Long‑term high‑dose L-ARG supplementation in patients with vasculogenic erectile dysfunction

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Abstract

Purpose
The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N=51) compared to placebo (N=47), in patients with vasculogenic ED, with the comparison between mild-moderate and severe vasculogenic ED.

Methods The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU).

Results l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p<0.0001) and in subgroups of patients with mild-moderate (p<0.0001) and severe (p=0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p<0.0001) and in patients with mild-moderate (p<0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with the absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild-moderate vasculogenic ED, reached PSV values compatible with the absence of ED.

Conclusion The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild-moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild-moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.




Introduction

Penis erection, or tumescence, is the physiological process of spontaneous or sexually induced enlargement and hardening of the penis, as a result of a complex interaction of psychological, neural, vascular, and endocrine factors [1]. The first trigger of penis tumescence derives from the peripheral nervous system, which induces, through the inhibition of sympathetic and the stimulation of parasympathetic activity, the relaxation of the smooth muscle belonging either to the wall of the arterial system, which flows into the typical lacunar spaces or to the trabecular structure, which delimitates the lacunar spaces, of the corpora cavernosa; the smooth muscle relaxation leads to cavernous arteries vasodilation and cavernous lacunar spaces extension, with consequent increase of blood inflow into the corpora cavernosa of the penis [1]. The engorgement of cavernous lacunar spaces induces a compression of the cavernous venous system, with a consequent decrease of blood outflow from the corpora cavernosa, ultimately entrapping the blood into the penis and maintaining penis tumescence [1]. The process is reversed by the inhibition of parasympathetic and the stimulation of sympathetic activity, which induces the contraction of the cavernous smooth muscle, leading to a decrease in blood inflow, and the consequent gradual decompression of the cavernous venous system, leading to an increase of blood outflow, ultimately inducing the passage from tumescence to detumescence of the penis, till the achievement of penis flaccidity, a condition characterized by a tonic contraction of the cavernous smooth muscle allowing a small amount of arterial blood flow for nutritional purpose [1]

The process of cavernous smooth muscle relaxation, which is crucial for penis erection, is not only due to sympathetic adrenergic inhibition and parasympathetic cholinergic stimulation, but predominantly induced by the concomitant activation of the nitrergic system and the consequent production of nitric oxide (NO), an important mediator of smooth muscle relaxation [1]. In particular, the activation of the parasympathetic cholinergic neurons determines the release of acetylcholine, which stimulates NO production by the cavernous arteries endothelial NO synthase (eNOS), whereas the activation of the parasympathetic non-adrenergic non-cholinergic (NANC) neurons determines NO production by the NANC neuronal NO synthase (nNOS) [1]. The mechanism of action of NO is based on the activation in the cavernous smooth muscle of the enzyme guanylate cyclase, responsible for the generation of the cyclic GMP (cGMP), activating a molecular signaling pathway determining a decrease of intracellular calcium concentration and consequently the cavernous smooth muscle relaxation, which is at the basis of the penis tumescence [1]. The process is reversed by the enzyme phosphodiesterase type 5 (PDE5), which induces the cGMP hydrolysis, determining an increase of intracellular calcium concentration and consequently the cavernous smooth muscle contraction, which is at the basis of penis detumescence, testifying PDE5 to be a crucial enzyme in the reversion of penis erectile process and in the maintenance of penis flaccid state [1]. It is noteworthy that penis tumescence is modulated by psychological conditions, as well as by the endocrine system, particularly by the androgenic status, which essentially exerts a permissive role for the penile erectile function; indeed, testosterone displays a positive action on desire and sexual function and specifically contributes, through the enhancing of the activity of penile NOS enzymes, to the cavernous smooth muscle relaxation and ultimately to penis erection [2, 3].

