Menafra D, de Angelis C, Garifalos F, et al. Long-term high-dose L-arginine supplementation in patients with vasculogenic erectile dysfunction: a multicentre, double-blind, randomized, placebo-controlled clinical trial. J Endocrinol Invest. 2022;45:941-961.
Twelve-week, multicenter, double-blind, randomized, placebo-controlled clinical trial
To assess the effects of high-dose L-arginine (L-ARG) as a single-agent, therapeutic vasodilator in patients with vasculogenic erectile dysfunction (ED)
High-dose L-arginine improves erectile dysfunction that is mild to moderate and vascular in origin. There was no improvement in men with severe ED.
Investigators recruited 100 Caucasian males, aged 20 to 75 years. These men were evaluated for vasculogenic etiology for ED and assessed with an IIEF-6 (International Index Erectile Function, Six Questions) questionnaire and penile duplex ultrasonography (PDU). Inclusion at baseline was a score for ED on the IIEF-6 and a peak system velocity (PSV) of the cavernous arteries under 35 cm/s on PDU. Values were assessed again after 12 weeks of intervention.
Ninety-eight men completed the study. This initial cohort was further divided into 2 subgroups, classed by the IIEF and PSV as “Mild-to-Moderate” and “Severe.” The entire cohort was randomized to L-ARG or placebo, regardless of severity of ED. Both patients and clinicians were blinded to who was in each group.
Mild to Moderate
PSV by dynamic PDU
- Age: 20–75 years
- Stable sexual relationship
- International Index of Erectile Function (IIEF-6) Questionnaire score equal to or below 21 (mild-to-moderate ED)
- Normal serum total testosterone
- Normal serum prolactin levels
- PSV<35 cm/s
- Use of vasodilatory medications
- Drugs that impact erectile function
- System and organ disease
- Suspicion of alcohol abuse
- Endocrine disorders that affect erectile function (EF)
- Use or abuse of addictive substances
- Cardiovascular or cerebrovascular events within the last 6 months
- Unstable hemodynamic conditions
- Radical pelvic surgery
- Psychiatric disorders and/or treatment of psychiatric disorders
Study Medication & Dosage
The experimental group of 51 men received 2 grams, 3 times a day, of L-ARG as Bioarginina™. Bioarginina is manufactured by Damor Pharmaceuticals in Naples, Italy, and is accessible over the counter. The ingredients include: sucrose; L-arginine, citric acid, and preservatives.
Participants in the control group received a placebo indistinguishable from the intervention.
At baseline (T0), patients answered the IIEF-6, underwent a dynamic PDU, gave a medical, pharmacological, and sexual history, and had a complete physical examination including body mass index (BMI), blood pressure, and labs (fasting glucose, triglycerides, total and high-density lipoprotein [HDL] cholesterol, renal and liver function tests, testosterone, and prolactin). This same assessment was repeated at the end of 12 weeks (T1).
The study had 2 endpoints. The primary was to assess the change in erectile function by patient report and PSV following 3 months of 6 grams per day of L-ARG.
The secondary aim of the study was to ascertain whether there was a difference in response to L-ARG based on the degree of vasculogenic ED assessed by dynamic PDU at baseline.
At 6 g/day of L-ARG, there was significant improvement in the mild- and moderate-ED subgroup versus the placebo group, but there was no improvement in the arterial function of those in the severe ED group.
Outcome as measured by the IIEF-6
Intervention group as reported by the IIEF-6:
Of note is that researchers observed the benefits in the mild-to-moderate ED group only. Specifically, 74% of men improved in the ED category, with average scores of 20 (range 16–24) on the IIEF-6 rising 4 points to average scores of 24 (range 19–25.3) at T1 (P<0.0001]. Of the 51 men in the intervention group, 24% (12 men) reported an absence of ED after 12 weeks of treatment.
There was no significant response in those who reported severe vasculogenic ED at baseline.
Control group as reported by the IIEF-6:
In the placebo group, at T1, IIEF-6 score was unchanged compared to T0.
Outcome as measured by dynamic PDU
Intervention group as reported by PDU:
Of note is that researchers observed the benefits in the mild-to-moderate ED group only. In the L-ARG group, PSV significantly increased by approximately 5 cm/s, from 25.9 (range 24.6–28) to 30.5 (range 23.4–34.3) cm/s (P<0.0001). The prevalence of mild-to-moderate vasculogenic ED significantly decreased in the intervention group from 64.7% to 44% (P=0.047). Of the 51 men in the intervention group, 20% (10 men) reported an absence of ED after 12 weeks of treatment.
