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 adenosine monophosphate (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

Diagnosis of Erectile Dysfunction

The diagnosis of ED involves a clinical evaluation including medical/physical examination as well as documentation of sexual and psychosocial history. ^{11, 12} Erectile dysfunction is one of many symptoms of sexual disorders including premature ejaculation, increased latency time associated with age, psycho-sexual relationship problems, and loss of libido. During diagnosis of ED, it is important that other sexual dysfunctions (e.g. loss of libido) be recognized and taken into account. ^{13, 14} A few validated instruments are used in diagnosing ED, grading its severity, and assessing treatment satisfaction. Some examples of such instruments are the International Index of Erectile Function (IIEF), ¹⁵ the modified 5-item version of IIEF (IIEF-5), ¹⁶ and the Erectile Dysfunction Index of Treatment Satisfaction (EDITS). ¹⁷ The IIEF is a self-administered 15-item questionnaire consisting of five distinct domains: erectile function (total score range 1–30), orgasmic function (total score range 0–10), sexual desire (total score range 2–10), intercourse satisfaction (total score range 0–15), and overall satisfaction (total score range 2–10). ¹⁸

Recommendations based on biochemical investigation may consist of hormonal screening to detect hypogonadism or other underlying common diseases such as hyperprolactinemia, diabetes and dyslipidemia. ^{19, 20} Other methods that may be used are urine analysis, blood count, lipid levels, or prostate-specific antigen (PSA) concentration. ¹ There are also specialized evaluation techniques such as duplex ultrasonography, penile tumescence studies, RigiScan, test injections, audio-visual stimulation and penile brachial index measurement. ²¹

Epidemiology of Erectile Dysfunction

ED is a common disorder of male sexual function that affects all age groups and has a profound impact on quality of life. ² Given the increasing trends in life expectancy across the Western world (i.e., the aging of the general population) and the high prevalence of diabetes and cardiovascular disease, the impact on lifestyle and quality of life imposed by ED in men is projected to be substantial. ¹ It was estimated that, in 1995, over 152 million men worldwide experienced ED. For 2025, the prevalence of ED is predicted to be approximately 322 million worldwide. ²² The severity, prevalence and incidence of ED increase with age. ^{2, 22, 23} The Massachusetts Male Aging Study ² surveyed 1,709 men aged 40–70 years between 1987 and 1989, using a self-administered questionnaire that asked participants to rate themselves as not having ED, or having minimal ED, moderate ED, or complete ED. There was a total prevalence of erectile dysfunction of 52 percent when participants with minimal (17.2 percent), moderate (25.2 percent) and complete (9.6 percent) dysfunction were combined. ² Both the prevalence and severity of erectile dysfunction increased proportionally with age. When adjusted for age, patients with lower level of education, heart disease, hypertension, and diabetes had a higher probability of ED. ^{2, 23} In the same study, a sample of 847 men without ED at baseline (1987-1989) was followed prospectively until 1995-1997. ²³ The crude incidence rate of ED in this population was estimated to be about 26 cases per 1,000 man-years (95% CI: 22.5–29.9). The annual age-specific incidence rate of ED increased with each decade of age. For example, the incidence rates (and 95% CIs) for men in two age groups of 50–59 and 60–69 years were 29.8 cases per 1,000 man-years (95% CI: 24.0–37.0) and 46.4 cases per 1,000 man-years (95% CI: 36.9–58.4), respectively. ²³ In a Canadian cross-sectional survey of primary care facilities, about 50 percent of 3,921 men aged 40–88 years had ED (IIEF “EF” domain score <21). ²⁴ The presence of cardiovascular diseases or diabetes was associated with an increased risk of having ED after adjustment for age and other confounders. ²⁴

Classification of Erectile Dysfunction and Related Conditions

Today, ED is considered a disorder with multiple causes. The current evidence suggests that about 80 percent of ED cases are of organic origin. ¹ Organic causes of ED may be vascular (e.g. cardiovascular disease, hypertension, lipid disorders, endothelial dysfunction), neurological (e.g. spinal cord injury, Parkinson's disease, multiple sclerosis), iatrogenic (e.g. pelvic surgery, prostatectomy, antipsychotic agents, antidepressants, beta-blockers, diuretics, antitestosterone hormonal agents), penile injury/anatomic abnormalities (e.g. Peyronie's disease, priapism), tumors (e.g. prostate cancer, colorectal cancer), various conditions (chronic renal or hepatic failure, lower urinary tract symptoms, prostatic hyperplasia), substance use and abuse (e.g. alcohol, tobacco) or endocrine disorders (e.g. diabetes, andropause, hypogonadism, hyperprolactinemia, hypothyroidism). Some of the psychogenic causes of ED may be depression, dysphoria, or anxiety states. ¹ The majority of ED patients with organic causes present with vascular diseases and have decreased blood flow to the penis. ^{2, 21, 25} In many patients the cause of ED may be a combination of psychological and organic factors. ²⁶

