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Testosterone Replacement, Low T, HCG, & Beyond
When Testosterone Is Not Enough
Targeting of PDE5 for Preservation of Penile Health
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<blockquote data-quote="madman" data-source="post: 218508" data-attributes="member: 13851"><p><strong>Penile Vascular Protection</strong></p><p></p><p><em><strong>The medical literature widely supports vascular health objectives as a means toward achieving long-term health maintenance and longevity</strong>. Several thought leaders in sexual medicine have further pointed to penile vascular health as a critical gauge of this outcome (Kloner et al, 2003; Solomon et al, 2003). <strong>The pathogenesis of vascular disease both systemically and locally in the penis is linked with NO imbalance via endothelial defects and/or oxidative stress, which subsequently diminishes the physiologic actions of NO and its effectors (Cooke and Dzau, 1997; Bonetti et al, 2003) (Figure 4).</strong> To address this pathophysiology, suggested preventative practices have been advocated to include increasing physical fitness, improving healthful dietary habits, and reducing obesity (Esposito et al, 2004; Esposito et al, 2006). <strong>Additional consideration has been given to medical therapies such as regularly used PDE5 inhibitors under the premise that this treatment may afford long-term vascular healthful benefits for the penis (Montorsi et al, 2000; Burnett, 2005a).</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Basic scientific evidence supports a penile vasculoprotective premise associated with long-term PDE5 inhibitor use. <u>Several scientific studies have shown the utility of chronically applied PDE5 inhibitors in improving the structure and function of the cavernosal tissue and provided plausible mechanisms for these beneficial effects</u>. </strong>In experimental paradigms involving rats that were chemically diabetogenic (De Young et al, 2003; Ahn et al, 2005), intact (Behr-Roussel et al, 2005), or aged (Musicki et al, 2005b; Ferrini et al, 2007) or had cavernous nerve injuries (Vignozzi et al, 2006; Ferrini et al, 2006a; Lagoda et al, 2007), continuous systemic PDE5 inhibitor treatment ranging from several days to 3 months preserved erectile tissue morphology and erection physiology to a better extent than did control treatments. Improved erectile responses were found to be sustained after confirmed drug clearance or withdrawal of the active drug in vivo (Musicki et al, 2005a; Lagoda et al, 2007) and in vitro (Behr-Roussel et al, 2005) protocols, respectively.<strong> Foremost possible biologic mechanisms by which PDE5 inhibitors afford penile vascular protection include antioxidation (De Young et al, 2003; Lagoda et al, 2007), antiapoptosis (Ahn et al, 2005; Musicki et al, 2005b), and activation of blood flow-associated vasodilatory effectors (BehrRoussel et al, 2005; Musicki et al, 2005b; Ferrini et al, 2006a; Vignozzi et al, 2006; Ferrini et al, 2007).</strong></em></p><p><em><strong></strong></em></p><p><em><strong>A growing body of clinical literature also suggests that chronically used PDE5 inhibitors exert sustained healthful effects on the penile vasculature.</strong> Efficacy and tolerability have been demonstrated for sildenafil and tadalafil using once-daily or alternate day dosing regimens in men with ED enrolled in uncontrolled, open-label design studies (McMahon, 2004; Caretta et al, 2005; McMahon, 2005; Mirone et al, 2005; Sommer and Schulze, 2005; Buvat et al, 2006). In clinical trials with the rigor of randomization and placebo control design, efficacy and safety endpoints have also been shown for tadalafil (Porst et al, 2006; Rajfer et al, 2007). <strong>A substantial groundswell of interest has been generated to apply this mode of therapy to the postradical prostatectomy population according to a conceptual ‘‘penile rehabilitation’’ strategy.</strong> <strong>This population experiences at least some temporary degree of ED as a consequence of the surgery, even when cavernous nerve-sparing techniques are applied (Burnett, 2005b).