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This article focuses on the evaluation and treatment of erectile dysfunction. The penis contains three cylinders, the two corpora cavernosa, which are on the top of the penis (see figure 1 below). The third cylinder contains the urethra, the tube that the urine and ejaculate passes through, runs along the underside of the penis.

Spongy tissue that has muscles, fibrous tissues, veins, and arteries within it makes up the corpora cavernosa.

The inside of the corpora cavernosa is like a sponge, with potential spaces that can fill with blood and distend (known as sinusoids).

A layer of tissue that is like Saran Wrap, called the tunica albuginea, surrounds the corpora. Veins located just under the tunica albuginea drain blood out of the penis. Erectile dysfunction (ED, impotence) varies in severity; some cannot have an erection at all, whereas other men sometimes have troubles getting a hard erection, and others get a hard erection but it only lasts for a short period of time.

Approximately 50% of men over the age of 40 have troubles with erectile dysfunction.

While erectile dysfunction can occur at any age, the risk of developing erectile dysfunction increases with age.

According to the Massachusetts Male Aging Study, the prevalence of erectile dysfunction was 52% in men 40-70 years of age.

The prevalence of complete erectile dysfunction increases from 5% at 40 years of age to 15% among men 70 years of age and older.

Erections are neurovascular events, meaning that nerves and blood vessels (arteries and veins) are involved in the process of an erection and all must work properly to develop a hard erection that lasts long enough.

Sexual stimulation can be tactile (for example, by a partner touching the penis or by masturbation) or mental (for example, by having sexual fantasies, viewing porn).

Sexual stimulation or sexual arousal causes the nerves going to the penis to release a chemical, nitric oxide.

Nitric oxide increases the production of another chemical, cyclic GMP (cGMP), in the muscle of the corpora cavernosa.

The cGMP causes the muscles of the corpora cavernosa to relax, and this allows more blood to flow into the penis. The incoming blood fills the corpora cavernosa, making the penis expand.

As blood flows into the penis, the corpora cavernosa swell, and this swelling compresses the veins (blood vessels that drain the blood out of the penis) against the tunica albuginea.

Compression of the veins prevents blood from leaving the penis.

When the amount of cGMP decreases by the action of a chemical called phosphodiesterase type 5 (PDE5), the muscles in the penis tighten, and the blood flow into the penis decreases.

With less blood coming into the penis, the veins are not compressed, allowing blood to drain out of the penis, and the erection goes down.

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The ability to achieve and sustain erections requires the following: A healthy nervous system that conducts nerve impulses in the brain, spinal column, and penis Healthy arteries in and near the corpora cavernosa that when stimulated can bring increased blood flow into the penis Healthy muscles and fibrous tissues within the corpora cavernosa, which can distend to allow the penis to fill with blood Adequate levels of nitric oxide in the penis Normal-functioning tunica albuginea that allows for compression of the veins Appropriate psychosocial interactions. Erectile dysfunction can occur if a man doesn't meet one or more of these requirements.

The following are causes of erectile dysfunction, and many men have more than one potential cause: Aging : There are two reasons why older men are more likely to experience erectile dysfunction than younger men.

First, older men are more likely to develop diseases (such as heart attacks, angina, cardiovascular disease, strokes, diabetes mellitus, and high blood pressure) that are associated with erectile dysfunction.

Second, the aging process alone can cause erectile dysfunction in some men by causing changes in the muscle and tissue within the penis.

Diabetes mellitus : Erectile dysfunction tends to develop 10 to 15 years earlier in diabetic men than among nondiabetic men.

The increased risk of erectile dysfunction among men with diabetes mellitus may be due to the earlier onset and greater severity of atherosclerosis (hardening of the arteries) that narrows the arteries and thereby reduces the delivery of blood to the penis. Atherosclerosis can affect the arteries in the penis, as well as the arteries in the pelvis that supply the penile arteries. Diabetes mellitus also causes erectile dysfunction by damaging nerves that go to the penis, much like the effect of diabetes on nerves in other areas of the body (diabetic neuropathy).

Diabetes can also affect the muscles in the penis, leading to troubles with erections. Smoking cigarettes, obesity, poor control of blood glucose levels, and having diabetes mellitus for a long time further increase the risk of erectile dysfunction in people with diabetes. Hypertension (high blood pressure) : Men with high blood pressure have an increased risk of developing erectile dysfunction. Hypertension can cause troubles with erections related to atherosclerosis or from low levels of nitric oxide production from the arteries in the penis. Medications to treat hypertension may cause erectile dysfunction.

