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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: 218502" data-attributes="member: 13851"><p><strong>Molecular Pharmacotherapeutic Review Targeting of PDE5 for Preservation of Penile Health (2008) </strong></p><p><em>ARTHUR L. BURNETT</em></p><p></p><p></p><p><strong>ABSTRACT</strong></p><p></p><p><em><strong>The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. </strong>Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3’, 5’- cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). <strong>A new investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of <u>erectile disorders including hypogonadism associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis</u>.</strong> This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying to existing and emerging therapeutic strategies for erectile disorders.</em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em><strong>Phosphodiesterase type 5 (PDE5) is an important molecular player in the biology of penile erection.</strong> Acknowledged for its role in controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 39,59-cyclic guanosine monophosphate (cGMP), the enzyme has been targeted for sexual medicine purposes. Presently available orally administered PDE5 inhibitors in the United States (ie, sildenafil, tadalafil, and vardenafil) comprise a foremost intervention for erectile dysfunction (ED), and they are now considered standard, first-line therapy for this indication (Montague et al, 2005). <strong>The advent of PDE5 inhibitor therapy has been momentous in advancing multiple clinical and scientific aspects surrounding this sexual dysfunction.</strong> <strong>Furthermore, the therapy can be credited with revolutionizing the entire field of sexual medicine, having brought increased awareness and legitimacy to all matters of sexual health across medical and public communities, and supporting sexual well-being as a foundation for general good health.</strong></em></p><p><em></em></p><p><em>Such recent progress not only signifies increasing scientific rigor in the field of sexual medicine but also heralds the prospect of multiple new scientific directions that could lead to further therapeutic breakthroughs. This statement aptly applies to a range of disorders of penile erection, beyond the categorization of all erectile impairments generically as ED, classically defined as the inability to attain and maintain an erection satisfactorily for sexual performance (NIH Consensus Conference, 1993). <strong>Less well-recognized erectile disorders include hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. </strong>Accordingly, the new science of erection physiology implies an expansion in concepts of the pathogeneses of all such disorders and the development of specific evidence-based rationales for their effective treatment. <strong>The ultimate goal of clinical management for any erectile disorder would be that of preserving erectile function as much as possible and preventing its loss.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>In light of PDE5’s major involvement in the molecular mechanisms of penile erection, it is timely to conjecture how it may be further exploited beyond its direct pharmacologic inactivation for temporary erectogenesis.</strong> One may also surmise that the conventional practice of using PDE5 inhibitors for ED management as a short-term intervention is restrictive, and opportunities likely exist for applying these drugs in various novel ways to derive further penile health benefits. <strong>These ‘‘outside the box’’ thoughts are not at all illogical, and in fact, they are consistent with steady advances in the science of penile erection and in the molecular biology of PDE5.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>In this review, I examine the multifaceted role of the PDE5 regulatory system in the penis and its relevance for furthering therapeutics for a spectrum of penile health indications.</strong> We begin with an overview of the basic biology of PDE5 by highlighting the general properties and molecular interactions of this fascinating molecule. I also briefly describe its familiar characterization in the penis and summarize the conventional ‘‘on-demand’’ use of PDE5 inhibitors for the clinical management of ED. <strong>Then within the context of several specific erectile disorders, I explore the convergence of currently understood PDE5 molecular biologic principles and advancing knowledge of erectile mechanisms. Applying this framework, I discuss the potential pharmacotherapeutic advantages of PDE5 as a molecular target for interventions aimed toward preserving penile health and submit plausible strategies that employ PDE5 inhibitors for this endeavor.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>*Molecular Biology of PDE5</strong></p><p><strong></strong></p><p><strong>*Role of PDE5 in Erectogenesis</strong></p><p><strong></strong></p><p><strong>*Clinical Applications</strong></p><p><em>-Hypogonadism-Associated ED Treatment</em></p><p><em>-Management of Recurrent Priapism</em></p><p><em>-Penile Vascular Protection</em></p><p><em>-Penile Tissue Health Restoration</em></p><p></p><p></p><p></p><p></p><p><strong>Summary</strong></p><p></p><p><em><strong>The significance of PDE5 in the penis is well understood in terms of its role in penile erection. There is ample evidence that this enzyme serves an important regulatory role for this biological function. However, increasing attention has been given recently to the regulatory basis of PDE5, which influences its operation in the penis. This concept implies that the regulatory determinants of PDE5 biology in this organ are as important for the mechanistic effects of PDE5 as its biologic activity alone. Regulators in this regard include both endogenous and exogenous factors. Endogenously, androgens and upstream components of the NO signaling cascade affect PDE5 expression and activity in the penis. Derangements in their actions account for pathologic consequences in the penis, and conversely, interventions such as exogenous androgen replacement or pharmacologic optimization of NO signaling in the penis using PDE5 inhibitors improve or restore penile physiology. <u>The current understanding that PDE5 biology in the penis is not static but rather is modifiable and subject to various forms of modulation suggests that the enzyme is an opportune pharmacotherapeutic target for preserving penile health</u>. Ongoing investigation in the field may suggest additional innovative strategies that may be specifically applied to advance this health objective.</strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 218502, member: 13851"] [B]Molecular Pharmacotherapeutic Review Targeting of PDE5 for Preservation of Penile Health (2008) [/B] [I]ARTHUR L. BURNETT[/I] [B]ABSTRACT[/B] [I][B]The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. [/B]Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3’, 5’- cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). [B]A new investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of [U]erectile disorders including hypogonadism associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis[/U].[/B] This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying to existing and emerging therapeutic strategies for erectile disorders. [B]Phosphodiesterase type 5 (PDE5) is an important molecular player in the biology of penile erection.[/B] Acknowledged for its role in controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 39,59-cyclic guanosine monophosphate (cGMP), the enzyme has been targeted for sexual medicine purposes. Presently available orally administered PDE5 inhibitors in the United States (ie, sildenafil, tadalafil, and vardenafil) comprise a foremost intervention for erectile dysfunction (ED), and they are now considered standard, first-line therapy for this indication (Montague et al, 2005). [B]The advent of PDE5 inhibitor therapy has been momentous in advancing multiple clinical and scientific aspects surrounding this sexual dysfunction.[/B] [B]Furthermore, the therapy can be credited with revolutionizing the entire field of sexual medicine, having brought increased awareness and legitimacy to all matters of sexual health across medical and public communities, and supporting sexual well-being as a foundation for general good health.[/B] Such recent progress not only signifies increasing scientific rigor in the field of sexual medicine but also heralds the prospect of multiple new scientific directions that could lead to further therapeutic breakthroughs. This statement aptly applies to a range of disorders of penile erection, beyond the categorization of all erectile impairments generically as ED, classically defined as the inability to attain and maintain an erection satisfactorily for sexual performance (NIH Consensus Conference, 1993). [B]Less well-recognized erectile disorders include hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. [/B]Accordingly, the new science of erection physiology implies an expansion in concepts of the pathogeneses of all such disorders and the development of specific evidence-based rationales for their effective treatment. [B]The ultimate goal of clinical management for any erectile disorder would be that of preserving erectile function as much as possible and preventing its loss. In light of PDE5’s major involvement in the molecular mechanisms of penile erection, it is timely to conjecture how it may be further exploited beyond its direct pharmacologic inactivation for temporary erectogenesis.[/B] One may also surmise that the conventional practice of using PDE5 inhibitors for ED management as a short-term intervention is restrictive, and opportunities likely exist for applying these drugs in various novel ways to derive further penile health benefits. [B]These ‘‘outside the box’’ thoughts are not at all illogical, and in fact, they are consistent with steady advances in the science of penile erection and in the molecular biology of PDE5. In this review, I examine the multifaceted role of the PDE5 regulatory system in the penis and its relevance for furthering therapeutics for a spectrum of penile health indications.[/B] We begin with an overview of the basic biology of PDE5 by highlighting the general properties and molecular interactions of this fascinating molecule. I also briefly describe its familiar characterization in the penis and summarize the conventional ‘‘on-demand’’ use of PDE5 inhibitors for the clinical management of ED. [B]Then within the context of several specific erectile disorders, I explore the convergence of currently understood PDE5 molecular biologic principles and advancing knowledge of erectile mechanisms. Applying this framework, I discuss the potential pharmacotherapeutic advantages of PDE5 as a molecular target for interventions aimed toward preserving penile health and submit plausible strategies that employ PDE5 inhibitors for this endeavor.[/B][/I] [B]*Molecular Biology of PDE5 *Role of PDE5 in Erectogenesis *Clinical Applications[/B] [I]-Hypogonadism-Associated ED Treatment -Management of Recurrent Priapism -Penile Vascular Protection -Penile Tissue Health Restoration[/I] [B]Summary[/B] [I][B]The significance of PDE5 in the penis is well understood in terms of its role in penile erection. There is ample evidence that this enzyme serves an important regulatory role for this biological function. However, increasing attention has been given recently to the regulatory basis of PDE5, which influences its operation in the penis. This concept implies that the regulatory determinants of PDE5 biology in this organ are as important for the mechanistic effects of PDE5 as its biologic activity alone. Regulators in this regard include both endogenous and exogenous factors. Endogenously, androgens and upstream components of the NO signaling cascade affect PDE5 expression and activity in the penis. Derangements in their actions account for pathologic consequences in the penis, and conversely, interventions such as exogenous androgen replacement or pharmacologic optimization of NO signaling in the penis using PDE5 inhibitors improve or restore penile physiology. [U]The current understanding that PDE5 biology in the penis is not static but rather is modifiable and subject to various forms of modulation suggests that the enzyme is an opportune pharmacotherapeutic target for preserving penile health[/U]. Ongoing investigation in the field may suggest additional innovative strategies that may be specifically applied to advance this health objective.[/B][/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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