</strong> Much attention was paid to the placebo-controlled study involving postoperative nightly administration of sildenafil, which found a 27% return of spontaneous, normal erectile activity rate compared with the 4% rate found in the placebo arm at 1 year after surgery (Padma-Nathan et al, 2004b). In other reports involving open-label study designs, investigators attempted to define an optimal therapeutic regimen in terms of such variables as dosing schedule, duration of administration, and timing of application while also describing improvements in spontaneous erectile function resulting from chronic PDE5 inhibitor use (Gontero et al, 2005; Mulhall et al, 2005)</em></p><p><em></em></p><p><em><strong>Several caveats should be addressed in considering the utility of long-term PDE5 inhibitor treatment for this clinical application.</strong> One early identified controversy was whether the therapeutic strategy could cause pharmacologically induced ‘‘tachyphylaxis,’’ as suggested by a report that described a 20% dose elevation rate and 17% discontinuation rate due to loss of efficacy in patients with ED using sildenafil ‘‘on-demand’’ over a 2-year interval (El-Galley et al, 2001). <strong>However, likely explanations for declines in treatment effect over the long term are underlying disease state progression, inadequate dosing, application of the therapy, relationship difficulties, and psychogenic factors (Steers, 2002). Furthermore, findings of consistent efficacy and tolerability of treatment following both long-term, ‘‘on-demand’’ schedules reported previously (Carson, 2003) and long-term, continuous dosing reported more recently (Porst et al, 2006; Rajfer et al, 2007) argue against the development of treatment tolerance.</strong> <strong><u>It is acknowledged that PDE5 expression levels apparently increase with continuous treatment in basic science experimental paradigms</u> (Lin et al, 2003; Musicki et al, 2005a),<u> but the consequence of increasing PDE5 expression above normative levels in the penis was not demonstrated to negatively impact physiologic erectile responses</u> (Musicki et al, 2005a; Behr-Roussel et al, 2005).</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Another matter for consideration is whether prophylactic PDE5 inhibitor therapy should be given only to patients with certain underlying medical conditions.<u> Much interest exists to apply the therapy to patients with severe forms of ED or conditions that would predict the likely development of ED</u>. In this vein, the therapy would apply to those individuals with such risk factors as diabetes, cardiovascular disease, prior pelvic surgery, and aging.</strong> In their rat model study of chronic sildenafil dosing, Musicki et al (2005b) found that erections improved only in erection-impaired, aged rats but not in erection-intact, young rats. Compensatory homeostatic mechanisms were found to develop in young rats, suggesting to the investigators that such mechanisms are operable in the penis of the ‘‘healthy’’ individual in response to long-term PDE5 inhibitor treatment which limits supernormal erectogenic effects and concurrently prevents potentially harmful excessive erections.</em></p><p><em></em></p><p><em><strong>Continued study is needed to confirm clinical impressions of a penile vascular protection benefit, which at this stage should be considered preliminary.</strong> <strong>Additionally, further investigation is needed to clarify molecular mechanisms associated with the presumed therapeutic benefit.</strong> Investigative work done in the cardiovascular field has shown the preconditioning effects of PDE5 inhibition against ischemic/reperfusion injury in the intact heart (Das et al, 2002; Kukreja, 2007). Cardioprotective effects have been related to activation of protein kinase C/extracellular signal-regulated kinase signaling, the opening of mitochondrial adenosine triphosphate-sensitive potassium channels, and attenuation of cell death resulting from necrosis and apoptosis (Kukreja, 2007).<strong> Further investigation may reveal whether or not such cellular or subcellular effects actually occur in the penis following long-term PDE5 inhibitor treatment.</strong> It is recognized that advancing the knowledge base in this area may occur most readily at the experimental animal model level, in which penile tissues are more easily obtained for molecular studies and objective erection testing is also more feasible. However, important inferences may still result from continued active research efforts expended at the clinical level. Recent work in men by Foresta et al (2007) showing that vardenafil increases circulating progenitor cells, which are involved in the process of neovascularization and continuous repair of the endothelium, via bone marrow stimulation has contributed to defining the endothelial protective role of PDE5 inhibitors.</em></p></blockquote><p></p>
