Premature ejaculation: old story, new insights
2015; Elsevier BV; Volume: 104; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2015.08.035
ISSN1556-5653
AutoresEmmanuele A. Jannini, Giacomo Ciocca, Erika Limoncin, Daniele Mollaioli, Stefania Di Sante, Daniele Gianfrilli, Francesco Lombardo, Andrea Lenzi,
Tópico(s)Sexuality, Behavior, and Technology
ResumoConventional theories and therapies for premature ejaculation (PE) are based on assumptions not always supported by evidence. This review of the current literature on the physiology of the ejaculatory control, pathogenesis of PE, and available therapies shows that PE is still far from being fully understood. However, several interesting hypotheses have been formulated, and solid, evidence-based clinical data are currently available for dapoxetine, the unique, first-line, officially approved pharmacotherapy for PE. Further growth in the field of PE will occur only when we shift from opinion-based classifications, definitions, and hypotheses to robust, noncontroversial data grounded on evidence. Conventional theories and therapies for premature ejaculation (PE) are based on assumptions not always supported by evidence. This review of the current literature on the physiology of the ejaculatory control, pathogenesis of PE, and available therapies shows that PE is still far from being fully understood. However, several interesting hypotheses have been formulated, and solid, evidence-based clinical data are currently available for dapoxetine, the unique, first-line, officially approved pharmacotherapy for PE. Further growth in the field of PE will occur only when we shift from opinion-based classifications, definitions, and hypotheses to robust, noncontroversial data grounded on evidence. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/janninie-premature-ejaculation/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/janninie-premature-ejaculation/ Anatomically, the male genital tract is designed for coitus citus, the Latin term used by zoologists to indicate the adaptive behavior in the animal kingdom of ejaculating in the fastest possible time. Even during coital activity an animal should be ready to attack or flee, thus making it essential to deposit semen with the fastest, safest technique (1Dixon A. Primate sexuality. Oxford University Press, Oxford1998Google Scholar). The sequence of approach, penetration, and ejaculation in chimpanzees lasts just 6 seconds (Table 1). However, one of the principal aims of human sexuality is pleasure, so men have learned to control ejaculation to enhance their own and their partner's enjoyment. On the basis of these considerations, it can be postulated that ejaculation control is not natural but cultural. In the evolution of human sexuality, the ability to control the timing of ejaculation has become one of the most important features of a couple's sexual health.Table 1Duration of copulation and intercopulation intervals.[Modified from Dixon 1Dixon A. Primate sexuality. Oxford University Press, Oxford1998Google Scholar, 118, 105.]SpeciesIntromission duration (s)Interejaculatory interval (min)Common chimpanzee (Pan troglodytes)7.0<5.0Bonobo (Pan paniscus)15.0NDWestern gorilla (Gorilla gorilla)96 (median)14.0–30.0Bonnet macaque (Macaca radiata)103–85 (40.0 median)Grivet (Cercopithecus aethiops)<60NDMandrill (Mandrillus sphinx)<60 1803.1–139 (14.6 median)Bornean orangutan (Pongo pygmaeus)840 (median)NDHuman (Homo sapiens)300300 (large variability)Note: Intromission duration and interejaculation intervals in some primate species. ND = no data available. Open table in a new tab Note: Intromission duration and interejaculation intervals in some primate species. ND = no data available. Premature ejaculation (PE), or ejaculatio praecox, was rarely described in the classic sexologic literature. As reviewed by Waldinger (2Waldinger M.D. The neurobiological approach to premature ejaculation.J Urol. 2002; 168: 2359-2367Abstract Full Text Full Text PDF PubMed Google Scholar), the first case report of PE was described in 1887 (3Gross S. Practical treatise on impotence and sterility. Pentland, Edinburg1887Google Scholar); the term "premature ejaculation" would be introduced later in 1917 by a psychoanalyst (4Abraham K. Über ejaculatio praecox.Zeitschr Aerztl Psychoanal. 