Erectile Dysfunction (ED) stands as a predominant sexual dysfunction in men, manifesting as a consistent inability to achieve or maintain an erection conducive to satisfactory sexual intercourse (Najari and Kashanian, 2016). Current estimates indicate that over 150 million men globally grapple with varying intensities of ED (Travison et al., 2007). Utilizing assessment tools such as IIEF, IIEF-5, and their related variants, there’s a discernible year-on-year escalation in ED incidence, mirroring the global aging demographic trend. Projections suggest that by 2025, the worldwide ED-afflicted populace might approach 322 million (Costa and Potempa, 2012).

The mainstay therapeutic intervention remains the Type 5 Phosphodiesterase inhibitors (PDE5i), yet its efficacy hovers between 60% and 70% (Ji et al., 2023). This has driven a substantial fraction of patients towards alternative medicine, predominantly herbal therapies (Muncey et al., 2021). Herbal formulations have a long-standing history and are widely used across Asia, particularly in China, Korea, and Japan, where they form an integral part of traditional medicinal practices (Bailly, 2024). The efficacy of herbal remedies or herbal formulations in treating erectile dysfunction has been corroborated by numerous studies (Qi et al., 2004; Kamenov et al., 2017; Borrelli et al., 2018; Choi et al., 2019; Chung et al., 2023). A burgeoning corpus of research intimates that Traditional Chinese Medicine (TCM) offers tangible benefits for ED (Wang et al., 2020; Wu et al., 2023), though some studies proffer equivocal conclusions (Xiong et al., 2014). Hence, there’s a pressing advocacy for rigorously orchestrated Randomized Controlled Trials (RCTs) to delve deeper into the subject.

Hongjing I granule (HJIG) is a traditional Chinese medicine prescribed by experienced physicians from the Second Affiliated Hospital of Zhejiang University School of Medicine and Dongzhimen Hospital of Beijing University of Chinese Medicine, with nearly 20 years of clinical application.

The traditional Chinese medicine theoretical basis for its application is elucidated as follows: The theory of Qi and Blood originates from the “Huangdi Neijing,” where the “Su Wen·Tiao Jing Lun” states, “Diseases arise and transform when the Qi and Blood are in disharmony.” Based on this, the harmony of Qi and Blood is closely associated with the onset and progression of diseases. Zhang Zhongjing, in his creation of the Six Meridian Diagnosis and Treatment System, also reflected the academic notion that all diseases are ultimately governed by the regulation of Qi and Blood. The “Zheng Zhi Gai Yao” mentions, “The penis, being constituted by sinews, relies on the nourishment of Qi and the moistening of Blood to become strong and vigorous.” This indicates that the penis is “structured by sinews and functions through the utility of Qi and Blood.” (Zhang G. et al., 2017). In a clinical study, 80 patients with mild to moderate ED were randomized into two groups: one receiving Tadalafil (5 mg qd) and the other a combination of Tadalafil and HJIG (1 pack bid) for 3 months. Evaluations of penile length, circumference, rigidity, IIEF-5 scores, partner satisfaction, and CT cavernosography showed post-treatment improvements in both groups (P < 0.05), with the combination therapy outperforming Tadalafil alone. Specifically, in the Tadalafil group, 33 cases showed venous leakage improvement with 7 cases completely resolved; the combination group had 17 cases improved and 23 cases fully resolved, indicating a statistically significant difference (χ2 = 13.65, P < 0.05) (Ping et al., 2021).

Additionally, 76 patients with Qi deficiency and blood stasis type mild to moderate ED received either Tadalafil (5 mg nightly for 12 weeks) or a combined Tadalafil and HJIG treatment (45 cases) with a step-down Tadalafil regimen. Both treatments significantly enhanced IIEF-5 and EHS scores (P < 0.05). The combined treatment group showed more substantial improvements in IIEF-5 and EHS scores after 4 weeks of medication and 4 weeks post-discontinuation compared to the Tadalafil only group (P < 0.01) (Zhang G. et al., 2017). Animal models have corroborated HJIG’s potential to promote nerve regeneration, attenuate hypoxia, curtail phenotype transformation, and stymie tissue fibrosis (Yang et al., 2014; Ye et al., 2019; Ma et al., 2020).

However, the evidence supporting the efficacy of HJIG in treating ED remains limited, and many studies on Chinese herbal formulations suffer from a lack of correlation assessment with their traditional use. It is essential to conduct high-quality clinical research to evaluate the therapeutic effectiveness of HJIG for ED and the validity of its application within traditional Chinese medicine frameworks.

