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Nutrients and Botanicals for Erectile Dysfunction: Examining the Evidence

Nutrients and Botanicals for Erectile Dysfunction: Examining the Evidence

Abstract:
     Erectile dysfunction effects 50 percent of men ages 40-70 in the United States and is considered an important public health problem by the National Institutes of Health. Consumers are exposed to a plethora of natural products claiming to restore erection and sexual vitality. A review of the available empirical evidence reveals most naturally occurring compounds lack adequate clinical trials to support efficacy. However, arginine, yohimbine, Panax ginseng, maca, and Ginkgo biloba all have some degree of evidence they may be helpful for erectile dysfunction. Improvements in penile endothelial L-arginine-nitric oxide activity appear to be a unifying explanation for the actions of these naturally occurring agents. (Altern Med Rev 2004;9(1):4-16)

Introduction:
     Throughout history the erect penis has been a symbol of power and virility.1 In men the inability to achieve or maintain an erection suffi- cient for satisfactory sexual function, known as erectile dysfunction (ED),2 can have a consider- able impact on interpersonal relationships and quality of life. The prevalence, cost, and psycho- social impact of ED has been described as an im- portant public health problem by a National Insti- tutes of Health Consensus Panel.2 Results of a community-based, randomized, observational sur- vey of men conducted from 1987-1989 in cities and towns near Boston, Massachusetts, found 52 percent of men ages 40-70 had some degree of ED. Incidence of complete ED tripled – from 5 to 15 percent – between age 40 and 70, while the Incidence of moderate ED doubled from 17 to 34 percent during this same age span. In addition, 60 percent of men were estimated not to be impotent at age 40, with a decrease to 33 percent by age 70 (Figure 1).3 From this data, an estimated 30 mil- lion men in the United States are affected by some degree of ED.4 Researchers speculate that as baby boomers grow older and the global population ages, the prevalence of ED will more than double in the next 25 years, possibly affecting more than 330 million men worldwide.5 The annual cost of ED in the United States, as estimated from the number of physician-related visits in 1985, was $146,000,000.

     Internationally, most men with ED fail to pursue treatment due to the complex nature of sexuality, taboos, cultural restrictions, and accep- tance of ED as a normal sequela of aging. World- wide, an estimated 10 percent of patients with ED seek medical attention.6 Availability of oral sildenafil (Viagra‚) in 1998 as the first efficacious oral treatment for ED of various causes has re- sulted in increased awareness and number of pa- tients seeking treatment. Sildenafil has proven it- self a valuable tool in the management of ED, but is not without limitations. While it provides symp- tomatic relief, it is not a cure, it is costly, and the long-term risks and benefits are unproven.7 The success of sildenafil has led investigators on a fe- verish pursuit of other agents that can ultimately

     compete with this syn- thetic “love drug.”8 Scien- tists are beginning to gather empirical data on naturally occurring com- pounds that have been used historically as agents to increase male sexual function.

     Currently, the ef- ficacy of most natural agents remains moderate- to-uncertain. Many natu- ral agents used to treat ED are attractive because they provide health benefits beyond those related to ED and are inexpensive compared to prescription medications. This article explores the empirical evi- dence related to the effi- cacy of various orally available natural agents used to treat ED.

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Physiology of Normal Erection:
     Leonardo Da Vinci, through his dissec- tion of cadaverous penises, was the first scientist to realize that during an erection the penis fills with blood. During his investigation, Da Vinci wrote, “The penis does not obey the order of its master, who tries to erect or shrink it at will, whereas instead the penis erects freely while its master is asleep. The penis must be said to have its own mind, by any stretch of the imagination.”5 Since Da Vinci’s observations 500 years ago, in- vestigators have determined the penis does not have a mind of its own, but is largely under the control of the central nervous system.