There was no significant response in those who reported severe vasculogenic ED at baseline.
Control group as reported by PDU:
In the placebo group, at T1, PSV was unchanged compared to T0.
Conflict of Interest
One of the study authors received a “consultant honoraria” from Damor.
Erectile dysfunction is a serious health issue affecting up to one-third of adult men. It’s projected to impact up to 322 million by 2025.1 Defined as the inability to achieve and/or maintain an erection sufficient for satisfactory intercourse, it can have a profound negative impact on a man’s quality of life: loss of self-esteem; avoidance of intimacy; anxiety and depression. These can burden the relationship between sexual partners, lower libido, and challenge a man’s ability to connect to his authentic self and to others.1
ED could well be considered a syndrome with a multidimensional and complex pathology. ED is also an opportunity to look at health holistically, given that psychological, hormonal, immune, and/or metabolic issues underlie the pathogenesis. To emphasize this interplay, consider that ED is both an independent risk factor for the development of metabolic syndrome, cardiovascular disease, and type 2 diabetes and also a consequence of these disease processes. It can further be characterized as an increased mortality risk.1,2
Nitric oxide (NO) is believed to be the main vasoactive neurotransmitter and chemical mediator of tumescence. L-arginine (L-ARG) is the substrate and sole NO donor. This is accomplished through nitric oxide synthase cleaving the NO from L-ARG, resulting in L-citrulline and nitric oxide products. This reaction is critical to the vasodilatory cascade of physiologic erection.
When given orally, L-arginine is absorbed through the intestinal brush border membrane. It undergoes extensive first-pass metabolism, with a wide range of bioavailability, between 5% to 87%. It reaches peak plasma concentration in 30 minutes and has a half-life of 2 hours. In some cases, L-ARG can contribute to hypotension due to vasodilation; 3% of the population experiences nausea; cystic fibrosis patients may experience abdominal cramping; and those with renal failure may have elevation of BUN (blood urea nitrogen) and urea. In general, it’s well-tolerated at oral doses of <9 g/day.3
The most recent systemic review and meta-analysis of L-ARG on erectile function, published in the Journal of Sexual Medicine, looked at 10 randomized controlled trials with a total of 540 subjects. The analysis supported the outcomes of Menafra et al’s study, demonstrating that arginine ranging from 1,500 to 5,000 mg per day improved mild-to-moderate ED compared to placebo.4 However, most of this literature looked at the efficacy of L-ARG in combination with conventional and other therapies.1,5 The Menafra et al study reviewed here is notable because it illustrates the potential of L-ARG as a monotherapy to improve vasculogenic erectile dysfunction.
The 2018 American Urological Association (AUA) ED Guidelines approach management of ED by addressing psychosocial factors, underlying etiology (eg, use of antidepressants or antihypertensives), cardiovascular risk, and lifestyle (ie, smoking, obesity, nutrition). The AUA no longer advocates first-, second-, or third-line therapy for erectile dysfunction; rather the principles of shared decision are the new gold standard. After discussion about the risk, benefits, and alternatives to treatment options for ED, patients may select whichever form of therapy best fits their needs.
Despite a shared decision-making model, many clinicians still favor phosphodiesterase-5 inhibitors (PDE5i). However, this drug class is contraindicated with nitrate use, drugs used for benign prostatic hyperplasia, and cyp3A4 inhibitors, including natural therapies. Combining these with PDE5i can potentiate hypotension and extend the half-life of PDE5i increasing the duration of an erection to a painful degree, as well as causing adverse events including flushing, headaches, and dyspepsia.
Another drug approach to ED is prostaglandin E1 administration, such as alprostadil. Generally, alprostadil can be given as an intraurethral suppository or as an intracavernosal injection. Both approaches are contraindicated with anticoagulants and can cause blurred vision, confusion, dizziness, and sweating. Nondrug means, such as vacuum constriction, work best with daily use before and after surgery or radiation in patients with pelvic cancers (prostate, colorectal, or bladder). This method is ideal to facilitate oxygenation via vascularization of penile tissues but can be ineffective if introduced late. Inflatable prosthetics have a risk of adhesions and malfunction.
Problems with the Menafra et al study may lie primarily in the fact that the researchers attempted to isolate ED to a singular vascular etiology and exclude other causes. However, vascular causes are married to other types of injury. The probability of a patient presenting with exclusively vasculogenic ED—and no hormonal, psychosocial, metabolic, or nervous system injuries—is slim.
