Dapoxetine treatment of premature ejaculation.
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Benzylamines↗
Biomedical subjects
Marcel D Waldinger
Publications and source records attributed to Marcel D Waldinger.
Serotonin and the neurobiology of the ejaculatory threshold.
Disorders of the ejaculatory threshold, such as lifelong premature ejaculation, are fairly common in humans and can have a great impact on the quality of life. Research in humans and rats have indicated that increased serotonin levels in the central nervous system elevate the ejaculatory threshold, probably via 5-HT(1B) and 5-HT(2C) receptors, whereas depletion of serotonin decreases the ejaculatory threshold. 5-HT(1A) receptor activation strongly lowers the ejaculatory threshold, probably mediated by both the reduction of serotonin levels via presynaptic 5-HT(1A) receptors and yet unknown effects of postsynaptic 5-HT(1A) receptors. The present review attempts to integrate psychopharmacological data on serotonergic control over ejaculation with the knowledge of the neuroanatomical substrate of ejaculation, indicating the importance of the lumbosacral spinal cord, the nucleus paragigantocellularis, the lateral hypothalamic area and several other supraspinal areas. In addition, the gaps in our understanding of the role of serotonin in the ejaculatory threshold are discussed. Filling in those gaps might help to design specific drugs that alter the ejaculatory threshold, thereby alleviating ejaculatory disorders.
Animals↗
Changing paradigms from a historical DSM-III and DSM-IV view toward an evidence-based definition of premature ejaculation. Part I--validity of DSM-IV-TR.
BACKGROUND: In former days, information obtained from randomized well-controlled clinical trials and epidemiological studies on premature ejaculation (PE) was not available, thereby hampering the efforts of the consecutive DSM Work Groups on Sexual Disorders to formulate an evidence-based definition of PE. The current DSM-IV-TR definition of PE is still nonevidence based. In addition, the requirement that persistent self-perceived PE, distress, and interpersonal difficulties, in absence of a quantified ejaculation time, are necessary to establish the diagnosis remains disputable. AIM: To investigate the validity and reliability of DSM and ICD diagnosis of premature ejaculation. METHODS: The historical development of DSM and ICD classification of mental disorders is critically reviewed, and two studies using the DSM-IV-TR definition of PE is critically reanalyzed. RESULTS: Reanalysis of two studies using the DSM-IV-TR definition of PE has shown that DSM-diagnosed PE can be accompanied by long intravaginal ejaculation latency time (IELT) values. The reanalysis revealed a low positive predictive value for the DSM-IV-TR definition when used as a diagnostic test. A similar situation pertains to the American Urological Association (AUA) definition of PE, which is practically a copy of the DSM-IV-TR definition. CONCLUSION: It should be emphasized that any evidence-based definition of PE needs objectively collected patient-reported outcome (PRO) data from epidemiological studies, as well as reproducible quantifications of the IELT.
Coitus↗
Changing paradigms from a historical DSM-III and DSM-IV view toward an evidence-based definition of premature ejaculation. Part II--proposals for DSM-V and ICD-11.
BACKGROUND: In the Diagnostic and Statistical Manual of Mental Disorders (DSM), a descriptive definition for premature ejaculation (PE) that was based on historical assumptions has been accepted. AIM: To formulate a new functional definition of PE in the DSM. METHODS: A "syndrome" approach instead of a "complaint" approach is applied and evidence-based data from epidemiological and clinical studies are used. RESULTS: A new functional definition of PE should pertain to a cluster of "symptoms" of a distinct "syndrome." A syndrome rather than a descriptive definition should distinguish Lifelong and Acquired PE variants. Evidence-based data also suggest another PE type "Natural Variable PE," which is not a typical syndrome but rather a cluster of inconsistent symptoms of rapid ejaculation. Moreover, in "Natural Variable PE" the occurrence of rapid ejaculation is not based on neurobiological or psychological pathology, but belongs to the normal variability of sexual performance. Its prevalence is probably much higher than that of Lifelong and Acquired PE. We propose three separate operationalized definitions of these three PE types for the pending DSM-V and ICD-11, which include a quantification of the ejaculation time (intravaginal ejaculation latency time), inability of ejaculatory control, and a description of severity of PE in terms of psychological distress. CONCLUSION: The use of the intravaginal ejaculation latency time into the DSM-V and ICD-11 would mean that statistical evidence becomes accepted as one of the mainstays for establishing an evidence-based definition of the three PE types.
