Endogenous Deficiency of Brain-Derived Neurotrophic Factor Induces the Downregulation of Tryptophan Hydroxylase-2 Expression in Raphe Nuclei of Rapid Ejaculator Rats

BackgroundPremature ejaculation (PE) is one of the most common ejaculatory disorders. Recent studies have suggested a close relationship between the serotonin (5-hydroxytryptamine [5-HT]) system and brain-derived neurotrophic factor (BDNF), raising the question of whether BDNF plays a role in ejaculation regulation. To our knowledge, no previous studies have explored BDNF level of the central nervous system in ejaculatory disorders. At the same time, the interaction of central BDNF and 5-HT systems has not been undertaken in ejaculation regulation field.AimThe aim of this study was to investigate the interaction between BDNF and 5-HT levels in raphe nuclei which contains the serotonergic neurons in a rat animal model with different ejaculatory behavior.MethodsEighteen male rats were selected and classified as “sluggish,” “normal,” and “rapid” ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. BDNF and 5-HT levels were determined by enzyme-linked immunosorbent assay (ELISA). Real-Time Quantitative PCR and Western blot analyses were used to measure the mRNA level of Tryptophan Hydroxylase-2 (TPH2) gene and the expression of TPH2 protein (the rate-limiting enzyme in central 5-HT synthesis) in raphe nuclei, respectively.OutcomesMale rat sexual behavior, the levels of BDNF and 5-HT in raphe nuclei of rats with different ejaculatory behavior, the mRNA level of gene encoding TPH2 and the expression of TPH2 protein in raphe nuclei.ResultsThe primary finding of our study was that BDNF concentration was significantly decreased in raphe nuclei of rapid ejaculators. There was a strong positive correlation between the levels of BDNF and 5-HT (r = 0.944, P < .001). Further results showed that decreased TPH2 gene expression accompanied by TPH2 protein was shown in rapid ejaculators with lower BDNF level.Clinical ImplicationsWith refinement of current knowledge, BDNF may eventually serve as a promising biomarker in patients with PE.Strengths & LimitationsThere are no previous studies examining the interaction of the brain BDNF and 5-HT in ejaculation regulation field. The main limitation is the limited sample size.ConclusionBDNF may act via increasing the synthesis of central 5-HT in the process of ejaculation regulation. Our results suggest lack of endogenous BDNF induces the downregulation of TPH2 gene expression and the decrease of 5-HT synthesis in raphe nuclei of rapid ejaculator rats. Huang Y, Peng D, Geng H, et al. Endogenous Deficiency of Brain-Derived Neurotrophic Factor Induces the Downregulation of Tryptophan Hydroxylase-2 Expression in Raphe Nuclei of Rapid Ejaculator Rats. J Sex Med 2021;18:1491–1499.     

Anandamide Reduces the Ejaculatory Threshold of Sexually Sluggish Male Rats: Possible Relevance for Human Lifelong Delayed Ejaculation Disorder

IntroductionThe sexually sluggish (SLG) male rat has been proposed as an animal model for the study of lifelong delayed ejaculation, a sexual dysfunction for which no treatment is available. Low endocannabinoid anandamide (AEA) doses facilitate sexual behavior display in normal sexually active and in noncopulating male rats through the activation of CB1 receptors.AimTo establish whether low AEA doses reduced the ejaculatory threshold of SLG male rats by acting at CB1 receptors.MethodsSLG male rats were intraperitoneally injected with different doses of AEA (0.1–3.0 mg/kg), the CB1 receptor antagonist AM251 (0.1–3.0 mg/kg), or their vehicles and tested for copulatory behavior during 60 minutes. Animals receiving AEA effective doses were subjected to a second sexual behavior test, 7 days later under drug-free conditions. To determine the participation of CB1 receptors in AEA-induced actions, SLG rats were pretreated with AM251 prior to AEA.Main Outcome MeasuresThe sexual parameters, intromission latency, number of mounts and intromissions, ejaculation latency, and interintromission interval.ResultsAll sexual behavior parameters of SLG rats were significantly increased when compared with normal sexually experienced animals. Low AEA doses (0.3 and 1 mg/kg) significantly lowered the ejaculatory threshold of SLG rats, reducing the number of pre-ejaculatory intromissions and ejaculation latency. IL, M number, and locomotor activity were unaffected by AEA. Facilitation of the ejaculatory response of SLG rats disappeared 7 days after AEA injection. AM251 lacked an effect on copulation of SLG rats but blocked the AEA-induced lowering of the ejaculatory threshold.ConclusionsAEA appears to specifically target the ejaculatory threshold of SLG rats through the activation of CB1 receptors. This specificity along with the fact that AEA's effects are exerted acutely and at low doses makes this drug emerge as a promising treatment for the improvement of the ejaculatory response in men with primary delayed ejaculation. Rodríguez-Manzo G and Canseco-Alba A. Anandamide reduces the ejaculatory threshold of sexually sluggish male rats: Possible relevance for human lifelong delayed ejaculation disorder. J Sex Med 2015;12:1128–1135.     

