Paddy K.C. Janssen

Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation

INTRODUCTION Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning. AIM To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE. METHODS A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated. MAIN OUTCOME MEASURES IELT measured by stopwatch, 5-HTTLPR polymorphism. RESULTS In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P < or = 0.027); the LL genotypes had significantly shorter IELTs than the SS and SL genotypes. CONCLUSIONS The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

The 5-HT1A receptor C(1019)G polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

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.

Measurement errors in polymerase chain reaction are a confounding factor for a correct interpretation of 5-HTTLPR polymorphism effects on lifelong premature ejaculation: a critical analysis of a previously published meta-analysis of six studies.

Objective To analyze a recently published meta-analysis of six studies on 5-HTTLPR polymorphism and lifelong premature ejaculation (PE). Methods Calculation of fraction observed and expected genotype frequencies and Hardy Weinberg equilibrium (HWE) of cases and controls. LL,SL and SS genotype frequencies of patients were subtracted from genotype frequencies of an ideal population (LL25%, SL50%, SS25%, p = 1 for HWE). Analysis of PCRs of six studies and re-analysis of the analysis and Odds ratios (ORs) reported in the recently published meta-analysis. Results Three studies deviated from HWE in patients and one study deviated from HWE in controls. In three studies in-HWE the mean deviation of genotype frequencies from a theoretical population not-deviating from HWE was small: LL(1.7%), SL(−2.3%), SS(0.6%). In three studies not-in-HWE the mean deviation of genotype frequencies was high: LL(−3.3%), SL(−18.5%) and SS(21.8%) with very low percentage SL genotype concurrent with very high percentage SS genotype. The most serious PCR deviations were reported in the three not-in-HWE studies. The three in-HWE studies had normal OR. In contrast, the three not-in-HWE studies had a low OR. Conclusions In three studies not-in-HWE and with very low OR, inadequate PCR analysis and/or inadequate interpretation of its gel electrophoresis resulted in very low SL and a resulting shift to very high SS genotype frequency outcome. Consequently, PCRs of these three studies are not reliable. Failure to note the inadequacy of PCR tests makes such PCRs a confounding factor in clinical interpretation of genetic studies. Currently, a meta-analysis can only be performed on three studies-in-HWE. However, based on the three studies-in-HWE with OR of about 1 there is not any indication that in men with lifelong PE the frequency of LL,SL and SS genotype deviates from the general male population and/or that the SL or SS genotype is in any way associated with lifelong PE.

Serotonin Transporter Promoter Region (5-HTTLPR) Polymorphism Is Not Associated With Paroxetine-Induced Ejaculation Delay in Dutch Men With Lifelong Premature Ejaculation

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.

The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5-hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10–20, 20–30 and 30–60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys) is significantly lower (22.6 s; 95% CI 18.3–27.8 s) than in male homozygous mutants (Ser/Ser) (40.4 s; 95% CI 20.3–80.4 s) (P = 0.03). It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes.

Re: Polymorphisms of the serotonin transporter gene and their relation to premature ejaculation in individuals from Iran. M. R. Safarinejad. J Urol 2009; 181: 2656-2661.

To the Editor: We read with interest the article by Safarinejad regarding polymorphisms of the 5-HTT gene in Iranian men with lifelong premature ejaculation (LPE). However, reanalysis of the data listed in table 2 in the article yields a different outcome and conclusion. Since reanalysis shows that the observed number of genotypes in the patients is not in Hardy-Weinberg equilibrium, it is incorrect to conclude that there is a higher prevalence of SS genotypes in Iranian men with LPE, as stated by the author. Recalculation of the fraction of genotypes in this Iranian sample reveals the following observed and expected distributions. Observed distributions consist of SS 0.35, SL 0.35 and LL 0.22, and expected distributions consist of SS 0.28, SL 0.49 and LL 0.22, according to Hardy-Weinberg. Observed and expected distributions compared by chi-square test demonstrate a significant difference (p 0.032, rather than p 0.04, as stated by the author). Genotype prevalences that differ significantly from Hardy-Weinberg equilibrium are confounded by definition as a result of selection bias and/or inadequate laboratory DNA testing. Moreover, applying the required chi-square test with allelic distributed subgroups (La/La, La/Lg, Lg/Lg) confirms the imbalance of the reported Iranian sample, since the values differ significantly from Hardy-Weinberg (p 0.0013). These statistical checks would have alarmed the author, who failed to apply this subanalysis. In this study the outcome data were actually submitted to Bonferroni corrections to weed out inconsistencies. However, a multiple test correction by Bonferroni to the allele distribution of only 1 variation, eg L vs S allele, is not permitted. Notably the La and Lg variants are only located at the L-allele and not at the S-allele. Bonferroni corrections, as in the presented data, have masked the unfortunate but firm observation that the patient sample did not behave according to Hardy-Weinberg equilibrium. Consequently the conclusion of a higher SS genotype prevalence in Iranian men with LPE becomes doubtful and contradicts previously reported findings in a Dutch sample of men with LPE. In that study of 89 males, the first study on 5-HTTLPR and LPE, the prevalence of SS, SL and LL genotypes was not increased compared to controls. However, the observed and expected genotypes behaved according to Hardy-Weinberg, meaning there was no statistically significant difference between the observed and expected genotypes for patients (p 0.83) or controls (p 0.59), and showed that men with LPE and LL genotype have 100% faster intravaginal ejaculation latency times than men with SS and SL genotypes. For the sake of transparence in genetic LPE research we emphasize use and quoting of p values of the chi-square test for all aspects of Hardy-Weinberg calculations. Finally for 5-HTTLPR polymorphism Bonferroni corrections are not required, since Hardy-Weinberg equilibrium is a useful tool to demonstrate the existence and nonexistence of confounding factors.