Coitus↗
Emerging drugs for premature ejaculation.
Lifelong premature ejaculation (PE) is a frequent male sexual dysfunction and is thought to be mediated in part by disturbances of serotonergic (5-hydroxytryptamine; 5-HT) neurotransmission and ejaculation-mediating 5-HT receptors in the CNS. The aetiology of the dysfunction is unclear, but probably includes neurobiological and environmental factors. Lifelong PE is a syndrome characterised by a cluster of symptoms. Rapid ejaculations become manifest around the first sexual encounters in puberty or adolescence. Intravaginal ejaculation latency time usually occurs within 30-60 s, or maximally within 2 min after vaginal penetration, is present with nearly every sexual partner, and remains similar throughout life or may aggravate during ageing. The syndrome may lead to secondary psychological, sexual and relationship problems. Daily treatment with some selective serotonin re-uptake inhibitors (SSRIs) leads to strong ejaculation delay, but may be accompanied by side effects. New treatment with SSRIs with a short half-life (if approved) for on-demand use 1-2 h prior to coitus exerts less ejaculation-delaying effects than daily SSRI strategies. Animal studies have shown that strong, immediate ejaculation delay may be induced by the combination of an SSRI with a 5-HT(1A) receptor antagonist. The combination of an SSRI and any other compound that immediately strongly raises 5-HT neurotransmission may form the basis for the development of new on-demand drugs to treat PE.
Administration, Oral↗
Relevance of an evidence-based ejaculation time cutoff point for neurobiological research of premature ejaculation.
The Diagnostic and Statistical Manual (DSM)-IV definition of premature ejaculation is not based on evidence-based studies. In particular, the absence of a well-defined quantitative measure of the intravaginal ejaculation latency time (IELT) makes the DSM definition inadequate. Therefore, the DSM-IV definition should be replaced by a medical definition that incorporates both quantitative as qualitative parameters of premature ejaculation. An evidence-based medical definition should include a cutoff point of the IELT at the 0.5 and 2.5 percentiles of the IELT distribution in the general male population. Such a definition has recently been proposed on the basis of a stopwatch study of the IELT in 491 men from five different countries. Similarly, a cutoff point of ejaculation frequency in laboratory rats enhances the probability to distinguish genuine rapid-ejaculator rats. Only by the strict application of these cutoff points is the probability enhanced that human and animal neurobiological research can prove whether these sexual endophenotypes differ in brain activation, have particular genetic genotypes (polymorphisms), are strictly under genetic control, or are dependent on environmental conditions and/or genotypic/environmental interactions.
Animals↗
Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats.
Selective Serotonin Reuptake Inhibitors (SSRIs) are designed to treat adults, but are increasingly prescribed for adolescents. SSRIs might cause permanent changes in serotonin-related behavior in adolescents, since their serotonergic system is still developing. Male Wistar rats were treated with paroxetine (15 mg/kg p.o.) or fluvoxamine (30 mg/kg p.o.) throughout adolescence. After a washout period their behavior in the elevated plus-maze, prepulse inhibition test, Forced swimming test and elevated T-maze were studied. In addition, the effects of the 5-HT(1A) receptor agonist 8-OH-DPAT on sexual behavior and lower lip retraction were measured. Paroxetine mildly inhibited weight gain during treatment. Both SSRIs caused a reduction in ejaculation frequency and in time spent on the open arm of the elevated plus-maze in adult rats. Fluvoxamine slightly increased avoidance latency in the elevated T-maze compared to paroxetine. No differences between the groups were found in the other tests. Apparently, chronic treatment with SSRIs during adolescence may cause mild changes in adult behavior.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Animal models of premature and retarded ejaculation.