Differences in the Spinal Command of Ejaculation in Rapid Ejaculating Rats

IntroductionIt has been hypothesized that lifelong premature ejaculation is part of a biological variation in the intravaginal ejaculation latency, but what causes this variation remains poorly understood.AimThe aim of this study is to elucidate whether variations in ejaculation latencies in an experimental rat model for premature ejaculation are linked to differences in the spinal command of ejaculation.Main Outcome MeasuresElectrical microstimulation of the spinal generator for ejaculation revealed an accelerated expulsion phase in rapid ejaculating rats.MethodsAdult male Wistar rats were categorized as “sluggish,”“normal,” or “rapid” ejaculators on the basis of their ejaculation frequency in sexual mating tests. One to three weeks after selection, males were urethane anesthetized and electrically microstimulated in the spinal generator for ejaculation, evoking ejaculation. Bulbospongiosus muscle electromyographic and intraluminal vas deferens pressure were measured simultaneously, representing, respectively, the expulsion and emission phase in ejaculation.ResultsElectrical microstimulation of the spinal generator for ejaculation evoked ejaculation in “sluggish” (N = 9), “normal” (N = 13), and “rapid” (N = 11) ejaculating rats. Vas deferens contraction (emission phase) was evoked at different stimulation strengths, but response properties were not statistically different between “sluggish,”“normal,” and “rapid” ejaculator rats. Bulbospongiosus muscle contractions (expulsion phase) following microstimulation was significantly accelerated in “rapid” rats as compared with “sluggish” and “normal” rats. The total duration of bulbospongiosus muscle contractions remained unchanged between the three ejaculator groups.ConclusionsOur results provide the first scientific evidence supporting a neurophysiological difference between “rapid,”“normal,” and “sluggish” ejaculators, expressed as an accelerated expulsion phase in “rapid” ejaculator rats. This bridges the gap between a sexual behavior trait and the spinal command of ejaculation. Borgdorff A, Rössler A-S, Clément P, Bernabé J, Alexandre L, and Giuliano F. Differences in the spinal command of ejaculation in rapid ejaculating rats. J Sex Med 2009;6:2197–2205.     

Effect of Dapoxetine on Ejaculatory Performance and Related Brain Neuronal Activity in Rapid Ejaculator Rats

IntroductionA brain network specifically activated when ejaculation occurs has been described in rats. Increasing serotonin (5‐hydroxytryptamine [5‐HT]) tone impairs ejaculation and chronic 5‐HT selective serotonin reuptake inhibitors (SSRIs) are known to inhibit ejaculation. However, efficacy of acute treatment with SSRI varies from one compound to another. The SSRI dapoxetine has been reported to delay ejaculation when given on demand to men with premature ejaculation (PE), although the mechanism of action is unclear. Effects of acute SSRIs on activity of the brain ejaculation circuit in relation with ejaculation have never been examined.AimTo test the effects of acute administration of the short half‐life SSRI dapoxetine on ejaculatory performance and activity in brain ejaculation circuit in rapid ejaculator rats taken as PE model.MethodsStandard copulatory test was used to attribute one sexual category (sluggish, middle, or rapid) to male rats on the basis of their ejaculatory performance. Parameters of sexual, including ejaculatory, behavior, and Fos level of expression in discrete brain areas were assessed in the three sexual categories and in rapid category following acute oral treatment with dapoxetine.Main Outcome MeasuresEjaculation frequency (EF) and latency (EL) were measured as primary end points of ejaculatory behavior. Density of Fos‐immunopositive cells in specific brain areas of brain stem, hypothalamus, and thalamus was determined as marker of neuronal activity.ResultsEL and Fos level of expression in hypothalamic and thalamic structures were found related. Dapoxetine acute oral administration (300 mg/kg) to rapid ejaculator rats resulted in (i) diminution of ejaculatory performance (lengthened EL and decreased EF); and (ii) modulation of Fos level of expression in hypothalamic and thalamic nuclei of the brain ejaculatory circuit.ConclusionAcute treatment with dapoxetine, which reduced ejaculatory performance in rapid ejaculator rats, was also accompanied with changes in neuronal activity in components of the brain ejaculatory network. Clément P, Laurin M, Compagnie S, Facchinetti P, Bernabé J, Alexandre L, and Giuliano F. Effect of dapoxetine on ejaculatory performance and related brain neuronal activity in rapid ejaculator rats. J Sex Med **;**:**–**.     

Moderate Role of Oxytocin in the Pro-Ejaculatory Effect of the 5-HT1A Receptor Agonist 8-OH-DPAT

IntroductionThe neurobiological control of ejaculation is not completely understood. Both serotonin (5-HT) and oxytocin (OXT) play a role in the control of male sexual parameters, putatively via overlapping neuronal networks.AimThe aim of this study was to determine whether activation of 5-HT_1A receptors (5-HT_1ARs) reduces the ejaculatory threshold via the direct activation of (OXT) neurons in the paraventricular hypothalamic nucleus (PVN).MethodsIn experiment 1, male rats received acute bilateral infusions of the selective 5-HT_1AR antagonist WAY-100635 (1 and 10 μg) or vehicle into the PVN, followed by acute subcutaneous (SC) injection of the potent 5-HT_1AR agonist 8-OH-DPAT (0.4 mg/kg) or saline. In experiment 2, male rats received acute bilateral infusions of 8-OH-DPAT (1 and 10 μg) or vehicle into the PVN. In experiment 3, male rats received acute intracerebroventricular (ICV) infusion of a selective OXT receptor antagonist (OXTR-A, 75 and 750 ng) followed by acute SC injection of 8-OH-DPAT (0.4 mg/kg) or saline. The effects of these drug treatments on sexual behavior were measured.Main Outcome MeasuresCopulation latency, ejaculation latency, mount and intromission frequency, and ejaculation frequency of sexually experienced adult male Wistar rats during 30-minute sexual behavior tests with a receptive female were the main outcome measures.ResultsMale sexual behavior was not affected by intra-PVN infusion of WAY-100635 or 8-OH-DPAT, or by ICV infusion of OXTR-A alone. However, the facilitation of ejaculation (reduced mount and intromission frequency and ejaculation latency) induced by systemic 8-OH-DPAT could be attenuated by either intra-PVN infusion of WAY-100635 or by ICV infusion of OXTR-A.ConclusionsActivation of OXT neurons plays a moderate role in the pro-ejaculatory effects of systemic 8-OH-DPAT, but extracellular 5-HT levels may influence the strength of the effects. de Jong TR and Neumann ID. Moderate role of oxytocin in the pro-ejaculatory effect of the 5-HT_1A receptor agonist 8-OH-DPAT. J Sex Med 2015;12:17–28.     

