The widespread serotonergic system in the central nervous system and spinal cord is equipped with one neurotransmitter, 14 different serotonin receptors, and a transporter. The serotonergic system is involved in practically all behavioral and physiological functions, including sexual behavior. Serotonin (5-hydroxytryptamine (5-HT)) plays a modulatory role in both male and female sexual behavior and 5-HT1A and 5-HT2 receptors appear most clearly involved in modulating sexual activity. In general, activation of the serotonergic system decreases sexual behavior, while inhibition increases it. Selective 5-HT reuptake inhibitors (SSRIs) have inhibitory sexual side effects in both humans and rodents. SSRIs are first choice antidepressants and provide an interesting translational tool to better understand the role of the 5-HT system in healthy and disease conditions such as in major depression. Although available data do not indicate a large serotonergic role in sexual behavior under basal conditions, under stressed or depressed conditions it might play an important role.

Recently it was shown that a stopwatch-measured IELT distribution can be transformed to a mathematical formula of a specific mathematical type distribution. The IELT distribution of men in the general population is a Lognormal distribution whereas that of Caucasian men with lifelong premature ejaculation (PE) is a Gumbel Max distribution. In this article, we developed the mathematical formula of the IELT distribution of two other previously published stopwatch-mediated IELT studies in the general male population of the USA and Europe, respectively, by investigating the fitness of various well-known mathematical probability density distributions into the IELT distribution of the two studies. The better the fitness the lower is the goodnes of fit (GOF). We found that the lognormal distribution most accurately fitted the IELT distribution of 1405 men in the general population of the USA, and 1026 men in the general population of Europe, with a GOF of 0.056 and 0.061, respectively. The current study also shows that the Lognormal IELT distribution of two European studies in Caucasian males are quite similar but that the Lognormal IELT distribution of men in the USA deviates compared to the two European IELT distributions. As the USA study also included 25% of non-Caucasian males it may be speculated that ethnical factors play a role in this deviation of the IELT curve. In conclusion, the Lognormal distribution of the IELT distribution in USA and European general male populations reconfirms our previous finding of a Lognormal IELT distribution in two random samples of the general male population in four European countries and USA. The Lognormal IELT distributions of the general male population highly contrasts to the Gumbel Max IELT distribution in Caucasian males with lifelong PE, as has previously been found.

1. Ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE). 2. T he inability to delay ejaculation on all or nearly all vaginal penetrations. 3. Negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. Qeios · Definition, October 1, 2019

Men with Subjective premature ejaculation (PE) have complaints of PE but have normal intravaginal ejaculation latency time (IELT) durations. We found two previously published large epidemiological stopwatch-mediated IELT studies to encompass IELT details of men with Subjective PE, albeit this term was not mentioned in both studies or in reviews of them. In the current study we developed the mathematical formula of the IELT distribution of men with complaints of PE, as diagnosed by a clinician on basis of the DSM-IV-TR definition of PE, as reported in the two studies performed in the USA and Europe, respectively. The formula was calculated by investigation of the fitness of various well-known mathematical Probability Density distributions into the IELT distribution of the PE men and non-PE men of the two studies. The better the fitness the lower is the Goodnes of Fit (GOF). Another aim of the study was to investigate whether the IELT distribution of men with “complaints” of PE (Subjective PE) differs mathematically from the IELT distribution of the general male population and that of Lifelong PE. The overlap of the area under the curve (AUC) of the IELT distribution of the men with PE complaints and that of the general male population was calculated together with the cut-off point at which the AUC equals 10%. We found that the IELT distributions of the PE men in both studies were Lognormal distributions and that at the cut-off point at which the AUC is equal to 10% ( p = 0.10) the IELT is 1.5 min, indicating that after 1.5 min the IELT distribution of males with complaints of PE becomes mathematically identical to that of the general male population. In conclusion, there is hard mathematical evidence that the IELT distribution of men with complaints of PE with normal IELT values (e.g., the Lognormal IELT distribution of Subjective PE) and the IELT distribution of men with Lifelong PE (e.g. the Gumbel Max IELT distribution) belong to two independent populations. According to the applied mathematical calculations Subjective PE starts after an IELT of 1.5 min and encompasses all higher IELT values. It may imply that the current IELT cut-off point in Lifelong PE should be 1.5 min instead of the approximate 1 min, as has previously been stated by ISSM and DSM 5.

