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Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse (). ED may result from psychological, neurologic, hormonal, vascular, or medication-induced causes. Approximately 23% of men aged 40-80 years worldwide have symptoms of ED (). ED occurs in men of all ages; the prevalence increases with age (, ). Diabetes is a common and important case of ED due to the diseases impact on both neurological and vascular factors germane to penile erection ().

Penile erection is a neurovascular event modulated by psychological and hormonal status. The penis is innervated by autonomic and somatic nerves. The autonomic nervous innervation of the penis consists of sympathetic fibers (derived from the T11-L2 spinal cord level) and parasympathetic fibers (derived from the S2-4 spinal cord level) which merge to form the cavernous nerves in the pelvis. The autonomic nervous innervation of the penis regulates corporal smooth muscle and arterial contraction and relaxation, which are the primary drivers of penile tumescence. The somatic portion of the pudendal nerve is responsible for penile sensation and the contraction and relaxation of the bulbocavernosus and ischiocavernosus striated muscles. These muscles are important for maximal penile erection and for expulsion of semen during ejaculation (, ) .

The penis is flaccid in the resting state. Suppression of penile erection and maintenance of the flaccid state is mediated by the sympathetic nervous system and adrenergic nerve terminals. Vascular factors such as endothelin may also contribute to resting smooth muscle tone in the penis. Smooth muscle tone is ultimately mediated by activation of the myosin light chain, which tends to increase contraction. The RhoA/Rho kinase pathway also plays a critical role in smooth muscle contraction by suppressing myosin light chain phosphatase. A depiction of contractile molecules which mediate penile flaccidity is presented in . Penile erection is induced in part by suppression of sympathetic tone. A number of brain centers integrate erotic stimuli and contribute to erection by suppressing the sympathetic nervous system. The neurotransmitter dopamine appears to play a critical role in central nervous system-based stimulation of erection whereas serotonin plays a mostly (but not universally) inhibitory role (, ) .

Erection also requires activation of the parasympathetic nervous system; this is mediated in large part by release of nitric oxide (NO) from nonadrenergic-noncholinergic cavernous nerve terminals in the genital vascular system. NO is produced in nerve tissue by neuronal nitric oxide synthase (nNOS). NO activates soluble guanylyl cyclase, which cleaves guanosine triphosphate (GTP) to produce cyclic guanosine monophosphate (cGMP). cGMP in turn activates cGMP-specific protein kinases, which phosphorylates certain proteins and ion channels, resulting in: opening of the potassium channels and hyperpolarization; sequestration of intracellular calcium by the endoplasmic reticulum; and inhibition of calcium channels, blocking calcium influx. The consequence is a drop in cytosolic calcium content () . Decline in calcium content results in smooth muscle relaxation via relaxation of the actin myosin cross-bridges. There is resultant vasodilation in the arteries and arterioles supplying the erectile tissue. A several-fold increase in blood flow occurs, with a concomitant increase in compliance of the corporeal sinusoids from relaxed cavernous smooth muscle. The increase in blood flow triggers activation of endothelial nitric oxide synthase (eNOS) that further increases NO production and maintenance/enhancement of vasodilation (). A graphical depiction of the NO/cGMP relaxant pathway is depicted in . Additional vasodilation may be accomplished through the cyclic adenosine monophosphate pathway, depicted in .

With enhancement of corporal blood flow there is rapid filling and expansion of the corporal sinusoidal system against the tunica albuginea. The subtunical venular plexuses are compressed between the corporeal sinusoids and the tunica albuginea, resulting in almost total occlusion of venous outflow (, ). With trapping of blood within the corpora cavernosa the flaccid penis becomes erect; during the full erection phase intracavernous pressures increases to approximately 100 mm Hg. With increasing sexual arousal, the bulbocavernosus reflex is triggered, causing the ischiocavernosus muscles to forcefully compress the base of the blood-filled corpora cavernosa and the penis. During this rigid erection phase the penis (including the corpus spongiosum and glans) becomes very hard, with intracavernous pressure reaching several hundred mm Hg in some cases. During this phase, arterial inflow may cease or even reverse (i.e., arterial blood flows retrograde towards the heart) ()