Delayed Ejaculation and Associated Complaints: Relationship to Ejaculation Times and Serum Testosterone Levels

BackgroundAlthough delayed ejaculation (DE) is typically characterized as a persistently longer than anticipated or desired time to ejaculation (or orgasm) during sexual activity, a timing-based definition of DE and its association with serum testosterone has not been established in a large cohort.AimTo examine in an observational study estimated intravaginal ejaculatory latency time (IELT) and masturbatory ejaculation latency time (MELT) in men self-reporting DE, assess the association of IELT and MELT with serum testosterone levels, and determine whether correlation with demographic and sexual parameters exist.MethodsMen who resided in the United States, Canada, and Mexico were enrolled from 2011 to 2013. Self-estimated IELT and MELT were captured using an Ejaculatory Function Screening Questionnaire in a sample of 988 men screened for possible inclusion in a randomized clinical trial assessing testosterone replacement therapy for ejaculatory dysfunction (EjD) and who self-reported the presence or absence of DE and symptoms of hypogonadism. Additional comorbid EjDs (ie, anejaculation, perceived decrease in ejaculate volume, and decreased force of ejaculation) were recorded. Men with premature ejaculation were excluded from this analysis. IELT and MELT were compared between men self-reporting DE and men without DE. The associations of IELT and MELT with serum testosterone were measured.OutcomesIELT, MELT, and total testosterone levels.ResultsSixty-two percent of screened men self-reported DE with or without comorbid EjDs; 38% did not report DE but did report at least one of the other EjDs. Estimated median IELTs were 20.0 minutes for DE vs 15 minutes for no DE (P < .001). Estimated median MELTs were 15.0 minutes for DE vs 8.0 minutes for no DE (P < .001). Ejaculation time was not associated with serum testosterone levels. Younger men and those with less severe erectile dysfunction had longer IELTs and MELTs.Clinical ImplicationsEstimated ejaculation times during vaginal intercourse and/or masturbation were not associated with serum testosterone levels in this study; thus, routine androgen evaluation is not indicated in these men.Strengths and LimitationsThis large systematic analysis attempted to objectively assess the ejaculation latency in men with self-reported DE. Limitations were that ejaculation time estimates were self-reported and were queried only once; the questionnaire did not distinguish between failure to achieve orgasm and ejaculation; and assessment of DE was limited to heterosexual vaginal intercourse and masturbation.ConclusionIELT and MELT were longer in men with DE, and there was no association of ejaculation times with serum testosterone levels in this study population.Morgentaler A, Polzer P, Althof S, et al. Delayed Ejaculation and Associated Complaints: Relationship to Ejaculation Times and Serum Testosterone Levels. J Sex Med 2017;14:1116–1124.     

Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats

BackgroundWe previously reported that the combination of the dopamine (DA) receptor agonist apomorphine and the 5-hydroxytryptamine (5-HT₂) receptor agonist m-chlorophenylpiperazine (m-CPP) in rats potently and selectively facilitates the ejaculatory response through activation of D₂-like and 5-HT_2C receptors, respectively.AimThe aim of this study was to clarify the target level of the proejaculatory effects induced by combination of these agonists.MethodsFor in vivo behavioral studies, apomorphine and m-CPP were given intracerebroventricularly and intrathecally alone or in combination with either drug administered systemically. Male rats were acclimated to observational cages bedded in paper towels, and the occurrence of ex copula ejaculation was assessed by evaluating the presence and weight of ejaculatory plugs dropped from the tip of the penis to the paper towels or adhered to the tip of the penis at 30 min after drug administration. For in vitro contraction studies, seminal vesicles isolated from rats were suspended in an organ bath to test contractile responses to drug combinations, and the effects of the combined drugs on the contractile response of noradrenaline were also tested.Main Outcome MeasuresThe presence and weight of ejaculatory plugs produced by drug-induced ejaculation and the contractile responses of the seminal vesicle were evaluated.ResultsIntrathecal m-CPP (10 μg), but not intracerebroventricular m-CPP, evoked the synergistic effects on ejaculation when used in combination with systemically administered apomorphine (0.1 mg/kg, subcutaneous). Moreover, the synergy between m-CPP and apomorphine was completely abolished by the intrathecal 5-HT_2C receptor antagonist SB242084 (10 μg). Intrathecal or intracerebroventricular apomorphine (1–10 μg) evoked proejaculatory effects in combination with systemically administered m-CPP (0.3 mg/kg, intraperitoneal). The selective peripherally acting D₂-like receptor agonist carmoxirole did not evoke ejaculation when used in combination with m-CPP. Furthermore, isolated rat seminal vesicles were completely insensitive to the combination of apomorphine and m-CPP.ConclusionThese results indicated that the synergistic effects of the drugs on ejaculation were induced at the central level but not at peripheral sites. Our findings also suggested that the 5-HT_2C receptor mediated the stimulation of the spinal ejaculatory pattern generator and was synergistically potentiated by the spinal DA receptor and that activation of the supraspinal DA receptor was also involved in mediating these synergistic effects.Yoshizumi M, Yonezawa A, Kimura Y, et al. Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats. J Sex Med 2021;18:231–239.     