1917; 4: 171-181Google Scholar). The famous American sexologist Alfred Kinsey rejected the notion that PE is a sexual dysfunction, finding that 75% of men ejaculated within 2 minutes of penetration (5Kinsey A. Pomeroy W.B. Martin C.E. Sexual behavior in the human male. W.B. Saunders, Philadelphia1948Google Scholar). In contrast, in the same period, Shapiro argued that PE could be considered a combination of hyperanxious constitution and anatomic defects (6Shapiro B. Premature ejaculation: a review of 1130 cases.J Urol. 1943; 50: 374-377Abstract Full Text PDF Google Scholar). Only after the sexual and feminist revolution of the mid-1960s and the "discovery" of the female orgasm (7Jannini E.A. Rubio-Casillas A. Whipple B. Buisson O. Komisaruk B.R. Brody S. Female orgasm(s): one, two, several.J Sex Med. 2012; 9: 956-965Crossref PubMed Scopus (27) Google Scholar) did PE become important in the cohort of symptoms connected with male sexual performance. Premature ejaculation came to be considered an area of male sexual dysfunction, and new pathophysiologic and therapeutic discoveries led to renewed attention on lack of ejaculatory control (8Jannini E.A. Simonelli C. Lenzi A. Disorders of ejaculation.J Endocrinol Invest. 2002; 25: 1006-1019Crossref PubMed Google Scholar). At the time, PE was still considered a typical relational and psychological pathology (9Jannini E.A. Simonelli C. Lenzi A. Sexological approach to ejaculatory dysfunction.Int J Androl. 2002; 25: 317-323Crossref PubMed Scopus (45) Google Scholar) with few medical aspects. Recent advances in the understanding of the importance and frequency of PE, insights into its organic and nonorganic pathophysiology (10Jannini E.A. McCabe M.P. Salonia A. Montorsi F. Sachs B.D. Organic vs. psychogenic? The Manichean diagnosis in sexual medicine.J Sex Med. 2010; 7: 1726-1733Crossref PubMed Scopus (0) Google Scholar), and the efficacy of a growing range of pharmacologic therapies have led to a modern somatopsychic and holistic viewpoint (11Jannini E.A. Lenzi A. Introduction to the integrated model: medical, surgical and psychological therapies for the couple.J Endocrinol Invest. 2003; 26: 128-131Crossref PubMed Google Scholar). These new, integrated medical and psychological therapeutic alternatives, together with cooperation between basic researchers (geneticists, neurophysiologists, pharmacologists, ethologists) and clinicians (endocrinologists, andrologists, gynecologists, psychologists, psychosexologists, psychiatrists, and urologists), have improved and/or restored an active sexual life for many dysfunctional couples, thus enhancing their overall quality of life. The methodology of this review was a careful analysis of the literature, focused on the definitions, diagnosis, physiopathology, and treatment of PE. On this basis, we considered the main original studies and review articles on the clinical aspects of PE. We conducted a computerized search to identify all relevant studies in PubMed up to June 2015. The following search terms were used in PubMed: "definition of premature ejaculation," "diagnostic criteria of premature ejaculation," "physiopathology of premature ejaculation," "psychological etiology of premature ejaculation," "organic and medical etiology of premature ejaculation," "couple and premature ejaculation," and "therapies of premature ejaculation." Each of these strings produced a list of significant studies from which we selected on the basis of year of publication and research importance. In consideration of the complex history of PE, the definition of this condition has been—and still is—challenging. Masters and Johnson considered PE to be when a man is "unable to delay his ejaculation until his partner was sexually satisfied in at least 50% of their coital connections" (12Masters W. Johnson V.E. Human sexual inadequacy. Little, Brown, Boston1970Google Scholar). This definition was very successful and politically correct as well, as it took into account for the first time the female orgasm as the fundamental clinical output. It did not, however, take into account PE in homosexual couples, and the 50% figure they chose appears to have been arbitrary. Also, the devil is in the details: it considered the unique source of female pleasure to be male performance. And, as most women take longer to reach orgasm than men, the majority of men are therefore potentially "precocious." Despite their meritorious attempt to define PE using feminist categories, the two famous sexologists proposed, malgré soi, a definition of PE that is dramatically affected by machoism, in which the woman is a passive instrument in the hands of good or bad players. The American Psychiatric Association's (APA) initial attempt to define PE the Diagnostic and Statistical Manual of Mental Disorders (DSM) included vague, ambiguous terms ("persistent," "recurrent," "minimal," and "shortly after") (13American Psychiatric Association Diagnostic and statistical manual of mental disorders (DSM-IV-TR).4th ed. APA, Washington, D.C.2000Google Scholar). But its definition of PE as occurring "shortly after penetration or before the person wishes"—despite the lack of a timing cutoff creating obvious difficulties for