     An erection requires intact psychological, neural, and vascular responses and reflects a dy- namic balance of excitatory and inhibitory forces. Sexual stimulation causes excitatory signals to originate in the brain, resulting in the terminals of the axons of the parasympathetic nerves releasing nitric oxide (NO) gas directly and indirectly via endothelial cells in the penis (Figure 2). Simulta- neously, the outflow from the sympathetic nerves is inactivated. NO gas diffuses into smooth muscle cells lining the arteries of the corpus cavernosum (spongy erectile tissue) acting as a chemical mes- senger, which activates guanylate cyclase (GC) within the muscle. Subsequently, GC converts the nucleotide guanosine triphosphate (GTP) into cy- clic guanosine monophosphate (cGMP), which raises the intracellular concentration of cGMP. Guanosine monophosphate in turn causes smooth muscles of the penile arteries to relax, causing more blood to flow into the organ. The spongy erectile tissue of the penis becomes engorged with blood, causing compression of the veins that nor- mally drain blood from the penis. Pressure cre- ated by the additional blood squeezes the veins until they are nearly closed, trapping blood within the corpus cavernosum and producing an erection. The erection eventually subsides because cGMP is hydrolyzed by phosphodiesterase type 5 en- zymes (PDE5) to inactive GMP.

     The sympathetic nervous system is re- sponsible for maintaining the penis in the flaccid state. An increase in activity of the sympathetic nervous system, caused by such things as stress or exposure to cold, stimulates the muscles of the penile arteries to contract allowing blood to es- cape from the penis. Conversely, a reduction of sympathetic nervous system activity enhances erection. During REM sleep when the sympathetic nervous system is turned off, pro-erectile pathways predominate resulting in a nocturnal erection. Nocturnal erections are thought to serve as a sort of penis maintenance by providing a flush of oxy- genated blood to re-energize the organ.

     A quality erection is crucial to reproduc- tion and perpetuation of the human species. It is so critical for procreation that the capacity to cre- ate an erection has been wired into the nerve cir- cuits at the base of the spine. The ability to gener- ate an erection can be preserved in men with spi- nal cord injuries where communication between the brain erection generating centers and the spi- nal cord is lost.5 Physical stimulation of the penis sends sensory signals via the pudendal nerve to the erection-generating center located in the sac- ral segments of the spinal cord. The incoming sig- nals activate interneurons, which then stimulate the parasympathetic neurons to release NO gas into smooth muscle cells that line arteries of the cor- pus cavernosum. The NO gas diffuses into the smooth muscle and triggers an erection. If this reflex arc remains intact an erection is possible.5 While Da Vinci incorrectly predicted the penis has a mind of its own, it does have the ability to func- tion independently from the brain.

Testing Substances for Erectile Activity
     Any compound that promises sexual po- tency has the potential to be extremely profitable. Drug and health food stores are loaded with agents purported to alleviate male sexual problems. Much of the perceived benefit of available products is based on popular or cultural belief and personal testimonials. Several natural compounds that have been used for centuries as agents to improve male sexual function are now the subjects of scientific investigation. Unfortunately, there is no accepted uniform method for identifying substances that enhance male erectile function.

     The isolated rodent corpus cavernosum is a common model used to assess erectile activity of compounds. Strips of smooth muscle isolated from rabbit or rat corpus cavernosum are mounted in an organ bath. The strips of muscle are allowed to equilibrate in physiologic salt solution. The muscle is pre-contracted with phenylephrine and the relaxation of the muscle is measured after the addition of successive amounts of the test sub- stance. Relaxation of the cavernosum is consid- ered a positive result for the test substance.

     Other animal models to assess ED activity include observations of rodent behavior when given various doses of test substance. Studies cite increases in sexual responsiveness (as defined by a decreased latency to onset of erection), increase in frequency of copulatory attempts (indicative of sexual arousal), and decreased latency to ejaculation (measure of performance). Other copulatory behaviors include male rat orientation toward receptive female rats (anogenital sniffing, licking, and mounting), the environment (climbing, raring, exploration), and themselves (nongenital and genital grooming).