Most of our current understanding of the neurobiology of sexual behavior and ejaculatory function has been derived from animal studies using rats with normal sexual behaviour. However, none of these proposed models adequately represents human ejaculatory disorders. Based on the "ejaculation distribution theory", which postulates that the intravaginal ejaculation latency time in men is represented by a biological continuum, we have developed an animal model for the research of premature and delayed ejaculation. In this model, a large number of male Wistar rats are investigated during 4-6 weekly sexual behavioural tests. Based on the number of ejaculations during 30 min tests, rapid and sluggish ejaculating rats are distinguished, each representing approximately 10% at both ends of a Gaussian distribution. Together with other parameters, such as ejaculation latency time, these rats at either side of the spectrum resemble men with premature and delayed ejaculation, respectively. Comparable to the human situation, in a normal population of rats, endophenotypes exist with regard to basal sexual (ejaculatory) performance.
Animals↗
Retarded ejaculation in men: an overview of psychological and neurobiological insights.
Disorders of orgasm and ejaculation are erroneously mixed up in the DSM-IV classification system. Male Orgasmic Disorder to denote "delayed ejaculation" is inadequate as orgasm and ejaculation represent clinical expressions of different neurobiological phenomena. Unfortunately, the DSM-IV criteria for delayed ejaculation were accepted regardless of any research with appropriate methodology and design. The psychological approach and associated psychotherapy to solve this problem is rather disappointing. The neurobiological approach, which started with animal studies, has demonstrated various neurotransmitters with the potency to inhibit ejaculation. Indeed, several experimental drugs have been tested in rats, showing the successful acceleration of ejaculation. We propose that human research should start with the development of an operational definition of delayed ejaculation. To achieve this goal, we propose unselected epidemiological stopwatch studies which also provide information on the prevalence and incidence of delayed ejaculation in men. Currently, no effective and safe drugs are available to accelerate ejaculation time in men. The best way to treat lifelong delayed ejaculation is, thus far, to inform the patients about biological and psychological inhibiting factors which they need to avoid, and to remain critical about unrealistic expectations from psychotherapy. Psychotherapy may be useful in subgroups, particularly in the absence of effective and safe drugs.
Animals↗
Lifelong premature ejaculation: definition, serotonergic neurotransmission and drug treatment.
The ejaculation distribution theory (EDT) postulates a biological continuum of the intravaginal ejaculation latency time (IELT) in men. Such an continuum has recently been found in two epidemiological stopwatch studies. In addition, a continuum of ejaculation latency time has also been demonstrated in laboratory rats. It is suggested that the invariable parts of ejaculation, i.e. premature and retarded ejaculation are highly influenced by genetic and neurobiological factors. In contrast, superimposed on biological roots, ejaculation of men, in the middle part of the continuum, is probably more easily influenced by environmental and psychological factors. A meta-analysis of 35 daily SSRI and clomipramine treatment studies demonstrated a similar efficacy for paroxetine, clomipramine, sertraline and fluoxetine, with paroxetine exerting the strongest effect on ejaculation. Based on fundamental insights into serotonergic neurotransmission, it is suggested that on-demand conventional SSRI treatment will not lead to similarly impressive ejaculation delay as that found after daily conventional SSRI treatment. Future studies with SSRIs with short half-lives, short T(max) and high C(max )should elucidate whether these pharmacokinetic properties are able to affect the pharmacodynamics of 5-HT neurons in such a way that immediate clinically relevant ejaculation delay occurs.
Animals↗
Effects of chronic selective serotonin reuptake inhibitors on 8-OH-DPAT-induced facilitation of ejaculation in rats: comparison of fluvoxamine and paroxetine.
RATIONALE: Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) can delay ejaculation in humans, but the extent of this effect differs between SSRIs. The involvement of 5-HT1A receptors is likely, since 5-HT1A receptor agonists accelerate ejaculation and chronic SSRI treatment is thought to desensitize 5-HT1A receptors. OBJECTIVES: This study was conducted to examine the effects of chronic pretreatment with the SSRIs fluvoxamine and paroxetine on the facilitation of ejaculation induced by the 5-HT1A receptor agonist 8-OH-DPAT. METHODS: Sexually experienced Wistar rats with normal ejaculatory behavior were treated for 22 days with vehicle, fluvoxamine (30 mg/kg/day), or paroxetine (10 or 20 mg/kg/day, p.o.). On day 22, rats received a challenge with saline or 8-OH-DPAT (0.4 mg/kg, s.c.). Sexual behavior was tested on days 1, 8, 15, and 22 of the SSRI-treatment. RESULTS: Treatment with both doses of paroxetine, but not fluvoxamine, delayed ejaculation. 8-OH-DPAT strongly accelerated ejaculation under vehicle conditions. Pretreatment with paroxetine reduced the effects of 8-OH-DPAT on ejaculation in a dose-dependent manner and more strongly than fluvoxamine. CONCLUSIONS: SSRIs affect 5-HT1A receptors involved in ejaculation. The degree to which this occurs, with paroxetine exerting a stronger effect than fluvoxamine, might determine the extent of SSRI-induced delayed ejaculation.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity.
