Erectile Dysfunction: Treatments, Advances and New Therapeutic Strategies

Abstract

Erectile dysfunction (ED) is the inability to get and maintain an adequate penile erection for satisfactory sexual intercourse. Due to its negative impacts on men's life quality and increase during aging (40% of men between 40 and 70 years), ED has always attracted researchers of different disciplines, from urology, andrology and neuropharmacology to regenerative medicine, and vascular and prosthesis implant surgery. Locally and/or centrally acting drugs are used to treat ED, e.g., phosphodiesterase 5 inhibitors (first in the list) given orally, and phentolamine, prostaglandin E1 and papaverine injected intracavernously. Preclinical data also show that dopamine D₄ receptor agonists, oxytocin and α-MSH analogues may have a role in ED treatment. However, since pro-erectile drugs are given on demand and are not always efficacious, new strategies are being tested for long lasting cures of ED. These include regenerative therapies, e.g., stem cells, plasma-enriched platelets and extracorporeal shock wave treatments to cure damaged erectile tissues. Although fascinating, these therapies are laborious, expensive and not easily reproducible. This leaves old vacuum erection devices and penile prostheses as the only way to get an artificial erection and sexual intercourse with intractable ED, with penile prosthesis used only by accurately selected patients.

Keywords: erectile dysfunction; penile prosthesis; pharmacological treatments; regenerative strategies; surgical strategies; vacuum erection device.

Figure 1

Schematic representation of the neural control of the male genital apparatus. When sexual (visual, auditory, olfactory, tactile, and even imaginative in men) stimuli reach the central nervous system, they activate neural pathways, which are to date still unknown, mediating penile erection and sexual activity. These travel from brain, mainly from the medial preoptic area, hypothalamus and its nuclei (paraventricular nucleus), through the medulla oblongata and the spinal cord, to the genital apparatus. This is innervated mainly by pudendal nerves, which originate from the sacral tract of the spinal cord (S2-S4) and contain the primary afferent sensory and motor pathways to the penis, and by cavernous nerves, which contain the primary efferent sympathetic and parasympathetic pathways originating in the pelvic plexuses. These receive neural inputs by hypogastric nerves, originating in the thoracic-lumbar tract of the spinal cord (T12-L2), and by pelvic nerves originating in the sacral tract of the spinal cord (S2-S4). Pelvic plexuses also receive post-gangliar fibers, which originate from the paravertebral sympathetic ganglia of the thoracic-lumbar tract of the spinal cord (T11-L2). For details, see references [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30].

Figure 2

Schematic representation of local mechanisms controlling the tone of cavernous smooth muscles. When the penis is flaccid, cavernous smooth muscles are contracted by noradrenaline (NE), which acts on α₁ receptors to increase intracellular free Ca²⁺ by activating the phospholipase C/inositol triphosphate (IP₃)/diacylglycerol (DAG) pathway, by endothelins (ET) and contracting prostaglandins (C-Pgs), which act with mechanisms similar to that of NE, and by the RhoA-Rho kinase system, which keeps myosin light chain (MLC) phosphorylated (MLC-P) by inhibiting MLC phosphatase (MLCP), facilitating the myosin/actin interaction. Relaxation occurs when sexual stimuli increase nitric oxide (NO) levels in cavernous smooth muscles. NO is released from nitrergic nerve endings and from endothelial cells containing endothelial NO synthase (activated to produce NO by the stimulation of muscarinic (M) receptors by Ach), activating soluble guanylate cyclase (sGC) and increases cyclic guanosine monophosphate (cGMP). cGMP acts on protein kinase GK1 to decrease intracellular free Ca²⁺, facilitating relaxation and penile erection. cGMP action is terminated by phosphodiesterase type 5 (PDe5). Relaxation of cavernous smooth muscles is also obtained with peptides such VIP and relaxing prostaglandins (R-Pgs) that activate adenylate cyclase (AC) and increase cyclic adenosine monophosphate (cAMP). cAMP acts on protein kinase A (PKA), decreases intracellular free Ca²⁺, and facilitates relaxation and penile erection. cAMP action is terminated by PD type 3/4 (PDe3/4). Drugs that potentiate relaxation or reduce contraction mechanisms are suitable candidates for ED treatment.

Figure 3

Oxytocinergic neurons are a target for the central therapy of ED. These neurons, originating in the PVN and projecting to the spinal cord and extra-hypothalamic brain areas, mediate penile erection. When activated by neurotransmitters, such dopamine, excitatory amino acids, NO, oxytocin, hexarelin peptide analogues, VGF peptides or by the blockade of CB1 receptors in the PVN, they facilitate penile erection, while when inhibited, for instance by gamma-aminobutyric acid (GABA), opioid peptides and endocannabinoids, this sexual response is reduced. NOS = NO synthase. References are found in Section 3.1.2. (Section 3.1.2.2 and Section 3.1.2.3).