The authors did exclude endocrine system diseases that contribute to ED, primarily through their interference with testosterone. However, subclinical syndromes that demonstrate a link between hormonal health and metabolic health are difficult to parse out. Diabetes, while endocrinological in nature, has ruinous effects on the cardiovascular system, and it was not an exclusion by study authors. Additionally, the authors did not explicitly discuss neurologic erectile dysfunction or history of physical trauma, including spinal cord or back injuries, multiple sclerosis, peripheral neuropathy, autonomic dysfunction, pelvic surgeries (eg, radical prostatectomy), and pelvic radiation. Lastly, it’s unclear which drugs that may contribute to ED were excluded; the list of commonly prescribed drugs that result in ED or conflict with PDE5i is long.
It’s also worth discussing the age range of 20 to 75 years. It’s astute to include younger men, as anxiety, depression, sleep disturbances, and low body image continue to emerge as etiology of ED in men under 40. Most clinicians are aware that ED increases with age, but in our experience, it’s often missed in a routine psychosocial assessment of younger men.
The challenge here is that relational issues, mood, libido, cultural factors (social media and pornography), and psychological trauma and history of abuse often go underreported by patients and missed by clinicians.
The 100 participants were randomized into control and experimental groups and then placed into mild-to-moderate and severe ED subgroups. However, with regard to participants’ ages, it is unclear what the actual composition of the subgroups was. This obscures the secondary aim of looking at a differential impact based on severity of ED.6 Suppose the average age of the “Severe” ED group is older than the “Mild-to-Moderate” ED group; in that case, the results could indicate that L-arginine is less effective in older patients as there was no statistically significant improvement in this subgroup across the study.
ED could well be considered a syndrome with a multidimensional and complex pathology.
Additionally, the sample population was exclusively Caucasian, presumably Italian, with no stratification for socioeconomic factors that may affect the ability to afford supplementation and no discussion of lifestyle factors such as nutrition that may confound Table 1 data.
Indigenous Peoples, Pacific Islanders, Latin and Chicano men, and individuals from the African diaspora trend toward higher rates of metabolic dysfunction.7,8,9 The prevalence of metabolic disease in these men suggests that the endothelial nitric oxide synthase (eNOS) function and circulating endogenous L-ARG would be diminished.6,10 Future studies should conduct a similar study with recruitment of more diverse participants for a more realistic and clinically useful trial of L-ARG in ED.
Some studies identify the presence of eNOS polymorphisms and cardiovascular risk and other diseases.11,12 The homogeneity of the sample population would not account for these gene polymorphisms. It would stand to reason then that if the function of eNOS pathways can vary among ethnic groups, there is a need to understand how L-ARG affects erectile function in each of these groups. Again, future studies should be done with more diversity built into the design and recruitment.
As another point of discussion, using in a clinical setting the IIEF-6 questionnaire, though it’s a well-established and evidence-supported tool, has limitations.13
While the questionnaire asks about the use of erectile aids (eg, intracavernosal injections, vacuum devices, constriction rings), it is unclear if men using these aides should complete the questionnaire or if their scores should be evaluated differently from men who are not using erectile aides.13
The IIEF-6 opens with a prompt defining sexual function to include: “erectile response to foreplay, masturbation, intercourse, and other forms of sexual activity.”13 However, the questions themselves use only the term “intercourse,” which can lead the patient to exclude other means of experiencing erection and score for no response.
Moreover, the questionnaire specifies sexual activity within the “Last four (4) weeks.”13 Men may have low libido or abstinence practices, yet sufficient erectile function. The IIEF-6 questionnaire does not account for men who do not have partners, different sexual preferences and orientations, nonpenetrative sexual activity, or histories of trauma (sexual and otherwise). A patient who has not had sexual activity within 4 weeks would answer, “Almost never/Never,” with a score of zero. This would significantly lower their total score and inappropriately place them in the ED category.
Reframing clinical language is a critical piece of mediating health disparities. For example, the choices on the questionnaire include “A Few Times,” “Most Times,” and “Sometimes.” Also, there are no substitutes with colloquial terms. Patients don’t necessarily speak the language of their doctors. Terms for sexual activity and lifestyle can be subject to cultural interpretation. They may also be difficult for a patient to truly quantify. For example, 5 instances of poor erectile function can be “A Few Times” for someone with a high sexual frequency, but “Most Times” for a man with a lower frequency.