Tramadol is an effective pharmacological intervention in human premature ejaculation (PE). To investigate whether the inhibitory action of tramadol is primarily caused by its selective serotonin reuptake inhibitory (SSRI) effects we tested the dose-response effects of tramadol on sexual behavior in serotonin transporter wild type (SERT+/+), heterozygous (SERT+/-), and knockout (SERT-/-) rats. To investigate whether other mechanisms contribute to the inhibitory effects, WAY100,635, a 5-HT1A receptor antagonist and naloxone, a μ-opioid receptor antagonist, were tested on sexual behavior together with tramadol. Tramadol dose-dependently decreases sexual activity in all genotypes. In all studies, SERT+/- rats did not respond differently from SERT+/+ rats. WAY100,635 did not affect sexual activity in SERT+/+, but dose-dependently reduced sexual activity in SERT-/- rats. WAY100,635 (0.3 mg/kg) combined with tramadol (20 mg/kg) significantly reduced sexual activity in SERT+/+ and even stronger in SERT-/- rats. Naloxone did not affect sexual behavior consistently in SERT+/+ rats, while in SERT-/- rats all doses reduced ejaculation frequency mildly. Combining naloxone (20 mg/kg) and tramadol (20 mg/kg) decreased ejaculation frequencies in both genotypes. Interestingly, combining tramadol (20 mg/kg), WAY100,635 (0.3 mg/kg) and naloxone (20 mg/kg) led to complete elimination of all sexual activity in both SERT+/+ and SERT-/- rats. These findings suggest that the inhibitory effects of tramadol on male sexual behavior in SERT+/+ rats is mainly, if not exclusively, due to SERT inhibition, with an important role for 5-HT1A receptors, although influence of other systems (e.g., noradrenergic) cannot be excluded. As SSRIs exert their sexual inhibition after chronic administration, tramadol may be therapeutically attractive as "on demand" therapy for PE.

To investigate whether the inhibitory effects of tramadol on sexual behavior are solely due to the blockade of the serotonin (5-HT) transporter (SERT), using SERT knockout rats (SERT-/-). A crossover and randomized design was performed with 36 sexually experienced male Wistar rats (SERT+/+, SERT+/-, SERT-/-; N=12 each). Rats received acute intraperitoneal doses of 0, 5, 10, 20, 40 and 50 mg/kg tramadol hydrochloride. Furthermore, WAY100635 (5-HT1A receptor antagonist) was tested in doses 0, 0.1, 0.3 and 1 mg/kg IP and naloxone hydrochloride (μ-opioid receptor antagonist) in doses 0, 5, 10 and 20 mg/kg, IP. Finally, we tested combinations of vehicle + vehicle, vehicle + tramadol (20 mg/kg), tramadol (20mg/kg) + WAY (0.3 mg/kg), tramadol (20mg/kg) + naloxone (20mg/kg), and tramadol (20mg/kg), + WAY (0.3 mg/kg) + naloxone (20 mg/kg). Experiments were performed over several months on a 30-min sexual behavior test. In all SERT groups, intermediate and high doses of tramadol (20, 40 and 50 mg/kg) significantly decreased ejaculation, mount and intromission frequencies and at the highest dose a total inhibition effect was present. The latencies of ejaculation, mount and intromission were increased which in combination with the decreased frequencies resulted in a decreased efficiency to achieve ejaculation. WAY100635, did not affect sexual behavior in SERT+/+ animals. In accordance with previous findings, sexual behavior was inhibited in SERT-/- animals. Naloxone alone had no effect on sexual behavior, but in combination with WAY100635 or naloxone, tramadol strongly inhibited all sexual behavior parameters. The mixture of tramadol, WAY100635 and naloxone lead to complete elimination of sexual behavior in all groups.

Major depression is frequently associated with sexual dysfunctions. Most antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), induce additional sexual side effects and, although effective antidepressants, deteriorate sexual symptoms, which are the main reason that patients stop antidepressant treatment. Many strategies have been used to circumvent the additional sexual side effects, but results are rather disap - pointing. Recently, new antidepressants have been introduced, vilazodone and vortiox etine, which seem to lack sexual side effects in the early registration trials. Much research with large numbers of depressed patients and adequate methodological tools still has to confirm in daily use the absence of sexual side effects of new antidepressants. Animal models that in an early phase of drug development may predict putative sexual side effects of new antidepressants are extremely useful and could speed up development of new antidepressants. A rat model of sexual behavior is described that has a very high predictive validity for sexual side effects in man. Several characteristics of present antide pressants with regard to sexual dysfunctions are also present in the rat model and estab lish its validity. The animal model can also be used in the search for new psychotropics without sexual side effects or for drugs with sexual stimulating activity.