Treatment of Erectile Dysfunction

Today, unless contraindicated, the first-line therapies offered for the treatment of ED are lifestyle and risk factor modification (e.g. exercise and weight loss) ²⁷ and the use of the oral phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil, tadalafil, or vardenafil. ^{13, 28} Given that PDE-5 drugs may interact with nitrates with respect to vasodilatory effect, all PDE-5 drugs are contraindicated in patients taking nitrates for cardiac disease. The introduction, availability, and production of PDE-5 inhibitors have revolutionized the management of ED, allowing physicians to treat the condition in the primary care setting.

Although other types of medical treatments (e.g. intracavernosal injections, intraurethral suppositories) for erectile dysfunction have existed for years, their use has been associated with specific adverse events (e.g. local pain, priapism, fibrosis) and low compliance rates resulting from the invasive nature of these therapies. Topical therapies of agents that are approved by FDA for other indications have been explored as alternative options given their less invasive routes of administration (e.g. alprostadil, papaverine, organic nitrates). Other second-line treatment modalities for patients with refractory ED or who cannot tolerate PDE-5 therapy are hormonal treatments, vacuum constriction devices and surgical therapies (e.g. penile prosthesis implants, penile arterial bypass). ¹⁴ Psychological counseling (e.g. psychotherapy) and recommended lifestyle modifications (e.g. smoking cessation, low-fat diet, physical activity, weight loss) should be offered to men with ED either alone or in combination with other treatments.

Utilization and Costs Related to Treatment of ED

Estimates from the National Health and Nutrition Examination Survey (NHANES) suggests that the cost of treatment of ED in the U.S. could reach $15 billion if all men sought care. ²⁹ Analyses by the Erectile Dysfunction subgroup for the Urologic Diseases in America Project identified that almost 1.5 percent of privately insured males between the ages of 18 and 64 had at least 1 claim related to ED in 2002; shifting forms of health care were demonstrated, as the use of diagnostic tests for underlying causes of ED markedly decreased and utilization of pharmacological therapy especially with oral PDE-5 inhibitors, increased. ²⁹

National pharmacy claims data indicated an increased prevalence of sildenafil use from 1.5 percent in 1998 to 2.9 percent in 2002, with its use increasing with age. For example, in 2002, 6 percent of men aged 55 or older had one or more claims for sildenafil. ³⁰ Furthermore, the Department of Veteran Affairs (VA) indicated a nine-fold increase in treatment for ED between 1999 and 2003, with 9.3 percent of men 55–64 years of age reporting filling a prescription for oral agents in 2003. ²⁹ The overall use of pharmacological treatment for ED increased from 17,458/100,000 in 1999 to 56,716/100,000 in 2003. ²⁹ This is reflected by data from the VA Pharmacy Benefits Management Group, as prescriptions for specific ED drugs increased from 681/100,000 to 6,120/100,000 during this period. ²⁹ According to national sales, in 2005, the pharmaceutical costs of sildenafil, tadalafil, and vardenafil were $1.6 billion, $747 million, and $327 million, respectively. ^{31 – 33}

Harms Observed in Clinical Trials

Headache, flushing, rhinitis, and dyspepsia are the most commonly observed adverse events related to treatment with PDE-5 drugs. There also have been concerns regarding the excess incidence of cardiovascular events and visual disturbances occurring in patients receiving PDE-5 drugs; however, the current evidence does not indicate any marked trends for increased rates of these events in ED patients taking PDE-5 drugs compared with those in the general population. ^{13, 34}

