Aim: To evaluate the efficacy of hyaluronic acid (HA) injection in treating patients with premature ejaculation (PE).

Methods: Matching interventional studies from MEDLINE, CENTRAL, and CINAHL. Outcomes were intravaginal estimated latency time (IELT), glandular circumference, satisfaction score, and adverse event rate. Data were assessed with Open Meta Analyst, DerSimonian and Laird random-effects model.

Results: Ten interventional studies, three double-armed, with low to moderate bias risk, revealed significant differences in baseline IELT and 1, 3, and 6-month post-hyaluronic acid injection, with mean differences of 217.035 (95% CI, 89.330–344.739), 161.513 (95% CI, 37.262–285.764), and 196.350 (95% CI, 142.314–250.386) seconds. Glandular circumference increased by 10.956 mm (95% CI, 3.314–18.598) after six months.

Conclusion: Hyaluronic acid successfully extended IELT in premature ejaculation patients at one, three, and six months post-treatment with no severe side effects. It also enhanced glandular size and sexual satisfaction for patients and their partners.

Intravaginal ejaculation latency time, glandular circumference hyaluronic acid, premature ejaculation

As one of the most common sexual dysfunctions, premature ejaculation (PE) has been a major sexual problem among men worldwide. Its prevalence is estimated to be around 20–30% globally, and some reviews has reported up to 75% of men encountered this problem (Carson and Gunn 2006). To these dates, the universally accepted diagnostic criteria of premature ejaculation have not been established. The American Urological Association Guidelines 2020 (AUA) defined PE as poor ejaculation, associated bother, and ejaculation within about 2 minutes after the initiation of penetrative sex. Furthermore, the AUA classified PE as primary (lifelong) and acquired (secondary) PE. In primary PE, ejaculation occurs within 30–60 seconds, measured from the beginning of penetration to ejaculation. In acquired PE, there is a markedly reduced ejaculation latency time from prior experience of about 50% or approximately within 2–3 minutes from penetration to ejaculation (Shindel et al 2022).

PE has been known to affect the quality and satisfaction of sexual intercourse, even causing distress and anxiety to the patient and their partners (Kempeneers et al. 2018). To add to this problem, the exact cause of PE has not been established yet, rendering it challenging to treat the condition. However, biological and psychological risk factors are thought to play a role. Biological factors that potentially contribute to PE include abnormal serotonin levels, abnormal hormone levels, inflammation or infection of the prostate or urethra, and psychological factors, including depression, stress, anxiety, history of sexual repression, and sexual abuse (Kalejaiye et al. 2017; Zhang et al. 2019). Therefore, a wide range of treatment modalities have been applied, including behavioral therapies, psychological therapies, and pharmacological therapies such as the use of antidepressants (e.g., tricyclic antidepressants and serotonin reuptake inhibitors), topical anesthetics, phosphodiesterase-5-inhibitors, and opiate analgesics (e.g., tramadol) (Martin and Shindel 2020). The side effects and recurrence after drug cessation have been the main problem of these pharmacological therapies. Thus, procedural treatments have been performed, such as selective dorsal neurectomy and hyaluronic acid (HA) injection (Perri et al. 2022).

The treatment with hyaluronic acid injection is a technique in which HA is injected into the dermis of the glans penis approximately above the dorsal nerve terminals, creating a barrier between the dorsal nerve branches and the skin. This barrier diminishes the tactile stimuli, reaching the sensory receptors of the glans penis, thus; resulting in penile analgesia and a slower ejaculatory reflex (Alahwany et al. 2019) A pilot study including 60 patients with PE reported a significant increase in intravaginal ejaculation latency time (IELT) after one month of receiving a single injection of 2 ml HA (from 2.12 ± 1.16 minutes to 7.71 ± 7.86 minutes) (Abdallah et al. 2012) Ahn et al., reported an increase in penile girth in 32 subjects within 24 weeks after using HA filler, as well as an increased satisfaction level without any serious adverse effects reported (Ahn et al. 2022). Similarly, Abdelazeem and Esawy also reported increased intravaginal latency time, glandular circumference, and patients’ and partners’ satisfaction levels at the 6-month follow-up after HA injection (Abdelazeem and Esawy 2019). Another study on 38 patients reported a positive long-term effect of HA injection after five years (Kwak et al. 2008). In contrast, several studies found a markedly decrease in IELT at a 3-month follow-up, suggesting that HA injection only provides a temporary solution to PE. In addition, the patient’s satisfaction level was also found to be the same as the baseline at a 3-month follow-up (Kewei et al. 2022). Furthermore, Shebl et al., have also reported that although the patients’ satisfaction at three months reached approximately 70%, their partners’ sexual satisfaction at three months was less than 50% (Sterne et al. 2016).

Although HA injection might be a promising approach to treating PE, the same benefit of HA injection in treating PE remains inconclusive. Therefore, we performed a systematic review and meta-analysis of available randomized-clinical trials to obtain more conclusive information regarding the efficacy of HA injection in treating patients with PE.