The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.
Administration, Oral↗
Individual differences in male rat ejaculatory behaviour: searching for models to study ejaculation disorders.
In addition to investigating sexual function in rats that display normal ejaculatory behaviour, studying rats that are either 'hyposexual' or 'hypersexual' may provide important insights into the aetiology of ejaculatory dysfunctions in men, such as premature and retarded ejaculation. To this end, rats were matched into groups of 'sluggish', 'normal' and 'rapid' ejaculators based on their ejaculation frequencies displayed in a series of weekly sexual behaviour tests. Selecting rats on this parameter revealed large and stable differences in other parameters of sexual behaviour as well, including ejaculation latency and mount frequency but not intromission frequency and mount latency, putative indices of sexual motivation. Neuroanatomically, Fos immunoreactivity as a measure of neuronal activation was increased in rapid ejaculators compared with sluggish ejaculators in ejaculation-related brain areas, presumably associated with the differences in ejaculatory behaviour. Although the total number of oxytocin neurones within subregions of the hypothalamus did not differ between groups, in the supraoptic nucleus of the hypothalamus more oxytocin neurones were activated in rapid ejaculators compared with the other groups. Apart from the differences observed in ejaculatory behaviour, groups did not differ with respect to their locomotor activity and approach-avoidance behaviour as measured in the elevated plus-maze. Finally, apomorphine-induced stereotypy was similar in sluggish and rapid ejaculators, suggesting no large differences in dopamine susceptibility. Altogether, the present results suggest stable differences in male rat ejaculatory behaviour. Further exploring the neurobiological mechanisms underlying these differences may be a promising approach to gain insights into the aetiology of sexual dysfunctions such as premature, retarded or an-ejaculation.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Lifelong premature ejaculation: from authority-based to evidence-based medicine.
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Circumcision, Male↗
Proposal for a definition of lifelong premature ejaculation based on epidemiological stopwatch data.
INTRODUCTION: Consensus on a definition of premature ejaculation has not yet been reached because of debates based on subjective authority opinions and nonstandardized assessment methods to measure ejaculation time and ejaculation control. AIM: To provide a definition for lifelong premature ejaculation that is based on epidemiological evidence including the neurobiological and psychological approach. METHODS: We used the 0.5 and 2.5 percentiles as accepted standards of disease definition in a skewed distribution. We applied these percentiles in a stopwatch-determined intravaginal ejaculation latency time (IELT) distribution of 491 nonselected men from five different countries. The practical consequences of 0.5% and 2.5% cutoff points for disease definition were taken into consideration by reviewing current knowledge of feelings of control and satisfaction in relation to ejaculatory performance of the general male population. MAIN OUTCOME MEASURES: Literature arguments to be used in a proposed consensus on a definition of premature ejaculation. RESULTS: The stopwatch-determined IELT distribution is positively skewed. The 0.5 percentile equates to an IELT of 0.9 minute and the 2.5 percentile an IELT of 1.3 minutes. However, there are no available data in the literature on feelings of control or satisfaction in relation to ejaculatory latency time in the general male population. Random male cohort studies are needed to end all speculation on this subject. Exact stopwatch time assessment of IELT in a multinational study led us to propose that all men with an IELT of less than 1 minute (belonging to the 0.5 percentile) have "definite" premature ejaculation, while men with IELTs between 1 and 1.5 minutes (between 0.5 and 2.5 percentile) have "probable" premature ejaculation. Severity of premature ejaculation (nonsymptomatic, mild, moderate, severe) should be defined in terms of associated psychological problems. CONCLUSION: We define lifelong premature ejaculation as a neurobiological dysfunction with an unacceptable increase of risk to develop sexual and psychological problems anywhere in a lifetime. By defining premature ejaculation from an authority-defined disorder into a dysfunction based on epidemiological evidence it is possible to establish consensus based on epidemiological evidence. Additional epidemiological stopwatch studies are needed for a final decision of IELT values at both percentile cutoff points.
