Testosterone and phosphodiesterase type-5 inhibitors: New strategy for preventing endothelial damage in internal and sexual medicine? Fisiopatologia Medica, Room 37, Viale Policlinico 155, 00161 Rome Italy.
Therapeutic Advances in Urology 10/2009; 1(4):179-97. DOI: 10.1177/1756287209344992
Source: PubMed

ABSTRACT Normal vascular endothelium is essential for the synthesis and release of substances affecting vascular tone (e.g. nitric oxide; NO), cell adhesion (e.g. endothelins, interleukins), and the homeostasis of clotting and fibrinolysis (e.g. plasminogen inhibitors, von Willebrand factor). The degeneration of endothelial integrity promotes adverse events (AEs) leading to increased atherogenesis and to the development of vascular systemic and penile end-organ disease. Testosterone (T) is an important player in the regulation of vascular tone through non-genomic actions exerted via blockade of extracellular-calcium entry or activation of potassium channels; also, adequate T concentrations are paramount for the regulation of phosphodiesterase type-5 (PDE5) expression and finally, for the actions exerted by hydrogen sulphide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue. It is known that an age-related decline of serum T is reported in approximately 20 to 30% of men whereas T deficiency is reported in up to 50% of men with metabolic syndrome or diabetes. A number of laboratory and human studies have shown the combination of T and other treatments for erectile dysfunction (ED), such as PDE5 inhibitors, to be more beneficial in patients with ED and hypogonadism, who fail monotherapy for sexual disturbances.The aim of this review is to show evidence on the role of T and PDE5 inhibitors, alone or in combination, as potential boosters of endothelial function in internal medicine diseases associated with reduced T or NO bioavailability, i.e. metabolic syndrome, obesity, diabetes, coronary artery disease, hyperhomocysteinemia, that share common risk factors with ED. Furthermore, the possibility of such a strategy to prevent endothelial dysfunction in men at increased cardiovascular risk is discussed.

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Available from: Antonio Aversa, Aug 30, 2015
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    • "Most of these studies were also limited in the length of treatment. Whereas early responses may be expected as late as 4 weeks [70], studies have rarely extended beyond 12 weeks [66,69], at which point one study even noted a decline in efficacy [69]. Hence, a longer period of observation of a more homogeneous cohort of patients is required to propound any definite conclusion. "
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    ABSTRACT: Testosterone is the principal androgen in the human male. The decline of testosterone with aging was recognized to be associated with a number of symptoms and signs that reduce the quality of life and that may even have severe, debilitating consequences. Clinically, late-onset hypogonadism (LOH) is diagnosed by use of biochemical and clinical measures. Despite published guidelines and recommendations, however, uncertainty surrounds the profile of clinical symptoms as well as the biochemical threshold of diagnosis. Clinicians should be aware of these shortcomings while adhering to the guidelines. Current treatment methods are centered on restoring testosterone to mid to lower levels of young men with natural testosterone replacements. Although recent studies have highlighted possible additional benefits involving improvement of systemic disorders, the goal of treatment is to improve sexual function, while observing for adverse effects in the prostate. Overall, the problem of LOH in debilitating the quality of life and well-being is real, and by following proper guidelines with attentiveness to the results of treatment trials, testosterone replacement therapy presents a safe and effective treatment option.
    Korean journal of urology 11/2011; 52(11):725-35. DOI:10.4111/kju.2011.52.11.725
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    • "Furthermore, the researchers showed that chronic PDE5 inhibition resulted in increased energy expenditures, with improved energy balance and weight reduction that might be responsible for the enhanced insulin activity (Ayala et al, 2007). Several studies have examined the effects of sildenafil on endothelial function (DeSouza et al, 2002; Aversa et al, 2007; Grover-Paez et al, 2007; Burnett et al, 2009), with chronic PDE5 inhibition having the potential to limit diabetic nephropathy (Grover-Paez et al, 2007); however, much work still needs to be conducted in this area. Previous studies have suggested that brachial artery FMD equates with penile endothelial function, which in turn may be associated with ED (Sorenson et al, 1995; DeSouza et al, 2002; Hadi and Suwaidi, 2007; Vardi et al, 2009). "
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    ABSTRACT: Diminished vascular endothelial function results in decreased vasodilator capacity and is associated with erectile dysfunction (ED) in patients afflicted with type 2 diabetes. The current study was designed to evaluate whether daily use of sildenafil could alter endothelial function and improve penile rigidity in a group of patients with diabetic ED. A double-blind, placebo-controlled, prospective trial was conducted with 24 men with type 2 diabetes who were randomized into 2 groups: one receiving daily sildenafil (50 mg, n = 12) and the other placebo (n = 12) for 10 weeks. Erectile function was captured subjectively using the International Index of Erectile Function (IIEF-5), and endothelial function was objectively monitored via brachial artery flow-mediated dilation. Among the placebo and sildenafil groups, there were no significant differences in average patient age, time from type 2 diabetes diagnosis, duration of ED, or baseline IIEF-5 scores. Past medical histories, including smoking, alcohol consumption, hypertension, and hyperlipidemia, were also similar. At the conclusion of the 10-week trial, patients who received daily sildenafil had significantly improved erectile rigidity as captured by IIEF-5 (P < .001) and increased endothelial function via brachial artery flow-mediated dilation (P < .01). Endothelial function in men with type 2 diabetes was enhanced with daily sildenafil. Improved erectile rigidity and enhanced vascular circulation was noted after 10 weeks of daily sildenafil use.
    Journal of Andrology 06/2011; 33(2):176-80. DOI:10.2164/jandrol.111.013367 · 1.69 Impact Factor
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    ABSTRACT: Introduction: Phosphodiesterase type 5 inhibitors (PDE5-i) are used for the oral treatment of erectile dysfunction (ED). Since the launch of sildenafil more than 15 years ago, new molecules have become available. At present, in addition to tadalafil and vardenafil, there are three other drugs, udenafil, avanafil and mirodenafil, marketed in some countries which appear to be promising. Areas covered: The clinical pharmacological differences in dosage and side effects of all PDE5-i are evaluated. Expert opinion: All PDE5-i are equally effective and safe for the treatment of ED. On-demand use of any PDE5-i is also safe for patients with comorbid conditions. Tadalafil seems to be the preferred drug by patients and physicians, probably due to its peculiar pharmacological profile that makes sexual intercourse more spontaneous for the patients. Preliminary data suggest that the use of vardenafil may also be beneficial in cases of ED associated with premature ejaculation. Daily treatment is another option in men with ED and documented vascular or prostate disease. In geriatric or in difficult-to-treat populations, the evaluation of testosterone plasma levels will help to predict the efficacy of any PDE5-i. Remarkably, when such drugs are withdrawn for any reason, ED most often continues to occur because of the presence of an underlying disease.
    Expert Opinion on Pharmacotherapy 05/2013; 14(10). DOI:10.1517/14656566.2013.799665 · 3.09 Impact Factor
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