oxytocin and Premature-Ejaculation

Premature ejaculation (PE) is a prevalent male sexual dysfunction. Current standard treatment regimens include behavioural therapies, topical anaesthetics, dapoxetine and other selective serotonin reuptake inhibitors (SSRIs). Most of the pharmacotherapeutic options target neurotransmitters (such as serotonin and oxytocin) that have a role in the ejaculation mechanism. However, these treatments are mildly effective and only provide a temporary delay in the ejaculation latency time, and PE recurs when the treatment is stopped. Thus, a treatment for PE is urgently needed and research is ongoing to find the ideal PE therapy. The efficacy and safety of topical anaesthetics and SSRIs in delaying ejaculation have been confirmed in many well-designed controlled trials. Both preclinical and clinical studies on new-generation SSRIs are ongoing. Moreover, promising results came from clinical trials in which the efficacy of on-demand PE therapies targeting neurotransmitters other than serotonin, such as α1-adrenoceptor antagonists and oxytocin antagonists, was assessed. Surgical intervention and neuromodulation have been proposed as potential treatment options for PE; however, current PE guidelines do not recommend these treatments owing to safety concerns.

Topics: Anesthetics, Local; Ejaculation; Humans; Male; Oxytocin; Premature Ejaculation; Selective Serotonin Reuptake Inhibitors; Serotonin; Treatment Outcome

A growing number of genetic association studies have been performed to investigate the association between the genetic susceptibility alleles and the risk of premature ejaculation (PE); however, the results remain inconclusive.. This systematic review aimed: (i) to determine whether an association exists between gene(s) or allelic variant(s) and PE; (ii) to assess whether the associations are consistent across studies in magnitude and direction, and (iii) to identify any limitation, gap, or shortcoming in the included studies.. The literature search was conducted in PubMed, MEDLINE, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases.. Different gene variants associated with PE were assessed. 25 genetic association studies met the inclusion criteria that investigated 11 genes, 2,624 men with PE compared with 9,346 men as controls, twins, and siblings. 19 studies demonstrated a significant association with PE, whereas 4 studies denied such a relationship. SLC6A4 gene polymorphism was investigated in 11 studies (7 studies demonstrated a significant relationship with PE, and 4 studies denied such a relationship). Dopamine transporter gene (DAT1) polymorphism was investigated in 4 studies exhibiting a significant relationship. Androgen receptor gene polymorphisms were investigated in 2 studies, 1 with a significant relationship and the other with a non-significant relationship. Oxytocin gene polymorphisms and tryptophan hydroxylase 2 gene polymorphisms were investigated in 2 studies with a significant relationship.. While this review has highlighted several genes that may be potentially associated with PE such as SLC6A4, limitations such as variance in study methods, lack of robust findings, small sample sizes, lack of reproducibility, quality of reporting, and quality of assessment remain a major concern. Further efforts such as standardizing reporting, exploring complementary designs, and the use of genome-wide association studies technology are warranted to test the reproducibility of these early findings. Mostafa T, Abdel-Hamid IA, Taymour M, et al. Gene Variants in Premature Ejaculation: Systematic Review and Future Directions. Sex Med Rev 2020;8:586-602.

Topics: Dopamine Plasma Membrane Transport Proteins; Genetic Association Studies; Humans; Male; Oxytocin; Polymorphism, Genetic; Premature Ejaculation; Receptors, Androgen; Receptors, Serotonin; Reproducibility of Results; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase

