muscle relaxation and endothelium-dependent vasodilation mechanisms [40–45]. In elderly erectile tissue, it was observed that
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the endothelium produces high levels of the reactive oxygen species, the superoxide anion (O2•−), which affects endothelial and erectile function by altering the redox status [42]. One of the most important mechanisms of action of O2•− is to accelerate the degradation of NO. The diffusion-controlled reaction between NO and O2•− leads to formation of the peroxynitrite anion (ONOO−), which can easily penetrate cells, causing oxidative modifications of macromolecules [43]. On the other hand, it was recently proposed that the uncoupling of eNOS in the aged penis increases O2•− production, thus exacerbating EDys and ED [45]. In addition, eNOS/NO activity/bioavailability is reported to be downregulated in elderly erectile tissue as result of several molecular alterations [46]. In the aging penis, a decrease in the expression of vascular endothelial growth factor (VEGF), a known regulator of NO production, has been observed [47]. Another mechanism involves an increase in the endothelial activity of arginase, the enzyme that competes with eNOS for the substrate l-arginine, thereby reducing NO formation [40]. Alterations in eNOS activation have also been described as a result of multiple molecular mechanisms that act in concert to affect its function both positively and negatively. In fact, a decrease in phosphorylation of the eNOS positive regulatory site (serine-1177) and an increase in the phosphorylation at its negative regulatory site (threonine-495) have been reported in elderly cavernosal tissue [44]. Confirming the relevant role of NO in erectile physiology, it was shown that penile NOS3 gene (encoding eNOS) transfer improves erectile responses in older animals [41]. Given that aging is accompanied by the simultaneous presence of multiple VRFs, it is important to take into account all of the synergistic deleterious actions they have on the endothelium that exacerbate penile EDys and ED. In certain cases, damage to the endothelium is so extensive that the endothelial monolayer activates programmed cell death [48]. Furthermore, the presence of atherosclerosis has been reported to decrease penile oxygen tension, thus causing molecular and structural alterations that affect cavernosal functionality [49,50]. Low oxygen tension may dysregulate the production of vasoactive substances present in the penile vascular bed, including NO [50]. Additionally, hypoxic conditions are also responsible for altering the synthesis of cytokines and growth factors, which play major roles in regulating trabecular smooth muscle tone/content and in connective tissue metabolism. As result, changes in the SMC layer and a predisposition to corporeal fibrosis, through the increased activation of collagen synthesis, have been reported [51–53]. All of these age-related modifications contribute to the impairment of cavernosal vasorelaxation and altered penile compliance, thus aggravating ED conditions.
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Hypogonadism, Endothelial Dysfunction, and Erectile Dysfunction: How Testosterone Affects Penile Endothelial Function Reduced testosterone levels are a common feature of the aging male, designated as late-onset hypogonadism or androgen decline in the aging male [54]. There are multiple signs and symptoms of testosterone deficiency; at the level of sexual function, these include diminished libido, difficulty in achieving orgasm, diminished intensity of the experience of orgasm, reduced penile sensation, and a reduction in the number and quality of erections [55,56]. In addition, it has been reported that testosterone plays a role in endothelial health by stimulating the release of endothelial vasorelaxation factors. Therefore, its decrease with aging may directly affect vascular and sexual function [26,57]. Additionally, in aged men, hypogonadism and ED are closely linked with comorbidities including metabolic syndrome, diabetes, and hypertension, all of which are involved in CVD and have EDys as a common precursor [58]. These VFRs also predispose to the development of atherosclerosis. In fact, a hypogonadal state stimulates visceral fat formation and central obesity. Low testosterone has also been associated with metabolic syndrome, insulin resistance, type II diabetes, an unfavorable lipid profile, and hypertension. The relationship of each of these risk factors to hypogonadism is most likely to be bidirectional. On the other hand, reduced testosterone levels have been implicated in the pathogenesis of atherosclerosis through modulating vascular endothelial function [59]. Testosterone is thought to have beneficial effects on vascular reactivity by regulating inflammatory cytokines and modulating adhesion molecules and serum lipids; thus, it has a protective effect on both endothelial and erectile function [60]. As mentioned above, the major role of testosterone in the endothelium is reported to be associated with vasodilation events. In fact, testosterone is an important player in the regulation of vascular tone through nongenomic actions exerted via the blockade of extracellular calcium entry or activation of potassium channels; increasing NO and VEGF production; modulating PDE5 expression; and finally, by promoting the production of hydrogen sulfide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue [61–65]. These effects exert dual actions on cavernosal ECs and SMCs, thus improving erectile function. Furthermore, androgen decline may also affect the integrity of other penile structures, synergistically altering its anatomical and hemodynamic properties. Effectively, testosterone deprivation also induces the accumulation of adipocytes in corporeal tissue; promotes SMC degeneration; increases extracellular matrix deposition; and induces modifications to the arrangement of elastic fibers [66–68]. In conjunction with the effects on vascular