     Current animal models do not provide an accurate method of assessing ED activity of new compounds. Animal models do not allow for hu- man cerebral aspects of sex to be evaluated and rely only on the basic mechanical or instinctive sexual functions observed in animals. In addition, human trials for ED can be difficult to interpret because most include some degree of subjective self-evaluation. Despite complications in assess- ing ED activity of various compounds, random- ized, controlled trials are generally considered the most accurate technique for determining causal- ity.

Natural Agents Used to Treat ED
     L-arginine is the biologic precursor of NO, which is involved in a variety of endothelium-de- pendent physiologic effects.9 Impaired endothe- lial L-arginine-NO activity has been demonstrated in atherosclerotic coronary arteries in humans and animal models.10-13 Impaired penile endothelial L- arginine-NO activity also appears to play a role in the pathogenesis of ED.14 Similar mechanisms have been established for alterations in L-argin- ine-NO pathways for both ED and atherosclero- sis, supporting the concept there is a reduction in NO bioavailability contributing to vascular changes in both conditions.15

The prevalence of ED among men with ischemic heart disease is approximately 75 percent.16 In addition, ED is associated with other conditions, including hypertension, dyslipidemia, diabetes, and smoking.17-19 It has been hypothesized that vasculogenic erectile function is a manifestation of atherosclerosis and that the endothelial L-arginine-NO pathway provides a unifying explanation for such an association.15 The risk of moderate or complete ED in patients with cardiovascular risk factors was 11 percent higher than in an age-matched, disease-free control cohort.3 Studies have also shown correlations between the presence of ED and clinical or subclinical ischemic heart disease. Anderson et al demonstrated that patients with severe vasculogenic ED (assessed by duplex sonography) had a 16-percent risk of suffering severe, although asymptomatic, ischemic heart disease.20 Greenstein et al found correlations between ED and the number of coronary vessels occluded on angiography.

Human clinical trials of L-arginine for ED have yielded mixed results. In one small, uncon- trolled trial of men with ED who were adminis- tered 2.8 g arginine per day for two weeks, posi- tive results were demonstrated. Forty percent of men in the treatment group reported improvement, compared to none in the placebo group.22 In a larger, double-blind trial, 50 men with confirmed ED were administered 5 g L-arginine per day or matching placebo for six weeks. Thirty-one per- cent of patients taking L-arginine reported a sig- nificant subjective improvement in sexual func- tion, while objective variables assessed remained unchanged. All patients reporting subjective im- provements had had initially low urinary NO ex- cretion, which had doubled by the end of the study.23 It can be speculated that L-arginine may be more effective in ED patients with alterations in endothelial L-arginine-NO activity and a reduc- tion in NO availability.

Researchers interested in further investi- gation of the effect of endogenous NO for ED found significant improvement in men given a combination of oral pycnogenol (oligomeric proanthocyanidins; OPCs) from pine bark and L- arginine. Pycnogenols have been shown to stimu- late the enzyme nitric oxide synthase (NOS) for enhanced production of NO.24 The combination of pycnogenol and L-arginine is thought to have a synergistic effect on the production of NO by stimulating activity of NOS with pycnogenol and providing the substrate for this enzyme with argi- nine. The three-month trial consisted of 40 men, ages 25-45. During the first month patients re- ceived only 1.7 g L-arginine daily; the second month 40 mg pycnogenol twice daily was added to the protocol; during the third month the dosage of pycnogenol was increased to 40 mg three times daily. After the first month five percent of patients experienced a normal erection. The following month, with the addition of 80 mg pycnogenol, 80 percent of men reported normal erection, and after the third month of treatment this increased to 92.5 percent. These men also experienced a decrease in time until erection developed in re- sponse to stimulation, as well as extended dura- tion of erection.

