Serotonin and premature ejaculation: From physiology to patient management

Introduction: Premature ejaculation (PE), whose pathophysiology is still not clearly identified, is the most common male sexual dysfunction, yet it remains underdiagnosed and undertreated. The aims of this paper are to provide a scientific and pharmacologic rationale, and to discuss to what extent selective serotonin reuptake inhibitors (SSRIs) can help patients with PE. Materials and Methods: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1981 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed. Results: The central ejaculatory neural circuit comprises spinal and cerebral areas that form a highly interconnected network. The sympathetic, parasympathetic, and somatic spinal centers, under the influence of sensory genital and cerebral stimuli integrated and processed at the spinal cord level, act in synergy to command physiologic events occurring during ejaculation. Experimental evidence indicates that serotonin (5-HT), throughout brain descending pathways, exerts an inhibitory role on ejaculation. To date, three 5-HT receptor subtypes (5-HT1A, 5-HT1B, and 5-HT2C) have been postulated to mediate 5-HT's modulating activity on ejaculation. Pharmacologic manipulation of the serotonergic system has been performed in rats, with the antidepressant selective serotonin reuptake inhibitors (SSRIs) exhibiting the greatest efficacy in delaying ejaculation. The mechanism of action by which SSRIs modulate central 5-HT tone has been studied in depth, but gaps in this knowledge prevent an explanation of the efficacy of acute treatment in delaying ejaculation. Emerging clinical evidence indicates chronic and on-demand dosing of SSRIs has a beneficial effect for the treatment of men with PE, at least for paroxetine. On-demand dapoxetine, and SSRI with a short half-life, recently has been shown to significantly increase intravaginal latency time and PE patient-related outcomes in phase 3 clinical trials. Conclusions: Nowadays there is no doubt that PE can be treated effectively by SSRIs. Nevertheless their mechanism of action is not yet well understood and deserves more research. In particular it is not understood why all the SSRIs are not equal in terms of their ability to delay ejaculation. Therefore, there is a need for more research to better characterize the mechanism of action of SSRIs as well their clinical benefit in, patients affected by PE. (c) 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.