ECs, cellular and molecular impairment of these components will have an impact on erectile function [69]. Age-Induced Impairment of Vascular Repair Mechanisms Endothelial integrity and EDys depend on the balance between endothelium damage and the endogenous repair capacity [30]. When the endothelial monolayer suffers injuries, vascular repair mechanisms, consisting of angiogenesis and vasculogenesis, are activated in order to regenerate the affected area. Angiogenesis is a local repair process that involves the proliferation and migration of adjacent ECs to repair injured sites [70]. In addition, disrupted endothelium may also be regenerated through the activation of vasculogenesis. During postnatal vasculogenesis, endothelial progenitor cells (EPCs) are mobilized from the bone marrow to neovascular sites, where they differentiate into mature ECs, which integrate into and regenerate the vasculature [71]. Aging and the simultaneous presence of VRFs are reported to dysregulate angiogenesis and vasculogenesis mechanisms, thereby preventing effective re-endothelialization, and sustaining and exacerbating EDys, ED, and CVD. Angiogenesis and Vascular Aging With aging, the angiogenesis process is suggested to be delayed, therefore contributing to EDys. However, angiogenesis in aging is not merely hindered, but is altered due to multiple impairments in the local neovascular response, including dysregulation in growth factor expression, the extracellular matrix, and inflammatory modifications, as well as reduced NO bioavailability [72,73]. For these reasons, impaired angiogenic function has been linked to the increased risk of vascular disease in geriatric men [74]. Additionally, the concomitant presence of VRFs with advancing age and increased oxidative stress may act synergistically to hamper these mechanisms, further aggravating the EDys state. All of these mechanisms affect aging peripheral endothelium, including penile lining v ascular ECs. In fact, in age-prone experimental ED, cavernosal molecular therapies with VEGF and NO were reported to have beneficial effects on corporeal EC and erectile function [41,75]. These effects may be due to a transient induction of angiogenic mechanisms that improve local repair and vasodilation processes. Nonetheless, it is known that mature ECs have limited proliferative and regenerative potential, which becomes more restricted with the advancement of age. These factors significantly restrict the application of local proangiogenic treatments. For this reason, currently focus is on the vasculogenesis process and the role of immature EPCs, both as markers of EDys and as the basis of vascular regenerative therapies.
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Assessment
Vasculogenesis and Aging Aging EPCs are thought to play a critical role in determining the decline/impairment of vascular regenerative mechanisms, vascular function, and organ integrity in the elderly. It is reported that with age progression, the bioavailability, circulating numbers, and most of the relevant re-endothelialization properties of EPCs are altered, thus impairing endogenous vascular regeneration and enhancing both EDys and vascular disease risk [76–78]. In fact, aging is associated with a decrease in the number of circulating EPCs (cEPCs) in patients with ED and CVD [79,80]. In agreement, the progressive reduction of cEPCs was found to correlate with the severity of cavernous artery atherosclerosis [81]. In addition to the aging process, hypogonadism, exposure to VRFs, and increased oxidative stress can affect the biological roles of EPCs, including mobilization, homing, differentiation, and integration at injured vascular sites [82–86]. Reduced concentrations of testosterone are associated to impaired vasculogenesis. Hypogonadal men were reported to have low numbers of cEPCs, which significantly increased after testosterone replacement therapy [86,87]. Since EPCs express androgen receptors, testosterone may directly modulate EPC functions [88]. In addition, an age-related decline in the expression of proangiogenic factors, including growth factors and mobilizing cytokines, is likely to contribute to impaired EPC generation, mobilization, migration, and survival. Mobilization of EPCs from the bone marrow and homing to sites of injury/neovascularization are dependent upon a number of factors, including stromal-derived factor-1 (SDF-1), VEGF, and NO [89,90]. In addition, it was reported that altered constitutive telomerase activity can also affect the regenerative ability of human EPCs, thus preventing their response to adequate stimuli [91]. In the elderly, alterations in vasculogenesis may also result from the accelerated senescence and apoptosis of EPCs, and from an age-associated quantitative reduction of the available pool of EPCs in the bone marrow [31,92,93]. Highlighting the relevance of the vasculogenesis process to endothelial health and erectile function, it has been reported that EPC function may be improved by ED therapeutic strategies involving PDE5i administration [94,95]. In fact, besides transiently regulating the cavernosal NO-cGMP axis, PDE5i intake was shown to increase cEPC levels in ED patients. Furthermore, the mechanism by which PDE5is act on EPCs was recently identified: PDE5 inhibition was shown to increase the expression of C-X-C chemokine receptor type 4 (CXCR4), the receptor for SDF-1, in EPCs, thus potentiating their recruitment to the peripheral circulation. Further studies are required to confirm whether PDE5i modulates the CXCR4-SDF-1 pathways in EPCs under conditions of severe EDys. Nonetheless, cEPCs are currently considered to be a useful research tool. However, age-related impairments
in EPC biological functions may reveal the extent of EDys, thus indicating their use as a potential biomarker for endothelial health status. For this reason, it is crucial to assess and manage the status of penile and systemic EDys to prevent cardiovascular events.