operationalizing the definition in clinical practice—had the merit of highlighting the role of the loss of control as the main aspect to be considered when dealing with PE. In contrast, in the 5th edition the APA departed from the clinical reality: in a clear attempt to artificially reduce the prevalence of PE, the APA imposed a cutoff of ejaculation within "approximately 1 minute following vaginal penetration and before the individual wishes it… for at least 6 months and… on almost all or all occasions of sexual activity" (14American Psychiatric Association DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5.5th ed. APA, Washington, D.C.2013Crossref Google Scholar). Although some epidemiologic data do show that the majority (but not all) of patients with lifelong (LL) PE ejaculate in 1 minute or less (15Giuliano F. Patrick D.L. Porst H. La Pera G. Kokoszka A. Merchant S. et al.Premature ejaculation: results from a five-country European observational study.Eur Urol. 2008; 53: 1048-1057Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 16Waldinger M.D. Quinn P. Dilleen M. Mundayat R. Schweitzer D.H. Boolell M. A multinational population survey of intravaginal ejaculation latency time.J Sex Med. 2005; 2: 492-497Crossref PubMed Scopus (196) Google Scholar), the APA assigned the questionable cutoff of 1 minute to all forms of PE. Clearly the panel of experts who prepared this definition must be changed for the next edition of the manual. The World Health Organization's (WHO) 1992 International Classification of Diseases (ICD-10) definition of PE also has some high and low points. Premature ejaculation is "the inability to control ejaculation sufficiently for both partners to enjoy sexual interaction" and "an inability to delay ejaculation sufficiently to enjoy lovemaking, and manifest as either of the following: (i) occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required: before or within 15 seconds of the beginning of intercourse); and (ii) ejaculation occurs in the absence of sufficient erection to make intercourse possible" (17World Health Organization International classification of diseases and related health problems.10th ed. WHO, Geneva1994Google Scholar). Although WHO provided an objective definition of PE, highlighting again the importance of the loss of control, the cutoff of 15 seconds is not only very unrealistic but also without supporting evidence. In October 2007, the International Society for Sexual Medicine (ISSM) defined LL-PE as "characterized by ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy" (18McMahon C.G. Althof S.E. Waldinger M.D. Porst H. Dean J. Sharlip I.D. et al.An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation.J Sex Med. 2008; 5: 1590-1606Crossref PubMed Scopus (207) Google Scholar). On the basis of these criteria, the key points characterizing this pathologic condition are the timing, measured as the intravaginal ejaculatory latency time (IELT) (19Waldinger M.D. Towards evidence-based drug treatment research on premature ejaculation: a critical evaluation of methodology.Int J Impot Res. 2003; 15: 309-313Crossref PubMed Scopus (82) Google Scholar), the feeling of loss of control over ejaculation, and the presence of distress within the couple (20Jannini E.A. Lenzi A. Ejaculatory disorders: epidemiology and current approaches to definition, classification and subtyping.World J Urol. 2005; 23: 68-75Crossref PubMed Scopus (70) Google Scholar). The latter aspect and the partner's perception of the problem support the clinical evidence that the relationship factors often influence the sexual function (21Rosen R.C. McMahon C.G. Niederberger C. Broderick G.A. Jamieson C. Gagnon D.D. Correlates to the clinical diagnosis of premature ejaculation: results from a large observational study of men and their partners.J Urol. 2007; 177: 1059-1064Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). In this respect, PE could be considered the only partner-oriented male sexual symptom. Both of the currently used adjectives—premature and rapid—refer to the partner's sexual physiology and to the time course of female sexual response. Hence, PE could be considered a partner-generated symptom. More recently, the ISSM found scientific reasons to define acquired PE (A-PE). Both LL-PE and A-PE share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. The unified definition of PE is that of "a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (LL-PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (A-PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy" (22Serefoglu E.C. McMahon C.G. Waldinger M.D. Althof S.E. Shindel A. Adaikan G. et al.An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation.J Sex Med. 2014; 11: 1423-1441Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Their