Possible pathophysiologic roles of neurotransmitter systems in men with lifelong premature ejaculation: a scoping review

Lifelong premature ejaculation (LPE) is a subtype of premature ejaculation. Genetic research on LPE has primarily focused on neurotransmitters such as serotonin, dopamine, and norepinephrine, whereas LPE treatment studies have focused on drugs such as selective serotonin reuptake inhibitors. However, findings from genetic association and pharmacotherapeutic studies have been inconsistent. To provide a quality overview of neurobiological targets that are potentially associated with LPE by investigating genetic association and pharmacotherapeutic studies. This scoping review was conducted per the PRISMA-ScR tool (Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews). Five databases were searched in March 2023 without timeline- or language-related restrictions. After deduplication, 3949 records were obtained for review. Following screening and full-text review with citation tracking, 52 studies were included: 18 genetic and 34 pharmacotherapy studies. Serotonergic targets, such as the serotonin transporter and pre- and postsynaptic serotonergic receptors, were most often associated with LPE in genetic and pharmacotherapeutic studies. Mixed results were found among polymorphisms within genetic studies. This mechanism is in accordance with pharmacotherapeutic studies, as the highest efficacy was found for potent serotonergic antidepressants. Successful treatment was also observed with medication acting on phosphodiesterase-5 enzyme, such as tadalafil and vardenafil. Analyses of other genetic association studies did not yield any further evidence for associated targets. This review is the first comprehensive scoping review on LPE. We found that serotonergic targets are most often associated with LPE, suggesting that the serotonergic pathway is a predisposing factor in LPE. Furthermore, there is some evidence for phosphodiesterase 5 inhibitors, which should be investigated. Other previously investigated neurobiological targets appear less likely to contribute to LPE. Future studies should focus on multiple targets, ideally in a genome-wide association study design.This review has been registered with the Open Science Framework (doi:10.17605/OSF.IO/JUQSD).