The majority of studies using L-arginine to treat ED show positive treatment results. One that did not was a randomized, placebo-controlled, crossover comparison of 1.5 g L-arginine daily versus placebo.26 Patients were treated with 500 mg L-arginine three times daily or matching pla- cebo for 17 days. After a seven-day washout pe- riod the L-arginine and placebo groups were switched. The dose of L-arginine in this study, however, was smaller than previous positive stud- ies.

The notion that ED and ischemic heart disease may not occur coincidentally in the same patients is clinically relevant. Although the data on efficacy of L-arginine is mixed, it appears to benefit a limited number of patients. It would ap- pear to be of greatest benefit in patients with al- terations in endothelial L-arginine-NO activity and a reduction in NO availability. Patients with con- comitant ED and ischemic heart disease might doubly benefit from treatment with L-arginine and increased NO availability. Supplementation with L-arginine on a regular basis may increase sexual function as well as improve other aspects of vas- cular disease. Patients who respond positively to L-arginine have the added benefit of spontaneous response to their partner’s stimulation without the necessity of taking a prescribed pill in advance.

Yohimbine
     L-arginine is the biologic precursor of NO, which is involved in a variety of endothelium-de- pendent physiologic effects.9 Impaired endothe- lial L-arginine-NO activity has been demonstrated in atherosclerotic coronary arteries in humans and animal models.10-13 Impaired penile endothelial L- arginine-NO activity also appears to play a role in the pathogenesis of ED.14 Similar mechanisms have been established for alterations in L-argin- ine-NO pathways for both ED and atherosclero- sis, supporting the concept there is a reduction in NO bioavailability contributing to vascular changes in both conditions.

     Yohimbine is an alkaloid derived from the African tree, Pausinystalia yohimbe. Yohimbine has been used as a pharmacological agent in the treatment of ED for over 70 years. The drug is pharmacologically characterized as an alpha-2- adrenergic receptor antagonist. Its activity is mediated by blocking presynaptic alpha-2-adrenergic receptors in the brain. Through a reduction of brain and spinal cord norepinephrine levels the sympathetic inhibitory tone that suppresses sexual arousal is blocked. A blockade of presynaptic alpha-2 adrenergic receptors by yohimbine subsequently enhances NO release from the penile nerves.27

      Studies in animals have shown yohimbine has a positive effect on male sexual perfor- mance.28,29 Human studies have also shown an advantage of yohimbine over placebo.30-33 Al- though yohimbine appears to have therapeutic benefit, it has not yet been subjected to scientifi- cally rigid human clinical trials. There have been fewer than a dozen controlled human trials of yo- himbine for ED and most of them lack sufficient power for credible statistical analysis. In addition, clinical trials of yohimbine have been criticized for having methodological problems and incon- sistent data.

      A systematic review published in 1998 of rigorous controlled trials of yohimbine for erec- tile dysfunction concluded yohimbine is a reason- able therapeutic option that should be considered as an initial pharmacological intervention.35 In this review, studies were only considered for analysis if they were randomized, placebo-controlled, double-blind clinical trials with adequate statisti- cal evaluation. Without exception, the seven tri- als evaluated suggest yohimbine is relatively safe and more effective than placebo. It was further concluded its cost and oral administration make it an attractive therapeutic option.

     One of the more exceptional trials was a multicenter, double-blind, crossover study of 61 men with ED. Participants received 5.4 mg yo- himbine hydrochloride three times daily for eight weeks or placebo. Subsequently, they were crossed over for another eight weeks. After the first eight weeks of treatment 36.7 percent of the treatment group and 12.9 percent of the placebo group re- ported restoration of erection. In the placebo group this figure rose to 41.9 percent after crossover to drug.

      A second notable study was a partial crossover study on 82 patients with ED. Participants received tablets of 5.4 mg yohimbine hydrochloride or placebo. Initially the dose was one tablet four times daily, which was increased by one tablet daily to a maximum of two tablets four times daily. After one month placebo-treated patients were crossed over to yohimbine and yohimbine patients continued in the same manner. If adverse effects occurred, dosage was reduced by one tablet per day until side effects diminished. After one month of treatment 14 percent of the treatment group experienced full-stimulated erections, 20 percent had a partial response, and 65 percent reported no improvement. Three patients reported a positive placebo effect.37 It took two to three weeks to establish a therapeutic effect and patients responded regardless of the etiology of ED.