HJIG is comprised of nine traditional Chinese plants, including Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba [Crassulaceae; Rhodiola crenulata (Hook. f. et Thomas.) H. Ohba] (红景天), Astragalus mongholicus Bunge [Fabaceae; astragali radix praeparata cum melle] (黄芪), Codonopsis pilosula (Franch.) Nannf. [Campanulaceae; Codonopsis pilosula (Franch.) Nannf.] (党参), Salvia miltiorrhiza Bunge [Lamiaceae; Salvia miltiorrhiza Bge.] (丹参), Angelica sinensis (Oliv.) Diels [Apiaceae; Angelica sinensis (Oliv.) Diels] (全当归), Paeonia lactiflora Pall. [Paeoniaceae; Paeonia lactiflora Pall.] (白芍), Cyathula officinalis K.C.Kuan [Amaranthaceae; Cyathula officinalis Kuan] (川牛膝), Lycium chinense Mill. [Solanaceae; Lycium chinense Mill.] (枸杞), and Epimedium brevicornu Maxim. [Berberidaceae; Epimedium brevicornu Maxim.] (淫羊藿). The pharmacopoeial names are all referenced from the Chinese Pharmacopoeia 2015. The botanical names have been verified with MPNS (http://mpns.kew.org) (Access date: January 4, 2024).

Therefore, we designed this multicenter, double-blind, placebo-controlled randomized study. In addition to strict inclusion and exclusion criteria, we have also incorporated Traditional Chinese Medicine (TCM) syndrome scoring to evaluate whether the traditional medical basis of using HJIG (TCM syndrome) aligns with improvements in patient erectile function.

Herbal remedies and natural products have gained traction worldwide for treating erectile dysfunction (ED) (Magheli and Burnett, 2009; Feng et al., 2022), with substantial research underpinning their utility in recent years (Ciocanel et al., 2019; Wang et al., 2020; Wu et al., 2023). Traditional Chinese Medicine (TCM) originates from ancient China, with its primary therapeutic approach focusing on symptom differentiation and improving the overall health of the patient. Herbal formulation treatments constitute a significant component of TCM. Meta-analyses suggest that coupling Chinese herbs with PDE5i (phosphodiesterase-5 inhibitors) enhances efficacy without amplifying side effects (Wang et al., 2020). This corroborates the conclusions drawn from our preliminary studies on HJIG (Zhang G. et al., 2017; Ping et al., 2021). Another analysis indicates that singular Chinese herbal treatments can elevate IIEF (International Index of Erectile Function) scores and amplify clinical recovery rates (Wu et al., 2023). However, previous studies have touted the need for more rigorous clinical trials for Chinese herbal medicine (Xiong et al., 2014). Recognizing the pivotal role of accurate symptom differentiation in TCM and its association with ED, we advocate for randomized controlled trials (RCTs) targeting explicit symptom patterns to genuinely gauge Chinese medicine’s potency.

Our study indicates that exclusive use of HJIG can improve erectile function in patients with mild to moderate ED and enhance sexual completion (the ability to maintain an erection until ejaculation). Secondary outcomes also show that HJIG has the potential to increase sexual desire, as evidenced by an increase in sexual activity frequency. Clinical trail on herbal or herbal formula treatments for ED have yielded positive results (Kam et al., 2007; Shah et al., 2012; Xiong et al., 2014; Park et al., 2019).

A double-blind randomized controlled trial of a Thai herbal formulation composed of four medicinal plants showed improvements in IIEF-5 scores and sexual desire in patients with mild to moderate ED (Lin et al., 2022). Guojun et al.’s study indicated that acupuncture could improve IIEF-EF and SEP3 results in patients with psychogenic erectile dysfunction, although there was no significant difference in SEP2 between the treatment and placebo groups (Wang et al., 2023). A multicenter randomized controlled study provided a more detailed classification of patients and applied a TCM herbal formulation for those with liver depression and kidney deficiency symptoms related to psychogenic or mild arterial ED. By evaluating sexual success rates and erectile hardness in 500 patients, it was found that the herbal formulation Shugan Yiyang Capsule effectively improved erectile function and sexual completion (Qi et al., 2004). Nam Cheol Park et al. used a formula composed of five herbal granules for an 8-week intervention in ED patients. The results showed significant improvement in IIEF-EF scores in the treatment group compared to the placebo group, although there were no differences in SEP2 and SEP3 (Park et al., 2019). Gaurang R Shah used a mixture of eight herbal formulations to treat patients with mild to moderate ED, significantly improving their IIEF-EF scores. It is evident that the IIEF score remains a primary method for evaluating ED patients, especially in preliminary efficacy studies of new therapies (Shah et al., 2012).