Impact of Kidney Transplantation on Male Sexual Function: Results from a Ten-Year Retrospective Study

BackgroundThe effects of kidney transplantation on male sexual function are controversial.AimTo evaluate the impact of kidney transplantation on erectile and ejaculatory function and to assess a possible correlation between some selected characteristics of patients and their erectile and ejaculatory function after renal transplantation.MethodsAn observational retrospective analysis was conducted on male patients who had undergone kidney transplantation from January 2009 to April 2019. A prospectively maintained database was used to collect all data. Patients were evaluated before kidney transplant and 6 and 12 months after kidney transplant. Male patients undergoing renal transplantation for any cause who were sexually active with a stable partner were included in the study.OutcomesThe main outcome measures included the International Index of Erectile Function (IIEF-15) and the 4-item version of Male Sexual Health Quality–Ejaculation Disorders (MSHQ-EjD Short Form) questionnaires. The first 3 questions of the MSHQ-EjD Short Form were used to assess the ejaculatory function, whereas the fourth question was used to evaluate the ejaculation bother.ResultsA total of 95 patients were eligible in the study. The evaluation of sexual function was available in 56 patients (58.9%). Mean IIEF-15 significantly decreased at 6 months (P < .001) remaining unchanged at 12 months (P = .228). Mean MSHQ-EjD Short Form (1–3) significantly decreased at 6-month follow-up (P < .001) and at 12-month follow-up (P = .024). Mean MSHQ-EjD Short Form (4) was significantly increased compared with the baseline at both 6 and 12 months (P < .05). IIEF-15 was significantly related to the MSHQ-EjD Short Form at 6-month and 12-month follow-up (P < .001). Age, diabetes, hypertension, smoking, pretransplantation testosterone, time for transplantation, baseline IIEF-15, and baseline MSHQ-EjD Short Form (1–3) were significantly associated (P < .05) with both IIEF-15 and the MSHQ-EjD Short Form (1–3) at 6-month and 12-month follow-up after kidney transplantation.Clinical ImplicationsImprovement of knowledge regarding the effects of kidney transplantation on sexual function and about the patient characteristics related to sexual health after transplantation.Strength & LimitationsThis is the first article that analyzes in depth the ejaculatory function in patients who had undergone kidney transplantation assessing ejaculation with a validated questionnaire. The main limitation is the retrospective design of the study.ConclusionKidney transplantation appears to have a negative impact on sexual health, significantly worsening both erectile and ejaculatory functions. Age, diabetes, hypertension, smoking, pretransplantation testosterone levels, time for transplantation, as well as erectile and ejaculatory function before transplant were significantly related to erectile and ejaculatory functions after renal transplantation.Spirito L, Manfredi C, Carrano R, et al. Impact of Kidney Transplantation on Male Sexual Function: Results from a Ten-Year Retrospective Study. J Sex Med 2020;17:2191–2197.     

Changing Aspects of Male Sexual Functions Accompanying Treatment of Benign Prostatic Hyperplasia With Silodosin 8 mg Per Day

BackgroundAlpha-adrenergic antagonist treatment for benign prostatic hyperplasia (BPH) and drug-related sexual side effects are frequent in aging men.AimTo investigate functional changes in erectile and ejaculatory aspects of male sexuality under Silodosin 8 mg per day treatment for BPH.MethodsSexually active patients diagnosed with BPH and who initiated Silodosin treatment were the subjects of the study. The International Prostate Symptom Score, premature ejaculation patient profile (PEP-male) questionnaire, Sexual Health Inventory for Men (SHIM) questionnaire, and estimated intravaginal ejaculation latency time (IELT) values of the participants were used to evaluate sexual functions. Data evaluation was performed in 8 urology clinics retrospectively.OutcomesParticipant ratings for SHIM, PEP, and estimated IELT were the primary outcome measures in the study.ResultsAmong 187 recruited patients, data of 98 patients, who completed the trial period in the study, were eligible. The median age of the eligible participants who completed the trial period for 3 months was 59.5 years (range 45–82). 16 patients of 187 (8%) reported a desire for drug withdrawal for anejaculation during the recruitment period. 46 (46.9%) and 49 (50%) patients reported anejaculation in the first and third month of the treatment, respectively. De novo erectile dysfunction was noticed in 15 patients (15.3%). There was a significant increase in the estimated IELT of subjects in both the first (P = .01) and third (P = .002) month. SHIM-1 (P = .008), SHIM-total (P = .009), and PEP scores (P = .008) were also improved in the third month of the treatment. Neither baseline patient characteristics nor changes in the International Prostate Symptom Score after treatment predicted final outcomes with multivariable analysis. The subgroup analysis of participants who reported “anejaculation” also revealed better outcomes compared with participants ejaculating naturally in the third month as per SHIM ratings.Clinical ImplicationsDespite several male patients having dry orgasms due to Silodosin-induced anejaculation, the majority experienced improved erectile function.Strengths & LimitationsThe present study demonstrated pioneering results while investigating both erectile and ejaculatory dimensions of the male sexual function during Silodosin treatment for BPH. However, lack of partner evaluation, low follow-up rates, and lack of knowledge about reasons why subjects are lost to follow-up after drug initiation have limited our interpretation.ConclusionMost patients using Silodosin 8 mg per day for BPH treatment experienced improvement in their erectile function, estimated IELT, and premature ejaculation profile in the third month of the treatment. Underlying mechanisms and reasons for individual differences necessitate further investigation.Cihan A, Kazaz İO, Yıldırım Ö, et al. Changing Aspects of Male Sexual Functions Accompanying Treatment of Benign Prostatic Hyperplasia With Silodosin 8 mg Per Day. J Sex Med 2020;17:1094–1100.     

Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation?

BackgroundLorcaserin is an anti-obesity drug whose weight loss effect results from 5-hydroxytryptamin (5-HT)_2C receptors activation. The 5-HT_2C receptor was shown to participate in the physiological control of ejaculation, but no data addressing a putative effect of lorcaserin on ejaculation exist.AimTo investigate the effects of lorcaserin in different in vitro and in vivo experimental models of ejaculation in rats.MethodsContractile responses to lorcaserin in rat seminal emission organs in vitro (prostatic and epididymal vas deferens, cauda epididymis, and seminal vesicles), analysis of male rat copulatory behavior, and electromyographic recording of bulbospongiosus muscle in anesthetized animals were studied.Main Outcome MeasuresThe main outcome measures included in vitro contraction of seminal emission organs and evaluation of the male rat copulatory behavior. The male rat sexual behavior in terms of copulation latency, ejaculation latency, mount and intromission frequency, and ejaculation frequency of sexually experienced adult male rats with a receptive female were also recorded.ResultsLorcaserin (1.0 nM to 1.0 mM) had no significant effects on the in vitro contractility of seminal emission organs smooth muscle (cauda epididymis, vas deferens, and seminal vesicles). On the other hand, lorcaserin administration (0.3–1.0 mg/kg, intravenous) induced ejaculation in anesthetized rats, which was prevented by the 5-HT_2C-selective antagonist SB 242084 (0.1 and 0.3 mg/kg, intravenous). Single-dose treatment of non-anesthetized male rats with lorcaserin (1.0, 4.0, or 10 mg/kg, per os) induced non-copulating ejaculations in sexually naïve rats. Lorcaserin also had pro-ejaculation effects by decreasing the ejaculation threshold of copulating rats by half. The pro-ejaculatory effects of lorcaserin were reversible as the ejaculation threshold of treated rats recovered after a 1-week washout period.Clinical ImplicationsDue to its reported clinical safety, repurposing lorcaserin for the treatment of delayed ejaculation may be suggested.Strengths & LimitationsThe pro-ejaculatory effect of lorcaserin administration and the role of 5-HT_2C were demonstrated in different experimental models of ejaculation in rats. The lack of studies in putative experimental models of delayed ejaculation is a limitation of this study.ConclusionOur results demonstrate that the clinically approved 5-HT_2C agonist lorcaserin is a strong facilitator of ejaculation in rats.de Almeida Kiguti LR, Pacheco TL, Antunes E, et al. Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation? J Sex Med 2020;17:1060–1071.     

Effect of Botulinum‐A Toxin Injection into Bulbospongiosus Muscle on Ejaculation Latency in Male Rats

IntroductionPremature ejaculation (PE) is the most common male sexual dysfunction. A variety of pharmacotherapeutic strategies have been employed to treat men suffering with lifelong PE. However, there are currently no pharmaceuticals approved by the U.S. Food and Drug Administration specifically designed for PE treatment.AimGiven that the bulbospongiosus muscle is involved in the ejaculatory reflex in both humans and rodents and that local administration of botulinum‐A can abolish muscle contractions, the current study examined the effect of injection of botulinum‐A toxin into the bulbospongiosus muscle on the ejaculatory latency of male rats.MethodsAfter screening for normal sexual activity with sexually receptive female rats, 33 sexually experienced male Long‐Evans rats (Harlan Laboratories, Indianapolis, IN, USA) underwent an additional four pretreatment sexual exposures over the course of the following week, during which all components of sexual behavior were video recorded by trained observers. On the day after their fourth experience, rats were anesthetized and received a single injection of either 0.5 unit (n = 11) or 1 unit (n = 11) of botulinum‐A toxin or saline vehicle (n = 11). Botulinum‐A toxin was dissolved in 0.1 mL of saline vehicle and injected bilaterally into the bulbospongiosus muscle by the percutaneous route. Beginning 2 days after treatment, sexual behaviors were reexamined over the course of the following week on four separate occasions.Main Outcome MeasuresThe latency to achieve ejaculation, and the frequencies and latencies of mounts and intromissions were video recorded by trained observers in a blinded fashion.ResultsRelative to pretreatment measurements, bilateral injection of saline vehicle into the bulbospongiosus muscle did not affect ejaculation latencies. However, rats treated with either 0.5 or 1 unit of botulinum‐A toxin exhibited significantly longer latencies to achieve ejaculation relative to pretreatment performance. Of note, botulinum‐A toxin did not affect the ability to achieve mounts, intromissions, or ejaculation.ConclusionsThese results demonstrate that botulinum‐A toxin injection into the bulbospongiosus muscle is a safe and effective treatment that extends ejaculatory latency in rats without affecting the ability to engage in sexual activity or achieve ejaculation. Further studies are required to evaluate this therapeutic concept in PE patients. Serefoglu EC, Hawley WR, Lasker GF, Grissom EM, Mandava SH, Sikka SC, Dohanich GP, and Hellstrom WJG. Effect of botulinum‐A toxin injection into bulbospongiosus muscle on ejaculation latency in male rats. J Sex Med 2014;11:1657–1663.     