For many decades it has been thought that lifelong premature ejaculation (PE) is only characterized by persistent early ejaculations. Despite enormous progress of in vivo animal research, and neurobiological, genetic and pharmacological research in men with lifelong PE, our current understanding of the mechanisms behind early ejaculations is far from complete. The new classification of PE into four PE subtypes has shown that the symptomatology of lifelong PE strongly differs from acquired PE, subjective PE and variable PE. The phenotype of lifelong PE and therefore also the pathophysiology of lifelong PE is much more complex. A substantial number of men with lifelong PE not only have PE, but also premature erection and premature penile detumescence as part of an acute hypertonic or hypererotic state when engaged in an erotic situation or when making love. As both erectio praecox, ejaculatio praecox, detumescentia praecox, and the hypererotic state are part of the phenotype lifelong PE, it is argued that lifelong PE is not only a disturbance of the timing of ejaculation but also a disturbance of the timing of erection, detumescence and arousal. Since 1998, the pathophysiology of lifelong PE was thought to be mainly mediated by the central serotonergic system in line with genetic polymorphisms of specific serotonergic genes. However, by accepting that lifelong PE is characterized by the reversible hypertonic state the hypothesis of mainly serotonergic dysfunction is no longer tenable. Instead, it has been postulated that the pathophysiology of lifelong PE is mediated by a very complex interplay of central and peripheral serotonergic, dopaminergic, oxytocinergic, endocrinological, genetic and probably also epigenetic factors. Progress in research of lifelong PE can only be accomplished when a stopwatch is used to measure the IELT and the cut-off point of 1 minute for the definition of lifelong PE is maintained. Current use of validated questionnaires, neglect of stopwatch research, clinically inexperienced investigators and inclusion of anonymous men in a study performed by the Internet endanger the continuation of objective research of lifelong PE.

Introduction: Current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definitions of sexual dysfunction do not identify all sexual problems experienced clinically by women and are not necessarily applicable for biologic or biopsychosocial management of female sexual dysfunction. A unified nomenclature system enables clinicians, researchers, and regulatory agencies to use the same language and criteria for determining clinical end points, assessing research results, and managing patients.Aim: To develop nomenclature with classification systems for female sexual desire, arousal, and orgasm disorders with definitions pertinent to clinicians and researchers from multiple specialties who contribute to the field of sexual medicine.Methods: Key national and international opinion leaders diverse in gender, geography, and areas of expertise met for 2 days to discuss and agree to definitions of female sexual desire, arousal, and orgasm disorders and persistent genital arousal disorder. The attendees consisted of 10 psychiatrists and psychologists; 12 health care providers in specialties such as gynecology, internal medicine, and sexual medicine; three basic scientists; and one sexuality educator, representing an array of societies working within the various areas of sexual function and dysfunction.Main Outcome Measure: A unified set of definitions was developed and accepted for use by the International Society for the Study of Women's Sexual Health (ISSWSH) and members of other stakeholder societies participating in the consensus meeting.Results: Current DSM-5 definitions, in particular elimination of desire and arousal disorders as separate diagnoses and lack of definitions of other specific disorders, were adapted to create ISSWSH consensus nomenclature for distressing sexual dysfunctions. The ISSWSH definitions include hypoactive sexual desire disorder, female genital arousal disorder, persistent genital arousal disorder, female orgasmic disorder, pleasure dissociative orgasm disorder, and female orgasmic illness syndrome.Conclusion: Definitions for female sexual dysfunctions that reflect current science provide useful nomenclature for current and future management of women with sexual disorders and development of new therapies. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Recently I was invited to comment on the article by Ventus et al in this month's issue of European Urology Focus [ [1] Ventus D. Ristila M. Gunst A. et al. A longitudinal analysis of premature ejaculation symptoms raises concern regarding the appropriateness of a “lifelong” subtype. Eur Urol Focus. 2017; 3: 243-245 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar ]. I consented because it gives me the opportunity to clarify why I do not agree with its publication and to express my concern about current research of premature ejaculation (PE). A Longitudinal Analysis of Premature Ejaculation Symptoms Raises Concern Regarding the Appropriateness of a “Lifelong” SubtypeEuropean Urology FocusVol. 3Issues 2-3PreviewTake Home Message A longitudinal study of clinical and population-based samples show that the symptom severity of premature ejaculation varies considerably over time, which casts doubt on the appropriateness of the “lifelong” epithet. Full-Text PDF Reply from Authors re: Marcel D. Waldinger. The Dangers That Threaten Current Research of Premature Ejaculation: Using Validated Questionnaires, Performing Conjuring Tricks with Statistics, and Refusing to Use Real-Time Stopwatch Measurements of Intravaginal Ejaculation Latency Time. Eur Urol Focus. In press. http://dx.doi.org/10.1016/j.euf.2016.02.008European Urology FocusVol. 3Issues 4-5PreviewOur group recently published a brief report in European Urology Focus [1]. This study was the first to follow symptoms of premature ejaculation (PE) over a long time using valid measures and showed that PE symptoms were surprisingly unstable in both the general population and a group of diagnosed but untreated PE patients. We are hopeful that our study will, in due course, be subject to replication in various populations, with variable follow-up times and means of symptom assessment. This would provide necessary empirical evidence to inform the debate regarding diagnostic subcategories of PE. Full-Text PDF