This meta-analysis attempts to present the usefulness of injectable hyaluronic acid (HA) in improving the latency time of those with premature ejaculation (PE). The PE can be defined as a sooner ejaculation that happens uncontrollably during sexual activities, affecting at least a third of global male population (Kosseifi et al. 2020). Ejaculation itself occurs during a sensation distributed within the autonomic nerves to the glans penis, received by number of receptors. Moreover, this sensation is influenced by the threshold and accessibility of the stimuli to these receptors. The lower the accessibility of stimuli from the receptors to the center would be difficult to experience, which formed difficulties in sensation. This mechanism becomes the basis for the reason of PE treatment that aims to suppress the distribution of stimuli as well as increasing the threshold of stimulation at local receptors to the central nervous system. (Kim et al. 2004).

The HA acts as a bulking agent, blocking accessibility and inhibiting tactile stimulation to reach the nerve receptors (Kim et al. 2004). By being injected into the dermis of the glans penis just above the nerve terminals, this would prolong the latency time in PE patients (Kim et al. 2004) HA is also a glycosaminoglycan with a significant component which is stable, non-toxic, non-allergenic, and non-inflammatory. Thus, HA is a safe chemical substance with excellent long-term effectiveness (Zucchi et al. 2022)

Various studies have reported the effects HA on IELT, such as Abdallah and team (2011) reported a nearly 4-fold increase in IELT from baseline (Abdallah et al. 2012). Similarly, Kewei and co-workers (2022) found improvements in the IELT score from baseline within 1-month, 3-month, and 6-month after treatment by injecting the HA into two sites (glans penis and around the coronary sulcus). Even more, a more extreme increase in IELT score that was up to 8-fold from baseline at 1-month after treatment has been reported by Sakr et al. (2022) from 37.83 ± 11.01 to 323.03 ± 42.06 seconds (Kosseifi et al. 2020).

The IELT score variously occurs and gradually decrease after treatments. Compared to the baseline, a gradual decrease appears at three and six months of post-treatments. No studies have reported an improvement in IELT in three months after injection, compared to those in 1-month post-treatment. Similarly, at 6-month after treatment, the latency dime would algo decrease; nevertheless, the scores have never been to reach the baseline level. The highest decrease of latency time was reported by Alahwany et al. (2019) after 6 months of treatment, from 120 ± 66.21 seconds (1 month after treatment) to 85 ± 59.54 seconds. This figure seems to be continuously declining at 9-months after treatment to only 45 seconds (baseline time was 34 ± 20.35 seconds). However, a significant difference was still recorded on 9-month after treatment (Alahwany et al. 2019).

Glandular circumference (GC) was also found to be higher than the baseline. This increase in GC was assumed to have correlation with an increase in satisfaction of the patients and their sexual partners. Littara and co-workers (2013) have found a more than 4-fold increase in sexual satisfaction scores compared to the baseline scores at 6-months after treatment. The same study also found an increase in glandular circumference from 98.51 ± 0.71 mm to 114.35 ± 0.66 mm at 6-months after treatment (El-Hamd et al. 2019). Similarly, Kwak et al. (2008) reported an increase of GC by 16.58 ± 0.85 mm at 6-months after treatment (Kwak et al. 2008).

However, Shebl et al. (2021) and Kwak et al. (2008) have reported low rates of sexual satisfaction. There were 76.32% of satisfaction in the patients and 65.79% in their partners, while under 60% of both patients and their partners were found after 1-month to 6-months of post-injection, respectively. The feeling of sexual satisfaction at 3-month after treatment was found in almost a half of patient partners (Kewei et al. 2021). It should be underlined that the studies used instruments to measure sexual satisfaction, which was not scientifically validated. Perri et al. (2022) used the IIEF questionnaire to measure sexual satisfaction. Overall and Intercourse satisfaction were reported to have increased at 1-month and 2-months after treatment in this study. Sexual satisfaction is multifactorial, and latency time and glandular circumference are not the only influencing factors. Therefore, the instrument for successful premature ejaculation, defined as ejaculation occurring earlier than expected, should be assessed based on latency time.

One of the limitations in the administration of HA as a minimally invasive procedure is a direct risk after injection during the preparation of glans penis. None of the selected studies reported any serious adverse events as it is reported by Ahn et al. (2021) that showed post-injection inflammation in small number of patients (6.3%), which has been resolved by conservative therapy alone (Ahn et al. 2022). Abdallah and team (2011) recommended the multiple puncture techniques to reduce the number adverse events, which showed a smaller number of the adverse-event rate for 26.9% (30.4% for the fan technique) (Abdallah et al. 2012).

This meta-analysis has succeeded in providing an overview of the efficacy on injectable HA in improving patient’s conditions with PE. There was a significant increase in IELT up to 6-months after treatment, an increase in glandular circumference, and an increase in satisfaction scores based on scientifically validated instruments. This therapy also has a low risk of complications. However, some weaknesses need to be highlighted in this meta-analysis, (1) a high heterogeneity among studies suggest various outcomes compiled in forest plots, required a random-effect of measurements, (2) differences in types of punctures may lead to various results, (3) the strength of HA is also varied in among studies. Thus, these three features would appear to have different results and outcomes, experienced by both the patients and their sexual partners.

Hyaluronic acid effectively increased the IELT of patients with premature ejaculation at one, three, and six months after treatment without any serious adverse events. This therapy also increased glandular circumference and sexual satisfaction with the patient and the patient’s sexual partner. Further studies evaluating sexual satisfaction with validated instruments were needed to ensure that hyaluronic acid provides practical patient benefits.