revised definition is the most useful to date for clinical practice, as it recognizes a substantial contrast between LL-PE and A-PE: the former is more idiopathic in nature, and the latter is more related to psychological, endocrine, neurologic, and urologic factors. Figure 1 highlights the tridimensional aspects clinically characterizing PE according to the ISSM definitions: control, stress, and time as the main factors to be considered when dealing with PE patients. These three aspects are responsible of the consequences of PE—almost always a reduction in sexual activity, sexual satisfaction, and quality of life, with an increase in distress and interpersonal difficulties (23Rowland D.L. Patrick D.L. Rothman M. Gagnon D.D. The psychological burden of premature ejaculation.J Urol. 2007; 177: 1065-1070Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). The association of IELT with satisfaction in sexual intercourse and distress related to ejaculation is mediated by perceived control over ejaculation (24Patrick D.L. Rowland D. Rothman M. Interrelationships among measures of premature ejaculation: the central role of perceived control.J Sex Med. 2007; 4: 780-788Crossref PubMed Scopus (52) Google Scholar). Figure 2 connects the pivotal role of the serotoninergic pathway (to be discussed later) in the control of the ejaculatory reflex with the clinical issue of loss of control as the most important (but not unique) aspect of PE.Figure 2The patient with premature ejaculation (PE) needs more serotonin than normal in his synaptic cleft to improve the feeling of control over the entire reflex of ejaculation. Premature ejaculation should not be considered a condition characterized by low serotonin (5-HT) but rather a condition where, for a number of various reasons, more 5-HT is needed to improve the feeling of control, to decrease the condition-related distress in the couple, and to improve the intravaginal ejaculation latency time (IELT).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Finally, the epidemiology of PE is dramatically influenced by its definition. Pharmaceutic industry-sponsored population studies, limited by the possible conflict of interest but with the merit of huge enrollments (25Jannini E.A. Eardley I. Sand M. Hackett G. Clinical and basic science research in sexual medicine must rely, in part, on pharmaceutical funding?.J Sex Med. 2010; 7: 2331-2337Crossref PubMed Scopus (4) Google Scholar), show a 20% prevalence of concerns related to control over ejaculation in the general population (20Jannini E.A. Lenzi A. 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It is interesting that no evidence has been so far produced for the management of the large 15% (20% minus 5%) who complain of PE while not exactly fulfilling the official definitions. As with all sexual disorders, PE is a symptom rather than a disease. From a clinical point of view, this suggests that in any case of PE the disease behind the symptom must be carefully sought and possibly cured. Conventional algorithms of PE are based on an organic or psychogenic dichotomy, with the latter being considered the main etiologic cause. However, the adjective "psychogenic" is overtly inappropriate because, irrespective of the ultimate cause, lack of ejaculatory control is per se stressful and a source of psychological disturbance. All cases of PE thus are or become psychogenic, even where PE is a symptom of an organic etiology or risk factor (10Jannini E.A. McCabe M.P. Salonia A. Montorsi F. Sachs B.D. Organic vs. psychogenic? The Manichean diagnosis in sexual medicine.J Sex Med. 2010; 7: 1726-1733Crossref PubMed Scopus (0) Google Scholar). In the beginning, PE was considered as psychogenic in nature. However, some researchers believe that PE is not a psychological disorder but a neurobiological phenomenon (2Waldinger M.D. The neurobiological approach to premature ejaculation.J Urol. 2002; 168: 2359-2367Abstract Full Text Full Text PDF PubMed Google Scholar). The arguments sustaining both hypotheses are weak. The psychological (31Althof S.E. Abdo C.H. Dean J. Hackett G. McCabe M. McMahon C.G. et al.International Society for Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation.J Sex Med. 2010; 7: 2947-2969Crossref PubMed Scopus (127) Google Scholar) and neurobiological positions are extreme and also dangerous for the growth of sexual medicine and patient well-being. The mind-body separation is obsolete in modern medicine (32Sachs B.D. The false organic-psychogenic distinction and related problems in the classification of erectile dysfunction.Int J Impot Res. 2003; 15: 72-78Crossref PubMed Scopus (29) Google Scholar). Although it is clear that all psychological processes are regulated by