The strengths of the Menafra et al study are that it has a simple, elegant design, dose, and length of intervention and that it was randomized and double-blinded. It lends itself to a growing cache that considers alternatives as monotherapy. PSV via dynamic PDU is a clean measurement to support statistical strength.
Standard of care is to consider alternatives if patients have concerns about pharmacotherapy, and it’s clear that L-ARG is a promising alternative with enough positive data for a generalist to make a recommendation. If you are recommending L-ARG, consider that presystemic metabolism of L-ARG can affect its concentration as an eNOS donor. Cormio et al conducted a single-blind study in 2011 illuminating the potential for L-citrulline as an intervention for erectile dysfunction.14 L-citrulline as a precursor to L-arginine escapes presystemic metabolism and is available for nitric oxide production following conversion.
Success with L-ARG as a single therapeutic may depend on the dose and length of supplementation. Menafra et al bring attention to earlier data where L-ARG as a monotherapy did not yield similar outcomes.15 The authors attribute the difference in results to lower doses (1.5 g daily) and brevity of intervention (less than 3 weeks). It’s worth considering that high doses of L-ARG can upregulate the proliferation of herpes simplex virus (HSV), burdening an individual’s health. To that end, an integrative approach with combination therapy may, in fact, be more effective and allow the clinician to use lower doses of L-ARG, as low-dose L-ARG in combination with other inventions like PDE5i shows success. In fact, the combination of nutraceuticals with PDE5i potentiates the effect of Sildenafil in diabetic patients, and a combination of L-ARG and acetylcarnitine improves the clinical response to PGE1 injection in patients’ status post radical prostatectomy.1,5
It bears repeating that standard-of-care guidelines for the treatment of ED begin with psychological intervention. Redirecting men and their partners away from the idea of goal-oriented sex as a directive of masculine identity is a significant step in removing barriers to intimacy. A meta-analysis shows that psychotherapy and supplementation significantly improved ED versus supplementation alone and that the effects last longer.16 Sensate focus, a form of counseling that uses meditation, mindfulness, and sensory focus to improve intimacy and communication around sex, also has strong data in redressing male sexual dysfunction.17
It is equally important to address nutrition, smoking cessation, exercise, stress, and sleep modification in the initial protocols for ED treatment. Supportive care includes guided visualization, pelvic floor physical therapy, and visual, vibratory, pressure, and positional stimuli. Emerging first- or second-line therapy includes low-intensity shock, stem cell, and hyperbaric oxygen therapy.
In our practice, we see primarily oncology men who have received androgen deprivation therapy for prostate cancer and surgery and/or radiation for prostate and colorectal cancer. For us, supplementation with L-ARG would seem to be relatively useless as our patients usually score in the “Severe” category on the IIEF. It’s also worth considering that, given its contribution to vascularization of the tissue, it may serve as a metabolic substrate for cancer cell growth. We cannot confidently recommend L-ARG to an oncology population. However, if we offer early intervention in improving erectile function prior to treatment, are careful in choosing skill of surgeon and caseload, and start PDE5i, supportive care, and vacuum device early, we end up with decent residual nerve and vascular function.
When you make recommendations, consider cost. A 12-week course of L-ARG from a high-quality brand can run anywhere from $350 to $550, and one would suppose that a patient would need to continue therapy well after 12 weeks. Other considerations include source, as bioavailability can vary based on isomeric form. A solution to both cost and bioavailability could be combining L-citrulline with an L-arginine protocol. L-citrulline allosterically inhibits arginase in the gastrointestinal and hepatic tissues, blocking the first-pass metabolism of L-arginine and increasing plasma L-arginine concentrations.18
The Menafra et al study expands the conversation about alternatives to PDE5i and spotlights the impact of powerful therapeutics in the natural world. As a reminder for clinicians, developing strong relationships with urologists in your region and helping patients to navigate providers is important. Annual urological caseloads of more than 25 radical prostatectomies a year and total cumulative caseloads of more than 1,000 radical prostatectomies result in better erectile function outcomes. Honing skills in sex and other relevant history are foundational, as early aggressive intervention in vascular health is critical. On a scale of 1 to 10 for the quality of erection, patients who obtain a value of 6 or higher before treatment show substantially better outcomes.19
It’s easy for providers and patients alike to feel discouraged. However, it’s a matter of perspective. It’s not off the mark to consider the pressure many men feel to associate erectile function with masculine identity and the ability to please others. Studies show that patients report greater relationship satisfaction after holistic treatment for erectile dysfunction because such treatment includes self-exploration and a greater confidence in a man’s self and his ability to connect with others.20