Testosterone and phosphodiesterase type-5 inhibitors: new strategy for preventing endothelial damage in internal and sexual medicine?

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.

Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats

“…Testosterone modulates nearly every component involved in erectile function, including penis structure, function, innervation of smooth muscle cells, endothelial function, and fibroelastic properties of the corpus cavernosum [1,[37][38][39]. A previous study demonstrated that androgen deprivation results in trabecular smooth muscle cell apoptosis and an increase in the extracellular matrix [40].…”

“…A previous study demonstrated that androgen deprivation results in trabecular smooth muscle cell apoptosis and an increase in the extracellular matrix [40]. The therapeutic effect of T replacement has also been explained by multiple mechanisms including activation of the NO/cyclic guanosine monophosphate (cGMP) pathway, prevention of apoptosis, inhibition of the RhoA/Rho-kinase (ROCK) pathway, suppression of inflammation, and rehabilitation of endothelial function [38,39,[41][42][43].…”

Acute effect of sildenafil on inflammatory markers/mediators in patients with vasculogenic erectile dysfunction

“…Through the upregulation of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase cytokines not only increase formation of superoxide but they also upregulate the expression of PDE-5 [37]. PDE-5 inhibitors antagonize these inflammatory effects by enhancing the NO-cGMP axis, which, apart from augmenting smooth muscle cell relaxation, also inhibits NADPH-oxidase expression/activity [37,38].…”

Daily Use of Sildenafil Improves Endothelial Function in Men With Type 2 Diabetes

“…PDE5 inhibitors have also been shown to have beneficial effects on the inflammation seen with endothelial dysfunction through inhibition of NADPH‐oxidase activity (Hadi and Suwaidi, 2007; Vlachopoulos et al, 2007). Recent studies have described benefits of PDE5 inhibitors in diseases with systemic endothelial dysfunction like cardiovascular disease and diabetes (Gross, 2005; Rosano et al, 2005; Kim et al, 2006; Aversa et al, 2009).…”