Erectile Dysfunction

Erectile Dysfunction and Hormones

Testosterone

Many facets of male sexual function depend upon male hormones (androgens) such as testosterone (Morales 2011). Testosterone helps support the production of nitric oxide (Kolodny 2011), but also helps maintain libido (Morales 2011). As men age their androgen levels decline. Low androgen levels are observed in as many as one-third of men with erectile dysfunction (Burnett 2011).

Androgen deficiency can directly contribute to erectile dysfunction by negatively impacting penile blood flow and increasing breakdown of cGMP (Martin 2012; Heidelbaugh 2010). Low testosterone is the most common reason for failure to respond to Phosphodiesterase-5 (PDE5) inhibitors (eg, Viagra® and Cialis®), which are drugs that slow the breakdown of cGMP (Hackett 2012).

Clinical guidelines recommend hormone level testing for aging men who suffer from sexual dysfunction. Maintaining optimal testosterone levels is not only important for sexual function, but also for cardiovascular health (Cattabiani 2012). Moreover, low androgen levels are associated with depression, osteoporosis, insulin resistance, increased fat mass, decreased lean body mass, and cognitive dysfunction (Morales 2011; Kolodny 2011). Life Extension recommends that ageing men target optimal free testosterone blood levels of 20 – 25 pg/mL and total testosterone levels of 700 – 900 ng/dL.

Testosterone restoration can lead to improved erectile function and libido in men with low androgen levels (Heidelbaugh 2010). In fact, 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 (Heidelbaugh 2010; Kolodny 2011; Morales 2011; Hackett 2012).

DHEA

Dehydroepiandrosterone (DHEA) is a precursor to testosterone (Oloyo 2011; Maggi 2012). 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 (Maggi 2012). Low DHEA levels have been linked to erectile dysfunction (Mackay 2004; Feldman 1994). 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 (Reiter 1999; Reiter 2001). Life Extension recommends an optimal target blood level for DHEA-sulfate of 350 – 490 µg/dL.

Aromatase Inhibitors, Testosterone Restoration, and Testosterone/ Estrogen Balance

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 (Traish 2007). 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 (Traish 2007).

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 (Jankowska 2009).

Conventional Treatment Of Erectile Dysfunction

Phosphodiesterase-5 (PDE5) Inhibitors

The signaling molecule cyclic guanosine monophosphate (cGMP) is an important mediator of vasodilatation, penile blood flow, and therefore erection. The natural destruction of cGMP by the phosphodiesterase-5 (PDE5) enzyme effectively shuts down the erection process, returning the penis to its non-erect (flaccid) state (Kolodny 2011).
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 (Kolodny 2011). However, approximately one-third of men with erectile dysfunction do not respond to PDE5 inhibitors (Heidelbaugh 2010). Men whose erectile dysfunction is not improved by PDE5 inhibitors may have low testosterone levels and should have a testosterone blood test (Nehra 2012).

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 (Stroberg 2006; Rashid 2005; Burnett 2011; Wolfe 2005). 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 (Rashid 2005; Burnett 2011; Wolfe 2005; Heidelbaugh 2010). PDE5 inhibitors only improve erectile function, not overall sexual function (Heidelbaugh 2010).

Intracavernosal Medications

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 (MD Consult 2009a,b; MD Consult 2010).

• Alprostadil. Alprostadil is synthetic prostaglandin E1, which is a biochemical signaling molecule with vasodilatory properties (Lea 1996; Costabile 2008). Studies show alprostadil to be effective in about 70% of men with erectile dysfunction (Lea 1996). Alprostadil can now be delivered via topical cream as well, which has demonstrated a success rate similar to injectable forms (Rooney 2009; MD Consult 2012a).
• Papaverine. 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 (Pinsky 2010).
• Phentolamine. 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 (Pinsky 2010).

Vacuum Erection Devices (VEDs)

Another alternative is utilizing a vacuum device 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 (Pinsky 2010).

Behavioral Interventions

Erectile function and overall sexual satisfaction can be considerably impacted by psychological and interpersonal factors. Evidence suggests a psychogenic contribution to as many as 40% of erectile dysfunction cases. Psychosocial variables such as anxiety about seeking erectile dysfunction treatment undermine availability of effective treatment options as well. A comprehensive review conducted in 2008 showed that group psychotherapy can significantly improve erectile dysfunction and complement pharmacologic treatment strategies (Melnik 2008).

Shock Wave Therapy

Extracorporeal ultrasound shock wave therapy is used to treat some penile disorders such as Peyronie’s disease (Palmieri 2012; MD Consult 2012b). Application of low-intensity ultrasound shock waves to the penis is emerging as a treatment for erectile dysfunction among men without other penile disorders. In a pioneering, randomized, double-blind, sham-controlled study on 67 men, researchers showed that shock wave therapy significantly improved erectile function and penile blood flow among previous responders to PDE-5 inhibitors. Treatment was well tolerated with none of the subjects reporting discomfort or adverse events (Vardi 2012). Another study showed that shock wave therapy improved erectile function in 29 men who responded poorly to PDE5 inhibitors (Gruenwald 2012).