In the last two decades, in vivo animal research and human neurobiological, genetic and pharmacological research of lifelong premature ejaculation (PE) have much contributed to a better understanding of the role of the central and peripheral nervous systems in mediating ejaculation. Research of genetic polymorphisms in men with lifelong PE and clinical research of the validity of the classification into four PE subtypes have provided a better insight into lifelong PE and its distinction from the three other PE subtypes. Nevertheless, a number of symptoms of lifelong PE and its treatment by SSRIs are still not well understood. In the current article, it will be argued that lifelong PE is characterized not only by early ejaculations (ejaculatio praecox), a diminished control over ejaculation, and negative personal consequences, but also by early erections (erectio praecox) and an immediately occurring detumescence of the penis after ejaculation (detumescentia praecox) as symptoms of an (sub)acute hypertonic or hypererotic physical state when making love. Based on animal research it is postulated that the facilitated erection, facilitated ejaculation and facilitated penile detumescence are associated with centrally and peripherally increased oxytocin release. In addition, it is postulated that mechano- and thermosensory activity of transient receptor potential (TRP) ion channels, located in skin receptors of the glans penis, are associated with lifelong PE. Research into the three characteristics of the (sub)acute hypererotic state will presumably contribute to a better phenomenological description of and better neurobiological understanding of lifelong PE and its delineation to the three other PE subtypes.

Topics: Female; Humans; Male; Models, Biological; Oxytocin; Penile Erection; Polymorphism, Genetic; Premature Ejaculation; Receptor, Serotonin, 5-HT1A; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Transient Receptor Potential Channels

Topics: Double-Blind Method; Ejaculation; Humans; Male; Oxytocin; Patient Reported Outcome Measures; Premature Ejaculation; Pyridines; Triazoles

Topics: Humans; Male; Oxytocin; Premature Ejaculation; Pyridines; Triazoles

Topics: Double-Blind Method; Ejaculation; Humans; Male; Oxytocin; Patient Reported Outcome Measures; Premature Ejaculation; Pyridines; Triazoles

Premature ejaculation is one of the most common sexual disorders in men due to uncontrolled modulation of spinal reflexes controlled by cortico-limbic centers in the brain. In this study, we investigate the combinatorial effects of trinucleotide repeats of androgen receptor and allelic variants of the 5-HTTLPR gene on sex steroids, hypophyseal hormones, sexual performance, and premature ejaculation assessment parameters among evidence-based lifelong premature ejaculation subjects. A total of 271 outpatients (age 26.6 ± 1.9) consulting for evidence-based lifelong premature ejaculatory dysfunction were selected in this study. The control group consists of 155 men with normal IELT (>4 min). The study revealed that the subjects who have the highest (≥26) CAG stretches depicted a significantly higher serum oxytocin levels (102.1 pg/ml; n = 126, p < 0.001) compared with the control group (71.2 pg/ml; n = 75, p = <0.001) and patients which have medium (22-25) and short (≤21) CAG stretches (76.63 ng/ml; n = 64, p < 0.001 vs. 77.4 ng/ml; n = 81, p < 0.001). Almost 33 (26.1%) lifelong premature ejaculatory patients had AR variant of longer (≥26) CAG repeats was homozygous for S alleles (SS), 45 (35.7%) was homozygous for L allele (LL), and 48 (38%) had the L/S or S/L genotype of 5-HTTLPR gene. Homozygous (SS) alleles have a significant positive correlation (r = 0.44, p < 0.0001) with the high score of BDI-II (39.1, n = 126, p < 0.001). However, LL alleles have shown a significant positive correlation with PEDT (r = 0.46, p < 0.001) and negative correlation with self-estimated IELT and intercourse satisfaction (r = -0.35, p < 0.001). The innovative study design elaborates that androgen receptor trinucleotide repeats and 5-HTTLPR genotypes have combinatorial impact on hormonal milieu and sexual function regarding evidence-based lifelong premature ejaculatory dysfunction patients.