Men with post orgasmic illness syndrome (POIS) become ill rather immediately after ejaculation, whether spontaneously at night, during sexual intercourse or masturbation. Two subtypes are distinguished: primary and secondary POIS. It also occurs before or after a man has been sterilized. POIS is an invalidating most probably auto-immune disease leading to much distress in males and their partners. It is characterized by five criteria. Its symptoms are described by seven clusters. However, the manifestation of these symptoms varies from one male to the other but is relatively constant in the person himself. Among men the symptoms vary in intensity, durations and sort of symptoms. POIS is a chronic disorder that manifests itself in POIS "attacks" that occur within a few minutes to a few hours after ejaculation, and disappear spontaneously after 3 to 7 days. POIS is not associated with increased total serum IgE concentrations. On the contrary, there are indications that POIS is triggered by specific cytokines that are released by an auto-immune reaction to the man's seminal fluid. Indirect clinical evidence suggests that the antigen (Ag) triggering the POIS systemic reaction is not bound to spermatozoa but to seminal fluid produced by prostatic tissue. In addition, POIS may also occur-although rarely-in females. In those cases, it is hypothesized that the Ag is associated with female prostatic tissue around the vagina.

Treatment of paroxetine-induced penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) by Low-power Laser Irradiation (LPLI) is unknown in medical literature. The aim of the current article is to report partial efficacy of LPLI for paroxetine-induced persistent penile anesthesia. We report on a male patient who presented with a history of reversible loss of smell, taste and skin sensitivity occurring within a week after start of 20mg/day paroxetine-hemihydrate for a depressive period. Concurrently, patient suffered from penile anesthesia, scrotum hypesthesia, anejaculation and erectile difficulties with normal sexual desire. During 2.5 years of paroxetine treatment and throughout 2 years after paroxetine discontinuation, genital and sexual complaints persisted. Penile anesthesia was treated by LPLI with single and multi diode pulsed laser probes. After 20 LPLI-treatment sessions of 15min each, patient reported partial return of penile touch and temperature sensation. Clinical improvement of glans penis sensitivity was reported to 20% and 40%, compared to pre-paroxetine treatment penile sensitivity during erect and flaccid states, respectively. However, anejaculation and erectile difficulties remained unchanged. Briefly, in the current patient with early onset of PSSD, LPLI treatment reduced paroxetine-induced penile anesthesia. It is hypothesized that SSRI treatment induces disturbances of transient receptor potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. It is further hypothesized that there are two types of PSSD, one of which occurs soon after the start of SSRI treatment.

Sexual problems are highly prevalent among patients with psychiatric disorders. They may be caused by the psychopathology of the psychiatric disorder but also by its pharmacotherapy. Both positive symptoms (e.g., psychosis, hallucinations) as well as negative symptoms (e.g., anhedonia) of schizophrenia may negatively interfere with interpersonal and sexual relationships. Atypical antipsychotics have fewer sexual side-effects than the classic antipsychotics. Mood disorders may affect libido, sexual arousal, orgasm, and erectile function. With the exception of bupropion, agomelatine, mirtazapine, vortioxetine, amineptine, and moclobemide, all antidepressants cause sexual side-effects. Selective serotonin reuptake inhibitors (SSRIs) may particularly delay ejaculation and female orgasm, but also can cause decreased libido and erectile difficulties. SSRI-induced sexual side-effects are dose-dependent and reversible. Very rarely, their sexual side-effects persist after SSRI discontinuation. This is often preceded by genital anesthesia. Some personality characteristics are a risk factor for sexual dysfunction. Also patients with eating disorders may suffer from sexual difficulties. So far, research into psychotropic-induced sexual side-effects suffers from substantial methodologic limitations. Patients tend not to talk with their clinician about their sexual life. Psychiatrists and other doctors need to take the initiative to talk about the patient's sexual life in order to become informed about potential medication-induced sexual difficulties.