Lifestyle And Erectile Dysfunction

Certain modifiable conditions and behaviors increase the chances of developing erectile dysfunction. These include lack of physical activity and obesity, as well as alcohol, tobacco, and illicit drug use (Sadeghi-Nejad 2007; Fortney 2012; Meldrum 2011). Eating an unhealthy diet low in antioxidants is also linked to erectile dysfunction (Meldrum 2011; Ledda 2010).
The following lifestyle modifications may improve erectile function (Heidelbaugh 2010):

Targeted Natural Interventions

A variety of natural modalities may improve erectile function and male sexual health (Ho 2011; Chung 2011; Burnett 2011; de Andrade 2007).

Kaempferia parviflora - Kaempferia parviflora, a member of the ginger family, is a plant native to Southeast Asia. It has traditionally been used for male sexual health (Saokaew 2016), and emerging clinical research has established that Kaempferia can enhance erectile function, erectile response time, penile size, and intercourse satisfaction (Stein 2018; Wannanon 2012). Kaempferia extracts contain 5,7-dimethoxyflavone, a compound shown in laboratory studies to inhibit phosphodiesterase-5 activity—the same mechanism as leading erectile dysfunction medications—and to enhance vasorelaxation (Temkitthawon 2011; Tep-Areenan 2010). Kaempferia extract appears also to activate central nervous system pathways involved in sexual responsiveness (Wattanathorn 2012). These clinical findings confirm evidence from animal models in which Kaempferia improved sexual and copulation behavior (Wattanathorn 2012; Chaturapanich 2008; Chaturapanich 2012).

In a 30-day open-label clinical study, 13 generally healthy men aged 50‒68 with self-reported mild erectile dysfunction received 100 mg of a Kaempferia extract standardized to a 5% content of 5,7-dimethoxyflavone. At the end of the trial, the men reported significant improvements in erectile function and intercourse satisfaction, as well as in total scores on a standardized inventory of erectile function. The Kaempferia extract was found to be safe and well-tolerated (Stein 2018).

In a randomized, placebo-controlled trial, 45 men of an average age of 65 received 25 or 90 mg of Kaempferia extract, once daily, for 60 days. Although the authors concluded that the 25 mg dosage likely was insufficient to reach therapeutic levels, men receiving 90 mg were able, at the 30- and 60-day evaluation, to achieve a full erection in roughly half the time of those receiving placebo. Men in the 90 mg group also experienced an increase in size of roughly ½ inch in length and circumference in both flaccid and erect states, compared with baseline (Wannanon 2012).

L-arginine – L-arginine is an essential amino acid with numerous metabolic actions (NIH 2012; Gentile 2009). It plays a significant role in erectile function by contributing to the formation of the vasodilator nitric oxide (Paroni 2012; Mathers 2009; Masuda 2008; Nunes 2011).

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 (Cormio 2011; Aoki 2012; Ledda 2010; Giles 2006). The efficacy of L-arginine, combined with Pycnogenol®, a bioactive compound derived from French maritime pine bark with vasodilatory properties, has been tested in 5 independent clinical studies and been shown to improve male sexual function (Stanislavov 2003,2008,2009; EBDR 2005; Nikolova 2007). This combination is called Prelox®. The first clinical trial to report successful treatment of erectile dysfunction with Pycnogenol® and L-arginine aspartate involved 40 men between 25 and 45 years of age suffering from mild erectile dysfunction. A regimen of 80 mg of Pycnogenol® and 1.7 grams of L- arginine daily yielded significant improvement, with 32 patients (80%) enjoying normal erections. L-arginine, together with an increased amount of Pycnogenol® (120 mg per day), further increased the number of patients with restored normal erectile function. At the end of the three month trial, 37 patients, equivalent to 92.5% of all participants, achieved normal erectile function (Stanislavov 2003).
L-arginine supplementation has also been shown to attenuate endothelial dysfunction associated with high cholesterol and coronary heart disease (Gianfrilli 2012). 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 (Gianfrilli 2012; Porst 2010; Gentile 2009).

Epimedium – 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 (Ma 2011; Metz 2009; Shindel 2010).

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 (Xin 2003; Shindel 2010). 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 (Shindel 2010; Liu 2005,2011; Zhang 2012; Metz 2009).

