Because I scheduled a botulinum toxin injection with a chief andrology physician at a top-tier hospital in Beijing (Peking University People's Hospital) on Monday — primarily to reduce retraction — I reviewed the relevant literature and am sharing it here.
Botulinum Toxin shows multiple potential applications in the genitourinary system, especially in penis-related issues, including its effect on flaccid penile length or penile length. Based on existing research evidence, the applications of botulinum toxin mainly focus on alleviating penile retraction, treating Peyronie's disease, and addressing issues related to erectile function, rather than directly increasing the actual length of the penis.
Known clinical applications of botulinum toxin:
1. Alleviating Penile Retraction to Improve Flaccid Length
Penile retraction refers to the shortening of the penis in the flaccid state due to contraction of the dartos muscle. This is particularly noticeable in cold, stress, or exercise; although erect length is normal, it can still cause embarrassment and dissatisfaction.
A preliminary study aimed to evaluate the potential effect of injecting botulinum toxin A (Botox) into the dartos muscle to induce muscle relaxation and thereby alleviate penile retraction. The study included 10 patients whose main complaint was that the penis was too short in the flaccid state, despite normal and satisfactory length in the erect and stretched states. Researchers injected 100 units of Botox into the dartos muscle.
The study results showed that 70% (7 of 10 patients) subjectively reported a decrease in the frequency and magnitude of penile retraction, along with improvement in flaccid length. Although clinical measurements were not as pronounced as the subjective reports, they also showed improvement, mainly through reduced retraction rather than length increase. No side effects were reported during the study. However, the improvement completely subsided by the 6th month.
The conclusion of this study is that botulinum toxin A injection into the dartos muscle may have a potential effect on temporarily reducing the frequency and magnitude of penile retraction. This means that by relaxing the dartos muscle, botulinum toxin can reduce the muscle contraction that causes the penis to appear shorter in the flaccid state, thereby visually or subjectively improving flaccid length. However, it should be noted that this effect is temporary and is achieved primarily through reducing retraction rather than actual tissue growth.
2. The Role of Botulinum Toxin in the Treatment of Peyronie's Disease
Peyronie's disease (PD) is a condition characterized by penile deformity, pain, and possibly accompanied by erectile dysfunction. Treatments for PD include a variety of intralesional and topical interventions, including botulinum toxin injection.
A narrative review evaluated existing intralesional/topical interventions for Peyronie's disease, including collagenase (CCH), interferon, platelet-rich plasma (PRP), hyaluronic acid, botulinum toxin, stem cells, extracorporeal shockwave therapy (ESWT), and traction therapy. The review aimed to provide clinicians with an in-depth understanding of the efficacy and safety profiles of these treatment options, assessing their impact on penile curvature, length improvement, and patient-reported symptoms and outcomes.
The review noted that although Peyronie's disease remains a challenge for urologists, the best-evaluated options are intralesional CCH injection and penile traction devices, used alone or in combination. This means that in the current treatment of Peyronie's disease, although botulinum toxin is mentioned as an intervention, it is not considered one of the "best options," at least compared to CCH and traction devices.
Regarding whether botulinum toxin can directly improve penile length in Peyronie's disease, the evidence is currently unclear. The potential role of botulinum toxin in PD may be more in alleviating pain or improving tissue elasticity, rather than directly increasing length. The penile curvature and length loss caused by Peyronie's disease are usually due to fibrotic plaque formation; botulinum toxin may exert indirect effects by influencing local muscle or nerve activity, but its specific effect on length improvement requires further research.
3. Insights from Other Related Urological Applications on Penile Length
Although the following studies are not directly about flaccid penile length or penile length, they demonstrate other applications of botulinum toxin in the genitourinary system, helping to understand its mechanism of action and thereby indirectly infer its potential range of effects on penile length.
Chronic prostatic pain: A study explored a protocol for treating chronic prostatic pain through periurethral sphincter injection of botulinum toxin type A (BTX). The study found that all patients with chronic prostatic pain had pathological pelvic floor tenderness, insufficient voluntary control of pelvic floor muscles, urethral hypersensitivity/hyperalgesia, and urethral muscle overactivity. After BTX injection, patients' pelvic floor muscles weakened, and prostatic pain and urethral hypersensitivity/hyperalgesia were relieved. Objectively, botulinum toxin resulted in decreased functional urethral length, decreased urethral sphincter closure pressure, reduced residual urine volume, and increased maximum and average urinary flow rates.