With sexual climax or cessation of arousal, the penis returns to the flaccid state. Flaccidity is initiated in large part by hydrolysis of cGMP to guanosine monophosphate by phosphodiesterase type 5 (PDE5). Other phosphodiesterases are found in the corpus cavernosum, but they do not appear to play a major role in detumescence. Detumescence is also mediated by sympathetic discharge during ejaculation, leading to vasoconstriction and cessation of NO release from the cavernous nerves and corporal endothelium. The sub-tunical venous channels open with contraction of the trabecular smooth muscle, permitting egress of trapped blood and restoring flaccidity ().

ED may be mediated by defects in the neuronal, hormonal, arterial, or cavernosal systems. ED is commonly associated with specific medications. ED is also strongly associated with psychological distress. ED is in most cases multifactorial, with at least some element of a psychogenic component as a primary cause or as secondary development in reaction to the ED state. Some disease states (e.g., diabetes) may cause ED via multiple mechanisms (). Sexual function progressively declines as men age, although this decline need not be considered any more “natural” than the development of diabetes, hypercholesterolemia, hypertension, or any other disease state more common in the aged. With age, the latency period between sexual stimulation and erection increases, erections are less turgid, ejaculation is less forceful, ejaculatory volume decreases, and the refractory period between erections lengthens (). In most cases aging is also associated with a decrease in penile sensitivity to tactile stimulation, a decrease in serum testosterone concentration, and an increase in cavernous muscle tone () .

Erectile dysfunction is more common in patients with neurologic disorders such as Parkinson's and Alzheimer's diseases, stroke and cerebral trauma (). This may be due to both a decrease in libido and/or inability to initiate the erectile process. Spinal cord injury patients have varying degrees of erectile dysfunction largely dependent on the location and extent of the lesion. Men with lesions of the sacral spine may have disruption of the sacral reflex arc and may not respond to genital stimulation. Men with spinal cord injury that preserves the sacral segments may retain reflexogenic erections but may struggle to obtain erection related to mental arousal, which is generated by cortical suppression of sympathetic tone (). Although erections of some form are often possible in men with spinal cord injury, they are typically less rigid and of shorter duration compared to erections in men without spinal cord injury. Even in men without spinal cord injury, sensory input from the genitalia remains essential to achieving and maintaining reflexogenic erection. This input may be compromised due to peripheral neuropathy in men with diabetes ().

About 50 percent of men with chronic diabetes mellitus are reported to have ED, although this number dramatically increases with age. In addition to the disease's effect on small vessels, it may also affect the cavernous nerve terminals and endothelial cells, resulting in deficiency of neurotransmitters (). Additionally, corporal smooth muscle relaxation in response to neuronal- and endothelial-derived nitric oxide (NO) is impaired in men with diabetes, possibly due to the accumulation of glycosylation products (-). Chronic renal insufficiency (CRI) has frequently been associated with diminished erectile function, impaired libido, and infertility (, ).The mechanism of ED in CRI is likely multifactorial and includes low serum testosterone, vascular insufficiency, medication-related, depressed libido, and autonomic and somatic neuropathy (-). Diabetes is a major risk factor for CRI and hence CRI is a relevant consideration in men with diabetes. Psychogenic ED may relate to performance anxiety, strained relationship, lack of sexual arousal, and overt psychiatric disorders such as depression and schizophrenia (). The strong relationship between psychogenic stress and sexual dysfunction is well established ().

Androgen deficiency is associated with diminished libido and less frequent nocturnal erections (). However, erection response is preserved in many men with low serum testosterone, suggesting that androgens are beneficial but not essential for erection (). Men with diabetes are at increased risk of androgen deficiency; serum testosterone testing is often warranted in diabetic men with or without ED (, ). Prolactin is another pituitary hormone that has inhibitory activity on central dopaminergic activity and gonadotropin-releasing hormone secretion. Hyperprolactinemia has been linked to reproductive and sexual dysfunction. Vascular disease is a common and important cause of ED (). Common vascular risk factors associated with generalized penile arterial insufficiency include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, trauma, and pelvic irradiation (). Focal stenosis of the common penile artery is not common but can be a cause of ED in men who have sustained repetitive and/or severe pelvic or perineal trauma (e.g. biking accidents, pelvic fractures) () .