Relationship Between Amyloid Precursor Protein in Seminal Plasma and Abnormal Penile Sympathetic Skin Response in Lifelong Premature Ejaculation

IntroductionHyperactivity of the sympathetic nervous system can play an important role in lifelong premature ejaculation (PE). Our previous study found that amyloid precursor protein (APP) levels in seminal plasma of patients with PE were clearly increased. Amyloid-β (Aβ) is derived from APP. Excessive Aβ, especially Aβ42, can cause neuronal dysfunction.AimTo determine whether APP and Aβ42 are associated with an abnormal penile sympathetic skin response (PSSR).MethodsFrom November 2015 to April 2016, 24 patients with lifelong PE (mean age = 29.2 ± 5.3) with self-estimated intravaginal ejaculatory latency time no longer than 2 minutes and 10 control subjects (mean age = 28.0 ± 5.5) were enrolled consecutively from andrology clinics. PSSR was measured in patients with lifelong PE. APP and Aβ42 levels in seminal plasma were determined.Main Outcome MeasuresPSSR in patients with lifelong PE and APP and Aβ42 levels in all subjects.ResultsPatients with PE presented 1.5-fold higher levels of APP (P = .004) than control subjects. Seminal plasma protein concentration (C) in the PE group was lower than that in the control group (P = .007). APP divided by C (APP/C) was 2.0-fold higher (P < .001) in the PE group. Aβ42 level was not different between the PE and control groups, but Aβ42 divided by C (Aβ42/C) was significantly higher in the PE group (P < .001). No differences in APP and APP/C were found between patients with PE in the abnormal and normal PSSR groups. The abnormal PSSR group presented significantly higher Aβ42 (P = .007) and Aβ42/C (P < .001) levels. The latency of PSSR was negatively correlated with Aβ42/C (r = −0.436; P = .033).ConclusionThese results showed that patients with lifelong PE had higher APP and Aβ42 levels in seminal plasma. Abnormal PSSR was related to a higher Aβ42 level. Drugs that decrease Aβ could be treatment of PE.     

The comparison of premature ejaculation assessment questionnaires and their sensitivity for the four premature ejaculation syndromes: results from the Turkish society of andrology sexual health survey

IntroductionIn addition to the previously defined “lifelong” and “acquired” premature ejaculation (PE), the existence of two more subtypes of PE, namely “natural variable PE” and “premature‐like ejaculatory dysfunction,” has been proposed.AimsTo evaluate the diagnostic value of the Premature Ejaculation Diagnostic Tool (PEDT) and Arabic Index of Premature Ejaculation (AIPE) in a population‐based study, in relation to their sensitivity across these four different PE syndromes and to assess the Premature Ejaculation Profile (PEP) scores of patients with lifelong, acquired, natural variable PE and premature‐like ejaculatory dysfunction.MethodsBetween June 2009 and December 2009, couples were randomly selected from 17 provinces of Turkey. Subjects with the complaint of ejaculating prematurely were classified as lifelong, acquired, natural variable PE, and premature‐like ejaculatory dysfunction according to the medical and sexual history they described. PE status was also assessed with PEDT, AIPE and PEP. The sensitivity, specificity, positive predictive value and negative predictive value were calculated for PEDT and AIPE in the study population whereas detection rates of these two questionnaires were also compared among the four PE syndromes. Moreover, PEP scores of patients with lifelong, acquired, natural variable PE and premature‐like ejaculatory dysfunction were compared. Significance level was considered as P < 0.05.Main Outcome MeasuresScores obtained from PEDT, AIPE, and PEP questionnaires.ResultsA total of 2,593 couples were enrolled where 512 (20.0%) male subjects reported PE. PEDT, AIPE, and PEP measures of the PE patients indicated worse sexual function (P < 0.001 each). Mean scores obtained from questionnaires were significantly better in patients with premature‐like ejaculatory dysfunction and they were the worst in patients with acquired PE (P < 0.001 each). The sensitivity values of PEDT and AIPE were 89.3 and 89.5, whereas their specificity values were 50.5 and 39.1, respectively. There were statistically significant differences in detection rates of PEDT and AIPE among the four PE syndromes (P = 0.006 and P < 0.001). They were higher in acquired and lifelong PE and lower in premature‐like ejaculatory dysfunction.ConclusionsPEDT and AIPE can diagnose PE with high sensitivity, especially in patients with lifelong and acquired PE. The complaint of patients with acquired PE seems to be more severe than those complaining of lifelong, natural variable PE and premature‐like ejaculatory dysfunction patients. Serefoglu EC, Yaman O, Cayan S, Asci R, Orhan I, Usta MF, Ekmekcioglu O, Kendirci M, Semerci B, and Kadioglu A. The comparison of premature ejaculation assessment questionnaires and their sensitivity for the four premature ejaculation syndromes: Results from the Turkish Society of Andrology Sexual Health Survey.     

Subjectively Measured Ejaculation Latency Time and Its Association with Different Sexual Activities while Controlling for Age and Relationship Length

IntroductionRecently, attempts to formulate valid and suitable definitions for (different subcategories of) premature ejaculation have resulted in substantial progress in the pursuit to gain knowledge about ejaculatory function. However, the association between ejaculatory dysfunction and different types of sexual activities has yet to be thoroughly investigated, and (due to conflicting results between studies) the potential effects of age and relationship length still need to be taken into account.AimThe aim of this study is to investigate the associations of age, relationship length, frequency of different sexual activities, and different modes of achieving ejaculation with self-reported ejaculation latency time.Main Outcome MeasuresThe main outcome is establishing associations between age, relationship length, self-reported ejaculation latency time, and frequency of different kinds of sexual activities and different modes of achieving ejaculation (such as achieving ejaculation through oral or vaginal sex).MethodsStatistical analyses of data on age, relationship length, self-reported ejaculation latency time, and frequency of different sexual activities and different modes of achieving ejaculation were conducted on a population-based sample of 3,189 males aged 18–48 years (mean = 29.9 years, standard deviation = 6.94).ResultsAge and relationship length were significantly negatively associated with self-reported ejaculation latency time. Frequency of different kinds of sexual behavior generally had a positive association with self-reported ejaculation latency time, as had different modes of achieving ejaculation.ConclusionsThe findings highlight the need for more extensive studies on and increased knowledge of different aspects of ejaculatory function before a valid and suitable definition for premature ejaculation can be formulated. Jern P, Santtila P, Johansson A, Varjonen M, Witting K, von der Pahlen B, and Sandnabba K. Subjectively measured ejaculation latency time and its association with different sexual activities while controlling for age and relationship length. J Sex Med 2009;6:2568–2578.     

