Medications used to treat erectile dysfunction, such as sildenafil (Viagra®), vardenafil (Levitra®), and tadalafil (Cialis®), improve erectile function by inhibiting the PDE5 enzyme, allowing an erection to persist. These medications provide only temporary benefits and may cause minor to severe side effects such as headache, indigestion and visual disturbances. However, approximately one-third of men with erectile dysfunction do not respond to PDE5 inhibitors; Men whose erectile dysfunction is not improved by PDE5 inhibitors may have low testosterone levels.
Erectile dysfunction is the inability to achieve or sustain a penile erection sufficient for satisfactory male sexual performance. The condition affects up to 30 million American men, and is typically age-dependent. Erectile dysfunction can cause substantial emotional distress by negatively impacting intimate relationships, self-esteem, and overall quality of life.
The underlying physiology of erectile function is tied very closely to cardiovascular health. Therefore, men who wish to perform at their sexual peak must take steps to optimize their blood vessel health.
An erection is triggered by a complex interplay between the sympathetic and parasympathetic nervous system, with local sensory stimulation of the genital area and/ or central psychogenic stimulation resulting from visual, tactile, auditory, olfactory, and/or imaginative input. The endothelial cells that line the blood vessels of the penis produce vasoactive factors that dilate blood vessels, one of the most important being nitric oxide. Nitric oxide, by initiating production of another chemical messenger called cyclic guanosine monophosphate (cGMP), triggers a biochemical cascade leading to expansion (vasodilatation) of penile blood vessels and allows for increased blood flow into the corpus cavernosum, the two columns of spongy tissue that run along the top length of the penis. As the corpus cavernosum fills with blood it stretches, compressing the primary site where blood exits the penis, called the subtunical venules. This compression causes resistance to blood flow out of the penis, producing and maintaining an erection
TREATMENT OF ERECTILE DYSFUNCTION
Testosterone restoration can lead to improved erectile function and libido in men with low androgen levels. When PDE5 inhibitors fail, the addition of testosterone therapy is associated with substantial improvement in erectile function among men with low testosterone and may eliminate the need for PDE5 inhibitors altogether.
Dehydroepiandrosterone (DHEA) is a precursor to testosterone. As with testosterone, aging is associated with decreased levels of DHEA. Circulating levels of DHEA can decline by up to 80% from age 25 to 80. Low DHEA levels have been linked to erectile dysfunction. Studies have shown that oral DHEA supplementation may improve sexual performance, as measured by erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction in some men. An optimal target blood level for DHEA-sulfate of 350 – 490 µg/dL
Physicians versed in male hormone restoration know that exogenous administration of testosterone may increase estrogen (estradiol) levels in aging men, in particular aging men with significant amounts of visceral fat. The conversion of testosterone into estrogen is called aromatization and is mediated by an enzyme called aromatase. Aromatase inhibitors (eg, anastrozole [Arimidex®]) are drugs that inhibit the activity of the aromatase enzyme, thereby reducing the amount of testosterone converted into estradiol.
When used concurrently with testosterone supplementation, aromatase inhibitors allow testosterone levels to rise without being converted into excess estrogen. Reports suggest that aromatase inhibitor therapy can improve sexual function in men.
Maintaining healthy testosterone/estrogen balance has other important implications for aging males. For example, in a study among men with heart failure, both low and high estradiol levels were associated with significantly increased chances of death compared to “balanced” levels Although PDE5 inhibitors are generally well tolerated, they can cause a number of side effects including headache, indigestion, visual disturbances, priapism (ie, painful, prolonged erection lasting more than 6 hours), and even blindness. Furthermore, the use of PDE5 inhibitors is limited in some men by contraindications such as cardiovascular disease. These drugs can also interact with other medications (eg, nitrates) and cause negative reactions. PDE5 inhibitors only improve erectile function, not overall sexual function.