brain function (somatopsychic evidence), it is also plain that all psychogenic dysfunctions involve organic processes (psychosomatic evidence). This holistic approach allows PE to be considered as a psycho-neuro-endocrine and urologic disorder affecting the couple. To understand the pathogenesis of PE and its psychological and pharmacologic therapies, it must be remembered that normal male copulation culminates in three psychologically and physiologically distinct events (33Kandeel F.R. Koussa V.K. Swerdloff R.S. Male sexual function and its disorders: physiology, pathophysiology, clinical investigation, and treatment.Endocr Rev. 2001; 22: 342-388Crossref PubMed Scopus (119) Google Scholar):1.Emission. Contraction of smooth muscle cells of the male genital tract involving testicular tubules, efferent ducts, the epididymis, and vasa deferentia, and the secretion of seminal fluid due to rhythmic contractions of the seminal vesicles and prostate.2.Ejaculation. Reflex response, not requiring cerebral input, which is triggered by the accumulation of semen in the bulbous urethra. The pelvic floor muscles actively collaborate to achieve ejaculation, with from three to seven contractions.3.Orgasm. A perceptual-cognitive event of pleasure that, in normal conditions, coincides with the time of ejaculation. Even though principally controlled by the same sympathetic nerves, these three elements are separate from one another and provoke different psychological perceptions (34Rowland D. McMahon C.G. Abdo C. Chen J. Jannini E. Waldinger M.D. et al.Disorders of orgasm and ejaculation in men.J Sex Med. 2010; 7: 1668-1686Crossref PubMed Scopus (108) Google Scholar). As first suggested by Kaplan (35Kaplan H.S. How to overcome premature ejaculation. Brunner-Mazel, New York1989Google Scholar), the central control of ejaculation mirrors that of micturition. In fact, both can be essentially considered voiding activities, depending on supraspinal influences. Positron emission tomography shows that ejaculation results in activation of localized regions within the dorsolateral pontine tegmentum, tentatively termed the "pelvic organ-stimulating center" and "pelvic floor-stimulating center." The former, via projections to the sacral parasympathetic motoneurons, controls pelvic organs involved in voiding functions. The latter, via direct projections to pelvic floor motoneurons, produces the pelvic floor contractions characteristic of ejaculation (36Huynh H.K. Willemsen A.T. Lovick T.A. Holstege G. 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Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181.Br J Pharmacol. 1998; 125: 1733-1743Crossref PubMed Scopus (89) Google Scholar, 45Rowland D.L. Houtsmuller E.J. 8-OH-DPAT interacts with sexual experience and testosterone to affect ejaculatory response in rats.Pharmacol Biochem Behav. 1998; 60: 143-149Crossref PubMed Scopus (26) Google Scholar). In contrast, stimulation of presynaptic 5-HT1B autoreceptors and postsynaptic 5-HT2C is responsible for inhibition of ejaculation in rat (44Hillegaart V. Ahlenius S. Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181.Br J Pharmacol. 1998; 125: 1733-1743Crossref PubMed Scopus (89) Google Scholar). Furthermore, 5-HT1A receptors in different locations (brain, raphe nuclei, spinal cord, and autonomic ganglia) may modulate rat ejaculation in opposite ways (46Rehman J. Kaynan A. Christ G. Valcic M. Maayani S. Melman A. Modification of sexual behavior of Long-Evans male rats by drugs acting on the 5-HT1A receptor.Brain Res. 1999; 821: 414-425Crossref PubMed Scopus (40) Google Scholar). Different selective 5-HT1A receptor agonists such as 8-OH-DPAT, FG-5893, and flesinoxan (47Haensel S.M. Rowland D.L. Kallan K.T. Clomipramine and sexual function in men with premature ejaculation and controls.J Urol. 1996; 156: 1310-1315Abstract Full Text Full Text PDF PubMed Google Scholar) selectively decrease ejaculation latencies and intromission and mount frequencies. It is interesting that the comparable ejaculation-delaying effects of SSRIs in humans and rats suggest high predictive validity with regard to the regulation of ejaculation (48Waldinger M.D. Olivier B. Animal models of premature and retarded ejaculation.World J Urol. 2005; 23: 115-118Crossref PubMed Scopus (33) Google Scholar). Nevertheless, face validity is low when trying to extend the results in rats with normal sexual behavior to ejaculatory dysfunctions (49Pattij T. de Jong T.R. Uitterdijk A. Waldinger M.D. Veening J.G. Cools A.R. et al.Individual differences in male rat ejaculatory behaviour: searching for models to study ejaculation disorders.Eur J Neurosci. 2005; 22: 724-734Crossref PubMed Scopus (0) Google Scholar). In con
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