ASSESSMENT ED in the aging male is of multifactorial origin, and therefore a multimodal treatment approach is needed, which should always include counseling and relationship assessment. In addition, a thorough medical assessment is necessary for the evaluation of erectile complaints in the older male. The primary goal should be not only to understand the specific erectile problem but also to identify possible underlying and reversible or treatable disorders. Therefore, the initial evaluation of ED should include a complete medical, psychosocial, and sexual history. Since ED often is a sentinel symptom of generalized vascular/endothelial disease, it is important to screen for cardiovascular risk factors, especially in aging men, as specified in the previous section “Pathophysiology of Erectile Dysfunction in the Aging Man.” The use of questionnaires, such as the Sexual Health Inventory for Men, may be helpful for initiating a conversation about ED [9,96]. Sexual problems other than ED, such as lack of sexual interest and difficulty reaching orgasm, may point to underlying hypogonadism or concomitant relationship factors. The effect on the quality of life and satisfaction should be discussed, as well as partner issues and sexual satisfaction. Treatment goals and viable alternative means for intimacy and sexual expression should also be discussed [97]. Medical and psychosocial history should be taken for the evaluation of possible chronic diseases that contribute to ED or which can complicate treatment, such as depression, diabetes, CVD, and iatrogenic causes of ED. Furthermore, the use of medication by the patient should be thoroughly reviewed since certain medications (antidepressants, diuretics, β-blockers) can exacerbate ED, and others (e.g. nitrates) are contraindications for oral treatment with PDE5is [97,98]. Physical examination should include a general screening for risk factors and comorbidities that are associated with ED, such as CVD, neurological disease, and obesity. Special consideration should be given to a physical examination of the genitalia, a digital rectal examination, and evaluation of secondary sexual characteristics [9,97]. Recommended laboratory tests include urinalysis, a complete blood count, and measurements of serum glucose, creatinine, cholesterol, triglycerides, and testosterone, the latter particularly in patients with decreased libido or regression of secondary sexual characteristics.
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Prostate-specific antigen measurement is advised when ED is accompanied by voiding problems [97,99]. Radiological testing, nocturnal penile rigidity testing, or penile Doppler ultrasound are not routinely indicated in primary care settings but may be performed by a sexual medicine specialist in specific cases [99].
TREATMENT The treatment of ED in older patients should be holistic and is best started with patient and partner education and counseling. An effort should be made to translate the results of the assessment and further investigations into an understandable and clear management strategy with consideration for the preferences of the patient and his partner. Realistic outcome goals for therapy should be discussed; very few older men will be able to regain the potency of their youth but most should be able to experience restoration of satisfying sexuality of some sort [9,98]. Reversible causes of ED and its contributing factors such as hypogonadism should be identified and treated accordingly.
