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Abstract

l-arginine, being a natural precursor of nitric oxide, is one of the more commonly used adjuvants to regular medicines in the treatment of erectile dysfunction.

Objectives: Here, in this review article, we aim to highlight various studies and the research studies done on l-arginine in the treatment of erectile dysfunction.

Method: Reviewing the databases such as Medline (PubMed), Cochrane Library, Excerpta Medica dataBASE, Trip, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, and the British Nursing Index.

Results: l-arginine has been studied alone as well as in combination with various other molecules for the treatment of erectile dysfunction, but the studies are very limited in number and have very small sample sizes.

Conclusion: Positive evidence is available for the efficacy of l-arginine and its various combinations. Further research with larger sample sizes and standardized tools are required to recommend the routine use of these products in erectile dysfunction.

Keywords

arginine erectile dysfunction impotence

Introduction

Disorders of sexual function are major health care problems with the erectile problems forming a major part of them. According to the Massachusetts Male Aging Study, 52% of males between 40 and 70 years of age are affected with erectile problems, and about 70% of males are having some subjective issues with erections.^1,² Many of the patients have only mild to moderate severity and often report their problems as intermittent and unpredictable, but not requiring regular use of prescription drugs with unpleasant side effects. There are only a few alternatives for such patients and, even in them, efficacy is many times not more than placebo.

Erection is a neurovascular event in which a key mediator is nitric oxide (NO). It has been shown that there is reduced NO bioactivity in erectile dysfunctions (ED)³ as l-arginine is a natural precursor of NO and its good availability is understood to have positive effect on NO production. Data regarding the pattern of use of l-arginine for sexual problems, which is considered one of the more widely used alternatives or adjuncts to regular drugs used in the patients of ED, is lacking.

The purpose of this review is to look at the evidence available for supporting the use of arginine in such patients, either as a standalone agent or in combination with other molecules.

Pharmacology of l-arginine

l-arginine is a semi-essential amino acid present in the dietary proteins. It is also produced in the body from l-citrulline, another semi-essential amino acid produced in the gastrointestinal tract from glutamine, which is converted into l-arginine in the kidneys. l-arginine is acted upon by the NO synthase isoforms to produce NO, which is released from the cavernosal nerve endings and endothelial cells in the penile artery,⁴ upon reception of stimuli from the spinal cord. The release of NO starts a cascade effect which ultimately results in the smooth muscle relaxation in the corpora cavernosa, veno-occlusion, and erection of the penis. When given orally, l-arginine is almost entirely absorbed through the intestinal brush border membrane. It undergoes extensive first pass metabolism, with bioavailability varying between 5 to 50% and 51 to 87%.⁵ It reaches peak plasma concentration in 20 to 30 minutes and has a half-life of 1.5 to 2 hours. l-arginine is generally well tolerated in oral doses of 9 g/day or less. It may lead to decrease in blood pressure but that is not significant.⁵ There may be nausea and vomiting in 3% of the patients. Abdominal cramps and bloating have been seen in those with cystic fibrosis. Blood urea nitrogen and urea may increase in patients with impaired renal function.⁵ The qualities that make arginine a widely used supplement for ED are natural origin, good bioavailability after oral absorption, and its good tolerance allowing for long duration of treatment.⁶

Results

Our literature search yielded 14 human subject trials of either l-arginine alone or l-arginine in combination with other molecules for the treatment of EDs. The numbers of study subjects were uniformly small: the largest study by Ledda et al⁷. Almost all the studies were placebo-controlled. Many of these studies describe themselves as “pilot studies,” intended to explore the feasibility and appropriateness of future research, rather than having a goal of definitively determining the relative efficacy of l-arginine in ED.

l-arginine Alone

It has been reported that l-arginine, when given below the daily dose of 3 g/day, is ineffective for general therapeutic implications and, specifically for ED, 1.5 g/day has been shown to be ineffective.¹¹ Some studies have evaluated l-arginine in doses between 2.8 and 6 mg/day for up to 6 weeks, and have reported beneficial effects,^8-¹⁰ but these studies have not evaluated the subjective improvements using a validated questionnaire, and thus the results remain circumspect. Interestingly with Chen et al,¹⁰ it was noted that those reported improvement had low urinary nitrite/nitrate, the excreted metabolic products of NO, suggesting that those with low NO levels are more likely to improve with l-arginine supplementation.

