Hypothesis / aims of study
Erectile dysfunction affects a large proportion of mainly the aging male population. In the era of minimally invasive medicine, a novel treatment strategy emerges necessary to avoid morbid and irreversible surgeries. The aim of this review is to evaluate the role of botulinum toxin in treating erectile dysfunction.
Study design, materials and methods
This study was based on the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The study protocol on the part of human studies was registered on PROSPERO (CRD42021283751). A systematic review of literature of PubMed, Embase and Medline databases was conducted, in order to identify studies investigating the role of botulinum toxin to treat erectile dysfunction, published in English, from January 1990 through July 31, 2021. Evidence included human and animal data.
The study design was established according to the Population, Intervention, Comparator, Outcome, Studies (PICOS) process. Population: Patients with erectile dysfunction. Intervention: Intracavernosal injection of botulinum toxin. Comparator: Standard-of-care or other techniques. Outcomes: improvement of sexual function, improvement in erectile function. Studies: Case series, retrospective/prospective cohorts, comparative studies and randomized controlled trials (RCT) were included. Reviews, case reports, non-English language articles, congress abstracts, letters to editor, and editorial comments were excluded.
A meta-analysis was performed on three outcomes included commonly in at least two studies. Among the different parameters assessed were, Erection Hardness Score (EHS), Peak Systolic Velocity in cavernosal artery (PSV) and the Sexual Health Inventory for Men (SHIM) score.
Results
Seven studies in total were included in our review including two pre-clinical studies. Table 1 summarizes the studies included. Figure 1 represent the respective meta-analysis done regarding EHS, PSV and SHIM. The Cochrane bias risk assessment was performed for the 3 studies from which data were extracted. A clear benefit was noted for intracavernosal injection (ICI) of botulinum toxin (BoNT-A) on PSV (Figure 1) with a HR of 10.82 [4.99, 16.65] and a heterogeneity of I2=61%. EHS results favored BoNT-A as well over placebo with a HR of 0.7 [0.47, 0.93] and a heterogeneity of I2=94%. As for SHIM score, with a heterogeneity of I2=85%, no statistically significant difference was found (HR 0.58 [-0.03, 1.20]) (Figure 1).
Interpretation of results
The rationale for using ICI of BoNT-A arises from its mechanism of action. One of the physiological hypotheses of its mode of action is that BoNT-A disables the exocytotic activity of presynaptic neurons by inhibiting neurotransmitter containing vesicles to fuse at the level of the synapse hence decreasing the influx of norepinephrine (NE) inhibiting the contraction of the cavernosal muscle cells. In addition to its effect on inhibiting NE release, BoNT-A increases the generation of nitric oxide (NO) by blocking the release of Acetylcholine (Ach) from cholinergic neurons which inhibits NO synthase [1]. The interplay of these effects results in a clinically inhibited cavernosal smooth muscle tone hence a more satisfactory blood flow is attained. This is the first systematic review to include 2 pre-clinical and 5 clinical studies results with a meta-analysis performed on 3 primary outcomes showing an efficacy of ICI of BoNT-A compared to other strategies on 2 of the 3 identified criteria, in particular EHS and PSV. There is, however, a narrative review in the literature from 2020 that supports the use of BoNT-A in male sexual pathologies extending to primary ejaculation, Peyronie's disease, and penile retraction [2].
The studies included in our review did not adapt a single treatment strategy, each studied different parameters and questionnaires during the study to objectify improvement in erectile dysfunction, there were different doses, serotypes and regimen of botulinum toxin as depicted in Table 1. However, the meta-analysis was done on the three similar trials adopting resembling regimens, and there was a significant benefit in PSV and EHS.