Erectile dysfunction (ED) results from pathological derangement of the crosstalk among the nervous, vascular, and smooth muscle systems, involved in the regulation of penis tumescence and detumescence processes [4, 5].
ED is a common pathological condition affecting the male sexual activity and is defined as the inability to attain or maintain a penis erection sufficient for successful intercourse [5]. The prevalence of ED increases with age and is therefore much higher in the elderly than in young men, but still relatively frequent during middle age; the prevalence rates are estimated to range from 1 to 15% and from 6 to 40% in men aged 30–50 and 50–80 years, respectively, whereas a 50 to 100% prevalence is estimated in men older than 70 years of age [6]. The etiology of ED comprises psychogenic and organic diseases, the latter being determined by vascular, neurological, or endocrine disorders, as well as pharmacological factors, which could also occur simultaneously; vasculogenic ED is the most common form of organic ED, and is determined by the reduction of cavernous blood inflow, a consequence of arterial insufficiency, generally induced by vascular disease and, particularly, endothelial dysfunction [4, 7]. The diagnosis of ED is made on the basis of clinical and andrological history and examination, scoring derived by the International Index of Erectile Function questionnaire (IIEF), as well as the performance of penile duplex ultrasonography (PDU) in flaccid status (basal PDU) and/or pharmacologically induced erectile status (dynamic PDU) [4].

The oral PDE5 inhibitors (PDE5i) currently represent the first-line treatment for ED [8–10]. PDE5i inhibits cGMP degradation and increases penile cavernous smooth muscle relaxation, therefore prolonging the effects of cGMP to potentiate the erection [10–12]. Although the great efficacy of PDE5i has been widely demonstrated for the treatment of ED, regardless of the etiology, some factors might limit their employment; in particular, the generally favorable safety profile is limited by contraindications and/or the occurrence of adverse effects, whereas the relevant efficacy is limited by partial or complete resistance in a subgroup of patients, and lastly, the relatively high cost might have a negative impact on the chronic use of this category of drugs; these factors contribute to treatment discontinuation [7–13]. On the other hand, several nutraceuticals, including yohimbine, ginseng, niacin, l-carnitine, and l-arginine (l-ARG), supplemented as single agents and/or in different combinations, have been reported to offer benefits in the treatment of ED, without adverse effects and with the added advantage to have a more affordable cost [14, 15]. Taking into account the concept that nutraceuticals are considered safer and are generally less costly than PDE5i, these agents might represent a valid therapeutic alternative in the treatment of ED, particularly for the treatment of non-severe or at least mild ED, or ED unresponsive to PDE5i, or in case of intolerance to PDE5i.

l-ARG, a conditionally essential amino acid introduced by dietary proteins and produced in the body from the amino acid l-citrulline (l-CIT), has been recognized as a potential candidate in the treatment of ED since it represents the physiological substrate for NO biosynthesis [7, 16, 17].
Indeed, NO is synthesized from l-ARG and oxygen by the nNOS and eNOS enzymes, in the neurons of cavernous NANC fibers and arteries endothelial cells, respectively, with the release of l-CIT, which can be reconverted into lARG, therefore fueling a further NO-producing cycle [18]. Noteworthy, the potential role of l-ARG supplementation is corroborated by the evidence that a significant proportion of patients with ED, particularly of vasculogenic etiology, are characterized by a decrease of NO production in the penile vascular endothelium, such as in the case of ED caused by diabetes and atherosclerosis [16, 17, 19], and by low l-ARG or l-CIT levels, compared to men without ED, therefore suggesting that low levels of these amino acids might increase the risk of ED by inducing the reduction of NO availability [20].

Taking into consideration that NO plays a crucial role as a mediator of penile erectile function and l-ARG represents the physiological precursor for the penile NO biosynthesis, research has been focused on l-ARG supplementation by yielding promising results in the treatment of ED [7]. A meta-analysis of 10 randomized clinical trials (RCTs) with l-ARG supplementation, as a single agent or in combination with additional compounds, demonstrated that supplementation with l-ARG at a daily dose ranging from 2.8 to 8 g, with supplementation schedules from 2 weeks to 6 months, significantly improved mild-moderate ED or overall ED of unspecified severity, compared to placebo-treated or untreated patients, with ED heterogeneously assessed by different tools comprising subjective and/or validated questionnaires, including IIEF, and results being consistent across different dosage and duration of l-ARG supplementation; conversely, a very low dose (1.5 g) of l-ARG administered daily for a very short time (17 days) was ineffective [7].


