AB54. Pathophysiology of premature ejaculation and serotonin

According to the epidemiologic studies conducted so far, premature ejaculation (PE) is the most common male sexual dysfunction in younger men (<30 years); its prevalence is higher than that of ED, and varies from 9% and up to 31% of the male population. The etiology of PE is uncertain in almost all cases, and might include a combination of organic and psychogenic factors. Negative conditioning and penile hypersensitivity are the most frequently cited etiological factors in PE, although neither mechanism has received adequate experimental support to date. Accordingly from a scientific perspective, it is fair to state that PE pathophysiology is largely unknown. Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness. There are currently 15 known 5-HT receptor subtypes, which are grouped into seven major classes (5-HT1–7). With the exception of the 5-HT3 receptor, all 5-HT receptors are coupled to second messengers by G proteins. All 5-HT receptors have been reported to exist postsynaptically. Although some authors have suggested the existence of facilitatory 5-HT3 autoreceptors, only the 5-HT1 receptor subtypes (5-HT1A and 5-HT1B) are widely accepted to function as presynaptic autoreceptors. At least three of the 5-HT receptor subtypes have a role in ejaculation: 5-HT1A, 5-HT1B and 5-HT2C receptors. Activation of postsynaptic 5-HT2C or 5-HT1B receptors prolongs ejaculatory latency, whereas activation of presynaptic 5-HT1A autoreceptors, which inhibits 5-HT release, decreases ejaculatory latency. Subcutaneous administration of the 5-HT1B receptor agonists anpirtoline and m-trifluoromethylphenyl piperazine and systemic, acute administration of the 5-HT2C agonist 2, 5-dimethoxy-4-iodoamphetamine have been shown to impair ejaculation in rats. Based on the role of 5-HT neurotransmission in the physiology of ejaculatory control and possibly in the pathogenesis of PE, and because SSRI antidepressants have the well-established side-effect of delaying ejaculation when used to treat depressed patients, currently marketed SSRIs such as paroxetine, fluoxetine, and sertraline, which increase synaptic 5-HT concentration via blockade of 5-HT transporters, have been investigated in numerous clinical studies for managing PE. Paroxetine and sertraline have provided significant benefits in patients with PE, either via daily administration or on-demand use before intercourse, and fluoxetine has shown some efficacy for PE as continuously dosed therapy. Although none of these agents has received an indication for the treatment of PE, current guidelines from the AUA and recommendations from the Second International Consultation on Sexual Dysfunctions recommend the off-label use of SSRIs for managing PE.