Compliance With Fluoxetine Use in Men With Primary Premature Ejaculation

BackgroundPremature ejaculation (PE) is a common sexual dysfunction for which selective serotonin reuptake inhibitors (SSRIs) have been used effectively for treatment. However, compliance with therapy and predictors of long-term SSRI use in the treatment of PE are not well known.AimTo analyze our experience with drop-out rates with fluoxetine in the primary PE population and to identify predictors of continued use of this agent.MethodsMen with primary PE constituted who used fluoxetine and had at least 12 months follow-up constituted the study population. Subjects underwent a comprehensive interview to ascertain self-reported (non-stopwatch) intravaginal ejaculatory latency time (IELT), self-rated control over ejaculation, and personal and patient-reported partner distress due to PE. Patients were treated with fluoxetine 20 mg daily, with the possibility of dose titration up or down based on efficacy and side effects.OutcomesThe PE parameters of interest included self-reported IELT, self-rated control over ejaculation, personal and partner distress due to PE, and medication adherence.Results130 men were included in the study. Dropout rates at 6 and 12 months were 56% and 72%. Self-rated “poor” ejaculatory control decreased from 98%–41% (P < .01), high personal distress from 47%–11% (P < .01), and high partner distress rates from 72%–27% (P < .01). Predictors of continued use at 12 months included high partner distress, being unpartnered, and having a post-treatment IELT ≥5 minutes (P < .01). Overall side effects included headache (5%), dizziness (4%), nausea (5%), nervousness (5%), and sleepiness (8%); however, moderate to severe side effects reported included nausea (2%), sleepiness (2%), headache (2%), and dizziness (2%).Clinical ImplicationsCompliance with SSRIs is a well-described problem in the depression literature, but data are sparse regarding continued use of SSRIs in the treatment of PE.Strengths and LimitationsWe report on 12-month compliance with SSRIs for the treatment of PE. Our early compliance rates were more encouraging than what has been reported in the past. However, IELT was self-reported and not measured objectively, and we did not use validated patient-reported outcomes but rather self-reported ejaculatory control and distress levels, which have limitations.ConclusionsFluoxetine is an effective agent for the treatment of PE with significant improvement realized in IELT, ejaculatory control, and distress levels for both men and their partners. Despite its efficacy, continued use of fluoxetine beyond 6 months is poor.Jenkins LC, Gonzalez J, Tal R, et al. Compliance with Fluoxetine Use in Men with Primary Premature Ejaculation. J Sex Med 2020;16:1895–1899.     

Understanding Men's Attributions of Why They Ejaculate Before Desired: An Internet Study

IntroductionRecent developments in the study of men's sexual response have raised significant issues related to the definition and diagnosis of premature ejaculation (PE).AimWe wanted to understand men's perceived reasons for “ejaculating before they wanted,” whether they selected attributions from the same broad category when allowed to endorse multiple reasons, and whether younger and older cohorts differed in their attributions.MethodsA subsample of 376 men who indicated that they “ejaculated before they wanted” was drawn from a larger pool of 1,249 men participating in an online survey on men's sexual health. This subsample responded to a number of items regarding their ejaculatory patterns, including two questions listing 10 possible self‐reported attributions/reasons for their quick ejaculation—one item allowed respondents to endorse multiple reasons, the other limited the response to the most important reason.Main Outcome MeasuresThe primary outcome measure was men's attributions for ejaculating before desired, with choices from 10 possible pretested reasons. In addition, concordance across attributions was determined, that is, if a man responded to one category, was he also likely to select another category?ResultsMen who met the ejaculatory latency criterion for PE were generally no different from those who did not. Overall, when required to select the most important attribution, most men identified a specific issue with “lack of self‐efficacy” (lack of control or aroused too quickly). Few respondents identified erection loss, partner issues, or medical/medication concerns as the reason—and these patterns were independent of age. Concordance was high across self‐efficacy attributions but low across other attributions.ConclusionsMost men who complain of ejaculating before desired attribute this response to problems with self‐efficacy. Only a small percent of men identified other possible reasons for their quick ejaculation. Such findings have implications for both the diagnostic process and definitional language for PE. Rowland DL and Neal CJ. Understanding men's attributions of why they ejaculate before desired: An internet study. J Sex Med 2014;11:2554–2561.     