In men who are not good candidates for or do not respond well to PDE5 inhibitors, intracavernosal vasodilating medications are a second-line treatment option. These treatments are delivered via self-injection into the cavernosum. Adverse effects may include pain, prolonged erection, and fibrosis. Alprostadil is synthetic prostaglandin E1, which is a biochemical signaling molecule with vasodilatory properties. Studies show alprostadil to be effective in about 70% of men with erectile dysfunction. Alprostadil can now be delivered via topical cream as well, which has demonstrated a success rate similar to injectable forms. Papaverine, a compound derived from the poppy plant, nonspecifically inhibits phosphodiesterase enzymes and modulates calcium signaling. It does not possess opiate properties like some other poppy derivatives such as morphine. Studies suggest a patient satisfaction rate of about 44%. Papaverine use may increase liver function tests with the potential for hepatotoxicity. Phentolamine blocks alpha-1 and -2 adrenergic receptors. This helps facilitate erection by impairing muscle constriction. Phentolamine alone is not sufficient to trigger and sustain rigid erection, so it is used in combination with other intracavernosal agents for an additive effect. Because phentolamine is expensive and needs to be refrigerated, it may be less convenient. Another alternative is utilizing a vacuum device (VED) to artificially increase penile blood flow. These devices consist of plastic cylinders that are placed over the penis and vacuumed by a pump to negative pressure to allow cavernosal expansion and erection. Constriction rings are then placed at the base of the penis to retain blood. Vacuum erection devices provide a relatively safe and efficacious alternative for those unresponsive to or unable to take oral medications. Disadvantages include lack of penile stability, which may interfere with sexual performance, and inhibited ejaculation.
L-arginine supplementation is an essential amino acid with numerous metabolic actions. It plays a significant role in erectile function by contributing to the formation of the vasodilator nitric oxide. Supplementation with L-arginine has been shown to restore erectile quality and increase sexual satisfaction by boosting nitric oxide bioactivity and improving penile blood flow. The efficacy of L-arginine, combined with Pycnogenol, a bioactive compound derived from French maritime bark with vasodilatory properties, has been tested and been shown to improve male sexual function. This combination is called Prelox. L-arginine supplementation has also been shown to attenuate endothelial dysfunction associated with high cholesterol and coronary heart disease. Since endothelial dysfunction diminishes the effects of PDE-5 inhibitors, L-arginine supplementation may be a useful add-on therapy for men who do not respond to these drugs.
Epimedium is a genus of over 50 distinct species of plants. It is colloquially referred to as horny goat weed because it was observed that goats who ate it subsequently engaged in intense sexual activity. Epimedium has been used in traditional Chinese medicine for centuries as a natural aphrodisiac and for the treatment of erectile dysfunction. Research has shown that icariin, a bioactive component derived from the aerial portion of the Epimedium plant, improves erectile and sexual function when administered orally. Laboratory data show that icariin can inhibit PDE5, improve penile blood flow, and support endothelial integrity. Icariin also has testosterone-like properties and is associated with increased intracavernosal pressure and nitric oxide levels.
Yohimbine, a compound derived from the bark of the Yohimbe tree, has been utilized in the treatment of erectile dysfunction for over 70 years. Yohimbine’s mechanism of action is thought to be its ability to enhance smooth muscle relaxation, thereby promoting penile erection. It is thought to accomplish this by blocking the effects of neurotransmitter receptors called alpha-2 adrenergic receptors, which promote smooth muscle contraction when activated. Clinical studies of yohimbine, alone or in combination with L-arginine, have shown improved erectile function. In one clinical trial, yohimbine was effective for up to 84% of male volunteers, depending on the type of erectile dysfunction. Compared to placebo, yohimbine was more effective at improving self-reported sexual function and penile rigidity. Another study found that yohimbine improved erectile function in 42% of men with erectile dysfunction, compared to 27% of subjects taking placebo. Additionally, yohimbine may be particularly effective among type 2 diabetics and those with non-biological causes of erectile dysfunction. Yohimbine may cause some side effects including heart palpitations, anxiety, fine tremor, and high blood pressure. These occur infrequently and are usually reversible.
Ginseng belongs to the genus Panax, which is a group of slow-growing perennial plants with distinctively fleshy roots. Five thousand years after it was first used for the treatment of erectile dysfunction in ancient China, ginseng continues to be a popular natural aphrodisiac. An estimated 6 million Americans have used ginseng for the improvement of sexual dysfunction. Ginsenosides, the principle active constituents in ginseng, have cardio-protective, immune-stimulatory, anti-fatigue, hepato-protective, and antioxidant effects. In addition, they also increase the synthesis of nitric oxide. In animal studies, ginsenosides have been shown to relax penile smooth muscle tissue (through the release of nitric oxide) and potentially affect chemical pathways involving cGMP and testosterone. A 2009 clinical study showed that 1000 mg of Panax ginseng twice daily improved erectile function and overall sexual satisfaction among men with erectile dysfunction. The study also found that ginseng potentially increased testosterone levels. The authors concluded that ginseng could be effective for improving erectile function regardless of age and severity of dysfunction. Another study showed that ginseng significantly improved penile rigidity, libido, and satisfaction among men with erectile dysfunction.