     Despite controversy regarding yohimbine’s efficacy, it has a long history of use and encouraging preliminary research findings. Basic pharmacological and animal research infor- mation regarding yohimbine has been available for 15 years, yet it has not generated appreciable scientific and/or financial interest. One expert opinion suggests yohimbine has not captured the attention of the research community because it is an old drug that has no patent protection or com- mercial viability.

     Yohimbine’s action on alpha-2-adrenergic receptors is not limited to erectile function and can therefore cause headache, sweating, agitation, hypertension, and sleeplessness. Long-term toxi- cological and carcinogenicity studies of yohim- bine are not available.39 Yohimbine is reportedly contraindicated in patients taking tricyclic anti- depressants, phenothiazines, antihypertensive agents, or central nervous system stimulants.

     The documented, yet modest beneficial effect of yohimbine should not exclude it from the erectogenic armamentarium. Yohimbine’s ac- tion on alpha-2-adrenergic receptors and subse- quent enhancement of NO release by the penile arteries suggest the possibility it may work syner- gistically with other agents that increase NO bioavailability. Lebret et al demonstrated that on- demand administration of 3.25 g L-arginine and 6 mg yohimbine, administered 1-2 hours before in- tended sexual intercourse, significantly improved erectile function in patients with mild-to-moder- ate ED.41 Such results provide hope that contin- ued interest in yohimbine can eventually lead to its proper evaluation as an agent for ED alone and in combination with other agents.

Panax Ginseng
     or 2,000 years Panax ginseng has had a rich medicinal history. Practitioners of Chinese medicine use it as a tonic and restorative to pro- mote health and longevity. It has been prescribed to improve stamina, concentration, stress resis- tance, and work efficiency in the healthy as well as to improve well-being in patients with degen- erative conditions associated with old age and chronic disease.42 The tonic and adaptogenic ac- tivity of Panax ginseng is thought to enhance physical performance, which includes sexual stamina.

     Laboratory studies of Panax ginseng have shown it may improve vascular endothelial abnor- malities by increasing the production of NO. Sev- eral studies suggest Panax ginseng possesses an- tioxidant and organ-protective action associated with enhanced NO synthesis in the endothelium of the lung, heart, kidney, and corpus cavernosum.43-45 The principal active constituents of Panax ginseng are thought to be the saponin glycosides, ginsenosides. Ginsenosides have been shown to cause a dose-dependent relaxation of the corpus cavernosal smooth muscle in rabbits by increasing release of nitric oxide.

    Clinical studies have also supported the use of Panax ginseng to assist the phallodynamically challenged. Choi et al demon- strated Panax ginseng was superior to placebo for the treatment of ED. Ninety patients were divided into three groups and given Panax ginseng, pla- cebo, or trazodone orally. Frequency of inter- course, premature ejaculation, and morning erec- tions after treatment were unchanged in all three groups. However, in the Panax ginseng-treated group a significant improvement in erectile pa- rameters such as penile rigidity, girth, duration of erection, improved libido, and patient satisfaction were reported. No changes in serum testosterone were observed. The overall therapeutic efficacy on erectile dysfunction was 60 percent for the Panax ginseng group and 30 percent for the trazodone and placebo groups.

    A more recent, double-blind, placebo-con- trolled, crossover study produced data showing Panax ginseng is an effective alternative for treat- ing ED. Forty-five men diagnosed with ED were randomized and received either 900 mg Panax ginseng or placebo (starch capsule with ginseng flavor) three times daily for eight weeks. The first eight weeks of treatment were followed by a two- week washout period, after which the patients re- ceived crossover treatment of placebo or Panax ginseng for another eight weeks. Treatment effi- cacy was determined based on changes observed in indexes of erectile function, including the In- ternational Index of Erectile Function (IIEF), RigiScan, serum testosterone levels, and penile duplex ultrasonography with audiovisual sexual stimulation.