Veno-occlusive dysfunction (VOD) results from disruption of the blood trapping capacity of the tunica albuginea of the corpora. In this situation there may be inadequate compression of the subtunical venules during the full erection phase (). Venous leak ED may also be the result of degenerative changes that affect the penis including Peyronie's disease, penile scarring, and diabetes mellitus. A patient may develop VOD from traumatic injury to the tunica albuginea such as a penile fracture. Venous leak can also be seen in anxious men with excessive adrenergic tone causing structural alterations of the cavernous smooth muscle and endothelium and insufficient trabecular smooth muscle relaxation ().

Virtually all drugs have been associated with ED although some classes are more prone to sexual side effects than others. Central neurotransmitter pathways, including serotonergic, noradrenergic, and dopaminergic pathways involved in sexual function, may be disturbed by antipsychotics and antidepressants (). Although any antihypertensive agent could theoretically cause ED by decreasing the availability of blood to the corporal arteries (i.e., a pressure-head phenomenon), differences are noted between various classes of medications (). Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are relatively less likely to cause ED. Beta-adrenergic blocking drugs may lead to erectile dysfunction by potentiating a-1 adrenergic activity in the penis, although more modern beta blockers with eNOS activity (such as nebivolol) may help minimize this effect () . Thiazide diuretics have been reported to cause erectile dysfunction by an unknown mechanism () . Anti-androgens are another common drug type that may contribute to ED().

Recreational drugs including cigarettes and alcohol affect erectile function. Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle. More importantly, chronic use may accelerate atherosclerotic changes in penile microvasculature (). Alcohol in small amounts may improve erections and increase libido because of its vasodilatory effect and the suppression of performance anxiety. However, large amounts of alcohol can cause central sedation, decreased libido and transient erectile dysfunction. Chronic alcoholism may cause hypogonadism and polyneuropathy; this may in turn affect penile nerve function ().

Erectile dysfunction may be the first manifestation of many disease states, including diabetes mellitus, coronary artery disease, hyperlipidemia, hypertension, spinal-cord compression, pituitary tumors, and pelvic malignancies. ED is a sentinel event for major adverse cardiac events and is therefore an indication for formal cardiovascular evaluation (). The evaluation of a patient with ED requires a thorough history (medical, sexual, and psycho-social), physical examination and appropriate laboratory tests (creatinine, fasting glucose, lipid profile, total testosterone, and bioavailable or free testosterone) aimed at detecting underlying metabolic disease states (). If the man's testosterone concentration (free, total, or bioavailable) is low, serum prolactin and luteinizing hormone should be assayed to detect abnormalities of the hypothalamic-pituitary axis (, ).

After assessing the therapeutic needs and goals of the patient, further diagnostic and treatment options can be offered. The patient’s partner(s) should be involved in treatment planning and decision making (). In men who do not have a sexual partner, there should be discussion about goals in terms of future sexual relationships. Decisions on treatment should be based on patient goals and risk tolerance. If the patient has a regular partner, it is beneficial to involve them in conversations about goals and treatment options. The most recent AUA guideline on ED recommends that all treatments be considered first line. Most men are best served by a progression from minimally to maximally invasive options; however, a properly counseled man may elect to bypass less invasive options if he so desires and if deemed medically appropriate (). The patient's performance status and cardiovascular health should be evaluated, in consultation with a cardiologist, if necessary, in order to assess the patient's ability to tolerate sexual activity (). Patients who have poor exercise tolerance should consider physical conditioning prior to resuming sexual activity (). Exercise, healthy diet, and weight loss may be sufficient to partially restore erection response in some men ()