[QUOTE="madman, post: 218508, member: 13851"] [B]Penile Vascular Protection[/B] [I][B]The medical literature widely supports vascular health objectives as a means toward achieving long-term health maintenance and longevity[/B]. Several thought leaders in sexual medicine have further pointed to penile vascular health as a critical gauge of this outcome (Kloner et al, 2003; Solomon et al, 2003). [B]The pathogenesis of vascular disease both systemically and locally in the penis is linked with NO imbalance via endothelial defects and/or oxidative stress, which subsequently diminishes the physiologic actions of NO and its effectors (Cooke and Dzau, 1997; Bonetti et al, 2003) (Figure 4).[/B] To address this pathophysiology, suggested preventative practices have been advocated to include increasing physical fitness, improving healthful dietary habits, and reducing obesity (Esposito et al, 2004; Esposito et al, 2006). [B]Additional consideration has been given to medical therapies such as regularly used PDE5 inhibitors under the premise that this treatment may afford long-term vascular healthful benefits for the penis (Montorsi et al, 2000; Burnett, 2005a). Basic scientific evidence supports a penile vasculoprotective premise associated with long-term PDE5 inhibitor use. [U]Several scientific studies have shown the utility of chronically applied PDE5 inhibitors in improving the structure and function of the cavernosal tissue and provided plausible mechanisms for these beneficial effects[/U]. [/B]In experimental paradigms involving rats that were chemically diabetogenic (De Young et al, 2003; Ahn et al, 2005), intact (Behr-Roussel et al, 2005), or aged (Musicki et al, 2005b; Ferrini et al, 2007) or had cavernous nerve injuries (Vignozzi et al, 2006; Ferrini et al, 2006a; Lagoda et al, 2007), continuous systemic PDE5 inhibitor treatment ranging from several days to 3 months preserved erectile tissue morphology and erection physiology to a better extent than did control treatments. Improved erectile responses were found to be sustained after confirmed drug clearance or withdrawal of the active drug in vivo (Musicki et al, 2005a; Lagoda et al, 2007) and in vitro (Behr-Roussel et al, 2005) protocols, respectively.[B] Foremost possible biologic mechanisms by which PDE5 inhibitors afford penile vascular protection include antioxidation (De Young et al, 2003; Lagoda et al, 2007), antiapoptosis (Ahn et al, 2005; Musicki et al, 2005b), and activation of blood flow-associated vasodilatory effectors (BehrRoussel et al, 2005; Musicki et al, 2005b; Ferrini et al, 2006a; Vignozzi et al, 2006; Ferrini et al, 2007). A growing body of clinical literature also suggests that chronically used PDE5 inhibitors exert sustained healthful effects on the penile vasculature.[/B] Efficacy and tolerability have been demonstrated for sildenafil and tadalafil using once-daily or alternate day dosing regimens in men with ED enrolled in uncontrolled, open-label design studies (McMahon, 2004; Caretta et al, 2005; McMahon, 2005; Mirone et al, 2005; Sommer and Schulze, 2005; Buvat et al, 2006). In clinical trials with the rigor of randomization and placebo control design, efficacy and safety endpoints have also been shown for tadalafil (Porst et al, 2006; Rajfer et al, 2007). [B]A substantial groundswell of interest has been generated to apply this mode of therapy to the postradical prostatectomy population according to a conceptual ‘‘penile rehabilitation’’ strategy.[/B] [B]This population experiences at least some temporary degree of ED as a consequence of the surgery, even when cavernous nerve-sparing techniques are applied (Burnett, 2005b).[/B] Much attention was paid to the placebo-controlled study involving postoperative nightly administration of sildenafil, which found a 27% return of spontaneous, normal erectile activity rate compared with the 4% rate found in the placebo arm at 1 year after surgery (Padma-Nathan et al, 2004b). In other reports involving open-label study designs, investigators attempted to define an optimal therapeutic regimen in terms of such variables as dosing schedule, duration of administration, and timing of application while also describing improvements in spontaneous erectile function resulting from chronic PDE5 inhibitor use (Gontero et al, 2005; Mulhall et al, 2005) [B]Several caveats should be addressed in considering the utility of long-term PDE5 inhibitor treatment for this clinical application.