l-arginine and Pycnogenol

l-arginine has been studied and marketed in combination with pycnogenol, in a branded formulation named prelox. Pycnogenol, a pine bark extract, consists of phenolic acids such as p-hydroxybenjoic, p-cumaric, caffeic and ferulic acid, and taxifolin and catechin.²¹ It has been shown to be a good antioxidant22 and has positive effect on cardiovascular functions.²³ It has been shown to have a role to play in enhancing endothelial nitric oxide synthase to produce more NO from l-arginine,²⁴ which also forms the rationale behind combining the two. It is one of the better studied arginine products for ED. The studies12-14 show a significant improvement in erectile function, including decreased time to achieve erection and increased duration of erection. Interestingly, this combination has also seen to have a positive effect on sperm quality and sperm motility. One study has also claimed that out of 50 couples, with the male having bad sperm quality, 21 conceived during the treatment period of the study.¹³

These studies have found a lesser percentage of subjects reporting improvement in erectile function till they were being given l-arginine alone and showed significant improvements when pycnogenol was added to it. All of them have used the dose of l-arginine about 3 g/day and pycnogenol 40 to 120 mg/day.

l-arginine and PDE-5 Inhibitors

Phosphodiesterase-5 (PDE-5) inhibitors are the first-line drugs for the treatment of ED. Since l-arginine supplementation and PDE-5 inhibitors act at different points in the physiological process of erection, it is logical to hypothesize that there might be some synergistic effect between the 2. Only two studies were found evaluating the effect of combining a PDE-5 inhibitor with l-arginine for erectile dysfunction and comparing with PDE-5 inhibitor alone: one for sildenafil15 and one for vardenafil.¹⁷ Both the studies showed a small but significant advantage of adding l-arginine to the treatment.

l-arginine and l-citrulline

l-citrulline, a semi-essential amino acid like l-arginine, can be converted to l-arginine physiologically. Both l-arginine and l-citrulline levels have been shown to get lowered in severe ED/arteriogenic ED²⁵. l-citrulline and l-arginine supplementations have been shown to rapidly and effectively increase NO bioavailability and cyclic guanosine monophosphate (cGMP) concentrations²⁶. l-citrulline supplementation has been shown to improve erectile function in rats with acute arteriogenic ED²⁷ and one study has shown improved erection in mild ED patients,²⁸ though there have been no studies in humans with l-citrulline and l-arginine combination. The advantage of l-citrulline over l-arginine is that it does not undergo first-pass metabolism nor it is metabolized by intestinal bacteria.

l-arginine and Yohimbine

Yohimbine, an alpha adrenergic antagonist, was one of the oral erectogenic agents prescribed before the advent of PDE-5 inhibitors. Several randomized control trials have assessed yohimbine in ED, individually, reporting an efficacy of about 34% to 73%.^29-³¹ It has been assessed in combination with l-arginine in one study, with the rationale being the penile vasodilation induced by the blockage of adrenergic tone and the NO that is being released by the arginine. A 2005 study found the combination to be safe, well tolerated and bioavailable.³² There has been only one study assessing this combination in ED.¹⁷ The combination was used on an on-demand basis and showed significant results but the development of this combination for ED was abandoned due to regulatory issues involving yohimbine.

l-arginine and Propionyl-L-carnitine

Propionyl-L-carnitine (PLC), a short chain fatty ester of carnitine, is a natural part of energy metabolism in mammals.³³ It has been found useful in several conditions including peripheral artery disease, diabetic neuropathy, and resistant Peyronie’s disease.^34-³⁶ Though its mechanism of action is not very well understood, the beneficial effects are thought to be, in part, due to vasodilation and improved blood flow.³⁷ It has also been reported that it protects against and restores damaged cells.³⁶ It has been studied for ED, especially due to organic causes in combination with PDE-5 inhibitors¹⁶ and acetyl carnitine.³⁸ It has been studied in combination with l-arginine with statistically significant improvements,^16,¹⁸ suggesting favorable cardiovascular effects reflecting in the erectile function.

