(222) POSSIBLE PATHOPHYSIOLOGICAL ROLES OF NEUROTRANSMITTER SYSTEMS IN MEN WITH LIFELONG PREMATURE EJACULATION: A SCOPING REVIEW
Authors: Van Raaij J , Janssen P , Serefoglu EC , Van Amelsvoort TA 
Published: December 2024

Abstract

Introduction
Lifelong premature ejaculation (LPE) is a subtype of premature ejaculation. Genetic research on LPE has primarily focused on neurotransmitters like serotonin, dopamine, and norepinephrine. LPE treatment studies have focused on drugs like serotonin reuptake inhibitors (SSRIs). However, findings from both genetic association and pharmacotherapeutic studies have been inconsistent, likely due to the lack of standardized definitions and measurement methods for LPE, such as the stopwatch method for clocking intravaginal ejaculation latency times (IELTs). In addition, some genetic studies in LPE have shown to be prone to genotyping errors which has led to inconclusive results.

Objective
To provide a quality assured overview of neurobiological targets that are potentially associated with LPE by investigating genetic and pharmacotherapeutic studies.

Methods
This scoping review was conducted using the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR tool). Five databases were searched in March 2023 without timeline- or language-related restrictions. We included pharmacological studies with multiple study designs: randomized clinical trials, cross-over studies, single arm trials or case reports. Studies were only eligible if pre- and posttreatment stopwatch measured IELTs were reported in order to measure a factor increase in IELTs. Studies that did not use the ISSM 2008 or 2014- or the DSM-5 definition for LPE or a cut-off IELT of approximately 1.5 minutes after vaginal penetration were excluded.

Results
After deduplication, 3949 records were obtained for reviewing. Following screening and full text review with citation tracking, 52 studies were included. Studies consisted of 18 genetic and 34 pharmacotherapy studies. Serotonergic targets, like the serotonin transporter and pre- and postsynaptic serotonergic receptors, were most often associated with LPE in both genetic and pharmacotherapeutic studies. Mixed results were found among polymorphisms within genetic studies. However, most serotonergic polymorphisms suggest up- or downregulation on serotonergic targets eventually leading to decreased synaptic levels of serotonin. This mechanism is in accordance with pharmacotherapeutic studies as the highest efficacy was found for potent serotonergic antidepressants such as paroxetine, sertraline, fluoxetine, dapoxetine, citalopram and clomipramine. Successful treatment was also observed with medication acting on phospoidesterase-5 enzyme (PDE5), such as tadalafil and vardenafil. Analyses of other genetic association studies did not yield any further evidence for associated targets.

Conclusions
This review is the first comprehensive scoping review on LPE, performed according to PRISMA-ScR guidelines. 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 PDE5 which should be further investigated. Other previously investigated neurobiological targets appear less likely to contribute to LPE. However LPE is thought to be a complex disorder in which a subset of polymorphisms contribute to this phenotype. Therefore future studies should focus on multiple targets, ideally in a genome wide association study design.

Disclosure
Any of the authors act as a consultant, employee or shareholder of an industry for: In2, Virility, Israel.