Oral Treatment Oral therapy should be considered as a first-line treatment for the majority of older patients, since these agents demonstrate a good risk-to-benefit ratio and are easy to administer. Phosphodiesterase 5 Inhibitors PDE5is are the oral pharmacotherapy of choice for ED. Over 400 substances are currently under investigation for their inhibitory effect on PDE5, but only three are available for clinical use in the United States: sildenafil, tadalafil, and vardenafil [100]. The three currently available drugs differ from each other in time to onset of action and duration of action (sildenafil and vardenafil, up to 5 h; tadalafil, up to 24–36 h) [98]. PDE5is possess the broadest efficacy and tolerability of all currently available oral ED treatment options, and all three PDE5is have been shown to be safe and effective in treating ED in older men [101]. Because of its prolonged half-life, tadalafil was approved for use as a daily medication for the treatment of ED, signifying a paradigm shift in the concept of ED as a chronic condition rather than a condition in need of only acute management [101,102]. While some men report that PDE5is are not efficacious with the first dose, results generally improve with repeated dosing. Patient education should cover this topic, address proper dosing intervals, and stress the fact that sexual stimulation is necessary for the drug to be effective. Current recommendations advise starting treatment with a dose of 50 mg for sildenafil and 10 mg
for both vardenafil and tadalafil [99]. This dose should be adapted according to effectiveness and adverse effects; furthermore, men with liver or kidney problems should start at lower doses (25 mg for sildenafil and 5 mg for the other drugs). A recent prospective, randomized, multicenter crossover study demonstrated an overall equivalence in the subjective perception of treatment benefits between all PDE5is, although patients and their partners may have had individual preferences [103]. Adverse events from PDE5is include headache, facial flushing, nasal congestion, myalgia, back pain, and blurred or disturbed vision; these effects are generally attributed to cross reactivity with other PDE isoforms. The nature and frequency of adverse events are similar in patients older than 65 years compared to their younger counterparts. Patients who are treated with nitrates or nitrate-donors should not take PDE5is, since PDE5is can potentiate the vasodilatory effects of nitrates resulting in precipitous declines in blood pressure [97,99]. PDE5is may also interact with α-blockers and result in postural hypertension. PDE5is are further relatively contraindicated or to be used with caution in patients with unstable angina pectoris, recent myocardial infarction, certain arrhythmias, and poorly controlled hypertension [9,97–99]. A synergistic effect between testosterone and PDE5i treatment has been demonstrated based on the finding that testosterone plays a major role in the homeostasis of erectile mechanisms by altering corporal smooth muscle content and thus expression of PDE5 [104]. Adjunctive testosterone therapy may be considered in hypogonadal men who fail a proper trial of PDE5i.
Local Therapy Intracavernous Injection Therapy For patients who fail to respond to oral therapy, intracavernous injections with vasoactive substances provide an alternative with broad efficacy, a good safety profile, and a rapid onset of action. The most commonly utilized substances include prostaglandin E1 (the only substance with formal US. US Food and Drug Administration approval), phentolamine, and papaverine. These substances can be injected alone or in combination (so-called bimix or trimix). Vasoactive intestinal peptide is also available for intracavernous injection therapy in some countries, although its efficacy is low and it is therefore typically used as part of a combination therapy. The major risks of injection therapy include priapism, painful erections, and (theoretically) penile fibrosis after long-term use [98]. A training program is required for the patient and his partner to learn the correct injection procedure [99]. The effectiveness of injection therapy declines with age and is less effective in older than in
Conclusions
younger patients, although the dose may be escalated to preserve efficacy [105]. Intraurethral Therapy Prostaglandin E1 is available for intraurethral administration in the form of a semisolid pellet called MUSE (Medicated Urethral Suppository for Erection). MUSE may have some side effects in common with intracavernous injection, and may also be associated with hypotension, syncope, urethral burning, or pain in the patient, as well as vaginal irritation in the partner [98,99]. Vacuum Constriction Device The vacuum constriction device (VCD) creates negative pressure around the penis, thereby initiating passive engorgement of the sinusoidal spaces and creating an erection. Maintenance of erection is facilitated by application of a rubber cuff around the base of the penis. VCD is a low-cost alternative for men who dislike pharmacological therapy, or who have cardiac or other contraindications for PDE5i use, although some men find it cumbersome to use. Its use is accompanied by relatively minor local side effects such as bruising, some discomfort, and ejaculatory obstruction.
CONCLUSIONS ED is one of the most prevalent sexual complaints in the aging population. The disease is multifactorial in origin and shares common pathophysiological alterations with vascular and cardiac diseases, which makes the penis the antenna of the heart, especially in the aging male. ED can be safely and effectively treated in aging men.
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