Men with complex ED may benefit from a referral for further testing and treatment by a sexual medicine specialist, sex therapist, or medical provider with expertise in a specific health condition germane to sexual responses (). The indications for specialty referral include complex gonadal or other endocrine disorders, neurologic deficit suggestive of brain or spinal cord disease, deep-seated psychologic or psychiatric problems, post-traumatic or lifelong erectile dysfunction and unstable cardiovascular disease (). Peyronie’s disease (PD) is an acquired fibrotic disorder of the penis that merits specific mention in the context of managing ED (). The condition remains poorly understood but is thought to involve a genetic predisposition to collagen deposition and inflammation in connective tissues after minor traumas as may be experienced during sexual activity. Men with PD are at increased risk of other fibrotic conditions including Dupuytren’s contractures and tympanosclerosis (). PD was once thought to be quite rare; with the introduction of highly effective therapy for ED many cases of PD that might have once gone unrecognized are now diagnosed. Prevalence estimates vary but signs of PD may be detected by experienced examiners in approximately 9% of men presenting for evaluation by an experienced urologist ().

The classical manifestation of PD is penile curvature, but the disorder may also be associated with pain, narrowing, corporal fibrosis, and hinging (). The single US-FDA approved medical therapy for PD is injections of Clostridial collagenase into the tunica albuginea of the corporal bodies followed by a course of penile modeling. This therapy has been associated with modest but significant improvements in penile curvature compared to placebo injections (). In cases of severe deformity and/or failure of medical therapy, surgical intervention may be required. Surgery for PD can take the form of 1) plication of the convex side of the penis with sutures to induce straightening, 2) incision with grafting of the concave or narrowed portion of the corpora, or 3) placement of a penile prosthetic device in cases where there is concomitant severe ED (, ).

Historically, androgens were thought to enhance male sexual function. However, androgen therapy has only been shown to be of clinical benefit in men with low serum testosterone and symptoms potentially referable to hypogonadism () . There is controversy over what constitutes a “low” level of testosterone with cut points for normal ranging between 264-350 ng/dL depending on definitions based on population norms and/or increased odds of symptoms potentially referable to low serum testosterone. (, , , ). Assessment of serum free testosterone (ideally with equilibrium dialysis or other highly precise methodology) is controversial and recommended in select cases by some experts () but not by others (, ). The sexual benefits of supplementation in men with low serum testosterone primarily pertains to libido but mild improvements in erectile function in patients may occur with testosterone supplementation alone (). The United States Testosterone Trial demonstrated moderate improvement of erectile function with testosterone gel therapy compared to placebo in men ≥ 65 years and serum total testosterone concentrations ≤ 275 ng/dl; these men were not a priori screened for erectile dysfunction.()

Testosterone cypionate, enanthate, and undecanoate may be used for intramuscular replacement therapy. A standard dosing regimen is 200 mg intramuscularly every two weeks although different dosing regimens have been described. Lower doses at shorter intervals may produce less pronounced variation in serum testosterone levels between doses. Several daily transdermal testosterone preparations (testosterone patches or gels) are available. Daily application of these preparations raises serum testosterone concentrations to within the normal range in over 90 percent of men. The most common adverse effects of testosterone patches are skin irritation and contact dermatitis. Gel formulations are less prone to skin irritation but care must be taken to avoid skin-to-skin contact and transfer of testosterone to others (e.g., spouse, children) for at least 2 hours post dosing () .

Recent refinements in testosterone supplementation include novel testosterone pellets, which are implanted in a minor office procedure and provide 2-4 months of therapeutic testosterone levels (). A ten week depot testosterone preparation was recently approved for use in the United States; this long acting formulation may obviate the need for frequent injections (). These long-acting formulations may be considered for patients who have tolerated shorter acting formulations and reported significant benefit. Additional recent innovations that have achieved FDA approval include subcutaneous injectable testosterone and nasal testosterone (). Testosterone treatment may contribute to polycythemia, acne, edema, and decreased HDL cholesterol. Testosterone may also lead to estrogen by aromatization in adipose tissue; this may lead to gynecomastia and theoretically to higher risk of deep venous thrombosis. Men receiving androgen replacement therapy require routine follow up appointments with measurement of hematocrit, serum testosterone, and PSA. It is prudent to have more frequent checks in the early phase after initiation of therapy ().