Table 1:

Articles reviewed on the use of l-arginine in erectile dysfunction

Study	Methodology	Diagnosis	Drug Used	Sample Size	Instrument Used	Results
Boucharlat et al⁸			l-arginine			Significant improvement
Zorgniotti et al⁹			l-arginine			Significant improvement
Chen et al¹⁰	Prospective,randomized, double-blind, placebo-controlled	Organic ED	l-arginine5 g/day for 6 weeks	50	O’Leary’s questionnairePlasma and urine nitrite and nitrate	31% patients taking l-arginine showed significant subjective improvement and all these patients had low urine nitrite/nitrate at the start of the trial.
Klotz et al¹¹	Randomized,placebo-controlled,crossover, comparison	Mixed type impotence	l-arginine - 3×500 mg/day	32	KEED	Only 5% patients had significant improvement
Lamm et al¹²	Randomized, double-blind, placebo-controlled		l-arginine 3 g/day + pycnogenol 80 mg/day for 1 month	40	International index of erectile function (IIEF)	73% reported erections are easier to initiate and 70.3% reported erections are easier to sustain
Stanislavov¹³	Randomized, double-blind, placebo-controlled	ED	l-arginine 3 g/day for 1 month, followed by l-arginine 3 g/day + pycnogenol 80 mg/day for 1 year	50 men of age >45 years	IIEF	Significant improvements in restoration of normal erectile function in 80% of the subjects.Significant improvements are also seen in sperm quantity and sperm quality
Stanislav et al¹⁴	Randomized, double-blind, placebo-controlled	Mild to moderate ED	Prelox l-arginine and pycnogenol, compared toplacebo for 1 month	50	Patient diaries, endothelial nitric oxide synthase (e-NOS) in spermatozo—ablood testosterone routine clinical chemistry	Intercourse frequency doubled, e-NOS and testosterone levels increased significantly, and cholesterol levels decreased
Ledda et al^l7	Double-blind, placebo-controlled, randomizedparallel arm study	Moderate ED	Preloxformulation of l-arginine and pine bark extractcompared to placebo for 6 months	124	IIEF	Significant improvement in erectile function (P<.005)Significant increase in mean serum testosterone levels (P<.05)
Mantovani et al¹⁵	Double-blind, placebo-controlled, randomized clinical trial	ED in patients who had undergone radical pelvic floor surgery in last 3 years	l-arginine with sildenafil, compared with sildenafil alone	1¹⁶	Buckling test, telephonic interview	Starter dose was 50 mg which was inefficient in both groups (Buckling test between 0 and 250).
						100-mg doses gave significant results (Buckling test >500) in both groups, especially the second
Gentile et al¹⁶	Randomized, placebo-controlled	EDin patients of insulin dependent diabetes mellitus of 50 to 60 years of age	1 sachet of propionyl-l-carnitine (PLC), l-arginine (l-arg) and nicotinic acid dailyvsvardenafil 20 mg twice a week vs 1 sachet of PLC, l-arginine, nicotinic acid + vardenafil 20 mg twice a weekvs placebowith total duration of treatment being 12 weeks	40	IIEF-5	Vardenafil alone showed an improvement of 4 on IIEF-5 and in combination with PLC, l-arginine, and nicotinic acid there was improvement of 5
Lebret et al¹⁷	Double-blind, placebo-controlled, 3-way crossover, randomized controlled trial	ED	l-arginine – 6 g with yohimbine 6 mg, 1 to 2 hrs before intercourse,compared to 6 g l-arginine with placebo	45	IIEF	Significant improvement (P<.0006)
Gianfrilli et al¹⁸	Single-blind, one-arm study	ED	PLC, l-arginine and niacinfor 3 months	54	IIEFGlobal Assessment Questionnaire (GAQ) Routine investigations	Statistically significant improvement with 40% cases reporting improved erections and 77% showing partial response
Neuzillet et al¹⁹	Double-blind, placebo-controlled, two-way crossover, randomized clinical trial	Mild to moderate ED	l-arginine 8 g with 200 mg adenosine monophosphate orally 1 to 2 hrs before intercourse,compared with placebo alone	26	IIEFErection hardness score Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS)	Significant improvement in both patient and investigator assessment of treatment success
Ito et al²⁰	Open label intervention study	Mild to moderate ED	Arginmax tablets twice, daily for 4 weeks	25	Sexual FunctionQuestionnaire	Significant improvement in both ability to maintain erection and overall sexual satisfaction

