The application progress of L-Arginine in the Treatment of Erectile Dysfunction in Men

Male Erectile Dysfunction (ED) is a multifactorial andrological disorder, with penile cavernosal endothelial dysfunction being one of its core pathological mechanisms. This dysfunction is characterized by insufficient nitric oxide (NO) synthesis and impaired vasodilation capacity, leading to inadequate cavernosal congestion. As the rate-limiting substrate for NO synthesis, L-arginine can improve cavernosal blood perfusion by regulating the NO-cyclic guanosine monophosphate (cGMP) signaling pathway, which provides a solid theoretical basis and promising clinical application potential for ED treatment. It is particularly suitable for subtypes such as vasculogenic ED and diabetic ED. Recent studies have further expanded its application boundaries in combination therapy and precision intervention.

I. Core Mechanisms of L-Arginine in the Treatment of ED

Penile erection relies on the relaxation of cavernosal smooth muscle and vasodilation, a process primarily mediated by the NO-cGMP signaling pathway. L-arginine directly modulates this pathway through the following mechanisms:

Serving as a Specific Substrate for NO SynthesisNitric oxide synthase (NOS) in the vascular endothelial cells and neurons of the penile corpus cavernosum catalyzes the conversion of L-arginine into NO and citrulline. NO diffuses into cavernosal smooth muscle cells, activates guanylate cyclase, and promotes the conversion of guanosine triphosphate (GTP) into cGMP. cGMP reduces the intracellular calcium ion concentration in smooth muscle cells, causing smooth muscle relaxation and sinusoidal congestion and expansion in the corpus cavernosum, thereby achieving erection. ED patients, especially those with vasculogenic ED, often suffer from endothelial damage, which leads to decreased NOS activity and reduced L-arginine utilization efficiency, resulting in insufficient NO production. Supplementation with exogenous L-arginine can directly increase substrate concentration, promote NO synthesis, and improve vasodilation function.

Improving Vascular Endothelial Function and MicrocirculationUnderlying diseases such as chronic hypertension, diabetes, and hyperlipidemia can trigger oxidative stress and inflammatory responses, damaging vascular endothelium, reducing the elasticity of cavernosal blood vessels, and decreasing blood perfusion. L-arginine repairs endothelial function through two approaches:

It promotes the proliferation and repair of endothelial cells, up-regulates the expression and activity of endothelial nitric oxide synthase (eNOS), and enhances endothelium-dependent vasodilation responses.

It inhibits oxidative stress reactions, scavenges excess reactive oxygen species (ROS), reduces the inactivation of NO by ROS, prolongs the duration of NO action in the body, and improves its bioavailability.

Synergistically Regulating Erection-Related Signaling PathwaysPolyamines (putrescine, spermine) generated from L-arginine metabolism can enhance the toughness and relaxation capacity of cavernosal smooth muscle cells. Meanwhile, L-arginine promotes the secretion of vascular endothelial growth factor (VEGF), which induces neovascularization in the corpus cavernosum, improves local microcirculation, and further strengthens erectile function.

II. Clinical Application Progress of L-Arginine in ED Treatment

Applicable Scenarios and Efficacy Data of MonotherapyL-arginine monotherapy is mainly indicated for mild-to-moderate vasculogenic ED and diabetic ED, and it has particular advantages for patients with poor response or intolerance to conventional medications:

Vasculogenic ED: Clinical studies have shown that oral administration of L-arginine (3–6 g daily) for 8–12 consecutive weeks can increase the International Index of Erectile Function-5 (IIEF-5) score by an average of 4–6 points in patients with mild-to-moderate vasculogenic ED, significantly improve erectile hardness and duration, with an effective rate of approximately 60%–70%. Its efficacy is correlated with the patient’s baseline endothelial function, yielding more pronounced results in patients with partially preserved eNOS activity.

Diabetic ED: Due to long-term endothelial damage caused by hyperglycemia, the incidence of ED in diabetic patients is as high as 50%–70%. L-arginine supplementation can alleviate diabetic ED symptoms by improving endothelial function and reducing oxidative stress. A randomized controlled trial involving 120 patients with type 2 diabetes complicated by ED demonstrated that daily oral administration of 6 g L-arginine combined with antioxidants (e.g., vitamin C, vitamin E) for 12 weeks resulted in a significantly greater improvement in IIEF-5 scores compared with the group receiving antihyperglycemic therapy alone, without increasing the risk of hypoglycemia.

Adjuvant Treatment for Psychogenic ED: Patients with psychogenic ED often experience sympathetic hyperactivity and vasoconstriction. L-arginine can alleviate anxiety-induced erectile difficulties by improving cavernosal blood flow, and its combination with psychological counseling can enhance treatment efficacy.