Age Factors↗
A multinational population survey of intravaginal ejaculation latency time.
INTRODUCTION: Intravaginal ejaculation latency time (IELT), defined as the time between the start of vaginal intromission and the start of intravaginal ejaculation, is increasingly used in clinical trials to assess the amount of selective serotonin reuptake inhibitor-induced ejaculation delay in men with premature ejaculation. Prospectively, stopwatch assessment of IELTs has superior accuracy compared with retrospective questionnaire and spontaneous reported latency. However, the IELT distribution in the general male population has not been previously assessed. AIM: To determine the stopwatch assessed-IELT distribution in large random male cohorts of different countries. METHODS: A total of 500 couples were recruited from five countries: the Netherlands, United Kingdom, Spain, Turkey, and the United States. Enrolled men were aged 18 years or older, had a stable heterosexual relationship for at least 6 months, with regular sexual intercourse. The surveyed population were not included or excluded by their ejaculatory status and comorbidities. This survey was performed on a "normal" general population. Sexual events and stopwatch-timed IELTs during a 4-week period were recorded, as well as circumcision status and condom use. MAIN OUTCOME MEASURES: The IELT, circumcision status, and condom use. RESULTS: The distribution of the IELT in all the five countries was positively skewed, with a median IELT of 5.4 minutes (range, 0.55-44.1 minutes). The median IELT decreased significantly with age, from 6.5 minutes in the 18-30 years group, to 4.3 minutes in the group older than 51 years (P<0.0001). The median IELT varied between countries, with the median value for Turkey being the lowest, i.e., 3.7 minutes (0.9-30.4 minutes), which was significantly different from each of the other countries. Comparison of circumcised (N=98) and not-circumcised (N=261) men in countries excluding Turkey resulted in median IELT values of 6.7 minutes (0.7-44.1 minutes) in circumcised compared with 6.0 minutes (0.5-37.4 minutes) in not-circumcised men (not significant). The median IELT value was not affected by condom use. CONCLUSION: The IELT distribution is positively skewed. The overall median value was 5.4 minutes but with differences between countries. For all five countries, median IELT values were independent of condom usage. In countries excluding Turkey, the median IELT values were independent of circumcision status.
Adolescent↗
Thyroid-stimulating hormone assessments in a Dutch cohort of 620 men with lifelong premature ejaculation without erectile dysfunction.
INTRODUCTION: Apart from the involvement of central serotonergic neurotransmission on lifelong premature ejaculation, interference of thyroid function has been speculated. AIM: To study thyroid function in a large group of men with lifelong premature ejaculation (LPE). METHODS: Lifelong premature ejaculation was defined as an intravaginal ejaculation latency time (IELT) of less than 1 minute. Any consecutive man with LPE and no erectile dysfunction assessed by medical history and the International Index of Erectile Function (IIEF-5) was eligible for the study. Apart from the assessment of thyroid-stimulating hormone (TSH) also free thyroxin (f T4) was determined in case of a TSH of <0.3 mU/L or TSH of >4.0 mU/L (being the lower and upper limits of normal values, respectively). Blood samples were drawn throughout the day within office hours. MAIN OUTCOME MEASURES: Thyroid-stimulating hormone and f T4. RESULTS: Included were 620 men; age (mean+/-SD) was 39.9+/-9.4 years (range 19-65). TSH concentrations from morning, early and late afternoon samples did not differ. The geometrical mean TSH concentration was 0.85 mU/L (95% confidence intervals: 0.82-0.90) with a coefficient of variation of 57.9%. Fourteen men had a TSH of <0.3 mU/L (2.2%), while five men (0.8%) of >4.0 mU/L. All men with an abnormal TSH had a normal f T4 (between 10 and 20 pmol/L). No relationship was found between age and TSH concentrations. CONCLUSION: Thyroid-stimulating hormone distribution was analyzed in a cohort of Dutch men with lifelong premature ejaculation and no erectile dysfunction. According to statistical analysis, there appeared to be no interaction between this ejaculatory complaint and the prevalence of thyroidal dysfunction. However, further studies are needed to gain more insight into the role of thyroid dysfunction and regulation of ejaculation time.
Adult↗