Markers of erectile dysfunction

Abstract

With the development and marketing of oral pharmacotherapy that is both noninvasive and successful in treating erectile dysfunction (ED), the quest to identify markers of organic ED lost ground. Indeed, the multi-factorial nature of ED may have led many researchers to conclude that searching for a universal marker of ED was futile. However, the realization that ED is strongly correlated with the overall health of men, and may act as a predictor for the development of cardiovascular disease (CVD) and diabetes, has stimulated interest in identifying genes that can distinguish organic ED. In addition, the potential ability to suggest to the patient that ED is reversible (i.e., psychogenic) with a simple test would be of significance to both the physician and patient, as well as for reimbursement issues for therapy by insurance companies. Such a marker may also act as a non-subjective measure of the degree of ED and the efficacy of treatment. This review discusses the importance of identifying such markers and recent work identifying potential markers in human patients.

Keywords: Biomarker; erectile dysfunction.

Figure 1

Factors involved in the regulation of corporal smooth muscle tone. Agonists such as Sphingosine-1-phosphate (S-1-P), endothelin-1 (ET-1), C-type natriuretic peptide (CNP) Angiotensin-II (Agt-II) bind to their respective membrane receptor on corporal endothelial and smooth muscle cells and activate downstream signaling pathways most commonly through the mechanism using cyclic guanine monophosphate (cGMP) secondary messenger. Peptide agonists are degraded by neutral endopeptidase (NEP). However, in the presence of sialorphin (or the human homologues which act as NEP inhibitors), these agonists potentially have a prolonged effect, activating downstream mechanisms that result in smooth muscle relaxation. Among these downstream activators is Nitric Oxide (NO) synthesized from L-arginine (L-arg) by nitric oxide synthase (NOS) which is predominantly expressed in the endothelial cells. Nitric oxide diffuses into the corporal smooth muscle cells where it activates guanylate cyclase (GC) contributing to the intracellular pool of cGMP. One of the downstream effects of cGMP is the activation of Maxi-K channels though protein kinases (PK). Efflux of potassium from the cells causes hyperpolarization of the smooth muscle cell membrane, inhibiting influx of Ca²⁺ through calcium channels. Lowered intracellular calcium causes inactivation of myosin light chain kinase (MLCK), thereby promoting smooth muscle relaxation. Activation of the RhoA-GTP pathway inhibits relaxation and results in calcium sensitization. Some markers of endothelial cells, discussed in more detail below, are secreted into the plasma. These include S-1-P, ET-1 and assymetric dimethylarginine (ADMA). GTP = guanosine triphosphate; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; MLC20 = myosin light chain