    Mean scores on the IIEF for Panax gin- seng were significantly higher than for placebo after eight weeks of each treatment. Although the number of patients examined was small, the sig- nificant increases in IIEF data have been suggested to represent clinically relevant success. Penile tip rigidity, based on RigiScan parameters, was sig- nificantly better after eight weeks of Panax gin- seng compared to placebo. No significant changes in hemodynamics on duplex ultrasonography with audiovisual stimulation were recorded. No changes in serum testosterone were observed in this or the previously mentioned human trial of ginseng for ED. The authors speculate that thera- peutic efficacy of Panax ginseng for ED is not mediated through improvements in hemodynam- ics alone or a hormonal effect, but through mul- tiple mechanisms that have not yet been com- pletely elucidated.

     From the available data it appears Panax ginseng may possess the ability to improve erectile function. Preliminary conclusions suggest its primary mechanism is mediated through increased NO levels, resulting in improved penile hemodynamics. This mechanism suggests therapeutic success of Panax ginseng for the treatment of ED may be dependent on the presence of impaired endothelial L-arginine-NO activity. Although Panax ginseng activity is modest in comparison to the current treatments of choice for ED, the possibility of increased erectile capacity, if used in concert with other mediators of NO production, should be further investigated.

Maca
     Lepidium meyenii (maca) is a root veg- etable cultivated in the central Peruvian Andes that belongs to the brassica (mustard) family. Dried maca root is rich in amino acids, iodine, iron, and magnesium. Traditionally maca root has been used in the Andean region for its supposed aphrodisiac and/or fertility-enhancing properties.52 Modest empirical support exists for its ability to improve male sexual function.

     Rodents studies suggest maca may im- prove sexual behavior.53-55 Scientific studies on humans are limited to one randomized, double- blind trial published in a Peruvian journal. The trial showed maca improved subjective evaluation of sexual desire in 57 men treated with 1.5 or 3.0 g maca for 12 weeks compared to placebo. No other information on this trial was attainable.

     The same Peruvian researchers followed up with an investigation of the affect of maca on serum testosterone levels. It was demonstrated that the same doses of maca (presumably doses effec- tive for improving male sexual function) admin- istered in healthy men did not affect serum test- osterone levels. Doses of 1.5 or 3.0 g maca for 12 weeks in healthy males also produced no more side effects than placebo.

     Maca is a nutritious herbal health supple- ment with positive effects on overall health and nutritional status. Its continued use by Peruvians for several thousands of years as a nutritious root vegetable establishes ample evidence of safety. Specific data relating to its therapeutic value as a specific prosexual or erectile-enhancing agent is minimal.

Ginkgo biloba
     Recent research suggests Ginkgo biloba can be used to ameliorate antidepressant-induced sexual dysfunction. The notion that Ginkgo may benefit ED started with the observation that male geriatric patients on Ginkgo for memory enhance- ment reported improved erections.58 Sexual dys- function in these patients was determined to be secondary to antidepressant medications.

     The mechanism of antidepressant-induced ED appears to be related to the therapeutic activ- ity of selective serotonin reuptake inhibitors (SSRIs). One of the main roles of the central ner- vous system (CNS) in human sexual response is to suppress erections through the sympathetic ner- vous system and a cluster of neurons known as the paragigantocellular nucleus (PGN). The PGN neurons send signals down their axons to the erec- tion-generating center in the spine. There the PGN neurons release serotonin, which acts as a chemi- cal messenger within the erection-generating cen- ter that suppresses erections by inhibiting the ef- fects of pro-erectile neurotransmitters.5 As a re- sult, NO synthase is inhibited and NO release into penile smooth muscle is reduced. Millions of Americans take SSRI drugs that work in part by increasing CNS levels of serotonin. It has been proposed that, by increasing the level of seroto- nin in the CNS, pro-erectile physiologic mecha- nisms are inhibited.