Improved Ejaculatory Latency,Control and Sexual Satisfaction When PSD502 is Applied Topically in Men with Premature Ejaculation: Results of a Phase III,Double-Blind,Placebo-Controlled Study

IntroductionPSD502 is a novel aerosolized, lidocaine-prilocaine, spray being developed for the treatment of lifelong premature ejaculation. The clinical profile of PSD502 is described in one of two double-blind, placebo-controlled, phase III studies.AimTo determine the effect of PSD502 on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency (IELT) of men with lifelong PE.MethodsMen with lifelong PE who documented an IELT ≤ 1 minute with two or more of the first three sexual encounters during a 4-week baseline period were randomized to receive double-blind treatment with PSD502 or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile questionnaires at entry and monthly visits, and recorded stop-watch timed IELT during each encounter. Safety was assessed by collecting adverse event data and standard safety measures.Main Outcome MeasuresStopwatch timed IELT recordings and a patient-reported outcome questionnaire the IPE were used in this study to determine the effect of PSD502 applied topically 5 minutes before intercourse.ResultsTwo hundred fifty-six men with PE were randomized from 38 centers in the U.S., Canada, and Poland. The geometric mean IELT over the 3-month treatment period increased from a baseline of 0.56 minute and 0.53 minute in the PSD502 and placebo group respectively to 2.60 and 0.80 minute. There were significantly greater increases in the scores for the IPE domains of ejaculatory control, sexual satisfaction and distress in the PSD502 group than in the placebo group, with a mean 5.0 point difference between treatments in change from baseline in the IPE domain for ejaculatory control, 4.6 point difference in change from baseline in the IPE domain for sexual satisfaction, and a 2.5 point difference in change from baseline in the IPE domain for distress. This was supported by improvements in all secondary endpoints.ConclusionIn this study, PSD502 applied topically to the glans penis 5 minutes before intercourse showed significantly improved ejaculatory latency, ejaculatory control, sexual satisfaction and distress and was shown to be well tolerated by patients and partners. Carson C, and Wyllie M. Improved ejaculatory latency, control and sexual satisfaction when PSD502 is applied topically in men with premature ejaculation: Results of a phase III, double-blind, placebo-controlled study.     

Moving Toward Empirically Based Standardization in the Diagnosis of Delayed Ejaculation

BackgroundCriteria for delayed ejaculation (DE) rely on a long ejaculation latency (EL) time, lack of control/advancement regarding ejaculation, and associated bother/distress; yet, few studies have investigated these criteria in men who indicate the desire to ejaculate sooner during partnered sex.AimTo help standardize criteria for DE by better understanding characteristics of men who desire to ejaculate sooner during partnered sex in terms of their EL, reported ejaculatory control, and level of bother/distress, as well as their perceptions of typical and ideal ELs for men in general and of ELs for men with premature ejaculation (PE).MethodsA total of 572 men recruited through social media responded to an online survey regarding their EL, as well as typical, ideal, and PE ELs of men in general. They also rated (i) their ability to control and/or advance ejaculation and (ii) their level of associated bother/distress. 4 comparison groups were then established: men with probable DE (with [DE1] and without [DE2] ejaculatory control issues), a reference group with no ejaculatory disorders, and men who identified as having PE.OutcomesTo demonstrate differences in EL, ejaculatory control, and bother/distress between men with delayed ejaculation and the control and PE reference groups.ResultsELs for men with probable DE were twice as long as those with no ejaculatory disorders. When probable DE men were further subdivided into DE2 and DE1, differences were greater for the DE2 group. DE2 men also differed significantly from the reference group on ejaculatory control/advancement but not on bother/distress. Both DE and reference groups differed from the PE group.Clinical ImplicationsUsing both EL and ejaculatory control are useful in distinguishing men with delayed ejaculation from men without delayed ejaculation.Strengths & LimitationsA sizable sample drawn from a multinational population powered the study, whereas the use of social media for recruitment limited the generalizability of findings.ConclusionBoth EL and ejaculatory control differentiate men with probable DE from a control reference group having no ejaculatory disorders. Differences in bother/distress did not emerge as significant. Implications for diagnosing men with DE are presented.Rowland DL, Cote-Leger P. Moving Toward Empirically Based Standardization in the Diagnosis of Delayed Ejaculation. J Sex Med 2020;17:1896–1902.     

Participation of Endogenous Opioids in the Inhibition of the Spinal Generator for Ejaculation in Rats

IntroductionA spinal pattern generator controls the expression of ejaculation. When this ejaculation generator is activated it can be phasically controlled, at a spinal level, by intrinsic mechanisms that eventually lead to the establishment of both short‐ and long‐lasting inhibitory processes.AimTo evaluate the hypothesis that endogenous opioids participate in the control of ejaculation by exerting an inhibitory influence upon the spinal generator for ejaculation.Main Outcome MeasuresElectromyographic recordings of the ejaculatory motor pattern recorded in the bulbospongiosus muscles were obtained as physiological markers of ejaculation.MethodsBy using a model for the study of ejaculation in spinal male rats, we analyze the effects of the intravenous injection of the opioid agonist morphine and the opioid antagonist naloxone on the expression of the ejaculatory motor pattern. In addition, the effect of pre‐treatment with systemic naloxone on the establishment of the inhibition of the ejaculatory motor pattern resulting from its repeated sensory‐induced elicitation was evaluated.ResultsData obtained show that: (i) the i.v. injection of morphine (1–10 µg/rat) inhibits whereas that of naloxone (1–10 µg/rat) induces the expression of the genital ejaculatory motor pattern; (ii) naloxone pretreatment dose‐dependently blocks the inhibitory effects of the high dose of morphine upon the rhythmic motor pattern of ejaculation; (iii) the inhibition of the ejaculatory response induced by repeated urethral stimulation can be delayed, and the ejaculatory capacity augmented, by naloxone injection (10 µg/rat).ConclusionsTogether, these evidences support the notion that endogenous opioids modulate the activity of the spinal generator for ejaculation by exerting an inhibitory influence. Carro‐Juárez M, and Rodríguez‐Manzo G. Participation of endogenous opioids in the inhibition of the spinal generator for ejaculation in rats.