Purpose To investigate the association between the 5-HT-transporter-gene-linked promoter region (5-HTTLPR) polymorphism and 20-mg paroxetine-induced ejaculation delay in men with lifelong premature ejaculation (LPE). Materials and Methods This was a prospective study of 10 weeks of paroxetine treatment in 54 men with LPE. Intravaginal ejaculation latency time (IELT) was measured by stopwatch. Controls consisted of 92 Caucasian men. All men with LPE were genotyped for the 5-HTTLPR polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of the polymorphism were compared between patients and controls. Associations between the LL, SL, and SS genotypes and fold increase of mean IELT were investigated. Results Of the 54 patients, 43 (79.6%) responded to 20-mg paroxetine treatment with an ejaculation delay, whereas 11 patients (20.4%) did not respond; 44%, 18%, and 18% of the patients showed a fold increase in mean IELT of 2-10, 10-20, and more than 20, respectively. Of the 54 men, 14 (25.9%) had the LL genotype, 29 (53.7%) had the SL genotype, and 11 (20.4%) had the SS genotype. In the 92 controls, the LL, SL, and SS genotypes were present in 27 (29.3%), 41 (44.6%), and 24 (26.1%), respectively. No statistically significant differences were found in 5-HTTLPR allelic variations or in 5-HTTLPR gene variations. In all men treated with 20 mg paroxetine, analysis of variance of the natural logarithm of fold increase in the IELT showed no statistically significant difference according to genotype (p=0.83). Conclusions The 5-HTTLPR polymorphism is not associated with daily 20-mg paroxetine treatment-induced ejaculation delay in men with LPE.

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling.

Introduction: Four premature ejaculation (PE) subtypes are distinguished on the basis of the duration of the intravaginal ejaculation latency time (IELT), its course in life, and frequency of complaints. Since the 1930s oral drug treatment and local anesthetics have been used to treat PE. Apart from dapoxetine, all currently available drugs to treat PE (SSRIs, clomipramine, and local anesthetics) are off-label. Not only men with lifelong and acquired PE, but also men with normal IELT values may want to postpone their ejaculation time.Areas covered: The guideline of the International Society for Sexual Medicine for the treatment of PE has provided evidence-based recommendations for the pharmacotherapy of lifelong and acquired PE. Selective serotonin reuptake inhibitors (SSRIs) delay ejaculation by interfering with the serotonin (5-HT) neurotransmission system in the central nervous system. Attention is given not only to the well-known but also to the recently published, very rare side effects of SSRIs.Expert opinion: Men with normal IELT values who want to postpone ejaculation do not need drugs for the treatment of PE but ejaculation delaying drugs. Pharmacological research of these ejaculation-delaying drugs ought to be investigated in men with normal IELT values, such as in men with subjective PE, variable PE, and in male volunteers.

Introduction: Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 min, and has been postulated as a neurobiological dysfunction related to diminished serotonergic neurotransmission with 5-HT1A receptor hyperfunction and 5-HT2C hypofunction.Aim: To investigate the relationship between 5-HT1A receptor gene (HTR1A)-C(1019)G promoter polymorphism and IELT in men with LPE. This polymorphism is known to increase 5-HT1A receptor expression.Methods: A prospective study was conducted in 54 Dutch Caucasian men with LPE: Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for HTR1A gene polymorphism. Allele frequencies and genotypes of C and G variants of HTR1A Polymorphism were determined. Association between CC, CG, and GG genotypes and the IELT in men with LPE were investigated.Main outcome measures: IELT measured by stopwatch, HTR1A Polymorphism.Results: In this cohort of men with LPE, the geometric mean IELT was 23.8 s. Of the 54 men, the CC, CG and GG genotype frequency for the C(1019)G polymorphism of the 5-HT1A gene was 33%, 43% and 24%, respectively. The geometric mean IELT for the CC, CG and GG genotypes were 14.5, 27.7 and 36.0 s, respectively (p =0.019). Compared to GG and CG genotypes, men with CC genotype had a 250% and 190% shorter ejaculation time, respectively.Conclusions: HTR1A gene polymorphism is associated with the IELT in men with LPE. Men with CC genotype have shorter IELTs than men with GG and CG genotypes. (C) 2014 Elsevier Inc. All rights reserved.