     An open trial of Ginkgo to alleviate anti- depressant-induced sexual dysfunction found Ginkgo to be 76-percent effective in alleviating symptoms related to all phases of the sexual re- sponse cycle in men, including erectile function.58 Thirty men were prescribed 40- or 60-mg capsules of Ginkgo to be taken twice daily, titrated up to 120 mg twice daily, as tolerated. The average dose was 207 mg daily. All patients remained on anti- depressant medication. After a four-week trial period patients were evaluated for changes in sexual function based on clinical interview and self-reporting assessment by the patient. This ini- tial investigation of Ginkgo for SSRI-induced sexual dysfunction suggested a positive response.

     Subsequent trials have been less convinc- ing. In 1999 Wheatly et al published an open trial to investigate the effect of Ginkgo on antidepres- sant-induced sexual dysfunction. Twenty-four patients (12 men and 12 women) reported signifi- cant improvement in sexual response after both three and six weeks of use. This trial provides little data to assess efficacy of Ginkgo for ED. There was substantial variability among responses, with both ends of the spectrum represented – two pa- tients reported complete restoration of sexual func- tion and two others reported no response at all.

     In 2000 Ashton et al presented minimal data to support the use of Ginkgo for sexual dys- function related to antidepressant use. Improve- ment from Ginkgo was found in only three of 13 women tested and no improvement was reported in nine men.

     Subsequently, in 2002 the first placebo- controlled, double-blind trial of Ginkgo for anti- depressant-induced sexual dysfunction reported no statistically significant difference in sexual func- tion between Ginkgo and placebo. Thirty-seven patients were randomized to receive placebo or 120 mg Ginkgo daily for the first two weeks and 160 mg for the second two weeks; 240 mg was dispensed for four weeks thereafter. A question- naire was used immediately before the medica- tion and at weeks 2, 4, and 8 following the medi- cation.62 Ginkgo showed no statistical difference from placebo after medication.

     Elevated serotonin in the CNS is thought to inhibit the effects of pro-erectile neurotransmit- ters in the erection-generating center of the spine. This in turn decreases the activity of NO synthase and reduces NO availability to penile smooth muscle cells. Ginkgo is presumed to mitigate the effects of SSRIs on sexual function by increasing NO availability. Marcocci et al has shown Ginkgo can strengthen the activity of NO synthase, pre- sumably bypassing serotonin’s ability to block NO production.63 Chen et al has shown Ginkgo’s suc- cess in the treatment of ischemia-induced cere- bral dysfunction64 may be mediated via NO re- lease from both the endothelium and perivascular nitrergic nerves of the cerebral arteries.

     In addition, several studies conducted on isolated rabbit aorta have shown Ginkgo induced a dose-dependent relaxation of vascular smooth muscle.66-68 Jae-Seung and Jin Haeng showed Ginkgo extract exhibited a relaxing effect on iso- lated human and rodent corpus cavernosum tis- sue.69 Collectively, this evidence suggests Ginkgo has vascular smooth muscle relaxing activity in the heart, brain, and penis, and it appears NO ac- tivity provides a unifying association for Ginkgo’s effects. Increasing NO bioavailability may not only improve sexual function and vascular health, but may positively impact other age-related chronic diseases.

     Although there is minimal evidence for the use of Ginkgo alone for the treatment of ED, it may improve overall vascular perfusion by in- creasing NO availability. Ginkgo may not be the “magic bullet” for ED patients, but it may have a place in “whole patient” management of ED.

DHEA and Tribulus terrestris
     The most current epidemiological study on the prevalence of ED in the United States dem- onstrated an inverse relationship between serum levels of dehydroepiandrosterone (DHEA) and the incidence of erectile dysfunction.3 A logical relationship exists between the increase in the prevalence of ED with increasing age,3 decrease of serum DHEA levels with increasing age,70 and the inverse relationship between serum DHEA levels and the incidence of ED found in the Massachusetts Male Aging Study.3 The question remains if oral DHEA treatment will benefit patients with ED.