Maca (Lepidium meyenii) is a root vegetable belonging to the mustard (ie, Brassica) family. Ancient Peruvians have cultivated maca for millennia and taken advantage of its aphrodisiac properties. The dried root of the maca plant is a rich source of amino acids, iodine, iron, and magnesium. Scientific studies support the aphrodisiac activity of maca, and show that it stimulates metabolism, helps control body weight, increases energy, improves memory, and reduces stress and depression. It also shows androgen-like effects in animals. Human clinical studies suggest that maca enhances the production of sex hormones, increases libido, and improves well-being. The aphrodisiac activity of maca may be due to local effects on erectile function and/or central nervous system effects.
Extracts of leaves from the Ginkgo biloba tree have been used for centuries in the treatment of asthma, fatigue, circulatory problems, and vertigo. It has more recently been associated with enhanced sexual desire, excitement, orgasm, and resolution, as well as neuroprotective properties. The sexual benefits of ginkgo were discovered serendipitously when male geriatric patients taking Ginkgo biloba for memory enhancement reported improved erections. In addition to experimental data showing that Ginkgo biloba can enhance sexual behavior in rats, clinical studies have revealed it can increase penile blood supply and improve erectile function in humans. Ginkgo contributes to increased blood flow by increasing nitric oxide bioavailability to vascular smooth muscles of the penis. In one study, 120-240 mg of Ginkgo biloba extract was associated with a 76% improvement in sexual dysfunction among men being treated with antidepressants.
Muira Puama, also known as potency wood, is an herb that comes from a small bush in the rain forests of Brazil. It has been associated with enhanced erectile function and orgasm in aging men suffering the effects of fatigue or age-related complaints. In one study of 262 men suffering from poor sexual desire, more than 60% reported improvements with Muira Puama supplementation. In addition, more than half of the men with erectile dysfunction reported that Muira Puama was beneficial. While Muira Puama’s mechanism of action remains unknown, its actions may be related to its plant sterol content. Plant sterols may contribute to increased synthesis of testosterone.
The bioflavonoid chrysin is a natural aromatase inhibitor that helps minimize the conversion of testosterone to estrogen. Although chrysin has low oral bioavailability, its bioavailability may be improved by co-administration with the black pepper extract piperine, thus enhancing its actions as an aromatase inhibitor.
Carnitine (including acetyl-L-carnitine [ALC] and propionyl-L-carnitine [PLC]) are natural amino acid compounds. Studies have linked carnitines to a variety of positive effects among men with low testosterone, including improved erection quality/function, orgasm, and general sexual well-being. Carnitines may have testosterone-like effects in the body. A 2012 study showed that 250 mg of PLC daily for 3 months (in combination with 2500 mg of L-arginine and 20 mg of niacin) successfully improved erections in 40% of men with erectile dysfunction, while nearly 77% of men reported a partial response. Carnitines may improve endothelial function by acting as antioxidants in these cells. For this reason, carnitine supplementation may be generally beneficial for cardiovascular health. Carnitine may also have a place as a combination therapy with PDE5 inhibitors, especially among patients whose erectile dysfunction is caused by underlying endothelial disorders, such as diabetes.
Vitamin D insufficiency (as defined by serum levels <30 ng/mL) affects over 75% of the United States population. Vitamin D deficiency may be a risk factor for erectile dysfunction, since it contributes to arterial stiffness and vascular dysfunction. Researchers have theorized that optimizing vitamin D levels could reduce certain risk factors for erectile dysfunction, such as arterial stiffness, diabetes mellitus, hypertension, and inflammation of the endothelium. Vitamin D has also been shown to stimulate the production of nitric oxide.
B vitamins – Inadequate intake of B vitamins, especially folate, B6, and B12, can contribute to elevated levels of homocysteine. Homocysteine is a metabolic amino acid derivative that can damage endothelial cells and contribute to cardiovascular disease. In one study, homocysteine impaired carvernosal smooth muscle relaxation. The authors proposed homocysteine as a risk factor for erectile dysfunction. B vitamin supplementation can help keep homocysteine levels in a healthy range; therefore, may mitigate erectile dysfunction.
Vitamin E – Erectile dysfunction is often associated with oxidative stress, which impairs endothelial function and reduces nitric oxide bioavailability. Both experimental and clinical data has shown that vitamin E may be beneficial for erectile dysfunction, since it enhances endothelial cell function, scavenges free radicals, improves nitric oxide-mediated relaxation, preserves nerve function, and increases intracavernosal pressure. Through these various actions, vitamin E has shown promising results in experimental models of erectile dysfunction caused by aging and hypertension. Vitamin E may also be beneficial when added to PDE5 inhibitor treatment, especially if treatment with a PDE5 inhibitor alone has not been successful in the past.