l-arginine and Adenosine Monophosphate

Adenosine monophosphate (AMP) is a purine nucleotide that has been shown to have erectogenic action, and it has also been found that l-arginine and AMP potentiate other’s action.³⁹ AMP is converted to adenosine in the bloodstream which further causes smooth muscle relaxation leading to erection.⁴⁰ The rationale for combining l-arginine, apart from the mutually potentiating action, is the close pharmacokinetic profile, with both reaching the plasma peak between 30 and 60 min, and decrease in 1 to 2 hours.^5,⁴¹ This profile favors the “as in when required” use of the combination. There has been only one study on this combination and it found positive effect for use in mild to moderate ED.¹⁹

Arginmax

Arginmax is a combination of l-arginine and vitamins such as B-complex, C, and E, and minerals such as zinc and selenium as well as ginseng and ginkgo. It has been shown that the deficiency of the vitamins of B-complex can result in low mood, low energy, and low sexual desire.⁴² The vitamins B6, B9, and B12 are known to regulate the levels of homocysteine, the high levels of which can result in decreased NO production and ED.⁴³ There are also some reports of the improvement of erectile function with vitamin B114 and B344,⁴⁵ supplementations. Zinc deficiency has been known to be associated with testosterone deficiency,⁴⁶ and zinc supplementation has been shown to reverse the reduced testosterone levels,⁴⁷ though the results are mixed. It has not been shown whether zinc supplementation results in increased testosterone in normal individuals, thereby resulting in increased sexual desire. Selenium has no evidence for efficacy in increasing sexual desire or ED, though it has been found to have some role in infertility.⁴⁸ Ginseng is a popular herbal product used for male sexual enhancement. It helps release NO and induces carvernosal smooth muscle relaxation. A placebo-controlled trials of ginseng in male have shown positive effect.⁴⁹ Ginkgo biloba is also a herbal product thought to have a positive effect on depression and sexual dysfunction, though results on sexual performance are mixed.^50,⁵¹ Arginmax has mostly been studied in women.^52,⁵³ In men, only one small study has been done using arginmax, showing improvement in their erectile functioning.²⁰

Conclusion

l-arginine is one of the more commonly used adjunctive agents used, in routine practice, for patients of erectile function and we tried to take a look at the evidence justifying its use. l-arginine has been studied alone as well as in combination with different molecules, with varying rationales. Though there is positive evidence for the use of l-arginine in combination with other molecules, this evidence is restricted to a very limited number of studies and even those studies have very small sample sizes, and should rather be considered pilot researches instead of full-fledged evidence of efficacy in ED. l-arginine or its combinations need to be evaluated with bigger sample sizes and well-designed methodologies with the use of standardized tools of erectile function.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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l-arginine and Erectile Dysfunction

Abstract

Abstract

Keywords

Introduction

Pharmacology of l-arginine

Results

l-arginine Alone

l-arginine and Pycnogenol

l-arginine and PDE-5 Inhibitors

l-arginine and l-citrulline

l-arginine and Yohimbine

l-arginine and Propionyl-L-carnitine

Articles reviewed on the use of l-arginine in erectile dysfunction

l-arginine and Adenosine Monophosphate

Arginmax

Conclusion

Declaration of Conflicting Interests

Funding

References