Combination Therapy: A Core Strategy to Enhance EfficacyL-arginine monotherapy has limited efficacy in severe ED, and combination therapy has become a research focus in recent years, as it amplifies therapeutic effects through synergistic actions:

Combination with Phosphodiesterase 5 Inhibitors (PDE5i)

PDE5i (e.g., sildenafil, tadalafil) are first-line drugs for ED treatment, which function by inhibiting cGMP degradation to prolong its smooth muscle relaxant effect. The combination of L-arginine and PDE5i achieves a synergistic effect of “substrate supplementation + signal prolongation”: L-arginine increases NO production, while PDE5i reduces cGMP breakdown. Together, they significantly enhance cavernosal congestion, reduce the required dosage of PDE5i, and minimize adverse reactions such as headache and flushing. Clinical data indicate that the combination of L-arginine (3 g/day) and low-dose sildenafil (25 mg per dose) achieves an effective rate of over 80% in severe vasculogenic ED, which is significantly higher than monotherapy.

Combination with Antioxidants

Oxidative stress is a major contributor to ED; excess ROS inactivates NO and reduces its biological activity. The combination of L-arginine with antioxidants such as vitamin C, vitamin E, and glutathione can scavenge ROS, protect NO from degradation, and improve treatment efficiency. A study on elderly ED patients showed that 12-week treatment with L-arginine combined with vitamin E increased NO levels twice as much as the monotherapy group, with more significant improvements in IIEF-5 scores.

Combination with Hormone Modulators

Low testosterone levels cause atrophy of cavernosal smooth muscle cells and decreased NOS activity, and testosterone supplementation can enhance the efficacy of L-arginine. For ED patients with low testosterone levels, the combination of L-arginine and testosterone replacement therapy can simultaneously improve hormone levels and endothelial function, increasing the treatment effective rate by approximately 30% compared with monotherapy. However, attention should be paid to the risk of benign prostatic hyperplasia induced by excessive testosterone.

Optimization of Administration Routes: From Oral to Targeted DeliveryTraditional oral administration is associated with issues such as low absorption efficiency and first-pass hepatic metabolism. The development of targeted drug delivery technology in recent years has improved the local efficacy of L-arginine:

Intracavernous Injection: Direct injection of L-arginine solution into the corpus cavernosum can rapidly increase local NO concentration, with an onset time shortened to 15–30 minutes. It is suitable for severe ED patients unresponsive to oral medications. However, this approach is associated with adverse reactions such as injection pain and local hematoma, and strict dosage control is required in clinical application.

Transdermal Delivery Preparations: Transdermal absorption technologies (e.g., iontophoresis, liposomal encapsulation) deliver L-arginine locally to the penis, avoiding hepatic metabolism and improving bioavailability. Currently, transdermal gels and patches of L-arginine are in clinical trials, and preliminary data show significant local efficacy with a lower incidence of systemic adverse reactions compared with oral administration.

III. Limitations and Precautions in Clinical Application

Individual Differences in EfficacyThe therapeutic effect of L-arginine is closely related to the patient’s etiology and NOS activity: it yields significant results in patients with mild-to-moderate ED and partially preserved endothelial function, but has poor efficacy in neurogenic ED (e.g., ED caused by spinal cord injury) and organic ED (e.g., penile cavernosal fibrosis). Some patients exhibit “L-arginine resistance”, which may be associated with eNOS gene polymorphism and excessive oxidative stress.

Dosage and Safety

Recommended Dosage: The conventional oral dosage for treatment is 3–6 g daily, administered in 2–3 divided doses. Excessive supplementation (> 10 g daily) may lead to elevated blood ammonia levels, causing adverse reactions such as headache, nausea, and diarrhea, and poses higher risks for patients with hepatic or renal insufficiency.

Contraindicated Populations: It is contraindicated in patients with severe hepatic/renal insufficiency, hyperammonemia, and bleeding tendency (NO inhibits platelet aggregation). Concurrent use with nitrates may cause severe hypotension and is strictly prohibited.

Lack of Unified Treatment StandardsCurrently, there are no unified guidelines for the dosage, course of treatment, and combination regimens of L-arginine in ED treatment. Different studies vary in inclusion criteria and efficacy evaluation indicators. Further large-sample, multi-center randomized controlled trials are needed to clarify its clinical application specifications.

Based on its regulatory effect on the NO-cGMP signaling pathway, L-arginine has clear clinical value in the treatment of mild-to-moderate vasculogenic ED and diabetic ED. Its combination with PDE5i, antioxidants, and other drugs can significantly enhance efficacy, making it an important component of comprehensive ED treatment. Future research will focus on three aspects: first, screening advantageous populations for L-arginine therapy through genetic testing to achieve precision intervention; second, developing efficient targeted delivery preparations to improve local efficacy and reduce systemic adverse reactions; third, exploring the combination of L-arginine with emerging technologies such as stem cell therapy and gene therapy to provide new treatment options for patients with severe ED. With the deepening of research, L-arginine is expected to evolve from an adjuvant medication to a core therapeutic agent in ED treatment, bringing benefits to more patients.