Cardiovascular diseases : The most common cause of cardiovascular diseases in the United States is atherosclerosis, the narrowing and hardening of arteries that reduces blood flow. Atherosclerosis (a type of vascular disease) typically affects arteries throughout the body; hypertension, high blood cholesterol levels, cigarette smoking, and diabetes mellitus aggravate atherosclerosis. Hardening of the arteries to the penis and pelvic organs, atherosclerosis, causes insufficient blood flow into the penis. There is a close correlation between the severity of atherosclerosis in the coronary arteries and erectile dysfunction. For example, men with more severe coronary artery atherosclerosis (hardening of the arteries in the heart) also tend to have more erectile dysfunction than men with mild or no coronary artery atherosclerosis.

Some doctors suggest that men with new onset erectile dysfunction undergo evaluation for silent coronary artery diseases (advanced coronary artery atherosclerosis that has not yet caused angina or heart attacks).

Metabolic syndrome is associated with multiple risk factors for erectile dysfunction including diabetes, abnormal lipid profile, hypertension, and obesity.

Cigarette smoking : Cigarettesmoking aggravates atherosclerosis and can cause vasospasm (spasms of the arteries) and thereby increases the risk for erectile dysfunction.

Nerve or spinal cord damage : Damage to the spinal cord and nerves in the pelvis can cause erectile dysfunction. Nerve damage can be due to disease, trauma, or surgical procedures.

Examples include injury to the spinal cord from automobile accidents, injury to the pelvic nerves from prostate surgery for

cancer

BPH : Benign enlargement of the prostate is associated with erectile dysfunction. Trauma : Trauma to the pelvis, including pelvic fracture, may cause erectile dysfunction, and an untreated penile fracture may result in erectile dysfunction.

Substance abuse : Marijuana, heroin, cocaine, methamphetamines, crystal meth, and narcotic and alcohol abuse contribute to erectile dysfunction. Alcoholism, in addition to causing nerve damage, can lead to atrophy (shrinking) of the testicles and lower testosterone levels.

Low testosterone levels : Testosterone (the primary sex hormone in men) is not only necessary for sex drive (libido) but also is necessary to maintain nitric oxide levels in the penis. Therefore, men with hypogonadism (low testosterone with symptoms) can have low sex drive and erectile dysfunction. Medications : Many common medicines produce erectile dysfunction as a side effect.

Medicines that can cause erectile dysfunction include many used to treat high blood pressure, antihistamines, antidepressants, tranquilizers, and appetite suppressants.

Examples of common medicines that can cause erectile dysfunction include propranolol (Inderal) or other beta-blockers, hydrochlorothiazide, digoxin (Lanoxin), amitriptyline (Elavil), famotidine (Pepcid), cimetidine (Tagamet), metoclopramide (Reglan), naproxen, indomethacin (Indocin), lithium (Eskalith, Lithobid), verapamil (Calan, Verelan, Isoptin), phenytoin (Dilantin), gemfibrozil (Lopid), amphetamine/dextroamphetamine (Adderall), and phentermine. Prostate cancer medications that lower testosterone levels such as leuprolide (Lupron) may affect erectile function. Some chemotherapies such as cyclophosphamide (Cytoxan) may affect erectile function.

Recreational drugs : Recreational drugs, including alcohol, amphetamines, barbiturates, marijuana, nicotine, heroin and cocaine, are associated with erectile dysfunction.

Depression and anxiety : Psychological factors may be responsible for erectile dysfunction. These factors include stress, anxiety, guilt, depression, widower syndrome, low self-esteem, posttraumatic stress disorder, and fear of sexual failure (performance anxiety). It is also worth noting that many medications used for treatment of depression and other psychiatric disorders may cause erectile dysfunction or ejaculatory problems. The common risk factors for ED include the following: Advanced age Cardiovascular disease Hypertension Diabetes mellitus High cholesterol Cigarette smoking Recreational drug use Depression or other psychiatric disorders Pelvic surgery, including radical prostatectomy and colorectal surgery Pelvic radiation, such as for prostate cancer and some colorectal cancers Trauma to the pelvis (pelvic fracture), penis (penile fracture), and perineum.