Previous studies suggest that drugs like tadalafil are insufficient in alleviating auxiliary ED-related symptoms, whereas herbal interventions may fill this therapeutic gap (Zixue and Pengchao, 2018). This is a key advantage of herbal formulations. Therefore, in high-quality, large-scale studies focusing on other diseases, clinical research on traditional Chinese herbal formulas often incorporates TCM syndromes as criteria for inclusion, exclusion, or as a basis for evaluating treatment efficacy (Zhong et al., 2019). We adopted this model, and our results indicate significant improvement in patients’ specific TCM symptoms. Additionally, we used difference scores to evaluate treatment efficacy, which significantly reduces the impact of individual differences. By calculating the pre- and post-treatment differences, we can more accurately assess treatment effects, minimizing the influence of individual variability such as baseline levels. Furthermore, stratification results indicate that differences in patient age and duration of ED history may influence treatment efficacy. Older patients and those with a longer duration of ED may require longer treatment and recovery periods to achieve optimal therapeutic outcomes.

From a pharmacological perspective, the efficacy of HJIG may stem from the synergistic properties of its botanical drug metabolites. The main active metabolite in Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba., salidroside, has been proven to improve hypoxic conditions (Zhao et al., 2020), inhibit fibrosis (Ma et al., 2020), and reduce phenotypic transformation of smooth muscle cells (Zhang X. et al., 2017). Astragali radix praeparata cum melle, a traditional herb used in ED treatment, though not fully explored mechanistically, has shown potential in improving cardiac diastolic function in postmenopausal women with hypertension, suggesting a similar beneficial effect on cavernous smooth muscle cells (Li et al., 2018). Salvia miltiorrhiza Bge. has been shown to inhibit oxidative stress and reduce apoptosis, thereby improving erectile function in diabetic rats (Zhang et al., 2018). Angelica sinensis (Oliv.) Diels has been found to enhance nitric oxide synthase (NOS) activity in rats with damaged cavernous nerves (Li et al., 2017). Cyathula officinalis Kuan has demonstrated efficacy in improving erectile function in diabetic rats (Wang et al., 2021). Lycium Chinense Miller. through its antioxidative stress properties improves erectile function in aged rats (Moon et al., 2017). Epimedium brevicornu Maxim. has been proven to induce erection in rats (Chen and Chiu, 2006), and its metabolites exhibit PDE5 inhibitory effects. Although not every herbs in the HJIG formulation has been extensively studied for its mechanism, most herbs have been proven beneficial in improving erectile function.

Our study, being exploratory in nature, still presents a range of aspects that necessitate further refinement and improvement. We lack bolstering through objective measures like NPTR (Nocturnal Penile Tumescence and Rigidity) or CT (Computed Tomography) tests. Additionally, even though five participants admitted to intermittent PDE5i usage and subsequently exited the study, there remains a latent ambiguity regarding undisclosed PDE5i usage, potentially skewing our results. The self-selection bias, where participants more inclined toward herbal treatment remain, while skeptics drop out, may also tilt outcomes.

In summary, HJIG demonstrates significant enhancements in sexual functionality for ED patients, complemented by improvements in their TCM symptomatology. We are planning broader real-world TCM studies to eliminate biases, reaffirm the therapeutic efficacy of HJIG, and extend the follow-up duration. Incorporating HJIG into a structured treatment regimen offers promise for a more favorable prognosis for patients. In future research endeavors, we are considering incorporating effectiveness parameters, such as time-efficiency and cost-effectiveness. The reduction in time and financial costs can alleviate patients’ burdens, increasing their engagement in the treatment, exemplifying one of the inherent benefits of herbal intervention.

We acknowledge that the sample size in this study is relatively small compared to large-scale clinical trials. However, given the exploratory nature of this research and the promising preliminary results, we believe the findings provide valuable insights into the efficacy of HJIG for mild to moderate ED. It is also important to note that collecting patients who meet the criteria for using Chinese herbal medicine alone, without involving ethical concerns, is particularly challenging. This recruitment difficulty further limits the sample size, but we are confident that the data gathered offers a solid foundation for future research. Larger studies with more extended follow-up periods are necessary to validate these findings and explore HJIG’s full therapeutic potential.