Insight: This study shows that botulinum toxin can weaken the urethral sphincter muscle by blocking acetylcholine release, thereby relieving pain and improving symptoms. Although "decreased functional urethral length" is mentioned here, this is due to sphincter relaxation, which is a different concept from the overall length of the penis (especially flaccid length). However, it suggests the possibility that botulinum toxin can alter organ function and morphology through muscle relaxation.
Urethral stricture: A pilot study evaluated the effect of botulinum toxin (Masport) injection after endoscopic internal urethrotomy in patients with bulbar urethral stricture, aiming to reduce stricture recurrence. The results showed that the treatment group combining endoscopic internal urethrotomy with intralesional Masport injection had better recurrence-free survival than the control group undergoing endoscopic internal urethrotomy alone. The Masport group also showed significantly better mean score improvements in EuroQol Visual Analogue Scale (EQ-VAS), International Prostate Symptom Score (IPSS), and maximum urinary flow rate (Q-max) than the saline group.
Insight: The role of botulinum toxin here is to improve the prognosis of urethral stricture, possibly by relaxing local smooth muscle or reducing scar tissue proliferation. This again emphasizes botulinum toxin's ability to improve physiological function through muscle relaxation, but it is still distinct from the concept of directly affecting flaccid penile length or actual length.
References for this section:
1.Botulinum toxin a (Botox) for relieving penile retraction.
2.The Effect of Botulinum Toxin (Masport) Injection Following Internal Urethrotomy of Bulbar Urethral Stricture: A Pilot Study.
3.Perisphincteric injection of botulinum toxin type A. A treatment option for patients with chronic prostatic pain?
Botulinum neurotoxin (BoNT) has emerged as a promising potential treatment for erectile dysfunction (ED), especially in patients who respond inadequately to phosphodiesterase type 5 inhibitors (PDE5-Is) or other standard pharmacological treatments. This comprehensive analysis will delve into the safety and efficacy of BoNT, specifically incobotulinumtoxinA (Xeomin), for the treatment of refractory ED, drawing on various study results including randomized controlled trials and case series.
Background on Erectile Dysfunction and Current Treatments:
Erectile dysfunction is a common condition characterized by the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual activity. Although PDE5-Is are typically the first-line pharmacological treatment, approximately 30% of affected men do not achieve adequate improvement with these medications alone, leading to classification as "refractory ED" or ED refractory to PDE5-Is. For these patients, alternative or add-on therapies are urgently needed. Prostaglandin E1 (PGE1) intracavernosal injection (ICI) is another standard pharmacological treatment, but like PDE5-Is, some patients may still respond inadequately.
Mechanism of Action of Botulinum Neurotoxin in Erectile Dysfunction:
The exact mechanism by which BoNT improves ED is still under investigation, but it is believed to involve its ability to inhibit acetylcholine release at the neuromuscular junction, thereby causing muscle relaxation. In the context of ED, this relaxation may affect smooth muscle cells within the penile vasculature, potentially improving blood flow and facilitating erection. Studies have shown that intracavernosal injection of BoNT-A can alleviate ED in inadequate responders by improving penile hemodynamics.
Safety of Intracavernosal Botulinum Neurotoxin Injection:
Multiple studies have consistently demonstrated that intracavernosal injection of BoNT-A for ED has a good safety profile.
IncobotulinumtoxinA (Xeomin): A double-blind, placebo-controlled, multicenter randomized phase 2 trial studied 100 U of incobotulinumtoxinA combined with 100 mg sildenafil and found the treatment to be safe. Similarly, a case series using 100 U of incobotulinumtoxinA as add-on therapy reported it as safe, with only a few mild adverse events. The most commonly reported side effect in that case series was mild penile pain during injection, affecting only 3 of 66 men.
BoNT-A (general): A randomized controlled trial involving 70 ED patients refractory to PDE5-Is also concluded that BoNT-A is safe as a potential treatment. Although not all abstracts describe specific adverse events in extensive detail beyond penile pain, the consistently reported "good" or overall safety profile indicates that serious or frequent side effects are not a major concern.
It should be noted that while the safety profile appears good, limitations in some studies, such as inconsistent penile crura clamping after incobotulinumtoxinA injection, highlight areas for improvement in future trials to ensure optimal safety and efficacy.
Efficacy of Intracavernosal Botulinum Neurotoxin Injection:
The efficacy of BoNT for ED, particularly in patients refractory to PDE5-Is, is more nuanced, with some studies showing positive results and others indicating the need for further robust evidence.