Topics: Adult; Case-Control Studies; Ejaculation; Genetic Association Studies; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Male; Oxytocin; Phenotype; Premature Ejaculation; Receptors, Androgen; Risk Factors; Serotonin Plasma Membrane Transport Proteins; Testosterone; Trinucleotide Repeats

Few treatments are available for men with premature ejaculation (PE); oxytocin (OT) receptor antagonism in the central nervous system (CNS) is a potential new approach.. To determine if cligosiban selectively inhibits human OT receptors, penetrates the CNS, shows pharmacology in the CNS, and effects ejaculatory physiology in pre-clinical systems.. Experiments complied with United Kingdom legislation and were subject to local ethical review. In vitro potency and selectivity of cligosiban was assessed using recombinant and native OT receptor systems including both neuronal and non-neuronal cell types. Selectivity was determined over neighboring V. These were functional measures of pharmacology in vitro, in cell lines and tissues, and in vivo in rats.. As the first highly selective and centrally penetrant OT receptor antagonist, cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE.. The pharmacology and selectivity of cligosiban is determined using functional assays in recombinant cell lines, native cell lines, and tissue. Functional outcomes in in vivo systems are linked to CNS measures of pharmacology. The translation of the animal models of ejaculation to PE in man is unproven.. Cligosiban, a potent, selective OT receptor antagonist, demonstrated CNS penetration and pharmacology and, using the same dosing regimen, inhibited apomorphine-induced ejaculation in rats. Cligosiban is a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. Wayman C, Russell R, Tang K, et al. Cligosiban, A Novel Brain Penetrant Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents. J Sex Med 2018;15:1698-1706.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Ejaculation; Hormone Antagonists; Humans; Male; Oxytocin; Premature Ejaculation; Rats; Receptors, Oxytocin; Receptors, Vasopressin; Rodentia; United Kingdom

What's known on the subject? and What does the study add? There is also evidence that the etiology of premature ejaculation is partially genetic. So far, all molecular genetic studies of premature ejaculation have focused on serotonergic and dopaminergic genes. Serotonergic and dopaminergic neurotransmission aside, studies on both animals and humans have shown that both oxytocin and vasopressin are also involved in ejaculatory function. The present study is, to our knowledge, the first to investigate effects of polymorphisms in oxytocin and vasopressin receptor genes on ejaculatory function. Although a large sample (1517 men) was available for the present study, we could not detect any clear-cut effects of any gene variant on ejaculatory function. We detected a heterozygote effect of one polymorphism (rs75775) in the oxytocin receptor gene. Rare variants of the vasopressin receptor 1A gene may theoretically have a stronger impact on ejaculatory function, but would need a very large sample in order to be established. Based on our results, we conclude that the oxytocin and vasopressin receptor genes are unlikely targets for successful pharmacogenetic interventions.. • To investigate associations between single nucleotide polymorphisms (SNPs) linked to the oxytocin, and arginine vasopressin 1A and 1B receptor genes and ejaculatory function. • To investigate these associations in a large, population-based sample.. • In all, 1517 male twins and non-twin brothers of twins aged 18-45 years (mean = 26.43; sd = 4.87) provided questionnaire data regarding ejaculatory function and relevant covariates and saliva samples for genotyping. • A Bayesian linear mixed-effects model, which appropriately controls for between-subjects dependence, was used to estimate genotype associations. • We corrected for multiple testing using a linkage disequilibrium correlation measure.. • We found a heterozygote effect on one SNP in the oxytocin receptor gene (rs75775), so that individuals heterozygous for this SNP had significantly elevated risk for premature ejaculation symptoms compared with carriers of either homozygote. • Several SNPs in the arginine vasopressin receptor genes had rare or very rare genotypes. This study may be underpowered to detect potential effects of rare genotypic variants in arginine vasopressin receptor genes.. • Our results regarding the oxytocin receptor polymorphisms support previous studies that indicate a complex relationship between oxytocin and ejaculatory function. • Oxytocin receptor genes are, for example, unlikely suitable targets for pharmacogenetic intervention studies. • Rare variants in arginine vasopressin receptor genes may have significant effects on premature ejaculation, but would need larger sample sizes or case-control designs to be detected.

Topics: Adolescent; Adult; Bayes Theorem; DNA; Ejaculation; Genotype; Humans; Male; Middle Aged; Oxytocin; Polymorphism, Single Nucleotide; Premature Ejaculation; Receptors, Vasopressin; Retrospective Studies; Young Adult