Erectile dysfunction (ED) refers to the persistent or recurring phallic erection that is difficult to obtain or maintain enough to meet sexual needs (1, 2). ED is a very common and increasingly serious male disease worldwide, and the risk of the disease is increasing with age (3, 4). It is estimated that nearly 140 million men worldwide are suffering from varied degrees of ED, and ED is expected to affect 322 million people by 2025 (5, 6). There are many reasons for ED. Age, smoking, psychological disorders, unfavorable socio-economic conditions, depression and psychiatric illness, cardiovascular diseases, diabetes, hypercholesterolemia (7), obstructive sleep apnea (8), and celiac disease (9) are all risk factors for ED. ED is often caused by other diseases, so it is easy to be ignored.

Priapism is a normal physiological response (10). When the body experiences sexual stimulation, paraspathetic nerve activity from the sacral part of the spinal cord triggers a series of reactions, releasing nitric oxide (NO) and increasing the intracellular cyclic guanosine monophosphate (cGMP). NO is essential for achieving an erection. NO is the messenger cell of penile erection, which is produced by neuronal NO synthase (NOS) of penile non-adrenergic, non-cholinergic nerve terminals and endothelial NOS (E-NOS) of penile artery endothelial cells. After NO production, it binds to guanylate cyclase in the smooth muscle cells of the corpus cavernosum to generate cGMP. Increased cGMP leads to relaxation of vascular smooth muscle and increased blood flow into the corpus cavernosum. This rapid blood inflow leads to compression of the venous network and reduction of venous outflow, thereby increasing the intracavernous pressure of the penis and leading to erection (11, 12). When cGMP is degraded by phosphodiesterase type 5 (PDE5) enzymes, the erection eventually subsides (13). Patients with mild ED can be treated with medications such as oral PDE5 inhibitors (PDE5is) (14). Although PDE5i is now widely considered a first-line treatment for ED, up to 35% of patients do not respond to it (15). Patients with moderate to severe ED need to be treated with cavernosal active drug injection, vacuum erection device, and even prosthesis implantation (14). These methods are often not acceptable to patients because they are invasive, complex, and expensive (16). Therefore, a more effective treatment for ED is required.

L-arginine is an amino acid compound obtained by the human body from diet and endogenous metabolism. L-arginine is the substrate of many enzyme pathways involved in the regulation of vascular tone, immune activation, and cell growth (17). As a substrate of NOS, it is catalyzed by NOS to convert to NO. Studies have shown that oral administration of L-arginine can improve sperm quality and erectile function in male infertility patients (18). Pycnogenol, an extract from the bark of French Marine pine, is a substance composed of proanthocyanidins, monocatechin, paclitaxel, phenolic acid, and other flavonoids. Pycnogenol is a very strong antioxidant (19), which increases NO synthesis by catalyzing E-NOS (19, 20). When Pycnogenol ® is administered in combination with L-arginine, the substrate of E-NOS, a synergistic effect of NO production can be achieved (21). Clinically, the combination of Pycnogenol ® and L-arginine (PAL) has been evaluated in several randomized controlled trials (RCTs). Existing research results showed that the combined treatment of PAL had inconsistent results in improving the sexual function index of patients with ED.

Because of the limited number of studies available on the combination of PAL in patients with ED, there is a lack of uniform evaluation criteria for efficacy and safety of combination therapy. Therefore, it is necessary to study the efficacy and safety of the combination of PAL in the treatment of patients with ED. To our knowledge, this study is the first meta-analysis to compare their therapeutic effects. It is expected to provide more reliable evidence for the efficacy and safety of the combination of PAL in patients with ED.

ED is a disorder common in men and has extremely serious negative effects on the quality of life of men worldwide (27). Vascular, hormonal, neurological, psychological, lifestyle, and aging factors all play a role in the development of ED, and, when the role of one of them is unusual, all of them can lead to the occurrence of ED (12, 28). The mechanism of erectile process has been extensively studied, and major breakthroughs have been made in many complex molecular pathways (29). This study compared the efficacy and safety of daily concomitant administration of PAL or oral placebo in patients with ED. The main observation indicators of this study were IIEF scores (erectile domain), whereas the secondary observation indicators were overall satisfaction scores, intercourse satisfaction scores, sexual desire scores, orgasmic function scores and T. The results showed that the combined treatment group showed a significant advantage in improving the index of sexual function compared with the placebo group. However, there was no significant difference in raising T levels between the two groups. It has been reported that the combination of PAL may increase T concentration (24). This may be due to the difference in intervention duration between the two groups affecting the statistical efficacy. Therefore, more and better designed clinical trials are needed for further investigation. All three studies included middle-aged and elderly patients with mild to moderate ED. No adverse events were reported in any of the three studies. In summary, PAL may be safe and effective in improving sexual function in patients with mild to moderate ED.

One study (25), which could not be combined with other studies because of the use of the IIEF-5 and salivary T assessment, showed an improvement in total IIEF-5 scores compared with placebo after 8 weeks of PAL intake. There were also significant improvements in “hardness of erection” and “satisfaction with sexual intercourse.” Salivary T was slightly elevated but not statistically significant. It consistent with our results. One self-controlled before and after trial (21) reported that oral administration of PAL significantly improved sexual function in men with ED without any side effects. Another self-controlled before and after trial (18) found that, after 4 months of combined treatment with PAL, the total scores of IIEF and the international erectile function index in the orgasmic function domain were significantly improved without adverse events. However, in this study, there was no significant statistical significance in IIEF scores (erectile domain), overall satisfaction, intercourse satisfaction, sexual desire, and IIEF-5, which may be related to the low dose of oral PAL.

Several limitations should be considered in this systematic review and meta-analysis. Among the three studies included in this meta-analysis, the intervention time of each study was different and varied greatly, which may affect the statistical power. The limitations of this meta-analysis include that similar questionnaires, such as the IIEF scores and IIEF-5 scores used in the included studies, tend to be subjectively evaluated by patients, so proper objectivity of the data cannot be fully obtained. Because of searching Chinese database and screening out zero articles, it is proved that this kind of research is lacking in China, so it is very important to carry out domestic research. The biggest limitation of this paper is that there are few articles included and limited data available for analysis. Therefore, in the future, it will be necessary to conduct more large-scale and well-designed trials to confirm the observations on the efficacy and safety of the combination of PAL for ED.

Together, the above findings indicated that the combined treatment of PAL had a significant effect on improving sexual function in aged patients with mild to moderate ED. We hope that this study will provide clinicians with more options for treating patients with ED.

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding author.

YT and QC contributed to the conception and design of the study. Data collection and extraction were carried out by YT and QZ. WL, ML, and QL planned the data evaluation and statistical analysis. The first draft of the manuscript was written by YT. QC provided guidance and resolved disagreements during this process. All authors contributed to the article and approved the submitted version.