Due to the well-established benefits of surgical or medical castration for the management of advanced prostate cancer there has been a long-standing concern that testosterone supplementation may increase the risk of prostate cancer (, ). This relationship is based primarily on conjecture; there is an emerging body of literature which suggests that testosterone supplementation does not materially alter the risk of prostate cancer development (). There is limited evidence that men with low serum testosterone may be at greater risk of aggressive prostate cancer (), although there is currently no evidence that supplementation moderates this risk. Numerous reports have been published of men with successfully treated prostate cancer using testosterone supplements with no increase in risk for PSA recurrence (). Some clinicians have also reported continued testosterone supplementation in men with untreated prostate cancer; until more data are available providers in general practice should exercise caution with respect to testosterone supplementation in men with untreated prostate cancer (, ).

The issue of cardiac safety and testosterone received a great deal of media attention in the mid 2010s. High profile publications in prestigious journals reported increased rates of cardiovascular events and mortality in men using testosterone supplements (, ). Testosterone is known to exert several effects that may increase cardiac risk. At the same time, the known benefits of testosterone include increased lean body mass, decreased adiposity, and improved insulin sensitivity (). Men with low serum testosterone are known to be at greater risk of all-cause mortality (). Higher rates of cardiac events in men taking testosterone supplement may be due to baseline risk rather than additional risk from supplementation.

Oral therapy with a type 5 phosphodiesterase inhibitor (PDE5I, e.g., sildenafil, vardenafil, tadalafil, and avanafil) is in the most frequently utilized first-line therapy men with ED (). PDE5I block the inactivation of cGMP and result in increased smooth muscle relaxation and penile arterial blood flow. In the absence of sexual stimulation these medications have minimal effect on penile blood flow; this relationship may explain frequent PDE5I “failure” in men not properly counseled on proper use of this class of drugs. Numerous placebo-controlled studies have been conducted on the safety and efficacy of sildenafil since it was approved for clinical use in 1998 () . Sildenafil has been consistently shown to increase the number of erections, penile rigidity, orgasmic function, and overall sexual satisfaction compared to placebo in men with ED of every etiology, including diabetes and radical prostatectomy. Similar data exist for the other drugs in this class.

Most clinical trials of PDE-5 inhibitors show only mild to moderate, self-limited adverse events associated with all of the PDE-5 inhibitors (). The most common complaints in men using PDE-5 inhibitors are headache (16 percent), flushing (10 percent), dyspepsia (7 percent), nasal congestion (4 percent), and visual disturbances/ color sensitivity (3 percent). Tadalafil distinguishes itself from vardenafil and sildenafil by the relative lack of visual side effects. It does however have the possible adverse effect of back pain and/or myalgia ().

PDE5I have an excellent track record of cardiac safety (). To date, tens of millions of men in over 100 countries have used sildenafil. Since the release of the drug, over 200 deaths temporally associated with sildenafil therapy were reported to the Food and Drug Administration in the United States of America. Sexual activity is a likely contributor to myocardial infarction in men with heart disease, with sildenafil acting to enable men not previously active to engage in sexual activity (, ). PDE5I therapy is safe for most men, although men with cardiovascular disease should consult with their cardiologist prior to engaging in sexual activity. The Princeton III guidelines provide recommendations for management of ED in men with cardiovascular disease. Princeton III recommends risk stratification before initiation of therapy; men at low-risk may be treated whereas men with high-risk (e.g., recent MI, unstable angina, NYHA Class III or IV heart failure, unstable arrythmia) should not be treated until their situation stabilizes. Men who do not fall neatly into low- or high-risk categories should undergo cardiac evaluation () .