Signs and symptoms of erectile dysfunction may include the following: Penile erection occurs, but the penis does not remain hard enough for completion of sex. Penile erections are not hard enough for penetration.

One can still achieve an orgasm and ejaculate with erectile dysfunction.

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How

Your doctor will try to get information to answer the following questions: Is the patient suffering from erectile dysfunction or from some other form of sexual dysfunction such as loss of libido or a disorder of ejaculation (for example, premature ejaculation) or orgasm, or problems with penile curvature/pain (Peyronie's disease)?

Is your erectile dysfunction due to psychological (stress, relationship problems, etc.) or physical factors?

Your doctor may ask if you note erections at night or in the early morning.

Men have involuntary erections in the early morning and during REM sleep (a stage in the sleep cycle with rapid eye movements). Men with psychogenic erectile dysfunction (erectile dysfunction due to psychological factors such as stress and anxiety rather than physical factors) usually maintain these involuntary erections.

Men with physical causes of erectile dysfunction (for example, atherosclerosis, smoking, and diabetes) usually do not have these involuntary erections.

Men with psychogenic erectile dysfunction may relate the onset of problems to a "stressor," such as failed relationship.

Your doctor may suggest a test to determine if you have erections during sleep, which may suggest that there may be a psychological cause of the erectile dysfunction. Erectile dysfunction may be a symptom of underlying medical conditions, which if not detected may cause further medical problems. A prior history of cigarette smoking, heart attacks, strokes, and poor circulation in the extremities (for example, intermittent claudication or cramping in your leg[s] when you walk) suggest atherosclerosis as the cause of the erectile dysfunction. Loss of sexual desire and drive, lack of sexual fantasies, gynecomastia (enlargement of breasts), and diminished facial hair suggest low testosterone levels.

A prior history of pelvic surgery or radiation and trauma to the penis/pelvis/perineum can cause problems with the nerves and blood vessels.

Symptoms of intermittent claudication of the lower extremities with exercise may suggest a vascular problem as a cause of the erectile dysfunction.

Is the patient taking medications that can contribute to erectile dysfunction (see causes above), including prescribed, over-the-counter, or recreational drugs?

It is important to discuss your prescribed medications, as well as over-the-counter medications and drugs of abuse such as opiates, alcohol, etc. The physical examination can reveal clues for physical causes of erectile dysfunction. A doctor will perform an assessment of BMI and waist circumference to evaluate for abdominal obesity. A genital examination is part of the evaluation of erectile dysfunction. The examination will focus on the penis and testes. The doctor will ask you about penile curvature and will examine the penis to see if there are any plaques (hard areas) palpable. The doctor will examine the testes to make sure they are in the proper location in the scrotum and are normal in size. Small testicles, lack of facial hair, and enlarged breasts (gynecomastia) can point to hormonal problems such as hypogonadism with low testosterone levels. A health care provider may check pulses in your groin and feet to determine if there is a suggestion of hardening of the arteries that could also affect the arteries to the penis.

The lab testing obtained for the evaluation of erectile dysfunction may vary with the information obtained on the health history, physical examination, and recent lab testing.

A testosterone level is not necessary in all men; however, a physician will order labs to determine a patient's testosterone level if other signs and symptoms of hypogonadism (low testosterone) such as decreased libido, loss of body hair, muscle loss, breast enlargement, osteoporosis, infertility, and decreased penile/testicular size are present. A doctor may ask for the following laboratory tests in the evaluation of erectile dysfunction: Complete blood counts Urinalysis : A high level of sugar (glucose) in the urine may be a

sign

Blood glucose levels : Abnormally high blood glucose (sugar) levels may be a sign of diabetes mellitus.

Blood hemoglobin A1C : Abnormally high levels of blood hemoglobin A1C in patients with diabetes mellitus indicate that there is poor control of blood glucose levels. Serum creatinine : An abnormal serum creatinine, a chemical that reflects kidney function, may be the result of kidney damage.

Liver enzymes and liver function tests : Liver disease (cirrhosis) can cause low testosterone.

Thus, a physician may need to test some men for liver disease. Total testosterone levels : Health care professionals should obtain a patient's blood samples for total testosterone levels in the early morning (before 8 a.m.) because the testosterone levels go up and down throughout the day.