Yohimbine – Yohimbine, a compound derived from the bark of the Yohimbe tree, has been utilized in the treatment of erectile dysfunction for over 70 years (Tamler 2007). 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 (Traish 2000).
Clinical studies of yohimbine, alone or in combination with L-arginine, have shown improved erectile function (Kernohan 2005; Dinsmore 2005; Ho 2011). In one clinical trial, yohimbine was effective for up to 84% of male volunteers, depending on the type of erectile dysfunction (Pushkar 2002). Compared to placebo, yohimbine was more effective at improving self-reported sexual function and penile rigidity (Tharyan 2006; Ernst 1998). Another study found that yohimbine improved erectile function in 42% of men with erectile dysfunction, compared to 27% of subjects taking placebo (Morales 1987). Additionally, yohimbine may be particularly effective among type 2 diabetics and those with non-biological causes of erectile dysfunction (Tamler 2007; Tanweer 2010).

Yohimbine may cause some side effects including heart palpitations, anxiety, fine tremor, and high blood pressure. These occur infrequently and are usually reversible (Tamler 2007; Tharyan 2006; Ernst 2011).

Ginseng – Ginseng belongs to the genus Panax, which is a group of slow-growing perennial plants with distinctively fleshy roots (Shamloul 2010). 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 (Nair 2012). An estimated 6 million Americans have used ginseng for the improvement of sexual dysfunction (de Andrade 2007; Chan 2012).

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 (Kim 2009). 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 (Jang 2008; Wang 2010).

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 (Kim 2009). Another study showed that ginseng significantly improved penile rigidity, libido, and satisfaction among men with erectile dysfunction (de Andrade 2007).

Maca – Maca (Lepidium meyenii) is a root vegetable belonging to the mustard (ie, Brassica) family (Zenico 2009; MacKay 2004). Ancient Peruvians have cultivated maca for millennia and taken advantage of its aphrodisiac properties (Hudson 2008; MacKay 2004). The dried root of the maca plant is a rich source of amino acids, iodine, iron, and magnesium (Zenico 2009; Shin 2010).

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 (Zheng 2000; Hudson 2008). It also shows androgen-like effects in animals (Shin 2010). Human clinical studies suggest that maca enhances the production of sex hormones, increases libido, and improves well-being (Hudson 2008; Shin 2010; Zenico 2009; Gonzales 2002). The aphrodisiac activity of maca may be due to local effects on erectile function and/or central nervous system effects (Zenico 2009).

Ginkgo biloba – Extracts of leaves from the Ginkgo biloba tree have been used for centuries in the treatment of asthma, fatigue, circulatory problems, and vertigo (Cybulska-Heinrich 2012). It has more recently been associated with enhanced sexual desire, excitement, orgasm, and resolution, as well as neuroprotective properties (Moyad 2002; Cybulska-Heinrich 2012). The sexual benefits of ginkgo were discovered serendipitously when male geriatric patients taking Ginkgo biloba for memory enhancement reported improved erections (MacKay 2004).

In addition to experimental data showing that Ginkgo biloba can enhance sexual behavior in rats (Yeh 2008), clinical studies have revealed it can increase penile blood supply and improve erectile function in humans (Moyad 2002). Ginkgo contributes to increased blood flow by increasing nitric oxide bioavailability to vascular smooth muscles of the penis (MacKay 2004; Rowland 2003). 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 (Cohen 1998).

Muira Puama - 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 (Rowland 2003).

Chrysin: The bioflavonoid chrysin is a natural aromatase inhibitor that helps minimize the conversion of testosterone to estrogen (Kellis 1984). Although chrysin has low oral bioavailability (Walle 2001), its bioavailability may be improved by co-administration with the black pepper extract piperine, thus enhancing its actions as an aromatase inhibitor (Srinivasan 2007).
Carnitines – 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 (Gianfrilli 2012; Malaguarnera 2012). Carnitines may have testosterone-like effects in the body (Cavallini 2004). 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 (Gianfrilli 2012).

Carnitines may improve endothelial function by acting as antioxidants in these cells (Ginafrilli 2012). For this reason, carnitine supplementation may be generally beneficial for cardiovascular health (Malaguarnera 2012; Mingorance 2011). 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 (Gentile 2004).

Vitamin D – 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. In a 2012 paper, researchers 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 (Sorenson 2012).

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 (Wang 2011; Lombardo 2010). In one study, homocysteine impaired carvernosal smooth muscle relaxation. The authors proposed homocysteine as a risk factor for erectile dysfunction (Khan 1999). B vitamin supplementation can help keep homocysteine levels in a healthy range; therefore, may mitigate erectile dysfunction (Wang 2011; Ng 2011; Lombardo 2010). Life Extension recommends homocysteine levels be kept below 8 µmol/L for optimal health.

Vitamin E – Erectile dysfunction is often associated with oxidative stress, which impairs endothelial function and reduces nitric oxide bioavailability (Meldrum 2012; Helmy 2012). 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 (Helmy 2012; Kondoh 2008). Through these various actions, vitamin E has shown promising results in experimental models of erectile dysfunction caused by aging and hypertension (Helmy 2012; Ushiyama 2008). 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 (Kondoh 2008).