Physiology of Erection

Introduction

Objectives of the Systematic Review

The purpose of this evidence report was to review systematically the literature on the diagnosis and pharmaceutical treatments of erectile dysfunction (ED) and to address the following objectives put forth by the Agency for Healthcare Research and Quality (AHRQ) and the American College of Physicians (ACP).

The primary objectives of this evidence report were:

KQ 1. To determine the clinical utility of routine blood tests - testosterone, prolactin, luteinizing hormone (LH), follicle stimulating hormone (FSH) - in identifying and affecting therapeutic outcomes for treatable causes of ED.

KQ 2. To determine the benefits of pharmaceutical treatments for patients with ED.

KQ 3. To determine the harms of pharmaceutical treatments for patients with ED.

The secondary objectives of this evidence report were:

KQ 2a. To explore how patient-specific characteristics (e.g. specific symptoms, age, comorbid conditions) may affect prognosis and treatment success for ED patients.

KQ 2b. To determine if the likelihood of treatment success varies by underlying cause of ED.

KQ 3a. To identify specific harms, such as nonarteritic ischemic optic neuropathy (NAION) and penile fibrosis of pharmaceutical treatments in patients with ED.

The findings of this report are intended to assist the AHRQ and the ACP in identifying areas for future research and in the development of practical information for healthcare providers and consumers.

Background

Definition of Erectile Dysfunction

Erectile dysfunction (ED) is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance.¹ The 1992 National Institutes of Health (NIH) Consensus Development Conference recommended the use of erectile dysfunction as the preferred term to impotence, the former being more precise.¹ There is no universal consensus or agreed criteria as to how consistent the problem (i.e., inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance) has to be and for what duration it should last to fulfill this definition. A period of persistence over 3 months has been suggested as a reasonable clinical guideline.^{1, 2}

Physiology of Erection

Penile erection is a complex process involving interactions between neural, psychological, vascular, and hormonal factors. The pathway of normal sexual function in males consists of four stages: sexual desire (i.e., libido), erection, ejaculation (i.e., orgasm), and detumescence (penile flaccidity).³ The erection cycle is initiated by sexual stimulation. Erection subsides at ejaculation or cessation of sexual stimulation and the subsequent flaccidity state is maintained until the next sexual stimulation or nocturnal erection occurs. Thus, both the erection and the flaccidity states of the penis exist in two phases, initiation and maintenance. Pathways responsible for penile flaccidity are no less important than pro-erectile mechanisms, and may play critical roles in certain types of erectile dysfunction (ED).⁴ Additionally, hormones function not only at the libido level, but help maintain anatomical and physiological integrity of penile cavernosal structures; testosterone deficiency interferes not only with normal function, but can also diminish response to ED treatment.⁵

The mechanism of erection involves responses to external sensory stimuli through parasympathetic activity, which leads to release of nitric oxide (NO) from nonadrenergic-noncholinergic (NANC) cavernous (penile) nerve endings and the endothelium of the penis. The initial phase of smooth muscle relaxation results in reduced peripheral resistance of cavernosal arterioles and thereby allows blood to flow into the penis under the driving force of systemic blood pressure.⁴ Once blood rushes into the sinusoids of the corpora cavernosa, shear stress can also release NO from endothelium to augment smooth muscle relaxation and erection. In addition, oxygen tension and substances secreted by endothelium lining the sinusoidal spaces, (i.e. prostaglandins, endothelins, and angiotensin) may also be involved in penile erection and detumescence.^{6, 7}

The somatic sensory nerves originate at receptors in the penis to transmit pain, temperature, touch, and vibratory sensations, and the brain modulates the spinal pathways of erection via the medial preoptic area and paraventricular nucleus of the hypothalamus, periaqueductal gray of the midbrain, and the nucleus paragigantocellularis of the medulla.³ During sexual stimulation, NO released from the penile cavernosal nerve endings and endothelium, diffuses into the trabecular and arterial smooth muscle cells to activate guanylyl cyclase, thereby catalyzing the formation of second messenger cyclic guanosine monophasphate (cGMP). The cGMP in turn activates protein kinase G, phosphorylating potassium and calcium channels; the end result is hyperpolarization, reduced intracytosolic calcium, and dissociation of the myosin head from acting as smooth muscle relaxes. Cyclic adenosinemonophosphate (cAMP) is another second messenger involved in smooth muscle relaxation and is activated by cAMP-signaling molecules including adenosine, calcitonin gene-related peptides, and prostaglandins.⁴

On the other hand, norepinephrine, phenylephrine, and endothelin appear to activate phospholipase C, leading to the formation of inositol triphosphate and diacylglycerol. The net result is increased cytoplasmic calcium and subsequent smooth-muscle contraction. Detumescence occurs following degradation of cGMP and cAMP to GMP and AMP, respectively, by specific phosphodiesterases. Sympathetic discharge occurs if sexual stimulation results in ejaculation.^{8, 9} Activated Rho-kinase phosphorylates, inhibits the regulatory subunit of smooth muscle myosin phosphatase, preventing dephosphorylation of myofilaments and maintaining contractile tone.¹⁰ In the flaccid state, these smooth muscles are tonically contracted due to intrinsic smooth-muscle tone, adrenergic discharge, and other signaling molecules such as endothelin.⁴