*The current study aimed at unequivocally addressing the effects of a relatively high-dose l-ARG supplementation, administered as a single compound in a long-term treatment schedule, on penile erectile function in a large cohort of male patients with vasculogenic ED, with comparison of response between mild-moderate to severe vasculogenic ED.




Patients and methods

Study design


The current study is a randomized, double-blind, placebo-controlled clinical trial on the effects of a 3-month l-ARG supplementation on penile erectile function in male patients with vasculogenic ED. The main outcome of the study was the penile erectile function assessed by IIEF 6-item (IIEF6) score and cavernous arteries peak systolic flow velocity (PSV) obtained at dynamic PDU. A secondary aim of the study was to detect differential responses to l-ARG supplementation according to the degree of baseline vasculogenic ED assessed at dynamic PDU. At study entry, patients were allocated to l-ARG or placebo group using standard randomization tables; patients and clinicians were blinded regarding the treatment modality. The intervention schedule included a 3-month treatment with l-ARG (6 g/day), administered orally thrice a day after standard meals, using vials containing 2 g l-ARG/20 ml (Bioarginina®, Farmaceutici Damor S.p.A., Napoli, Italy), or placebo.




The limitations of the current study included the assessment of erectile dysfunction by IIEF-6 rather than IIEF-15 questionnaire, with a consequent potential underestimation of additional domains of sexual function which might have been positively influenced by l-ARG supplementation. Moreover, a relatively small sample size of the subgroup of patients with severe vasculogenic ED might have prevented to capture of slightly significant improvements in PSV at dynamic PDU upon l-ARG supplementation, particularly in patients with borderline scores indicating severity, therefore making it challenging to provide conclusive information concerning the potential effect of l-ARG supplementation in patients with borderline severe vasculogenic ED. The current study has several strengths; to the best of our knowledge, the current study is the largest randomized, double-blind, placebo-controlled clinical trial evaluating the effects of l-ARG supplementation as a single agent in vasculogenic ED, using a longer-term supplementation period with a relatively high dose of l-ARG supplementation. Moreover, this is also the largest randomized, double-blind, placebo-controlled clinical trial with l-ARG supplementation evaluating the penile erectile function at dynamic PDU, the gold standard for the diagnosis of vasculogenic ED; to the best of our knowledge, no other studies addressed the effects of l-ARG supplementation in patients with severe ED of any etiology, and, particularly, no studies specifically focused on severe ED of vasculogenic etiology, by excluding different forms of the disease.





In conclusion, the results of the current study allow speculating that l-ARG might represent a potential alternative for patients with mild-moderate vasculogenic ED with contraindication to PDE5i or who had experienced adverse effects upon PDE5i treatment and might require a different therapeutic approach, or, in association to lower PDE5i doses, to reduce the occurrence and severity of PDE5i-associated adverse effects meanwhile potentially exerting an additive or synergistic effect. Moreover, l-ARG might be also generally preferred in patients with economic constraints and in clinical settings in which tolerability should be privileged over efficacy, such as in the elderly or polypharmacotherapy. Therefore, l-ARG supplementation might be regarded as a potential alternative approach in a variety of clinical settings, spanning different therapeutic requirements in the management of ED; nevertheless, additional studies would be suited to further corroborate the encouraging results presented by the current study and to further widen the field of l-ARG supplementation clinical applicability.
 

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Defy Medical TRT clinic doctor

MIP1950

Active Member
I say this as someone with bipolar illness; high dose arginine for someone with a mood disorder is dangerous. I tried it a few years ago and it brought about dysphoric mania, which is extreme irritability, anger and rage. I didn't tell my wife why I was a walking trip wire as we shouted at each other on and off for three days, when the severe manic episode finally subsided. I was frightened and thought I might have to go in-patient.
 
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