If you have a low testosterone level, a health care professional should check it again to confirm that it is truly low. In some men, a specialized test measuring the active form of testosterone (free or bioavailable testosterone) may be recommended. Other hormone levels : Measurement of other hormones beside testosterone (luteinizing hormone [LH], prolactin level, and cortisol level) may provide clues to other underlying causes of testosterone deficiency and erectile problems, such as pituitary disease or adrenal gland abnormalities.

Doctors may check thyroid levels in some individuals as both hypothyroidism (low thyroid function) and hyperthyroidism (overactive thyroid function) can contribute to erectile dysfunction.

PSA levels : PSA (prostate specific antigen) blood levels and prostate examination to exclude prostate cancer is important before starting testosterone treatment since testosterone can aggravate prostate cancer.

Other blood tests : Evaluation for hemochromatosis, lupus, scleroderma, zinc deficiency, sickle cell anemia, and cancers (leukemia, colon cancer) are some of the other potential tests that a physician may perform based on each individual's health history and symptoms.

Health care professionals do not routinely obtain imaging tests in the evaluation of erectile dysfunction. Ultrasound with Doppler imaging (ultrasound plus evaluation of blood flow in the arteries and veins) can provide additional information about blood flow of the penis and may help in the evaluation of patients prior to surgical intervention. This study is typically performed after the injection of a chemical that causes the arteries to open up, a vasodilator (prostaglandin E1), into the corpora cavernosa in order to cause dilation of blood vessels and promote blood flow into the penis.

The rate of blood flow into the penis can be measured along with an evaluation of problems with compression of the veins. Rarely, a doctor may perform an angiogram (injecting a dye into the arteries that supply the penis and taking X-rays to look for areas of narrowing of the arteries) in cases in which possible vascular surgery could be beneficial.

Monitoring erections that occur during sleep (nocturnal penile tumescence) can help you and your doctor to understand if the erectile dysfunction is due to psychological or physical causes. The nocturnal penile tumescence test is a study to evaluate erections at night.

Normally men have three to five erections per eight hours of sleep.

The test can be performed at home or in a sleep lab. The most accurate way to perform the test involves a special device that is connected to two rings. The rings are placed around the penis, one at the tip of the penis and the other at the bottom (base) of the penis.

The device records how many erections occur, how long they last, and how rigid they are. The test is limited in that it does not assess the ability to penetrate.

If there seems to be a psychological cause contributing to your erectile dysfunction, the doctor may ask the patient questions to help determine stressor, events, and relationship issues that may be causing your erectile troubles. It may be helpful to have your sexual partner involved in this assessment. Novel therapies are promising but face questions about patient selection and efficacy.

Erectile dysfunction is a common concern among aging males. Not only does ED affect quality of life, but it is also linked to cardiovascular disease, hypertension, diabetes, and overall health. Currently, there are three categories of ED treatments. Oral medications such as phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil, vardenafil, tadalafil, and avanafil) have comparable efficacy. Intracavernosal injections (alprostadil, phentolamine, papaverine, and/or atropine) or intraurethral suppositories (alprostadil) are alternatives in patients who are non-responders to oral medications or have side effects.

Penile implants are the most invasive treatment but provide durable results and the highest satisfaction rates of all of treatments.

Given the prevalence of ED, there is significant incentive to find more effective and less invasive treatment options. Here we review new and emerging treatment options for this common condition.

We also review the use of nutraceuticals, which are not new but have seen explosive growth in recent years (see, “Nutraceuticals for ED at a glance.") New oral agents and pathways. PDE-5 inhibitors remain the cornerstone of oral therapies.

Researchers have explored alternative pathways for novel therapeutics (table), although success has been limited. Currently, no novel oral medications are in clinical development.

Prior targets have focused on central pathways (dopaminergic and melanocortin) and peripheral pathways (guanylyl cyclase and Rho-A/Rho kinase), but novel oral therapies directed at these pathways have shown limited efficacy and tolerability.

An overview of the cellular pathways is shown in the figure. Initially, the use of dopamine agonists for Parkinson’s disease was associated with increased libido. Apomorphine is a dopamine D1 and D2 receptor agonist that was approved for ED in Europe in 2001.

In a phase III double-blind, parallel-arm, crossover study of nearly 900 men with ED, more than 50% of those using apomorphine were able to obtain an erection sufficient for intercourse compared to 33% of men using placebo viagra without a doctor prescription paypal (BJU Int 2002; 89:409-15).

However, the FDA did not approve the drug in the United States because of concerns about hypotension.