All NOS subtypes produce NO, but each may play a different biologic role in various tissues. nNOS and eNOS are considered constitutive forms because they share biochemical features: They are calcium-dependent, they require calmodulin and reduced nicotinamide adenine dinucleotide phosphate for catalytic activity, and they are competitively inhibited by arginine derivatives. nNOS is involved in the regulation of neurotransmission, and eNOS is involved in the regulation of blood flow.
When we say it’s a barometer of men’s health, it’s a signal. It’s an indicator that things may be right or not. And so when a man develops an erectile problem– and we’re talking about something that is occurring over time. It’s not something that just occurred overnight. When it occurs overnight, it’s more often than not a psychogenic, an anxiety reaction.
Circulatory problems: An erection occurs when the penis fills with blood and a valve at the base of the penis traps it. Diabetes, high blood pressure, cholesterol, clots, and atherosclerosis (hardening of the arteries) can all interfere with this process. Such circulatory problems are the number one cause of erectile dysfunction. Frequently, erectile dysfunction is the first noticeable symptom of cardiovascular disease.
The availability of phosphodiesterase-5 (PDE5) inhibitors—sildenafil, vardenafil, tadalafil, and avanafil—has fundamentally altered the medical management of ED. In addition, direct-to-consumer marketing of these agents over the last 15 years has increased the general public’s awareness of ED as a medical condition with underlying causes and effective treatments.
The severity of ED has been correlated with the extent of CVD. Banks et al reported that the risk of future CV events increased progressively according to ED severity.28 This was shown in both men with and without known CVD at baseline and after controlling for confounders. Solomon and colleagues found an inverse correlation between international index of erectile function (IIEF) scores and plaque burden seen on coronary angiography.29 In addition, Yaman et al demonstrated a significant correlation between ED severity on IIEF questionnaires and coronary artery calcification.30
ED means no erections from masturbation. According to the American Urological Association, ED is “the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.” Huh? That’s absurdly vague. If you define “an erection” as what you see in porn, and “satisfactory sexual performance” as porn sex—instant, hard-as-rock erections that last forever with climaxes always on cue—then just about every guy has ED. What is ED, really? For practical purposes, it means that a man who’s sober (no alcohol or other erection-impairing drugs) cannot raise even a semi-firm erection after extended masturbation.

In patients with low testosterone, testosterone treatment can improve libido and erectile dysfunction, but many men still may need additional oral medications such as sildenafil, vardenafil, or tadalafil. Some studies suggest that men with ED and low testosterone may respond better to PDE5 inhibitors when given testosterone therapy; however, this is controversial.
If PDE-5 inhibitors are not suitable or don’t work, other therapies include injections into the base of the penis, which cause flow of blood into the penis and a fairly immediate erection that lasts around an hour. The drugs injected are alprostadil (Caverject and Erectile dysfunctionex) and Invicorp (VIP and phentolamine). Alprostadil may also be inserted as a gel into the opening of the penis. This is not suitable if your partner is pregnant.
The Massachusetts Male Aging Study (MMAS) documented an inverse correlation between ED risk and high-density lipoprotein (HDL) cholesterol levels but did not identify any effect from elevated total cholesterol levels. [15] Another study involving male subjects aged 45-54 years found a correlation with abnormal HDL cholesterol levels but also found a correlation with elevated total cholesterol levels. The MMAS included a preponderance of older men.
However, men are affected psychologically when it comes to achieving erections. For instance, if a man is with a woman for the first time, or even before he feels comfortable with her, he may suffer from performance anxiety. In such a situation, his mind and body are both saying yes, but then they become out of sync. The body is then saying yes, but the mind is filled with question. “Will I be able to perform?” “How long will I last?” “Am I big enough to satisfy her?” “Is she looking at that mole on my stomach?” All kinds of questions may be going through a man’s mind upon getting in bed, and these can be distracting, they can lead to self-doubt, and therefore, failure to achieve or maintain an erection.

PDE5 inhibitors, the primary second-line therapy, have been the mainstay of ED treatment since the release of sildenafil (Viagra) in 1998, with the subsequent development of many others, and still more in the development stage. These medications do improve erectile quality for the majority of men, and they work by enhancing blood flow in the corpora cavernosa. These medications are generally used on demand and need to be taken about an hour before sexual intimacy. Tadalafil (Cialis) is longer acting and does come in a daily preparation potentially eliminating the ‘on-demand’ need. The daily dosing of tadalafil, 2.5–5 mg\day, has also been approved by the FDA for treatment of symptoms of BPH.41 PDE5 inhibitors are contraindicated in men taking nitrates, but otherwise PDE5 inhibitors are very safe and effective. When PDE5 inhibitors are coadministered with nitrates, pronounced systemic vasodilation and severe hypotension are possible. Many patients with ED are elderly and have the same risk factors as patients with CAD, so these drug combinations are commonly considered or encountered in clinical practice.42