     A double-blind, placebo-controlled study of 40 men with ED and low DHEA levels found DHEA at a dose of 50 mg daily for six months improved sexual performance. Efficacy of DHEA was defined as the ability to achieve or maintain an erection sufficient for satisfactory sexual performance according to the National Institutes of Health Consensus Development Panel on Impo- tence. The patient database was considered too small to do relevant statistical analysis.

     Despite minimal evidence supporting the clinical use of DHEA for ED, Bulgarian research- ers have proposed that protodioscin extracted from the plant Tribulus terrestris improves erectile func- tion via increasing DHEA levels. An abstract pub- lished in the International Journal of Andrology states, “Protodioscin is a phytochemical agent derived from Tribulus terrestris plant, which has been clinically proven to improve sexual desire and enhance erection via the conversion of protodioscine to DHEA ....”

     Several studies of questionable worth are used to support the pro-erectile effects of Tribulus. According to this research, oral Tribulus increases serum DHEA,73 increases sexual function in men,74 exhibits a pro-erectile effect in isolated rabbit cor- pus cavernosum,75 and improves sexual behavior and intracavernous pressure in rats.

     Well-controlled clinical trials regarding the effects of DHEA or potential precursors to DHEA such as protodioscin are nonexistent. Due to the absence of quality research on DHEA and Tribulus terrestris there is minimal information regarding the long-term safety or efficacy of these agents when used to treat ED. Pro-sexual activity of these agents via increased steroid hormone pro- duction is plausible, but a clear causative relation- ship is yet to be determined.

Conclusion
     Adequate clinical evidence to support natural agents for the management of ED is mini- mal and the compounds discussed here appear to have only a modest effect. Sildenafil offers the first orally effective symptomatic treatment of ED. Oral sildenafil therapy, while effective in circum- venting the cause of ED, provides only short-term symptomatic relief of the condition. Whole pa- tient management of ED might also include psy- chological or relationship counseling, treatment of associated underlying chronic conditions, and the use of natural agents shown to improve de- rangements in penile endothelial L-arginine-NO activity. Oral supplementation with L-arginine, yohimbine, Panax ginseng, Ginkgo biloba, and maca root all appear to benefit penile endothelial L-arginine-NO activity. These substances are far from providing a “magic bullet” or cure for ED. Practitioners and consumers should not be fooled by unsubstantiated claims made by the manufac- turers of natural agents to treat ED. However, these natural agents should not be omitted from the erectogenic armamentarium. L-arginine, yohim- bine, Panax ginseng, Ginkgo biloba, and maca root may provide moderate benefit while affecting un- derlying endothelial dysfunction that contributes to ED. If effective, these agents have the added benefit of allowing patients to respond spontane- ously to their partners.

     aising the penis from a dependent posi- tion to an erect position is a complex neurovascu- lar event modulated by psychological factors and hormonal status. For men, a rigid penis is the cen- terpiece of successful reproduction. Aside from its importance in reproduction, an erect penis pro- vides pleasure, bolsters self-esteem, allows one to foster intimacy, and can act as a means to re- duce stress. Erectile dysfunction is an important public health problem affecting over half of all men ages 40-70. Currently, the majority of re- search pertaining to ED is focused on the mechan- ics of penile erection. Limiting the treatment of ED to the mechanics of erection can be compared to fixing an active smoke detector by removing the battery. The cause of the condition is left ig- nored. We are still far from understanding how to permanently reverse some of the fundamental physiological derangements underlying ED. Truly successful treatment strategies for ED must in- clude the interplay between the mind and the ner- vous, vascular, and endocrine systems that results in erection. As scientists gain increasing insight into the brain’s role in controlling sexuality and the complex mechanics of erections, there is a movement toward a more holistic view of male sexual well being.

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