Two studies, two outcomes: botulinum toxin in lifelong premature ejaculation treatment

Dear Editor,

We recently reviewed two important studies that investigate the use of botulinum-A toxin (BoNT-A) injections into the bulbospongiosus muscle as a treatment for lifelong premature ejaculation (PE). While both studies share the goal of evaluating the efficacy and safety of BoNT-A in this context, they reached very different conclusions. The study by Shaher et al.1 demonstrated significant improvements in ejaculatory latency, indicating that BoNT-A injections may be a helpful treatment for PE. On the other hand, Almekaty et al.2 reported no meaningful improvements in ejaculatory latency or partner satisfaction, raising doubts about the effectiveness of BoNT-A. These conflicting results prompt an important question: what could explain these differing outcomes?

One possible reason for the differing outcomes stems from the variation in patient populations between the studies. Almekaty et al.2 reported a lower baseline Premature Ejaculation Profile (PEP) score of 2.3 and a mean (±standard deviation [s.d.]) baseline intravaginal ejaculatory latency time (IELT) of 31.4 (±9) s, suggesting their cohort had more severe PE with poorer ejaculatory control. From a neurobiological perspective, these patients may have exhibited more pronounced neuromuscular dysregulation, characterized by heightened sensitivity in the ejaculatory reflex arc (Table 1). The ejaculatory reflex is mediated by a complex interaction between spinal cord reflexes and supraspinal centers. Increased excitability in these pathways, particularly within the lumbosacral spinal cord and perigenital nerves, could lead to PE.3 In these more severe cases, the neural circuits responsible for ejaculatory control are hyperactive. The therapeutic potency of BoNT-A, which primarily inhibits acetylcholine release at the neuromuscular junction, may not have been sufficient. This could be due to the complexity of the condition.4 Thus, the limited efficacy of BoNT-A in Almekaty et al.’s cohort could be attributed to the deeper neural dysregulation at both the central and peripheral levels.2

Table 1.

Metrics of two studies in which botulinum-A toxin was applied for the treatment of premature ejaculation

Metrics	Study
	Shaher et al.1	Almekaty et al.2
Group (n)
Control	45	28
Botox	47	29
Ultrasound-guided	Yes	Yes
Injection point count (point)	1	2
Patient selection	Failed other options	Not clear
Previous surgical operations for any pelvic or urethral pathology	Excluded	Not clear
IELT (s), mean±s.d.
Baseline	35.79±14.23	31.4±9
1 month	70.00±47.64	33.1±11
3 months	60.36±40.08	33±7
6 months	42.64±30.35	31.9±10
PEDT (mean±s.d.)
Baseline	16.11±1.77	NA
1 month	13.19±3.84	NA
3 months	14.23±2.88	NA
6 months	15.49±2.87	NA
PEP (mean±s.d.)
Baseline	5.49±2.17	2.3±0.8
1 month	8.36±4.20	3.1±0.7
3 months	7.19±3.43	2.9±0.3
6 months	6.11±3.27	2.4±0.6
Baseline female satisfaction (mean±s.d.)
Baseline	NA	2±0.8
1 month	NA	2.2±0.9
3 months	NA	2.1±0.9
6 months	NA	2±0.4
Improvement in IELT
Baseline–1 month	P<0.001	P=0.6
Baseline–3 months	P<0.001	P=0.6
Baseline–6 months	P=0.162	P=0.5
Improvement in PEP
Baseline–1 month	P<0.001	P=0.7
Baseline–3 months	P=0.027	P=0.6
Baseline–6 months	P=0.472	P=0.4
Complication ratio (%)	8.5	5.3

IELT: intravaginal ejaculation latency time; PEDT: premature ejaculation diagnostic tool; PEP: Premature Ejaculation Profile; NA: not applicable; s.d.: standard deviation

In contrast, Shaher et al.1 reported a higher mean (±s.d.) baseline PEP score of 5.49 (± 2.17) and a mean (±s.d.) baseline IELT of 35.79 (±14.23) s, indicating that their patients had better ejaculatory control at baseline and less severe PE. In these cases, neuromuscular dysregulation was likely less pronounced, with reduced spinal reflex excitability and less involvement of supraspinal modulation (Table 1). BoNT-A, by inhibiting presynaptic acetylcholine release, effectively reduces muscle contractions in the bulbospongiosus muscle, a key muscle involved in ejaculation. In patients with milder PE, where the neuromuscular pathways remain more intact but are still slightly overactive, BoNT-A may be better aligned with the degree of dysfunction, allowing for more favorable outcomes in ejaculatory latency. Additionally, the central serotonergic pathways, which modulate ejaculatory control, may have been less dysregulated in this cohort, further contributing to the greater efficacy of BoNT-A.

Another crucial factor that could explain the different outcomes is the injection technique used in each study. Shaher et al.1 employed a more widespread injection approach, distributing 100 U of BoNT-A across a larger area of the bulbospongiosus muscle. This broader distribution may have resulted in more effective muscle relaxation, which would prolong ejaculatory latency by reducing the rhythmic contractions of the muscle involved in ejaculation. In addition, the procedure was performed under ultrasound guidance, ensuring accurate delivery of the toxin into the muscle.

Almekaty et al.,2 however, used a more localized injection technique, targeting specific points within the bulbospongiosus muscle. This could have led to less diffusion of the BoNT-A within the muscle, potentially limiting its impact on muscle activity. Furthermore, their technique involved a “fanning” method, which may have contributed to a less uniform distribution of the toxin. These differences in technique are key, as they could directly affect how well the toxin works to modulate muscle function during ejaculation.

In conclusion, the differences between these two studies seem to stem from several factors, such as patient severity and the injection techniques used. While Shaher et al.1 found that BoNT-A provided short-term relief for patients with less severe PE, the results from Almekaty et al.2 suggest that this benefit might not extend to patients with more severe, treatment-resistant forms of the condition.

Looking ahead, future research should focus on standardizing the injection methods, being clear about which patients are most likely to benefit and exploring the idea of repeated treatments to keep the benefits going. Only through larger, well-designed studies can we really understand the potential of BoNT-A in managing lifelong PE over the long term.

AUTHOR CONTRIBUTIONS

ECS was responsible for study supervision and critical revision of the manuscript. MG and AS were responsible for study conception and design, acquisition of data, and manuscript drafting. AS was responsible for data interpretation. All authors read and approved the final manuscript.

COMPETING INTERESTS

ECS serves as a consultant for Kanna Health, In2, Viatris companies. MG and AS declare no competing interests.