Early evidence and case series (positive signs):
One case series: analyzed data from 66 men with refractory ED who received single or repeated 100 U incobotulinumtoxinA intracavernosal injections as add-on therapy to PDE5-Is or PGE1 ICIs, providing preliminary evidence of efficacy. The response rate, defined as an increase of ≥ minimum clinically important difference in the International Index of Erectile Function - Erectile Function (IIEF-EF) domain score, was 52%. The median response time after injection was 43.5 days (interquartile range: 34-71 days). The study also found that ED etiology (except spinal cord injury) and severity did not affect efficacy, and that a clinically significant response to the first injection predicted the need for a second injection (OR = 5.6, 95% CI 1.6-19.4). These findings support conducting multicenter randomized clinical trials.
Another randomized controlled trial: involving 70 ED patients refractory to PDE5-Is, evaluated the safety and efficacy of a single intracavernosal injection of 100 units BoNT-A in 2 ml saline compared to a placebo group receiving 2 ml saline. The study reported statistically significant improvements in the treatment group on several key measures:
2 weeks post-treatment: Compared to the control group, mean Erection Hardness Score (EHS), peak systolic velocity (PSV), end-diastolic velocity (EDV), and positive responders on the General Assessment Questionnaire (GAQ-Q1) improved significantly.
6 and 12 weeks post-treatment: Compared to the control group, Sexual Health Inventory for Men (SHIM) scores, Sexual Experience Profile (SEP)-Q2 (insertion ability), and GAQ-Q1&Q2 positive responders showed statistically significant improvements.
Specific SHIM improvement: At 6 weeks, the mean SHIM score in the treatment group improved by 5 points (from 5.4±1.7 at baseline), while the placebo group showed no improvement.
Insertion ability: At 6 weeks, 18 patients (53%) in the treatment group were able to achieve an erection firm enough for vaginal insertion, compared to only 1 patient in the control group.
The trial authors: concluded that BoNT-A is effective as a potential treatment for ED refractory to PDE5-I therapy.
Randomized controlled trial (nuanced results):
A recent double-blind, placebo-controlled, multicenter randomized phase 2 trial: studied 100 U of incobotulinumtoxinA combined with on-demand 100 mg sildenafil in men with ED who responded inadequately to on-demand 100 mg sildenafil. The study enrolled 165 randomized patients (mean age: 60.1 years, mean IIEF-EF on on-demand 100 mg sildenafil: 11.1).
The primary outcome was the mean change in IIEF-EF score at 3 months and the proportion of "yes" responses to SEP-Q2 (insertion ability) and SEP-Q3 (ability to maintain erection for successful intercourse).
Intention-to-treat (ITT) analysis: The ITT analysis included all randomized patients regardless of treatment compliance and showed no significant improvement in IIEF-EF score at 3 months when 100 U of incobotulinumtoxinA was combined with 100 mg sildenafil. Although 100 U of incobotulinumtoxinA did improve insertion (SEP-Q2) and erection maintenance (SEP-Q3), these improvements were not statistically significant. Full-case analysis and per-protocol analysis further confirmed these findings.
Compliance and efficacy potential: Interestingly, an adjusted analysis of 100% compliance with 100 mg sildenafil showed a significant interaction (P = 0.032), indicating that fully compliant patients had greater IIEF-EF improvement. This finding suggests a possible synergistic effect when both treatments are used consistently as prescribed.
Conclusion of this specific trial: Despite negative ITT efficacy results, the study demonstrated the safety of intracavernosal BTX/A injection. The authors concluded based on the ITT analysis that "there is no robust evidence to support its use for the treatment of ED," but also stated that the results "raise hypotheses about its potential role in combination with PDE5-Is that warrant further investigation."
References for this section:
1.Efficacy and safety of intracavernosal incobotulinumtoxinA (Xeomin) as add-on therapy to sildenafil for the treatment of erectile dysfunction insufficiently responsive to phosphodiesterase type 5 inhibitors.
2.Effectiveness and Safety of Intracavernosal IncobotulinumtoxinA (Xeomin) 100 U as an Add-on Therapy to Standard Pharmacological Treatment for Difficult-to-Treat Erectile Dysfunction: A Case Series.
3.Safety and efficacy of botulinum neurotoxin in the treatment of erectile dysfunction refractory to phosphodiesterase inhibitors: Results of a randomized controlled trial.