Modern drug therapy for ED made a significant advance in 1983, when British physiologist Giles Brindley dropped his trousers and demonstrated to a shocked Urodynamics Society audience his papaverine-induced erection.[32] The drug Brindley injected into his penis was a non-specific vasodilator, an alpha-blocking agent, and the mechanism of action was clearly corporal smooth muscle relaxation. The effect that Brindley discovered established the fundamentals for the later development of specific, safe, and orally effective drug therapies.[33][better source needed][34][better source needed]
The FDA does not recommend alternative therapies to treat sexual dysfunction.[24] Many products are advertised as "herbal viagra" or "natural" sexual enhancement products, but no clinical trials or scientific studies support the effectiveness of these products for the treatment of erectile dysfunction, and synthetic chemical compounds similar to sildenafil have been found as adulterants in many of these products.[25][26][27][28][29] The United States Food and Drug Administration has warned consumers that any sexual enhancement product that claims to work as well as prescription products is likely to contain such a contaminant.[30]

It is normal for a man to have five to six erections during sleep, especially during rapid eye movement (REM). Their absence may indicate a problem with nerve function or blood supply in the penis. There are two methods for measuring changes in penile rigidity and circumference during nocturnal erection: snap gauge and strain gauge. A significant proportion of men who have no sexual dysfunction nonetheless do not have regular nocturnal erections.
The common PDE5 inhibitor drugs approved in the United States are sildenafil (Viagra), vardenafil (Levitra and Staxyn, the generic form), tadalafil (Cialis), or avanafil (Stendra). All of the currently approved PDE5 inhibitors work in the same way. They differ in the number of available doses, how quickly they work and last in your system, the dosing, and to some extent in the side effects. However, they generally share the same indications and contraindications. Currently, tadalafil is the only medication that patients can take on a daily basis and is approved for the treatment of both ED and BPH (benign enlargement of the prostate).
When pills don’t work, an ED implant offers hope. Penile implants are custom-fitted devices that are surgically implanted to allow you to obtain an erection when desired. They are undetectable to the naked eye, so no one will know you have one unless you tell them. The Titan® penile implant from Coloplast produces a totally natural, controlled and spontaneous erection that will restore your confidence, relationships and pleasure.
Although not indicated for routine use, nocturnal penile tumescence (NPT) testing may be useful in the patient who reports a complete absence of erections (exclusive of nocturnal "sleep" erections) or when a primary psychogenic etiology is suspected. Such testing should be performed by those with expertise and knowledge of its interpretation, pitfalls, and usefulness. Various methods and devices are available for the evaluation of nocturnal penile tumescence, but their clinical usefulness is restricted by limitations of diagnostic accuracy and availability of normative data. Further study regarding standardization of NPT testing and its general applicability is indicated.
One study examined the role of testosterone supplementation in hypogonadal men with ED. These men were considered nonresponders to sildenafil, and their erections were monitored by assessing nocturnal penile tumescence (NPT). After these men were given testosterone transdermally for 6 months, the number of NPTs increased, as did the maximum rigidity with sildenafil. [18] This study suggests that a certain level of testosterone may be necessary for PDE5 inhibitors to function properly.
Psychotherapy and/or behavioral therapy may be useful for some patients with erectile dysfunction without obvious organic cause, and for their partners. These may also be used as an adjunct to other therapies directed at the treatment of organic erectile dysfunction. Outcome data from such therapy, however, have not been well-documented or quantified, and additional studies along these lines are indicated.
Trauma to the pelvic blood vessels or nerves can also lead result in ED. Bicycle riding for long periods has been implicated as an etiologic factor; direct compression of the perineum by the bicycle seat may cause vascular and nerve injury. [37] On the other hand, bicycling for less than 3 hours per week may be somewhat protective against ED. [37] Some of the newer bicycle seats have been designed to diminish pressure on the perineum. [37, 38]

Cosgrove et al reported a higher rate of sexual dysfunction in veterans with posttraumatic stress disorder (PTSD) than in veterans who did not develop this problem. [42] The domains on the International Index of Erectile Function (IIEF) questionnaire that demonstrated the most change included overall sexual satisfaction and erectile function. [43, 44] Men with PTSD should be evaluated and treated if they have sexual dysfunction.

Several pathways have been described to explain how information travels from the hypothalamus to the sacral autonomic centers. One pathway travels from the dorsomedial hypothalamus through the dorsal and central gray matter, descends to the locus ceruleus, and projects ventrally in the mesencephalic reticular formation. Input from the brain is conveyed through the dorsal spinal columns to the thoracolumbar and sacral autonomic nuclei.
This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. The NIDDK translates and disseminates research findings through its clearinghouses and education programs to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by the NIDDK is carefully reviewed by NIDDK scientists and other experts.
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