A lower starting dose (25 mg of sildenafil, 5 mg of vardenafil or tadalafil, 50 mg of avanafil) is recommended in patients who may attain and maintain higher plasma levels of PDE5I. These include patients who are older than 65, have severe renal impairment, or take potent CYP450 3A4 inhibitors. Patients who take ritonavir should not take more than 25 mg of Sildenafil in a 48-hour period. Patients using PDE5I and requiring alpha-blocker therapy for hypertension or benign prostate hyperplasia should start at low doses of PDE5 inhibitor, which can be titrated to affect. To avoid symptomatic hypotension, PDE5 inhibitors should not be taken within 4 hours of an alpha-blocker. One study found a significant rate of hypotension (28% versus 6% with placebo) in patients taking concomitant doxazosin and tadalafil (). The rate of hypotension matched that seen in placebo-treated patients in patients taking tamsulosin and tadalafil, and some studies suggest that the interaction has less clinical relevance in patients who have undergone long-term alpha-blocker therapy. It is likely that all four PDE5I commercially available in the US interact to some degree with alpha-blockers and that concurrent use of alpha-blockers and PDE5I may cause patients to develop orthostatic hypotension. Other antihypertensive agents appear to be well tolerated by men concurrently taking PDE5I.

PDE5I have been associated with spontaneous non-arteritic ischemic optic neuropathy (NAION), the most common acute optic neuropathy. Estimated annual incidence is 2.3 to 10.3 per 100,000 and is more common in Caucasians than African Americans, Asians, or Latinx persons. Most NAION patients do not become legally blind, but the degree of visual acuity and visual field loss is typically significant. Risk factors common to NAION and ED include hypertension, diabetes mellitus, hypercholesterolemia, age over 50 years, coronary artery disease, and smoking (). A large review of ophthalmology records in the United States and Europe reported a very slight but statistically significant relationship between NAION and PDE5I use within the last 30 days. The authors concluded that use of PDE5I may be associated with an increase of approximately three NAION cases per 100,000 men over the age of 50 (, ). Men using PDE5I should be counseled to stop treatment and contact their physician immediately should visual changes or loss occur. Men with a history of NAION should not use PDE5 inhibitors ().

PDE5I have also been implicated in several cases of hearing loss. Several dozen cases of PDE5 inhibitor associated hearing loss have been reported and some research has indicated mechanisms by which hearing loss may be attributable to action of these drugs (, ). Men who experience hearing impairment while using PDE5 inhibitors should halt treatment until they are able to speak with their doctors regarding long-term risk of hearing loss.

Sildenafil (Viagra®, Pfizer) works best when taken on an empty stomach (especially avoiding high lipid foods) and reaches maximum plasma concentrations within 30 to 120 minutes (mean 60 minutes). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about 4 hours. The recommended starting dose is 50 mg taken one hour before sexual activity. The maximal recommended frequency is once per day. The efficacy of sildenafil has been extensively studied in patients with other coexisting diseases (). No significant difference in response rate was noted comparing a normal cohort of patients with patients with hypertension (), spinal cord injury (), depression (), and the elderly (). Patients with a neurogenic etiology for ED (e.g., radical prostatectomy, diabetes) have a lower response rate to sildenafil compared to patients without a neurogenic cause; the drug is still effective for many of these men, however (, ) ().

Vardenafil (Levitra® and Staxyn®, Bayer/GSK) is a potent and highly selective PDE5I. Its chemical structure is quite similar to sildenafil however in in vitro studies the selectivity and potency of vardenafil are superior. The medication can be given in either 10 or 20 mg oral dosage (Levitra®) or a 10 mg sublingual dissolving lozenge (Staxyn®). The time to peak plasma concentration is 40-55 minutes. Vardenafil has been shown to be highly efficacious in a wide range of clinical indications (, ). In one multicenter phase III trial patients with diabetes (type I and II) were found to respond to 20 mg dosage of vardenafil significantly better than a similar control group. The effect also seemed to improve after 12 weeks of treatment () . Although similar in chemical structure, the in vitro potency and selectivity of vardenafil are superior to that of sildenafil. Evidence that these in vitro effects translate to superior results in vivo are lacking.