Measures of Efficacy in Erectile Dysfunction Therapy

From the patient's perspective, the most important measures for defining successful ED treatment are: “cure, pleasure, partner satisfaction, reproduction, and naturalness.” ³⁵ To address the lack of well-defined standardized guidelines for the assessment of clinical outcomes in comparative trials of ED therapies, an International Consensus Advisory Panel was convened in 2002 in Montréal, Canada, where a new conceptual framework for treatment effectiveness was adopted. ³⁶

According to this framework, treatment effectiveness consists of two dimensions: treatment response and treatment satisfaction. Treatment response, in turn, consists of an integrated assessment of efficacy (i.e., ability of an agent to promote achievement and maintenance of adequate erection) and tolerability (i.e., side effects). The response was categorized as complete responder (e.g. consistent achievement and maintenance of full erection and ability to tolerate side effects), partial responder (e.g. ability to achieve full erection but not on a consistent basis over time and/or patients who experienced adequate efficacy but also had bothersome side effects of treatment), or nonresponder (e.g. patients who failed to respond in a clinically significant manner to the treatment and/or those who experienced intolerable effects at any dosage). Generally, the treatment efficacy in ED trials is assessed using event-log or diary-based questionnaires such as the IIEF and IIEF-5, the sexual encounter profile (SEP), and global assessment questions (GAQs). ³⁶ These measures are all based on patient responses and therefore are subjective in nature. ¹⁸ The other domain of treatment effectiveness—treatment satisfaction—is defined as the degree to which the effects of any particular treatment correspond or exceed the expectations of a patient and his partner. ³⁶ This domain was categorized as complete satisfaction (e.g. both the patient and his partner were satisfied), partial satisfaction (e.g. either the patient or the partner was not satisfied), and no satisfaction (neither the patient nor the partner was satisfied). In summary, according to this framework, the overall measure of treatment effectiveness should ideally integrate the information on both treatment response (i.e., efficacy and tolerability) and treatment satisfaction (i.e., self-rated degree of patient-partner satisfaction).

Knowledge Gaps and Uncertainties

Currently there are several knowledge gaps in the management of ED. There is still insufficient information regarding the effectiveness and safety related to the use of different treatment modalities in various clinical subgroups of patients (e.g. diabetes, cardiovascular disease). Furthermore, there is insufficient data with regard to long-term adverse effects of oral ED medications that have been used by millions of users for over a decade. Comparative data on the efficacy and safety profiles of PDE-5 drugs have not yet been accumulated. Safety and efficacy data from trials with head-to-head comparisons of PDE-5 drugs are needed to establish the relative superiority of one drug over the others.

Some controversy has surrounded the issue of the clinical utility of and indications for routine endocrinological blood tests (e.g. testosterone, prolactin) for all patients presenting with ED. ^{19, 20, 37, 38} Current American Urological Association Practice Guidelines Committee (AUA PGC) recommend the determination of hormone levels based on initial clinical assessment or failure of initial PDE-5 management; these tests are not mandatory for all patients. ¹⁴ This is in contrast to the guidelines of the European Urological Association and the British Society for Sexual Medicine, both of which define endocrinological “screening” as a mandatory component of the initial evaluation of ED. ³⁹ The purpose of this testing is to identify and treat endocrinopathies such as hypogonadism and hyperprolactinemia as underlying causes of ED. In these cases, therapeutic outcomes for hormonal disorders and resultant ED are thought to be optimized. ^{20, 40} The debate regarding the optimal approach still continues. One group of experts recommends basic endocrine screening to measure serum levels of testosterone and prolactin, to guide treatment of the patients with testosterone and its analogs to correct specific endocrinopathies and symptoms of ED, ^{41 – 43} as well as to detect pituitary tumors. ^{38, 44} Other experts do not recommend the administration of routine hormone tests to all ED patients because of the high cost of these tests and the low prevalence of endocrinopathies in the ED population. ^{20, 37, 45} These authors suggested that the screening tests for serum hormonal levels be restricted to those patients with clinical signs of hypogonadism (e.g. decreased libido, small testes, reduced body hair) as revealed by a physical examination, or to those in whom the initial PDE-5 inhibitor therapy was ineffective. ^{20, 38, 45} Authors of one empirical study advocated routine determination of serum testosterone levels for all ED patients older than 50 years and serum prolactin levels for only those with low testosterone levels (<4ng/mL), decreased libido, and/or gynecomastia. ³⁸ . Clearly, a universally accepted guideline of “standard of practice” for endocrinological testing of the ED patient is yet to be defined and established.