The mathematical formula of the intravaginal ejaculation latency time (IELT) distribution of lifelong premature ejaculation differs from the IELT distribution formula of men in the general male population.

Purpose To find the most accurate mathematical description of the intravaginal ejaculation latency time (IELT) distribution in the general male population. Materials and Methods We compared the fitness of various well-known mathematical distributions with the IELT distribution of two previously published stopwatch studies of the Caucasian general male population and a stopwatch study of Dutch Caucasian men with lifelong premature ejaculation (PE). The accuracy of fitness is expressed by the Goodness of Fit (GOF). The smaller the GOF, the more accurate is the fitness. Results The 3 IELT distributions are gamma distributions, but the IELT distribution of lifelong PE is another gamma distribution than the IELT distribution of men in the general male population. The Lognormal distribution of the gamma distributions most accurately fits the IELT distribution of 965 men in the general population, with a GOF of 0.057. The Gumbel Max distribution most accurately fits the IELT distribution of 110 men with lifelong PE with a GOF of 0.179. There are more men with lifelong PE ejaculating within 30 and 60 seconds than can be extrapolated from the probability density curve of the Lognormal IELT distribution of men in the general population. Conclusions Men with lifelong PE have a distinct IELT distribution, e.g., a Gumbel Max IELT distribution, that can only be retrieved from the general male population Lognormal IELT distribution when thousands of men would participate in a IELT stopwatch study. The mathematical formula of the Lognormal IELT distribution is useful for epidemiological research of the IELT.

Genotype scores predict drug efficacy in subtypes of female sexual interest/arousal disorder: A double-blind, randomized, placebo-controlled cross-over trial

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of ‘one size fits all’, and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects’ genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

Nonresponders to daily paroxetine and another SSRI in men with lifelong premature ejaculation : a pharmacokinetic dose-escalation study for a rare phenomenon

Purpose Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. Materials and Methods Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. Results Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. Conclusions Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.

Re: gene mapping of serotoninergic system polymorphisms provides insight on pathology and treatment of men with lifelong premature ejaculation

We appreciate and thank Drs Saitz and Serefoglu for their positive and sympathetic words on our article.1 Indeed, our genetic studies have shown that 5‐HTTLPR polymorphism, 5‐HT1A receptor gene polymorphism and 5‐HT2C receptor gene polymorphism are associated with the duration of the intravaginal ejaculatory latency time in men with lifelong premature ejaculation. In line with the remarks,1 we hope that our stopwatch method will be used by other investigators to investigate the role of serotonergic gene polymorphisms on the duration of the intravaginal ejaculatory latency time. But lifelong premature ejaculation is not only characterized by persistent short intravaginal ejaculatory latency times, inability to delay ejaculation and negative personal consequences. Recently, lifelong premature ejaculation is characterized by an acute hypertonic state with facilitated ejaculation (ejaculatio praecox), together with either facilitated erections (erectio praecox) and/or facilitated penile detumescence (detumescentia praecox).2 Future research is required to answer the question whether this combination of symptoms is associated with polymorphisms of various serotonergic gene and other neurotransmitter gene systems.This opens a floodgate opportunity with regards to further gene mapping of the serotonergic system, with a potential to clinically correlate results.This exciting study sheds light on the pathophysiology of LPE and we hope that it will serve as a springboard to inspire others to investigate other possible genetic polymorphisms that could be contributing to LPE. As multiple serotonin system genetic polymorphisms have been associated with the increased intravaginal ejaculatory latency time of LPE,