[/B] One early identified controversy was whether the therapeutic strategy could cause pharmacologically induced ‘‘tachyphylaxis,’’ as suggested by a report that described a 20% dose elevation rate and 17% discontinuation rate due to loss of efficacy in patients with ED using sildenafil ‘‘on-demand’’ over a 2-year interval (El-Galley et al, 2001). [B]However, likely explanations for declines in treatment effect over the long term are underlying disease state progression, inadequate dosing, application of the therapy, relationship difficulties, and psychogenic factors (Steers, 2002). Furthermore, findings of consistent efficacy and tolerability of treatment following both long-term, ‘‘on-demand’’ schedules reported previously (Carson, 2003) and long-term, continuous dosing reported more recently (Porst et al, 2006; Rajfer et al, 2007) argue against the development of treatment tolerance.[/B] [B][U]It is acknowledged that PDE5 expression levels apparently increase with continuous treatment in basic science experimental paradigms[/U] (Lin et al, 2003; Musicki et al, 2005a),[U] but the consequence of increasing PDE5 expression above normative levels in the penis was not demonstrated to negatively impact physiologic erectile responses[/U] (Musicki et al, 2005a; Behr-Roussel et al, 2005). Another matter for consideration is whether prophylactic PDE5 inhibitor therapy should be given only to patients with certain underlying medical conditions.[U] Much interest exists to apply the therapy to patients with severe forms of ED or conditions that would predict the likely development of ED[/U]. In this vein, the therapy would apply to those individuals with such risk factors as diabetes, cardiovascular disease, prior pelvic surgery, and aging.[/B] In their rat model study of chronic sildenafil dosing, Musicki et al (2005b) found that erections improved only in erection-impaired, aged rats but not in erection-intact, young rats. Compensatory homeostatic mechanisms were found to develop in young rats, suggesting to the investigators that such mechanisms are operable in the penis of the ‘‘healthy’’ individual in response to long-term PDE5 inhibitor treatment which limits supernormal erectogenic effects and concurrently prevents potentially harmful excessive erections. [B]Continued study is needed to confirm clinical impressions of a penile vascular protection benefit, which at this stage should be considered preliminary.[/B] [B]Additionally, further investigation is needed to clarify molecular mechanisms associated with the presumed therapeutic benefit.[/B] Investigative work done in the cardiovascular field has shown the preconditioning effects of PDE5 inhibition against ischemic/reperfusion injury in the intact heart (Das et al, 2002; Kukreja, 2007). Cardioprotective effects have been related to activation of protein kinase C/extracellular signal-regulated kinase signaling, the opening of mitochondrial adenosine triphosphate-sensitive potassium channels, and attenuation of cell death resulting from necrosis and apoptosis (Kukreja, 2007).[B] Further investigation may reveal whether or not such cellular or subcellular effects actually occur in the penis following long-term PDE5 inhibitor treatment.[/B] It is recognized that advancing the knowledge base in this area may occur most readily at the experimental animal model level, in which penile tissues are more easily obtained for molecular studies and objective erection testing is also more feasible. However, important inferences may still result from continued active research efforts expended at the clinical level. Recent work in men by Foresta et al (2007) showing that vardenafil increases circulating progenitor cells, which are involved in the process of neovascularization and continuous repair of the endothelium, via bone marrow stimulation has contributed to defining the endothelial protective role of PDE5 inhibitors.[/I] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
When Testosterone Is Not Enough
Targeting of PDE5 for Preservation of Penile Health
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